Paper Picnic 🧺: Multidisciplinary

We checked 7 multidisciplinary journals on Friday, November 29, 2024 using the Crossref API. For the period November 22 to November 28, we retrieved 18 new paper(s) in 6 journal(s).

Nature

GPT-4o mini: Non-social science research article

MCM double hexamer loading visualized with human proteins

Florian Weissmann, Julia F. Greiwe, Thomas Pühringer, Evelyn L. Eastwood, Emma C. Couves, Thomas C. R. Miller, John F. X. Diffley, Alessandro Costa

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Eukaryotic DNA replication begins with the loading of the MCM replicative DNA helicase as a head-to-head double hexamer at origins of DNA replication 1–3 . Our current understanding of how the double hexamer is assembled by the origin recognition complex (ORC), CDC6 and CDT1 comes mostly from budding yeast. Here we characterize human double hexamer (hDH) loading using biochemical reconstitution and cryo-electron microscopy with purified proteins. We show that the human double hexamer engages DNA differently from the yeast double hexamer (yDH), and generates approximately five base pairs of underwound DNA at the interface between hexamers, as seen in hDH isolated from cells 4 . We identify several differences from the yeast double hexamer in the order of factor recruitment and dependencies during hDH assembly. Unlike in yeast 5–8 , the ORC6 subunit of the ORC is not essential for initial MCM recruitment or hDH loading, but contributes to an alternative hDH assembly pathway that requires an intrinsically disordered region in ORC1, which may work through a MCM–ORC intermediate. Our work presents a detailed view of how double hexamers are assembled in an organism that uses sequence-independent replication origins, provides further evidence for diversity in eukaryotic double hexamer assembly mechanisms 9 , and represents a first step towards reconstitution of DNA replication initiation with purified human proteins.

GPT-4o mini: Non-social science research article

Cancer cells impair monocyte-mediated T cell stimulation to evade immunity

Anais Elewaut, Guillem Estivill, Felix Bayerl, Leticia Castillon, Maria Novatchkova, Elisabeth Pottendorfer, Lisa Hoffmann-Haas, Martin Schönlein, Trung Viet Nguyen, Martin Lauss, Francesco Andreatta, Milica Vulin, Izabela Krecioch, Jonas Bayerl, Anna-Marie Pedde, Naomi Fabre, Felix Holstein, Shona M. Cronin, Sarah Rieser, Denarda Dangaj Laniti, David Barras, George Coukos, Camelia Quek, Xinyu Bai, Miquel Muñoz i Ordoño, Thomas Wiesner, Johannes Zuber, Göran Jönsson, Jan P. Böttcher, Sakari Vanharanta, Anna C. Obenauf

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The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses 1,2 . Within the tumour microenvironment, CD8 + T cells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches 3–7 . Although interactions with type 1 conventional dendritic cells have been implicated in this process 3–5,8–10 , the underlying cellular players and molecular mechanisms remain incompletely understood. Here we show that inflammatory monocytes can adopt a pivotal role in intratumoral T cell stimulation. These cells express Cxcl9 , Cxcl10 and Il15 , but in contrast to type 1 conventional dendritic cells, which cross-present antigens, inflammatory monocytes obtain and present peptide–major histocompatibility complex class I complexes from tumour cells through ‘cross-dressing’. Hyperactivation of MAPK signalling in cancer cells hampers this process by coordinately blunting the production of type I interferon (IFN-I) cytokines and inducing the secretion of prostaglandin E 2 (PGE 2 ), which impairs the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I cytokine production and blocking PGE 2 secretion restores this process and re-sensitizes tumours to T cell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral T cell stimulation, elucidates how oncogenic signalling disrupts T cell responses through counter-regulation of PGE 2 and IFN-I, and proposes rational combination therapies to enhance immunotherapies.

GPT-4o mini: Non-social science research article

Author Correction: Enhanced silica export in a future ocean triggers global diatom decline

Jan Taucher, Lennart T. Bach, A. E. Friederike Prowe, Tim Boxhammer, Karin Kvale, Ulf Riebesell

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GPT-4o mini: Non-social science research article

Soil microbiomes show consistent and predictable responses to extreme events

Christopher G. Knight, Océane Nicolitch, Rob I. Griffiths, Tim Goodall, Briony Jones, Carolin Weser, Holly Langridge, John Davison, Ariane Dellavalle, Nico Eisenhauer, Konstantin B. Gongalsky, Andrew Hector, Emma Jardine, Paul Kardol, Fernando T. Maestre, Martin Schädler, Marina Semchenko, Carly Stevens, Maria Α. Tsiafouli, Oddur Vilhelmsson, Wolfgang Wanek, Franciska T. de Vries

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Increasing extreme climatic events threaten the functioning of terrestrial ecosystems 1,2 . Because soil microbes govern key biogeochemical processes, understanding their response to climate extremes is crucial in predicting the consequences for ecosystem functioning 3,4 . Here we subjected soils from 30 grasslands across Europe to four contrasting extreme climatic events under common controlled conditions (drought, flood, freezing and heat), and compared the response of soil microbial communities and their functioning with those of undisturbed soils. Soil microbiomes exhibited a small, but highly consistent and phylogenetically conserved, response under the imposed extreme events. Heat treatment most strongly impacted soil microbiomes, enhancing dormancy and sporulation genes and decreasing metabolic versatility. Microbiome response to heat in particular could be predicted by local climatic conditions and soil properties, with soils that do not normally experience the extreme conditions being imposed being most vulnerable. Our results suggest that soil microbiomes from different climates share unified responses to extreme climatic events, but that predicting the extent of community change may require knowledge of the local microbiome. These findings advance our understanding of soil microbial responses to extreme events, and provide a first step for making general predictions about the impact of extreme climatic events on soil functioning.

