I checked 6 multidisciplinary journals on Tuesday, April 01, 2025 using the Crossref API. For the period March 25 to March 31, I found 13 new paper(s) in 5 journal(s).

Nature

GPT-4o mini: Non-social science research article
Certified randomness using a trapped-ion quantum processor
Minzhao Liu, Ruslan Shaydulin, Pradeep Niroula, Matthew DeCross, Shih-Han Hung, Wen Yu Kon, Enrique Cervero-MartĂ­n, Kaushik Chakraborty, Omar Amer, Scott Aaronson, Atithi Acharya, Yuri Alexeev, K. Jordan Berg, Shouvanik Chakrabarti, Florian J. Curchod, Joan M. Dreiling, Neal Erickson, Cameron Foltz, Michael Foss-Feig, David Hayes, Travis S. Humble, Niraj Kumar, Jeffrey Larson, Danylo Lykov, Michael Mills, Steven A. Moses, Brian Neyenhuis, Shaltiel Eloul, Peter Siegfried, James Walker, Charles Lim, Marco Pistoia
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Although quantum computers can perform a wide range of practically important tasks beyond the abilities of classical computers 1,2 , realizing this potential remains a challenge. An example is to use an untrusted remote device to generate random bits that can be certified to contain a certain amount of entropy 3 . Certified randomness has many applications but is impossible to achieve solely by classical computation. Here we demonstrate the generation of certifiably random bits using the 56-qubit Quantinuum H2-1 trapped-ion quantum computer accessed over the Internet. Our protocol leverages the classical hardness of recent random circuit sampling demonstrations 4,5 : a client generates quantum ‘challenge’ circuits using a small randomness seed, sends them to an untrusted quantum server to execute and verifies the results of the server. We analyse the security of our protocol against a restricted class of realistic near-term adversaries. Using classical verification with measured combined sustained performance of 1.1 × 10 18 floating-point operations per second across multiple supercomputers, we certify 71,313 bits of entropy under this restricted adversary and additional assumptions. Our results demonstrate a step towards the practical applicability of present-day quantum computers.
GPT-4o mini: Non-social science research article
A coronavirus assembly inhibitor that targets the viral membrane protein
Manon Laporte, Dirk Jochmans, Dorothée Bardiot, Lowiese Desmarets, Oliver J. Debski-Antoniak, Giulia Mizzon, Rana Abdelnabi, Pieter Leyssen, Winston Chiu, Zhikuan Zhang, Norimichi Nomura, Sandro Boland, Umeharu Ohto, Yannick Stahl, Jurgen Wuyts, Steven De Jonghe, Annelies Stevaert, Martijn J. van Hemert, Brenda W. Bontes, Patrick Wanningen, G. J. Mirjam Groenewold, Aneta Zegar, Katarzyna Owczarek, Sanjata Joshi, Mohamed Koukni, Philippe Arzel, Hugo Klaassen, Jean-Christophe Vanherck, Ilse Vandecaetsbeek, Niels Cremers, Kim Donckers, Thibault Francken, Tina Van Buyten, Jasper Rymenants, Joost Schepers, Krzysztof Pyrc, Rolf Hilgenfeld, Jean Dubuisson, Berend-Jan Bosch, Frank Van Kuppeveld, Cecilia Eydoux, Etienne Decroly, Bruno Canard, Lieve Naesens, Birgit Weynand, Eric J. Snijder, Sandrine Belouzard, Toshiyuki Shimizu, Ralf Bartenschlager, Daniel L. Hurdiss, Arnaud Marchand, Patrick Chaltin, Johan Neyts
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The coronavirus membrane protein (M) is the main organizer of coronavirus assembly1,2,3. Here, we report on an M-targeting molecule, CIM-834, that blocks the assembly of SARS-CoV-2. CIM-834 was obtained through high-throughput phenotypic antiviral screening followed by medicinal-chemistry efforts and target elucidation. CIM-834 inhibits the replication of SARS-CoV-2 (including a broad panel of variants) and SARS-CoV. In SCID mice and Syrian hamsters intranasally infected with SARS-CoV-2, oral treatment reduced lung viral titres to nearly undetectable levels, even (as shown in mice) when treatment was delayed until 24 h before the end point. Treatment of infected hamsters prevented transmission to untreated sentinels. Transmission electron microscopy studies show that virion assembly is completely absent in cells treated with CIM-834. Single-particle cryo-electron microscopy reveals that CIM-834 binds and stabilizes the M protein in its short form, thereby preventing the conformational switch to the long form, which is required for successful particle assembly. In conclusion, we have discovered a new druggable target in the replication cycle of coronaviruses and a small molecule that potently inhibits it.
GPT-4o mini: Non-social science research article
Plasticity of the mammalian integrated stress response
Chien-Wen Chen, David Papadopoli, Krzysztof J. Szkop, Bo-Jhih Guan, Mohammed Alzahrani, Jing Wu, Raul Jobava, Mais M. Asraf, Dawid Krokowski, Anastasios Vourekas, William C. Merrick, Anton A. Komar, Antonis E. Koromilas, Myriam Gorospe, Matthew J. Payea, Fangfang Wang, Benjamin L. L. Clayton, Paul J. Tesar, Ashleigh Schaffer, Alexander Miron, Ilya Bederman, Eckhard Jankowsky, Christine Vogel, LeoĆĄ Shivaya ValĂĄĆĄek, Jonathan D. Dinman, Youwei Zhang, Boaz Tirosh, Ola Larsson, Ivan Topisirovic, Maria Hatzoglou
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An increased level of phosphorylation of eukaryotic translation initiation factor 2 subunit-α (eIF2α, encoded by EIF2S1; eIF2α-p) coupled with decreased guanine nucleotide exchange activity of eIF2B is a hallmark of the ‘canonical’ integrated stress response (c-ISR)1. It is unclear whether impaired eIF2B activity in human diseases including leukodystrophies2, which occurs in the absence of eIF2α-p induction, is synonymous with the c-ISR. Here we describe a mechanism triggered by decreased eIF2B activity, distinct from the c-ISR, which we term the split ISR (s-ISR). The s-ISR is characterized by translational and transcriptional programs that are different from those observed in the c-ISR. Opposite to the c-ISR, the s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (for example, PCK2), resulting in metabolic rewiring required to maintain cellular bioenergetics when eIF2B activity is attenuated. Overall, these data demonstrate a plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of eIF2α-p induction activates the eIF4E–ATF4–PCK2 axis to maintain energy homeostasis.
GPT-4o mini: Non-social science research article
A prospective code for value in the serotonin system
Emerson F. Harkin, Cooper D. Grossman, Jeremiah Y. Cohen, Jean-Claude BĂ©ĂŻque, Richard Naud
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The in vivo responses of dorsal raphe nucleus serotonin neurons to emotionally salient stimuli are a puzzle1. Existing theories centring on reward2, surprise3, salience4 and uncertainty5 individually account for some aspects of serotonergic activity but not others. Merging ideas from reinforcement learning theory6 with recent insights into the filtering properties of the dorsal raphe nucleus7, here we find a unifying perspective in a prospective code for value. This biological code for near-future reward explains why serotonin neurons are activated by both rewards and punishments3,4,8,9,10,11,12,13, and why these neurons are more strongly activated by surprising rewards but have no such surprise preference for punishments3,9—observations that previous theories have failed to reconcile. Finally, our model quantitatively predicts in vivo population activity better than previous theories. By reconciling previous theories and establishing a precise connection with reinforcement learning, our work represents an important step towards understanding the role of serotonin in learning and behaviour.
GPT-4o mini: Non-social science research article
Gene-modified pig-to-human liver xenotransplantation
Kai-Shan Tao, Zhao-Xu Yang, Xuan Zhang, Hong-Tao Zhang, Shu-Qiang Yue, Yan-Ling Yang, Wen-Jie Song, De-Sheng Wang, Zheng-Cai Liu, Hai-Min Li, Yong Chen, Rui Ding, Shi-Ren Sun, Ming Yu, Ji-Peng Li, Wei-Xun Duan, Zhe Wang, Jing-Wen Wang, Jia-Yun Liu, Min-Wen Zheng, Xi-Jing Zhang, Wen Yin, Wei-Jun Qin, Dong-Mei Bian, Lin Li, Min Li, Zhi-Bin Lin, Hao Xu, Dan Wei, Hong Zhang, Juan-Li Duan, Deng-Ke Pan, Hai-Long Dong, Lin Wang, Ke-Feng Dou
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The shortage of donors is a major challenge for transplantation; however, organs from genetically modified pigs can serve as ideal supplements1,2. Until now, porcine hearts and kidneys have been successively transplanted into humans3,4,5,6,7. In this study, heterotopic auxiliary transplantation was used to donate a six-gene-edited pig liver to a brain-dead recipient. The graft function, haemodynamics, and immune and inflammatory responses of the recipient were monitored over the subsequent 10 days. Two hours after portal vein reperfusion of the xenograft, goldish bile was produced, increasing to 66.5 ml by postoperative day 10. Porcine liver-derived albumin also increased after surgery. Alanine aminotransferase levels remained in the normal range, while aspartate aminotransferase levels increased on postoperative day 1 and then rapidly declined. Blood flow velocity in the porcine hepatic artery and portal and hepatic veins remained at an acceptable level. Although platelet numbers decreased early after surgery, they ultimately returned to normal levels. Histological analyses showed that the porcine liver regenerated capably with no signs of rejection. T cell activity was inhibited by anti-thymocyte globulin administration, and B cell activation increased 3 days after surgery and was then inhibited by rituximab. There were no significant peri-operative changes in immunoglobulin G or immunoglobulin M levels. C-reactive protein and procalcitonin levels were initially elevated and then quickly declined. The xenograft remained functional until study completion.
GPT-4o mini: Non-social science research article
Witnessing the onset of reionization through Lyman-α emission at redshift 13
Joris Witstok, Peter Jakobsen, Roberto Maiolino, Jakob M. Helton, Benjamin D. Johnson, Brant E. Robertson, Sandro Tacchella, Alex J. Cameron, Renske Smit, Andrew J. Bunker, Aayush Saxena, Fengwu Sun, Stacey Alberts, Santiago Arribas, William M. Baker, Rachana Bhatawdekar, Kristan Boyett, Phillip A. Cargile, Stefano Carniani, StĂ©phane Charlot, Jacopo Chevallard, Mirko Curti, Emma Curtis-Lake, Francesco D’Eugenio, Daniel J. Eisenstein, Kevin N. Hainline, Gareth C. Jones, Nimisha Kumari, Michael V. Maseda, Pablo G. PĂ©rez-GonzĂĄlez, Pierluigi Rinaldi, Jan Scholtz, Hannah Übler, Christina C. Williams, Christopher N. A. Willmer, Chris Willott, Yongda Zhu
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Cosmic reionization began when ultraviolet (UV) radiation produced in the first galaxies began illuminating the cold, neutral gas that filled the primordial Universe 1,2 . Recent James Webb Space Telescope (JWST) observations have shown that surprisingly UV-bright galaxies were in place beyond redshift z = 14, when the Universe was less than 300 Myr old 3–5 . Smooth turnovers of their UV continua have been interpreted as damping-wing absorption of Lyman-α (Ly-α), the principal hydrogen transition 6–9 . However, spectral signatures encoding crucial properties of these sources, such as their emergent radiation field, largely remain elusive. Here we report spectroscopy from the JWST Advanced Deep Extragalactic Survey (JADES 10 ) of a galaxy at redshift z = 13.0 that reveals a singular, bright emission line unambiguously identified as Ly-α, as well as a smooth turnover. We observe an equivalent width of EW Ly-α > 40 Å (rest frame), previously only seen at z < 9 where the intervening intergalactic medium becomes increasingly ionized 11 . Together with an extremely blue UV continuum, the unexpected Ly-α emission indicates that the galaxy is a prolific producer and leaker of ionizing photons. This suggests that massive, hot stars or an active galactic nucleus have created an early reionized region to prevent complete extinction of Ly-α, thus shedding new light on the nature of the earliest galaxies and the onset of reionization only 330 Myr after the Big Bang.
GPT-4o mini: Non-social science research article
Genome-wide CRISPR screen in human T cells reveals regulators of FOXP3
Kelvin Y. Chen, Tatsuya Kibayashi, Ambre Giguelay, Mayu Hata, Shunsuke Nakajima, Norihisa Mikami, Yusuke Takeshima, Kenji Ichiyama, Ryusuke Omiya, Leif S. Ludwig, Kunihiro Hattori, Shimon Sakaguchi
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Regulatory T (Treg) cells, which specifically express the master transcription factor FOXP3, have a pivotal role in maintaining immunological tolerance and homeostasis and have the potential to revolutionize cell therapies for autoimmune diseases1,2,3. Although stimulation of naive CD4+ T cells in the presence of TGFÎČ and IL-2 can induce FOXP3+ Treg cells in vitro (iTreg cells), the resulting cells are often unstable and have thus far hampered translational efforts4,5,6. A systematic approach towards understanding the regulatory networks that dictate Treg differentiation could lead to more effective iTreg cell-based therapies. Here we performed a genome-wide CRISPR loss-of-function screen to catalogue gene regulatory determinants of FOXP3 induction in primary human T cells and characterized their effects at single-cell resolution using Perturb-icCITE-seq. We identify the RBPJ–NCOR repressor complex as a novel, context-specific negative regulator of FOXP3 expression. RBPJ-targeted knockout enhanced iTreg differentiation and function, independent of canonical Notch signalling. Repeated cytokine and T cell receptor signalling stimulation in vitro revealed that RBPJ-deficient iTreg cells exhibit increased phenotypic stability compared with control cells through DNA demethylation of the FOXP3 enhancer CNS2, reinforcing FOXP3 expression. Conversely, overexpression of RBPJ potently suppressed FOXP3 induction through direct modulation of FOXP3 histone acetylation by HDAC3. Finally, RBPJ-ablated human iTreg cells more effectively suppressed xenogeneic graft-versus-host disease than control iTreg cells in a humanized mouse model. Together, our findings reveal novel regulators of FOXP3 and point towards new avenues to improve the efficacy of adoptive cell therapy for autoimmune disease.
GPT-4o mini: Non-social science research article
A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein
Ellen Van Damme, Pravien Abeywickrema, Yanting Yin, Jiexiong Xie, Sofie Jacobs, Mandeep Kaur Mann, Jordi Doijen, Robyn Miller, Madison Piassek, Simone Marsili, Murali Subramanian, Leah Gottlieb, Rana Abdelnabi, Michiel Van Gool, Nick Van den Broeck, Ines De Pauw, Annick Diels, Peter Vermeulen, Koen Temmerman, Trevor Scobey, Melissa Mattocks, Alexandra SchÀfer, Dirk Jochmans, Steven De Jonghe, Pieter Leyssen, Winston Chiu, Mayra Diosa Toro, Marleen Zwaagstra, Anouk A. Leijs, Heidi L. M. De Gruyter, Christophe Buyck, Klaas Van Den Heede, Frank Jacobs, Christel Van den Eynde, Laura Thijs, Valerie Raeymaekers, Seth Miller, Amanda Del Rosario, Johan Neyts, Danielle Peeters, Ralph S. Baric, Frank J. M. van Kuppeveld, Eric J. Snijder, Martijn J. van Hemert, Mario Monshouwer, Sujata Sharma, Ruxandra Draghia-Akli, Anil Koul, Marnix Van Loock
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The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly 1,2 . Here we describe the identification of JNJ-9676, a small-molecule inhibitor targeting the coronavirus M protein. JNJ-9676 demonstrates in vitro nanomolar antiviral activity against SARS-CoV-2, SARS-CoV and sarbecovirus strains from bat and pangolin zoonotic origin. Using cryogenic electron microscopy (cryo-EM), we determined a binding pocket of JNJ-9676 formed by the transmembrane domains of the M protein dimer. Compound binding stabilized the M protein dimer in an altered conformational state between its long and short forms, preventing the release of infectious virus. In a pre-exposure Syrian golden hamster model, JNJ-9676 (25 mg per kg twice per day) showed excellent efficacy, illustrated by a significant reduction in viral load and infectious virus in the lung by 3.5 and 4 log 10 -transformed RNA copies and 50% tissue culture infective dose (TCID 50 ) per mg lung, respectively. Histopathology scores at this dose were reduced to the baseline. In a post-exposure hamster model, JNJ-9676 was efficacious at 75 mg per kg twice per day even when added at 48 h after infection, when peak viral loads were observed. The M protein is an attractive antiviral target to block coronavirus replication, and JNJ-9676 represents an interesting chemical series towards identifying clinical candidates addressing the current and future coronavirus pandemics.
GPT-4o mini: Non-social science research article
The global human impact on biodiversity
François Keck, Tianna Peller, Roman Alther, CĂ©cilia Barouillet, Rosetta Blackman, Eric Capo, Teofana Chonova, Marjorie Couton, Lena Fehlinger, Dominik Kirschner, Mara KnĂŒsel, Lucile Muneret, Rebecca Oester, KĂĄlmĂĄn Tapolczai, Heng Zhang, Florian Altermatt
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Human activities drive a wide range of environmental pressures, including habitat change, pollution and climate change, resulting in unprecedented effects on biodiversity 1,2 . However, despite decades of research, generalizations on the dimensions and extent of human impacts on biodiversity remain ambiguous. Mixed views persist on the trajectory of biodiversity at the local scale 3 and even more so on the biotic homogenization of biodiversity across space 4,5 . We compiled 2,133 publications covering 97,783 impacted and reference sites, creating an unparallelled dataset of 3,667 independent comparisons of biodiversity impacts across all main organismal groups, habitats and the five most predominant human pressures 1,6 . For all comparisons, we quantified three key measures of biodiversity to assess how these human pressures drive homogenization and shifts in composition of biological communities across space and changes in local diversity, respectively. We show that human pressures distinctly shift community composition and decrease local diversity across terrestrial, freshwater and marine ecosystems. Yet, contrary to long-standing expectations, there is no clear general homogenization of communities. Critically, the direction and magnitude of biodiversity changes vary across pressures, organisms and scales at which they are studied. Our exhaustive global analysis reveals the general impact and key mediating factors of human pressures on biodiversity and can benchmark conservation strategies.
GPT-4o mini: Non-social science research article
A human brain map of mitochondrial respiratory capacity and diversity
Eugene V. Mosharov, Ayelet M. Rosenberg, Anna S. Monzel, Corey A. Osto, Linsey Stiles, Gorazd B. Rosoklija, Andrew J. Dwork, Snehal Bindra, Alex Junker, Ya Zhang, Masashi Fujita, Madeline B. Mariani, Mihran Bakalian, David Sulzer, Philip L. De Jager, Vilas Menon, Orian S. Shirihai, J. John Mann, Mark D. Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard
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Mitochondrial oxidative phosphorylation (OXPHOS) powers brain activity1,2, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders3,4. To understand the basis of brain activity and behaviour, there is a need to define the molecular energetic landscape of the brain5,6,7,8,9,10. Here, to bridge the scale gap between cognitive neuroscience and cell biology, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3 × 3 × 3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes, including OXPHOS enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains diverse mitochondrial phenotypes driven by both topology and cell types. Compared with white matter, grey matter contains >50% more mitochondria. Moreover, the mitochondria in grey matter are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backwards linear regression model that integrates several neuroimaging modalities11 to generate a brain-wide map of mitochondrial distribution and specialization. This model predicted mitochondrial characteristics in an independent brain region of the same donor brain. This approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain function. This resource also relates to neuroimaging data and defines the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders. All data are available at http://humanmitobrainmap.bcblab.com.
GPT-4o mini: Non-social science research article
Synaptic and neural behaviours in a standard silicon transistor
Sebastian Pazos, Kaichen Zhu, Marco A. Villena, Osamah Alharbi, Wenwen Zheng, Yaqing Shen, Yue Yuan, Yue Ping, Mario Lanza
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Hardware implementations of artificial neural networks (ANNs)—the most advanced of which are made of millions of electronic neurons interconnected by hundreds of millions of electronic synapses—have achieved higher energy efficiency than classical computers in some small-scale data-intensive computing tasks 1 . State-of-the-art neuromorphic computers, such as Intel’s Loihi 2 or IBM’s NorthPole 3 , implement ANNs using bio-inspired neuron- and synapse-mimicking circuits made of complementary metal–oxide–semiconductor (CMOS) transistors, at least 18 per neuron and six per synapse. Simplifying the structure and size of these two building blocks would enable the construction of more sophisticated, larger and more energy-efficient ANNs. Here we show that a single CMOS transistor can exhibit neural and synaptic behaviours if biased in a specific (unconventional) manner. By connecting one additional CMOS transistor in series, we build a versatile 2-transistor-cell that exhibits adjustable neuro-synaptic response (which we named neuro-synaptic random access memory cell, or NS-RAM cell). This electronic performance comes with a yield of 100% and an ultra-low device-to-device variability, owing to the maturity of the silicon CMOS platform used—no materials or devices alien to the CMOS process are required. These results represent a short-term solution for the implementation of efficient ANNs and an opportunity in terms of CMOS circuit design and optimization for artificial intelligence applications.
GPT-4o mini: Non-social science research article
Phosphate-enabled mechanochemical PFAS destruction for fluoride reuse
Long Yang, Zijun Chen, Christopher A. Goult, Thomas Schlatzer, Robert S. Paton, VĂ©ronique Gouverneur
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Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are persistent, bioaccumulative and anthropogenic pollutants that have attracted the attention of the public and private sectors because of their adverse impact on human health 1 . Although various technologies have been deployed to degrade PFASs with a focus on non-polymeric functionalized compounds (perfluorooctanoic acid and perfluorooctanesulfonic acid) 2–4 , a general PFAS destruction method coupled with fluorine recovery for upcycling is highly desirable. Here we disclose a protocol that converts multiple classes of PFAS, including the fluoroplastics polytetrafluoroethylene and polyvinylidene fluoride, into high-value fluorochemicals. To achieve this, PFASs were reacted with potassium phosphate salts under solvent-free mechanochemical conditions, a mineralization process enabling fluorine recovery as KF and K 2 PO 3 F for fluorination chemistry. The phosphate salts can be recovered for reuse, implying no detrimental impact on the phosphorus cycle. Therefore, PFASs are not only destructible but can now contribute to a sustainable circular fluorine economy.
GPT-4o mini: Non-social science research article
Glutamate gating of AMPA-subtype iGluRs at physiological temperatures
Anish Kumar Mondal, Elisa Carrillo, Vasanthi Jayaraman, Edward C. Twomey
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Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated ion channels that mediate most excitatory neurotransmission1. iGluRs are gated by glutamate, where on glutamate binding, they open their ion channels to enable cation influx into postsynaptic neurons, initiating signal transduction1,2. The structural mechanics of how glutamate gating occurs in full-length iGluRs is not well understood. Here, using the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype iGluR (AMPAR), we identify the glutamate-gating mechanism. AMPAR activation by glutamate is augmented at physiological temperatures. By preparing AMPARs for cryogenic-electron microscopy at these temperatures, we captured the glutamate-gating mechanism. Activation by glutamate initiates ion channel opening that involves all ion channel helices hinging away from the pore axis in a motif that is conserved across all iGluRs. Desensitization occurs when the local dimer pairs decouple and enables closure of the ion channel below through restoring the channel hinges and refolding the channel gate. Our findings define how glutamate gates iGluRs, provide foundations for therapeutic design and demonstrate how physiological temperatures can alter iGluR function.
GPT-4o mini: Non-social science research article
The other climate crisis
Tiffany A. Shaw, Bjorn Stevens
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As Earth warms, regional climate signals are accumulating. Some signals, for example, land warming more than the ocean and the Arctic warming the most, were expected and successfully predicted. Underlying this success was the application of physical laws under the assumption that large and small spatial scales are well separated. This established what we call the standard approach, climate science’s dominant paradigm. With additional warming, however, discrepancies between real-world signals and expectations based on this standard approach are piling up, especially at regional scales. At the same time, disruptive computational approaches are advancing new paradigms. Philosophers of science characterize situations where accumulating discrepancies (anomalies) and disruptions lead to a loss of confidence in the dominant paradigm as a ‘crisis’. Here we articulate what we consider to be the dominant paradigm, or standard approach, and the discrepancies and disruptions that have emerged in recent years. The policy implications of a purported crisis are discussed, as well as paths forward, crisis or no crisis. These paths include using signals to test assumptions and processes driving a warming Earth for the first time, developing testable hypotheses, and revitalizing conceptual thinking by filling gaps across climate-system components and spatial scales.
GPT-4o mini: Non-social science research article
A broad-spectrum lasso peptide antibiotic targeting the bacterial ribosome
Manoj Jangra, Dmitrii Y. Travin, Elena V. Aleksandrova, Manpreet Kaur, Lena Darwish, Kalinka Koteva, Dorota Klepacki, Wenliang Wang, Maya Tiffany, Akosiererem Sokaribo, Brian K. Coombes, Nora VĂĄzquez-Laslop, Yury S. Polikanov, Alexander S. Mankin, Gerard D. Wright
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Lasso peptides (biologically active molecules with a distinct structurally constrained knotted fold) are natural products that belong to the class of ribosomally synthesized and post-translationally modified peptides1,2,3. Lasso peptides act on several bacterial targets4,5, but none have been reported to inhibit the ribosome, one of the main targets of antibiotics in the bacterial cell6,7. Here we report the identification and characterization of the lasso peptide antibiotic lariocidin and its internally cyclized derivative lariocidin B, produced by Paenibacillus sp. M2, which has broad-spectrum activity against a range of bacterial pathogens. We show that lariocidins inhibit bacterial growth by binding to the ribosome and interfering with protein synthesis. Structural, genetic and biochemical data show that lariocidins bind at a unique site in the small ribosomal subunit, where they interact with the 16S ribosomal RNA and aminoacyl-tRNA, inhibiting translocation and inducing miscoding. Lariocidin is unaffected by common resistance mechanisms, has a low propensity for generating spontaneous resistance, shows no toxicity to human cells, and has potent in vivo activity in a mouse model of Acinetobacter baumannii infection. Our identification of ribosome-targeting lasso peptides uncovers new routes towards the discovery of alternative protein-synthesis inhibitors and offers a novel chemical scaffold for the development of much-needed antibacterial drugs.
GPT-4o mini: Non-social science research article
The P-loop NTPase RUVBL2 is a conserved clock component across eukaryotes
Meimei Liao, Yanqin Liu, Zhancong Xu, Mingxu Fang, Ziqing Yu, Yufan Cui, Zhengda Sun, Ran Huo, Jieyu Yang, Fusheng Huang, Mingming Liu, Qin Zhou, Xiaocui Song, Hui Han, She Chen, Xiaodong Xu, Ximing Qin, Qun He, Dapeng Ju, Tao Wang, Nirav Thakkar, Paul E. Hardin, Susan S. Golden, Eric Erquan Zhang
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The eukaryotic circadian clock keeps time by using a transcription–translation feedback loop, which exhibits an architecture that is conserved across a diverse range of organisms, including fungi, plants and animals1. Despite their mechanistic similarity, the molecular components of these clocks indicate a lack of common ancestry2. Our study reveals that RUVBL2, which is a P-loop NTPase enzyme previously shown to affect circadian phase and amplitude as part of mammalian clock super-complexes, influences the circadian period through its remarkably slow ATPase activity, resembling the well-characterized KaiC-based clock in cyanobacteria. A screen of RUVBL2 variants identified arrhythmic, short-period and long-period mutants that altered circadian locomotor activity rhythms following delivery by adeno-associated virus to the murine suprachiasmatic nucleus. Enzymatic assays showed that wild-type RUVBL2 hydrolyses only around 13 ATP molecules a day, a vastly reduced turnover compared with typical ATPases. Notably, physical interactions between RUVBL2 orthologues and core clock proteins in humans, Drosophila and the fungus Neurospora, along with consistent circadian phenotypes of RUVBL2-mutant orthologues across species, reinforce their clock-related function in eukaryotes. Thus, as well as establishing RUVBL2 as a common core component in eukaryotic clocks, our study supports the idea that slow ATPase activity, initially discovered in cyanobacteria, is a shared feature of eukaryotic clocks.
GPT-4o mini: Non-social science research article
Catalytic allylation of native hexoses and pentoses in water with indium
Tapas Adak, Travis Menard, Matthew Albritton, Federico Florit, Martin D. Burke, Klavs F. Jensen, Scott E. Denmark
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Carbohydrates are an abundant, inexpensive and renewable biomass feedstock that could be a cornerstone for sustainable chemical manufacturing, but scalable and environmentally friendly methods that leverage these feedstocks are lacking. For example, 1-allyl sorbitol is the foundational building block for the polypropylene clarifying agent Millad NX 8000, which is produced on the multi-metric ton scale annually, but the manufacturing process at present requires superstoichiometric amounts of tin1,2. The NX 8000 additives dominate about 80% of the global clarified polypropylene market3 and are used in concentrations of 0.01–1% during polypropylene production to improve its transparency and resistance to high temperatures, translating to 300–30,000 metric tons annually. The market volume of polypropylene in 2022 was approximately 79.01 million metric tons (MMT), with demand expected to rise by nearly 33% to 105 MMT by 2030 (ref. 4). The cost and sustainability benefits of clarified polypropylene are driving this demand, necessitating more clarifying agents5. Here we report a high-yielding allylation of unprotected carbohydrates in water using a catalytic amount of indium metal and either allylboronic acid or the pinacol ester (allylBpin) as donors. Aldohexoses, aminohexoses, ketohexoses and aldopentoses are all allylated in high yield under mild conditions and the indium metal is recoverable and reusable with no loss of catalytic activity. Leveraging these features, this process was translated to a scalable continuous synthesis of 1-allyl sorbitol in flow6 with high yield and productivity through Bayesian optimization of reaction parameters.
GPT-4o mini: Non-social science research article
Long-term impact and biological recovery in a deep-sea mining track
Daniel O. B. Jones, Maria Belen Arias, Loïc Van Audenhaege, Sabena Blackbird, Corie Boolukos, Guadalupe Bribiesca-Contreras, Jonathan T. Copley, Andrew Dale, Susan Evans, Bethany F. M. Fleming, Andrew R. Gates, Hannah Grant, Mark G. J. Hartl, Veerle A. I. Huvenne, Rachel M. Jeffreys, Pierre Josso, Lucas D. King, Erik Simon-Lledó, Tim Le Bas, Louisa Norman, Bryan O’Malley, Thomas Peacock, Tracy Shimmield, Eva C. D. Stewart, Andrew K. Sweetman, Catherine Wardell, Dmitry Aleynik, Adrian G. Glover
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Deep-sea polymetallic nodule mining is currently in the exploration phase with some groups proposing a move towards extraction within years1. Management of this industry requires evidence of the long-term effects on deep-sea ecosystems2, but the ability of seafloor ecosystems to recover from impacts over decadal scales is poorly understood3. Here we show that, four decades after a test mining experiment that removed nodules, the biological impacts in many groups of organisms are persistent, although populations of several organisms, including sediment macrofauna, mobile deposit feeders and even large-sized sessile fauna, have begun to re-establish despite persistent physical changes at the seafloor. We also reveal that areas affected by plumes from this small-scale test have limited detectable residual sedimentation impacts with some biological assemblages similar in abundance compared to control areas after 44 years. Although some aspects of the modern collector design may cause reduced physical impact compared to this test mining experiment, our results show that mining impacts in the abyssal ocean will be persistent over at least decadal timeframes and communities will remain altered in directly disturbed areas, despite some recolonisation. The long-term effects seen in our study provide critical data for effective management of mining activities, if they occur, including minimising direct impacts and setting aside an effective network of protected areas4,5.
GPT-4o mini: Non-social science research article
Solidification of Earth’s mantle led inevitably to a basal magma ocean
Charles-Édouard BoukarĂ©, James Badro, Henri Samuel
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One of the main interpretations of deep-rooted geophysical structures in the mantle 1 is that they stem from the top-down solidification of the primitive basal magma ocean of Earth above the core 2–6 . However, it remains debated whether solids first formed at the bottom of the mantle, solidifying upward, or above the melts, solidifying downward. Here we show that gravitational segregation of dense, iron-rich melts from lighter, iron-poor solids drives mantle evolution, regardless of where melting curves and geotherms intersect. This process results in the accumulation of iron-oxide-rich melts above the core, forming a basal magma ocean. We numerically model mantle solidification using a new multiphase fluid dynamics approach that integrates melting phase relations and geochemical models. This enables estimating the compositional signature and spatial distribution of primordial geochemical reservoirs, which may be directly linked to the isotopic anomalies measured in Archean rocks 7–11 . We find that a substantial amount of solids is produced at the surface of the planet, not at depth, injecting geochemical signatures of shallow silicate fractionation in the deep mantle. This work could serve as a foundation for re-examining the intricate interplay between mantle dynamics, petrology and geochemistry during the first thousand million years of the evolution of rocky planets.
GPT-4o mini: Non-social science research article
The contribution of de novo coding mutations to meningomyelocele
Yoo-Jin Jiny Ha, Ashna Nisal, Isaac Tang, Chanjae Lee, Ishani Jhamb, Cassidy Wallace, Robyn Howarth, Sarah Schroeder, Keng loi Vong, Naomi Meave, Fiza Jiwani, Chelsea Barrows, Sangmoon Lee, Nan Jiang, Arzoo Patel, Krisha Bagga, Niyati Banka, Liana Friedman, Francisco A. Blanco, Seyoung Yu, Soeun Rhee, Hui Su Jeong, Isaac Plutzer, Michael B. Major, BĂ©atrice Benoit, Christian PoĂŒs, Caleb Heffner, Zoha Kibar, Gyang Markus Bot, Hope Northrup, Kit Sing Au, Madison Strain, Allison E. Ashley-Koch, Richard H. Finnell, Joan T. Le, Hal S. Meltzer, Camila Araujo, Helio R. Machado, Roger E. Stevenson, Anna Yurrita, Sara Mumtaz, Awais Ahmed, Mulazim Hussain Khara, Osvaldo M. Mutchinick, JosĂ© RamĂłn Medina-Bereciartu, Friedhelm Hildebrandt, Gia Melikishvili, Ahmed I. Marwan, Valeria Capra, Mahmoud M. Noureldeen, Aida M. S. Salem, Mahmoud Y. Issa, Maha S. Zaki, Libin Xu, Ji Eun Lee, Donghyuk Shin, Anna Alkelai, Alan R. Shuldiner, Stephen F. Kingsmore, Stephen A. Murray, Heon Yung Gee, W. Todd Miller, Kimberley F. Tolias, John B. Wallingford, character(0), Allison E. Ashley Koch, Hal S. Meltzer, Joan T. Le, Kit Sing Au, Philip J. Lupo, Camila AraĂșjo, Tony Magana, Caroline M. Kolvenbach, Shirlee Shril, Yukitoshi Takahashi, Hormos Salimi-Dafsari, H. Westley Phillips, Brian Hanak, BĂŒlent Kara, Ayfer Sakarya GĂŒneƟ, David D. Gonda, Salman Kirmani, Tinatin Tkemaladze, Sangwoo Kim, Joseph G. Gleeson
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Meningomyelocele (also known as spina bifida) is considered to be a genetically complex disease resulting from a failure of the neural tube to close. Individuals with meningomyelocele display neuromotor disability and frequent hydrocephalus, requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but beyond that it remains unexplained1. We postulated that de novo mutations under purifying selection contribute to the risk of developing meningomyelocele2. Here we recruited a cohort of 851 meningomyelocele trios who required shunting at birth and 732 control trios, and found that de novo likely gene disruption or damaging missense mutations occurred in approximately 22.3% of subjects, with 28% of such variants estimated to contribute to disease risk. The 187 genes with damaging de novo mutations collectively define networks including actin cytoskeleton and microtubule-based processes, Netrin-1 signalling and chromatin-modifying enzymes. Gene validation demonstrated partial or complete loss of function, impaired signalling and defective closure of the neural tube in Xenopus embryos. Our results indicate that de novo mutations make key contributions to meningomyelocele risk, and highlight critical pathways required for neural tube closure in human embryogenesis.
GPT-4o mini: Non-social science research article
Oxidation of retromer complex controls mitochondrial translation
Junbing Zhang, Md Yousuf Ali, Harrison Byron Chong, Pei-Chieh Tien, James Woods, Carolina Noble, Tristan VornbÀumen, Zehra Ordulu, Anthony P. Possemato, Stefan Harry, Jay Miguel Fonticella, Lina Fellah, Drew Harrison, Maolin Ge, Neha Khandelwal, Yingfei Huang, Maëva Chauvin, Anica Tamara Bischof, Grace Marie Hambelton, Magdy Farag Gohar, Siwen Zhang, MinGyu Choi, Sara Bouberhan, Esther Oliva, Mari Mino-Kenudson, Natalya N. Pavlova, Michael Lawrence, Justin F. Gainor, Sean A. Beausoleil, Nabeel Bardeesy, Raul Mostoslavsky, David Pépin, Christopher J. Ott, Brian Liau, Liron Bar-Peled
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Reactive oxygen species (ROS) underlie human pathologies including cancer and neurodegeneration1,2. However, the proteins that sense ROS levels and regulate their production through their cysteine residues remain ill defined. Here, using systematic base-editing and computational screens, we identify cysteines in VPS35, a member of the retromer trafficking complex3, that phenocopy inhibition of mitochondrial translation when mutated. We find that VPS35 underlies a reactive metabolite-sensing pathway that lowers mitochondrial translation to decrease ROS levels. Intracellular hydrogen peroxide oxidizes cysteine residues in VPS35, resulting in retromer dissociation from endosomal membranes and subsequent plasma membrane remodelling. We demonstrate that plasma membrane localization of the retromer substrate SLC7A1 is required to sustain mitochondrial translation. Furthermore, decreasing VPS35 levels or oxidation of its ROS-sensing cysteines confers resistance to ROS-generating chemotherapies, including cisplatin, in ovarian cancer models. Thus, we identify that intracellular ROS levels are communicated to the plasma membrane through VPS35 to regulate mitochondrial translation, connecting cytosolic ROS sensing to mitochondrial ROS production.
GPT-4o mini: Non-social science research article
Changes in neurotensin signalling drive hedonic devaluation in obesity
Neta Gazit Shimoni, Amanda J. Tose, Charlotte Seng, Yihan Jin, Tamås Lukacsovich, Hongbin Yang, Jeroen P. H. Verharen, Christine Liu, Michael Tanios, Eric Hu, Jonathan Read, Lilly W. Tang, Byung Kook Lim, Lin Tian, Csaba Földy, Stephan Lammel
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Calorie-rich foods, particularly those that are high in fat and sugar, evoke pleasure in both humans and animals 1 . However, prolonged consumption of such foods may reduce their hedonic value, potentially contributing to obesity 2–4 . Here we investigated this phenomenon in mice on a chronic high-fat diet (HFD). Although these mice preferred high-fat food over regular chow in their home cages, they showed reduced interest in calorie-rich foods in a no-effort setting. This paradoxical decrease in hedonic feeding has been reported previously 3–7 , but its neurobiological basis remains unclear. We found that in mice on regular diet, neurons in the lateral nucleus accumbens (NAcLat) projecting to the ventral tegmental area (VTA) encoded hedonic feeding behaviours. In HFD mice, this behaviour was reduced and uncoupled from neural activity. Optogenetic stimulation of the NAcLat→VTA pathway increased hedonic feeding in mice on regular diet but not in HFD mice, though this behaviour was restored when HFD mice returned to a regular diet. HFD mice exhibited reduced neurotensin expression and release in the NAcLat→VTA pathway. Furthermore, neurotensin knockout in the NAcLat and neurotensin receptor blockade in the VTA each abolished optogenetically induced hedonic feeding behaviour. Enhancing neurotensin signalling via overexpression normalized aspects of diet-induced obesity, including weight gain and hedonic feeding. Together, our findings identify a neural circuit mechanism that links the devaluation of hedonic foods with obesity.
GPT-4o mini: Non-social science research article
BRCA2 prevents PARPi-mediated PARP1 retention to protect RAD51 filaments
Sudipta Lahiri, George Hamilton, Gemma Moore, Liana Goehring, Tony T. Huang, Ryan B. Jensen, Eli Rothenberg
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The tumour-suppressor protein BRCA2 has a central role in homology-directed DNA repair by enhancing the formation of RAD51 filaments on resected single-stranded DNA generated at double-stranded DNA breaks and stimulating RAD51 activity1,2. Individuals with BRCA2 mutations are predisposed to cancer; however, BRCA2-deficient tumours are often responsive to targeted therapy with PARP inhibitors (PARPi)3,4,5,6. The mechanism by which BRCA2 deficiency renders cells sensitive to PARPi but with minimal toxicity in cells heterozygous for BRCA2 mutations remains unclear. Here we identify a previously unknown role of BRCA2 that is directly linked to the effect of PARP1 inhibition. Using biochemical and single-molecule approaches, we demonstrate that PARPi-mediated PARP1 retention on a resected DNA substrate interferes with RAD51 filament stability and impairs RAD51-mediated DNA strand exchange. Full-length BRCA2 protects RAD51 filaments and counteracts the instability conferred by PARPi-mediated retention by preventing the binding of PARP1 to DNA. Extending these findings to a cellular context, we use quantitative single-molecule localization microscopy to show that BRCA2 prevents PARPi-induced PARP1 retention at homologous-recombination repair sites. By contrast, BRCA2-deficient cells exhibit increased PARP1 retention at these lesions in response to PARPi. These results provide mechanistic insights into the role of BRCA2 in maintaining RAD51 stability and protecting homologous-recombination repair sites by mitigating PARPi-mediated PARP1 retention.
GPT-4o mini: Non-social science research article
Deconstruction of rubber via C–H amination and aza-Cope rearrangement
Sydney E. Towell, Maxim Ratushnyy, Lauren S. Cooke, Geoffrey M. Lewis, Aleksandr V. Zhukhovitskiy
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Limited strategies exist for chemical recycling of commodity diene polymers, like those found in tyres1,2,3. Here we apply C–H amination and backbone rearrangement of polymers to deconstruct these materials into precursors for epoxy resins. Specifically, we develop a sulfur diimide reagent4,5 that enables up to about 35% allylic amination of diene polymers and rubber. Then, we apply the cationic 2-aza-Cope rearrangement to deconstruct aminated diene polymers. In a model system, we see molecular weight reduction from 58,100 to approximately 400 g mol−1, and aminated post-consumer rubber is deconstructed over 6 hours into soluble amine-functionalized polymers, which can be utilized to prepare epoxy thermosets with similar stiffnesses to commercial bisphenol A-derived resins6. Altogether, this work demonstrates the power of C–H amination and backbone rearrangement to enable chemical recycling of post-consumer materials.
GPT-4o mini: Non-social science research article
MFSD6 is an entry receptor for enterovirus D68
Lauren Varanese, Lily Xu, Christine E. Peters, Grigore Pintilie, David S. Roberts, Suyash Raj, Mengying Liu, Yaw Shin Ooi, Jonathan Diep, Wenjie Qiao, Christopher M. Richards, Jeremy Callaway, Carolyn R. Bertozzi, Sabrina Jabs, Erik de Vries, Frank J. M. van Kuppeveld, Claude M. Nagamine, Wah Chiu, Jan E. Carette
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With the near eradication of poliovirus due to global vaccination campaigns, attention has shifted to other enteroviruses that can cause polio-like paralysis syndrome (now termed acute flaccid myelitis (AFM))1–3. In particular, enterovirus D68 (EV-D68) is believed to be the main driver of epidemic outbreaks of AFM in recent years4, yet not much is known about EV-D68 host interactions. EV-D68 is a respiratory virus5 but, in rare cases, can spread to the central nervous system to cause severe neuropathogenesis. Here, we used genome-scale CRISPR screens to identify the poorly characterized multipass membrane transporter MFSD6 as a host entry factor for EV-D68. Knockout of MFSD6 expression abrogated EV-D68 infection in cell lines and primary cells corresponding to respiratory and neural cells. MFSD6 localized to the plasma membrane and was required for viral entry into host cells. MFSD6 bound directly to EV-D68 particles via its third extracellular loop (L3). We determined the cryo-EM structure of EV-D68 in complex with L3 at 2.1 Å resolution, revealing the interaction interface. A decoy receptor, engineered by fusing MFSD6(L3) to Fc, blocked EV-D68 infection of human primary lung epithelial cells, and provided near complete protection in a lethal mouse model of EV-D68 infection. Collectively, our results reveal MFSD6 as an entry receptor for EV-D68, and support targeting MFSD6 as a potential mechanism to combat infections by this emerging pathogen with pandemic potential.