GPT-4o mini: Non-social science research article

Multiple mechanisms for licensing human replication origins

Ran Yang, Olivia Hunker, Marleigh Wise, Franziska Bleichert

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GPT-4o mini: Non-social science research article

Digestive contents and food webs record the advent of dinosaur supremacy

Martin Qvarnström, Joel Vikberg Wernström, Zuzanna Wawrzyniak, Maria Barbacka, Grzegorz Pacyna, Artur Górecki, Jadwiga Ziaja, Agata Jarzynka, Krzysztof Owocki, Tomasz Sulej, Leszek Marynowski, Grzegorz Pieńkowski, Per E. Ahlberg, Grzegorz Niedźwiedzki

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The early radiation of dinosaurs remains a complex and poorly understood evolutionary event 1–4 . Here we use hundreds of fossils with direct evidence of feeding to compare trophic dynamics across five vertebrate assemblages that record this event in the Triassic–Jurassic succession of the Polish Basin (central Europe). Bromalites, fossil digestive products, increase in size and diversity across the interval, indicating the emergence of larger dinosaur faunas with new feeding patterns. Well-preserved food residues and bromalite-taxon associations enable broad inferences of trophic interactions. Our results, integrated with climate and plant data, indicate a stepwise increase of dinosaur diversity and ecospace occupancy in the area. This involved (1) a replacement of non-dinosaur guild members by opportunistic and omnivorous dinosaur precursors, followed by (2) the emergence of insect and fish-eating theropods and small omnivorous dinosaurs. Climate change in the latest Triassic 5–7 resulted in substantial vegetation changes that paved the way for ((3) and (4)) an expansion of herbivore ecospace and the replacement of pseudosuchian and therapsid herbivores by large sauropodomorphs and early ornithischians that ingested food of a broader range, even including burnt plants. Finally, (5) theropods rapidly evolved and developed enormous sizes in response to the appearance of the new herbivore guild. We suggest that the processes shown by the Polish data may explain global patterns, shedding new light on the environmentally governed emergence of dinosaur dominance and gigantism that endured until the end-Cretaceous mass extinction.

GPT-4o mini: Non-social science research article

Durable all inorganic perovskite tandem photovoltaics

Chenghao Duan, Kaicheng Zhang, Zijian Peng, Shiang Li, Feilin Zou, Feng Wang, Jiong Li, Zheng Zhang, Chang Chen, Qiliang Zhu, Jianhang Qiu, Xinhui Lu, Ning Li, Liming Ding, Christoph J. Brabec, Feng Gao, Keyou Yan

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GPT-4o mini: Non-social science research article

Gut microbiota strain richness is species specific and affects engraftment

Alice Chen-Liaw, Varun Aggarwala, Ilaria Mogno, Craig Haifer, Zhihua Li, Joseph Eggers, Drew Helmus, Amy Hart, Jan Wehkamp, Esi S. N. Lamousé-Smith, Robert L. Kerby, Federico E. Rey, Jean Frédéric Colombel, Michael A. Kamm, Bernat Olle, Jason M. Norman, Rajita Menon, Andrea R. Watson, Emily Crossett, Elisabeth M. Terveer, Josbert J. Keller, Thomas J. Borody, Ari Grinspan, Sudarshan Paramsothy, Nadeem O. Kaakoush, Marla C. Dubinsky, Jeremiah J. Faith

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GPT-4o mini: Non-social science research article

Pan-genome bridges wheat structural variations with habitat and breeding

Chengzhi Jiao, Xiaoming Xie, Chenyang Hao, Liyang Chen, Yuxin Xie, Vanika Garg, Li Zhao, Zihao Wang, Yuqi Zhang, Tian Li, Junjie Fu, Annapurna Chitikineni, Jian Hou, Hongxia Liu, Girish Dwivedi, Xu Liu, Jizeng Jia, Long Mao, Xiue Wang, Rudi Appels, Rajeev K. Varshney, Weilong Guo, Xueyong Zhang

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GPT-4o mini: Non-social science research article

Stereochemistry in the disorder–order continuum of protein interactions

Estella A. Newcombe, Amanda D. Due, Andrea Sottini, Steffie Elkjær, Frederik Friis Theisen, Catarina B. Fernandes, Lasse Staby, Elise Delaforge, Christian R. O. Bartling, Inna Brakti, Katrine Bugge, Benjamin Schuler, Karen Skriver, Johan G. Olsen, Birthe B. Kragelund

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GPT-4o mini: Non-social science research article

Opponent control of reinforcement by striatal dopamine and serotonin

Daniel F. Cardozo Pinto, Matthew B. Pomrenze, Michaela Y. Guo, Gavin C. Touponse, Allen P. F. Chen, Brandon S. Bentzley, Neir Eshel, Robert C. Malenka

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GPT-4o mini: Non-social science research article

Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer

Gabe S. Sonke, Annemiek van Ommen-Nijhof, Noor Wortelboer, Vincent van der Noort, Astrid C. P. Swinkels, Hedwig M. Blommestein, Cristina Guerrero Paez, Linda Mol, Aart Beeker, Karin Beelen, Lisanne C. Hamming, Joan B. Heijns, Aafke H. Honkoop, Paul C. de Jong, Quirine C. van Rossum-Schornagel, Christa van Schaik-van de Mheen, Jolien Tol, Cathrien S. Tromp-van Driel, Suzan Vrijaldenhoven, A. Elise van Leeuwen-Stok, Inge R. Konings, Agnes Jager, character(0), Paul C. de Jong, Quirine C. van Rossum-Schornagel, Christa van Schaik-van de Mheen

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GPT-4o mini: Non-social science research article

Study design features increase replicability in brain-wide association studies

Kaidi Kang, Jakob Seidlitz, Richard A. I. Bethlehem, Jiangmei Xiong, Megan T. Jones, Kahini Mehta, Arielle S. Keller, Ran Tao, Anita Randolph, Bart Larsen, Brenden Tervo-Clemmens, Eric Feczko, Oscar Miranda Dominguez, Steven M. Nelson, character(0), Aaron F. Alexander-Bloch, Damien A. Fair, Jonathan Schildcrout, Damien A. Fair, Theodore D. Satterthwaite, Aaron Alexander-Bloch, Simon Vandekar

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Brain-wide association studies (BWAS) are a fundamental tool in discovering brain–behaviour associations 1,2 . Several recent studies have shown that thousands of study participants are required for good replicability of BWAS 1–3 . Here we performed analyses and meta-analyses of a robust effect size index using 63 longitudinal and cross-sectional MRI studies from the Lifespan Brain Chart Consortium 4 (77,695 total scans) to demonstrate that optimizing study design is critical for increasing standardized effect sizes and replicability in BWAS. A meta-analysis of brain volume associations with age indicates that BWAS with larger variability of the covariate and longitudinal studies have larger reported standardized effect size. Analysing age effects on global and regional brain measures from the UK Biobank and the Alzheimer’s Disease Neuroimaging Initiative, we showed that modifying study design through sampling schemes improves standardized effect sizes and replicability. To ensure that our results are generalizable, we further evaluated the longitudinal sampling schemes on cognitive, psychopathology and demographic associations with structural and functional brain outcome measures in the Adolescent Brain and Cognitive Development dataset. We demonstrated that commonly used longitudinal models, which assume equal between-subject and within-subject changes can, counterintuitively, reduce standardized effect sizes and replicability. Explicitly modelling the between-subject and within-subject effects avoids conflating them and enables optimizing the standardized effect sizes for each separately. Together, these results provide guidance for study designs that improve the replicability of BWAS.

GPT-4o mini: Non-social science research article

Direct visualization of relativistic quantum scars in graphene quantum dots

Zhehao Ge, Anton M. Graf, Joonas Keski-Rahkonen, Sergey Slizovskiy, Peter Polizogopoulos, Takashi Taniguchi, Kenji Watanabe, Ryan Van Haren, David Lederman, Vladimir I. Fal’ko, Eric J. Heller, Jairo Velasco

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GPT-4o mini: Non-social science research article

Author Correction: Gamma frequency entrainment attenuates amyloid load and modifies microglia

Hunter F. Iaccarino, Annabelle C. Singer, Anthony J. Martorell, Andrii Rudenko, Fan Gao, Tyler Z. Gillingham, Hansruedi Mathys, Jinsoo Seo, Oleg Kritskiy, Fatema Abdurrob, Chinnakkaruppan Adaikkan, Rebecca G. Canter, Richard Rueda, Emery N. Brown, Edward S. Boyden, Li-Huei Tsai

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GPT-4o mini: Non-social science research article

Fungal symbiont transmitted by free-living mice promotes type 2 immunity

Yun Liao, Iris H. Gao, Takato Kusakabe, Woan-Yu Lin, Alexander Grier, Xiangyu Pan, Olga Morzhanaeva, Terrance P. Shea, Hiroshi Yano, Danielle Karo-Atar, Kaitlin A. Olsen, Ji Hoon Oh, Kurt J. Vandegrift, Irah L. King, Christina A. Cuomo, David Artis, Barbara Rehermann, Neil Lipman, Iliyan D. Iliev

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GPT-4o mini: Non-social science research article

Organ-specific sympathetic innervation defines visceral functions

Tongtong Wang, Bochuan Teng, Dickson R. Yao, Wei Gao, Yuki Oka

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GPT-4o mini: Non-social science research article

Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers

David Steffin, Nisha Ghatwai, Antonino Montalbano, Purva Rathi, Amy N. Courtney, Azlann B. Arnett, Julien Fleurence, Ramy Sweidan, Tao Wang, Huimin Zhang, Prakash Masand, John M. Maris, Daniel Martinez, Jennifer Pogoriler, Navin Varadarajan, Sachin G. Thakkar, Deborah Lyon, Natalia Lapteva, Mei Zhuyong, Kalyani Patel, Dolores Lopez-Terrada, Carlos A. Ramos, Premal Lulla, Tannaz Armaghany, Bambi J. Grilley, Stephen Gottschalk, Gianpietro Dotti, Leonid S. Metelitsa, Helen E. Heslop, Malcolm K. Brenner, Pavel Sumazin, Andras Heczey

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GPT-4o mini: Non-social science research article

Addendum: Accurate structure prediction of biomolecular interactions with AlphaFold 3

Josh Abramson, Jonas Adler, Jack Dunger, Richard Evans, Tim Green, Alexander Pritzel, Olaf Ronneberger, Lindsay Willmore, Andrew J. Ballard, Joshua Bambrick, Sebastian W. Bodenstein, David A. Evans, Chia-Chun Hung, Michael O’Neill, David Reiman, Kathryn Tunyasuvunakool, Zachary Wu, Akvilė Žemgulytė, Eirini Arvaniti, Charles Beattie, Ottavia Bertolli, Alex Bridgland, Alexey Cherepanov, Miles Congreve, Alexander I. Cowen-Rivers, Andrew Cowie, Michael Figurnov, Fabian B. Fuchs, Hannah Gladman, Rishub Jain, Yousuf A. Khan, Caroline M. R. Low, Kuba Perlin, Anna Potapenko, Pascal Savy, Sukhdeep Singh, Adrian Stecula, Ashok Thillaisundaram, Catherine Tong, Sergei Yakneen, Ellen D. Zhong, Michal Zielinski, Augustin Žídek, Victor Bapst, Pushmeet Kohli, Max Jaderberg, Demis Hassabis, John M. Jumper