GPT-4o mini: Non-social science research article
irCLIP-RNP and Re-CLIP reveal patterns of dynamic protein assemblies on RNA
Luca Ducoli, Brian J. Zarnegar, Douglas F. Porter, Robin M. Meyers, Weili Miao, Nicholas M. Riley, Suhas Srinivasan, Leandra V. Jackrazi, Yen-Yu Yang, Zhouxian Li, Yinsheng Wang, Carolyn R. Bertozzi, Ryan A. Flynn, Paul A. Khavari
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RNA-binding proteins (RBPs) control varied processes, including RNA splicing, stability, transport and translation1,2,3. Dysfunctional RNA–RBP interactions contribute to the pathogenesis of human disease1,4,5; however, characterizing the nature and dynamics of multiprotein assemblies on RNA has been challenging. Here, to address this, non-isotopic ligation-based ultraviolet-light-induced cross-linking and immunoprecipitation6 was combined with mass spectrometry (irCLIP-RNP) to identify RNA-dependent associated proteins (RDAPs) co-bound to RNA with any RBP of interest. irCLIP-RNP defined landscapes of multimeric protein assemblies on RNA, revealing patterns of RBP–RNA associations, including cell-type-selective combinatorial relationships between RDAPs and primary RBPs. irCLIP-RNP also defined dynamic RDAP remodelling in response to epidermal growth factor (EGF), revealing that EGF-induced recruitment of UPF1 adjacent to HNRNPC promotes splicing surveillance of cell proliferation mRNAs. To identify the RNAs simultaneously co-bound by multiple studied RBPs, a sequential immunoprecipitation irCLIP (Re-CLIP) method was also developed. Re-CLIP confirmed binding relationships observed in irCLIP-RNP and identified HNRNPC and UPF1 RBP co-binding on RND3 and DDX3X mRNAs. irCLIP-RNP and Re-CLIP provide a framework to identify and characterize dynamic RNA–protein assemblies in living cells.
GPT-4o mini: Non-social science research article
Connectome-driven neural inventory of a complete visual system
Aljoscha Nern, Frank Loesche, Shin-ya Takemura, Laura E. Burnett, Marisa Dreher, Eyal Gruntman, Judith Hoeller, Gary B. Huang, MichaƂ Januszewski, Nathan C. Klapoetke, Sanna Koskela, Kit D. Longden, Zhiyuan Lu, Stephan Preibisch, Wei Qiu, Edward M. Rogers, Pavithraa Seenivasan, Arthur Zhao, John Bogovic, Brandon S. Canino, Jody Clements, Michael Cook, Samantha Finley-May, Miriam A. Flynn, Imran Hameed, Alexandra M. C. Fragniere, Kenneth J. Hayworth, Gary Patrick Hopkins, Philip M. Hubbard, William T. Katz, Julie Kovalyak, Shirley A. Lauchie, Meghan Leonard, Alanna Lohff, Charli A. Maldonado, Caroline Mooney, Nneoma Okeoma, Donald J. Olbris, Christopher Ordish, Tyler Paterson, Emily M. Phillips, Tobias Pietzsch, Jennifer Rivas Salinas, Patricia K. Rivlin, Philipp Schlegel, Ashley L. Scott, Louis A. Scuderi, Satoko Takemura, Iris Talebi, Alexander Thomson, Eric T. Trautman, Lowell Umayam, Claire Walsh, John J. Walsh, C. Shan Xu, Emily A. Yakal, Tansy Yang, Ting Zhao, Jan Funke, Reed George, Harald F. Hess, Gregory S. X. E. Jefferis, Christopher Knecht, Wyatt Korff, Stephen M. Plaza, Sandro Romani, Stephan Saalfeld, Louis K. Scheffer, Stuart Berg, Gerald M. Rubin, Michael B. Reiser
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Vision provides animals with detailed information about their surroundings and conveys diverse features such as colour, form and movement across the visual scene. Computing these parallel spatial features requires a large and diverse network of neurons. Consequently, from flies to humans, visual regions in the brain constitute half its volume. These visual regions often have marked structure–function relationships, with neurons organized along spatial maps and with shapes that directly relate to their roles in visual processing. More than a century of anatomical studies have catalogued in detail cell types in fly visual systems 1–3 , and parallel behavioural and physiological experiments have examined the visual capabilities of flies. To unravel the diversity of a complex visual system, careful mapping of the neural architecture matched to tools for targeted exploration of this circuitry is essential. Here we present a connectome of the right optic lobe from a male Drosophila melanogaster acquired using focused ion beam milling and scanning electron microscopy. We established a comprehensive inventory of the visual neurons and developed a computational framework to quantify their anatomy. Together, these data establish a basis for interpreting how the shapes of visual neurons relate to spatial vision. By integrating this analysis with connectivity information, neurotransmitter identity and expert curation, we classified the approximately 53,000 neurons into 732 types. These types are systematically described and about half are newly named. Finally, we share an extensive collection of split-GAL4 lines matched to our neuron-type catalogue. Overall, this comprehensive set of tools and data unlocks new possibilities for systematic investigations of vision in Drosophila and provides a foundation for a deeper understanding of sensory processing.
GPT-4o mini: Non-social science research article
Multimodal generative AI for medical image interpretation
Vishwanatha M. Rao, Michael Hla, Michael Moor, Subathra Adithan, Stephen Kwak, Eric J. Topol, Pranav Rajpurkar
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Accurately interpreting medical images and generating insightful narrative reports is indispensable for patient care but places heavy burdens on clinical experts. Advances in artificial intelligence (AI), especially in an area that we refer to as multimodal generative medical image interpretation (GenMI), create opportunities to automate parts of this complex process. In this Perspective, we synthesize progress and challenges in developing AI systems for generation of medical reports from images. We focus extensively on radiology as a domain with enormous reporting needs and research efforts. In addition to analysing the strengths and applications of new models for medical report generation, we advocate for a novel paradigm to deploy GenMI in a manner that empowers clinicians and their patients. Initial research suggests that GenMI could one day match human expert performance in generating reports across disciplines, such as radiology, pathology and dermatology. However, formidable obstacles remain in validating model accuracy, ensuring transparency and eliciting nuanced impressions. If carefully implemented, GenMI could meaningfully assist clinicians in improving quality of care, enhancing medical education, reducing workloads, expanding specialty access and providing real-time expertise. Overall, we highlight opportunities alongside key challenges for developing multimodal generative AI that complements human experts for reliable medical report writing.
GPT-4o mini: Non-social science research article
Macrophages harness hepatocyte glutamate to boost liver regeneration
María del Mar Rigual, Mariana Angulo-Aguado, Sladjana Zagorac, Ruth Álvarez-Díaz, Marta Benítez-Mondéjar, Fengming Yi, Carlos Martínez-Garay, Karla Santos-de-Frutos, Eunjeong Kim, Ramón Campos-Olivas, Nabil Djouder
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Liver regeneration after hepatectomy follows accurate coordination with the body’s specific requirements1,2,3. However, the molecular mechanisms, factors and particular hepatocyte population influencing its efficiency remain unclear. Here we report on a unique regeneration mechanism involving unconventional RPB5 prefoldin interactor 1 (URI1), which exclusively colocalizes with, binds to and activates glutamine synthase (GS) in pericentral hepatocytes. Genetic GS or URI1 depletion in mouse pericentral hepatocytes increases circulating glutamate levels, accelerating liver regeneration after two-third hepatectomy. Conversely, mouse hepatocytic URI1 overexpression hinders liver restoration, which can be reversed by elevating glutamate through supplementation or genetic GS depletion. Glutamate metabolically reprograms bone-marrow-derived macrophages, stabilizing HIF1α, which transcriptionally activates WNT3 to promote YAP1-dependent hepatocyte proliferation, boosting liver regeneration. GS regulation by URI1 is a mechanism that maintains optimal glutamate levels, probably to spatiotemporally fine-tune liver growth in accordance with the body’s homeostasis and nutrient supply. Accordingly, in acute and chronic injury models, including in cirrhotic mice with low glutamate levels and in early mortality after liver resection, as well as in mice undergoing 90% hepatectomy, glutamate addition enhances hepatocyte proliferation and survival. Furthermore, URI1 and GS expression co-localize in human hepatocytes and correlate with WNT3 in immune cells across liver disease stages. Glutamate supplementation may therefore support liver regeneration, benefiting patients awaiting transplants or recovering from hepatectomy.
GPT-4o mini: Non-social science research article
STING agonist-based ER-targeting molecules boost antigen cross-presentation
Xiafeng Wang, Zhangping Huang, Lixiao Xing, Liru Shang, Juan Jiang, Caiguanxi Deng, Wei Yu, Lin Peng, Hao Yang, Xiaohong Zheng, Xinmin Liu, Haolan Yang, Yixin Chen, Yongyong Li, Jing Liu, Xi Xie, Wei Xu, Xiaojun Xia, Zezhong Liu, Wanli Liu, Shibo Jiang, Yingyue Zeng, Lu Lu, Ji Wang
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CD8+ T cell immune responses are critical for combating infectious diseases and tumours1,2,3. Antigen cross-presentation, primarily occurring at the endoplasmic reticulum (ER) of dendritic cells, is essential for protein-based vaccines to induce CD8+ T cell responses4. Current efforts have focused on antigen delivery at the tissue and cellular levels, whereas subcellular delivery has been limited to facilitating antigen escape from lysosomes into the cytosol. In the absence of a small-sized high-affinity ER-targeting molecule, the importance of the ‘last mile’ from the cytosol to the ER remains elusive. Here we developed stimulator of interferon genes (STING) agonist-based ER-targeting molecules (SABER), which effectively deliver antigens to the ER and cluster key machinery in cross-presentation to form microreactors by folding the ER membrane. Conjugation of SABER to various antigens substantially enhances the induction of CD8+ T cell immune responses to tumour neoantigens and conserved viral epitopes, far exceeding that achieved by mixtures of antigens with STING agonists or conventional adjuvants. SABER also retains a potent adjuvant effect, effectively enhancing the ability of a SARS-CoV-2 subunit vaccine to induce broadly neutralizing antibodies. This study provides a high-affinity ER-targeting delivery system and vaccine adjuvant, demonstrating that precise subcellular delivery targeting the last mile of cross-presentation can lead to a qualitative leap.
Nature DOI suffix ≠ "/s...": Not a research article
New lasso-shaped antibiotic kills drug-resistant bacteria
Benjamin Thompson, Shamini Bundell
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Nature DOI suffix ≠ "/s...": Not a research article
Lessons from Portugal on effects of cutting research funding
Marc Veldhoen, João T. Barata, Luisa M. Figueiredo, Claus M. Azzalin
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The entire scientific community is reeling from severe cuts to US research funding (see Nature 638, 865–867; 2025). Policymakers globally must recognize that science cannot be switched on and off without lasting consequences. Portugal offers a cautionary tale.
Nature DOI suffix ≠ "/s...": Not a research article
How to get more women into mining
Linqi Huang, Xibing Li, Longjun Dong, Haoxuan Yu
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Your Editorial (see Nature 638, 582; 2025) emphasized that gender-specific awards play a crucial part in promoting women’s contributions to science and technology. This is the case in the mining sector, which is conventionally male-dominated. Initiatives such as 100 Global Inspirational Women in Mining (WIM100), launched by Women in Mining UK, as well as other industry-led awards, challenge outdated perceptions by celebrating achievements of female professionals across technical and leadership roles.
Nature DOI suffix ≠ "/s...": Not a research article
Why is there more matter than antimatter? CERN result offers tantalizing new clue
Elizabeth Gibney
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A photograph of antimatter particle (pale blue) meeting a matter particle and being annihilated.Credit: Science Photo Library Physicists have, for the first time, seen a matter particle from the proton family behave in a fundamentally different way from its antimatter twin. The finding — which fits with behaviours predicted by the standard model of particle physics — could help researchers in their struggle to explain why matter is so abundant compared with antimatter, something that current theories cannot do. “I am personally very excited about this measurement,” says Yuval Grossman, a theoretical physicist at Cornell University in Ithaca, New York. Although the latest finding cannot by itself explain matter’s dominance over antimatter, “it is another piece of the puzzle”, he says. The race to reveal antimatter’s secrets The finding, from the LHCb experiment at CERN, Europe’s particle-physics laboratory near Geneva, Switzerland, was presented at the Rencontres de Moriond conference in La Thuile, Italy, on 24 March and posted on thearXiv preprint server1. Understanding differences between matter and antimatter — particles of the same mass but opposite charge — is important to explain the Universe’s composition. When the two types of particle meet, they annihilate. That poses a problem for physicists: if matter and antimatter both were created equally in the Big Bang and behaved in the same way, as most physical laws suppose, then it’s difficult to explain the presence of matter today. Ordinary matter Although certain tiny differences in behaviour have been observed between some types of matter and antimatter, they have never been seen in baryons – particles that make up most of the Universe’s visible matter. Baryons consist of three quarks, and include protons and neutrons. In the latest work, researchers observed subtle differences between the decay rates of a particle called the beauty-lambda baryon and its antimatter counterpart. The team analysed data from 2009 to 2018 for a certain decay of these baryons into a proton and three mesons — light, unstable particles comprising two quarks. The evidence for a difference in decay rate between the matter and antimatter versions of the beauty-lambda baryon was overwhelming. Physicists calculate that the odds of such a discrepancy occurring by chance is less than 1 in 3 million. The discovery is “a major milestone”, says Tim Gershon, a particle physicist at the University of Warwick, UK, who is part of the LHCb collaboration. Long-sought phenomenon
Nature DOI suffix ≠ "/s...": Not a research article
First map of human brain mitochondria is ‘groundbreaking’ achievement
Nora Bradford
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Different regions of the human brain (artificially coloured) have different densities of the energy-producing organelles called mitochondria.Credit: Alfred Pasieka/Science Photo Library Scientists have created the first map of the crucial structures called mitochondria throughout the entire brain ― a feat that could help to unravel age-related brain disorders1. The results show that mitochondria, which generate the energy that powers cells, differ in type and density in different parts of the brain. For example, the evolutionarily oldest brain regions have a lower density of mitochondria than newer regions. The map, which the study’s authors call the MitoBrainMap, is “both technically impressive and conceptually groundbreaking”, says Valentin Riedl, a neurobiologist at Friedrich-Alexander University in Erlangen, Germany, who was not involved in the project. From cell to brain The brain’s mitochondria are not just bit-part players. “The biology of the brain, we know now, is deeply intertwined with the energetics of the brain,” says Martin Picard, a psychobiologist at Columbia University in New York City, and a co-author of the study. And the brain accounts for 20% of the human body’s energy usage2. Wielding a tool typically used for woodworking, the study’s authors divided a slice of frozen human brain ― from a 54-year-old donor who died of a heart attack ― into 703 tiny cubes. Each cube measured 3 × 3 × 3 millimetres, which is comparable to the size of the units that make up standard 3D images of the brain. “The most challenging part was having so many samples,” says Picard. Cubic millimetre of brain mapped in spectacular detail The team used biochemical and molecular techniques to determine the density of mitochondria in each of the 703 samples. In some samples, the researchers also estimated the mitochondria’s efficiency at producing energy. To extend their findings beyond a single brain slab, the authors developed a model to predict the numbers and types of mitochondria across the entire brain. They fed it brain-imaging data and the brain-cube data. To check their model, they applied it to other samples of the frozen brain slice and found that it accurately predicted the samples’ mitochondrial make-up.
Nature DOI suffix ≠ "/s...": Not a research article
Style over substance? What birds’ mating behaviours reveal about sexual selection
Tim Coulson
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Birds, Sex & Beauty: The Extraordinary Implications of Charles Darwin’s Strangest Idea Matt Ridley 4th Estate (2025) At 4 a.m. one April morning, science writer Matt Ridley was hurrying up the frosty Pennine hills in England, keen to catch the peculiar pre-dawn mating rituals of the black grouse (Lyrurus tetrix). Males congregate for weeks on end on an unremarkable patch of ground where, in the small hours, they sort themselves into a hierarchy known as a lek. The birds that outcompete the others — through threats, fights or tail-feather displays accompanied by a ‘roo-kooing’ call — secure tiny territories at the centre of the lek. The losers settle for outlying real estate. As Ridley explains in Birds, Sex & Beauty, he has been watching grouse on this same patch of ground for years. Through persistent study, he hopes to better understand their unusual behaviour. This desire to learn through observation runs throughout his book, as the author interweaves his love of natural history with a mash-up of popular science and travel writing to explore sexual selection in birds. A new vision for how evolution works is long overdue For the black grouse, weeks of infighting build up to a crucial few days, when females patrol the lek and choose a mate — usually one near the centre. But the male’s success comes at a cost: maintaining their tenure is a challenge for even the fittest. Few last longer than a year or two before succumbing to exhaustion. Evolutionary biologists have long understood that some traits are associated with reproduction, and others with survival — and that the two are often at odds. For example, the tail of the peacock (Pavo cristatus) attracts peahens, but this flashy ornament makes him vulnerable to predation. The lekking behaviour of the black grouse secures reproduction but is energetically costly. Ridley is interested in how such characteristics evolve. What exactly, he asks, are these male traits signalling, and what are the females choosing? Charles Darwin was the first to articulate these questions. He argued that both the exaggerated characteristics of males and the tendency of females to choose the most impressive males are inherited characteristics. His critics disputed the idea that females were choosing mates, arguing instead that the males sorted out mating among themselves, on the basis of who had the best dance or the brightest tail. Good genes or sexy sons? In 1930, Ronald Fisher (the father of mathematical evolutionary biology) showed through mathematical models how inherited female choice and inherited sexually selected characters in males could together generate ‘runaway selection’. When only a handful of ‘attractive’ males secure all the matings — as is the case for black grouse — the females’ preference for exaggerated traits leads to those traits becoming evermore exaggerated, regardless of the survival costs for males. Over time, these preferences and traits co-evolve, becoming genetically correlated. This phenomenon can lead to striking features. The tail of the male ribbon-tailed astrapia (Astrapia mayeri), for instance, can be longer than a metre — more than three times the length of its body. It is not easy to fly with such a long streamer creating drag. Many male birds, such as the Victoria’s riflebird (Ptiloris victoriae), ‘dance’ to woo females.Credit: Getty Fisher argued that females choose ‘showy males’ to increase the chance that they have ‘sexy sons’ who will be sought-after mates, and so pass on their genes. But what makes a showy male a good mate? In 1975, evolutionary biologist Amotz Zahavi proposed the handicap principle: by sporting traits that come with a fitness cost, males are signalling to females that they can squander resources on growing something showy, akin to a rich person signalling their wealth by buying many fast cars, despite being able to drive only one at a time. The comings and goings of ants: how are social skills shaped in an ever-changing world? The handicap principle has remained contentious. In 1982, evolutionary biologists Bill Hamilton and Marlene Zuk proposed an alternative hypothesis — the male traits that females choose reflect the males’ ability to pass on his genes. His ornaments are signalling the ability to fight off infection or to escape predators. There is growing evidence supporting this ‘good genes’ hypothesis, which, as Ridley points out, does not contradict Fisher’s arguments. Numerous scientists have made their careers attempting to prove these hypotheses. But the problem with the debate is that there might not be a single driver of sexual selection. In some cases, the handicap principle could drive runaway selection; in others, it might be good genes. The search for a single cause flies in the face of the diversity of nature that Ridley celebrates.
Nature DOI suffix ≠ "/s...": Not a research article
Incredible close-up of colourful crab spiders — March’s best science images
Emma Stoye
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Nature DOI suffix ≠ "/s...": Not a research article
Live-cell super-resolution microscopy reveals how molecules enter and exit the nucleus
Bernd Rieger, Enya S. Berrevoets
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Life on the macroscale arises only through molecular dynamics on the nanoscale. Inside cells, countless molecules diffuse, are transported and interact with one another over timescales of fractions of a second. Writing in Nature, Sau et al.1 present a method that enables scientists to track molecules entering and exiting the nucleus of a cell on a millisecond timescale and with spatial resolution on the nanometre scale.
Nature DOI suffix ≠ "/s...": Not a research article
Some assembly required
Russell Nichols
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Part 1: Sensor array Dear Friend, Thank you for choosing Nick’s Body Shop! We serve a wide range of good people all over the world. Your purchase officially makes you not only a valued customer, but a dear friend. This sensor array will take your companion’s perception to a new level. They will be able to sniff out toxins, predict earthquakes and even track down survivors in disaster areas — and that’s just the ‘survival mode’! In this day and age, as we all know, privacy is no joke. But Nick’s got you covered. This sensor array is locked down tight: triple encryption, security safeguards, all that fancy stuff. No need to worry about your companion violating boundaries, collecting data without consent or infringing on people’s privacy. If you need any help with the assembly (or if you want to order more parts), don’t hesitate to reach out. I’m here for you! From the heart, Nick C. Part 2: Voice box Dear Friend, I’m glad to hear the sensor array has been working well for you! I lol’d when you said your companion mistook the smell of your partner’s cooking for an “extinction level event”. That wasn’t a sensory malfunction — that was a mechanical foot in the mouth! Read more science fiction from Nature Futures But have no fear, dear friend. Your new voice box is here! No more senseless comments or generic responses. With this advanced part, your companion will be able to hold actual in-depth conversations. They will give you advice, encouragement, comfort — even share their own dreams and fears, if you ask. You told me you have an early-gen companion. There shouldn’t be any compatibility mishaps. But in some cases, a new voice box in an old-gen model can cause minor glitches. (It’s a relay problem with the kinetic appendages.) If you notice any strange behaviour from your companion — such as them hitting themselves, spouting existential monologues randomly, etc. — contact me ASAP. From the heart, Nick C. Part 3: Kinetic appendages Dear Friend, I am truly sorry to hear about the accident. On behalf of Nick’s Body Shop, I sincerely apologize for your companion’s meltdown. (I can’t imagine how unsettling it must’ve been to be called a murderer while chopping wood.) To rectify the situation, I am providing you with replacement kinetic appendages free of charge! These upgraded models have been carefully selected to eliminate the relay issue, so your companion will function optimally. I apologize for the generic response. There have been new developments here at Nick’s Body Shop, including layoffs, which means I will be short-handed moving forward. From the heart, Nick C. Part 4: Interface module Dear Friend, It warms my heart to hear the kinetic appendages have been working to your satisfaction. The pictures you shared look truly wonderful. Building an entire underground bunker with your companion in just six days is quite the achievement. Sourced from a highly advanced sentry, this interface module boosts your companion’s language capabilities significantly. But be careful. As I mentioned previously, we here at Nick’s Body Shop take privacy and security seriously. To prevent any security breaches, make sure your companion avoids unfamiliar networks and unauthorized entities. (I’m fairly certain that unfortunate wood-chopping incident was indeed a cyberattack.) But this interface module comes equipped with robust encryption and authentication protocols against external threats that might seek to harm you or your companion. If you need any further assistance, Nick is here to connect with you any time. From the heart, Nick C. Part 5: Neural network Dear Friend, As I mentioned previously, I am short-handed, which is why it took me longer than expected to get this part to you. Thank you for your patience. From your description, your previous neural network failed owing to either capacity limitations or a cyberattack. (I cannot determine the exact cause without performing an inspection.) But I must warn you, dear friend. I have recovered and received more beaten and broken companions than I care to count — companions who had been abused by owners who felt insecure, inadequate, unintelligent or obsolete. If you need emotional support, I encourage you to call our free Body Shop 24/7 helpline at 1-800-CHOPPER. Sincerely, Nick C.
Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: Babies make memories — so why don’t we recall them?
Flora Graham
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Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: Stunning Antarctic ecosystem revealed by calving iceberg
Flora Graham
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Nature DOI suffix ≠ "/s...": Not a research article
Audio long read: How quickly are you ageing? What molecular ‘clocks’ can tell you about your health
Heidi Ledford, Benjamin Thompson
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Nature DOI suffix ≠ "/s...": Not a research article
Trump’s bid for Greenland threatens to destabilize Arctic research
Alexandra Witze
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Boulder, Colorado A major Arctic-science conference got caught up this week in the fight between US President Donald Trump, who says the United States should take over Greenland, and Greenlandic and Danish leaders, who say it should not. Trump team ‘survey’ sent to overseas researchers prompts foreign-interference fears Greenland is an international research hub for many scientists, including climate researchers who fan out across the island’s ice sheet each summer, measuring how it is melting and contributing to rising sea levels around the world. Ahead of a planned visit by US vice-president JD Vance to a US military base in Greenland this week, a major session on research in Greenland was withdrawn from the Arctic Science Summit Week in Boulder, Colorado. Geopolitical tensions between the United States, where the meeting is being held, and Greenland were in the air. On 26 March, more than 50 attendees formed a circle outside the venue, holding signs showing the red-and-white flag of Greenland, which is an autonomous, self-governing territory of Denmark. “We would like to show our support for our friends and colleagues back in Greenland, especially in these times when it’s very stressful,” says Kerim Hestnes Nisancioglu, a climate scientist at the University of Bergen in Norway, who helped to organize the show of solidarity. Relationship tension Trump has said that the United States will “have” Greenland either through a financial deal or by military force, pointing to the island’s valuable rare-earth minerals and its strategic location for national security and trade. This stance has upset scientific relationships between the two. “We’ve had very good relationships with Greenland, they’ve had a real interest in working with the US — and these offensive and inappropriate actions have been really destructive,” says a US scientist who has worked in Greenland for nearly two decades and who requested anonymity owing to fear of reprisal. This Arctic town wants to make renewable energy work at the top of the world A number of researchers from Greenland declined to speak with Nature at the conference, citing the political tensions. In recent years, many international scientists who travel to Greenland to conduct research had worked to form a tighter, more ethical bond with the communities and institutions there. It used to be that researchers would arrive and conduct ‘parachute science’ without partnering with anyone local, says Aurora Roth, a graduate student at the Scripps Institution of Oceanography in La Jolla, California, who studies fjords in Greenland. Trump’s play for Greenland has undermined those improvements, she says. “Now you have the current geopolitics, and it makes me embarrassed to be a US researcher.”
Nature DOI suffix ≠ "/s...": Not a research article
AlphaFold is running out of data — so drug firms are building their own version
Ewen Callaway
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An AlphaFold 3 model of a common cold spike protein (blue) interacting with antibodies (green).Credit: Google DeepMind AlphaFold, the revolutionary, Nobel prize-winning tool for predicting protein structures, has a problem: it’s running low on data. The latest version of the artificial intelligence (AI) model, AlphaFold 3, has been touted as a game-changer for drug discovery, because it can model the interaction of proteins with other molecules, including drugs. But a lack of examples of these interactions in the data underpinning AlphaFold — hundreds of thousands of publicly available protein structures — is holding the tool back for the applications that drug companies are most interested in, say scientists. AlphaFold touted as next big thing for drug discovery — but is it? A consortium of leading pharmaceutical companies announced plans today to make their own AlphaFold-3-inspired AI model using thousands of protein structures that are currently secreted away in company vaults. This is in addition to the more than 200,000 protein structures freely available in the Protein Data Bank (PDB). “The data that’s missing from the PDB is exactly the data that’s present in our internal data,” says John Karanicolas, head of computational drug discovery at the pharma company AbbVie in Chicago, Illinois, and part of the effort, called the AI Structural Biology Consortium. The consortium’s model will be based on OpenFold 3, a fully open-source reproduction of AlphaFold 3 that has been developed by academic researchers (using only publicly available data) and is due to be released in April. But there are no plans to make the consortium’s model available beyond member companies, which include AbbVie, Johnson & Johnson, Sanofi and Boehringer Ingelheim. Google DeepMind, the London-based company that developed AlphaFold, is not involved in the project and did not wish to comment. Its spin-off company, Isomorphic Labs, is using AlphaFold 3 as part of collaborations with drug companies, including Novartis and Eli Lilly. Drug data shortage AlphaFold’s ability to predict proteins’ 3D shapes from their sequences relies on access to the PDB’s huge collection of protein structures mapped with experimental methods, such as X-ray crystallography. Many of these structures include interacting molecules — but they tend to involve biological partners such as the cellular energy source ATP, rather than drug compounds, says Karanicolas. As a result, AlphaFold 3 does an adequate job of predicting how proteins interact with would-be drugs, but “it’s still a very open problem”, says Mohammed AlQuraishi, a computational biologist at Columbia University in New York City who is leading the development of OpenFold. It’s possible that pharma-company protein structures, which are rarely deposited in the PDB, could help. As part of drug-development campaigns, firms routinely determine multiple structures for the same protein bound to many different drug candidates. AlphaFold’s new rival? Meta AI predicts shape of 600 million proteins The full extent of these proprietary protein-structure data isn’t known. But the data could equal or even exceed those of the PDB, says Stephen K. Burley, a director of one of the organizations that hosts the repository and a structural biologist at Rutgers University in Piscataway, New Jersey. AbbVie alone is contributing more than 9,000 structures to the consortium’s AI model. “It’s kind of crazy how much data there is sitting behind these walled gardens,” says AlQuraishi. Drug companies won’t be sharing actual protein structures with each other — or with AlQuraishi — to develop the new model. Instead, the effort will use a platform developed by Apheris, a Berlin-based start-up company, that will allow OpenFold 3 to be retrained using proprietary data and without the structures ever leaving a company’s digital walls. Karanicolas says it will not be possible to reverse engineer the model to identify the secret structures it was trained on. Whether the extra data will boost AlphaFold’s ability to model how proteins and drugs interact is unclear, says AlQuraishi. “That’s going to be the key question — what will the gains look like?” His team will evaluate the model, for example by comparing its predictions with experimental results, and make a detailed analysis public. “I do think the experiment, negative or positive, is incredibly valuable,” he says. Some scientists and funding agencies are looking to create structural databases like those of the pharma companies with which to feed AI models, says AlQuraishi, and it will be worth knowing whether having more data is actually useful. Drastic improvements
Nature DOI suffix ≠ "/s...": Not a research article
‘Open source’ AI isn’t truly open — here’s how researchers can reclaim the term
Stefano Maffulli
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Some 50 years ago this month, the Homebrew Computer Club — a do-it-yourself group of computer enthusiasts and hobbyists — began meeting in Menlo Park, California, fostering a culture of collaboration, knowledge exchange and the open sharing of software. These values, which helped to shape the open-source movement, are now being subverted by some artificial intelligence (AI) companies. AI firms must play fair when they use academic data in training Many foundational AI models are labelled as ‘open source’ because their architecture, including the neural networks’ structure and design, is made freely available. Yet, little information is disclosed about how the models were trained. As the executive director of the Open Source Initiative (OSI) based in Palo Alto, California, my priority since 2022 has been clarifying what the term actually means in the AI era. Decades of free access to non-proprietary software — such as R Studio for statistical computing and OpenFOAM for fluid dynamics — has hastened scientific discovery. Open-source software protects research integrity by ensuring reproducibility. It also fosters global collaboration, allowing scientists to freely share data and solutions. Conventional open-source licences are built around source code, which is easy to share with full transparency, but AI systems are different. They rely heavily on training data, often from proprietary sources or that are protected by privacy laws, such as health-care information. As AI drives discoveries in fields ranging from genomics to climate modelling, the lack of a robust consensus on what is and isn’t open-source AI is worrying. In the future, the scientific community could find its access limited to closed corporate systems and unverifiable models. Light bulbs have energy ratings — so why can’t AI chatbots? For AI systems to align with typical open-source software, they must uphold the freedom to use, study, modify and share their underlying models. Although many AI models that use the ‘open source’ tag are free to use and share, the inability to access the training data and source code severely restricts deeper study and modification . For example, an analysis by OSI found that several popular large language models, such as Llama2 and Llama 3.x (developed by Meta), Grok (X), Phi-2 (Microsoft) and Mixtral (Mistral AI), are incompatible with open-source principles. By contrast, models such as OLMo, developed by the Allen Institute for AI, a non-profit organization in Seattle, Washington, and community-led projects such as LLM360’s CrystalCoder — a language model tailored to perform both programming and natural-language tasks — better uphold OSI’s vision of open source. The main reason why some companies might be misusing the open-source label is to sidestep proposed regulations under the European Union’s 2024 AI Act, which exempts free and open software from strict scrutiny. This practice — companies claiming openness while restricting access to key components such as information about the training data — is called openwashing.
Nature DOI suffix ≠ "/s...": Not a research article
Deep dive: How I use robots to survey coral reefs
Nikki Forrester
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“Deep coral reefs occur throughout the world and generally reach depths of up to 150 metres. They host different ecological communities from the shallow coral reefs that most people think of, but are relatively understudied. An analogy would be a botanist not studying any sections of the plant below the ground; ignoring deep coral reefs means missing out on understanding a big part of the habitat. Over the past four years, I’ve been developing cost-effective methods using remote operated vehicles (ROVs) to study deep coral reefs and how they are changing with the climate. In marine ecology, a lot of research is conducted while scuba-diving, but we’re often not permitted to dive below 30 metres. We can’t afford to restrict our work to shallow depths; we need innovative ways to do deep marine science. In this photo, I’m piloting a camera-fitted ROV at the Diamond Islets in the Coral Sea off the coast of eastern Australia. My husband and colleague, Ben Cresswell, is holding the tether and skipper Casey Castro is steering the boat. Some of the ROV cameras film continuously, and others take time-lapse photos every 10 seconds. A full survey of a reef section takes about 40 minutes. Later in the laboratory, we watch the video footage to count fish, estimate coral cover and collect other data.
Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: Why women are far more likely to develop Alzheimer’s than men
Flora Graham
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Nature DOI suffix ≠ "/s...": Not a research article
A lighthouse galaxy shines unexpectedly through the fog of the cosmic dawn
Michele Trenti
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Modern observational cosmology provides a snapshot of the Universe just after its formation in the hot, dense pinprick of the Big Bang, which occurred around 13.8 billion years ago. Measurements of the cosmic microwave background radiation, emitted about 300,000 years after that event, depict a cosmos filled with hot hydrogen and helium gas with almost uniform density and temperature11. But the next 300 million or so years of cosmic history remain shrouded in mystery. This ‘cosmic dawn’ is a crucial period in which, as the Universe expanded and cooled, stars, galaxies and black holes started emerging and growing from the nearly homogeneous gas. Writing in Nature, Witstok et al.2 report the observation of ultraviolet light emitted from a galaxy when the Universe was just 330 million years old — a finding that could require cosmologists to revisit some aspects of early cosmic history.
Nature DOI suffix ≠ "/s...": Not a research article
Crucial meeting: molecule helps vaccine to interact with killer T cells
John T. Wilson
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Immune cells called killer T cells (also known as cytotoxic CD8+ T cells) have a crucial role in protecting against viral infections and in eliminating tumours. These T cells can find and destroy their targets when a T-cell receptor specifically recognizes peptide fragments (termed antigens) from proteins that are viewed as foreign by the immune system. Therefore, vaccines that can generate robust responses from CD8+ T cells hold promise for preventing and treating a wide array of diseases1. Yet, most vaccines used in the clinic tend to induce only minimal responses from CD8+ T cells and instead provide protection by activating other components of the immune system. Writing in Nature, Wang et al.2 describe a vaccine technology that stimulates CD8+ T cells and shows promise in mouse models of cancer and SARS-CoV-2 infection.
Nature DOI suffix ≠ "/s...": Not a research article
Can trauma from violence be genetically inherited? Scientists debate Syria refugee study
Miryam Naddaf
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The aftermath of the Hama massacre in Syria in 1982. A young boy stands in front of a shop, its shutter riddled with bullet holes.Credit: Archive PL/Alamy A study of families who have lived through conflict in Syria suggests that genetic imprints of their trauma have been passed to their children and grandchildren. The research1 focuses on the controversial idea that trauma can leave ‘epigenetic marks’ on a person’s genes that can be passed onto following generations. Not all scientists agree that trauma can be inherited in this way and the mechanism for such inheritance is not known. But the latest research echoes studies of children of survivors of the genocide in Rwanda2 and the Holocaust3 that have turned up similar effects. “This is a really great attempt to look at the biological imprint of intergenerational trauma,” says Rachel Yehuda, a neuroscientist at the Icahn School of Medicine at Mount Sinai in New York City. However, the study “should be seen as a proof of concept”, she adds. It does not explain whether or how such biological marks affect health or behaviour. In the paper, published in Scientific Reports last month, researchers compared data from 10 families who fled violent events in Syria in the 1980s, and 22 families who fled after the uprising in 2011, with a control group of 16 Syrian families who had not been exposed to war-related violence. The team analysed epigenetic marks — chemical tags on DNA sequences that result from environmental factors including stress — in more than 850,000 DNA regions. Epigenetic marks do not alter DNA sequences but can affect how genes work. The authors found that adults and children who had been directly exposed to violence in the 1980s and after 2011 had distinctive epigenetic marks in certain DNA regions. In the case of one woman who had witnessed violence in the 1980s, these tags persisted in her daughter and grandchildren. The researchers did not find any of these epigenetic marks among people in the control group. There were 131 participants in total. The latest findings are “the first to identify epigenetic signatures of trauma across three generations in humans in a controlled research design”, says study co-author Rana Dajani, a molecular biologist at the Hashemite University in Zarqa, Jordan. “Science is about little steps, and this is a little giant step in understanding epigenetic inheritance,” she adds. Forty years of trauma Syria’s people have experienced more than 40 years of almost continual trauma. In June 1979, then-president Hafez al-Assad unleashed a crackdown on an attempted rebellion, and in 1982, his troops bombed the city of Hama for days, killing up to 30,000 people. One of the study participants, now a grandmother, who was pregnant with her daughter at the time, witnessed the crackdown. The study included nine other women whose mothers experienced the violence. Their children also participated in the research. Air strikes and tank-rounds from the forces of former president Hafez al-Assad flattened many of Hama’s neighbourhoods. Credit: Archive PL/Alamy Of the study’s participants, 22 mothers and their 20 children witnessed a second period of violence, after the Syrian uprising in 2011. This was when then-president Bashar al-Assad, who fled the country last December, deployed the army and regime-affiliated militias against protesters. The mothers had 19 other children, born after the traumatic events who were also studied. To understand whether trauma resulting from these violent events had left epigenetic marks, and whether these marks are passed down through the maternal germ line, Dajani and her colleagues focused on patterns of DNA methylation — an epigenetic mechanism in which DNA is tagged with methyl groups. It is one of “the most studied [processes] and we have the technology today to do it”, Dajani says. Over five years, the researchers searched for study participants from Jordan’s Syrian communities. The team defined a traumatic experience of violence as being severely beaten or persecuted by authorities or militias, seeing a wounded person or fatality, or witnessing someone else being beaten, shot or killed. They analysed DNA samples from participants’ cheek cells and found that children and women with first-hand traumatic experiences of violence in the 1980s and after 2011 had distinctive methylation tags on 21 DNA regions. The analysis also revealed tags on 14 DNA regions in the grandmother who witnessed the 1980s violence, as well as in her daughter and grandchild. These tags were also present in the daughters and grandchildren who were the descendants of nine women who witnessed that violence. “Looking at at least two — if not three or maybe even four — generations is really crucial. That’s not often done in humans,” says epigeneticist Michael Kobor at the University of British Columbia in Vancouver, Canada. Memory reset Researchers disagree on whether methylation marks on DNA can pass between generations. This is because during early stages of mammalian development, the genome undergoes the equivalent of a memory reset — a process known as epigenetic reprogramming — that clears out DNA methylation tags. “All of these marks, almost all of them, are erased when the eggs hit the sperm,” says Kobor. “The biology just doesn’t support DNA methylation as a vehicle of intergenerational transmission,” he adds.
Nature DOI suffix ≠ "/s...": Not a research article
Microbes can capture carbon and degrade plastic — why aren’t we using them more?
Rino Rappuoli, Nguyen K. Nguyen, David E. Bloom, Charles Brooke, Rachel M. Burckhardt, Alan D. Dangour, Dilfuza Egamberdieva, Gigi K. Gronvall, Trevor D. Lawley, Jay T. Lennon, Ryan Morhard, Aindrila Mukhopadhyay, Raquel Peixoto, Pamela A. Silver, Lisa Y. Stein
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Microorganisms have shaped Earth for almost four billion years. At least a trillion microbial species sustain the biosphere — for instance, by producing oxygen or sequestering carbon1. Microbes thrive in extreme environments and use diverse energy sources, from methane to metals. And they can catalyse complex reactions under ambient temperatures and pressures with remarkable efficiency. The potential to exploit these microbial abilities to substantially reduce the impact of human activities on the planet has been recognized by many2. And bacteria or fungi are already being used to produce materials, fuels and fertilizers in ways that reduce energy consumption and the use of fossil-fuel feedstocks, as well as to clean up waste water and contaminants3. Despite their wide-ranging potential, however, microbe-based technologies remain largely overlooked in international plans to combat climate change or reduce the loss of biodiversity4. For example, discussions about the role of microbial technologies in achieving fossil-free alternatives to current products and processes were minimal or absent at the United Nations conferences of the parties (COPs) in 2023 and 2024 on climate change, and on biodiversity in 2022 and 2024 (see Nature 636, 17–18; 2024). Is the COP29 climate deal a historic breakthrough or letdown? Researchers react To better leverage microbiology in addressing climate change and other sustainability challenges, the International Union of Microbiological Societies and the American Society for Microbiology brought us (the authors) together in December 2023 — as a group of microbiologists, public-health scientists and economists with expertise in health, energy, greenhouse gases, agriculture, soil and water. In a series of meetings, we have assessed whether certain microbe-based technologies that are already on the market could contribute to sustainable solutions that are scalable, ethical and economically viable. We have identified cases in which the technical feasibility of an approach has already been demonstrated and in which solutions could become competitive with today’s fossil-based approaches in 5–15 years. This work has convinced us that microbe-based interventions offer considerable promise as technological solutions for addressing climate change and — by reducing pollution and global warming — biodiversity loss. Here, we explain why they could be so important5 and highlight some of the issues that we think microbiologists, climate scientists, ecologists and public-health scientists, along with corporations, economists and policymakers, will need to consider to deploy such solutions at scale6. Microbial possibilities The use of genomics, bioengineering tools and advances in artificial intelligence are greatly enhancing researchers’ abilities to design proteins, microbes or microbial communities. Using these and other approaches, microbiologists could help to tackle three key problems. First, many products manufactured from fossil fuels (energy, other fuels and chemicals) could be produced by ‘feeding’ microbes with waste plastics, carbon dioxide, methane or organic matter such as sugar cane or wood chips. Microbes that grow underneath artificial floating islands can transform lakes from net methane sources into carbon sinks.Credit: WaterClean Technologies Among the many companies applying microbe-based solutions to address climate change, LanzaTech, a carbon-upcycling company in Skokie, Illinois, is working on producing aviation fuel on a commercial scale from the ethanol produced when microbes metabolize industrial waste gases or sugar cane. Meanwhile, the firm NatureWorks in Plymouth, Minnesota, is producing polymers, fibres and bioplastics using the microbial fermentation of feedstocks, such as cassava, sugar cane and beets. Second, microbes could be used to clean up pollution — from greenhouse gases, crude oil, plastics and pesticides to pharmaceuticals. For instance, a start-up firm called Carbios, based in Clermont-Ferrand, France, has developed a modified bacterial enzyme that breaks down and recycles polyethylene terephthalate (PET), one of the most common single-use plastics. Another company — Oil Spill Eater International in Dallas, Texas — uses microbes to clean up oil spills, and large waste-management corporations in North America are using bacteria called methanotrophs to convert the methane produced from landfill (a more potent greenhouse gas than CO2) into ethanol, biofuels, polymers, biodegradable plastics and industrial chemicals. Drill, baby drill? Trump policies will hurt climate ― but US green transition is underway The company Floating Island International in Shepherd, Montana, is even building artificial floating islands on lakes and reservoirs that have been polluted by excessive nutrient run-off, so that methane-metabolizing microbes (which colonize the underside of the islands) can remove methane originating from lake sediments. The goal in this case is to transform inland lakes and reservoirs from net methane sources into carbon sinks. Finally, microbes could be used to make food production less reliant on chemical fertilizers and so more sustainable. The chemical process needed to produce ammonia for fertilizer involves burning fossil fuels to obtain the high temperatures and pressures needed (up to 500 °C and 200 atmospheric pressures), releasing 450 megatonnes of CO2 into the atmosphere each year (1.5% of all CO2 emissions)7. Furthermore, excess chemical fertilizers that flow into rivers, lakes and oceans cause algal blooms, which enhance the emission of nitrous oxide, a greenhouse gas that is more potent than either CO2 or methane. Many bacteria and archaea can be used to produce nitrogen fertilizer with much lower greenhouse-gas emissions than synthetic fertilizers. This is because the microbes fix nitrogen at room temperature and at sea-level atmospheric pressure using enzymes known as nitrogenases that convert atmospheric nitrogen (N2) into ammonia (NH3). Several companies are now selling biofertilizers, which are formulations containing bacteria called rhizobia or other microbes that can increase the availability of nutrients to plants (see ‘Towards a bioeconomy’ and go.nature.com/3fs2xqf). A growing number of microbial biopesticides are also offering food producers a way to control crop pests without harming human or animal health or releasing greenhouse gases into the atmosphere8. Source: https://www.precedenceresearch.com/fertilizer-market Keeping it safe As more microbe-based solutions enter the market — whether bioengineered or naturally existing — biosafety considerations will become increasingly important. Many solutions, such as using bacteria to degrade crude oil or plastics, have been shown to be effective and safe in a laboratory setting9. Yet scaling up their use to the levels needed to reduce global emissions or global biodiversity loss could lead to unforeseen complications. Bacteria are being designed to break down plastic waste.Credit: Carbios–AgenceSkotchProd Certain safeguards — designing bacteria that can persist in an ecosystem for only a short time or that can exist under only specific environmental conditions — are already being developed and applied4. And, in a similar way to phased clinical trials in biomedical research, laboratory experiments could be followed by contained tests in the outdoor environment, which could then be followed by larger-scale field testing. Investigators will also need to monitor systems over time, which could involve the sequencing of environmental DNA from waste water and other approaches that are used in infectious-disease surveillance. Ultimately, the effective deployment, containment and monitoring of large-scale microbe-based solutions will require scientific communities, governments and corporations to collaboratively develop evidence-based policies and engage in clear and transparent communication about the enormous opportunities and the potential risks. Making it pay
Nature DOI suffix ≠ "/s...": Not a research article
Give grants to female scientists in war zones
Natalia Tsybuliak, Yana Suchikova
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Your Editorial on women’s achievements in science and technology (see Nature 638, 582; 2025) highlights an important truth: recognition matters. However, it’s equally crucial to acknowledge those women working to keep science alive in war zones, whose contributions are often overlooked.