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Climate scientists flock to France’s call

Declan Butler

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Nature DOI suffix ≠ "/s...": Not a research article

The United States, as a marine superpower, must ratify the high seas biodiversity treaty now

Alice B. M. Vadrot

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Nature DOI suffix ≠ "/s...": Not a research article

Cosmic map reveals a not-so-lumpy Universe

Davide Castelvecchi

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Nature DOI suffix ≠ "/s...": Not a research article

This billion-dollar firm plans to build giant quantum computers from light. Can it succeed?

Elizabeth Gibney

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Nature DOI suffix ≠ "/s...": Not a research article

Why antimatter might be the answer to life, the Universe and everything

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Nature DOI suffix ≠ "/s...": Not a research article

Daily briefing: Squid-inspired pills squirt drugs straight into your gut

Flora Graham

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Nature DOI suffix ≠ "/s...": Not a research article

Hopes, fears and uncertainty: life scientists react to Trump’s election victory

Amander Clark, Eric Topol, Hank Greely, Salim S. Abdool Karim, Quarraisha Abdool Karim, Ramanan Laxminarayan

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Affirmative action slow to take hold in Brazil’s graduate science education

Rodrigo de Oliveira Andrade

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Nature DOI suffix ≠ "/s...": Not a research article

Daily briefing: NASA finds secret ice base in Greenland

Flora Graham

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Nature DOI suffix ≠ "/s...": Not a research article

Let the data talk: embrace exploratory research

Balazs Aczel

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Fossilized faeces helps explain dinosaurs’ rise to dominance

Nick Petrić Howe, Emily Bates

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Nature DOI suffix ≠ "/s...": Not a research article

Quantum scars make their mark in graphene

Dmitry Abanin, Maksym Serbyn

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Nature DOI suffix ≠ "/s...": Not a research article

Evidence of ‘disability bias’ in research grant awards

Fei Qi

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Nature DOI suffix ≠ "/s...": Not a research article

Bacteria could be key to freeing South Pacific of mosquitoes

Emma Marris

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Epiphanies

David Gullen

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Nature DOI suffix ≠ "/s...": Not a research article

Daily briefing: Why the man behind a ‘mouse utopia’ disappeared from the scientific literature

Jacob Smith

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Nature DOI suffix ≠ "/s...": Not a research article

How the invasion of Ukraine is affecting Russian expat researchers

Benjamin Plackett

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Forty years of crazy crystals

Sharon C. Glotzer

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Turning a scientific lens on the wonderful world of fungi

Nicholas P. Money

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Order matters: neurons in the human brain fire in sequences that encode information

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In the big data era, prioritize statistical significance in study design

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High-performance perovskite–organic tandem solar cells

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Falling enrolments and funding cuts force Australian universities to take stock

Jackson Ryan

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Why build a muon collider: a three minute guide

Dan Fox, Elizabeth Gibney

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European Commission urges logging ban in ancient Białowieża Forest

Quirin Schiermeier

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FDA advisers back gene therapy for rare form of blindness

Heidi Ledford

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Daily briefing: ‘We mourned together every day’: life at the heart of an outbreak

Flora Graham

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Evidence of oldest known alphabet unearthed among Syrian tomb treasures

Miryam Naddaf

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Antimatter to be transported outside a lab for first time — in a van

Elizabeth Gibney

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Nature DOI suffix ≠ "/s...": Not a research article

Shifting sands threaten flood-mitigation measures

Kristen L. Cook

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This dwarf planet might have its very own ice volcano

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Top performers hold steady in Australia’s declining research landscape

Bec Crew

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How to stop plastic pollution: three strategies that actually work

Nicola Jones

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Design tips for reproducible studies linking the brain to behaviour

Roselyne J. Chauvin, Nico U. F. Dosenbach

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Nature DOI suffix ≠ "/s...": Not a research article

Toxicity and costs of cancer treatment reduced by deferring CDK4/6 inhibitor use

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The birth of Bronze Age pastoralism where Europe meets Asia

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How to thank your lab mates: eight ways to show gratitude at the end of year

Anne Marie Conlon

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Antarctica’s first known amber whispers of a vanished rainforest

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How I’m creating career opportunities for researchers back home in Mexico

David Posner

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I defend the planet from asteroid collisions

Nikki Forrester

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Why tumour geography matters — and how to map it

Michael Eisenstein

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Seek climate advice through established routes

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Success of gravity-wave satellite paves way for three-craft mission

Davide Castelvecchi

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Big names in statistics want to shake up much-maligned P value

Dalmeet Singh Chawla

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Italy’s anti-nepotism drive picked up in surname study

Nicola Nosengo

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Is the COP29 climate deal a historic breakthrough or letdown? Researchers react

Ehsan Masood

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US defence agencies grapple with gene drives

Ewen Callaway

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Martian weather kicks into high gear at night

Rachael Lallensack

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Customer reviews for Mystery Gadget 1.0, sorted in chronological order

Alex Shvartsman

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Australia must boost R&D investment to reclaim global research standing

Bec Crew

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Humble scientists earn more trust

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Limits on foreign students are harming research, universities warn

Smriti Mallapaty

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Fossilized poo and vomit show how dinosaurs rose to rule Earth

Helena Kudiabor

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Act now to stop millions of research papers from disappearing

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I fled the war in Ukraine. Now I work on ways to help the country’s soil heal

Ankita Arora

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DNA need not apply: Books in brief

Andrew Robinson

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How the world’s biggest laser smashed a nuclear-fusion record

Jeff Tollefson

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Largest-ever study of controversial pesticides finds harm to bees

Daniel Cressey

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Home-grown scientists step up to save Africa’s primates

Declan Butler

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Why the word scientist was controversial 100 years ago

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Scientists in limbo as US Supreme Court allows modified travel ban

Sara Reardon

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Conferences: The secrets of a standout seminar

Amber Dance

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US lawmakers seek $1.1-billion boost for the NIH

Lauren Morello

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Drug approval needs a helping hand

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Europe’s next big science-funding programme urged to double its budget

Alison Abbott

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Vaccines promoted as key to stamping out drug-resistant microbes

Alison Abbott

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Spain’s flash floods reveal a desperate need for improved mitigation efforts

María Carmen Llasat

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Don’t let watermarks stigmatize AI-generated research content

Natalia Tsybuliak, Yana Suchikova

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The cells that help the immune system fight lung cancer

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Wastes of time — faeces and vomit track how dinosaurs rose to prominence

Lawrence H. Tanner

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How to create psychedelics’ benefits without the ‘trip’

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White House’s dwindling science office leaves major research programmes in limbo

Sara Reardon

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Chimpanzees are first animal shown to develop telltale markers of Alzheimer’s disease

Sara Reardon

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Engineered cell therapy for cancer gets thumbs up from FDA advisers

Heidi Ledford

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Tricks to mute quantum noise aid hunt for gravitational waves

Elizabeth Gibney

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Google spin-off deploys wearable electronics for huge health study

Amy Maxmen

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Attacks on democracy are attacks on science — and vice versa

Francesca Falk

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A guide to the Nature Index

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From exploitation to empowerment: how researchers can protect Indigenous peoples’ rights to own and control their data

Cassandra Sedran-Price

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Why ‘open’ AI systems are actually closed, and why this matters

David Gray Widder, Meredith Whittaker, Sarah Myers West

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Nature Human Behaviour

GPT-4o mini: Non-social science research article

Large language models surpass human experts in predicting neuroscience results

Xiaoliang Luo, Akilles Rechardt, Guangzhi Sun, Kevin K. Nejad, Felipe Yáñez, Bati Yilmaz, Kangjoo Lee, Alexandra O. Cohen, Valentina Borghesani, Anton Pashkov, Daniele Marinazzo, Jonathan Nicholas, Alessandro Salatiello, Ilia Sucholutsky, Pasquale Minervini, Sepehr Razavi, Roberta Rocca, Elkhan Yusifov, Tereza Okalova, Nianlong Gu, Martin Ferianc, Mikail Khona, Kaustubh R. Patil, Pui-Shee Lee, Rui Mata, Nicholas E. Myers, Jennifer K. Bizley, Sebastian Musslick, Isil Poyraz Bilgin, Guiomar Niso, Justin M. Ales, Michael Gaebler, N. Apurva Ratan Murty, Leyla Loued-Khenissi, Anna Behler, Chloe M. Hall, Jessica Dafflon, Sherry Dongqi Bao, Bradley C. Love

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Scientific discoveries often hinge on synthesizing decades of research, a task that potentially outstrips human information processing capacities. Large language models (LLMs) offer a solution. LLMs trained on the vast scientific literature could potentially integrate noisy yet interrelated findings to forecast novel results better than human experts. Here, to evaluate this possibility, we created BrainBench, a forward-looking benchmark for predicting neuroscience results. We find that LLMs surpass experts in predicting experimental outcomes. BrainGPT, an LLM we tuned on the neuroscience literature, performed better yet. Like human experts, when LLMs indicated high confidence in their predictions, their responses were more likely to be correct, which presages a future where LLMs assist humans in making discoveries. Our approach is not neuroscience specific and is transferable to other knowledge-intensive endeavours.

Evaluating the association between the introduction of mandatory calorie labelling and energy consumed using observational data from the out-of-home food sector in England

Megan Polden, Andrew Jones, Michael Essman, Jean Adams, Tom R. P. Bishop, Thomas Burgoine, Stephen J. Sharp, Martin White, Richard Smith, Aisling Donohue, Rozemarijn Witkam, I. Gusti Ngurah Edi Putra, Jane Brealey, Eric Robinson

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In April 2022, mandatory kilocalorie (kcal) labelling in the out-of-home food sector was introduced as a policy to reduce obesity in England. Here we examined whether the implementation of this policy was associated with a consumer behaviour change. Large out-of-home food sector outlets subject to kcal labelling legislation were visited pre- and post-implementation, and customer exit surveys were conducted with 6,578 customers from 330 outlets. Kcals purchased and consumed, knowledge of purchased kcals and reported noticing and use of kcal labelling were examined. The results suggested that the introduction of the mandatory kcal labelling policy in England was not associated with a significant decrease in self-reported kcals purchased ( B = 11.31, P = 0.564, 95% confidence interval (CI) −27.15 to 49.77) or consumed ( B = 18.51, P = 0.279, 95% CI −15.01 to 38 52.03). Post-implementation, participants underestimated the energy content of their purchased meal less ( B = 61.21, P = 0.002, 95% CI 21.57 to 100.86) and were more likely to report noticing (odds ratio 2.25, P < 0.001, 95% CI 1.84 to 2.73) and using (odds ratio 2.15, P < 0.001, 95% CI 1.62 to 2.85) kcal labelling, which may have wider public health implications.