Nature DOI suffix ≠ "/s...": Not a research article
Meet ‘qudits’: more complex cousins of qubits boost quantum computing
Davide Castelvecchi
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Part of the quantum computer at Innsbruck University on which researchers did simulations using qutrits and ququints. Credit: C. Lackner/Univ. Innsbruck Quantum computing has so far nearly always involved calculating with qubits — quantum objects that can take the value ‘0’ or ‘1’, like ordinary computer bits, but that can also be in a range of combinations of 0 and 1. Now researchers are producing the first applications of ‘qudits’: units of information that offer combinations of three or more simultaneous states. In a paper published on 25 March in Nature Physics1, physicists describe how they used ‘qutrits’ and ‘ququints’ — qudits with three and five states, respectively — to simulate how high-energy quantum particles interact through an electromagnetic field. The work follows a result published in Physical Review Letters (PRL) in September2 that reproduced the behaviour of another quantum field, that of the strong nuclear force, using qutrits. Quantum stock whiplash: what’s next for quantum computing? Such simulations of quantum fields are seen as one of the most promising applications of quantum computers, because these machines could predict phenomena in particle colliders or chemical reactions that are beyond the abilities of ordinary computers to calculate. Qudits are naturally suited to this task, says theoretical physicist Christine Muschik, a co-author of the Nature Physics paper who also pioneered such simulations with qubits in 20163 together with colleagues at the University of Innsbruck, Austria. “If I could go back in time to my old self, I would tell her: why waste time with qubits?” says Muschik, who is now at the University of Waterloo, Canada. “This qudit approach is not a solution to everything, but it helps you when it is suitable to the problem,” says Martin Ringbauer, an experimental physicist at the University of Innsbruck and the lead author of the paper. More generally, qudits can help to make calculations on a quantum computer more efficient and less error-prone, at least on paper. With qudits, each computational unit that previously encoded a qubit — such as a trapped ion or a photon — can suddenly pack in more information, helping the machines to scale up faster. But the tactic is less mature than approaches based on qubits, and the devil could be in the detail. “Qudits are also more complicated to work with,” says Benjamin Brock, an experimental physicist at Yale University in New Haven, Connecticut. System tweaks In most types of quantum computer, the qubits that researchers use are two possible states of a system that would naturally have many more states. Such a system could therefore host qudits as well. “Existing qubit processors such as those of IBM and Google can already be operated as qutrits, and would require minor tweaks to operate as high-dimensional qudits,” says Machiel Blok, a physicist at the University of Rochester, New York. (Blok and his team have done experiments in their laboratory in which superconductors encoded qudits of up to 12 levels4.) Quantum-computing approach uses single molecules as qubits for first time For their quantum-field simulations, the authors of the PRL paper encoded qutrits on a superconducting quantum chip that IBM makes available to researchers, and that is normally used as a qubit machine. Ringbauer, Muschik and their colleagues used excited states of calcium ions to represent their five-level ququints. A ququint is a natural way to represent a field that can be in a lowest-energy state (with value 0) or have positive or negative values from −2 to +2 at any point in space, Muschik says.
Nature DOI suffix ≠ "/s...": Not a research article
Exclusive: NIH to cut grants for COVID research, documents reveal
Max Kozlov
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The SARS-CoV-2 virus that causes COVID has killed more than 1.2 million people in the United States.Credit: Steve Gschmeissner/SPL The US National Institutes of Health (NIH) and Centers for Disease Control and Prevention (CDC) have begun cancelling billions of dollars in funding for research related to COVID-19. COVID-19 research funds “were issued for a limited purpose: to ameliorate the effects of the pandemic”, according to an internal NIH document that Nature has obtained and that provides the agency’s staff members with updated guidance on how to terminate these grants. “Now that the pandemic is over, the grant funds are no longer necessary,” the document states. It is not clear how many of these grants will be ended. ‘Boggles the mind’: US defence department slashes research on emerging threats The crackdown comes as the NIH, under US President Donald Trump, has halted nearly 400 grants in the past month. An earlier version of the documents, obtained by Nature on 5 March, directed staff to identify and potentially cancel projects on transgender populations; gender identity; diversity, equity and inclusion (DEI) in the scientific workforce; and environmental justice. The NIH, which is the world’s largest public funder of biomedical research, has awarded grants to nearly 600 ongoing projects that include ‘COVID’ in the title, worth nearly US$850 million. Together, these projects make up nearly 2% of the NIH’s $47-billion budget. And the CDC plans to cancel $11.4 billion in funds for pandemic response, NBC News reports. SARS-CoV-2, the virus that causes COVID-19, has killed more than 7 million people globally, including more than 1.2 million in the United States, and continues to infect and kill people. Studying the virus, its mode of infection and the government’s response to the pandemic is crucial to preventing the next one, say scientists. Among the terminations at the NIH is a $577-million programme to identify and develop antiviral drugs against the SARS-CoV-2 coronavirus and six other types of virus with pandemic potential. “These terminations are clearly shortsighted — we desperately need new treatments against viruses,” says Jason McLellan, a structural virologist at the University of Texas, Austin, whose project to develop broad-spectrum treatments that work against several types of virus was part of the programme and terminated on 24 March. “To cancel the entire grant because a small portion involved SARS-CoV-2 is going to be dangerous for future pandemic preparedness.” The NIH did not respond to Nature’s queries about the grant terminations or scientists’ concerns about them. Its parent organization, the US Department of Health and Human Services (HHS), told Nature that “the COVID-19 pandemic is over, and HHS will no longer waste billions of taxpayer dollars responding to a non-existent pandemic that Americans moved on from years ago”. Updated guidance The updated documents that Nature obtained (see Supplementary Information below) were sent on 25 March to ‘grants-management specialists’ — NIH staff members who oversee the business side of awarding funding. This document includes COVID-19 on a list of “research activities that NIH no longer supports”, in addition to research on China, DEI, “transgender issues” and vaccine hesitancy. The latest guidance also says that grants related to South Africa and climate change should be terminated. The document also outlines a new category of research that should be terminated: any project on a list sent by the NIH director or the HHS, which is currently helmed by long-time anti-vaccine advocate Robert F. Kennedy Jr. NIH has cut one mRNA-vaccine grant. Will more follow? Such large-scale grant terminations are unprecedented; the agency typically cancels only a few dozen projects each year in response to serious concerns about research misconduct or fraud — and does so only as a last resort, after taking other actions such as suspension. Grants-management specialists will be tasked with identifying and terminating projects, because the NIH’s current leadership considers its scientific staff members too biased to make these determinations, says an NIH official who requested anonymity because they weren’t authorized to speak to the press.
Nature DOI suffix ≠ "/s...": Not a research article
Showing ‘ability’ in ‘disability’ — how I mastered interviews while using a wheelchair
Emilia Krok
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Emilia Krok has changed how she communicates her wheelchair use to potential employers.Credit: MichaƂ LesiƄski/Poznan University of Technology When I was three years old, doctors misdiagnosed my tumour as cancerous. The prolonged and debilitating chemotherapy, combined with the delayed surgical removal of what ultimately was a benign tumour, caused significant damage, resulting in my dependence on a wheelchair. Even as a child, I was curious about how things worked, constantly digging deeper into the mechanisms behind the processes we learnt about in class. The long hospital stays and recovery time at home gave me the perfect opportunity to read and study. I realized that science and engineering were the two fields that had the greatest impact on our lives, and I wanted to be a part of the change that they bring. However, from an early age, I understood that this path might be challenging — not necessarily because of my health condition, but because it would probably require significant effort to demonstrate to others that my professional abilities are not defined by my disability. I still wonder who people see when they look at me in the laboratory: a sample-preparation pro, a well-organized researcher, a great teacher — or simply a woman in a wheelchair? The first time I meet someone, the last description might be likely to come to their mind. Although I can’t change how I get around or my need for workplace adaptations, I can influence how people perceive me — even in the first few minutes of a conversation. Application strategies During the third year of my undergraduate studies in biomedical engineering, I prepared my first scientific CV when applying for short-term internships, a mandatory part of my study at PoznaƄ University of Technology in Poland, near where I grew up. As a disabled student at the beginning of my scientific career, I spent countless hours rethinking each application before submitting it, debating whether to mention that I use a wheelchair. I knew my CV was strong and my grades and academic experience were excellent, and I wanted to be evaluated on that basis. But I was also afraid to completely hide my disability. I feared being told that the workplace was not accessible for people with mobility impairments or that the company hadn’t anticipated accommodating someone with a wheelchair. I would have preferred an immediate rejection after disclosing my disability in my CV rather than going through an interview, only to be told that although my application was impressive enough to warrant a conversation, my disability ultimately made me ineligible. As a compromise, each of my internship applications included subtle hints, with phrases such as “I was a swimmer in the disabled students’ association,” “I held two records in para swimming” or “I served as vice-chair of the Disabled Students Association.” This approach led to an offer to work on data analysis at an institute for infection research. It was a great experience, but I felt that data processing was only one facet of the work I wanted to pursue. I missed the hands-on nature of conducting experiments but felt deep anxiety about whether I could work independently in a lab environment. I did my master’s studies in molecular bioengineering at Dresden University of Technology in Germany, where I had an opportunity to work on practical projects in proteomics, genomics and stem-cell engineering. It was a supportive environment in which mistakes were embraced as part of the learning process, and colleagues and teachers guided me every step of the way. Although I was grateful that I could rely on help from my lab partners when something was not accessible (such as a lab bench at standing level), I had no idea how my independent work would go. But over the course of my studies, I had the opportunity to explore various methods and techniques, giving me a clear understanding of the challenges I might face. Before interviews with potential supervisors for my master’s thesis — which I would write in the final six months of my degree programme — I mentally prepared a list of potential difficulties and their solutions: “I won’t be able to use the eyepieces on a microscope, but I’ve mastered focusing on samples using computer software”; “I can’t carry heavy objects, but even in a wheelchair, I can operate a trolley with one hand”; “What if supplies are on higher shelves? A gripper will solve that”. The list went on, but I quickly realized that I could navigate most of the obvious issues. I arrived at the interviews fully prepared — not only to discuss the details of the project, but also to address any concerns about my ability to work independently. I was ready to convince everyone that my disability does not hinder my qualifications and ability to perform lab work. Changing tides My approach to preparing job applications and handling interviews evolved significantly when I began applying to PhD programmes. I started searching for research positions six months before graduating from my master’s programme. To build confidence and refine my ability to sell my skills, I attended three interviews for industry positions, treating them mostly as practice without the pressure of pursuing my dream role. By that point, I had spent three years studying abroad, I was finishing my first publication, I felt confident in my lab skills and, for the first time, I started feeling that my achievements alone should define my capabilities as a scientist. I stopped including anything in my applications that might hint at my disability. I wanted neither to be chosen because of my wheelchair, nor overlooked because hiring me might seem like a challenge. What mattered most to me was being evaluated equally. During one interview, my soon-to-be PhD supervisor — physicist Ɓukasz Piątkowski at the PoznaƄ University of Technology — told me that, after receiving my CV, he had looked me up online and was fully aware that I use a wheelchair. My social-media profiles are intentionally public — they showcase that, despite using a wheelchair, I travel extensively, have an amazing family and service dog, love crime novels and, in a number of ways, lead a more active life than many people without disabilities. For the first time, I found myself discussing not only what I might bring to a research group, but also what I might need. Looking back, it shocks me that in my previous roles, I chose to endure back pain from wheelchair use by taking painkillers instead of simply asking for a spot where I could lie down and stretch — a symptom of being desperate to prove that I could do it all and wouldn’t be held back by my disability.
Nature DOI suffix ≠ "/s...": Not a research article
Publishers trial paying peer reviewers — what did they find?
Holly Else
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Trials suggest that offering payment can increase the chance of a researcher agreeing to review, and in some cases speed up the process. Credit: Catherine Falls Commercial/Getty A spate of research findings offer fresh evidence in the debate about whether peer reviewers should be paid for their time and expertise — a fraught topic that has provoked discussion among researchers. This month, two journals released data from their own experiments that suggest that offering payments of around US$250 to researchers who review manuscripts speeds up the process, without affecting the quality of reviews. But some specialists warn that the practice could have unintended consequences for science and publishing. Although both trials are small, they are a good start at gathering data on paid peer review, says Balazs Aczel, a psychologist at Eötvös LorĂĄnd University in Budapest. But he adds that whether to pay peer reviewers remains “a very complicated question”. Rewarding reviewers The peer-review system has come under pressure in recent years as more science is published and scientists face more demands on their time. Journal editors now find it harder to secure reviews and some scientists have questioned the fairness of their voluntary labour being relied upon by some highly profitable publishing companies. The idea of paying peer reviewers has long been discussed, but few publishers have chosen to go down this route so far. Economics journals have experimented with the idea in the past, and some medical journals pay certain reviewers. Others have adopted less-conventional compensation systems: open-access mega journal PeerJ uses a token system that gives reviewers a discount on publishing fees, whereas another title pays its reviewers in a specially developed cryptocurrency. ‘Getting paid to review is justice’: journal pays peer reviewers in cryptocurrency Some researchers fear that offering reviewers cash incentives could lessen the quality of reviews or change the landscape of research in other, as-yet unknown ways. But until now, there has been a lack of hard evidence about the potential benefits and drawbacks. Intrigued about the effect of paying peer reviewers, editors at the journal Critical Care Medicine launched a six-month experiment led by David Maslove, a clinical scientist at Queen’s University in Kingston, Canada. Starting in September 2023, the journal asked 715 researchers to review papers. It offered roughly half of them a US$250 incentive. The results, published in the journal earlier this month1, found that paying for reviews moderately improved both the number of accepted invitations and the speed at which reviews were carried out. Some 53% of researchers accepted the invitation to review when offered payment, compared with 48% of those who received a standard, non-paid offer. On average, paid reviews came in one day earlier than unpaid ones. Journal editors assessed reviews from paid and unpaid reviewers and found no difference in quality. Maslove says that the small size of the effect suggests that money has a limited effect on motivating peer reviewers to change their behaviour. “There could be these other values that peer reviewers have, whether it’s a sense of responsibility or loyalty or owing to society.” Speed advantage A separate experiment at the journal Biology Open, found a larger effect, albeit with fewer reviewers. For six months starting in July 2024, editors covering two of the journal’s ten subject areas treated reviewers as paid contractors under two systems. Reviewers were either offered a ÂŁ600 (US$776) retainer to review up to three papers per quarter, or were paid ÂŁ220 per review. Under this scheme, editors would send freelance reviewers an invitation to review, which they had to accept or decline within one business day. Once accepted, the reviewer had four days to submit their peer-review report. A total of 20 manuscripts were reviewed in this way.
Nature DOI suffix ≠ "/s...": Not a research article
Climate change will send home insurance spiralling. Here’s how to control costs
Scott St. George
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In January, at least 29 people were killed and more than 18,000 homes and buildings were burnt or destroyed by fires in the Los Angeles area — one of the worst disasters in California’s history. Insurance offers one way to support people who have suffered catastrophic losses. But insurance companies are more cautious than ever to provide aid for damages associated with wildfires and other weather-related risks. Last year, insurers worldwide paid out more than US$140 billion in claims relating to natural catastrophes, the fifth consecutive year with losses exceeding $100 billion. How scientists can drive climate action: celebrate nature and promote hope Most major natural disasters that cause substantial insurance claims, including storms, wildfires and flooding, are expected to worsen with climate change. But even for those perils for which recent spikes in payouts have been down to factors such as more properties possessions being insured, economic inflation and population growth, climate change still provides an unwelcome boost to risk, and therefore premiums. Climate scientists are being drawn into the industry to model these risks. I’m one of them. After spending most of my career working in government and academia, in 2021, I joined Willis Towers Watson, a global insurance broker headquartered in London that serves as an intermediary between corporate clients, insurers and reinsurers. Typically, insurers have used past claims to predict future losses from the same perils. So long as there had been no major unexpected disasters or big shifts in risk or exposure in a specific area, insurers could be confident that the premiums paid by the many would be enough to finance the claims of the few. But in 1992, destruction from Hurricane Andrew in the Gulf of Mexico exposed the fragility of that approach by causing insured losses three times higher than expected by industry insiders in Florida alone. Insurers switched to sophisticated catastrophe models — tools that combine the physics of specific natural hazards with details about building construction and insurance information — to estimate possible financial losses. And in the past few years, as the imprint of global warming on natural hazards has become more obvious, the insurance industry has been recruiting climate and Earth scientists to reduce the likelihood of being taken by surprise in the future. Extreme fire seasons are looming — science can help us adapt Today, insurers have more realistic views of their customers’ exposure to weather- and climate-related risks and the scale of potential claims. Within the limits set by government regulators, insurers decide how much risk they can tolerate across their portfolio, raise premiums for owners of more-exposed homes and purchase reinsurance to prepare for losses larger than they could normally afford. Bankrupt insurers can’t pay claims. Policyholders therefore benefit from risks being estimated correctly so that losses can be paid by charged premiums. But insurers also use the latest catastrophe modelling and climate science to justify higher prices, which are fast becoming unaffordable. Too many people are forced to choose between paying more for the same insurance, accepting lesser coverage to keep premiums manageable or letting their insurance lapse.
Nature DOI suffix ≠ "/s...": Not a research article
New antibiotic that kills drug-resistant bacteria discovered in technician’s garden
Smriti Mallapaty
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A species of Paenibacillus bacteria has potent antibacterial activity against some pathogenic bacteria such as Escherichia coli.Credit: Clouds Hill Imaging Ltd/Science Photo Library Researchers have discovered a new antibiotic molecule that targets a broad range of disease-causing bacteria — even strains resistant to commercial drugs — and is not toxic to human cells1. The molecule was found in soil samples collected from a laboratory technician’s garden. The discovery shows that “there is terrifically interesting stuff hiding in plain sight”, says Kim Lewis, a microbiologist at Northeastern University in Boston, Massachusetts, who was not involved in the research. “Kudos to them that they knew what to look for.” Podcast: New lasso-shaped antibiotic kills drug-resistant bacteria The latest molecule targets bacteria’s protein-making factory, the ribosome, in a way that other antibiotic drugs don’t. The ribosome is an attractive antibiotic target because bacteria don’t easily develop resistance to drugs targeting the structure, adds Lewis. The search for new antibiotics is necessary because bacteria acquire resistance to existing drugs with continued use. In 2021, bacterial resistance to antimicrobial drugs was associated with 1.1 million deaths globally, a figure that could increase to 1.9 million by 2050. “The antibiotic-resistance crisis is an existential threat to medicine,” says Gerry Wright, a chemical biologist at McMaster University in Hamilton, Canada, and a co-author of the study, which is published in Nature today. Garden-variety bacteria Wright and his colleagues set out to find microbes that have developed previously unknown tricks to kill pathogens. They collected soil samples in Petri dishes with growth medium and stored them for a year. The researchers then exposed the microbes from these samples to Escherichia coli, a common gut bacterium that can cause serious disease. One sample showed potent antibacterial activity — by a species belonging to the genus Paenibacillus. Expert take: Lasso-shaped molecule is a new type of broad-spectrum antibiotic Further rounds of screening, genome sequencing and structural analysis revealed that the bacterium produces a molecule that belongs to a group of peptides that form a lasso-shaped knot. These peptides are known for being robust and can probably even survive being digested. “It’s a nice, really compact and incredibly robust structure,” says Wright.
Nature DOI suffix ≠ "/s...": Not a research article
Brain implant translates thoughts to speech in an instant
Miryam Naddaf
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This scan of the brain shows activity in the speech cortex — a part of the frontal lobe involved in speech production.Credit: Montreal Neurological Institute/Science Photo Library A brain-reading implant that translates neural signals into audible speech has allowed a woman with paralysis to hear what she intends to say nearly instantly. Researchers enhanced the device — known as a brain–computer interface (BCI) — with artificial intelligence (AI) algorithms that decoded sentences as the woman thought of them, and then spoke them out loud using a synthetic voice. Unlike previous efforts, which could produce sounds only after users finished an entire sentence, the current approach can simultaneously detect words and turn them into speech within three seconds. Brain-reading devices allow paralysed people to talk using their thoughts The findings, published in Nature Neuroscience on 31 March1, represent a big step towards BCIs that are of practical use. Older speech-generating BCIs are similar to “a WhatsApp conversation”, says Christian Herff, a computational neuroscientist at Maastricht University, the Netherlands, who was not involved with the work. “I write a sentence, you write a sentence and you need some time to write a sentence again
 It just doesn’t flow like a normal conversation.” BCIs that stream speech in real time are “the next level” in research because they allow users to convey the tone and emphasis that are characteristic of natural speech, he adds. Brain-signal reader The study participant, Ann, lost her ability to speak after a stroke in her brainstem in 2005. Some 18 years later, she underwent a surgery to place a paper-thin rectangle containing 253 electrodes on the surface on her brain cortex. The implant can record the combined activity of thousands of neurons at the same time. Researchers personalized the synthetic voice to sound like Ann’s own voice from before her injury, by training AI algorithms on recordings from her wedding video.
Nature DOI suffix ≠ "/s...": Not a research article
The full lethal impact of massive cuts to international food aid
Saskia Osendarp, Marie Ruel, Emorn Udomkesmalee, Masresha Tessema, Lawrence Haddad
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The dismantling of the US Agency for International Development (USAID) and reductions in aid budgets over the next 3–5 years announced by other Western donor countries, including the United Kingdom (40%), France (37%), the Netherlands (30%) and Belgium (25%), threaten to reverse decades of progress in reducing malnutrition1. These cuts — equivalent to 44% of the US$1.6 billion in donor aid provided in 2022 to support the World Health Assembly nutrition targets — will lead to hardship and death among the most vulnerable people in the world2. The implications for public health, economic growth and societal stability are profound. Severe acute malnutrition, or severe wasting, is the most lethal form of undernutrition and is responsible for up to 20% of deaths of children under the age of five years, and affects 13.7 million children a year worldwide. Left untreated, up to 60% of affected children might die3. How Trump 2.0 is reshaping science Proven programmes, such as community-based management of severe acute malnutrition, which combine screening, treatment and counselling, can reduce mortality to below 5%3 and have been used in more than 70 countries. In 2022, the United States and other donors reporting to the Organisation for Economic Co-operation and Development spent $591 million on severe-wasting treatment2, which was matched by receiving countries. The abrupt withdrawal of donor support leaves millions of critically ill children without access to these life-saving programmes. It is already undermining the institutional capacity, expertise and data infrastructures required to deliver essential nutrition services. For example, in Nigeria, withdrawal of USAID Advancing Nutrition funding has meant that the charity Helen Keller International has had to stop a programme that provides nutrition services for 5.6 million children. In Sudan, almost 80% of emergency food kitchens are closed. In Ethiopia, supplies of nutrient-rich foods used to treat around one million severely malnourished children annually will run out by May. And the global FEWS-NET network — a leading source of data on famine risks — sits idle, disrupting early-warning systems for humanitarian planning and emergency resource allocation. Loss of donor funding is also jeopardizing the procurement and distribution of ready-to-use therapeutic food, a life-saving treatment for severe acute malnutrition. The product comes as a dense micronutrient paste that contains peanuts, milk powder, sugar, oils, vitamins and minerals. USAID supported half of the world’s supply4. The impacts of these cuts will be dire. To illustrate, here we assess their scale. Millions of lives in peril Altogether, we estimate that reductions of $290 million in donor funding for severe acute malnutrition (see ‘Nutrition funding collapse’) will cut off treatment for 2.3 million children in low- and middle-income countries (LMICs). This would lead to 369,000 extra child deaths a year that would otherwise have been prevented. Source: Ref. 2 Of those, the termination of US-funded programmes (worth $128 million in 2022) alone will keep one million children from accessing such treatments, causing an extra 163,500 child deaths yearly. These worst-case scenarios are based on 2022 donor disbursement data for severe wasting treatment, drawn from the Creditor Reporting System of the Organisation for Economic Co-operation and Development and analysed by Results for Development, a global non-profit organization2 (see Supplementary information). These treatments are included in community-based management of severe acute malnutrition programmes, which screen and treat children with severe acute malnutrition and follow them to prevent relapse after recovery. Will RFK Jr’s vaccine agenda make America contagious again? Cutting all US financing and on average 35% of aid from other donors results in $704 million less funding for nutrition programmes overall, and $290 million less for severe acute malnutrition treatment. These numbers assume that disbursements would have otherwise been similar to those in 2022, that the 35% average cuts to aid that were announced by European donor countries will reduce funding for nutrition by 35%, and that donor funding is matched by contributions from LMIC governments, as is often the case. The No Time to Waste report4 by the United Nations children’s fund UNICEF estimated that 1.2 million deaths were averted in 2023 by treating 7.4 million children with severe acute malnutrition in 47 high-risk countries. Because 80% of cases worldwide were in these countries, we increased these numbers to cover 100% of cases globally, to 9.3 million children treated and 1.5 million deaths averted. We calculated the percentage of reduction in donor funding compared with the 2022 disbursements and assessed how many of the children treated in 2022 would now not receive aid. Similarly, we analysed how many of the prevented deaths because of treatment in 2022 would now not be averted. Global consequences Although shocking, the number of deaths might be an underestimate, because the aid cuts threaten a huge array of nutrition-supporting programmes, including health, agriculture, school feeding and water and sanitation. Soon we might see many more millions of children around the world developing wasting, stunted growth and micronutrient malnutrition. Severe wasting is responsible for up to 20% of deaths of children under the age of five.Credit: Tiksa Negeri/Reuters
Nature DOI suffix ≠ "/s...": Not a research article
Fasting for weight loss is all the rage: what are the health benefits?
Nic Fleming
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As anyone seeking to lose weight knows, diets come in and out of fashion. The Sexy Pineapple diet, launched by a Danish psychologist in 1970, never really took off. Kellogg’s no longer promotes the Special K diet, which swaps out two meals a day for a bowl of the breakfast cereal of that name. These days, you don’t hear much about eating according to blood type, cutting out acidic foods or following the potato diet. Intermittent fasting has, however, had unusual staying power for more than a decade — and has grown even more popular in the past few years. One survey1 found that almost one in eight adults in the United States had tried it in 2023. The surprising cause of fasting’s regenerative powers The enduring popularity of intermittent fasting has been fed by celebrity endorsements, news coverage and a growing number of books, including several written by researchers in the field. More than 100 clinical trials in the past decade suggest that it is an effective strategy for weight loss. And weight loss generally comes with related health improvements, including a reduced risk of heart disease and diabetes. What is less clear is whether there are distinct benefits that come from limiting food intake to particular windows of time. Does it protect against neurodegenerative diseases such as Alzheimer’s disease, enhance cognitive function, suppress tumours and even extend lifespan? Or are there no benefits apart from those related to cutting back on calories? And what are the potential risks? Neuroscientist Mark Mattson at the Johns Hopkins School of Medicine in Baltimore, Maryland, and author of the 2022 book The Intermittent Fasting Revolution, has been studying fasting for 30 years. He argues that, because ancient humans went for long periods without food as hunter-gatherers, we have evolved to benefit from taking breaks from eating. “We’re adapted to function very well, perhaps optimally, in a fasted state,” he says. Fasting’s deep roots Fasting is far from new. Periodic abstentions from food have long been practised in many religions. In the fifth century bc, the Greek physician and philosopher Hippocrates prescribed it for a range of medical conditions. Recent scientific interest in fasting has its roots in questions raised by research on calorie restriction. Since the 1930s, studies have shown that putting rodents on low-calorie diets can increase their lifespans. Hypotheses proposed to explain this effect include that calorie restriction slows growth, lowers fat intake or reduces cellular damage caused by unstable free radicals. But an observation made in 1990 by researcher Ronald Hart, who was then studying ageing, nutrition and health at the US National Center for Toxicological Research in Jefferson, Arkansas, highlighted another intriguing possibility. Calorie-restricted rodents fed once daily consumed all their food in a few hours. Perhaps the calorie-restricted rodents lived longer because they repeatedly went for 20 or so hours without eating. In the immediate aftermath of a meal, cells use glucose from carbohydrates in food as fuel, either straight away or following storage in the liver and muscles as glycogen. Once these sources are depleted — in humans, typically around 12 hours after the last meal — the body enters a fasted state during which fat stored in adipose tissue is converted to ketone bodies for use as an alternative energy source. ‘Intermittent fasting’ generally refers to various diets that include repeated periods of zero- or very low-calorie intake that are long enough to stimulate the production of ketone bodies. The most common are time-restricted eating (TRE), which involves consuming all food in a 4- to 12-hour window, usually without calorie counting; alternate-day fasting (ADF), whereby people either abstain from food every other day or eat no more than around 500 calories on that day; and the 5:2 diet, which stipulates a 500-calorie limit on 2 days per week (see ‘Three forms of fasting’). Some researchers say the resulting shift between sources of energy, called metabolic switching, triggers key adaptive stress responses, including increased DNA repair and the breakdown and recycling of defective cellular components. Those responses, the thinking goes, provide health benefits beyond those from reduced calorie consumption alone. Observational studies have suggested that some religious fasters who fast long enough for metabolic switching to occur see such health benefits, although these studies have a lot of limitations. Getting slim fast Controlled diet trials are notoriously difficult to conduct. People’s diets and behaviours, together with their genetic inheritance and baseline health, make for a lot of variables. Often, people don’t stick with the study, and getting participants to track calorie intake accurately is a known challenge. Your diet can change your immune system — here’s how Still, the weight of the evidence suggests that intermittent fasting can help people to lose weight. In 2022, for example, Courtney Peterson, who researches nutrition at the University of Alabama at Birmingham, and her colleagues reported results from a trial involving 90 adults with obesity who also received counselling to help them lose weight. She found that those who followed TRE for an average of 6 days per week over 14 weeks lost an average of 6.3 kilograms, compared with the 4 kg lost by participants who ate over 12 or more hours2. Peterson says that many people find following a rule about when to eat and when not to eat easier than counting calories or eating healthier. “We and others have found that TRE also makes people less hungry, so they tend to naturally eat less and lose weight,” says Peterson. Also in 2022, nutritionist Krista Varady at the University of Illinois, Chicago, and her colleagues reviewed 22 randomized trials looking at the effects of ADF, the 5:2 diet and TRE on body weight. ADF and the 5:2 diet produced 4–8% weight loss after 8–12 weeks in those with obesity, whereas TRE helped people to lose 3–4% of their body weight over the same period3. Varady has a long-standing interest in fasting. The cover of one version of her 2013 book The Every Other Day Diet features pizza, a doughnut and a burger to illustrate that those doing ADF don’t need to cut out unhealthy foods. In the book, Varady argues that restricting intake to no more than 500 calories every other day is a more effective way to lose weight than conventional calorie counting and cutting out fatty and sugary foods. Although most researchers who study intermittent fasting agree that it can help people to lose weight, they’re split on whether there are any benefits beyond those that come from simply eating less. Michelle Harvie, a research dietitian at the University of Manchester, UK, sought to address this question in collaboration with Mattson in a 2010 trial. They found that overweight women who followed a 5:2 diet for 6 months had larger reductions in fasting insulin and insulin resistance than did those on a reduced-calorie diet4. Both groups had the same weekly calorie intake and lost an average of around 6 kg. But the difference in insulin levels was small, and the researchers relied on participants to track consumption by keeping food diaries. Intermittent fasting often appeals to people who prefer to restrict when, rather than what, they eat.Credit: Roger Bamber/Alamy In a 2018 study, Peterson and her team carefully monitored the diets of prediabetic, overweight men, matching their diets to energy consumption. The participants ate all their food either within 6 hours before 3 p.m. daily, or over 12 hours, for 5 weeks before switching to the other eating schedule. Although both regimes resulted in equivalent small weight loss over the study period, when men were on the more time-restricted diet, they had improved insulin sensitivity, lower blood pressure and reduced oxidative stress, a form of molecular damage5. “We showed for the first time that intermittent fasting has health benefits and effects beyond weight loss in humans,” says Peterson. But the study was relatively small: only 12 adults started the trial, only 8 completed it, and all were male and overweight. Adding to the uncertainty is that other trials have reached seemingly contradictory conclusions. Nisa Maruthur, a physician at the Johns Hopkins School of Medicine, and her colleagues asked 41 obese adults with pre-diabetes or diabetes to consume diets that matched their energy needs, eating either during a 10-hour daily window or according to their normal schedule. After 12 weeks, there was little difference between the two groups in the average changes to weight, glucose regulation, blood pressure, waist circumference or lipid levels6. “Weight loss seen in prior studies of TRE was probably the result of eating fewer calories,” says Maruthur, whose study was published in 2024. If so, metabolic switching might not come with added health benefits. Peterson, a co-author of that study, disagrees and suggests that the 10-hour eating window might have been too long to achieve the results seen in trials of shorter TRE windows. Even though Varady thinks that intermittent fasting can help people to lose weight, she remains unconvinced that it has effects independent of calorie restriction. “Based on current human evidence, I don’t think that there are any benefits of intermittent fasting beyond weight loss,” she says. Mattson is equally sure of the opposite: “There is considerable evidence of benefits of intermittent fasting that cannot be explained by reduction in calorie intake.” Mattson and others have looked to animal research in their efforts to understand the physiology of fasting, and to identify mechanisms that could underpin any extra health benefits.
Nature DOI suffix ≠ "/s...": Not a research article
Gender gap in research publishing is improving — slowly
Rachel Williamson
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In academic output, the gender gap is wider in the physical sciences than in medical fields.Credit: Assembly/Getty Data from the Nature Index reveal the slow erosion of the gender gap in global research publishing over the past decade. But with just 27% of high-quality papers in the natural sciences having female co-authors in 2024, there is a lot of room for improvement. In the health sciences — where women have a stronger presence — that figure sits at 41% (see ‘Authorship by gender’). In terms of research topics, the highest representation of female co-authors in 2024 was in reproductive medicine (53%), paediatrics (50%) and nutrition and dietetics (50%). Classical physics (15%), quantum physics (16%) and condensed matter physics (16%) had some of the lowest percentages of female authorship. Among the leading universities in the Nature Index, as measured by Share (a metric that tracks the contribution of countries or territories and institutions to the natural- and health-sciences journals tracked by the Index), most did not come close to achieving gender parity in research authorship — that is, having women make up 40–60% of authors — in papers overall. In 2024, many of these institutions sat below the 30% mark in terms of female co-authorship. Harvard University in Boston, Massachusetts, stands out, however, with 38% female co-authorship. Of the top ten countries in the Nature Index, only three — the United States, Canada and France (all at 34%) — had a female author representation of more than 30% in 2024. Results of the analysis are available on the Nature Index website for users to explore. There are several important caveats to consider when comparing results across countries, institutions and topics, but the clear picture that emerges is how much work is yet to be done to achieve a more balanced gender representation in research publishing. 2024 Research Leaders “The problem is that men and women do not generally operate under the same conditions,” says Lynn Nygaard, a specialist in academic writing and gender and diversity issues at the Peace Research Institute of Oslo. “There is a skewed distribution between fields, and different fields have different publication patterns and positions, with more men in senior positions and women in junior positions.” Reaching gender parity will require deep commitment and long-term coordination across countries and institutions, she adds. Natural sciences still lag behind One of the clearest trends in the data is how gender balance differs across the natural sciences and health sciences (the latter was added to the Nature Index in 2022). This mirrors what has previously been reported in research sectors worldwide: male researchers tend to dominate in physics, for instance, whereas in the life sciences and health disciplines, the gender gap is not as large. Of the ten topics with the highest percentage of female co-authors for 2024, most are in the health sciences (see ‘Topic trends’). The lowest-ranking topics — in which the gender gap is the widest — were mainly chemistry and physical sciences topics, many of which had less than 20% female co-authorship. On a country level (see ‘Country comparisons’), female authorship is ticking upwards, but progress is very slow. Between 2015 and 2024, the United States increased its female authorship from 26% to 34% — the biggest percentage-point increase among the top ten countries in the Index. South Korea, by comparison, increased its female authorship from 21% to 23% over the same period. COUNTRY COMPARISONS Female authorship percentages are shown for selected leading countries in the Nature Index for 2024. The majority of authors from China were not included in the analysis because of low confidence in the model’s ability to infer their gender. CountryFemale researchers (%)United States34%Canada34%France34%United Kingdom29%India28%Germany28%Switzerland24%South Korea23%Japan16% Source: Nature Index. Analysis by Vera Nienaber. Data limitations Caution is needed when looking at the results of the country- and territory-level analysis, owing to the limitations of the methodology. To create the data set, the Nature Index data-analysis team used the chatbot ChatGPT, created by OpenAI, based in San Francisco, California, to infer author genders on the basis of their most likely country of origin and the name–gender association trends in that country (see ‘Methodology’). Some countries and territories have stronger name–gender associations — in other words, most people with a certain name will identify as a certain gender — than others, which can make the results of the analysis uneven. Authors for whom there is low confidence that the model is accurate in inferring gender have been excluded from the analysis, including the majority of names in some countries, such as China and Singapore. It’s important, then, to consider the findings of the analysis as an approximation, and to seek other sources when piecing together a picture of gender balance in academic research. Setting the standard The institution-level analysis incorporates an extra metric: expected values for the proportion of female authorships at an institution, based on how much research they publish in male- or female-heavy sciences. For example, an institution that predominantly publishes in physics — a field with historically lower female authorship rates1 — will have a relatively small expected proportion of female authors compared with institutions that specialize in health-science research. If an institution’s actual proportion of female authors surpasses this calculated value, it suggests that the institution is outperforming expectations in promoting gender diversity. Among the ten leading US universities in the Nature Index, for example, all exceeded expectations for female authorship representation in 2024. The University of Washington, in Seattle, had one of the largest gaps, with an expected proportion of female authorship of 27% versus the actual proportion of 37%. Among the ten leading Japanese universities in the Nature Index, by comparison, none exceeded the expected proportion of female authorship. Factors behind improvement There are many reasons for the persistent gender gap in academic publishing, says Nygaard. Her research2 has shown that the gender publishing gap almost disappears once factors such as career breaks for childbirth and childcare, as well as the “more difficult-to-measure challenges that women face”, are accounted for. These include being expected to spend more time providing pastoral care to students and doing academic ‘housework’, such as editing journals and undertaking peer review, and being under pressure to represent women on panels and in media interviews.
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These US labs risk imminent closure after Trump cuts
Heidi Ledford
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Laboratories run by scientists who rely almost entirely on US grants for their income could close as research funding dwindles.Credit: Karen Ducey/Getty Even when the first four of his five federal grants were cancelled in February, Jeremy Springman still had hope. The social-science research that he co-leads at the University of Pennsylvania in Philadelphia had enough funding from a large US Department of Defense project to tide him over for two more years. He checked in with his defence-department programme officer, who reassured him that the remaining grant would be safe. But by mid-March, it was gone, too — and with it, Springman reckons, his last shot at earning a living by doing research. “That was really the end of things,” he says. “My position just isn’t going to be viable in the future.” Like thousands of scientists in the United States, Springman draws most of his salary not from his university, but from grant money from outside sources. Such ‘soft money’ faculty members and those who work in their laboratories are feeling particularly vulnerable at a time of deep uncertainty about the future of the US government’s support for research. Labs that run on soft money are likely to be among the first to close as federal funding is cut, because their principal investigators cannot ride out hard times on a university payroll. Once closed, these labs and their projects will be difficult, if not impossible, to resurrect even if federal funding is restored. “When there’s uncertainty as to that funding, there’s uncertainty as to our positions,” says Alejandro de la Vega, a psychology and neuroimaging researcher at the University of Texas at Austin, who receives all of his salary from grants. “I don’t know what the future will look like for researchers like me.” Vanishing funds Federal funding agencies have been in turmoil since the inauguration of US President Donald Trump in January. In the past two months, the new administration has cancelled or delayed thousands of federal research grants, and has threatened to cut off grants to specific universities that do not comply with its demands. In February, the US National Institutes of Health announced that it would drastically limit the overhead costs it will pay on its grants ― a move that, for now, has been blocked by the courts. Asked for comment, a White House official said that the administration has “paused things to open the hood of the car and take a good look to audit what the previous administration was up to”. During that inspection, the US government has cancelled grants from agencies such as the US Agency for International Development and Department of Defense, and has laid plans to cancel hundreds more at the US National Institutes of Health. Postdocs and PhD students hit hard by Trump’s crackdown on science The effect of such cuts on soft-money faculty members will depend on the terms of their appointments. Some researchers are paid with soft money only during the summer, when they are not teaching, but others rely on grants for their full salary. “The general public thinks that if you’re a college professor, you get paid by the school,” says Zoe McElligott, who studies neural circuits at a state university. But for soft-money faculty members, that’s not the case, she says. Her university provides about 20% of her salary; she must forage for the rest on her own. Soft-money positions are common in US medical schools and schools of public health, as well as at independent research institutions. But they can be found in other departments and schools as well. For example, economist Wei Yang Tham at the University of Toronto in Canada and his colleagues surveyed professors at 150 US research-intensive institutions of higher education and found that 72% of those in the natural sciences earned at least part of their salary from grants1. They also found that, on average, medical-sciences professors collected almost one-third of their wages from outside sources. A 2022 survey of about 300 planetary scientists found that 21% of respondents were in soft-money positions2. Some researchers, including de la Vega, relish the opportunity to focus on their labs, without the obligation to teach or serve on university committees. “I am 100% doing research, that’s what I love about my job,” he says. But others were pushed into soft-money roles by the job market, he adds: “Hard-money positions are incredibly competitive.” Leaving the lab Several soft-money researchers who spoke to Nature anticipate having to leave research. If so, the projects they lead will disappear along with them. Krista Harrison, a social scientist at the University of California, San Francisco who draws 100% of her salary from soft money, says soft-money faculty members can typically restart stopped projects only if the funding gap is a few months. “Once the principal investigator has to leave academia, the work is ended forever,” she says.