Child literacy in low- and middle-income countries

Michelle Kaffenberger

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Proceedings of the National Academy of Sciences

GPT-4o mini: Non-social science research article

Stable isotopic signature of dissimilatory nitrate reduction is robust against enzyme mutation

Ciara K. Asamoto, Yeongjun Ryu, Kelly N. Eckartt, Julia Kelley-Kern, Lars E.P. Dietrich, Daniel M. Sigman, Sebastian H. Kopf

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The proportionality of oxygen-to-nitrogen isotope effects ( 18 ε/ 15 ε) is used as a key isotopic signature of nitrogen cycling processes in the environment. Dissimilatory nitrate reduction is observed to have an 18 ε/ 15 ε proportionality of ~0.9 in marine and ~0.6 in freshwater/terrestrial ecosystems. The origins of this difference are uncertain, with both geochemical and biological factors conceivably at play. One potential factor is variation in the isotope effect of nitrate reduction among different forms of the nitrate reductase enzyme. NarG nitrate reductases are observed to typically have an 18 ε/ 15 ε of ~0.9. However, a recent study uncovered an exception, with Bacillus NarG enzymes having an 18 ε/ 15 ε proportionality of ~0.6. This provides an opportunity to investigate genetic controls on 18 ε/ 15 ε. Furthermore, this atypical NarG signature also raises the question of whether intrinsic isotope signatures can evolve as the enzymes that produce them accumulate mutations through time. Here, we present data from site-directed mutagenesis experiments of key NarG residues, which suggest that the distinct Bacillus 18 ε/ 15 ε cannot be caused by single mutations alone and is potentially uncommon in nature. Variation in the intrinsic isotope effects of an enzyme through time may thus require more extensive evolutionary changes.

GPT-4o mini: Non-social science research article

Challenging the Bayesian confidence hypothesis in perceptual decision-making

Kai Xue, Medha Shekhar, Dobromir Rahnev

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The Bayesian confidence hypothesis (BCH), which postulates that confidence reflects the posterior probability that a decision is correct, is currently the most prominent theory of confidence. Although several recent studies have found evidence against it in the context of relatively complex tasks, BCH remains dominant for simpler tasks. The major alternative to BCH is the confidence in raw evidence space (CRES) hypothesis, according to which confidence is based directly on the raw sensory evidence without explicit probability computations. Here, we tested these competing hypotheses in the context of perceptual tasks that are assumed to induce Gaussian evidence distributions. We show that providing information about task difficulty gives rise to a basic behavioral signature that distinguishes BCH from CRES models even for simple 2-choice tasks. We examined this signature in three experiments and found that all experiments exhibited behavioral signatures in line with CRES computations but contrary to BCH ones. We further performed an extensive comparison of 16 models that implemented either BCH or CRES confidence computations and systematically differed in their auxiliary assumptions. These model comparisons provided overwhelming support for the CRES models over their BCH counterparts across all model variants and across all three experiments. These observations challenge BCH and instead suggest that humans may make confidence judgments by placing criteria directly in the space of the sensory evidence.

GPT-4o mini: Non-social science research article

Rescue of cochlear vascular pathology prevents sensory hair cell loss in Norrie disease

Aara Patel, Valda Pauzuolyte, Neil J. Ingham, Yeh Chwan Leong, Wolfgang Berger, Karen P. Steel, Jane C. Sowden

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Variants in the gene NDP cause Norrie disease, a severe dual-sensory disorder characterized by congenital blindness due to disrupted retinal vascular development and progressive hearing loss accompanied by sensory hair cell death. NDP encodes the secreted signaling molecule norrin. The role of norrin in the cochlea is incompletely understood. We investigated whether the Norrie disease cochlear pathology can be ameliorated in an Ndp -knockout ( Ndp -KO) mouse model by conditional activation of stabilized β-catenin in vascular endothelial cells. We hypothesized that in the cochlea microvasculature, β-catenin is the primary downstream intracellular effector of norrin binding to endothelial cell surface receptors and that restoration of this signaling pathway is sufficient to prevent sensory hair cell death and hearing loss. We show that tamoxifen induction of Cdh5CreERT2;Ctnnb1 flex3/+ ;Ndp- KO mice stabilizing β-catenin in vascular endothelial cells alone rescued defects in cochlear vascular barrier function, restored dysregulated expression of endothelial cell disease biomarkers ( Cldn5, Abcb1a, Slc7a1, and Slc7a5 ), and prevented progressive outer hair cell death and hearing loss. Single-cell transcriptome profiling of human cochleas showed NDP expression by fibrocytes and glial cells while receptor gene expression ( FZD4, TSPAN12, LRP5, and LRP6 ) coincided in vascular endothelial cells. Our findings support the conclusion that vascular endothelial cells are a primary target of norrin signaling in the cochlea of mice and humans and restoration of β-catenin regulation of target gene expression within cochlear endothelial cells is sufficient to maintain a cochlear microenvironment critical for hair cell survival.