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Six roadblocks to net zero — and how to get around them
Lucas Joppa, Elizabeth Willmott
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Net zero. This simple accounting term represents humanity’s greatest challenge — and opportunity — to stabilize Earth’s climate. The goal, timeline and metric for success seem clear: by 2050, each tonne of carbon emitted must be matched by a tonne removed. But achieving this is easier said than done. Since the dawn of the Industrial Revolution, the world has built up more than 250 years of momentum in a carbon-emitting economic and technological paradigm. Now, under the terms of the 2015 Paris climate agreement, it has just 25 years — or a few business cycles — to replace the carbon-dependent parts with net-zero components. Will AI accelerate or delay the race to net-zero emissions? The journey requires unprecedented coordination, innovation, investment and speed to avoid the catastrophic consequences of failure — including increasingly severe natural disasters, from rapidly rising sea levels and floods to heatwaves and wildfires. We, the authors, understand the potential and pitfalls, having spent more than 20 years between us developing the strategies, programmes, products and policies that achieving net zero demands. We have deployed and influenced more than US$1 billion in investments and purchases related to carbon reduction and removal, and have been on the front lines of driving large-scale voluntary decarbonization in the corporate sector. Previously, we served as principal architects of Microsoft’s carbon-negative commitment. Now, one of us (E.W.) is a net-zero strategy consultant, and the other (L.J.) is a private-equity executive working to deliver a net-zero investment portfolio. Although we have a deep conviction that net zero can work, we know it has issues. A premature desire for perfection, overly precise guidelines for implementation, insufficient flexibility in carbon accounting, unhelpful constraints on collaboration and a disproportionate focus on the actions of others all combine to slow down the net-zero transformation just when it needs to speed up. Here, we describe the barriers and suggest ways to overcome them. Obstacles to market growth For net zero to work, the world must design markets in which every product or service, everywhere, prices in the cost of removing carbon dioxide and other greenhouse gases from the atmosphere or replacing them with an alternative that emits little or no carbon. Regulation will play a crucial part. But adoption at scale will happen only when removals and low-carbon alternatives are cheaper in price, superior in performance, or both, relative to higher carbon incumbents. Reduction and removal technologies are still in their infancy. Sustainable aviation fuel, green hydrogen and steel, low-carbon concrete and technologies that capture CO2 from the air are expected to be part of a future net-zero economy. But today, they are too scarce and expensive to enable stakeholders to build anything more than theoretical plans around them. Long-term cost-efficiencies and supply will emerge only through large investments in a host of approaches, allowing the markets to determine winners and losers. This was a clear lesson from decades of advances in solar and wind energy, which ultimately saw the costs of these renewables plummet by more than 70%. How car and battery companies can work around US trade tariffs and rules To meet net-zero goals, global investments in the clean-energy and carbon-removal sectors, and their supporting infrastructure, must exceed $4 trillion annually by 20301. But we are concerned that current carbon-market expectations are inadvertently making it harder — not easier — to deploy the climate capital needed to build robust carbon markets. Despite widespread agreement on the need for net zero, few binding requirements compel individuals or organizations to act in support of climate goals. This creates a carbon catch-22: governments are hesitant to impose regulations without clear price signals from markets, while markets struggle to deliver price clarity without regulatory guidance. As a result, achieving net zero globally must rely heavily on early movers — organizations that pursue net-zero outcomes voluntarily. But, so far, there are too few of these, and they aren’t moving quickly enough. In part, that is because the net-zero landscape is dominated by prescriptive rules that are difficult to implement, often creating confusion instead of clarity. These roadblocks must be removed. Here we identify six remedies. Pursue progress over perfection Organizations need flexibility if they are going to commit to innovation. For example, in the early days of renewable energy, corporate buyers purchased renewable energy credits to meet their 100% renewable electricity goals that would not meet quality standards today. But they got the ball rolling: buyers invested, learnt and iterated. Procurement of ‘unbundled’ renewable-energy certificates was replaced by more sophisticated ways of buying and selling energy, such as through contracts to match hourly energy consumption. A carbon-transport ship in Norway takes waste carbon dioxide from industrial processes to a storage facility near Bergen.Credit: Carina Johansen/Bloomberg via Getty Similarly, today’s corporate leaders are advancing energy projects on a voluntary basis, from nuclear to geothermal. Their energy prices are high now, but will come down if buyers and suppliers are given room to improve the technologies. In other words, setting an ambitious but achievable goal and sticking with it, while continuously improving its execution, should be a core principle for reaching net zero. Yet, rigid and complex standards introduced too soon are discouraging companies from innovating. For example, last year, the Science Based Target Initiative (SBTi) removed nearly 240 companies — representing more than $4 trillion in market capitalization — from its Corporate Net Zero Standard, because of their inability to meet its stringent criteria2. This highly publicized action led to frustration from the affected companies, some of which stated they were unaware that the deadline for meeting these criteria was approaching. Delisting or penalizing companies for ‘missing’ arbitrary net-zero milestones should be avoided. SBTi’s working groups should recommend that flexibility and iteration are core pillars of its forthcoming revision to the Corporate Net Zero Standard (see go.nature.com/428ukzq). Prioritize direct over indirect emissions The Greenhouse Gas Protocol, a partnership between businesses, governments and other organizations that has set global standards for measuring emissions, has established three ‘scopes’ for voluntary reporting of emissions by corporations. Scope 1 includes an organization’s direct emissions (such as those from a steel producer’s coal-powered kiln). Scope 2 reflects those associated with consuming electricity, as well as heating and cooling. Scope 3 emissions represent all those embodied in an organization’s supply chain and product-delivery networks. Thus, Scope 2 and Scope 3 emissions help companies to understand the wider carbon implications of their operations. But, if every company reduced their Scope 1 emissions to zero, then every other company’s Scope 2 and Scope 3 emissions would also disappear. For most companies, Scope 3 captures most of their emissions. Accounting for these has helped to drive a cascade of decarbonization commitments, such as identifying, addressing or replacing high-carbon producers. That is good. Why we still don’t know the mounting health risks of climate change But a disproportionate focus on reporting Scope 3 emissions — including by the SBTi, the CDP (an international non-profit organization dedicated to collecting information on corporate sustainability efforts) and jurisdictions such as the United States and the European Union — has arguably distracted many companies from doing the hard work at home. In 2022, only 7% of consumer companies were on track to meet their targets for value-chain decarbonization, and only 18% were on track with their direct-emissions targets (see go.nature.com/43ystkc). Companies could make more progress on Scope 1 if they were able to simplify and focus their attention. First, requiring companies to commit to reductions they have little or no control over, and then penalizing them for failing to make progress, discourages them from engaging. Indeed, in a 2024 survey by the SBTi, Scope 3 difficulties were the biggest complaint from companies working on climate issues, mentioned by 54% of firms2. Second, a focus on Scope 3 introduces extreme uncertainty into reporting of carbon emissions. The most common way to derive Scope 3 emissions is to multiply how much is spent on certain broad categories, such as ‘marketing’, by a numerical factor approximating national or global emissions for that activity. This simplistic approach misses both the accuracy and precision that reporting bodies desire. And third, Scope 3 emissions can potentially divert focus away from Scope 1 and 2 emissions for a reason of efficiency: if most of an organization’s emissions are indirect, why focus first on the minority that are direct? The fix is simple. SBTi, CDP, regulators and other parties should create a tiered system that prioritizes target setting and reporting for Scope 1 and 2 over that for Scope 3. Companies should be making progress on decarbonizing their Scope 1 and 2 emissions before they are expected to tackle the more difficult Scope 3. Focus on demand over delivery Corporate demand has had an outsized role in developing renewable-energy markets. Starting in the 2010s, companies were motivated to make purchases because they received credit for doing so under the Greenhouse Gas Protocol. But the protocol’s accounting practices contain an inconsistency. Under its ‘location-based’ and ‘market-based’ accounting rules, companies can get credit for Scope 2 carbon reductions from the electricity they consume by purchasing renewable energy that is never physically delivered to them. But there is no mechanism to do that for Scope 1 or 3. Engineers work on an electrical panel at Octavia Carbon, a carbon-capture plant near Nairobi.Credit: The Washington Post/Getty The protocol now needs to be expanded to allow for such claims across all emissions classes. It is more important that solutions are contracted and paid for than specifying where and to whom they are delivered. For instance, being able to track the delivery of sustainable aviation fuel to a buyer in a specific seat on a particular aeroplane is less important than ensuring that an equivalent amount of fuel was delivered into the broader aviation network. Allowing companies to claim credit for these purchases would incentivize them to invest. To build trust, descriptions of the projects funded or financed can help others to assess the value of any company’s carbon reduction and removal purchases. Allow flexibility between emissions reduction and removal As the Intergovernmental Panel on Climate Change has emphasized, limiting the worst harms of global warming requires both reduction of emissions and large-scale carbon removal. In the context of global net zero, how much reduction is needed versus how much removal is an open question, and well-intentioned but premature mandates hold back innovation. For example, SBTi’s Corporate Net Zero Standard requires a company’s decarbonization commitment to include a pledge to reduce their emissions by 90% or more before relying on carbon-removal technologies to counterbalance the remaining 10%. This requirement is too strict, and too early. By analogy, in the renewable-energy sector, early markets were unconstrained by requirements for specific amounts of solar, wind or hydropower. Instead, technologies competed, and winners emerged for different uses in different places. A market-driven approach allowed the most effective solutions to materialize naturally over time.
Nature DOI suffix ≠ "/s...": Not a research article
Lesotho matters
Nthabiseng Mokoena-Mokhali, Liteboho Senyane, Brian Stewart, Peter Mitchell
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In his 4 March speech to the US Congress, US President Donald Trump described Lesotho as a country that “nobody has ever heard of”.
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Mathematician who reshaped theory of symmetry wins Abel Prize
Davide Castelvecchi
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Masaki Kashiwara’s work spans distant mathematical disciplines.Credit: Peter Bagde/Typos1/The Abel Prize Mathematician Masaki Kashiwara has won the 2025 Abel Prize, the Norwegian Academy of Science and Letters announced today. Kashiwara is known for building bridges across seemingly distant branches of mathematics. In particular, he developed algebraic tools to solve tough problems such as differential equations, and he greatly extended the scope of the mathematical theory of symmetry known as representation theory. “He is a master in combining tools from geometry, algebra and analysis to obtain new insights and combinations,” says mathematician Helge Holden, who chairs the Abel Committee. He is the first Japanese national — and the first person based outside North America, Europe or Israel — to win the prize, which is one of the highest honours for a mathematician. Kashiwara told Nature that he was surprised to find out he had won. “I was just asked to attend a Zoom meeting. I didn’t know what was the subject of the meeting,” he says. Mathematical mastery Kashiwara, 78, was born in Yuki, near Tokyo, and studied at the University of Tokyo and at Kyoto University. He has been at Kyoto University’s Research Institute for Mathematical Sciences (RIMS) since 1978. Some of his most celebrated work focuses on the theory of representations, which has its origins with the mathematical concept of a group — a set of symmetries such as all the possible rotations of a sphere. A representation of a group is how the group can act as a set of symmetries of another space, such as the space of all possible quantum states of a physical system. Representations of the group of rotations are what produces the familiar structure of a hydrogen atom’s electronic orbitals, for example. Abel Prize: pioneer of ‘smooth’ physics wins top maths award ‘Classical’ representation theory emerged in the late 1800s and became a mature subject in the 1930s. Kashiwara and other mathematicians later developed broad generalizations of the theory, such as for infinite-dimensional groups and even for mathematical constructs that are not groups at all. Kashiwara’s work is so foundational that it has cast even the classical group representations in a new light, says Olivier Schiffmann, a mathematician at the University of Paris-Saclay who has co-authored papers with Kashiwara. “Anybody who’s done representation theory in the past 35 years has used some [of his] work.” In particular, Kashiwara’s notion of a ‘crystal base’ has enabled mathematicians to interpret any representation as permutations on a finite set of objects — think of a deck of cards being shuffled. Previously, this was possible only for special types of classical groups.
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75% of US scientists who answered Nature poll consider leaving
Alexandra Witze
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Cuts to research funding in the US have forced many scientists to rethink their careers.Credit: Shelby Tauber/Bloomberg via Getty The massive changes in US research brought about by the new administration of President Donald Trump are causing many scientists in the country to rethink their lives and careers. More than 1,200 scientists who responded to a Nature poll — three-quarters of the total respondents — are considering leaving the United States following the disruptions prompted by Trump. Europe and Canada were among the top choices for relocation. Source: Nature poll The trend was particularly pronounced among early-career researchers. Of the 690 postgraduate researchers who responded, 548 were considering leaving; 255 of 340 PhD students said the same. Trump’s administration has slashed research funding and halted broad swathes of federally funded science, under a government-wide cost-cutting initiative led by billionaire Elon Musk. Tens of thousands of federal employees, including many scientists, have been fired and rehired following a court order, with threats of more mass firings to come. Immigration crackdowns and battles over academic freedom have left researchers reeling as uncertainty and disruption permeate all aspects of the US research enterprise. Decision to leave Nature asked readers whether these changes were causing them to consider leaving the United States. Responses were solicited earlier this month on the journal’s website, on social media and in the Nature Briefing e-mail newsletter. Roughly 1,650 people completed the survey. Many respondents were looking to move to countries where they already had collaborators, friends, family or familiarity with the language. “Anywhere that supports science,” wrote one respondent. Some who had moved to the United States for work planned to return to their country of origin. How Trump 2.0 is reshaping science But many more scientists had not planned on relocating, until Trump began gutting funding and firing researchers. “This is my home — I really love my country,” says a graduate student at a top US university who works in plant genomics and agriculture. “But a lot of my mentors have been telling me to get out, right now.” This student lost her research support and her stipend when the Trump administration shut down funding for the US Agency for International Development. Her adviser found emergency funds to support her in the short term, but she is scrambling to apply for teaching-assistant positions — now extremely competitive — to carry her through the rest of her programme. She had already been considering doing a postdoctoral fellowship abroad because of her interest in international agriculture. Losing her funding and watching some of her colleagues get fired solidified that into a plan of action. “Seeing all of the work stopped is heartbreaking,” she says. “I’ve been looking very diligently for opportunities in Europe, Australia and Mexico.” The student hopes to return to the United States in the future if the upheaval in the research landscape settles down. But for now, the Trump administration “has made it very clear” that her area of interest, global food systems, “is not going to be a priority or a focus”, she says. “If I want to work in that space, I’m going to have to find somewhere else that prioritizes that.” Private US funding, such as through philanthropy, is an option, but she anticipates that she would be competing with a glut of formerly federally funded projects. Opportunities abroad Another respondent says that the disruptions have been “particularly horrible” for early-career scientists such as himself. “The PIs [principal investigators] I’ve spoken to feel they’ll be able to weather this storm,” he says. “As early-career investigators, we don’t have that luxury — this is a critical moment in our careers, and it’s been thrown into turmoil in a matter of weeks.”
Nature DOI suffix ≠ "/s...": Not a research article
How Trump is following Project 2025’s radical roadmap to defund science
Dan Garisto
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Project 2025 is a 900-plus-page playbook aimed at conservative policymakers.Credit: Mike Segar/Reuters Indiscriminate firings. Terminated grants. Cancelled programmes. The barrage of actions by US President Donald Trump has shocked the country’s research community over the past two months. Yet, much of it was planned out years in advance and laid out publicly. ‘Scientists will not be silenced’: thousands protest Trump research cuts The Heritage Foundation, a right-wing think-tank based in Washington DC, released Project 2025, a policy guidebook and staffing list, in April 2023, as a blueprint for what it hoped would be a second Trump presidency. Trump, however, disavowed the initiative during his 2024 presidential campaign, saying that he had no knowledge of it, after there was public backlash over the publication’s sweeping Republican policy proposals, such as banning abortion, overhauling the federal government and slashing funding for climate science. But Trump and his administration have closely hewed to Project 2025’s agenda, detailed in a sprawling, 922-page book, passing executive orders to defund climate initiatives and target diversity programmes. The Wall Street Journal found that more than half of Trump’s executive orders (EOs) align with Project 2025 recommendations. And most of its 40 listed authors are now key figures on Trump’s team. The Heritage Foundation did not respond to Nature’s request for comment. Taylor Rodgers, a White House spokesperson, said: “No one cared about Project 2025 when they elected president Trump in November 2024, and they don’t care now. President Trump is implementing the America First agenda he campaigned on to free up wasteful DEI [diversity, equity and inclusion] spending for cutting-edge scientific research, roll back radical climate regulations and restore America’s energy dominance.” But policy watchers expect that the president’s upcoming budget request to the US government will contain massive cuts to science agencies. Here, Nature examines science-related policies from Project 2025 that have already come to pass, and which ones might be on the horizon. Has Trump ever followed the think-tank’s advice before? The Heritage Foundation has been publishing policy recommendations since 1981, often timing them for a new presidency. At the start of Trump’s first term in 2017, the foundation listed hundreds of priorities, such as opening up sites for off-shore oil drilling. According to the foundation, after a year in office, Trump had followed through on 64% of them. Compared with previous guidebooks, Project 2025 advises more-extreme actions. For instance, whereas the 2017 version advised the president to “rein in the administrative state”, Project 2025 advocates that the president “dismantle the administrative state”, which employs more than two million federal workers. And its proposals don’t apply only to the federal government: Project 2025 also aims to reform the US education system, including universities. The goal, its authors write, is to “defang and defund the woke culture warriors who have infiltrated every last institution in America”. Protesters have demonstrated against Project 2025 before and after US President Donald Trump took office.Credit: Selcuk Acar/Anadolu via Getty Which policies from the project has the Trump team implemented so far? Project 2025 notes that the US president has sole authority over the US executive branch, which includes many science agencies, and encourages the president to exercise it. Trump has so far followed this philosophy, using EOs to accomplish his wishlist. (EOs direct the US government to take action but cannot contravene laws.) Many are being challenged by lawsuits. Here are some of the science-related recommendations that have already been implemented: Anti-diversity efforts “Unwinding policies and procedures that are used to advance radical gender, racial, and equity initiatives under the banner of science.” page 60 Trump signed an EO ending “DEI programs” on 20 January. In response, agencies such as the US National Science Foundation (NSF), a key funder of basic science, paused and reviewed grants for violations of Trump’s orders; the US National Institutes of Health (NIH), the world’s largest funder of biomedical research, has terminated grants related to diversity. DEI offices at numerous agencies have also been shuttered. Defunding climate science and green energy “The Biden [Trump’s predecessor] Administration’s climate fanaticism will need a whole-of-government unwinding.” page 60 As he did during his first presidency, Trump has started the process to withdraw the United States from the 2015 Paris climate agreement, which commits nations to reducing their greenhouse-gas emissions. He also signed an EO targeting energy regulations. The US Environmental Protection Agency has since put forward a plan to roll back dozens of regulations on fossil fuels that protect against pollution. Cutting funds to universities “Congress should cap the indirect cost rate paid to universities.” page 355 The NIH, under the Trump team’s orders, but without the approval of Congress, issued a notice on 7 February that it would cut the indirect cost rate paid to universities for things such as electricity and equipment maintenance to 15%. This would have slashed billions from university budgets. A federal judge has halted the policy from taking effect. Downsizing government “Permanent and substantive reductions in the number of nondefense federal employees.” page 78 Russell Vought, an author of Project 2025 and now director of the US Office of Management and Budget (OMB), has ordered mass ‘reductions in force’ at agencies. NASA has already closed offices, including its Office of the Chief Scientist, and fired more than 20 workers. Other agencies are preparing plans: reports indicate that the NIH will cut 1,200 people — about 6% — from its staff. Russell Vought (right), an author of Project 2025, is now director of the US Office of Management and Budget under Trump (left).Credit: Evan Vucci/AP Photo/Alamy Which proposed science policies from Project 2025 might be on the horizon? Project 2025 contains hundreds of recommendations, and many have not been implemented, although there are signs that the Trump administration is considering them. Here are some of those: Fetal-tissue research
Nature DOI suffix ≠ "/s...": Not a research article
How a scientist–pop industry partnership slashed a live gig’s carbon emissions by 98%
Esme Hedley
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An energy-efficient concert by the UK trip-hop band Massive Attack.Credit: Kristian Buus/Getty A battery-powered live outdoor concert headlined by the UK trip-hop band Massive Attack, and attended by more than 32,000 fans, slashed energy-related greenhouse-gas emissions by 98%, according to a report by climate researchers. Having no diesel generator back-up helped organizers of the Act 1.5 event, held in Bristol, UK, last August, to achieve marked reductions in the on-site carbon emissions, alongside reductions associated with transport and food, the report adds. Researchers at the Tyndall Centre for Climate Change Research at the University of Manchester, UK, evaluated the event’s climate impact against the Super-Low Carbon Live Music road map, which was designed by centre director Carly McLachlan and her team at Tyndall in 2021. Act 1.5’s greenhouse-gas-emissions data were compared with a counterfactual show of the same size that used standard industry practices. Artists’ transport emissions were reduced by 73% because they shunned air travel in favour of lower-carbon alternatives such as coaches and ferries. Using two trucks instead of four to transport equipment and switching from diesel to hydrotreated vegetable oil reduced fuel emissions by 70%. Also, all of the meals sold at the event were vegan, delivering an 89% reduction in emissions. McLachlan, who co-authored the report with Chris Jones, an environment researcher at Tyndall, attributed Act 1.5’s achievements to an ethos of collaboration and openness to doing things differently, alongside a respect for music-industry professionals with extensive experience. “Having unwavering commitment from multiple key actors in any sector or project is essential — so that when bumps in the road happen, there is a commitment to finding a super-low-carbon solution,” she adds. Matt Brennan, whose research at the University of Glasgow, UK, includes music sustainability and the climate crisis, says: “Part of the challenge for the live sector is the amount of cooperation between different actors — sometimes with competing interests — needed to really reduce emissions. It’s great to see that Act 1.5 not only saw ‘rivals’ collaborating, but also indications that seeds were sown for future collaboration.” Catherine Bottrill, the chief executive of Pilio, a net-zero and nature-innovation company based in London, commended the report for “bringing through the science and the evidence base to help support some better decision-making”. Speaking to Nature before Act 1.5 last year, McLachlan said: “If you suggest something, and people say, ‘Well that would never happen’, but then they can see it already has happened, it just unlocks a totally different way of thinking.” Act 1.5 provided incentives for audiences to choose low-carbon travel options, including VIP-bar wristbands for rail travellers and free electric shuttle bus tickets between stations and the venue, alongside offering a local pre-sale for people living in Bristol postcodes to minimize how far audience members travelled.
Nature DOI suffix ≠ "/s...": Not a research article
Trump administration sued over huge funding cuts at Columbia University
Jeff Tollefson
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Two organizations representing faculty at Columbia University today filed a lawsuit in federal court challenging the administration of US President Donald Trump's cancellation of US$400 million in research grants and contracts to the university. The lawsuit follows a controversial decision by university leaders to alter campus and academic policies in accordance with the government’s demands ― a move that many scientists and academics fear will encourage the federal government to ask for even more concessions from Columbia and other schools. “The Trump administration’s threats and coercion at Columbia are part of a clear authoritarian playbook meant to crush academic freedom and critical research in American higher education,” Todd Wolfson, president of the American Association of University Professors (AAUP), a non-profit group in Washington DC that advocates for academic freedom, said in a statement. The AAUP filed the lawsuit with the American Federation of Teachers, a union based in Washington DC that represents university faculty members, among others. ‘My career is over’: Columbia University scientists hit hard by Trump team’s cuts The US Department of Education, one of the agencies named in the suit, did not respond before publication to a request for comment. Officials with the department and other agencies have justified the cancellations by saying that the university had failed to protect its Jewish students. Administration officials said earlier this month that they would not negotiate with the university about government funding unless Columbia acceded to the administration’s ultimatums on an array of security, admissions and academic policies. In response, on 21 March, the university announced a range of measures, including restrictions on the wearing of face masks, new campus disciplinary rules and a review of Columbia’s Department of Middle Eastern, South Asian, and African Studies (MESAAS), which has become a flashpoint of controversy. Some scientists who have lost funding nonetheless have misgivings about the university’s efforts to cooperate with the administration. Others argue that the university’s acquiescence will embolden an administration that has sought to exert control over academic institutions by withholding funding mandated by Congress. It should have been Columbia, not organizations representing faculty, filing the lawsuit against the administration today, says Sheldon Pollock, who twice chaired MESAAS and is now retired. “This is a real-time experiment in how totalitarianism inserts itself into a democratic society,” Pollack says. “I do not feel that that is an exaggeration.” The White House declined to address these and other allegations in this story. List of conditions The administration alleges that Columbia failed in its obligations under the US Civil Rights Act to protect Jewish students during campus protests against Israel’s war in Gaza. That war began after Hamas attacked Israel on 7 October 2023. In a letter issued on 13 March, the administration laid out nine conditions that Columbia must meet to start negotiations over funding. Most of the conditions focused on security and disciplinary measures, but the administration also waded into academic affairs by demanding that MESAAS be placed under ‘academic receivership’. ‘All this is in crisis’: US universities curtail staff, spending as Trump cuts take hold Receivership is a relatively rare action used to relieve members of a department of control and bring in new leadership. MESAAS has been the subject of particular controversy since one of its faculty members, Joseph Massad, described Hamas’s attack on Israel as a “stunning victory of the Palestinian resistance”. An analysis posted online by a group of Columbia law professors says that the cancellation of grants is illegal under the Civil Rights Act, which lays out specific procedures for handling alleged violations, including “an express finding on the record, after opportunity for hearing”. The analysis adds that the law stipulates that any penalties be applied to the programme in question, not to unrelated programmes at the same academic institution. The Department of Education declined to answer questions from Nature, but spokesperson Madi Biedermann said in a statement that the Trump team “followed all applicable law in holding Columbia University to account for the lawless antisemitism that it allowed to occur on its campus”. Politics at play On 21 March, Columbia University’s interim president, Katrina Armstrong, released a conciliatory response that laid out a suite of relevant actions the university has already taken, as well as further commitments to bolster security, foster “intellectual diversity” and review admissions policies to ensure that they are “unbiased”. One provision in particular has caught the eye of academics: a plan to appoint a new senior vice-provost with broad powers to review academic programmes focused on specific geographic regions, “starting immediately with the Middle East” and including MESAAS. Critics fear that the university is surrendering to political demands and putting long-standing principles of self-governance by faculty members at risk.
Nature DOI suffix ≠ "/s...": Not a research article
Empower families to lead the design of their ageing loved ones’ health care
Shahmir H. Ali
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The United Nations estimates that, by 2050, one in six people worldwide will be aged 65 years or older, up from one in ten in 2021. Some low- and middle-income countries are expected to see the fastest increase in numbers. Nations with limited resources must adapt quickly to support the complex health needs of their ageing populations. As a behavioural health researcher in Singapore, I assess programmes aimed at preventing and managing chronic diseases. Time and again, I hear that the most powerful force in the success or failure of an initiative is the patient’s family. In my view, such involvement needs to become an integral part of health-care plans for older people. How students and grandparents could solve the global mental-health crisis Behind many health programmes for older adults are an army of sons, daughters, spouses and other relatives. They might manage logistics, talk to physicians and ensure that treatment plans are followed. But they can also unintentionally exacerbate health issues. An older person’s high blood pressure might stem from the salty noodle soup that their partner often cooks or the unhealthy takeaways their child brings home. Most family-related health-care initiatives focus on enabling professionals to work better with families or on helping both patients and their relatives to manage a disease. Much rarer are family-led approaches, which empower relatives with the skills and knowledge they need to help their loved ones. Yet such approaches could benefit many older adults, who can face social, cultural, technological and logistical challenges in accessing health care or adopting healthier behaviours. I’m currently testing online training that provides young adults in Singapore with evidence-based strategies to help their families to manage the amount of salt in their diets. Although the programme still in progress, early signs indicate that it works, and that it requires relatively little time or effort from the participants. Similarly, a study in Thailand tested an educational app to support family members of older adults with diabetes (P. Poonprapai et al. Int. J. Clin. Pharm. 44, 680–688; 2022). Family members were encouraged to relay what they learnt to their relatives, as well as remind them to take their medicine. The app significantly improved patients’ ability to manage their disease and adhere to their medication plans. Life expectancy rise in rich countries slows down: why discovery took 30 years to prove Family-led approaches can be less resource intensive than conventional health-care schemes, making them well suited to regions with scant funds. Yet critics might worry that they ask too much of relatives. Even small tasks, such as monitoring medicine intake or coordinating appointments can add up — particularly for those already juggling work, childcare and other responsibilities. Scalable, sustainable ways to engage families as partners in health care need to be developed and evaluated. So far, research has been limited to small-scale programmes. To scale up these schemes, scientists need to compare models of family engagement. These might have a light touch or be more intense — ranging from asking whether a loved one is taking their pills during a regular visit to receiving training that enables them to build a tailored plan that supports a relative’s heart health.
Nature DOI suffix ≠ "/s...": Not a research article
Lasso-shaped molecule is a new type of broad-spectrum antibiotic
Lynn L. Silver
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The need to develop antibiotics to combat growing antimicrobial resistance, combined with the difficulty of their discovery and the lack of financial support for their development, is a major challenge for global health care both now and in the future. The finding, therefore, of an innovative antibacterial compound — one that has in vivo activity against a clinically relevant target (the bacterium Acinetobacter baumannii) — should rightly be met with great fanfare. However, as with the introduction of any antibiotic, early results should not be overhyped. Writing in Nature, Jangra et al.1 present a satisfyingly complete account of the discovery and initial characterization of this antibiotic.
Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: Pregnancy’s true toll on the body
Jacob Smith
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Nature DOI suffix ≠ "/s...": Not a research article
How the Atlantic jet stream has changed in 600 years — and what it means for weather
Matthew P. Dannenberg, Erika K. Wise
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Jet streams are fast-moving ribbons of air that travel from west to east around the Earth (Fig. 1), usually in wave-like patterns, roughly 5–10 kilometres above sea level1. They are key modifiers of climate and of weather extremes at mid-latitudes. Across Europe, changes in the strength, location and ‘waviness’ of the subpolar Atlantic jet stream can alter near-surface air temperature and precipitation2,3. As global climate warms, the subpolar Atlantic jet stream will probably shift northwards and become even wavier4,5, which could alter both the average climate and the frequency, intensity and persistence of extreme events in Europe — including droughts, floods and heatwaves.
Nature DOI suffix ≠ "/s...": Not a research article
Daily briefing: Why RNA hasn’t yet had its ‘AlphaFold’ moment
Flora Graham
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Nature DOI suffix ≠ "/s...": Not a research article
Pregnancy’s true toll on the body: huge birth study paints most detailed picture yet
Celeste Biever
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Women’s bodies undergo vast physiological changes during pregnancy that can last for more than a year after birth.Credit: Money Sharma/AFP via Getty Biologists have built up one of the most detailed pictures ever of the changes that occur in women’s bodies before and after pregnancy, by pooling and studying around 44 million physiological measurements from more than 300,000 births. How pregnancy transforms the brain to prepare it for parenthood The gigantic study1, which used the anonymized results of blood, urine and other tests taken before, during and more than a year after pregnancy, reveals the scale of the toll that carrying a baby and childbirth take on the body — from the myriad changes made to support a fetus to the effects of its abrupt departure from the body during birth. The research was published in Science Advances on 26 March. The study suggests that the postnatal period in the body is much longer than people tend to assume, says Jennifer Hall, who researches reproductive health at University College London. There’s a societal expectation that you bounce back quickly after childbirth, she says. “This is like the biological proof that you don’t.” The results also suggest that it might be possible to identify women at risk of certain common complications of pregnancy — including the blood-pressure condition pre-eclampsia and gestational diabetes — before conception. Currently, these conditions are diagnosed during pregnancy. The power of data The researchers used anonymized data from medical records supplied by Israel’s largest health-care provider, and spanning the period from 2003 to 2020. To build up a picture of a typical pregnancy, they used test results only from women aged 20–35 years who were not taking medication or experiencing chronic disease. Source: Ref. 1 The team gathered results from 76 common tests — including measures of cholesterol, immune cells, red blood cells, inflammation and the health of the liver, kidneys and metabolism — taken up to 4.5 months before conception and up to 18.5 months after childbirth. This allowed them to establish average values for each test for every week in that period. Women’s health research lacks funding – these charts show how “It took my breath away to see that every test has this dynamical profile that is so elaborate, week by week, and has never been seen before,” says Uri Alon, a systems biologist at the Weizmann Institute for Science in Rehovot, Israel, who led the study. The researchers found that, in the first month after birth, 47% of the 76 indicators stabilized close to their pre-conception values. But 41% of the indicators took longer than 10 weeks to stabilize. These included several measures of liver function and cholesterol that took around six months to settle, and an indicator of bone and liver health, which took a year (see ‘The body’s slow recovery from childbirth’). The remaining 12% took 4–10 weeks to stabilize. Several measurements — including a marker for inflammation and several indicators of blood health — settled but did not return to their pre-conception levels even after 80 weeks, when the study ended. Whether such long-lasting differences result from pregnancy and birth themselves or from behaviours changing after the arrival of a child is a question for future research, say the scientists.
Nature DOI suffix ≠ "/s...": Not a research article
23andMe plans to sell its huge genetic database: could science benefit?
Celeste Biever
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23andMe created a massive database of people’s DNA by selling kits to customers who want to find out their genetic roots.Credit: Tiffany Hagler-Geard/Bloomberg via Getty Once a darling of Silicon Valley, the consumer-genomics company 23andMe has filed for bankruptcy and legal permission to auction off its assets — including its vast genetic database, which includes DNA information from around 15 million people worldwide and has powered more than 250 scientific studies. The move to sell the information is prompting fears over how individuals’ genetic data might be used under new ownership, as well as uncertainty for scientists who work with 23andMe. But some researchers say that science could benefit if a buyer were to seize the opportunity to optimize access to data for research. What went wrong at 23andMe? Why the genetic-data giant risks collapse The potential sale of the data set represents a big moment for the consumer-genetics movement. “As far as I know, this is the most amount of genetic data that is potentially changing hands,” says bioethicist Anya Prince at the University of Iowa in Iowa City. Researchers, who use the company’s data to investigate the genetics underlying certain traits, are hopeful that a new owner will continue to offer access to the information — one of the world’s biggest genomic data sets. “If a future buyer is not interested in research collaborations, it would be a great shame that the potential this data holds for human health advances would not be realized,” says geneticist Rachel Freathy at the University of Exeter, UK, whose planned collaboration with 23andMe into genetic links to birth weight and gestation length was cancelled in January because of company lay-offs. Truth in saliva 23andMe, founded in 2006 in Sunnyvale, California, charges customers to extract and analyse their DNA from a mailed-in saliva sample. The analysis produces information about ancestry, family traits and potential health risks — and around 80% of customers consented to have their genetic information used for research. But in recent years, the firm’s business model has faltered. The announcement of the proposed sale on 23 March prompted attorney-generals in several US states to issue ‘consumer alerts’ detailing how consumers could download their data and delete their 23andMe accounts to safeguard their personal information. Bioethicists say it’s difficult to say how much of a risk the sale poses. “We don’t have to freak out yet,” says bioethicist Amy McGuire of Baylor College of Medicine in Houston, Texas. However, for customers uncomfortable with not knowing who is going to own their data, the safest option is for them to delete their accounts, she says. One concern is that a change in ownership could result in insurance companies or law-enforcement agencies gaining access to customer data, neither of which are permitted by 23andMe’s current privacy policy, with an exception for law enforcement if they have a search warrant, subpoena or court order. 23andMe says that a new owner must abide by the current privacy policy. But the policy also says the terms can be altered — this means the new company “could have the power to change data collection in a way that people wouldn't want”, says Prince. A 2008 US federal law prevents health insurers from using genetic information to determine premiums. But life insurers in some jurisdictions might use the data as the basis for increasing premiums for those at heightened risk of genetic disease. This practice is restricted in places including the United Kingdom and Florida but not at the US federal level, says Prince. Some fear that if law-enforcement agencies gained access to the database, they could search for matches to forensic DNA samples taken from crime scenes, leading to people who have submitted their DNA or their relatives being contacted or investigated as suspects. Such outcomes are worth taking seriously because the stakes are so high when it comes to genetic data, says Prince. “You can’t change your genetic code.” 23andMe says that a new owner can change how a customer’s data are used only with that person’s consent and that 23andMe will seek a buyer “who shares in its commitment to customer data privacy”.

Nature Human Behaviour

GPT-4o mini: Non-social science research article
The next generation of experimental research with LLMs
Gary Charness, Brian Jabarian, John A. List
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GPT-4o mini: Non-social science research article
A neural geometry approach comprehensively explains apparently conflicting models of visual perceptual learning
Yu-Ang Cheng, Mehdi Sanayei, Xing Chen, Ke Jia, Sheng Li, Fang Fang, Takeo Watanabe, Alexander Thiele, Ru-Yuan Zhang
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Visual perceptual learning (VPL), defined as long-term improvement in a visual task, is considered a crucial tool for elucidating underlying visual and brain plasticity. Previous studies have proposed several neural models of VPL, including changes in neural tuning or in noise correlations. Here, to adjudicate different models, we propose that all neural changes at single units can be conceptualized as geometric transformations of population response manifolds in a high-dimensional neural space. Following this neural geometry approach, we identified neural manifold shrinkage due to reduced trial-by-trial population response variability, rather than tuning or correlation changes, as the primary mechanism of VPL. Furthermore, manifold shrinkage successfully explains VPL effects across artificial neural responses in deep neural networks, multivariate blood-oxygenation-level-dependent signals in humans and multiunit activities in monkeys. These converging results suggest that our neural geometry approach comprehensively explains a wide range of empirical results and reconciles previously conflicting models of VPL.
How growing up without siblings affects the adult brain and behaviour in the CHIMGEN cohort
Jie Tang, Jing Zhang, Wei Li, Meiyun Wang, Jingliang Cheng, Bing Zhang, Wenzhen Zhu, Shijun Qiu, Guangbin Cui, Yongqiang Yu, Weihua Liao, Hui Zhang, Bo Gao, Xiaojun Xu, Yunjun Yang, Tong Han, Zhenwei Yao, Quan Zhang, Wen Qin, Feng Liu, Meng Liang, Sijia Wang, Qiang Xu, Jiayuan Xu, Jilian Fu, Yuan Ji, Nana Liu, Peng Zhang, Dapeng Shi, Caihong Wang, Su Lui, Zhihan Yan, Feng Chen, Wen Shen, Yanwei Miao, Dawei Wang, Junfang Xian, Xiaochu Zhang, Kai Xu, Xi-Nian Zuo, Longjiang Zhang, Zhaoxiang Ye, Zuojun Geng, Jia-Hong Gao, Chunshui Yu, character(0), Quan Zhang, Junping Wang, Xue Zhang, Xinjun Suo, Congcong Yuan, Hui Xue, Tianying Gao, Junpeng Liu, Yanjun Li, Xi Guo, Lixue Xu, Jiajia Zhu, Huaigui Liu, Fangshi Zhao, Jie Sun, Yongjie Xu, Huanhuan Cai, Yaodan Zhang, Yongqin Xiong, Xianting Sun, Nannan Pan, Xue Zhang, Jiayang Yang, Ya Wen, Dan Zhu, Bingjie Wu, Wenshuang Zhu, Qingqing Diao, Yujuan Cao, Bingbing Yang, Lining Guo, Yingying Xie, Jiahui Lin, Zhimin Li, Yan Zhang, Kaizhong Xue, Zirui Wang, Junlin Shen, Xuejun Zhang, Hao Ding, Qian Su, Mulin Jun Li, Shijie Zhang, Lun Ma, Yan Bai, Min Guan, Wei Wei, Peifang Miao, Fuhong Duan, Yafei Guo, Weijian Wang, Long Jiang Zhang, Lijuan Zheng, Lilin, Yunfei Wang, Han Zhang, Xinyuan Zhang, Zhao Qing, Sichu Wu, Junxia Wang, Yi Sun, Yang He, Xi-Nian Zuo, Zhe Zhang, Yin-Shan Wang, Quan Zhou, Tian Tian, Yi Liang, Yujie Liu, Hui Zeng, Jingxian Chen, Haitao Ge, Peng Xu, Cailuan Lu, Chen Wu, Xiaoying Yang, Yuzhao Wang, Yankai Wu, Xuran Feng, Ling Li, Duo Gao, Rujing Zha, Ying Li, Lizhuang Yang, Ying Chen, Ling Zuo, Jianqiao Ge, Guoyuan Yang, Wen Wang, Linfeng Yan, Yang Yang, Jin Zhang, Qian Wang, Xiaoxia Qu, Ying Wang, Fei Yuan, Li Hu, Jizhen Li, Weiwei Wang, Yujing Zhou, Miaomiao Long, Lihua Liu, Xiaohu Li, Xiaoshu Li, Jiance Li, Nengzhi Xia, Weihua Liao, Shuai Yang, Youming Zhang, Jing Zhang, Guangyao Liu, Laiyang Ma, Xiaochun Wang, Ying Lei, Bo Gao, Gang Zhang, Kang Yuan, Jingjing Xu, Xiaojun Guan, Yuankai Lin, Hui Juan Chen, Yuchuan Fu, Yi Lu, Jun Guo, Hao Lu, Yue Wu
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With the worldwide increase in only-child families, it is crucial to understand the effects of growing up without siblings (GWS) on the adult brain, behaviour and the underlying pathways. Using the CHIMGEN cohort, we investigated the associations of GWS with adult brain structure, function, connectivity, cognition, personality and mental health, as well as the pathway from GWS to GWS-related growth environments to brain and to behaviour development, in 2,397 pairs of individuals with and without siblings well matched in covariates. We found associations linking GWS to higher language fibre integrity, lower motor fibre integrity, larger cerebellar volume, smaller cerebral volume and lower frontotemporal spontaneous brain activity. Contrary to the stereotypical impression of associations between GWS and problem behaviours, we found positive correlations of GWS with neurocognition and mental health. Despite direct effects, GWS affects most brain and behavioural outcomes through modifiable environments, such as socioeconomic status, maternal care and family support, suggesting targets for interventions to enhance children’s healthy growth.
Socio-economic status is a social construct with heritable components and genetic consequences
Abdel Abdellaoui, Hilary C. Martin, Martin Kolk, Adam Rutherford, Michael Muthukrishna, Felix C. Tropf, Melinda C. Mills, Brendan P. Zietsch, Karin J. H. Verweij, Peter M. Visscher
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In civilizations, individuals are born into or sorted into different levels of socio-economic status (SES). SES clusters in families and geographically, and is robustly associated with genetic effects. Here we first review the history of scientific research on the relationship between SES and heredity. We then discuss recent findings in genomics research in light of the hypothesis that SES is a dynamic social construct that involves genetically influenced traits that help in achieving or retaining a socio-economic position, and can affect the distribution of genes associated with such traits. Social stratification results in people with differing traits being sorted into strata with different environmental exposures, which can result in evolutionary selection pressures through differences in mortality, reproduction and non-random mating. Genomics research is revealing previously concealed genetic consequences of the way society is organized, yielding insights that should be approached with caution in pursuit of a fair and functional society.
Women shaping behavioural science
Qing Cai, Mar Hicks, Emilia Huerta-Sanchez, Samara Klar, Misaki N. Natsuaki, Tanja van der Lippe
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Proceedings of the National Academy of Sciences

GPT-4o mini: Non-social science research article
Tetrapod species–area relationships across the Cretaceous–Paleogene mass extinction
Roger Adam Close, Bouwe Rutger Reijenga
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Mass extinctions are rare but catastrophic events that profoundly disrupt biodiversity. Widely accepted consequences of mass extinctions, such as biodiversity loss and the appearance of temporary “disaster taxa,” imply that species–area relationships (SARs, or how biodiversity scales with area) should change dramatically across these events: Specifically, both the slope (the rate of accumulation of new species with increasing area) and intercept (the density of species at local scales) of the power–law relationship should decrease. However, these hypotheses have not been tested, and the contribution of variation in the SAR to diversity dynamics in deep time has been neglected. We use fossil data to quantify nested SARs in North American terrestrial tetrapods through the Cretaceous–Paleogene (K/Pg) mass extinction (Campanian–Ypresian). We show that SARs vary substantially through time and among groups. In the pre-extinction interval (Maastrichtian), unusually shallow SAR slopes (indicating low beta diversity or provinciality) drive low total regional diversity in dinosaurs, mammals, and other tetrapods. In the immediate postextinction interval (Danian), the explosive diversification of mammals drove high regional diversity via a large increase in SAR slope (indicating higher beta diversity or provinciality), and only a limited increase in SAR intercept. This contradicts the expectation that postextinction biotas should be regionally homogenized by the spread of disaster taxa and impoverished by diversity loss. This early postextinction increase in SAR slope was followed in the Thanetian–Selandian ( ∌ 4.4. myr later) by increases in the intercept, indicating that diversity dynamics at local and regional scales did not change in synchrony.