GPT-4o mini: Non-social science research article

Multi-Component, Time-Course screening to develop combination cancer therapies based on synergistic toxicity

Michele Ceribelli, Frances Anne Tosto, Xiaohu Zhang, Christopher J. Melani, Mark Roschewski, Erin Beck, Carleen Klumpp-Thomas, Cody J. Peer, Kelli M. Wilson, Lu Chen, Crystal McKnight, Sam Michael, Zina Itkin, Paul Shinn, William D. Figg, Wyndham H. Wilson, Louis M. Staudt, Craig J. Thomas

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Clinical trials in cancer are ideally built on a foundation of sound mechanistic rationale and well-validated drug activity in relevant disease models. The screening of approved and investigational drugs in cell-based phenotypic assays can provide evidence of drug activity, but alternative screening paradigms are needed to develop and optimize multidrug combination regimens. Here, we utilize in vitro screening outcomes across a panel of lymphoma cell lines to dissect the activity of four small-molecule drugs (Venetoclax, Ibrutinib, Prednisolone, and Lenalidomide) currently under investigation within ongoing clinical trials in lymphoma. Data from multiple concentration ranges and time points show that synergistic drug combinations promote apoptosis and cytotoxicity responses at concentrations and time points that are consistent with in vivo drug exposures. To fully map the interaction landscape of these agents in relevant cell models, we developed an in vitro assay format that facilitated time-course evaluations involving concurrent multidrug exposure which further highlighted rapid, synergistic apoptosis induction as a central engine for the activity of this multicomponent targeted therapy. In addition to several instances of exceptional drug+drug synergy, the genetically similar diffuse large B cell lymphoma models also displayed substantial heterogeneity in the degree of synergism between drug pairs. A parallel survey of chemotherapies exhibited limited combination benefit, supporting recent findings that multicomponent chemotherapy outcomes are driven by individual drug activity. Collectively, these data demonstrate how in vitro drug screening data can identify multidrug combinations that exploit drug synergy to overcome the functional diversity of human malignancies.

GPT-4o mini: Non-social science research article

Spatiotemporal bifurcation of HY5-mediated blue-light signaling regulates wood development during secondary growth

Hyeona Hwang, Yookyung Lim, Myung-Min Oh, Hyunmo Choi, Donghwan Shim, Young Hun Song, Hyunwoo Cho

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Plants have evolved photoreceptors to optimize their development during primary growth, including germination, hypocotyl elongation, cotyledon opening, and root growth, allowing them to adapt to challenging light conditions. The light signaling transduction pathway during seedling establishment has been extensively studied, but little molecular evidence is available for light-regulated secondary growth, and how light regulates cambium-derived tissue production remains largely unexplored. Here, we show that CRYPTOCHROME (CRY)-dependent blue light signaling and the subsequent attenuation of ELONGATED HYPOCOTYL 5 (HY5) movement to hypocotyls are key inducers of xylem fiber differentiation in Arabidopsis thaliana. Using grafted chimeric plants and hypocotyl-specific transcriptome sequencing of light signaling mutants under controlled light conditions, we demonstrate that the perception of blue light by CRYs in shoots drives secondary cell wall (SCW) deposition at xylem fiber cells during the secondary growth of hypocotyls. We propose that HY5 is a blue light–responsive mobile protein that inhibits xylem fiber formation via direct transcriptional repression of NAC SECONDARY WALL THICKENING PROMOTING 3 ( NST3 ). CRYs retain HY5 in the nucleus, impede its long-distance transport from leaf to hypocotyl, and they initiate NST3- driven SCW gene expression, thereby triggering xylem fiber production. Our findings shed light on the long-range CRYs-HY5-NST3 signaling cascade that shapes xylem fiber development, highlighting the activity of HY5 as a transcriptional repressor during secondary growth.

GPT-4o mini: Non-social science research article

Hidden in plain sight: (Re)definition of a key lepidopteran color patterning gene

Nicholas W. VanKuren, Marcus R. Kronforst

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GPT-4o mini: Non-social science research article

Miniaturized, portable gustation interfaces for VR/AR/MR

Yiming Liu, Wooyoung Park, Chun Ki Yiu, Xingcan Huang, Shengxin Jia, Yao Chen, Hehua Zhang, Hongting Chen, Pengcheng Wu, Mengge Wu, Zhenyu Liu, Yuyu Gao, Kening Zhu, Zhao Zhao, Yuhang Li, Tomoyuki Yokota, Takao Someya, Xinge Yu

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Gustation is one of the five innate sensations for humans, distinguishing from vision, auditory, tactile, and olfaction, as which is a close and chemically induced sense. Despite the fact that a handful of gustation display technologies have been developed, the new technologies still pose significant challenges in miniaturization of the overall size for portability, enriching taste options within a limited working area, supporting natural human–device interaction, and achieving precisely controlled taste feedback. To address these issues, here, we report a set of intelligent and portable lollipop-shaped taste interfacing systems covering from 2 to 9 different taste options for establishing an adjustable taste platform in virtual reality (VR), augmented reality (AR), and mixed reality (MR) environments. Tasteful and food-grade chemicals embedded agarose hydrogels serve as taste sources based on iontophoresis operation principle, with an adjustable feedback intensity and independent operation time by tuning the voltage input. To achieve portability and user-friendly operation, the devices are miniaturized into a gustation interface with 9-channel taste generators in the dimension of 8 cm × 3 cm × 1 cm. To realize both gustation and olfaction feedbacks in Metaverse, an olfaction interface based on 7-channel odor generators is also introduced into the gustation interface system. As a result, the demonstrations of our gustation interface systems in intelligent medical gustation assessment, remote shopping, and mixed reality have proven their advances and great progress in various potential application areas, ranging from human–machine interfaces, to biomedical science, and to entertainment.