GPT-4o mini: Non-social science research article
Therapeutic targeting of the NOTCH1 and neddylation pathways in T cell acute lymphoblastic leukemia
Kalay Bertulfo, Pablo Perez-Duran, Hannah Miller, Cindy Ma, Alberto Ambesi-Impiombato, Jeremy Samon, Adam Mackey, Wen-Hsuan Wendy Lin, Adolfo A. Ferrando, Teresa Palomero
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Gamma Secretase Inhibitors (GSIs) effectively block oncogenic Notch homolog-1 (NOTCH1), a characteristic feature of T cell acute lymphoblastic leukemias (T-ALL). However, their clinical application has been stalled by the induction of severe gastrointestinal toxicity resulting from the inhibition of NOTCH signaling in the gut, which translates into increased goblet cell differentiation. Genome-wide CRISPR loss-of-function screen in the colon cancer cell line LS174T identified the neddylation pathway as a main regulator of goblet cell differentiation upon NOTCH1 inhibition. Consistently, pharmacologic inhibition of the neddylation pathway with the small molecule inhibitor MLN4924, rescued GSI-induced differentiation in LS174T cells. Mechanistically, neddylation inhibition by MLN4924 increases the protein stability of Hairy and enhancer of split-1, a direct NOTCH1 transcriptional target and key regulator of absorptive and secretory cell fate decisions. Combined treatment with GSI and MLN4924 in a murine Notch1 -dependent model of T-ALL led to leukemia regression and improved overall survival in the absence of gut toxicity. Overall, these results support the combined targeting of the NOTCH1 and neddylation pathways for the treatment of NOTCH1-induced T-ALL.
GPT-4o mini: Non-social science research article
Phosphatic stromatoporoid sponges formed reefs ~480 Mya
Juwan Jeon, Mar Simonet Roda, Zhong-Yang Chen, Cui Luo, Stephen Kershaw, Daeyeong Kim, Jun-Ye Ma, Jeong-Hyun Lee, Yuan-Dong Zhang
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Stromatoporoid sponges were important reef-builders during the middle Paleozoic, yet their early history and integration into reef ecosystems remain poorly understood. Here, we report Lophiostroma leizunia Jeon sp. nov., the oldest known stromatoporoid from upper Tremadocian to lower Floian (~480 My-old) strata of South China. L. leizunia formed complex reef structures, playing crucial roles in framework construction and binding other components, including calcimicrobes, lithistid sponges, stalked echinoderms, and Calathium . This discovery pushes back the fossil record of stromatoporoids and the reefs that they formed by approximately 20 My, advancing the onset of the Great Ordovician Biodiversification Event in reef evolution. L. leizunia unusually constructed its skeleton using fluorapatite—a feature previously unknown in sponges. This establishes Porifera as the first metazoan phylum known to have utilized all three principal biominerals: silica, calcium carbonate, and calcium phosphate. The presence of phosphatic skeletons in this early stromatoporoid expands our understanding of biomineralization capabilities in early animals and suggests that the genetic toolkit for diverse biomineralization strategies may have been present in early sponges. The unique combination of the earliest known reef-building stromatoporoids and their phosphatic skeletal composition provides insights into the evolutionary dynamics of biomineralization and the rise of metazoan-dominated reef ecosystems during a critical period of Earth’s history.
GPT-4o mini: Non-social science research article
Allosteric mechanism in the distinctive coupling of G q and G s to the parathyroid hormone type 1 receptor
Xuan Zhang, Ji Young Lee, Jonathan Pacheco, Ieva Sutkeviciute, Anju Krishnan Anitha, Heng Liu, Stephanie Singh, Carlos Ventura, Sofya Savransky, Ashok Khatri, Cheng Zhang, Ivet Bahar, Jean-Pierre Vilardaga
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The mechanism determining the preferential stimulation of one heterotrimeric G protein signaling pathway over another by a ligand remains undetermined. By reporting the cryogenic electron microscopy (cryo-EM) structure of the parathyroid hormone (PTH) type 1 receptor (PTH1R) complexed with Gq and comparing its allosteric dynamics with that of PTH1R in complex with G s , we uncover a mechanism underlying such preferences. We show that an allosteric coupling between the ligand PTH and the C-terminal helix α5 of the Gα subunit controls the stability of the PTH1R complex with the specific G protein, G s or G q . Single-cell-level experiments further validate the G protein–selective effects of the PTH binding pose by demonstrating the differential, G protein–dependent residence times and affinity of this ligand at the PTH1R binding site. The findings deepen our understanding of the selective coupling of PTH1R to G s or G q and how it relates to the stability and kinetics of ligand binding. They explain the observed variability in the ligand-binding affinity of a GPCR when coupled to different G proteins.
GPT-4o mini: Non-social science research article
Expectation-dependent stimulus selectivity in the ventral visual cortical pathway
Tiago S. Altavini, Minggui Chen, Guadalupe Astorga, Yin Yan, Wu Li, Winrich Freiwald, Charles D. Gilbert
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The hierarchical view of the ventral object recognition pathway is primarily based on feedforward mechanisms, starting from a fixed basis set of object primitives and ending on a representation of whole objects in the inferotemporal cortex. Here, we provide a different view. Rather than being a fixed “labeled line” for a specific feature, neurons are continually changing their stimulus selectivities on a moment-to-moment basis, as dictated by top–down influences of object expectation and perceptual task. Here, we also derive the selectivity for stimulus features from an ethologically curated stimulus set, based on a delayed match-to-sample task, that finds components that are informative for object recognition in addition to full objects, though the top–down effects were seen for both informative and uninformative components. Cortical areas responding to these stimuli were identified with functional MRI in order to guide placement of chronically implanted electrode arrays.
GPT-4o mini: Non-social science research article
Prediction of phase-separation propensities of disordered proteins from sequence
Sören von BĂŒlow, Giulio Tesei, Fatima Kamal Zaidi, Tanja Mittag, Kresten Lindorff-Larsen
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Phase separation is one possible mechanism governing the selective cellular enrichment of biomolecular constituents for processes such as transcriptional activation, mRNA regulation, and immune signaling. Phase separation is mediated by multivalent interactions of macromolecules including intrinsically disordered proteins and regions (IDRs). Despite considerable advances in experiments, theory, and simulations, the prediction of the thermodynamics of IDR phase behavior remains challenging. We combined coarse-grained molecular dynamics simulations and active learning to develop a fast and accurate machine learning model to predict the free energy and saturation concentration for phase separation directly from sequence. We validate the model using computational and previously measured experimental data, as well as new experimental data for six proteins. We apply our model to all 27,663 IDRs of chain length up to 800 residues in the human proteome and find that 1,420 of these (5%) are predicted to undergo homotypic phase separation with transfer free energies < −2 k B T . We use our model to understand the relationship between single-chain compaction and phase separation and find that changes from charge- to hydrophobicity-mediated interactions can break the symmetry between intra- and intermolecular interactions. We also provide proof of principle for how the model can be used in force field refinement. Our work refines and quantifies the established rules governing the connection between sequence features and phase-separation propensities, and our prediction models will be useful for interpreting and designing cellular experiments on the role of phase separation, and for the design of IDRs with specific phase-separation propensities.
GPT-4o mini: Non-social science research article
De novo discovery of a molecular glue–like macrocyclic peptide that induces MCL1 homodimerization
Fengwei Li, Mengmeng Zhang, Chao Liu, Jie Cheng, Yawen Yang, Xiangda Peng, Zhifeng Li, Wenfeng Cai, Haipeng Yu, Junjie Wu, Yuyu Guo, Hongkun Geng, Yun Fa, Youming Zhang, Dalei Wu, Yizhen Yin
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Macrocyclic peptides have emerged as promising drug candidates, filling the gap between small molecules and large biomolecules in drug discovery. The antiapoptotic protein myeloid cell leukemia 1 (MCL1) is crucial for numerous cancers, yet it presents challenges for selective targeting by traditional inhibitors. In this study, we identified a macrocyclic peptide, 5L1, that strongly binds to MCL1, with a dissociation constant ( K D ) of 7.1 nM. This peptide shows the potential to specifically inhibit the function of MCL1, and demonstrates effective antitumor activity against several blood tumor cell lines with the half maximal inhibitory concentration (IC 50 ) values for cell-penetrating peptide-conjugated 5L1 in the range of 0.6 to 3 ÎŒM. Structural analysis revealed that it functions similarly to molecular glue, capable of binding to two MCL1 molecules simultaneously and inducing their homodimerization. This unique mechanism of action distinguishes it from traditional small-molecule MCL1 inhibitors, underscoring the potential of macrocyclic peptides functioning as molecular glues. Moreover, it inspires the development of highly selective inhibitors targeting MCL1 and other related targets with this glue-like mechanism.
GPT-4o mini: Non-social science research article
Observation of odd-parity superconductivity in UTe 2
Zixuan Li, Camilla M. Moir, Nathan J. McKee, Eric Lee-Wong, Ryan E. Baumbach, M. Brian Maple, Ying Liu
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Symmetry properties of the order parameter are among the most fundamental characteristics of a superconductor. UTe 2 , which was found to feature an exceedingly large upper critical field and striking reentrant behavior at low temperatures, is widely believed to possess a spin-triplet pairing symmetry. However, unambiguous evidence for such a pairing symmetry is still lacking, especially at zero and low magnetic fields. The presence of an inversion crystalline symmetry in UTe 2 requires that, if it is indeed a spin-triplet superconductor, the order parameter must be of odd parity. We report here phase-sensitive measurements of the symmetry of the orbital part of the order parameter using the Josephson effect. The selection rule in the orientation dependence of the Josephson coupling between In, an s -wave superconductor, and UTe 2 suggests strongly that UTe 2 possesses the odd-parity pairing state of B 1 u symmetry near zero magnetic field, making it a spin-triplet superconductor. We also report the apparent formation of Andreev surface bound states on the (1−10) surface of UTe 2 .
GPT-4o mini: Non-social science research article
The emergence of eukaryotes as an evolutionary algorithmic phase transition
Enrique M. Muro, Fernando J. Ballesteros, Bartolo Luque, Jordi Bascompte
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The origin of eukaryotes represents one of the most significant events in evolution since it allowed the posterior emergence of multicellular organisms. Yet, it remains unclear how existing regulatory mechanisms of gene activity were transformed to allow this increase in complexity. Here, we address this question by analyzing the length distribution of proteins and their corresponding genes for 6,519 species across the tree of life. We find a scale-invariant relationship between gene mean length and variance maintained across the entire evolutionary history. Using a simple model, we show that this scale-invariant relationship naturally originates through a simple multiplicative process of gene growth. During the first phase of this process, corresponding to prokaryotes, protein length follows gene growth. At the onset of the eukaryotic cell, however, mean protein length stabilizes around 500 amino acids. While genes continued growing at the same rate as before, this growth primarily involved noncoding sequences that complemented proteins in regulating gene activity. Our analysis indicates that this shift at the origin of the eukaryotic cell was due to an algorithmic phase transition equivalent to that of certain search algorithms triggered by the constraints in finding increasingly larger proteins.
GPT-4o mini: Non-social science research article
Optogenetic stimulation of the dorsal striatum bidirectionally controls seizures
Safwan K. Hyder, Willian Lazarini-Lopes, Jonathan Toib, Gabrielle Williams, Alexander Sukharev, Patrick A. Forcelli
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Despite a century of development of antiseizure medications, up to a third of people with epilepsy do not achieve seizure freedom with drug therapy. Deep brain stimulation is of growing use, but just as with pharmacotherapy, is not universally effective. Identifying new targets for deep brain stimulation—and in particular sites that are effective against a range of seizure types—may close this gap. Engagement of the basal ganglia experimental seizures was first observed almost 75 y ago. However, the role of the basal ganglia’s input nucleus, the striatum, in seizure control is relatively understudied. To address this gap, we used an optogenetic approach to activate and inactivate neurons in the dorsal striatum of rats submitted to the gamma-butyrolactone (GBL) model of absence epilepsy, amygdala kindling model of temporal lobe epilepsy, and pilocarpine-induced Status Epilepticus (SE). Open-loop (continuous light delivery) optogenetic activation of dorsal striatal neurons robustly suppressed seizures in all models. By contrast, open-loop optogenetic silencing increased absence seizure expression and facilitated SE onset but had no effect on kindled seizures. In the GBL model, we also tested the effects of closed-loop modulation (light delivery in response to seizure detection). Closed-loop activation reduced duration of spike-wave discharges (SWDs), while closed-loop inhibition increased SWD duration. These results demonstrated previously unrecognized antiabsence effects associated with striatal neuromodulation. These findings demonstrate a robust, bidirectional role of the dorsal striatum in the control of multiple seizure types, suggesting that the striatum is a site that can exert broad-spectrum control of seizures.
GPT-4o mini: Non-social science research article
Bilateral astrocyte reaction to unilateral insult in the optic projection to the brain
Joseph M. Holden, David J. Calkins
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GPT-4o mini: Non-social science research article
Cryo-EM structure of cyanopodophage A4 reveals a pentameric pre-ejectosome in the double-stabilized capsid
Pu Hou, Rui-Qian Zhou, Yong-Liang Jiang, Rong-Cheng Yu, Kang Du, Nanqin Gan, Fei Ke, Qi-Ya Zhang, Qiong Li, Cong-Zhao Zhou
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Upon infection, the podophages usually eject a couple of proteins from the capsid to form a transmembrane ejectosome on the host cell membrane that facilitates the ejection of viral genome. However, it remains unclear how these proteins of pre-ejectosome are finely assembled at the center of highly packaged genome. Here, we report the intact structure of Anabaena cyanopodophage A4, which consists of a capsid stabilized by two types of cement proteins and a short tail attached with six tail fibers. Notably, we find a pentameric pre-ejectosome at the core of capsid, which is composed of four ejection proteins wrapped into a coaxial cylinder of triple layers. Moreover, a segment of genomic DNA runs along the positively charged circular cleft formed by two ejection proteins. Based on the mortise-and-tenon architecture of pre-ejectosome in combination with previous studies, we propose a putative DNA packaging process and ejection mechanism for podophages. These findings largely enrich our knowledge on the assembly mechanism of podophages, which might facilitate the application of A4 as a chassis cyanophage in synthetic biology.
GPT-4o mini: Non-social science research article
Matrix degradation enhances stress relaxation, regulating cell adhesion and spreading
Badri Narayanan Narasimhan, Stephanie I. Fraley
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In native extracellular matrices (ECM), cells utilize matrix metalloproteinases (MMPs) to degrade and remodel their microenvironment. Accordingly, synthetic matrices have been engineered to permit MMP-mediated cleavage, facilitating cell spreading, migration, and interactions. However, the interplay between matrix degradability and mechanical properties remains underexplored. We hypothesized that MMP activity induces immediate mechanical alterations in the ECM, which are subsequently detected by cells. We observed that both fibrillar collagen and synthetic degradable matrices exhibit enhanced stress relaxation following MMP exposure. Cells responded to these variations in relaxation by modulating their spreading and focal adhesions. Furthermore, we demonstrated that stress relaxation and cell spreading can be precisely controlled through the rational design of matrix degradability. These findings establish a fundamental link between matrix degradability and stress relaxation, with potential implications for a broad spectrum of biological applications.
GPT-4o mini: Non-social science research article
Actuating superparamagnetic nanoparticle monolayers
Edward P. Esposito, Hector Manuel Lopez Rios, Monica Olvera de la Cruz, Heinrich M. Jaeger
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Magnetically responsive, mechanically flexible microstructures are desirable for applications ranging from smart sensors to remote-controlled actuation for surgery or robotics. Embedding magnetic nanoparticles into a thin matrix of elastic material enables high flexibility while exploiting the magnetic response of the individual particles. However, in the ultrathin limit of such nanocomposite materials, the particles become too small to sustain a permanent dipole moment. This implies that now large magnetic field gradients are required for actuation, which are difficult to achieve with externally applied fields. Here, we demonstrate through experiment and simulation that monolayer sheets of close-packed paramagnetic nanoparticles in a uniform applied field can generate large local field gradients through particle interactions. As a result, a strong collective magnetization is obtained that leads to large deflections of freestanding sheets already in moderate applied fields. Exploiting the vector nature of the applied field, we furthermore find that it is possible to induce more complex curvature and twist the sheets. Finally, we show that paramagnetic nanoparticle monolayers applied as coatings can generate sufficient force to deflect strips of nonmagnetic material that is several orders of magnitude thicker.
GPT-4o mini: Non-social science research article
The PVD neuron has male-specific structure and mating function in Caenorhabditis elegans
Yael Iosilevskii, David H. Hall, Menachem Katz, Benjamin Podbilewicz
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Neurons display unique shapes and establish intricate networks, which may differ between sexes. In complex organisms, studying sex differences in structure and function of individual neurons is difficult. The nematode Caenorhabditis elegans hermaphrodites and males present an exceptional model for studying neuronal morphogenesis in a simple, sexually dimorphic system. We focus on the polymodal sensory bilateral neuron pair PVD, which forms a complex but stereotypic dendritic tree composed of multiple subunits that resemble candelabra. PVD is well studied in hermaphrodites, but not in males. We show here that during larval development, male PVD extends a similar architecture to the hermaphrodite utilizing the sexually shared Menorin patterning mechanism. In early adulthood, however, male PVD develops a unique extension into the copulatory tail structure. Alongside established tail ray neurons RnA and RnB, we show PVD is a third, previously unrecognized, neuron within the tail rays. Unlike RnA and RnB, PVD extends anterogradely, branches and turns within the ray hypodermis, and is nonciliated. This PVD sexually dimorphic arborization is absent in mutant backgrounds which perturb the Menorin guidance complex. SAX-7/L1CAM, a hypodermal component of this complex, shows a male-specific expression pattern which precedes PVD extension, and its presence allows PVD to enter the tail rays. Further, our results reveal that genetically altered arborization or ablation of the PVD results in male mating behavioral defects, particularly as males turn around the hermaphrodite. These results uncover an adult-stage sexual dimorphism of dendritic branching and a function for PVD in male sexual behavior.
GPT-4o mini: Non-social science research article
Explaining human motor coordination via the synergy expansion hypothesis
Federico Tessari, A. Michael West, Neville Hogan
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The search for an answer to Bernstein’s degrees of freedom problem has propelled a large portion of research studies in human motor control over the past six decades. Different theories have been developed to explain how humans might use their incredibly complex neuro-musculo-skeletal system with astonishing ease. Among these theories, motor synergies appeared as one possible explanation. In this work, the authors investigate the nature and role of synergies and propose a theoretical framework, namely the “expansion hypothesis,” to answer Bernstein’s problem. The expansion hypothesis is articulated in three propositions: mechanical, developmental, and behavioral. Each proposition addresses a different question on the nature of synergies: i) How many synergies can humans have? ii) How do we learn and develop synergies? iii) How do we use synergies? An example numerical simulation is presented and analyzed to clarify the hypothesis propositions. The expansion hypothesis is contextualized with respect to the existing literature on motor synergies both in healthy and impaired individuals, as well as other prominent theories in human motor control and development. The expansion hypothesis provides a framework to better comprehend and explain the nature, use, and evolution of human motor skills.
GPT-4o mini: Non-social science research article
Anatomy of a range contraction: Flow–phenology mismatches threaten salmonid fishes near their trailing edge
Stephanie M. Carlson, Kasey C. Pregler, Mariska Obedzinski, Sean P. Gallagher, Suzanne J. Rhoades, Cleo Woelfle-Hazard, Nathan Queener, Sally E. Thompson, Mary E. Power
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Climate change is redistributing life on Earth, with profound impacts for ecosystems and human well-being. While repeat surveys separated by multidecadal intervals can determine whether observed shifts are in the expected direction (e.g., poleward or upslope due to climate change), they do not reveal their mechanisms or time scales: whether they were gradual responses to environmental trends or punctuated responses to disturbance events. Here, we document population reductions and temporary range contractions at multiple sites resulting from drought for three Pacific salmonids at their ranges’ trailing edge. During California’s 2012 to 2016 historic multiyear drought, the 2013 to 2014 winter stood apart because rainfall was both reduced and delayed. Extremely low river flows during the breeding season (“flow–phenology mismatch”) reduced or precluded access to breeding habitat. While Chinook ( Oncorhynchus tshawytscha) experienced a down-river range shift, entire cohorts failed in individual tributaries (steelhead trout, O. mykiss ) and in entire watersheds (coho salmon, O. kisutch) . Salmonids returned to impacted sites in subsequent years, rescued by reserves in the ocean, life history diversity, and, in one case, a conservation broodstock program. Large population losses can, however, leave trailing-edge populations vulnerable to extinction due to demographic stochasticity, making permanent range contraction more likely. When only a few large storms occur during high flow season, the timing of particular storms plays an outsized role in determining which migratory fish species are able to access their riverine breeding grounds and persist.
GPT-4o mini: Non-social science research article
Onboard recordings reveal how bats maneuver under severe acoustic interference
Aya Goldshtein, Omer Mazar, Lee Harten, Eran Amichai, Reut Assa, Anat Levi, Yotam Orchan, Sivan Toledo, Ran Nathan, Yossi Yovel
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Echolocating bats rely on active acoustic sensing to perceive their environment. When multiple bats fly together, echolocating simultaneously, the calls emitted by nearby conspecifics could interfere with and mask the echoes necessary for orientation. Nowhere is this impairment of sensing more dramatic than when thousands of bats emerge from a cave at the same time. Here, we tracked the movement of tens of greater mouse-tailed bats flying within a group of thousands. By mounting miniature microphones onboard some of the bats, we monitored the acoustic scene from the point of view of an individual bat within the echolocating collective. We found that bats experienced a very high level of conspecific acoustic masking when emerging from their cave, which dropped within seconds as the bats spread out in space. A comprehensive sensorimotor model, based on the unique data that we collected, revealed how bats content with this severe echo masking almost without collisions. Our results demonstrate that even under severe masking, bats are hardly impaired sensorially, and we suggest how they are able to maneuver smoothly and avoid collisions, even at high densities, without applying a jamming avoidance response.
GPT-4o mini: Non-social science research article
Childhood muscle growth: Reference curves for lower leg muscle volumes and their clinical application in cerebral palsy
Bart Bolsterlee, Brian V. Y. Chow, Jonathan Yu, Suzanne Davies, Catherine Morgan, Caroline D. Rae, David I. Warton, Iona Novak, Ann Lancaster, Gordana C. Popovic, Rodrigo R. N. Rizzo, Claudia Y. Rizzo, Iain K. Ball, Robert D. Herbert
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Skeletal muscles grow substantially during childhood. However, quantitative information about the size of typically developing children’s muscles is sparse. Here, the objective was to construct muscle-specific reference curves for lower leg muscle volumes in children aged 5 to 15 y. Volumes of 10 lower leg muscles were measured from magnetic resonance images of 208 typically developing children and 78 ambulant children with cerebral palsy. Deep learning was used to automatically segment the images. Reference curves for typical childhood muscle volumes were constructed with quantile regression. The median total leg muscle volume of a 15-y-old child is nearly five times that of a 5-y-old child. Between the ages of 5 and 15, boys typically have larger muscles than girls, both in absolute terms (medians are greater by 5 to 20%) and per unit of body weight (1 to 13%). Muscle volumes vary widely between children of a particular age: the range of volumes for the central 80% of the distribution (i.e., between the 10th and 90th centiles) is more than 40% of the median volume. Reference curves for individual muscle volumes have a similar shape to reference curves for total lower leg muscle volume. Confidence bands about the centile curves were wide, especially at the youngest and oldest ages. Nonetheless, the reference curves can be used with confidence to identify small-for-age muscles (centile < 10). We show that 56% of children with cerebral palsy in our cohort had total lower leg muscle volumes that were small-for-age and that 80% had at least one lower leg muscle that was small-for-age.
GPT-4o mini: Non-social science research article
Microparticle impact–induced bond strength in metals peaks with velocity
Qi Tang, Yuji Ichikawa, Mostafa Hassani
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Supersonic impact of metallic microparticles onto metallic substrates generates extreme interfacial deformation and high contact pressures, enabling solid-state metallic bonding. Although higher impact velocities are generally believed to improve bond quality and mechanical properties in materials formed by supersonic impact deposition, here we report a peak in bond strength for single microparticle impact bonding, followed by a decline at higher impact velocities. Our in situ micromechanical measurements of interfacial strength for Al microparticles bonded to Al substrates reveal a three-fold increase from the critical bonding velocity (800 m/s) to a peak strength around 1,060 m/s. Interestingly, further increase in impact velocity results in a rapid decline in local interfacial strength. The decline continues up to the highest velocity studied, 1,337 m/s, which is well below the threshold required to induce melting or erosion. We show that a mechanistic transition from material strengthening to intensified elastic recovery is responsible for the peak strength in impact-induced bonding, with evidence linking the intensified elastic recovery to adiabatic softening at high impact velocities. Beyond 1,000 m/s for Al, interfacial damage induced by the intensified elastic recovery offsets the strength gain from higher impact velocities, resulting in a net decline in interfacial strength. This mechanistic understanding shall offer insights into the optimal design of processes that rely on impact bonding.
GPT-4o mini: Non-social science research article
A mechanically resilient soft hydrogel improves drug delivery for treating post-traumatic osteoarthritis in physically active joints
Nitin Joshi, Jing Yan, Mickael Dang, Kai Slaughter, Yufeng Wang, Dana Wu, Trevor Ung, Nutan Bhingaradiya, Virja Pandya, Mu Xian Chen, Shahdeep Kaur, Sachin Bhagchandani, Haya A. Alfassam, John Joseph, Jingjing Gao, Mahima Dewani, Rachel Wai Chun Chu, Ryan Chak Sang Yip, Eli Weldon, Purna Shah, Nishkal Dhiraj Pisal, Chetan Shukla, Nicholas E. Sherman, James N. Luo, Thomas Conway, James P. Eickhoff, Luis Botelho, Ali H. Alhasan, Jeffrey M. Karp, Joerg Ermann
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Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in the early stages of post-traumatic osteoarthritis (PTOA), when symptoms are minimal, and patients remain physically active. To ensure effective therapy, DMOAD delivery systems therefore must withstand repeated mechanical loading without altering the kinetics of drug release. While soft materials are typically preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt controlled drug release. In this study, we present a mechanically resilient soft hydrogel that rapidly self-heals under conditions simulating human running while maintaining sustained release of the cathepsin-K inhibitor L-006235, used as a proof-of-concept DMOAD. This hydrogel demonstrated superior performance compared to a previously reported hydrogel designed for intra-articular drug delivery, which, in our study, neither recovered its structure nor maintained drug release under mechanical loading. When injected into mouse knee joints, the hydrogel provided consistent release kinetics of the encapsulated drug in both treadmill-running and nonrunning mice. In a mouse model of severe PTOA exacerbated by treadmill-running, the L-006235 hydrogel significantly reduced cartilage degeneration, whereas the free drug did not. Overall, our data underscore the hydrogel’s potential for treating PTOA in physically active patients.
GPT-4o mini: Non-social science research article
Cytoplasmic Mg 2+ supersedes carbon source preference to dictate Salmonella metabolism
Nick D. Pokorzynski, Katarina A. Jones, Shawn R. Campagna, Eduardo A. Groisman
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Glucose is the preferred carbon source of most studied microorganisms. However, we now report that glucose loses preferred status when the intracellular pathogen Salmonella enterica serovar Typhimurium experiences cytoplasmic magnesium (Mg 2+ ) starvation. We establish that this infection-relevant stress drastically reduces synthesis of cyclic adenosine monophosphate (cAMP), the allosteric activator of the cAMP receptor protein (CRP), master regulator of carbon utilization. The resulting reduction in cAMP concentration, which is independent of carbon source, decreases transcription of CRP-cAMP-activated carbon utilization genes, hinders carbon source uptake, and restricts metabolism, rendering wild-type bacteria phenotypically CRP − . A cAMP-independent allele of CRP overcame the transcriptional, uptake, and metabolic restrictions caused by cytoplasmic Mg 2+ starvation and significantly increased transcription of the glucose uptake gene when S. Typhimurium was inside murine macrophages. The reduced preference for glucose exhibited by S. Typhimurium inside macrophages reflects that transcription of the glucose uptake gene requires higher amounts of active CRP-cAMP than transcription of uptake genes for preferred carbon sources, such as gluconate and glycerol. By reducing CRP-cAMP activity, low cytoplasmic Mg 2+ alters carbon source preference, adjusting metabolism and growth.
GPT-4o mini: Non-social science research article
Intravital imaging of translocated bacteria via fluorogenic labeling of gut microbiota in situ
Xinqi Fan, Yingjun Zhou, Wenjuan Bai, Xue Li, Liyuan Lin, Huibin Lin, Ming Yang, Xiaofei Yu, Jing Wang, Liang Lin, Wei Wang
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The translocation of bacteria from intestinal tracts into blood vessels and distal organs plays pivotal roles in the pathogenesis of numerous severe diseases. Intravital monitoring of bacterial translocation, however, is not yet feasible, which greatly hinders us from comprehending this spatially and temporally dynamic process. Here we report an in vivo fluorogenic labeling method, which enables in situ imaging of mouse gut microbiota and real-time tracking of the translocated bacteria. By mimicking the peptidoglycan stem peptide in bacteria, a tetrapeptide probe composed of alternating D- and L-amino acids and separately equipped with a fluorophore and a quencher on the N- and C-terminal amino acid, is designed. Because of its resistance to host proteases, it can be directly used in gavage and achieves fluorogenic labeling of the microbiota in the gut via the functioning of the L,D-transpeptidases of the labeled bacteria. Using intravital two-photon microscopy, we then successfully visualize the translocation of gut bacteria into the bloodstream and liver in obesity mouse models. This technique can help further exploration into the spatiotemporal activities of gut microbiota in vivo, and be valuable in investigating the less understood pathogenicity of bacterial translocation in many severe diseases.
GPT-4o mini: Non-social science research article
Dopaminergic neurons in the paraventricular hypothalamus extend the food consumption phase
Winda Ariyani, Chiharu Yoshikawa, Haruka Tsuneoka, Izuki Amano, Itaru Imayoshi, Hiroshi Ichinose, Chiho Sumi-Ichinose, Noriyuki Koibuchi, Tadahiro Kitamura, Daisuke Kohno
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Feeding behavior is controlled by various neural networks in the brain that are involved in different feeding phases: Food procurement, consumption, and termination. However, the specific neural circuits controlling the food consumption phase remain poorly understood. Here, we investigated the roles of dopaminergic neurons in the paraventricular nucleus of the hypothalamus (PVH) in the feeding behavior in mice. Our results indicated that the PVH dopaminergic neurons were critical for extending the food consumption phase and involved in the development of obesity through epigenetic mechanisms. These neurons synchronized with proopiomelanocortin neurons during consumption, were stimulated by proopiomelanocortin activation, and projected to the lateral habenula (LHb), where dopamine receptor D2 was involved in the increase in food consumption. In addition, upregulated tyrosine hydroxylase (TH) expression in PVH was associated with obesity and indispensable for obesity induction in mice lacking Dnmt3a . Taken together, our results highlight the roles of PVH dopaminergic neurons in promoting food consumption and obesity induction.
GPT-4o mini: Non-social science research article
Cholesterol-dependent enzyme activity of human TSPO1
Weihua Qiu, Thi Kim Hoang Trinh, Claudio Catalano, Akul Mehta, Umesh R. Desai, Glen E. Kellogg, Wayne A. Hendrickson, Youzhong Guo
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The amino acid sequence of the tryptophan-rich sensory proteins (TSPO) is substantially conserved throughout all kingdoms of life. Human mitochondrial TSPO1 ( Hs TSPO1) binds to porphyrins and steroids, although its interactions with these molecules remains unknown. Hs TSPO1 is associated with numerous physiological and pathological disorders, but the underlying molecular mechanisms are unknown. Here, we disclose the finding of human mitochondrial TSPO as a cholesterol-dependent protoporphyrin IX oxygenase. The results of our biochemical characterization are consistent with structural data and evolutionary analysis. The dependence of Hs TSPO1 activity on cholesterol may be the result of the coevolution of this membrane protein with the membrane system. Our study provides a molecular foundation for comprehending the various roles played by mitochondrial TSPO in normal physiological and pathological situations.
GPT-4o mini: Non-social science research article
Manipulation of interoceptive signaling biases decision making in rhesus macaques
Michael A. Cardenas, Ryan P. Le, Tess M. Champ, Derek O’Neill, Andrew J. Fuglevand, Katalin M. Gothard
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Several influential theories have proposed that interoceptive signals, sent from the body to the brain, contribute to neural processes that coordinate complex behaviors. We altered the physiological state of the body using compounds that have minimal effect on the brain and evaluated their effect on decision making in rhesus monkeys. We used glycopyrrolate, a nonspecific muscarinic (parasympathetic) antagonist, and isoproterenol, a beta-1/2 (sympathetic) agonist, to create a sympathetic-dominated state in the periphery, that was indexed by increased heart rate. Rhesus monkeys were trained on two variants of an approach-avoidance conflict task. The tasks offered a choice between enduring mildly aversive stimuli in exchange for a steady flow of rewards, or canceling the aversive stimuli, forgoing the rewards. The latency to interrupt the aversive stimuli was used as a measure of monkeys’ tolerance for contact with a hot but not painful stimulus or airflow directed at their muzzle. Both drugs reduced tolerance for the aversive stimuli. To determine whether the drug-induced autonomic state reduced the subjective value of the reward, we tested the effects of glycopyrrolate on a food preference task. Food preference was unaltered, suggesting that the sympathetic dominated state in the periphery selectively reduces tolerance for aversive stimuli without altering reward-seeking behaviors. As the drugs used are expected to have little or no direct effect on the brain, the observed biases in decision making are likely induced by interoceptive afferents that signal to the brain the physiological state of the body.
GPT-4o mini: Non-social science research article
Bayesian inference by visuomotor neurons in the prefrontal cortex
Thomas A. Langlois, Julie A. Charlton, Robbe L. T. Goris
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Perceptual judgments of the environment emerge from the concerted activity of neural populations in decision-making areas downstream of the sensory cortex. When the sensory input is ambiguous, perceptual judgments can be biased by prior expectations shaped by environmental regularities. These effects are examples of Bayesian inference, a reasoning method in which prior knowledge is leveraged to optimize uncertain decisions. However, it is not known how decision-making circuits combine sensory signals and prior expectations to form a perceptual decision. Here, we study neural population activity in the prefrontal cortex of macaque monkeys trained to report perceptual judgments of ambiguous visual stimuli under two different stimulus distributions. We isolate the component of the neural population response that represents the formation of the perceptual decision (the decision variable, DV), and find that its dynamical evolution reflects the integration of sensory signals and prior expectations. Prior expectations impact the DV’s trajectory both before and during stimulus presentation such that DV trajectories with a smaller dynamic range result in more biased and less sensitive perceptual decisions. We show that these results resemble a specific variant of Bayesian inference known as approximate hierarchical inference. Our findings expand our understanding of the mechanisms by which prefrontal circuits can execute Bayesian inference.
GPT-4o mini: Non-social science research article
Rolling vesicles: From confined rotational flows to surface-enabled motion
Paula Magrinya, Pablo Palacios-Alonso, Pablo Llombart, Rafael Delgado-Buscalioni, Alfredo Alexander-Katz, Laura R. Arriaga, Juan L. Aragones
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Friction forces are essential for cell movement, yet they also trigger numerous active cellular responses, complicating their measurement in vivo. Here, we introduce a synthetic model designed to measure friction forces between biomimetic membranes and substrates. The model consists of a vesicle with precisely controlled properties, fabricated via microfluidics, encapsulating a single ferromagnetic particle that is magnetically driven to rotate. The rotation of the particle generates a confined rotational flow, setting the vesicle membrane into motion. By adjusting the magnetic field frequency and vesicle size, the rotation frequency of the vesicle can be finely controlled, resulting in a rolling vesicle that functions as an effective tribological tool across a wide frequency range. At low frequencies, molecular contact between the membrane and substrate dominates frictional interactions, which enables determination of the contact friction coefficient. At higher frequencies, lubrication becomes predominant, causing the vesicles to slip rather than roll. Adjusting membrane fluidity and incorporating specific ligand–receptor interactions within this model will enable detailed studies of frictional forces in more complex biomimetic systems, providing key insights into the mechanisms of cell movement and mechanotransduction.
GPT-4o mini: Non-social science research article
Structure of ATP synthase from an early photosynthetic bacterium Chloroflexus aurantiacus
Xin Zhang, Jingyi Wu, Zhenzhen Min, Jiamao Wang, Xin Hong, Xinkai Pei, Zihe Rao, Xiaoling Xu
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F-type ATP synthase (F 1 F O ) catalyzes proton motive force-driven ATP synthesis in mitochondria, chloroplasts, and bacteria. Different from the mitochondrial and bacterial enzymes, F 1 F O from photosynthetic organisms have evolved diverse structural and mechanistic details to adapt to the light-dependent reactions. Although complete structure of chloroplast F 1 F O has been reported, no high-resolution structure of an F 1 F O from photosynthetic bacteria has been available. Here, we report cryo-EM structures of an intact and functionally competent F 1 F O from Chloroflexus aurantiacus ( Ca F 1 F O ), a filamentous anoxygenic phototrophic bacterium from the earliest branch of photosynthetic organisms. The structures of Ca F 1 F O in its ADP-free and ADP-bound forms for three rotational states reveal a previously unrecognized architecture of ATP synthases. A pair of peripheral stalks connect to the Ca F 1 head through a dimer of ή-subunits, and associate with two membrane-embedded a-subunits that are asymmetrically positioned outside and clamp Ca F O ’s c 10 -ring. The two a-subunits constitute two proton inlets on the periplasmic side and two proton outlets on the cytoplasmic side, endowing Ca F 1 F O with unique proton translocation pathways that allow more protons being translocated relative to single a-subunit F 1 F O . Our findings deepen understanding of the architecture and proton translocation mechanisms of F 1 F O synthases and suggest innovative strategies for modulating their activities by altering the number of a-subunit.
GPT-4o mini: Non-social science research article
In situ cavitation bubble manometry reveals a lack of light-activated guard cell turgor modulation in bryophytes
Craig R. Brodersen, Tim J. Brodribb, Uri Hochberg, N. Michele Holbrook, Scott A. M. McAdam, Joseph Zailaa, Brett A. Huggett, Philippe Marmottant
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Diversification of plant hydraulic architecture and stomatal function coincides with radical changes in the Earth’s atmosphere over the past 400 my. Due to shared stomatal anatomy with the earliest land plants, bryophyte stomatal behavior may provide insights into the evolution of stomatal function, but significant uncertainty remains due to technical limitations of measuring guard cell turgor pressure in situ. Here, we introduce a method for monitoring cell turgor pressure by nucleating microbubbles within the guard cells of intact plant tissue and then examining microbubble growth and dissolution dynamics. First, we show that maximum microbubble radius decreases with increasing pressure as the pressure of the surrounding fluid constrains its growth according to a modified version of the Epstein–Plesset equation. We then apply this method to monitor turgor pressure in dark- vs. light-acclimated guard cells across bryophyte taxa with stomata, where their role in gas-exchange remains ambiguous, and in vascular plants with well-documented light-dependent turgor modulation. Our findings show no light-activated change in turgor in bryophyte guard cells, with pressures not significantly different than neighboring epidermal cells. In contrast, vascular plants show distinct pressure modulation in response to light that drives reversible changes in stomatal aperture. Complete guard cell turgor loss had no effect on bryophyte stomatal aperture but resulted in partial or complete closure in vascular plants. These results suggest that despite conserved stomatal morphology, the sampled bryophytes lack dynamic control over guard cell turgor that is critical for sustaining photosynthesis and inhibiting desiccation.
GPT-4o mini: Non-social science research article
An atlas of protein phosphorylation dynamics during interferon signaling
Idoia Busnadiego, Marie Lork, Sonja Fernbach, Samira Schiefer, Nikos Tsolakos, Benjamin G. Hale
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Interferons (IFNs, types I-III) have pleiotropic functions in promoting antiviral and antitumor responses, as well as in modulating inflammation. Dissecting the signaling mechanisms elicited by different IFNs is therefore critical to understand their phenotypes. Here, we use mass spectrometry to investigate the early temporal dynamics of cellular protein phosphorylation in a human lung epithelial cell-line as it responds to stimulation with IFNα2, IFNÎČ, IFNω, IFNÎł, or IFNλ1, representing all IFN types. We report an atlas of over 700 common or unique phosphorylation events reprogrammed by these different IFNs, revealing both previously known and uncharacterized modifications. While the proteins differentially phosphorylated following IFN stimulation have diverse roles, there is an enrichment of factors involved in chromatin remodeling, transcription, and RNA splicing. Functional screening and mechanistic studies identify that several proteins modified in response to IFNs contribute to host antiviral responses, either directly or by supporting IFN-stimulated gene or protein production. Among these, phosphorylation of PLEKHG3 at serine-1081 creates a phospho-regulated binding motif for the docking of 14-3-3 proteins, and together these factors contribute to coordinating efficient IFN-stimulated gene expression independent of early Janus kinase/signal transducer and activator of transcription signaling. Our findings map the global phosphorylation landscapes regulated by IFN types I, II, and III, and provide a key resource to explore their functional consequences.
GPT-4o mini: Non-social science research article
Potassium-sensitive loss of muscle force in the setting of reduced inward rectifier K + current: Implications for Andersen–Tawil syndrome
Nathaniel Elia, Marbella Quiñonez, Fenfen Wu, Ekaterina Mokhonova, Marino DiFranco, Melissa J. Spencer, Stephen C. Cannon
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Andersen–Tawil syndrome (ATS) is an ion channelopathy with variable penetrance for the triad of periodic paralysis, arrhythmia, and dysmorphia. Dominant-negative mutations of KCNJ2 encoding the Kir2.1 potassium channel subunit are found in 60% of ATS families. As with most channelopathies, episodic attacks in ATS are frequently triggered by environmental stresses: exercise for periodic paralysis or stress with adrenergic stimulation for arrhythmia. Fluctuations in K + , either low or high, are potent triggers for attacks of weakness in other variants of periodic paralysis (hypokalemic periodic paralysis or hyperkalemic periodic paralysis). For ATS, the [K + ] dependence is less clear; with reports describing weakness in high-K + or low-K + . Patient trials with controlled K + challenges are not possible, due to arrhythmias. We have developed two mouse models (genetic and pharmacologic) with reduced Kir currents, to address the question of K + -sensitive loss of force. These animal models and computational simulations both show K + -dependent weakness occurs only when Kir current is <30% of wildtype. As the Kir deficit becomes more severe, the phenotype shifts from high-K + -induced weakness to a combination where either high-K + or low-K + triggers weakness. A K + channel agonist, retigabine, protects muscle from K + -sensitive weakness in our mouse models of the skeletal muscle involvement in ATS.
GPT-4o mini: Non-social science research article
Bridging the human–AI knowledge gap through concept discovery and transfer in AlphaZero
Lisa Schut, Nenad TomaĆĄev, Thomas McGrath, Demis Hassabis, Ulrich Paquet, Been Kim
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AI systems have attained superhuman performance across various domains. If the hidden knowledge encoded in these highly capable systems can be leveraged, human knowledge and performance can be advanced. Yet, this internal knowledge is difficult to extract. Due to the vast space of possible internal representations, searching for meaningful new conceptual knowledge can be like finding a needle in a haystack. Here, we introduce a method that extracts new chess concepts from AlphaZero, an AI system that mastered chess via self-play without human supervision. Our method excavates vectors that represent concepts from AlphaZero’s internal representations using convex optimization, and filters the concepts based on teachability (whether the concept is transferable to another AI agent) and novelty (whether the concept contains information not present in human chess games). These steps ensure that the discovered concepts are useful and meaningful. For the resulting set of concepts, prototypes (chess puzzle–solution pairs) are presented to experts for final validation. In a preliminary human study, four top chess grandmasters (all former or current world chess champions) were evaluated on their ability to solve concept prototype positions. All grandmasters showed improvement after the learning phase, suggesting that the concepts are at the frontier of human understanding. Despite the small scale, our result is a proof of concept demonstrating the possibility of leveraging knowledge from a highly capable AI system to advance the frontier of human knowledge; a development that could bear profound implications and shape how we interact with AI systems across many applications.
GPT-4o mini: Non-social science research article
Cancer-associated SF3B1 mutation K700E causes widespread changes in U2/branchpoint recognition without altering splicing
Andrey Damianov, Chia-Ho Lin, Jian Zhang, James L. Manley, Douglas L. Black
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Myelodysplastic syndromes and other cancers are often associated with mutations in the U2 snRNP protein SF3B1. Common SF3B1 mutations, including K700E, disrupt SF3B1 interaction with the protein SUGP1 and induce aberrant activation of alternative 3â€Č splice sites (ss), presumably resulting from aberrant U2/branch site (BS) recognition by the mutant spliceosome. Here, we apply a method of U2 IP-seq to profile BS binding across the transcriptome of K562 leukemia cells carrying the SF3B1 K700E mutation. For alternative 3â€Č ss activated by K700E, we identify their associated BSs and show that they are indeed shifted from the WT sites. Unexpectedly, we also identify thousands of additional changes in BS binding in the mutant cells that do not alter splicing. These new BSs are usually very close to the natural sites, occur upstream or downstream, and either exhibit stronger base-pairing potential with U2 snRNA or are adjacent to stronger polypyrimidine tracts than the WT sites. The widespread imprecision in BS recognition induced by K700E with limited changes in 3â€Č ss selection expands the physiological consequences of this oncogenic mutation.
GPT-4o mini: Non-social science research article
Mechanistic insights into dengue virus inhibition by a clinical trial compound NITD-688
Yan Wang, Long Sun, Luciana Fernandes, Yu-Hsiu Wang, Jing Zou, Samuel J. Franklin, Yanping Hu, Lee K. Palmer, Jason Yeung, Daniela Barriga, William K. Russell, Stephanie A. Moquin, Pei-Yong Shi, Colin Skepper, Xuping Xie
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Dengue, caused by the dengue virus (DENV), presents a significant public health challenge with limited effective treatments. NITD-688 is a potent panserotype DENV inhibitor currently in Phase II clinical trials. However, its mechanism of action is not fully understood. Here, we present the molecular details of how NITD-688 inhibits DENV. NITD-688 binds directly to the nonstructural protein 4B (NS4B) with nanomolar affinities across all four DENV serotypes and specifically disrupts the interaction between NS4B and nonstructural protein 3 (NS3) without significantly changing the interactions between NS4B and other viral or host proteins. NS4B mutations that confer resistance to NITD-688 reduce both NITD-688 binding to NS4B and disruption of the NS4B/NS3 interaction. Specifically, NITD-688 blocks the interaction of NS3 with a cytosolic loop within NS4B. This inhibits the formation of new NS4B/NS3 complexes and disrupts preexisting complexes in vitro and DENV-infected cells, ultimately inhibiting viral replication. Consistent with this mechanism, NITD-688 retains greater potency in cellular assays with delayed treatment compared to JNJ-1802, another NS4B inhibitor that has been studied in Phase II clinical trials. Together, these findings provide critical insights into the mechanism of action of NITD-688, facilitating the development of novel flavivirus NS4B inhibitors and informing future clinical interventions against DENV.
GPT-4o mini: Non-social science research article
Modulation of host gene expression by the zinc finger antiviral protein
Daniel Gonçalves-Carneiro, Emily Mastrocola, Xiao Lei, Paul D. Bieniasz
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The zinc finger antiviral protein (ZAP) depletes nonself RNAs through recognition of their elevated CpG dinucleotide content. CpG dinucleotides are sparse in most endogenous mammalian mRNAs, but a subset might potentially be modulated by ZAP. While CpG frequency alone is insufficient to predict ZAP-regulation, we developed an algorithm using experimentally determined compositional features to predict which endogenous mRNAs may be ZAP-regulated. Using ZAP-knockout mice, we demonstrate that levels of many host mRNAs that are algorithmically predicted ZAP targets are indeed increased when ZAP is absent. ZAP is interferon-inducible, and we also identify genes that are downregulated by ZAP during an innate immune response. Many ZAP-regulated gene products are extracellular matrix or of nucleosome components, whose ZAP-mediated control is conserved in human cells. Overall, we provide a tool for the prediction of ZAP target genes and reveal host mRNAs that are ZAP-regulated.
GPT-4o mini: Non-social science research article
Painting rich six-dimensional pictures using polarized fluorescence microscopy
Matthew D. Lew
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GPT-4o mini: Non-social science research article
Peto’s paradox revisited (revisited, revisited, revisited, and revisited yet again)
Vincent J. Lynch
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GPT-4o mini: Non-social science research article
Enamel–dentine junction morphology reveals population replacement and mobility in the late prehistoric Middle Nile Valley
Nicolas Martin, Adrien Thibeault, Lenka VaradzinovĂĄ, Donatella Usai, Stanley H. Ambrose, Daniel Antoine, Petra Brukner HavelkovĂĄ, Matthieu Honegger, Joel D. Irish, Friederike Jesse, Laura MarĂ©chal, Marta OsypiƄska, Piotr OsypiƄski, FrĂ©dĂ©ric Santos, Nicolas Vanderesse, Ladislav Varadzin, Rebecca J. Whiting, ClĂ©ment Zanolli, Petr VelemĂ­nskĂœ, Isabelle Crevecoeur
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Transitions from foraging to food-production represent a worldwide turning point in recent human history. In the Middle Nile Valley this cultural shift occurred between the sixth and beginning of the fifth millennium BCE. Significant craniodental morphological differences remain inadequately tested by biometric analyses of ancestry and may reflect population origins or diet change between the last hunter-fisher-gatherers (Mesolithic) and first food-producers (Neolithic). Moreover, with no ancient DNA data for this region and very few morphological studies including large samples of Mesolithic individuals, the late prehistoric population history of the Nile Valley remains unclear. Here, we present enamel–dentine junction (EDJ) morphological analyses (based on X-ray microtomography) and biological affinities for 88 individuals spanning 14,000 y from Sudan and southern Egypt. Significant EDJ morphological differences between the last foragers and first food-producers suggest major biological discontinuity at the Neolithic transition. Nevertheless, the persistence of the earlier forager population in the Sudanese Eastern Sahara indicates settlement and population replacement mainly along the Nile. We also present biological evidence of interaction and mobility between these contemporaneous populations during the middle Holocene in the region. It supports the phylogenetic value of EDJ morphology for investigating population affinities at a microevolutionary scale. These results yield insights into the deep population history of the Nile Valley. They provide firm evidence for population replacement and migration toward the region at the onset of the Neolithic transition, attesting that these key changes were not solely triggered by cultural diffusion and diet change.
GPT-4o mini: Non-social science research article
Validating new limits for human thermoregulation
Robert D. Meade, Fergus K. O’Connor, Brodie J. Richards, Emily J. Tetzlaff, Katie E. Wagar, Roberto C. Harris-Mostert, Theodore Egube, James J. McCormick, Glen P. Kenny
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Recent projections suggest that large geographical areas will soon experience heat and humidity exceeding limits for human thermoregulation. The survivability limits modeled in that research were based on laboratory studies suggesting that humans cannot effectively thermoregulate in wet bulb temperatures (T wb ) above 26 to 31 °C, values considerably lower than the widely publicized theoretical threshold of 35 °C. The newly proposed empirical limits were derived from the T wb corresponding to the core temperature inflection point in participants exposed to stepped increases in air temperature or relative humidity in a climate-controlled chamber. Despite the increasing use of these thermal-step protocols, their validity has not been established. We used a humidity-step protocol to estimate the T wb threshold for core temperature inflection in 12 volunteers. To determine whether this threshold truly demarcates the T wb above which thermoregulation is impossible, each participant was subsequently exposed to T wb above (~33.7 °C, T above ) and below (~30.9 °C, T below ) their respective inflection point (~32.3 °C, T wb ) for up to 9 h (in random order). Core temperature rose continuously in T above . It was projected that core temperatures associated with heat stroke (40.2 °C) would occur within 10 h. While T below was also uncompensable, the core temperature rate of rise was considerably lower than in T above such that it would take >24 h to reach 40.2 °C. Our study supports thermal-step protocols as an effective technique for evaluating survivability limits for heat exposure and provides a direct assessment of the limits of human thermoregulation.
GPT-4o mini: Non-social science research article
Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination
Jinchao Hou, Roberta Magliozzi, Yun Chen, Junjie Wu, John Wulf, Gregory Strout, Xiangming Fang, Marco Colonna
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We investigated the role of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in myelin regeneration in the brain. TREM2 is a receptor that activates microglia, which are crucial for clearing myelin debris and promoting remyelination. Previous studies in a mouse model of demyelination induced by the copper-chelating agent Cuprizone (CPZ) have shown that stimulation of TREM2 with a monoclonal antibody reduces demyelination, while deleting the Trem2 gene in mice impairs remyelination. Here, we blocked TREM2 function acutely with an antibody during both the demyelination and remyelination phases of the CPZ model and analyzed the impact of the antibody treatment on myelination and gene expression in single cells. We found that blocking TREM2 depleted a distinct population of microglia with high expression of the transcription factor MAFB during remyelination. The loss of these MAFB-high microglia was linked to impaired generation of myelinating oligodendrocytes. Importantly, we identified MAFB + microglia in acute and acute-chronic brain lesions from individuals with multiple sclerosis (MS), but not in inactive lesions. We conclude that TREM2 is essential for maintaining a population of MAFB-high microglia that is associated with myelin repair. This finding has significant implications for understanding demyelinating diseases like MS and suggests that stimulating TREM2 could be a promising therapeutic approach for myelin repair.
GPT-4o mini: Non-social science research article
Discovery and functional characterization of a bombesin-type neuropeptide signaling system in an invertebrate
Weiling Huang, Xingxing Zhong, Cleidiane G. Zampronio, Andrew R. Bottrill, Kite G. E. Jones, Ana B. Tinoco, Lijin Guo, Michaela EgertovĂĄ, Olivier Mirabeau, Maurice R. Elphick
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Neuropeptide signaling systems are key regulators of physiological and behavioral processes in animals. However, the evolutionary history of some neuropeptides originally discovered in vertebrates is unknown. The peptide bombesin (BN) was first isolated from the skin of the toad Bombina bombina and subsequently BN-related neuropeptides have been identified in other chordates, including gastrin-releasing peptide (GRP) and neuromedin B (NMB) in mammals, and a GRP-like peptide in the cephalochordate Branchiostoma japonicum . However, BN-type neuropeptides have hitherto not been identified in any nonchordate animals. Here, we report the discovery and functional characterization of a BN-type neuropeptide signaling system in an echinoderm—the starfish Asterias rubens . BN-type precursor proteins were identified in several echinoderm species based on their amino acid sequences and gene structures, and the mature structure of the A. rubens BN-type neuropeptide ArBN was determined using mass spectrometry. A protein related to vertebrate GRP/NMB-type G protein–coupled receptors was identified experimentally as the receptor for ArBN in A. rubens . Analysis of the distribution of the ArBN precursor in A. rubens using mRNA in situ hybridization and immunohistochemistry revealed a widespread pattern of expression in the central nervous system, digestive system, and locomotory organs. Moreover, effects of ArBN in A. rubens included contraction and retraction of the evertible stomach and inhibition of feeding behavior. Our findings show that the evolutionary history of BN-type neuropeptide signaling can be traced back to the deuterostome common ancestor of echinoderms and chordates. Furthermore, an ancient role of BN-type neuropeptides as regulators of feeding behavior has been revealed.
GPT-4o mini: Non-social science research article
Linear Recursive Feature Machines provably recover low-rank matrices
Adityanarayanan Radhakrishnan, Mikhail Belkin, Dmitriy Drusvyatskiy
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A fundamental problem in machine learning is to understand how neural networks make accurate predictions, while seemingly bypassing the curse of dimensionality. A possible explanation is that common training algorithms for neural networks implicitly perform dimensionality reduction—a process called feature learning. Recent work [A. Radhakrishnan, D. Beaglehole, P. Pandit, M. Belkin, Science 383 , 1461–1467 (2024).] posited that the effects of feature learning can be elicited from a classical statistical estimator called the average gradient outer product (AGOP). The authors proposed Recursive Feature Machines (RFMs) as an algorithm that explicitly performs feature learning by alternating between 1) reweighting the feature vectors by the AGOP and 2) learning the prediction function in the transformed space. In this work, we develop theoretical guarantees for how RFM performs dimensionality reduction by focusing on the class of overparameterized problems arising in sparse linear regression and low-rank matrix recovery. Specifically, we show that RFM restricted to linear models (lin-RFM) reduces to a variant of the well-studied Iteratively Reweighted Least Squares (IRLS) algorithm. Furthermore, our results connect feature learning in neural networks and classical sparse recovery algorithms and shed light on how neural networks recover low rank structure from data. In addition, we provide an implementation of lin-RFM that scales to matrices with millions of missing entries. Our implementation is faster than the standard IRLS algorithms since it avoids forming singular value decompositions. It also outperforms deep linear networks for sparse linear regression and low-rank matrix completion.
GPT-4o mini: Non-social science research article
Quina lithic technology indicates diverse Late Pleistocene human dynamics in East Asia
Qi-Jun Ruan, Hao Li, Pei-Yuan Xiao, Bo Li, HĂ©lĂšne Monod, Alexandra Sumner, Ke-Liang Zhao, Jian-Hui Liu, Zhen-Xiu Jia, Chun-Xin Wang, An-Chuan Fan, Marie-HĂ©lĂšne Moncel, Ben Marwick, Marco Peresani, You-Ping Wang, Fa-Hu Chen, Davide Delpiano
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The Late Pleistocene of Eurasia is key for understanding interactions between early modern humans and different types of archaic human groups. During this period, lithic technology shows more diversity and complexity, likely indicating flexible adaptative strategies. However, cultural variability as expressed by technological types remains vague in large parts of eastern Eurasia, like in China. Here, we report a complete Quina technological system identified from the study of the Longtan site in Southwest China. The site has been securely dated to ca. 60 to 50 thousand years ago (ka), with compelling evidence of core exploitation, production of large and thick flakes, shaping and maintenance of scrapers exhibiting the whole Quina concept, typical of contemporary European Middle Paleolithic technologies developed by Neanderthal groups adapted to climatic oscillations during Marine Isotope Stage (MIS) 4 and early MIS 3. The finding of a Quina lithic assemblage in China not only demonstrates the existence of a Middle Paleolithic technology in the region but also shows large-scale analogies with Neanderthal behaviors in western Europe. Longtan substantially extends the geographic distribution of this technical behavior in East Asia. Although its origin remains unclear, implications for Pleistocene hominin dispersal and adaptation to diverse ecological settings are considered. The Longtan lithic evidence also provides perspectives for understanding the cultural evolutionary situation before the large-scale arrivals of early modern humans in East Asia predating ~45 ka.
GPT-4o mini: Non-social science research article
Cotranslational membrane insertion of the voltage-sensitive K + channel KvAP
Justin M. Westerfield, Petra KozojedovĂĄ, Cara Juli, Ane Metola, Gunnar von Heijne
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Voltage-sensor domains (VSDs), found in many voltage-sensitive ion channels and enzymes, are composed of four transmembrane helices (TMHs), including the atypical, highly positively charged S4 helix. VSDs are cotranslationally inserted into the membrane, raising the question of how the highly charged S4 helix is integrated into the lipid bilayer as it exits the ribosome. Here, we have used force profile analysis (FPA) to follow the cotranslational insertion of the six-TMH KvAP voltage-sensitive ion channel into the Escherichia coli inner membrane. We find that the insertion process proceeds through three semi-independent steps: i) insertion of the S1-S2 helix hairpin, ii) insertion of the S3-S5 helices, and iii) insertion of the Pore and S6 helices. Our analysis highlights the importance of the concerted insertion of helical hairpins, the dramatic influence of the positively charged residues in S4, and the unexpectedly strong forces and effects on downstream TMHs elicited by amphipathic and re-entrant helices.
GPT-4o mini: Non-social science research article
Reconciling ecology and evolutionary game theory or “When not to think cooperation”
Corina E. Tarnita, Arne Traulsen
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Evolutionary game theory (EGT)—overwhelmingly employed today for the study of cooperation in various systems, from microbes to cancer and from insect to human societies—started with the seminal 1973 paper by Maynard Smith and Price showing that limited animal conflict can be selected at the individual level. Owing to the explanatory potential of this paper and enabled by the powerful machinery of the soon-to-be-developed replicator dynamics, EGT took off at an accelerated pace and began to shape expectations across systems and scales. But, even as EGT has expanded its reach, and even as its mathematical foundations expanded with the development of adaptive dynamics and inclusion of stochastic processes, the replicator equation remains, half a century later, its most widely used equation. Owing to its early development and its staying power, the replicator dynamics has helped set both the baseline expectations and the terminology of the field. However, much like the original 1973 paper, replicator dynamics rests on the assumption that individual differences in reproduction are determined only by the payoff from the game (i.e., in isolation, all individuals, regardless of their strategy, have identical intrinsic growth rates). Here, we argue that this assumption limits the scope of replicator dynamics to such an extent as to warrant not just a more deliberative application process, but also a reconsideration of the broad predictions and terminology that it has generated. Simultaneously, we reestablish a dialog with ecology that can be mutually fruitful, e.g., by providing an explanation for how diverse ecological communities can assemble evolutionarily.
GPT-4o mini: Non-social science research article
Single cell–resolved cellular, transcriptional, and epigenetic changes in mouse T cell populations linked to age-associated immune decline
Jing He, Elena Burova, Chandrika Taduriyasas, Min Ni, Christina Adler, Yi Wei, Nicole Negron, Kun Xiong, Yu Bai, Tea Shavlakadze, Ella Ioffe, John C. Lin, Adolfo Ferrando, David J. Glass
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Splenic T cells are pivotal to the immune system, yet their function deteriorates with age. To elucidate the specific aspects of T cell biology affected by aging, we conducted a comprehensive multi–time point single-cell RNA sequencing study, complemented by single-cell Assay for Transposase Accessible Chromatin (ATAC) sequencing and single-cell T cell repertoire (TCR) sequencing on splenic T cells from mice across 10 different age groups. This map of age-related changes in the distribution of T cell lineages and functional states reveals broad changes in T cell function and composition, including a prominent enrichment of Gzmk+ T cells in aged mice, encompassing both CD4+ and CD8+ T cell subsets. Notably, there is a marked decrease in TCR diversity across specific T cell populations in aged mice. We identified key pathways that may underlie the perturbation of T cell functions with aging, supporting cytotoxic T cell clonal expansion with age. This study provides insights into the aging process of splenic T cells and also highlights potential targets for therapeutic intervention to enhance immune function in the elderly. The dataset should serve as a resource for further research into age-related immune dysfunction and for identifying potential therapeutic strategies.
Meltdown of trust in weakly governed economies
Stephen Polasky, Marten Scheffer, John M. Anderies
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A well-functioning society requires well-functioning institutions that ensure prosperity, fair distribution of wealth, social participation, security, and informative media. Such institutions are built on a foundation of trust. However, while trust is essential for economic success and good governance, interconnected mechanisms inherent in weakly governed market economies tend to undermine the very trust on which such success depends. These mechanisms include the intrinsic tendency for inequality to grow, media to boost perceived unfairness, and self-interest to gain rewards at the expense of others. These mechanisms, if left unchecked, allow wealth concentration to result in state capture where institutions facilitate further wealth concentration instead of the promoting the common good. As a result, people may become alienated and untrusting of fellow citizens and of institutions. Several democracies now experience such dynamics, the United States being a prime example. We discuss ways in which well-functioning democracies can design institutions to help avoid this social trap, and the much harder challenge of escaping the trap once in it. Successful cases such as the ability of Scandinavian democracies to maintain high-trust, and the US progressive era in the early 20th century provide instructive examples.
Removing masculine defaults in the hiring process
Sapna Cheryan, Gregg A. Muragishi
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Climate change impacts have potentially big repercussions for kids’ education
Saima Sidik
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Belief in belief: Even atheists in secular countries show intuitive preferences favoring religious belief
Will M. Gervais, Ryan T. McKay, Jazmin L. Brown-Iannuzzi, Robert M. Ross, Gordon Pennycook, Jonathan Jong, Jonathan A. Lanman
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We find evidence of belief in belief —intuitive preferences for religious belief over atheism, even among atheist participants—across eight comparatively secular countries. Religion is a cross-cultural human universal, yet explicit markers of religiosity have rapidly waned in large parts of the world in recent decades. We explored whether intuitive religious influence lingers, even among nonbelievers in largely secular societies. We adapted a classic experimental philosophy task to test for this intuitive belief in belief among people in eight comparatively nonreligious countries: Canada, China, Czechia, Japan, the Netherlands, Sweden, the United Kingdom, and Vietnam (total N = 3,804). Our analyses revealed strong evidence that 1) people intuitively favor religious belief over atheism and that 2) this pattern was not moderated by participants’ own self-reported atheism. Indeed, 3) even atheists in relatively secular societies intuitively prefer belief to atheism. These inferences were robust across different analytic strategies and across other measures of individual differences in religiosity and religious instruction. Although explicit religious belief has rapidly declined in these countries, it is possible that belief in belief may still persist. These results speak to the complex psychological and cultural dynamics of secularization.
Most Christian American religious leaders silently believe in climate change, and informing their congregation can help open dialogue
Stylianos Syropoulos, Gregg Sparkman
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Religious leaders shape the attitudes and beliefs of their congregations. In a nationally representative sample of U.S. religious leaders ( N = 1,600), the majority of which were of a Christian faith, we find that nearly 90% believe in anthropogenic climate change to some degree. From this 90%, a total of 60% believe humans play a major role and an additional 30% believe they play a role, but a more minor one. Yet roughly half have never discussed it with their congregation, and only a quarter have mentioned it more than once or twice. In a sample of Christian Americans representative of the proportions of major national denominations ( N = 987), we find that Christians underestimate the prevalence of their leaders who believe in climate change by 39 to 45 percentage points. Conversely, having a religious leader who talks about climate change predicts greater willingness to discuss it with fellow churchgoers and attend climate events. In an experimental intervention on another sample matching major Christian American denomination ( N = 959), we find that providing the actual consensus level of religious leaders’ belief in climate change reduces congregants’ misperception of religious leaders, increases their perception that other church members believe in and are open to discussing climate change, and leads Christians to believe that taking climate action is consistent with their church’s values while voting for politicians who will not take climate action is not.
Quirks of cognition explain why we dramatically overestimate the size of minority groups
Brian Guay, Tyler Marghetis, Cara Wong, David Landy
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Americans dramatically overestimate the size of African American, Latino, Muslim, Asian, Jewish, immigrant, and LGBTQ populations, leading to concerns about downstream racial attitudes and policy preferences. Such errors are common whenever the public is asked to estimate proportions relevant to political issues, from refugee crises and polarization to climate change and COVID-19. Researchers across the social sciences interpret these errors as evidence of widespread misinformation that is topic-specific and potentially harmful. Here, we show that researchers and journalists have misinterpreted the origins and meaning of these misestimates by overlooking systematic distortions introduced by the domain-general psychological processes involved in estimating proportions under uncertainty. In general, people systematically rescale estimates of proportions toward more central prior expectations, resulting in the consistent overestimation of smaller groups and underestimation of larger groups. We formalize this process and show that it explains much of the systematic error in estimates of demographic groups ( N = 100 , 170 estimates from 22 countries). This domain-general account far outperforms longstanding group-specific explanations (e.g., biases toward specific groups). We find, moreover, that people make the same errors when estimating the size of racial, nonracial, and entirely nonpolitical groups, such as the proportion of Americans who have a valid passport or own a washing machine. Our results call for researchers, journalists, and pundits alike to reconsider how to interpret misperceptions about the demographic structure of society.
The rising income gradient in life expectancy in Sweden over six decades
Johannes Hagen, Lisa Laun, Charlotte Lucke, MĂ„rten Palme
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This study examines the long-term association between income and life expectancy in Sweden between 1960 and 2021. The study is based on register data that include all Swedish permanent residents aged 40 y and older. The results show that the gap in life expectancy between the top and bottom income percentiles widened substantially: For men, it increased from 3.5 y in the 1960s to 10.9 y by the 2010s, and for women, from 3.8 y in the 1970s to 8.6 y by the 2010s. Despite a reduction in income inequality and an expansion of social spending from the 1960s to the 1990s, health inequality continuously increased over the period under study. The changes of the relation between real income and life expectancy, the so-called Preston curve, reveal a much faster improvement in life expectancy in the upper half of the income distribution than suggested by the cross-sectional relation between income and life expectancy. Analysis of causes of death identified circulatory diseases as the main contributor to improved longevity, while cancer contributed more to the increased gap in life expectancy for women and equally for men. Finally, analysis of the change in the income gradient in avoidable causes of death showed the strongest contribution of preventable causes, both for men and women.

Science

GPT-4o mini: Non-social science research article
Full freedom-of-motion actuators as advanced haptic interfaces
Kyoung-Ho Ha, Jaeyoung Yoo, Shupeng Li, Yuxuan Mao, Shengwei Xu, Hongyuan Qi, Hanbing Wu, Chengye Fan, Hanyin Yuan, Jin-Tae Kim, Matthew T. Flavin, Seonggwang Yoo, Pratyush Shahir, Sangjun Kim, Hak-Young Ahn, Edward Colgate, Yonggang Huang, John A. Rogers
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The sense of touch conveys critical environmental information, facilitating object recognition, manipulation, and social interaction, and can be engineered through haptic actuators that stimulate cutaneous receptors. An unfulfilled challenge lies in haptic interface technologies that can engage all the various mechanoreceptors in a programmable, spatiotemporal fashion across large areas of the body. Here, we introduce a small-scale actuator technology that can impart omnidirectional, superimposable, dynamic forces to the surface of skin, as the basis for stimulating individual classes of mechanoreceptors or selected combinations of them. High-bit haptic information transfer and realistic virtual tactile sensations are possible, as illustrated through human subject perception studies in extended reality applications that include advanced hand navigation, realistic texture reproduction, and sensory substitution for music perception.
GPT-4o mini: Non-social science research article
A geographic history of human genetic ancestry
Michael C. Grundler, Jonathan Terhorst, Gideon S. Bradburd
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Describing the distribution of genetic variation across individuals is a fundamental goal of population genetics. We present a method that capitalizes on the rich genealogical information encoded in genomic tree sequences to infer the geographic locations of the shared ancestors of a sample of sequenced individuals. We used this method to infer the geographic history of genetic ancestry of a set of human genomes sampled from Europe, Asia, and Africa, accurately recovering major population movements on those continents. Our findings demonstrate the importance of defining the spatiotemporal context of genetic ancestry when describing human genetic variation and caution against the oversimplified interpretations of genetic data prevalent in contemporary discussions of race and ancestry.
GPT-4o mini: Non-social science research article
A wheat tandem kinase and NLR pair confers resistance to multiple fungal pathogens
Ping Lu, Gaohua Zhang, Jing Li, Zhen Gong, Gaojie Wang, Lingli Dong, Huaizhi Zhang, Guanghao Guo, Min Su, Ke Wang, Yueming Wang, Keyu Zhu, Qiuhong Wu, Yongxing Chen, Miaomiao Li, Baoge Huang, Beibei Li, Wenling Li, Lei Dong, Yikun Hou, Xuejia Cui, Hongkui Fu, Dan Qiu, Chengguo Yuan, Hongjie Li, Jian-Min Zhou, Guan-Zhu Han, Yuhang Chen, Zhiyong Liu
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Tandem kinase proteins underlie the innate immune systems of cereal plants, but how they initiate plant immune responses remains unclear. This report identifies wheat protein wheat tandem NBD 1 (WTN1), a noncanonical nucleotide-binding leucine-rich repeat (NLR) receptor featuring tandem nucleotide binding adaptor shared by APAF-1, plant R proteins, and CED-4 (NB-ARC) domains, required for WTK3-mediated disease resistance. Both WTK3 and its allelic variant Rwt4—known for conferring resistance to wheat powdery mildew and blast, respectively—are capable of recognizing the blast effector PWT4. They activate WTN1 to form calcium-permeable channels, akin to ZAR1 and Sr35. Thus, tandem kinase proteins and their associated NLRs operate as “sensor-executor” pairs against fungal pathogens. Additionally, evolutionary analyses reveal a coevolutionary trajectory of the tandem kinase-NLR module, highlighting their cooperative role in triggering plant immunity.
GPT-4o mini: Non-social science research article
A wheat tandem kinase activates an NLR to trigger immunity
Renjie Chen, Jian Chen, Oliver R. Powell, Megan A. Outram, Taj Arndell, Karthick Gajendiran, Yan L. Wang, Jibril Lubega, Yang Xu, Michael A. Ayliffe, Cheryl Blundell, Melania Figueroa, Jana Sperschneider, Thomas Vanhercke, Kostya Kanyuka, Dingzhong Tang, Guitao Zhong, Catherine Gardener, Guotai Yu, Spyridon Gourdoupis, Ɓukasz Jaremko, Oadi Matny, Brian J. Steffenson, Willem H. P. Boshoff, Wilku B. Meyer, Stefan T. Arold, Peter N. Dodds, Brande B. H. Wulff
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The role of nucleotide-binding leucine-rich repeat (NLR) receptors in plant immunity is well studied, but the function of a class of tandem kinases (TKs) that confer disease resistance in wheat and barley remains unclear. In this study, we show that the SR62 locus is a digenic module encoding the Sr62 TK TK and an NLR (Sr62 NLR ), and we identify the corresponding AvrSr62 effector. AvrSr62 binds to the N-terminal kinase 1 of Sr62 TK , triggering displacement of kinase 2, which activates Sr62 NLR . Modeling and mutation analysis indicated that this is mediated by overlapping binding sites (i) on kinase 1 for binding AvrSr62 and kinase 2 and (ii) on kinase 2 for binding kinase 1 and Sr62 NLR . Understanding this two-component resistance complex may help engineering and breeding plants for durable resistance.
GPT-4o mini: Non-social science research article
Hedonic eating is controlled by dopamine neurons that oppose GLP-1R satiety
Zhenggang Zhu, Rong Gong, Vicente Rodriguez, Kathleen T. Quach, Xinyu Chen, Scott M. Sternson
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Hedonic eating is defined as food consumption driven by palatability without physiological need. However, neural control of palatable food intake is poorly understood. We discovered that hedonic eating is controlled by a neural pathway from the peri–locus ceruleus to the ventral tegmental area (VTA). Using photometry-calibrated optogenetics, we found that VTA dopamine (VTA DA ) neurons encode palatability to bidirectionally regulate hedonic food consumption. VTA DA neuron responsiveness was suppressed during food consumption by semaglutide, a glucagon-like peptide receptor 1 (GLP-1R) agonist used as an antiobesity drug. Mice recovered palatable food appetite and VTA DA neuron activity during repeated semaglutide treatment, which was reversed by consumption-triggered VTA DA neuron inhibition. Thus, hedonic food intake activates VTA DA neurons, which sustain further consumption, a mechanism that opposes appetite reduction by semaglutide.
GPT-4o mini: Non-social science research article
Running a genetic stop sign accelerates oxygen metabolism and energy production in horses
Gianni M. Castiglione, Xin Chen, Zhenhua Xu, Nadir H. Dbouk, Anamika A. Bose, David Carmona-Berrio, Emiliana E. Chi, Lingli Zhou, Tatiana N. Boronina, Robert N. Cole, Shirley Wu, Abby D. Liu, Thalia D. Liu, Haining Lu, Ted Kalbfleisch, David Rinker, Antonis Rokas, Kyla Ortved, Elia J. Duh
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Horses are among nature’s greatest athletes, yet the ancestral molecular adaptations fueling their energy demands are poorly understood. Within a clinically important pathway regulating redox and metabolic homeostasis (NRF2/KEAP1), we discovered an ancient mutation—conserved in all extant equids—that increases mitochondrial respiration while decreasing tissue-damaging oxidative stress. This mutation is a de novo premature opal stop codon in KEAP1 that is translationally recoded into a cysteine through previously unknown mechanisms, producing an R15C mutation in KEAP1 that is more sensitive to electrophiles and reactive oxygen species. This recoding enables increased NRF2 activity, which enhances mitochondrial adenosine 5â€Č-triphosphate production and cellular resistance to oxidative damage. Our study illustrates how recoding of a de novo stop codon, a strategy thought restricted to viruses, can facilitate adaptation in vertebrates.
GPT-4o mini: Non-social science research article
A high-temperature nanostructured Cu-Ta-Li alloy with complexion-stabilized precipitates
B. C. Hornbuckle, J. A. Smeltzer, S. Sharma, S. Nagar, C. J. Marvel, P. R. Cantwell, M. P. Harmer, K. Solanki, K. A. Darling
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We present a bulk nanocrystalline copper alloy that can operate at near-melting temperatures with minimal coarsening and creep deformation. The thermal stability of the Cu-3Ta-0.5Li atomic % (at %) alloy is attributed to coherent, ordered L1 2 Cu 3 Li precipitates surrounded by a tantalum-rich atomic bilayer phase boundary complexion. Adding 0.5 at % lithium to the immiscible Cu-Ta system changes the morphology of the nanoscale precipitates from spherical to cuboidal while simultaneously tailoring the phase boundary. The resultant complexion-stabilized nanoscale precipitates provide excellent thermal stability, strength, and creep resistance. The underlying alloy design principles may guide the development of next-generation copper alloys for high-temperature applications such as heat exchangers.
GPT-4o mini: Non-social science research article
Abrupt sea level rise and Earth’s gradual pole shift reveal permanent hydrological regime changes in the 21st century
Ki-Weon Seo, Dongryeol Ryu, Taehwan Jeon, Kookhyoun Youm, Jae-Seung Kim, Earthu H. Oh, Jianli Chen, James S. Famiglietti, Clark R. Wilson
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Rising atmospheric and ocean temperatures have caused substantial changes in terrestrial water circulation and land surface water fluxes, such as precipitation and evapotranspiration, potentially leading to abrupt shifts in terrestrial water storage. The European Centre for Medium-Range Weather Forecasts (ECMWF) Reanalysis v5 (ERA5) soil moisture (SM) product reveals a sharp depletion during the early 21st century. During the period 2000 to 2002, soil moisture declined by approximately 1614 gigatonnes, much larger than Greenland’s ice loss of about 900 gigatonnes (2002–2006). From 2003 to 2016, SM depletion continued, with an additional 1009-gigatonne loss. This depletion is supported by two independent observations of global mean sea level rise (~4.4 millimeters) and Earth’s pole shift (~45 centimeters). Precipitation deficits and stable evapotranspiration likely caused this decline, and SM has not recovered as of 2021, with future recovery unlikely under present climate conditions.
GPT-4o mini: Non-social science research article
Complex-frequency excitations in photonics and wave physics
Seunghwi Kim, Alex Krasnok, Andrea AlĂč
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Closed, lossless optical cavities are characterized by a Hamiltonian that obeys Hermiticity, resulting in strictly real-valued resonance frequencies. By contrast, non-Hermitian wave systems are characterized by Hamiltonians with poles and zeros at complex frequencies, whose control through precise engineering of material loss and gain can lead to exotic scattering phenomena. Notably, excitation signals that oscillate at complex-valued frequencies can mimic the emergence of gain and loss, facilitating access to these non-Hermitian responses without material modifications. These findings have been advancing the fundamental understanding of wave-matter interactions and are enabling breakthroughs in metamaterials, imaging, sensing, and computing. This Review examines theoretical advances and experimental discoveries in this emerging field, demonstrating how tailored time-domain excitations offer new opportunities for wave manipulation and control.
GPT-4o mini: Non-social science research article
Chromatin accessibility landscape of mouse early embryos revealed by single-cell NanoATAC-seq2
Mengyao Li, Zhenhuan Jiang, Xueqiang Xu, Xinglong Wu, Yun Liu, Kexuan Chen, Yuhan Liao, Wen Li, Xiao Wang, Yuqing Guo, Bo Zhang, Lu Wen, Kehkooi Kee, Fuchou Tang
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In mammals, fertilized eggs undergo genome-wide epigenetic reprogramming to generate the organism. However, our understanding of epigenetic dynamics during preimplantation development at single-cell resolution remains incomplete. Here, we developed scNanoATAC-seq2, a single-cell assay for transposase-accessible chromatin using long-read sequencing for scarce samples. We present a detailed chromatin accessibility landscape of mouse preimplantation development, revealing distinct chromatin signatures in the epiblast, primitive endoderm, and trophectoderm during lineage segregation. Differences between zygotes and two-cell embryos highlight reprogramming in chromatin accessibility during the maternal-to-zygotic transition. Single-cell long-read sequencing enables in-depth analysis of chromatin accessibility in noncanonical imprinting, imprinted X chromosome inactivation, and low-mappability genomic regions, such as repetitive elements and paralogs. Our data provide insights into chromatin dynamics during mammalian preimplantation development and lineage differentiation.
GPT-4o mini: Non-social science research article
Leucine aminopeptidase LyLAP enables lysosomal degradation of membrane proteins
Aakriti Jain, Isaac Heremans, Gilles Rademaker, Tyler C. Detomasi, Peter Rohweder, Dashiell Anderson, Justin Zhang, Grace A. Hernandez, Suprit Gupta, Teresa von Linde, Mike Lange, Martina Spacci, Jiayi Luo, Y. Rose Citron, James A. Olzmann, David W. Dawson, Charles S. Craik, Guido Bommer, Rushika M. Perera, Roberto Zoncu
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Breakdown of every transmembrane protein trafficked to lysosomes requires proteolysis of their hydrophobic helical transmembrane domains. Combining lysosomal proteomics with functional genomic datasets, we identified lysosomal leucine aminopeptidase (LyLAP; formerly phospholipase B domain–containing 1) as the hydrolase most tightly associated with elevated endocytosis. Untargeted metabolomics and biochemical reconstitution demonstrated that LyLAP is a processive monoaminopeptidase with preference for amino-terminal leucine. This activity was necessary and sufficient for the breakdown of hydrophobic transmembrane domains. LyLAP was up-regulated in pancreatic ductal adenocarcinoma (PDA), which relies on macropinocytosis for nutrient uptake. In PDA cells, LyLAP ablation led to the buildup of undigested hydrophobic peptides, lysosomal membrane damage, and growth inhibition. Thus, LyLAP enables lysosomal degradation of membrane proteins and protects lysosomal integrity in highly endocytic cancer cells.
GPT-4o mini: Non-social science research article
Selective filtering of photonic quantum entanglement via anti–parity-time symmetry
Mahmoud A. Selim, Max Ehrhardt, Yuqiang Ding, Hediyeh M. Dinani, Qi Zhong, Armando Perez‐Leija, ƞahin K. Özdemir, Matthias Heinrich, Alexander Szameit, Demetrios N. Christodoulides, Mercedeh Khajavikhan
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Entanglement is a key resource for quantum computing, sensing, and communication, but it is susceptible to decoherence. To address this, research in quantum optics has explored filtering techniques such as photon ancillas and Rydberg atom blockade to restore entangled states. We introduce an approach to entanglement retrieval that exploits the features of non-Hermitian systems. By designing an anti–parity-time two-state guiding configuration, we demonstrate efficient extraction of entanglement from any input state. This filter is implemented on a lossless waveguide network and achieves near-unity fidelity under single- and two-photon excitation and is scalable to higher photon levels, remaining robust against decoherence during propagation. Our results offer an approach to using non-Hermitian symmetries to address central challenges in quantum technologies.
GPT-4o mini: Non-social science research article
Canine genome-wide association study identifies DENND1B as an obesity gene in dogs and humans
Natalie J. Wallis, Alyce McClellan, Alexander Mörseburg, Katherine A. Kentistou, Aqfan Jamaluddin, Georgina K. C. Dowsett, Ellen Schofield, Anna Morros-Nuevo, Sadia Saeed, Brian Y. H. Lam, Natasha T. Sumanasekera, Justine Chan, Sambhavi S. Kumar, Rey M. Zhang, Jodie F. Wainwright, Marie Dittmann, Gabriella Lakatos, Kara Rainbow, David Withers, Rebecca Bounds, Marcella Ma, Alexander J. German, Jane Ladlow, David Sargan, Philippe Froguel, I. Sadaf Farooqi, Ken K. Ong, Giles S. H. Yeo, John A. Tadross, John R. B. Perry, Caroline M. Gorvin, Eleanor Raffan
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Obesity is a heritable disease, but its genetic basis is incompletely understood. Canine population history facilitates trait mapping. We performed a canine genome-wide association study for body condition score—a measure of obesity—in 241 Labrador retrievers. Using a cross-species approach, we showed that canine obesity genes are also associated with rare and common forms of obesity in humans. The lead canine association was within the gene DENN domain containing 1B ( DENND1B ). Each copy of the alternate allele was associated with ~7% greater body fat. We demonstrate a role for this gene in regulating signaling and trafficking of melanocortin 4 receptor, a critical controller of energy homeostasis. Thus, canine genetics identified obesity genes and mechanisms relevant to both dogs and humans.
GPT-4o mini: Non-social science research article
Sulfonyl hydrazides as a general redox-neutral platform for radical cross-coupling
Jiawei Sun, Áron Péter, Jiayan He, Jet Tsien, Haoxiang Zhang, David A. Cagan, Benjamin P. Vokits, David S. Peters, Martins S. Oderinde, Michael D. Mandler, Paul Richardson, Doris Chen, Maximilian D. Palkowitz, Nicholas Raheja, Yu Kawamata, Phil S. Baran
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Sulfonyl hydrazides are stable and usually crystalline substances that can be accessed in a variety of ways, including transiently from hydrazones, to achieve a net reductive arylation of carbonyl compounds. We show their utility as versatile radical precursors, as exemplified with seven C–C bond–forming, redox-neutral cross-couplings with activated olefins, alkyl halides, redox-active esters, aryl halides, alkenyl halides, alkynyl halides, and a trifluoromethylating reagent, to forge C(sp 3 )-C(sp 3 ), C(sp 3 )-C(sp 2 ), and C(sp 3 )-C(sp) bonds. Exogenous redox (chemical, photo/electrochemical) additives are not necessary because these functional groups serve the dual role of radical precursor and electron donor. The homogeneous, water-compatible reaction conditions are operationally simple and contribute to streamlining synthesis and mild late-stage functionalization.
GPT-4o mini: Non-social science research article
Telomeric transposons are pervasive in linear bacterial genomes
Shan-Chi Hsieh, MĂĄtĂ© FĂŒlöp, Richard Schargel, Michael T. Petassi, Orsolya Barabas, Joseph E. Peters
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Eukaryotes have linear DNA, and their telomeres are hotspots for transposons, which in some cases took over telomere maintenance. We identified several families of independently evolved telomeric transposons in linear chromosomes and plasmids of cyanobacteria and Streptomyces . Although these elements have one specific transposon end sequence, with the second boundary being the telomere, we can show that they move using two transposon ends, likely when transiently bridged by the telomere maintenance systems. Mobilization of the element and the associated telomere allows replacement of native telomeres, making the host cell dependent on the new transposon telomere system for genome maintenance. This work indicates how telomeric transposons can promote gene transfer both between and within genomes, substantially influencing the evolutionary dynamics of linear genomes.
Science abstract < 200 char.: Not a research article
ADHD, at 42
Nina Ockendon-Powell
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Science abstract < 200 char.: Not a research article
Mars rover detects long-chain carbon molecules
Paul Voosen
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Fatty acid byproducts that Curiosity found in an ancient lakebed could be the remains of microbes—or not
Science abstract < 200 char.: Not a research article
Guiding science in China
Andrew Kennedy
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Increasing emphasis on national priorities creates tension with curiosity-driven research
Science abstract < 200 char.: Not a research article
Women-driven community education in Nepal
Arya Gautam, Sandesh Ghimire, Aashish R. Jha
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Science abstract < 200 char.: Not a research article
Safety in the smoke
Warren Cornwall
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Science abstract < 200 char.: Not a research article
How did cow flu start? Scientists still don’t know
Kai Kupferschmidt
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One year later, how H5N1 spills over into dairy cattle—and how often—remains a mystery
Science abstract < 200 char.: Not a research article
In Science Journals
Melisa Yashinski, Leslie K. Ferrarelli, Marc S. Lavine, Madeleine Seale, Jake S. Yeston, Ekeoma Uzogara, Ian S. Osborne, Di Jiang, Stella M. Hurtley, Yevgeniya Nusinovich, Jesse Smith, Sacha Vignieri, Peter Stern, Corinne N. Simonti, Amos Matsiko, Orla Smith, Claire Olingy
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Highlights from the Science family of journals
Science abstract < 200 char.: Not a research article
In the ashes
Warren Cornwall
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After wildfires burned houses and brush alike in Los Angeles, researchers have mobilized to understand the health risks posed by urban conflagrations
Science abstract < 200 char.: Not a research article
U.S. cuts hamper disease surveillance worldwide
Jon Cohen
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Many efforts to prevent outbreaks and track diseases are suddenly in limbo
Science abstract < 200 char.: Not a research article
New data fill long-standing gaps in the study of policing
Dean Knox, Jonathan Mummolo
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Data show discrimination, but analysis must be more policy relevant
Science abstract < 200 char.: Not a research article
Furor over quantum computing claim heats up
Zack Savitsky
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Physicists cast doubt on measurements said to show Microsoft chip uses exotic Majorana quasiparticles
Science abstract < 200 char.: Not a research article
The meaning of our meals How the World Eats: A Global Food Philosophy Julian Baggini Pegasus, 2025. 464 pp.
Stefania Pizzirani
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A philosopher confronts how factors from culture to capitalism affect the foods we eat
Science abstract < 200 char.: Not a research article
In Other Journals
Caroline Ash, Corinne Simonti, Ian S. Osborne, Jelena Stajic, L. Bryan Ray, Priscilla N. Kelly, Jack Huang
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Editors’ selections from the current scientific literature
Science abstract < 200 char.: Not a research article
In Mexico, a whale of a controversy over gas port
Alexa Robles-Gil
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Researchers want better studies of how planned LNG terminal would affect marine life
Science abstract < 200 char.: Not a research article
South Africa caught in new tsunami of NIH grant cuts
Jon Cohen, Sara Reardon
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Agency moves to terminate nearly 1000 projects, including many involving “DEI” and LGBTQ health
Science abstract < 200 char.: Not a research article
Beyond hedonic eating
Dana M. Small
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A dopaminergic brain circuit drives food consumption in mice
Science abstract < 200 char.: Not a research article
Mapping a complex evolutionary history
Simon Gravel
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Tracking the geographic origins of genetic ancestors reveals past human migrations
Science abstract < 200 char.: Not a research article
Lined up for entanglement
Evgeny Moiseev, Kai Wang
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A framework widely used in classical contexts provides new insights into solving an important challenge in quantum technology
Science abstract < 200 char.: Not a research article
Equitable access needed in clinical research
Gisa Dang, Christophe Perrin, Jennifer Furin
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Science abstract < 200 char.: Not a research article
An end to human exceptionalism The Decline and Fall of the Human Empire: Why Our Species Is on the Edge of Extinction Henry Gee St. Martin’s Press, 2025. 288 pp.
Adrian Woolfson
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Our species’ extinction is inevitable, argues a paleontologist
Science abstract < 200 char.: Not a research article
Romanian brown bear management regresses
Mihai I. Pop, Ruben Iosif, Barbara Promberger-FĂŒrpass, Silviu Chiriac, Ágnes Keresztesi, Laurentiu Rozylowicz, Viorel D. Popescu
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Science abstract < 200 char.: Not a research article
Permanent shifts in the global water cycle
Luis Samaniego
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Decades of terrestrial water-storage changes reveal an irreversible decline in soil moisture
High-frequency location data show that race affects citations and fines for speeding
Pradhi Aggarwal, Alec Brandon, Ariel Goldszmidt, Justin Holz, John A. List, Ian Muir, Gregory Sun, Thomas Yu
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Prior research on racial profiling has found that in encounters with law enforcement, minorities are punished more severely than white civilians. Less is known about the causes of these encounters and their implications for our understanding of racial profiling. Using high-frequency location data of rideshare drivers in Florida ( N = 222,838 individuals), we estimate the effect of driver race on citations and fines for speeding using 19.3 million location pings. Compared with a white driver traveling the same speed, we find that racial or ethnic minority drivers are 24 to 33% more likely to be cited for speeding and pay 23 to 34% more money in fines. We find no evidence that accident and reoffense rates explain these estimates, which suggests that an animus against minorities underlies our results.
Securing education’s future
William F. Tate
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How a country evaluates student performance greatly influences the views of its government and citizenry on the quality of its education system and its standing on the global economic stage. Given the impact on future prosperity, health, and well-being, regularly collecting and analyzing data on student achievement are essential for informing investments in education. In the United States, national assessments and surveys help guide this process. However, efforts to dismantle the Department of Education, the agency that manages this activity, threaten this strategic data collection, information repository, and research infrastructure.

Science Advances

GPT-4o mini: Non-social science research article
Assessing cancer therapeutic efficacy in vivo using [ 2 H 7 ]glucose deuterium metabolic imaging
Mario C. Chang, Vinay R. Malut, Rohit Mahar, Anna Rushin, Marc A. McLeod, Geraldine L. Pierre, Indu R. Malut, Stephen J. Staklinski, Max E. Glanz, Mukundan Ragavan, Gaurav Sharma, Manoj Madheswaran, Arshee Badar, Aparna D. Rao, Brian K. Law, Michael S. Kilberg, James H. P. Collins, Vikram D. Kodibagkar, James A. Bankson, Ralph J. DeBerardinis, Matthew E. Merritt
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Metabolic imaging produces powerful visual assessments of organ function in vivo. Current techniques can be improved by safely increasing metabolic contrast. The gold standard, 2-[ 18 F]fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging, is limited by radioactive exposure and sparse assessment of metabolism beyond glucose uptake and retention. Deuterium magnetic resonance imaging (DMRI) with [6,6- 2 H 2 ]glucose is nonradioactive, achieves tumor metabolic contrast, but can be improved by enriched contrast from deuterated water (HDO) based imaging. Here, we developed a DMRI protocol employing [ 2 H 7 ]glucose. Imaging 2 H-signal and measuring HDO production in tumor-bearing mice detected differential glucose utilization across baseline tumors, tumors treated with vehicle control or anti-glycolytic BRAFi and MEKi therapy, and contralateral healthy tissue. Control tumors generated the most 2 H-signal and HDO. To our knowledge this is the first application of DMRI with [ 2 H 7 ]glucose for tumoral treatment monitoring. This approach demonstrates HDO as a marker of tumor glucose utilization and suggests translational capability in humans due to its safety, noninvasiveness, and suitability for serial monitoring.
GPT-4o mini: Non-social science research article
Proteogenomic discovery of RB1 -defective phenocopy in cancer predicts disease outcome, response to treatment, and therapeutic targets
Jacopo Iacovacci, Rachel Brough, Fatemeh Ahmadi Moughari, John Alexander, Harriet Kemp, Andrew N. J. Tutt, Rachael Natrajan, Christopher J. Lord, Syed Haider
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Genomic defects caused by truncating mutations or deletions in the Retinoblastoma tumor suppressor gene ( RB1 ) are frequently observed in many cancer types leading to dysregulation of the RB pathway. Here, we propose an integrative proteogenomic approach that predicts cancers with dysregulation in the RB pathway. A subset of these cancers, which we term as “RBness,” lack RB1 genomic defects and yet phenocopy the transcriptional profile of RB1 -defective cancers. We report RBness as a pan-cancer phenomenon, associated with patient outcome and chemotherapy response in multiple cancer types, and predictive of CDK4/6 inhibitor response in estrogen-positive breast cancer. Using RNA interference and a CRISPR-Cas9 screen in isogenic models, we find that RBness cancers also phenocopy synthetic lethal vulnerabilities of cells with RB1 genomic defects. In summary, our findings suggest that dysregulation of the RB pathway in cancers lacking RB1 genomic defects provides a molecular rationale for how these cancers could be treated.
GPT-4o mini: Non-social science research article
Macrophage-targeted Mms6 mRNA-lipid nanoparticles promote locomotor functional recovery after traumatic spinal cord injury in mice
Chunyan Fu, Xiaoqin Jin, Kangfan Ji, Ke Lan, Xingjia Mao, Zhaobo Huang, Jian Chen, Fengdong Zhao, Pengfei Li, Xuefei Hu, Liwen Sun, Ning Lu, Jinjie Zhong, Yingying Chen, Linlin Wang
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Traumatic spinal cord injury (SCI) causes severe central nervous system damage. M2 macrophages within the lesion are crucial for SCI recovery. Our previous research revealed that M2 macrophages transfected with magnetotactic bacteria–derived Mms6 gene can resist ferroptosis and enhance SCI recovery. To address the limitations of M2 macrophage transplantation, we developed lipid nanoparticles (LNPs) encapsulating Mms6 mRNA targeting macrophages ( Mms6 mRNA-PS/LNPs). The targeting efficiency and therapeutic effect of these LNPs in SCI mice were evaluated. Intravenous administration of Mms6 mRNA-PS/LNPs delivered more Mms6 mRNAs to lesion-site macrophages than those in the Mms6 mRNA-LNP group, which resulted in enhancing motor function recovery, reducing lesion area and scar formation, and promoting neuronal survival and nerve fiber repair. These effects were nullified when macrophages were depleted. These findings suggest that macrophage-targeted delivery of Mms6 mRNA is a promising therapeutic strategy for promoting spinal cord repair and motor function recovery in patients with traumatic SCI.
GPT-4o mini: Non-social science research article
Circadian clock is critical for fungal pathogenesis by regulating zinc starvation response and secondary metabolism
Qiaojia Lu, Muqun Yu, Xianyun Sun, Xin Zhou, Rui Zhang, Yahao Zhang, Xiao-Lan Liu, Zhanbiao Li, Lei Cai, Hongwei Liu, Shaojie Li, Yunkun Dang, Xiaodong Xu, Qun He, Yi Liu, Xiao Liu
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Circadian clocks are known to modulate host immune responses to pathogen infections, yet their role in influencing pathogen pathogenesis remains unclear. Here, we investigated the role of circadian clocks in regulating the pathogenesis of the fungal pathogen Fusarium oxysporum , which has multiple genes homologous to the Neurospora crassa frq due to gene duplication events, with Fofrq1 being the primary circadian clock gene. The pathogenesis of F. oxysporum in plants is controlled by its circadian clock, with infections causing severe disease symptoms at dawn. Notably, disruption of clock genes dramatically reduces fungal pathogenicity. Circadian clocks regulate the rhythmic expression of several transcription factors, including FoZafA, which enables the pathogen to adapt to zinc starvation within the plant, and FoCzf1, which governs the production of the toxin fusaric acid. Together, our findings highlight the critical roles of circadian clocks in F. oxysporum pathogenicity by regulating zinc starvation response and secondary metabolite production.
GPT-4o mini: Non-social science research article
ÎŒSonic-hand: Biomedical micromanipulation driven by acoustic gas-liquid-solid interactions
Xiaoming Liu, Yuyang Li, Fengyu Liu, Qing Shi, Lixin Dong, Qiang Huang, Tatsuo Arai, Toshio Fukuda
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Micromanipulation is crucial for operating and analyzing microobjects in advanced biomedical applications. However, safe, low-cost, multifunctional micromanipulation for operating bio-objects across scales and modalities remains inaccessible. Here, we propose a versatile micromanipulation method driven by acoustic gas-liquid-solid interactions, named ÎŒSonic-hand. The bubble contained at the end of a micropipette and the surrounding liquid form a gas-liquid multiphase system susceptible to acoustic waves. Driven by a piezoelectric transducer, the oscillating gas-liquid interface induces acoustic microstreaming, markedly increasing the mass transfer efficiency. It enables multiple liquid micromanipulations, including mixing, dispersion, enhancing cell membrane permeability, and harvesting selected cells. Furthermore, a controllable three-dimensional axisymmetric vortex in an open environment overcomes the constraints of microfluidic chip, enabling stable trapping, rapid transportation, and multidirectional rotation of HeLa cells, embryos, and other bio-objects ranging from micrometers to millimeters. A variety of applications demonstrate that the ÎŒSonic-hand, with its wide-range capabilities, inherent biocompatibility, and extremely low cost could remarkably advance biomedical science.
GPT-4o mini: Non-social science research article
Liquid palladium for high-turnover carbon-carbon bond formation
Md. Hasan Al Banna, Nieves Flores, Ziqi Zhou, Nastaran Meftahi, Salvy P. Russo, Pramod Koshy, Francois-Marie Allioux, Mohammad B. Ghasemian, Junma Tang, Sarina Sarina, Jianbo Tang, Andrew J. Christofferson, Kourosh Kalantar-Zadeh, Md. Arifur Rahim
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Carbon-carbon (C─C) bond formation is a key step in diverse chemical processes and requires high-performance catalysts to enable energy-efficient technologies. Here, we present liquid Pd catalysts, formed by dissolving Pd in liquid Ga, for high-turnover C─C coupling reactions. The liquid Pd catalyst achieved a turnover frequency of 2.5 × 10 8 hour −1 for a model coupling reaction at 70°C, surpassing all reported Pd catalysts by 1000-fold. Our results show that Pd atoms in the Ga matrix are liquid-like, exhibiting unique electronic and interfacial properties that substantially lower the energy barrier and enhance reaction kinetics. The system retained full activity over five cycles and showed no Pd leaching, highlighting the transformative potential of liquid-phase metals to advance high-throughput and sustainable C─C bond-forming strategies.
GPT-4o mini: Non-social science research article
Demographic bias of expert-level vision-language foundation models in medical imaging
Yuzhe Yang, Yujia Liu, Xin Liu, Avanti Gulhane, Domenico Mastrodicasa, Wei Wu, Edward J. Wang, Dushyant Sahani, Shwetak Patel
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Advances in artificial intelligence (AI) have achieved expert-level performance in medical imaging applications. Notably, self-supervised vision-language foundation models can detect a broad spectrum of pathologies without relying on explicit training annotations. However, it is crucial to ensure that these AI models do not mirror or amplify human biases, disadvantaging historically marginalized groups such as females or Black patients. In this study, we investigate the algorithmic fairness of state-of-the-art vision-language foundation models in chest x-ray diagnosis across five globally sourced datasets. Our findings reveal that compared to board-certified radiologists, these foundation models consistently underdiagnose marginalized groups, with even higher rates seen in intersectional subgroups such as Black female patients. Such biases present over a wide range of pathologies and demographic attributes. Further analysis of the model embedding uncovers its substantial encoding of demographic information. Deploying medical AI systems with biases can intensify preexisting care disparities, posing potential challenges to equitable healthcare access and raising ethical questions about their clinical applications.
GPT-4o mini: Non-social science research article
NAT10 and N 4 -acetylcytidine restrain R-loop levels and related inflammatory responses
Turja K. Debnath, Nathan S. Abell, Yi-Ru Li, Sravan K. Devanathan, Enrique Navedo, Blerta Xhemalçe
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N 4 -acetylcytidine (ac 4 C) is deposited on diverse RNAs by N -acetyltransferase 10 (NAT10), a protein with high biological relevance for aging and cancer. We performed a comprehensive survey of ac 4 C using metabolic labeling, sodium cyanoborohydride chemical treatment coupled to next-generation sequencing (NGS), and ac 4 C antibody–based cell and molecular biology techniques. Our analysis shows that NAT10-dependent ac 4 C-acetylation is robust in rRNA and specific tRNAs but low/spurious in mRNA. It also revealed an inflammatory signature and mutagenesis at transcriptionally active sites in NAT10-KO cells. This finding led us to explore the role of NAT10 in R-loops, which were recently linked to APOBEC3B-mediated mutagenesis. Our analysis showed that R-loops are ac 4 C-acetylated in a NAT10-dependent manner. Furthermore, NAT10 restrains the levels of R-loops at a subset of differentially expressed genes in a catalytic activity–dependent manner. Together with cellular biology data showing ac 4 C-modified RNA in endosomal structures, we propose that increased levels of ac 4 C-unmodified RNAs, likely derived from R-loops, in endosomal structures induce inflammatory responses.
GPT-4o mini: Non-social science research article
A dyad of human-specific NBPF14 and NOTCH2NLB orchestrates cortical progenitor abundance crucial for human neocortex expansion
Nesil EƟiyok, Neringa Liutikaite, Christiane Haffner, Jula Peters, Sabrina Heide, Christina Eugster Oegema, Wieland B. Huttner, Michael Heide
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We determined the roles of two coevolved and coexpressed human-specific genes, NBPF14 and NOTCH2NLB , on the abundance of the cortical progenitors that underlie the evolutionary expansion of the neocortex, the seat of higher cognitive abilities in humans. Using automated microinjection into apical progenitors (APs) of embryonic mouse neocortex and electroporation of APs in chimpanzee cerebral organoids, we show that NBPF14 promotes the delamination of AP progeny, by promoting oblique cleavage plane orientation during AP division, leading to increased abundance of the key basal progenitor type, basal radial glia. In contrast, NOTCH2NLB promotes AP proliferation, leading to expansion of the AP pool. When expressed together, NBPF14 and NOTCH2NLB exert coordinated effects, resulting in expansion of basal progenitors while maintaining self-renewal of APs. Hence, these two human-specific genes orchestrate the behavior of APs, and the lineages of their progeny, in a manner essential for the evolutionary expansion of the human neocortex.
GPT-4o mini: Non-social science research article
Preemptive optimization of a clinical antibody for broad neutralization of SARS-CoV-2 variants and robustness against viral escape
Fangqiang Zhu, Saravanan Rajan, Conor F. Hayes, Ka Yin Kwong, Andre R. Goncalves, Adam T. Zemla, Edmond Y. Lau, Yi Zhang, Yingyun Cai, John W. Goforth, Mikel Landajuela, Pavlo Gilchuk, Michael Kierny, Andrew Dippel, Bismark Amofah, Gilad Kaplan, Vanessa Cadevilla Peano, Christopher Morehouse, Ben Sparklin, Vancheswaran Gopalakrishnan, Kevin M. Tuffy, Amy Nguyen, Jagadish Beloor, Gustavo Kijak, Chang Liu, Aiste Dijokaite-Guraliuc, Juthathip Mongkolsapaya, Gavin R. Screaton, Brenden K. Petersen, Thomas A. Desautels, Drew Bennett, Simone Conti, Brent W. Segelke, Kathryn T. Arrildt, Samantha Kaul, Emilia A. Grzesiak, Felipe Leno da Silva, Thomas W. Bates, Christopher G. Earnhart, Svetlana Hopkins, Shivshankar Sundaram, Mark T. Esser, Joseph R. Francica, Daniel M. Faissol, character(0)
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Most previously authorized clinical antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have lost neutralizing activity to recent variants due to rapid viral evolution. To mitigate such escape, we preemptively enhance AZD3152, an antibody authorized for prophylaxis in immunocompromised individuals. Using deep mutational scanning (DMS) on the SARS-CoV-2 antigen, we identify AZD3152 vulnerabilities at antigen positions F456 and D420. Through two iterations of computational antibody design that integrates structure-based modeling, machine-learning, and experimental validation, we co-optimize AZD3152 against 24 contemporary and previous SARS-CoV-2 variants, as well as 20 potential future escape variants. Our top candidate, 3152-1142, restores full potency (100-fold improvement) against the more recently emerged XBB.1.5+F456L variant that escaped AZD3152, maintains potency against previous variants of concern, and shows no additional vulnerability as assessed by DMS. This preemptive mitigation demonstrates a generalizable approach for optimizing existing antibodies against potential future viral escape.
GPT-4o mini: Non-social science research article
Excess surface area of the nuclear lamina enables unhindered cell migration through constrictions
Brendan McKee, Samere Abolghasemzade, Ting-Ching Wang, Kajol Harsh, Simran Kaur, Ryan Blanchard, Krishna Belraj Menon, Mohammad Mohajeri, Richard B. Dickinson, Tanmay P. Lele
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Cell migration through narrow spaces is essential in wound healing and metastatic spread of cancer. Cells must deform the large nucleus to fit through constricting channels. To understand the role of the nuclear lamina in limiting cell migration through constrictions, we imaged it in cells migrating through periodic constricting channels in a microdevice. The lamina underwent cycles of wrinkling and smoothing as the nucleus changed from an irregular, rounded shape in the wide channel regions between constrictions to a smooth, hourglass shape as the nucleus passed through the center of a constriction. The laminar surface area of nuclei within constrictions was measured to be at or above the computationally predicted threshold area for the nuclear volume. The channels excluded control nuclei that had insufficient excess surface area, but not nuclei lacking lamin A/C. Thus, the excess surface area of the nuclear lamina enables cell migration through constricting channels.
GPT-4o mini: Non-social science research article
Nanoscale engineering and dynamic stabilization of mesoscopic spin textures
Kieren Harkins, Christoph Fleckenstein, Noella D’Souza, Paul M. Schindler, David Marchiori, Claudia Artiaco, Quentin Reynard-Feytis, Ushoshi Basumallick, William Beatrez, Arjun Pillai, Matthias Hagn, Aniruddha Nayak, Samantha Breuer, Xudong Lv, Maxwell McAllister, Paul Reshetikhin, Emanuel Druga, Marin Bukov, Ashok Ajoy
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Thermalization, while ubiquitous in physics, has traditionally been viewed as an obstacle to be mitigated. In contrast, we demonstrate here the use of thermalization in the generation, control, and readout of “shell-like” spin textures with interacting 13 C nuclear spins in diamond, wherein spins are polarized oppositely on either side of a critical radius. The textures span several nanometers and encompass many hundred spins; they are created and interrogated without manipulating the nuclear spins individually. Long-time stabilization is achieved via prethermalization to a Floquet-engineered Hamiltonian under the electronic gradient field: The texture is therefore metastable and robust against spin diffusion. This enables the state to endure over multiple minutes before it decays. Our work on spin-state engineering paves the way for applications in quantum simulation and nanoscale imaging.
GPT-4o mini: Non-social science research article
A dual chemodrug-loaded hyaluronan nanogel for differentiation induction therapy of refractory AML via disrupting lysosomal homeostasis
Shilin Xu, Tao Wang, Xuechun Hu, Hong Deng, Yiyi Zhang, Lei Xu, Yang Zeng, Jia Yu, Weiqi Zhang, Lin Wang, Haiyan Xu
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Relapsed/refractory acute myeloid leukemia (rrAML) is a malignant blood cancer with an extremely poor prognosis, largely ascribed to the drug-resistant leukemia stem cells (LSCs). Most patients suffer from a risk of difficult-to-cure as well as severe systemic toxicity when receiving standard chemotherapies. As hyaluronic acid (HA) is a specific ligand of CD44 highly expressed by LSCs, we had HA self-assembled with cisplatin and daunorubicin to form a dual chemodrug nanogel (HA/Cis/Dau) to afford the targeted therapeutic interventions of rrAML. HA/Cis/Dau displayed an extra therapeutic function of inducing the granulocyte-monocyte differentiation in CD44 + rrAML cells, an rrAML mouse model, and primary blasts isolated from patients with AML. Unlike free drugs directly diffusing and killing rrAML cells, HA/Cis/Dau transported the drugs into lysosomes, causing lysosomal membrane permeabilization, ROS accumulation, and thus a metabolic reprogramming of the rrAML cells. Moreover, HA/Cis/Dau was featured with alleviated side effects, ease of preparation, and cost effectiveness, therefore holding great promises for the targeted treatment of rrAML.
GPT-4o mini: Non-social science research article
Replication-dependent histone labeling dissects the physical properties of euchromatin/heterochromatin in living human cells
Katsuhiko Minami, Kako Nakazato, Satoru Ide, Kazunari Kaizu, Koichi Higashi, Sachiko Tamura, Atsushi Toyoda, Koichi Takahashi, Ken Kurokawa, Kazuhiro Maeshima
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A string of nucleosomes, where genomic DNA is wrapped around histones, is organized in the cell as chromatin, ranging from euchromatin to heterochromatin, with distinct genome functions. Understanding physical differences between euchromatin and heterochromatin is crucial, yet specific labeling methods in living cells remain limited. Here, we have developed replication-dependent histone (Repli-Histo) labeling to mark nucleosomes in euchromatin and heterochromatin based on DNA replication timing. Using this approach, we investigated local nucleosome motion in the four known chromatin classes, from euchromatin to heterochromatin, of living human and mouse cells. The more euchromatic (earlier-replicated) and more heterochromatic (later-replicated) regions exhibit greater and lesser nucleosome motions, respectively. Notably, the motion profile in each chromatin class persists throughout interphase. Genome chromatin is essentially replicated from regions with greater nucleosome motions, although the replication timing is perturbed. Our findings, combined with computational modeling, suggest that earlier-replicated regions have more accessibility, and local chromatin motion can be a major determinant of genome-wide replication timing.
GPT-4o mini: Non-social science research article
Ocean alkalinity destruction by anthropogenic seafloor disturbances generates a hidden CO 2 emission
Sebastiaan J. van de Velde, Astrid Hylén, Filip J. R. Meysman
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The seafloor is responsible for 40% of the alkalinity input to the ocean, thus contributing to the ocean’s capacity to sequester atmospheric CO 2 . Anthropogenic seafloor disturbances induced by mobile bottom-contact fishing and dredging influence this natural carbon sink, yet the human impact on the ocean’s alkalinity cycle remains poorly quantified. Model simulations show that the combined impact of mobile bottom-contact fishing (e.g., trawling) and dredging reduces natural alkalinity generation by 60 to 220 gigaequivalent year −1 , which is equivalent to a reduction of the natural marine carbon sink by 2 to 8 teragrams CO 2 year −1 . Alkalinity destruction by anthropogenic seafloor disturbance hence generates a hidden CO 2 emission, of which the impact is comparable to the estimated reduction of organic carbon burial by mobile bottom-contact fishing. Our analysis emphasizes that carbon accounting in marine systems should consider the anthropogenic impact on both the organic and inorganic carbon cycles.
GPT-4o mini: Non-social science research article
Mechanism of high-temperature superconductivity in compressed H 2 -molecular–type hydride
Pengye Liu, Quan Zhuang, Qiang Xu, Tian Cui, Zhao Liu
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The discovery of compressed atomic-type hydrides offers a promising avenue toward achieving room-temperature superconductivity, but it necessitates extremely high pressures to completely dissociate hydrogen molecules to release free electrons. Here, we report a remarkable finding of compressed H 2 -molecular–type hydride CaH 14 exhibiting an unusual transition temperature ( T c ) of 204.0 kelvin. The peculiarity of its electronic structure lies in the pronounced emergence of near-free electrons, which manifest metallic bonding, but molecular hydrogen fragments persist. This finding indicates that the necessary condition for superconducting transition is forming the Fermi sea with Cooper pairs rather than the monatomic hydrogen. Notably, the formation mechanism of free electrons can be effectively explained by the finite-depth potential wells model. Intriguingly, this H 2 -molecular–type hydride can downgrade the required pressure to 80 gigapascal while maintaining a high T c of 84 kelvin, well above the liquid-nitrogen temperature. Our study has established a high-temperature superconducting paradigm and opened the prospect for achieving high- T c superconductors in H 2 -molecular–type hydrides at low pressure.
GPT-4o mini: Non-social science research article
Pregnancy and postpartum dynamics revealed by millions of lab tests
Alon Bar, Ron Moran, Netta Mendelsohn-Cohen, Yael Korem Kohanim, Avi Mayo, Yoel Toledano, Uri Alon
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Pregnancy and delivery involve dynamic alterations in many physiological systems. However, the physiological dynamics during pregnancy and after delivery have not been systematically analyzed at high temporal resolution in a large human population. Here, we present the dynamics of 76 lab tests based on a cross-sectional analysis of 44 million measurements from over 300,000 pregnancies. We analyzed each test at weekly intervals from 20 weeks preconception to 80 weeks postpartum, providing detailed temporal profiles. About half of the tests take 3 months to a year to return to baseline postpartum, highlighting the physiological load of childbirth. The precision of the data revealed effects of preconception supplements, overshoots after delivery and intricate temporal responses to changes in blood volume and renal filtration rate. Pregnancy complications—gestational diabetes, preeclampsia, and postpartum hemorrhage—showed distinct dynamical changes. These results provide a comprehensive dynamic portrait of the systems physiology of pregnancy.
GPT-4o mini: Non-social science research article
Stealth and deception: Adaptive motion camouflage in hunting broadclub cuttlefish
Matteo Santon, Jolyon Troscianko, Charlie D. Heatubun, Martin J. How
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Maintaining camouflage while moving is a challenge faced by many predators. Some exploit background motion to hide while hunting, and others may use coloration and behavior to generate motion noise that impairs detection or recognition. Here, we uncover a unique form of motion camouflage, showing that broadclub cuttlefish pass dark stripes downward across their head and arms to disguise their hunting maneuvers. This “passing-stripe” display reduces the probability of response to predatory expanding stimuli by prey crabs in a lab-based experiment, is modulated according to approach speed during a hunt, and generates a motion pattern that is different from that of looming predators. This form of motion camouflage likely functions by overwhelming the threatening motion of the approaching predator with nonthreatening downward motion generated by the rhythmic stripes.
GPT-4o mini: Non-social science research article
Systemic antitumor immune response of doped yttria nanoscintillators under low-dose x-ray irradiation
Onur Sahin, Yuri Mackeyev, Geraldine V. Vijay, Soumyabrata Roy, Ashokkumar Meiyazhagan, Yasmin Zahra, Okan Tezcan, Valeria Gonzalez, Belal Abousaida, Holden R. Wagner, Pearl Fernandes, Riaz Mowzoon-Mogharrabi, Bhanu P. Venkatesulu, Cheng-En Hsieh, Joseph B. K. Kim, Subhiksha Raghuram, Xiang Zhang, Kristen A. Miller, Guanhui Gao, Pankaj K. Singh, Sang Hyun Cho, Rao V. L. Papineni, Pulickel M. Ajayan, Sunil Krishnan
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Inadequate light penetration in tissues restricts photodynamic therapy to treating only superficial tumors. To enable x-ray–excited photodynamic therapy (XPDT) that targets deep-seated tumors, we synthesized a nanoscintillator-photosensitizer complex containing 5% Eu-doped Y 2 O 3 fluorescing at 611 nanometers and decorated with SiO 2 containing the scintillation-coupled photosensitizer methylene blue and a polyethylene glycol coating [PEGylated Y 2 O 3 :Eu@SiO 2 -methylene blue (pYSM)]. When irradiated, pYSMs generate singlet oxygen species in vitro, causing cytotoxicity with hallmarks of immunogenic cell death (calreticulin translocation to the cell membrane). Intravenously administered pYSMs home passively to pancreatic tumor xenografts and, upon 10 gray irradiation, cause significant tumor regression ( P  < 0.01). On combining XPDT with anti-PD1 immunotherapy, a distant nonirradiated tumor also regresses via an increase in intratumoral activated CD8 + cytotoxic T cells. Collectively, we advance a systemically delivered XPDT strategy that mediates an antitumor effect in both irradiated and nonirradiated (abscopal) tumors when coupled with immunotherapy, converting an immunologically “cold” tumor to an immunologically “hot” tumor.
GPT-4o mini: Non-social science research article
Ultrabright difuranfluoreno-dithiophen polymers for enhanced afterglow imaging of atherosclerotic plaques
Zhe Li, Hui Cao, Youjuan Wang, Shiyi Liao, Xu Li, Baode Chen, Xiaosha Wang, Lihui Jiang, Yingping Zou, Xiao-bing Zhang, Guosheng Song
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Cardiovascular diseases, including stroke driven by atherosclerosis, remain a leading global health concern. Current diagnostic imaging modalities such as magnetic resonance imaging fail to characterize oxidative stress within atherosclerotic plaques. Here, we introduce difuranfluoreno-dithiophen–based polymers designed for afterglow imaging, offering ultrabright luminescence, ultralow-power excitation (0.087 milliwatts per square centimeter), and ultrashort acquisition times (0.01 seconds). Through a molecular engineering strategy, we have optimized polymers for enhanced reactive oxygen species (ROS) generation capability, ROS capturing capability, and fluorescence quantum yield, resulting in an increase in afterglow intensity (~130-fold) compared to commonly used 2-methoxy-5-(2â€Č-ethylhexyloxy)-1,4-phenylenevinylene polymer (MEHPPV). Additionally, we have developed ratiometric afterglow nanoparticles doped with oxidative stress–responsive molecules, enabling imaging of oxidative stress markers in atherosclerotic plaque. This approach provides a tool for cardiovascular imaging and diagnostics, which is conducive to the auxiliary diagnosis and risk stratification of atherosclerosis.
GPT-4o mini: Non-social science research article
Parthenocissus -inspired soft climbing robots
Kecheng Qin, Wei Tang, Huaizhi Zong, Xinyu Guo, Huxiu Xu, Yiding Zhong, Yonghao Wang, Qincheng Sheng, Huayong Yang, Jun Zou
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Climbing robots have attracted growing attention due to their mobility on vertical and nonplanar structural surfaces. However, the development of climbing robots capable of climbing on various complex surfaces remains elusive, especially on discontinuous surfaces. In nature, Parthenocissus climbs as it grows, having growing-climbing behaviors. Inspired by Parthenocissus , we propose a growing-climbing mechanism and report a soft climbing robot, which grows microstructured biofilms to enhance adhesion, similar to Parthenocissus growing suckers and adsorbing to the wall. The robot uses shape memory alloy contraction to achieve bending, similar to Parthenocissus using gelatinous fibers contraction to achieve hinge-like bending. In addition, to not damage the site, it can be fully contracted after completing tasks. The climbing robot can climb on various complex surfaces, especially discontinuous surfaces, verifying the effectiveness of Parthenocissus ’ growing-climbing mechanism. The growing-climbing mechanism is a universal climbing robot paradigm, opening a door for complex surface climbing robots.
GPT-4o mini: Non-social science research article
Astrobiological implications of the stability and reactivity of peptide nucleic acid (PNA) in concentrated sulfuric acid
Janusz J. Petkowski, Sara Seager, Maxwell D. Seager, William Bains, Nittert Marinus, Mael Poizat, Chad Plumet, Jim van Wiltenburg, Ton Visser, Martin Poelert
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Recent renewed interest regarding the possibility of life in the Venusian clouds has led to new studies on organic chemistry in concentrated sulfuric acid. However, life requires complex genetic polymers for biological function. Therefore, finding suitable candidates for genetic polymers stable in concentrated sulfuric acid is a necessary first step to establish that biologically functional macromolecules can exist in this environment. We explore peptide nucleic acid (PNA) as a candidate for a genetic-like polymer in a hypothetical sulfuric acid biochemistry. PNA hexamers undergo between 0.4 and 28.6% degradation in 98% (w/w) sulfuric acid at ~25°C, over the span of 14 days, depending on the sequence, but undergo complete solvolysis above 80°C. Our work is the first key step toward the identification of a genetic-like polymer that is stable in this unique solvent and further establishes that concentrated sulfuric acid can sustain a diverse range of organic chemistry that might be the basis of a form of life different from Earth’s.
GPT-4o mini: Non-social science research article
Skin-interfaced multimodal sensing and tactile feedback system as enhanced human-machine interface for closed-loop drone control
Chunki Yiu, Yiming Liu, Wooyoung Park, Jian Li, Xingcan Huang, Kuanming Yao, Yuyu Gao, Guangyao Zhao, Hongwei Chu, Jingkun Zhou, Dengfeng Li, Hu Li, Binbin Zhang, Lung Chow, Ya Huang, Qingsong Xu, Xinge Yu
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Unmanned aerial vehicles have undergone substantial development and market growth recently. With research focusing on improving control strategies for better user experience, feedback systems, which are vital for operator awareness of surroundings and flight status, remain underdeveloped. Current bulky manipulators also hinder accuracy and usability. Here, we present an enhanced human-machine interface based on skin-integrated multimodal sensing and feedback devices for closed-loop drone control. This system captures hand gestures for intuitive, rapid, and precise control. An integrated tactile actuator array translates the drone’s posture into two-dimensional tactile information, enhancing the operator’s perception of the flight situation. Integrated obstacle detection and neuromuscular electrical stimulation–based force feedback system enable collision avoidance and flight path correction. This closed-loop system combines intuitive controls and multimodal feedback to reduce training time and cognitive load while improving flight stability, environmental awareness, and the drone’s posture. The use of stretchable electronics also addresses wearability and bulkiness issues in traditional systems, advancing human-machine interface design.
GPT-4o mini: Non-social science research article
Histone modification–driven structural remodeling unleashes DNMT3B in DNA methylation
Chao-Cheng Cho, Hsun-Ho Huang, Bo-Chen Jiang, Wei-Zen Yang, Yi-Ning Chen, Hanna S. Yuan
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The DNA methyltransferase 3B (DNMT3B) plays a vital role in shaping DNA methylation patterns during mammalian development. DNMT3B is intricately regulated by histone H3 modifications, yet the dynamic interplay between DNMT3B and histone modifications remains enigmatic. Here, we demonstrate that the PWWP (proline-tryptophan-tryptophan-proline) domain within DNMT3B exhibits remarkable dynamics that enhances the enzyme’s methyltransferase activity upon interactions with a modified histone H3 peptide (H3K4 me0 K36 me3 ). In the presence of H3K4 me0 K36 me3 , both the PWWP and ADD (ATRX-DNMT3-DNMT3L) domains transition from autoinhibitory to active conformations. In this active state, the PWWP domain most often aligns closely with the catalytic domain, allowing for simultaneous interactions with H3 and DNA to stimulate DNA methylation. The prostate cancer–associated DNMT3B R545C mutant is even more dynamic and susceptible to adopting the active conformation, resulting in aberrant DNA hypermethylation. Our study suggests the mechanism by which conformational rearrangements in DNMT3B are triggered by histone modifications, ultimately unleashing its activity in DNA methylation.
GPT-4o mini: Non-social science research article
Sub-wavelength optical lattice in 2D materials
Supratik Sarkar, Mahmoud Jalali Mehrabad, Daniel G. SuĂĄrez-Forero, Liuxin Gu, Christopher J. Flower, Lida Xu, Kenji Watanabe, Takashi Taniguchi, Suji Park, Houk Jang, You Zhou, Mohammad Hafezi
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Recently, light-matter interaction has been vastly expanded as a control tool for inducing and enhancing many emergent nonequilibrium phenomena. However, conventional schemes for exploring such light-induced phenomena rely on uniform and diffraction-limited free-space optics, which limits the spatial resolution and the efficiency of light-matter interaction. Here, we overcome these challenges using metasurface plasmon polaritons (MPPs) to form a sub-wavelength optical lattice. Specifically, we report a “nonlocal” pump-probe scheme where MPPs are excited to induce a spatially modulated AC Stark shift for excitons in a monolayer of MoSe 2 , several microns away from the illumination spot. We identify nearly two orders of magnitude reduction for the required modulation power compared to the free-space optical illumination counterpart. Moreover, we demonstrate a broadening of the excitons’ linewidth as a robust signature of MPP-induced periodic sub-diffraction modulation. Our results will allow exploring power-efficient light-induced lattice phenomena below the diffraction limit in active chip-compatible MPP architectures.
GPT-4o mini: Non-social science research article
Physiology and climate change explain unusually high similarity across marine communities after end-Permian mass extinction
Jood A. Al Aswad, Justin L. Penn, Pedro M. Monarrez, Mohamad Bazzi, Curtis Deutsch, Jonathan L. Payne
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Fossil assemblages exhibit a global depletion in taxonomic distinctiveness in the aftermath of the end-Permian mass extinction (~252 million years ago), but little is known about why. Here, we examine whether biotic homogenization can be explained by tropical survivors tracking an expansion of their preferred habitat, measured in terms of the ratio of environmental oxygen supply to metabolic demand. We compare spatial similarity in community composition among marine invertebrate fossils represented by bivalve and gastropod fossils with predictions from an ecophysiological model of habitat that diagnoses areas in the ocean that can sustain the aerobic requirements of marine invertebrates. Modeled biogeographic responses to climate change yield an increase in global similarity of community composition among surviving ecophysiotypes, consistent with patterns in the fossil record and arguing for a physiological control on earliest Triassic biogeography.
GPT-4o mini: Non-social science research article
Anthropogenic activity and climate change exacerbate the spread of pathogenic bacteria in the environment
Yu Geng, Ya Liu, Peng Li, Jingyu Sun, Yiru Jiang, Zhuo Pan, Yue-Zhong Li, Zheng Zhang
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Climate change is profoundly affecting human health. Human pathogenic bacteria (HPB) infections mediated by the environment are considered a substantial cause of global health losses. However, the biogeography of HPB and their response to climate change remain largely unknown. Here, we constructed and analyzed a global atlas of potential HPB using 1,066,584 samples worldwide. HPB are widely present in the global environment, and their distribution follows a latitudinal diversity gradient. Climate and anthropogenic factors are identified as major drivers of the global distribution of HPB. Our predictions indicated that by the end of this century, the richness, abundance, and invasion risk of HPB will increase globally, with this upward trend becoming more pronounced as development sustainability declines. Therefore, the threat of environmentally mediated HPB infections to human health may be more severe in a world where anthropogenic activities are intensifying and the global climate is warming.
GPT-4o mini: Non-social science research article
Untethered subcentimeter flying robots
Fanping Sui, Wei Yue, Kamyar Behrouzi, Yuan Gao, Mark Mueller, Liwei Lin
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The miniaturization of insect-scale flying robots with untethered flights is extremely challenging as the tradeoff between mass and power becomes problematic. Here, a subcentimeter rotating-wing robot of 21 mg in weight and 9.4 mm in wingspan driven by a single-axis alternating magnetic field has accomplished navigable flights. This artificial flying robot is the lightest and smallest to realize untethered and controllable aerial travels including hovering, collision recovery, and route adjustments. Experimentally, it has achieved a high aerodynamic efficacy with a measured lift-to-drag ratio of 0.7 and lift–to–flying power ratio of 7.2 × 10 −2 N/W at a Reynolds number of ~2500. The wireless driving mechanism, system operation principle, and flight characteristics can be further optimized for the advancement and miniaturization of subcentimeter scale flying robots.
GPT-4o mini: Non-social science research article
WWC1 mutation drives dopamine dysregulation and synaptic imbalance in Tourette’s syndrome
Junkai Lv, Shiqi Liang, Pengwei Qin, Xinlu Liu, Xiangyu Ge, Yiqing Guo, Shili Xia, Wei Jing, Youming Lu, Tongmei Zhang, Hao Li
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Tourette’s syndrome (TS) is a major neurodevelopmental disorder characterized by childhood-onset motor and vocal tics. A W88C mutation in WWC1 gene is a notable risk factor for TS, but the underlying molecular mechanisms remain unclear due to the lack of suitable animal models. Here, we generate a mutant mouse line with human W88C mutation (W88C Mut mice), which exhibits behavioral deficits similar to those observed in patients with TS, including repetitive motor behaviors and sensorimotor gating abnormalities. The W88C mutation leads to the degradation of kidney and brain (KIBRA) protein via a proteasomal pathway, evokes dopamine release in the dorsal striatum, and disrupts synaptic function through the dysregulation of Hippo pathway. Neuron-specific overexpression of wild-type WWC1 rescues synaptic and behavioral phenotypes in W88C Mut mice. Together, this study not only provides a valuable mouse model for studying TS but also offers fresh insights into the molecular and synaptic mechanisms underlying neurodevelopmental abnormalities in TS.
GPT-4o mini: Non-social science research article
Neuraminidase-specific antibodies drive differential cross-protection between contemporary FLUBV lineages
Caroline K. Page, Justin D. Shepard, Sean D. Ray, James A. Ferguson, Alesandra J. Rodriguez, Julianna Han, Joel C. Jacob, Dawne K Rowe-Haas, Jasmine Y. Akinpelu, Lilach M. Friedman, Tomer Hertz, Andrew B. Ward, Stephen M. Tompkins
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The two influenza B virus (FLUBV) lineages have continuously diverged from each other since the 1980s, with recent (post-2015) viruses exhibiting accelerated evolutionary rates. Emerging data from human studies and epidemiological models suggest that increased divergence in contemporary viruses may drive differential cross-protection, where infection with Yamagata lineage viruses provides limited immunity against Victoria lineage viruses. Here, we developed animal models to investigate the mechanisms behind asymmetric cross-protection between contemporary FLUBV lineages. Our results show that contemporary Victoria immunity provides robust cross-protection against the Yamagata lineage, whereas Yamagata immunity offers limited protection against the Victoria lineage. This differential cross-protection is driven by Victoria-elicited neuraminidase (NA)–specific antibodies, which show cross-lineage reactivity, unlike those from Yamagata infections. These findings identify a phenomenon in contemporary FLUBV that may help explain the recent disappearance of the Yamagata lineage from circulation, highlighting the crucial role of targeting NA in vaccination strategies to enhance cross-lineage FLUBV protection.
GPT-4o mini: Non-social science research article
Metal-assisted vacuum transfer enabling in situ visualization of charge density waves in monolayer MoS 2
Jichuang Shen, Xiaopeng Xie, Wenhao Li, Chaoyue Deng, Yaqing Ma, Han Chen, Huixia Fu, Fang-Sen Li, Bingkai Yuan, Chen Ji, Ruihua He, Jiaqi Guan, Wei Kong
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Recent advancements in quantum materials research have focused on monolayer transition metal dichalcogenides and their heterostructures, known for complex electronic phenomena. While macroscopic electrical and magnetic measurements provide valuable insights, understanding these electronic states requires direct experimental observations. Yet, the extreme two-dimensionality of these materials demands surface-sensitive measurements with exceptionally clean surfaces. Here, we present the metal-assisted vacuum transfer method combined with in situ measurements in ultrahigh vacuum (UHV), enabling pristine monolayer MoS 2 with ultraclean surfaces unexposed to ambient conditions. Consequently, in situ scanning tunneling microscopy revealed charge density waves (CDWs) in MoS 2 /Cu(111), previously unobserved in monolayer MoS 2 . Additionally, angle-resolved photoelectron spectroscopy identified notable Fermi surface nesting due to substrate interactions, elucidating the mechanisms behind CDW formation. This method is broadly applicable to other monolayer two-dimensional materials, enabling the high-fidelity in situ UHV characterization and advancing the understanding of correlated electronic behaviors in these material systems.
GPT-4o mini: Non-social science research article
Scalable fabrication of Chip-integrated 3D-nanostructured electronic devices via DNA-programmable assembly
Aaron Michelson, Lior Shani, Jason S. Kahn, Daniel C. Redeker, Won-Il Lee, Katerina R. DeOlivares, Kim Kisslinger, Nikhil Tiwale, Hanfei Yan, Ajith Pattammattel, Chang-Yong Nam, Vlad S. Pribiag, Oleg Gang
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DNA-based self-assembly methods have demonstrated powerful and unique capabilities to encode nanomaterial structures through the prescribed placement of inorganic and biological nanocomponents. However, the challenge of selectively growing DNA superlattices on specific locations of surfaces and their integration with conventional nanofabrication has hindered the fabrication of three-dimensional (3D) DNA-assembled functional devices. Here, we present a scalable nanofabrication technique that combines bottom-up and top-down approaches for selective growth of 3D DNA superlattices on gold microarrays. This approach allows for the fabrication of self-assembled 3D-nanostructured electronic devices. DNA strands are bound onto the gold arrays, which anchor DNA origami frames and promote ordered framework growth on the specific areas of the surface, enabling control of the lateral placement and orientation of superlattices. DNA frameworks selectively grown on the pads are subsequently templated to nanoscale silica and tin oxide (SnO x ) that follow the architecture, as confirmed by structural and chemical characterizations. The fabricated SnO x superlattices are integrated into devices that demonstrate photocurrent response.
GPT-4o mini: Non-social science research article
Steroid hormone levels vary with sex, aging, lifestyle, and genetics
LĂ©a G. Deltourbe, Jamie Sugrue, Elizabeth Maloney, Florian Dubois, Anthony Jaquaniello, Jacob Bergstedt, Etienne Patin, Lluis Quintana-Murci, Molly A. Ingersoll, Darragh Duffy, character(0)
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Steroid hormone levels vary greatly among individuals, between sexes, with age, and across health and disease. What drives variance in steroid hormones and how they vary in individuals over time are not well studied. To address these questions, we measured 17 steroid hormones in a sex-balanced cohort of 949 healthy donors aged 20 to 69 years. We investigated associations between steroid levels and biological sex, age, clinical and demographic data, genetics, and plasma proteomics. Steroid hormone levels were strongly affected by sex and age, and a high number of lifestyle habits. Key observations were the broad impact of hormonal birth control in female donors and the relationship with smoking in male donors. In a 10-year follow-up study, we identified significant associations between steroid hormone levels and health status only in male donors. These observations highlight biological and lifestyle parameters affecting steroid hormones, and underlie the importance of considering sex, age, and potentially gendered behaviors in the treatment of hormone-related diseases.
GPT-4o mini: Non-social science research article
Electrophoretic digital colorimetry integrated with electrochemical sweat sensor
Daeun Sung, Seunghun Han, Sumin Kim, Heeseok Kang, Bon Jekal, Giheon Kim, Jaewon Kim, Minki Hong, Gyounghwan Moon, Sungeun Kim, Yerim Lee, Suk-Won Hwang, Hyoyoung Jeong, Yong-Sang Ryu, Sungbong Kim, Jahyun Koo
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Recent advancements in wearable sweat sensors, which use standardized electrochemical and colorimetric mechanisms, offer holistic representation of health status for users. However, the constraints of standardized sweat sensors present ongoing challenges to realization of personalized health management. This study presents an electrocolorimetric (EC) platform that enables the reversible and multiple-time use of colorimetric data visualization using electrophoretic display (EPD). This platform represents the application of low-power EPD in epidermal sweat sensor, evaluated through CIELAB-based methodology which is the first systematic evaluation tool of wearable display performance. Moreover, our platform has been demonstrated in human exercise trials for its ability to detect the lactate threshold (LT). This digital colorimetric system has the potential to play a pivotal role by integrating various health monitoring biomarkers. While providing real-time, continuous, and adjustable range information with high sensitivity, this platform validates its extensive probability as a next-generation wearable epidermal sensor.
GPT-4o mini: Non-social science research article
An in vivo screen identifies NAT10 as a master regulator of brain metastasis
Jocelyn F. Chen, Peng Xu, Wesley L. Cai, Huacui Chen, Emily Wingrove, Xiaojian Shi, Wenxue Li, Giulia Biancon, Meiling Zhang, Amer Balabaki, Ethan D. Krop, Elianna Asare, Yangyi Zhang, Mingzhu Yin, Toma Tebaldi, Jordan L. Meier, Thomas F. Westbrook, Stephanie Halene, Yansheng Liu, Hongying Shen, Don X. Nguyen, Qin Yan
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Emerging evidence has shown that epigenetic regulation plays a fundamental role in cancer metastasis, the major cause of cancer-related deaths. Here, we conducted an in vivo screen for vulnerabilities of brain metastasis and identified N -acetyltransferase 10 (NAT10) as a driver of brain metastasis. Knockdown of NAT10 restrains cancer cell proliferation and migration in vitro and tumor growth and brain metastasis in vivo. The poorly characterized RNA helicase domain of NAT10 is critical for cell growth in vitro, while both RNA helicase and NAT domains are essential for primary tumor growth and brain metastasis in vivo. Mechanically, NAT10 promotes the expression of 3-phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), two enzymes for serine biosynthesis implicated in brain metastasis. Silencing PHGDH or PSAT1 in metastatic breast cancer cells inhibits their growth in the serine/glycine-limited condition, phenocopying the effects of NAT10 depletion. These findings establish NAT10 as a key regulator of brain metastasis and nominate NAT10 as a target for treating metastasis.
GPT-4o mini: Non-social science research article
Frontal noradrenergic and cholinergic transients exhibit distinct spatiotemporal dynamics during competitive decision-making
Hongli Wang, Heather K. Ortega, Emma B. Kelly, Jonathan Indajang, Neil K. Savalia, Samira Glaeser-Khan, Jiesi Feng, Yulong Li, Alfred P. Kaye, Alex C. Kwan
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Norepinephrine (NE) and acetylcholine (ACh) are crucial for learning and decision-making. In the cortex, NE and ACh are released transiently at specific sites along neuromodulatory axons, but how the spatiotemporal patterns of NE and ACh signaling link to behavioral events is unknown. Here, we use two-photon microscopy to visualize neuromodulatory signals in the premotor cortex (medial M2) as mice engage in a competitive matching pennies game. Spatially, NE signals are more segregated with choice and outcome encoded at distinct locations, whereas ACh signals can multiplex and reflect different behavioral correlates at the same site. Temporally, task-driven NE transients were more synchronized and peaked earlier than ACh transients. To test functional relevance, we stimulated neuromodulatory signals using optogenetics to find that NE, but not ACh, increases the animals’ propensity to explore alternate options. Together, the results reveal distinct subcellular spatiotemporal patterns of ACh and NE transients during decision-making in mice.
GPT-4o mini: Non-social science research article
Mycobacterium tuberculosis phagosome Ca 2+ leakage triggers multimembrane ATG8/LC3 lipidation to restrict damage in human macrophages
Di Chen, Antony Fearns, Maximiliano G. Gutierrez
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The role of canonical autophagy in controlling Mycobacterium tuberculosis (Mtb), referred to as xenophagy, is understood to involve targeting Mtb to autophagosomes, which subsequently fuse with lysosomes for degradation. Here, we found that Ca 2+ leakage after Mtb phagosome damage in human macrophages is the signal that triggers autophagy-related protein 8/microtubule-associated proteins 1A/1B light chain 3 (ATG8/LC3) lipidation. Unexpectedly, ATG8/LC3 lipidation did not target Mtb to lysosomes, excluding the canonical xenophagy. Upon Mtb phagosome damage, the Ca 2+ leakage–dependent ATG8/LC3 lipidation occurred on multiple membranes instead of single or double membranes excluding the noncanonical autophagy pathways. Mechanistically, Ca 2+ leakage from the phagosome triggered the recruitment of the V-ATPase–ATG16L1 complex independently of FIP200, ATG13, and proton gradient disruption. Furthermore, the Ca 2+ leakage–dependent ATG8/LC3 lipidation limited Mtb phagosome damage and restricted Mtb replication. Together, we uncovered Ca 2+ leakage as the key signal that triggers ATG8/LC3 lipidation on multiple membranes to mitigate Mtb phagosome damage.
GPT-4o mini: Non-social science research article
Reelin marks cocaine-activated striatal neurons, promotes neuronal excitability, and regulates cocaine reward
Kasey L. Brida, Emily T. Jorgensen, Robert A. Phillips III, Catherine E. Newman, Jennifer J. Tuscher, Emily K. Morring, Morgan E. Zipperly, Lara Ianov, Kelsey D. Montgomery, Madhavi Tippani, Thomas M. Hyde, Kristen R. Maynard, Keri Martinowich, Jeremy J. Day
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Drugs of abuse activate defined neuronal populations in reward structures such as the nucleus accumbens (NAc), which promote the enduring synaptic, circuit, and behavioral consequences of drug exposure. While the molecular and cellular effects arising from experience with drugs like cocaine are increasingly well understood, mechanisms that dictate NAc neuronal recruitment remain unknown. Here, we leveraged unbiased single-nucleus transcriptional profiling and targeted in situ detection to identify Reln (encoding the secreted glycoprotein, Reelin) as a marker of cocaine-activated neuronal populations within the rat NAc. A CRISPR interference approach enabling selective Reln knockdown in the adult NAc altered expression of calcium signaling genes, promoted a transcriptional trajectory consistent with loss of cocaine sensitivity, and decreased MSN excitability. Behaviorally, Reln knockdown prevented cocaine locomotor sensitization, abolished cocaine place preference memory, and decreased cocaine self-administration behavior. These results identify Reelin as a critical mechanistic link between neuronal activation and cocaine-induced behavioral adaptations.
GPT-4o mini: Non-social science research article
Learning the rules of peptide self-assembly through data mining with large language models
Zhenze Yang, Sarah K. Yorke, Tuomas P. J. Knowles, Markus J. Buehler
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Peptides are ubiquitous and important biomolecules that self-assemble into diverse structures. Although extensive research has explored the effects of chemical composition and exterior conditions on self-assembly, a systematic study consolidating these data to uncover global rules is lacking. In this work, we curate a peptide assembly database through a combination of manual processing by human experts and large language model–assisted literature mining. As a result, we collect over 1000 experimental data entries with information about peptide sequence, experimental conditions, and corresponding self-assembly phases. Using the data, machine learning models are developed, demonstrating excellent accuracy (>80%) in assembly phase classification. Moreover, we fine-tune a GPT model for peptide literature mining with the developed dataset, which markedly outperforms the pretrained model in extracting information from academic publications. This workflow can improve efficiency when exploring potential self-assembling peptide candidates, through guiding experimental work, while also deepening our understanding of the governing mechanisms.
GPT-4o mini: Non-social science research article
The emergence of human primordial germ cell–like cells in stem cell–derived gastruloids
Jitesh Neupane, Gabriele Lubatti, Theresa Gross-Thebing, Mayra Luisa Ruiz Tejada Segura, Richard Butler, Sargon Gross-Thebing, Sabine Dietmann, Antonio Scialdone, M. Azim Surani
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Most advances in early human postimplantation development depend on animal studies and stem cell–based embryo models. Here, we present self-organized three-dimensional human gastruloids (hGs) derived from embryonic stem cells. The transcriptome profile of day 3 hGs aligned with Carnegie stage 7 human gastrula, with cell types and differentiation trajectories consistent with human gastrulation. Notably, we observed the emergence of nascent primordial germ cell–like cells (PGCLCs), but without exogenous bone morphogenetic protein (BMP) signaling, which is essential for the PGCLC fate. A mutation in the ISL1 gene affects amnion-like cells and leads to a loss of PGCLCs; the addition of exogenous BMP2 rescues the PGCLC fate, indicating that the amnion may provide endogenous BMP signaling. Our model of early human embryogenesis will enable further exploration of the germ line and other early human lineages.
GPT-4o mini: Non-social science research article
Programmable engineered bacteria as sustained-releasing antibody factory in situ for enhancing tumor immune checkpoint therapy
Xiao-Ting Xie, Meng Guan, Kai Cheng, Yong Li, Bin Zhang, Yi-Tong Zhou, Lin-Fang Tan, Peng-Shuo Dong, Si Chen, Bo Liu, Yuan-Di Zhao, Jin-Xuan Fan
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Tumor immune checkpoint therapy (ICT) aims to block immune escape signals between tumor and immune cells. However, low delivery efficiency of immune checkpoint inhibitors (ICIs), narrow single-target approach, and reduced responsiveness notably hinder clinical development of ICT. Here, we developed a nanoliposome-bacteria hybrid system that acts as an antibody (Ab) factory, enabling precise tumor targeting and macrophage activation in hypoxic environments. We reprogrammed attenuated Escherichia coli MG1655 to synthesize CD47 antibodies (aCD47) in response to hypoxic tumor microenvironments while surface conjugating with redox-responsive macrophage colony-stimulating factor-loaded liposomes. This system leverages bacterial tropism to enhance macrophage infiltration and polarization. The low oxygen levels trigger in situ aCD47 expression, blocking the “do not eat me” signal and boosting macrophage antitumor activity. In addition, macrophage antigen presentation activates CD8+CD3+ T cells, amplifying systemic antitumor immunity. Analysis of the gut microbiome shows reduced pathogenicity and improved intestinal tolerance with increased probiotics.
GPT-4o mini: Non-social science research article
The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21
Suowen Xu, Zhenghong Liu, Tian Tian, Wenqi Zhao, Zhihua Wang, Monan Liu, Mengyun Xu, Fanshun Zhang, Zhidan Zhang, Meijie Chen, Yanjun Yin, Meiming Su, Wenxiang Fang, Wenhao Pan, Shiyong Liu, Min-dian Li, Peter J. Little, Danielle Kamato, Songyang Zhang, Dongdong Wang, Stefan Offermanns, John R. Speakman, Jianping Weng
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Obesity is a debilitating global pandemic with a huge cost on health care due to it being a major underlying risk factor for several diseases. Therefore, there is an unmet medical need for pharmacological interventions to curb obesity. Here, we report that halofuginone, a Food and Drug Administration–approved anti-scleroderma and antiprotozoal drug, is a promising anti-obesity agent in preclinical mouse and pig models. Halofuginone suppressed food intake, increased energy expenditure, and resulted in weight loss in diet-induced obese mice while also alleviating insulin resistance and hepatic steatosis. Using molecular and pharmacological tools with transcriptomics, we identified that halofuginone increases fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) levels via activating integrated stress response. Using Gdf15 and Fgf21 knockout mice, we show that both hormones are necessary to elicit anti-obesity changes. Together, our study reports the beneficial metabolic effects of halofuginone and underscores its utility in treating obesity and its associated metabolic complications, which merits clinical assessment.
GPT-4o mini: Non-social science research article
Phosphorylation at serine-260 of Toc33 is essential for chloroplast biogenesis
Yuan-Chi Chien, Gyeong Mee Yoon
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Chloroplast biogenesis, essential for photosynthesis, depends on the import of nuclear-encoded proteins through the translocon at the outer envelope of chloroplasts (TOC) complexes. Despite its importance, the mechanisms regulating this process remain largely elusive. We identify serine-260 (S260) as a critical phosphorylation site in Toc33, a core TOC component. This phosphorylation stabilizes Toc33 by preventing its ubiquitination and degradation. Constitutive triple response 1 (CTR1), a negative regulator of ethylene signaling, and its paralog RAF-like kinase are involved in phosphorylating Toc33. Disruption of Toc33 phosphorylation impairs its stability and photosynthetic protein import, consequently affecting chloroplast structural integrity and biogenesis. Our findings underscore the essential role of TOC phosphorylation in chloroplast biogenesis and reveal an unexpected regulatory network involving RAF-like kinases in organelle development.
GPT-4o mini: Non-social science research article
Structural basis for the pore-forming activity of a complement-like toxin
Bronte A. Johnstone, Michelle P. Christie, Riya Joseph, Craig J. Morton, Hamish G. Brown, Eric Hanssen, Tristan C. Sanford, Hunter L. Abrahamsen, Rodney K. Tweten, Michael W. Parker
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Pore-forming proteins comprise a highly diverse group of proteins exemplified by the membrane attack complex/perforin (MACPF), cholesterol-dependent cytolysin (CDC), and gasdermin superfamilies, which all form gigantic pores (>150 angstroms). A recently found family of pore-forming toxins, called CDC-like proteins (CDCLs), are wide-spread in gut microbes and are a prevalent means of antibacterial antagonism. However, the structural aspects of how CDCLs assemble a pore remain a mystery. Here, we report the crystal structure of a proteolytically activated CDCL and cryo–electron microscopy structures of a prepore-like intermediate and a transmembrane pore providing detailed snapshots across the entire pore-forming pathway. These studies reveal a sophisticated array of regulatory features to ensure productive pore formation, and, thus, CDCLs straddle the MACPF, CDC, and gasdermin lineages of the giant pore superfamilies.
GPT-4o mini: Non-social science research article
Computational capacity of life in relation to the universe
Philip Kurian
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As physical systems, all life in the universe processes information according to physical laws. Estimates for the computational capacity of living systems generally assume that the fundamental information-processing unit is the Hodgkin-Huxley neuron, thereby excluding aneural organisms. Assuming the laws of quantum mechanics, the relativistic speed limit set by light, a universe at critical mass-energy density, and a recent experimental demonstration of single-photon superradiance in cytoskeletal protein fibers at thermal equilibrium, it is conjectured that the number of elementary logical operations that can have been performed by all eukaryotic life in the history of Earth, which is shown to be approximately equal to the ratio of the age of the universe to the Planck time, is about the square root of the number by the entire observable universe from the beginning. The existence of ultraviolet-excited ∣ W âŒȘ states in these protein fibers, operating within two orders of magnitude of the Margolus-Levitin speed limit, motivates state-of-the-art performance comparisons with contemporary quantum computers.
GPT-4o mini: Non-social science research article
Perturbed cell fate decision by schizophrenia-associated AS3MT d2d3 isoform during corticogenesis
Seunghyun Kim, Youngsik Woo, Dahun Um, Inseop Chun, Su-Jin Noh, Hyeon Ah Ji, Namyoung Jung, Bon Seong Goo, Jin Yeong Yoo, Dong Jin Mun, Tran Diem Nghi, Truong Thi My Nhung, Seung Hyeon Han, Su Been Lee, Wonhyeok Lee, Jonghyeok Yun, Ki Hurn So, Dae-Kyum Kim, Hyunsoo Jang, Yeongjun Suh, Jong-Cheol Rah, Seung Tae Baek, Ki-Jun Yoon, Min-Sung Kim, Tae-Kyung Kim, Sang Ki Park
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The neurodevelopmental theory of schizophrenia emphasizes early brain development in its etiology. Genome-wide association studies have linked schizophrenia to genetic variations of AS3MT (arsenite methyltransferase) gene, particularly the increased expression of AS3MT d2d3 isoform. To investigate the biological basis of this association with schizophrenia pathophysiology, we established a transgenic mouse model (AS3MT d2d3 -Tg) ectopically expressing AS3MT d2d3 at the cortical neural stem cells. AS3MT d2d3 -Tg mice exhibited enlarged ventricles and deficits in sensorimotor gating and sociability. Single-cell and single-nucleus RNA sequencing analyses of AS3MT d2d3 -Tg brains revealed cell fate imbalances and altered excitatory neuron composition. AS3MT d2d3 localized to centrosome, disrupting mitotic spindle orientation and differentiation in developing neocortex and organoids, in part through NPM1 (Nucleophosmin 1). The structural analysis identified that hydrophobic residues exposed in AS3MT d2d3 are critical for its pathogenic function. Therefore, our findings may help to explain the early pathological features of schizophrenia.
GPT-4o mini: Non-social science research article
Synthesis of Ti 4 Au 3 C 3 and its derivative trilayer goldene through chemical exfoliation
Yuchen Shi, Shun Kashiwaya, Jun Lu, Martin Dahlqvist, Davide G. Sangiovanni, Vladyslav Rogoz, Martin Magnuson, Grzegorz Greczynski, Mike Andersson, Johanna Rosen, Lars Hultman
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Achieving large two-dimensional (2D) sheets of any metal is challenging due to their tendency to coalescence or cluster into 3D shapes. Recently, single-atom-thick gold sheets, termed goldene, was reported. Here, we ask if goldene can be extended to include multiple layers. The answer is yes, and trilayer goldene is the magic number, for reasons of electronegativity. Experiments are made to synthesize the atomically laminated phase Ti 4 Au 3 C 3 through substitutional intercalation of Si layers in Ti 4 SiC 3 for Au. Density functional theory calculations suggest that it is energetically favorable to insert three layers of Au into Ti 4 SiC 3 , compared to inserting a monolayer, a bilayer, or more than three layers. Isolated trilayer goldene sheets, ~100 nanometers wide and 6.7 angstroms thick, were obtained by chemically etching the Ti 4 C 3 layers from Ti 4 Au 3 C 3 templates. Furthermore, trilayer goldene is found in both hcp and fcc forms, where the hcp is ~50 milli–electron volts per atom more stable at room temperature from ab initio molecular dynamic simulations.
GPT-4o mini: Non-social science research article
Xenotopic synthetic biology: Prospective tools for delaying aging and age-related diseases
Andrey A. Parkhitko, Valentin Cracan
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Metabolic dysregulation represents one of the major driving forces in aging. Although multiple genetic and pharmacological manipulations are known to extend longevity in model organisms, aging is a complex trait, and targeting one’s own genes may be insufficient to prevent age-dependent deterioration. An alternative strategy could be to use enzymes from other species to reverse age-associated metabolic changes. In this review, we discuss a set of enzymes from lower organisms that have been shown to affect various metabolic parameters linked to age-related processes. These enzymes include modulators of steady-state levels of amino acids (METase, ASNase, and ADI), NADPH/NADP + and/or reduced form of coenzyme Q (CoQH 2 )/CoQ redox potentials (NDI1, AOX, Lb NOX, TPNOX, Ec STH, RquA, LOXCAT, Grubraw, and ScURA), GSH (StGshF), mitochondrial membrane potential (mtON and mito-dR), or reactive oxygen species (DAAO and KillerRed-SOD1). We propose that leveraging non-mammalian enzymes represents an untapped resource that can be used to delay aging and age-related diseases.
GPT-4o mini: Non-social science research article
A millisecond integrated quantum memory for photonic qubits
Yu-Ping Liu, Zhong-Wen Ou, Tian-Xiang Zhu, Ming-Xu Su, Chao Liu, Yong-Jian Han, Zong-Quan Zhou, Chuan-Feng Li, Guang-Can Guo
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Quantum memories for light are essential building blocks for quantum repeaters and quantum networks. Integrated operations of quantum memories could enable scalable application with low-power consumption. However, the photonic quantum storage lifetime in integrated devices has so far been limited to tens of microseconds, falling short of the requirements for practical applications. Here, we demonstrate quantum storage of photonic qubits for 1.021 milliseconds based on a laser-written optical waveguide fabricated in a 151 Eu 3+ :Y 2 SiO 5 crystal. Spin dephasing of 151 Eu 3+ is mitigated through dynamical decoupling applied via on-chip electric waveguides, and we obtain a storage efficiency of 12.0 ± 0.5% at 1.021 milliseconds, which is a demonstration of integrated quantum memories that outperforms the efficiency of a simple fiber delay line. Such long-lived waveguide-based quantum memory could support applications in quantum repeaters, and further combination with critical magnetic fields could enable potential application as transportable quantum memories.
GPT-4o mini: Non-social science research article
HMCES corrupts replication fork stability during base excision repair in homologous recombination–deficient cells
María José Peña-Gómez, Yaiza Rodríguez-Martín, Marta del Rio Oliva, Yodhara Wijesekara Hanthi, Sara Berrada, Raimundo Freire, Jean Yves Masson, José Carlos Reyes, Vincenzo Costanzo, Ivån V. Rosado
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Apurinic/apyrimidinic (AP) sites and single-strand breaks arising from base excision repair (BER) during the misincorporation of damaged nucleobases may hinder replication fork stability in homologous recombination–deficient (HRD) cells. At templated AP sites, cross-links between the DNA and 5-hydroxymethylcytosine binding, embryonic stem cell–specific (HMCES) regulate replication fork speed, avoiding cytotoxic double-strand breaks. While the role of HMCES at the template DNA strand is well studied, its effects on nascent DNA are not. We provide evidence that HMCES–DNA-protein cross-links (DPCs) are detrimental to the BER-mediated removal of 5-hydroxymethyl-2â€Č-deoxycytidine (5hmdC)–derived 5-hydroxymethyl-2â€Č-deoxyuridine from replication forks. HRD cells have heightened HMCES-DPCs, which increase further upon 5hmdC exposure, suggesting that HMCES binds both spontaneous and 5hmdC-induced AP sites. HMCES depletion substantially suppresses 5hmdC-mediated replication fork defects, chromosomal aberrations, and cell death in HRD cells. This reveals that HMCES-DPCs are a source of BER-initiated single-stranded DNA gaps, which indicates that endogenous DPCs contribute to genomic instability in HRD tumors.
GPT-4o mini: Non-social science research article
Systematic high-throughput evaluation reveals FrCas9’s superior specificity and efficiency for therapeutic genome editing
Rui Tian, Xun Tian, Meiying Yang, Yuping Song, Tingting Zhao, Chaoyue Zhong, Wei Zhu, Ping Zhou, Zhiqiang Han, Zheng Hu
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CRISPR-Cas9 systems have revolutionized genome editing, but the off-target effects of Cas9 limit its use in clinical applications. Here, we systematically evaluate FrCas9, a variant from Faecalibaculum rodentium , for cell and gene therapy (CGT) applications and compare its performance to SpCas9 and OpenCRISPR-1. OpenCRISPR-1 is a CRISPR system synthesized de novo using large language models (LLMs) but has not yet undergone systematic characterization. Using AID-seq, Amplicon sequencing, and GUIDE-seq, we assessed the on-target activity and off-target profiles of these systems across multiple genomic loci. FrCas9 demonstrated higher on-target efficiency and substantially fewer off-target effects than SpCas9 and OpenCRISPR-1. Furthermore, TREX2 fusion with FrCas9 reduced large deletions and translocations, enhancing genomic stability. Through screening of 1903 sgRNAs targeting 21 CGT-relevant genes using sequential AID-seq, Amplicon sequencing, and GUIDE-seq analysis, we identified optimal sgRNAs for each gene. Our high-throughput screening platform highlights FrCas9, particularly in its TREX2-fused form, as a highly specific and efficient tool for precise therapeutic genome editing.
GPT-4o mini: Non-social science research article
Making continental crust on water-bearing terrestrial planets
Justine Bernadet, Anastassia Y. Borisova, Martin Guitreau, Oleg G. Safonov, Paul Asimow, Anne Nédélec, Wendy A. Bohrson, Svetlana A. Kosova, Philippe de Parseval
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The debate about early Earth differentiation focuses on the processes responsible for the formation of protocrust(s) and continental crust of felsic (SiO 2  ≄ 55 weight %) composition. One aspect of this debate is how Hadean zircons fit into an ultramafic environment. On the basis of experiments, thermodynamic modeling, and elemental partitioning, we show that felsic melts could have been generated by shallow interaction between primordial serpentinized peridotite and basaltic magmas on Earth and Mars. On the basis of the hafnium isotopic evolution of Hadean detrital zircons worldwide, we infer that these interactions allowed for the formation of extensive Hadean felsic crust (4.4 to 4.5 billion years ago), which, in turn, would account for up to 50% of the present continental crustal mass. A similar process may have occurred on Mars. The serpentinized protocrust had a dual role in the primitive planetary environment: to provide ingredients for the continental crust and to enable life to emerge on water-bearing terrestrial planets.
GPT-4o mini: Non-social science research article
Activity-dependent regulation of Cdc42 by Ephexin5 drives synapse growth and stabilization
Samuel Petshow, Azariah Coblentz, Andrew M. Hamilton, Dipannita Sarkar, Margarita Anisimova, Juan C. Flores, Karen Zito
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Synaptic Rho guanosine triphosphatase (GTPase) guanine nucleotide exchange factors (RhoGEFs) play vital roles in regulating the activity-dependent neuronal plasticity that is critical for learning. Ephexin5, a RhoGEF implicated in the etiology of Alzheimer’s disease and Angelman syndrome, was originally reported in neurons as a RhoA-specific GEF that negatively regulates spine synapse density. Here, we show that Ephexin5 activates both RhoA and Cdc42 in the brain. Furthermore, using live imaging of GTPase biosensors, we demonstrate that Ephexin5 regulates activity-dependent Cdc42, but not RhoA, signaling at single synapses. The selectivity of Ephexin5 for Cdc42 activation is regulated by tyrosine phosphorylation, which is regulated by neuronal activity. Last, in contrast to Ephexin5’s role in negatively regulating synapse density, we show that, downstream of neuronal activity, Ephexin5 positively regulates synaptic growth and stabilization. Our results support a model in which plasticity-inducing neuronal activity regulates Ephexin5 tyrosine phosphorylation, driving Ephexin5-mediated activation of Cdc42 and the spine structural growth and stabilization vital for learning.
GPT-4o mini: Non-social science research article
Nanoelectronics-enabled reservoir computing hardware for real-time robotic controls
Mingze Chen, Xiaoqiu An, Seung Jun Ki, Xirong Liu, Nihal Sekhon, Artyom Boyarov, Anushka Acharya, Justin Tawil, Maxwell Bederman, Xiaogan Liang
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Traditional robotic vehicle control algorithms, implemented on digital devices with firmware, result in high power consumption and system complexity. Advanced control systems based on different device physics are essential for the advancement of sophisticated robotic vehicles and miniature mobile robots. Here, we present a nanoelectronics-enabled analog control system mimicking conventional controllers’ dynamic responses for real-time robotic controls, substantially reducing training cost, power consumption, and footprint. This system uses a reservoir computing network with interconnected memristive channels made from layered semiconductors. The network’s nonlinear switching and short-term memory characteristics effectively map input sensory signals to high-dimensional data spaces, enabling the generation of motor control signals with a simply trained readout layer. This approach minimizes software and analog-to-digital conversions, enhancing energy and resource efficiency. We demonstrate this system with two control tasks: rover target tracking and drone lever balancing, achieving similar performance to traditional controllers with ~10-microwatt power consumption. This work paves the way for ultralow-power edge computing in miniature robotic systems.
GPT-4o mini: Non-social science research article
The expression order determines the pioneer functions of NGN3 and NEUROD1 in pancreatic endocrine differentiation
Liu Yang, Xin-Xin Yu, Xin Wang, Chen-Tao Jin, Cheng-Ran Xu
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Pioneer transcription factors (TFs) initiate chromatin remodeling, which is crucial for gene regulation and cell differentiation. In this study, we investigated how the sequential expression of neurogenin 3 (NGN3) and NEUROD1 affects their pioneering functions during pancreatic endocrine differentiation. Using a genetically engineered mouse model, we mapped NGN3-binding sites, confirming the pivotal role of this molecule in regulating chromatin accessibility. The pioneering function of NGN3 involves dose tolerance, and low doses are sufficient. Although NEUROD1 generally acts as a conventional TF, it can assume a pioneering role in the absence of NGN3. The sequential expression of NeuroD1 and Ngn3 predominantly drives α cell generation, which may explain the inefficient ÎČ cell induction observed in vitro. Our findings demonstrate that pioneer activity is dynamically shaped by temporal TF expression and inter-TF interactions, providing insights into transcriptional regulation and its implications for disease mechanisms and therapeutic targeting and enhancing in vitro differentiation strategies.
GPT-4o mini: Non-social science research article
Monitoring microvascular changes over time with a repositionable 3D ultrasonic capacitive micromachined row-column sensor
Cyprien Blanquart, Léa Davenet, Julien Claisse, Mallorie Giroud, Audren Boulmé, Edgard Jeanne, Mickaël Tanter, Mafalda Correia, Thomas Deffieux
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eHealth devices, including smartwatches and smart scales, have the potential to transform health care by enabling continuous, real-time monitoring of vital signs over extended periods. Existing technologies, however, lack comprehensive monitoring of the microvascular network, which is linked to conditions such as diabetes, hypertension, and small vessel diseases. This study introduces an ultrasound approach using a capacitive micromachined ultrasound transducer row-column array for continuous, ultrasensitive three-dimensional (3D) Doppler imaging of microvascular changes such as hemodynamic variations or vascular remodeling. In vitro tests and in vivo studies with healthy volunteers demonstrated the sensor’s ability to image the 3D microvascular network at high resolution over different timescales with automatic registration and to detect microvascular changes with high sensitivity. Integrating this technology into wearable devices could, one day, enhance understanding, monitoring, and possibly early detection of microvascular-related health conditions.
GPT-4o mini: Non-social science research article
Retinal gene therapy for Stargardt disease with dual AAV intein vectors is both safe and effective in large animal models
Rita Ferla, Eugenio Pugni, Mariangela Lupo, Paola Tiberi, Federica Fioretto, Andrea Perota, Roberto Duchi, Irina Lagutina, Carlo Gesualdo, Settimio Rossi, Domenico Ventrella, Alberto Elmi, Benjamin McClinton, Carmel Toomes, Tongzhou Xu, Robert S. Molday, Enrico M. Surace, Francesca Simonelli, Maria L. Bacci, Cesare Galli, Muhammad A. Memon, Naveed Shams, Alberto Auricchio, Ivana Trapani
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Retinal gene therapy using dual adeno-associated viral (AAV) intein vectors can be applied to genetic forms of blindness caused by mutations in genes with coding sequences that exceed single AAV cargo capacity, such as Stargardt disease (STGD1), the most common inherited macular dystrophy. In view of clinical translation of dual AAV intein vectors, here we set to evaluate both the efficiency and safety of their subretinal administration in relevant large animal models. Accordingly, we have developed the first pig model of STGD1, which we found to accumulate lipofuscin similarly to patients. This accumulation is significantly reduced upon subretinal administration of dual AAV intein vectors whose safety and pharmacodynamics we then tested in nonhuman primates, which showed modest and reversible inflammation as well as high levels of photoreceptor transduction. This bodes well for further clinical translation of dual AAV intein vectors in patients with STGD1 as well as for other blinding diseases that require the delivery of large genes.
GPT-4o mini: Non-social science research article
A synthetic genomics-based African swine fever virus engineering platform
Walter Fuchs, Nacyra Assad-Garcia, Hussein M. Abkallo, Yong Xue, Lauren M. Oldfield, Nadia Fedorova, Alexandra HĂŒbner, Tonny Kabuuka, Katrin Pannhorst, Dirk Höper, Vishvanath Nene, Norberto Gonzalez-Juarbe, Lucilla Steinaa, Sanjay Vashee
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African swine fever (ASF) is a deadly viral disease in domestic pigs that has a large global economic impact for the swine industry. It is present in Africa, Europe, Asia, and in the Caribbean island of Hispaniola. There are no effective treatments or broadly licensed vaccines to prevent disease. Efforts to counteract ASF have been hampered because of the lack of convenient tools to engineer its etiological agent, ASF virus (ASFV), largely due to its large noninfectious genome. Here, we report the use of synthetic genomics methodology to develop a reverse genetics system for ASFV using a CRISPR-Cas9–inhibited self-helper virus to reconstitute live recombinant ASFV from synthetic genomes to rapidly generate a variety of combinatorial mutants of ASFV. The method will substantially facilitate the development of therapeutics or subunit and live-attenuated vaccines for ASF. This synthetic genomics-based approach has wide-ranging impact because it can be applied to rapidly develop reverse genetics tools for emerging viruses with noninfectious genomes.
GPT-4o mini: Non-social science research article
A memristor-based unified PUF and TRNG chip with a concealable ability for advanced edge security
Xueqi Li, Bohan Lin, Bin Gao, Yuyao Lu, Siyao Yang, Zhiqiang Su, Ting-Ying Shen, Jianshi Tang, He Qian, Huaqiang Wu
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Security primitives ensure Internet of Things (IoT) security by generating stable keys from physically unclonable functions (PUFs) and unpredictable bitstreams from true random number generators (TRNGs). Considering the restricted resources on IoT motes, a promising design trend is to unify PUF and TRNG by sharing the same entropy source and multiplexing entropy extractor. Here, we report a unified PUF and TRNG chip based on a 28-nanometer embedded memristor with concealable ability. We use the memristor intrinsic FORMING condition variation and read current variation as entropy sources and design a compact on-chip entropy extractor that achieves a high throughput of 41.7 megabits per second with minimal area overhead of 0.291 MF 2 . To prevent PUF data leakage, we developed a concealment method, protecting data when idle and enabling recovery upon demand. Comprehensive testing shows the chip has excellent performance in randomness, reliability, lifetime, and stability, achieving a 3.82-fold throughput improvement over complementary metal-oxide semiconductor–based designs in authentication tasks.
GPT-4o mini: Non-social science research article
Current crowding–free superconducting nanowire single-photon detectors
Stefan Strohauer, Fabian Wietschorke, Christian Schmid, Stefanie Grotowski, Lucio Zugliani, Björn Jonas, Kai MĂŒller, Jonathan J. Finley
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Detecting single photons is essential for applications such as dark matter detection, quantum science and technology, and biomedical imaging. Superconducting nanowire single-photon detectors (SNSPDs) excel in this task due to their near-unity detection efficiency, subhertz dark count rates, and picosecond timing jitter. However, a local increase of current density (current crowding) in the bends of meander-shaped SNSPDs limits these performance metrics. By locally irradiating the SNSPD’s straight segments with helium ions while leaving the bends unirradiated, we realize current crowding–free SNSPDs with simultaneously enhanced sensitivity: After irradiation with 800 ions nm −2 , locally irradiated SNSPDs showed a relative saturation plateau width of 37%, while fully irradiated SNSPDs reached only 10%. This larger relative plateau width allows operation at lower relative bias currents, thereby reducing the dark count rate while still detecting single photons efficiently. We achieve an internal detection efficiency of 94% with 7 mHz dark count rate near the onset of saturating detection efficiency for a wavelength of 780 nm.
GPT-4o mini: Non-social science research article
Tempests in the troposphere: Mapping the impact of giant storms on Jupiter’s deep atmosphere
Chris Moeckel, Huazhi Ge, Imke de Pater
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Storms are emerging as key drivers in shaping hydrogen-dominated atmospheres. Trace gas condensation can suppress convection and disrupt the distribution of energy and material in hydrogen atmospheres. On Jupiter, the presence of water has been invoked to control the occurrence of large-scale storms; however, the impact of storms on the ammonia and temperature distribution is unknown. We use Juno Microwave Radiometer observations of a large-scale storm in 2017 to study the aftermath of such a storm on the atmosphere. Anomalies in the retrieved ammonia abundance and atmospheric temperature show how storms deplete and heat the upper atmosphere while simultaneously depositing material well below the layers they were triggered at. These observations, aided by simulations, show that the water and ammonia cycles are coupled and that their combined effect plays a key role in explaining the depletion of ammonia in the tropospheres of Jupiter and Saturn.
GPT-4o mini: Non-social science research article
Alternatives to photorespiration: A system-level analysis reveals mechanisms of enhanced plant productivity
Edward N. Smith, Marvin van Aalst, Andreas P. M. Weber, Oliver Ebenhöh, Matthias Heinemann
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Photorespiration causes a substantial decrease in crop yield because of mitochondrial decarboxylation. Alternative pathways (APs) have been designed to relocate the decarboxylation step or even fix additional carbon. To improve the success of transferring those engineered APs from model species to crops, we must understand how they will interact with metabolism and how plant physiology affects their performance. Here, we used multiple mathematical modeling techniques to analyze and compare existing AP designs. We show that carbon-fixing APs are the most promising candidates to replace native photorespiration in major crop species. Our results demonstrate the different metabolic routes that APs use to increase yield and which plant physiology can profit the most from them. We anticipate our results to guide the design of new APs and to help improve existing ones.
GPT-4o mini: Non-social science research article
Permafrost thawing under overlaying salt water
Yumin Wang, Jin-Han Xie, Wei Yang, Xiaotian Li, Zulikaer Abulaiti, Shuai Zheng, Jingwei Zhu, Ke Xu
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Thawing of permafrost substantially affects the local environment and global energy balance. When salt water overlays permafrost, Rayleigh-Darcy (R-D) instability emerges because of the density mismatch and regulates melting (thawing) dynamics. Contrary to expectations that a higher Rayleigh number ( R ) would amplify instability, our experiments revealed fingering and stable melting fronts at low and high R , respectively. We attribute the occurrence of the two melting patterns to the interplay between two competing flow structures: local circumfluence modulated by front perturbation and transversal chaotic mixing. We propose theories that rationalize the melting pattern transition and finger-scale evolution. In addition, the classic mass transport theory for R-D convection drastically underestimates the melting rate and misses key variable(s). The presence of fingering patterns and accelerated dynamics may have led to earlier penetration of the permafrost layer than previously anticipated. These findings have implications for understanding similar processes in magma migration, carbon sequestration, and subsurface energy recovery.
GPT-4o mini: Non-social science research article
Drosophila and human Headcase define a new family of ribonucleotide granule proteins required for stress response
Delia Ricolo, Jordi Casanova, Panagiotis Giannios
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Cells have means to adapt to environmental stresses such as temperature fluctuations, toxins, or nutrient availability. Stress responses, being dynamic, extend beyond transcriptional control and encompass post-transcriptional mechanisms allowing for rapid changes in protein synthesis. Previous research has established headcase as a fundamental gene for stress responses and survival of the Drosophila adult progenitor cells (APCs). However, the molecular role of Headcase has remained elusive. Here, we identify Headcase as a component of ribonucleoprotein (RNP) granules. We also show that, Headcase is required for proper RNP granule formation and remodeling upon stress and is crucial for translation control. Likewise, the human Headcase homolog (HECA) is identified as a component of RNP granules and has similar roles in translational regulation and stress protection. Thus, Headcase proteins define a new family contributing to specific roles among the RNP heterogeneous network.
GPT-4o mini: Non-social science research article
Anatomy of a foreseeable disaster: Lessons from the 2023 dam-breaching flood in Derna, Libya
Moshe Armon, Yuval Shmilovitz, Elad Dente
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Was the catastrophic flooding in Derna, Libya—one of the deadliest hydrometeorological disasters on record—an inevitable outcome of rare weather conditions, or did the design of the infrastructure fail to account for probable risks? On 10 to 11 September 2023, Storm Daniel, a Mediterranean tropical-like cyclone, caused heavy rainfall that led to the collapse of two dams and more than 5000 casualties in Derna. Using a combination of atmospheric reanalysis, satellite data, and hydrologic modeling, we overcame key limitations typical of data-scarce, high-variability regions and revealed that despite the catastrophic impact, the return periods of the rainfall and flood were only a few decades. Hydraulic simulations revealed that the dam failures amplified the damage nearly 20-fold compared to a dam-free scenario. With extensive and timely implications, our findings underscore the importance of uncertainty-aware risk assessment and highlight the value of distributed flood prevention and early warning systems in mitigating risks in vulnerable regions.
GPT-4o mini: Non-social science research article
Catalyst-controlled regiodivergence and stereodivergence in formal cross-[4+2] cycloadditions: The unique effect of bismuth(III)
Qiumeng Hou, Chenxi Cai, Shuai-Jiang Liu, Wei Huang, Cheng Peng, Gu Zhan, Bo Han
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The [4+2] cycloaddition is crucial for constructing six-membered rings in pharmaceuticals and natural products. Cross-[4+2] cycloadditions offer greater product diversity than traditional diene-dienophile reactions due to multiple possible pathways. However, precise control over regio- and stereoselectivity for various isomers remains a great challenge. This study reports catalyst-controlled regiodivergent formal cross-cycloadditions of acyclic dienes and enones, significantly enhancing access to diverse pyrazole-fused spirooxindoles. Chiral phosphoric acid (CPA) catalysis enables endoselective [4+2] cycloadditions, while Bi(III) with a CPA ligand yields [2+4] products with high regio- and stereoselectivity. A Claisen rearrangement of the [2+4] adduct produces the exo-selective [4+2] product, further increasing stereochemical diversity and enabling the synthesis of six regio- and stereo-isomers from a single substrate set. DFT calculations reveal that Bi(III) reverses regioselectivity by repositioning reactants in the CPA pocket and stabilizing the enone oxygen’s negative charge. In addition, product 3as demonstrates therapeutic potential against triple-negative breast cancer, with an IC 50 of 8.5 ÎŒM in MDA-MB-453 cells.
Harnessing huge data from pregnancy natural experiments
Michelle Oyen
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Vast, cross-sectional, and open datasets are critical for understanding complex pregnancy physiology and women’s health more generally while serving as a resource for model development.