GPT-4o mini: Non-social science research article

Chronologically inappropriate morphogenesis ( Chinmo ) is required for maintenance of larval stages of fall armyworm

Xien Chen, Jinmo Koo, Surjeet Kumar Arya, Subba Reddy Palli

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Broad complex (Br-C) and eip93F (E93) transcription factors promote insect metamorphosis from larva to pupa and from pupa to adult, respectively. Recently, chronologically inappropriate morphogenesis (Chinmo) has been proposed as a larval specifier in Drosophila melanogaste r. However, whether Chinmo is required for larval maintenance in lepidopteran insects, the underlying mechanisms involved in maintaining the larval stage, and its interactions with the JH signaling pathway are not well understood. Here, we used a binary transgenic CRISPR/Cas9 system to knockout Chinmo and Kr-h1 (primary response gene in the JH signaling pathway) in the fall armyworm (FAW). Kr-h1 knockout induced premature metamorphosis only after L5 (penultimate), whereas Chinmo and Kr-h1 double knockout induced premature metamorphosis in L3. Sequencing and differential gene expression (DEG) analysis of RNA isolated from mutants and single-cell multiome ATAC analysis of Chinmo , Kr-h1 , and Chinmo and Kr-h1 double knockout Sf9 cells revealed that Chinmo participates in chromatin modifications that prevent the promoter accessibility and expression of metamorphosis promoting genes. These results suggest that Chinmo is a larval specifier that plays a major role in preventing metamorphosis in early larval stages by controlling chromatin accessibility near the promoters of genes such as Br-C and E93 required for pupal and adult development.

GPT-4o mini: Non-social science research article

Correlating enzymatic reactivity for different substrates using transferable data-driven collective variables

Sudip Das, Umberto Raucci, Rui P. P. Neves, Maria J. Ramos, Michele Parrinello

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Machine learning (ML) is transforming the investigation of complex biological processes. In enzymatic catalysis, one significant challenge is identifying the reactive conformations (RC) of the enzyme:substrate complex where the substrate assumes a precise arrangement in the active site necessary to initiate a reaction. Traditional methods are hindered by the complexity of the multidimensional free energy landscape involved in the transition from nonreactive to reactive conformations. Here, we applied ML techniques to address this challenge, focusing on human pancreatic α-amylase, a crucial enzyme in type-II diabetes treatment. Using ML-based collective variables (CVs), we correlated the probability of being in a RC with the experimental catalytic activity of several malto-oligosaccharide substrates. Our findings demonstrate a remarkable transferability of these CVs across various compounds, significantly streamlining the modeling process and reducing both computational demand and manual intervention in setting up simulations for new substrates. This approach not only advances our understanding of enzymatic processes but also holds substantial potential for accelerating drug discovery by enabling rapid and accurate evaluation of drug efficacy across different generations of inhibitors.

GPT-4o mini: Non-social science research article

The HUSH epigenetic repressor complex silences PML nuclear body-associated HSV-1 quiescent genomes

Simon Roubille, Tristan Escure, Franceline Juillard, Armelle Corpet, Rémi Néplaz, Olivier Binda, Coline Seurre, Mathilde Gonin, Stuart Bloor, Camille Cohen, Pascale Texier, Oscar Haigh, Olivier Pascual, Yonatan Ganor, Frédérique Magdinier, Marc Labetoulle, Paul J. Lehner, Patrick Lomonte

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Herpes simplex virus 1 (HSV-1) latently infected neurons display diverse patterns in the distribution of the viral genomes within the nucleus. A key pattern involves quiescent HSV-1 genomes sequestered in promyelocytic leukemia nuclear bodies (PML NBs) forming viral DNA-containing PML-NBs (vDCP NBs). Using a cellular model that replicates vDCP NB formation, we previously demonstrated that these viral genomes are chromatinized with the H3.3 histone variant modified on its lysine 9 by trimethylation (H3.3K9me3), a mark associated with transcriptional repression. Here, we identify the HUSH complex and its effectors, SETDB1 and MORC2, as crucial for the acquisition of H3K9me3 on PML NB-associated HSV-1 and the maintenance of HSV-1 transcriptional repression. ChIP-seq analyses show H3K9me3 association with the entire viral genome. Inactivating the HUSH–SETDB1–MORC2 complex before infection significantly reduces H3K9me3 on the viral genome, with minimal impact on the cellular genome, aside from expected changes in LINE-1 retroelements. Depletion of HUSH, SETDB1, or MORC2 alleviates HSV-1 repression in infected primary human fibroblasts and human induced pluripotent stem cell–derived sensory neurons (hiPSDN). We found that the viral protein ICP0 induces MORC2 degradation via the proteasome machinery. This process is concurrent with ICP0 and MORC2 depletion capability to reactivate silenced HSV-1 in hiPSDN. Overall, our findings underscore the robust antiviral function of the HUSH–SETDB1–MORC2 repressor complex against a herpesvirus by modulating chromatin marks linked to repression, thus presenting promising avenues for anti-herpesvirus therapeutic strategies.

GPT-4o mini: Non-social science research article

Compartmentalized pooling generates orientation selectivity in wide-field amacrine cells

Wanyu Lei, Damon A. Clark, Jonathan B. Demb

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Orientation is one of the most salient features in visual scenes. Neurons at multiple levels of the visual system detect orientation, but in many cases, the underlying biophysical mechanisms remain unresolved. Here, we studied mechanisms for orientation detection at the earliest stage in the visual system, in B/K wide-field amacrine cells (B/K WACs), a group of giant, nonspiking interneurons in the mouse retina that coexpress Bhlhe22 (B) and Kappa Opioid Receptor (K). B/K WACs exhibit orientation-tuned calcium signals along their long, straight, unbranching dendrites, which contain both synaptic inputs and outputs. Simultaneous dendritic calcium imaging and somatic voltage recordings reveal that individual B/K dendrites are electrotonically isolated, exhibiting a spatially confined yet extended receptive field along the dendrite, which we term “compartmentalized pooling.” Further, the receptive field of a B/K WAC dendrite exhibits center-surround antagonism. Phenomenological receptive field models demonstrate that compartmentalized pooling generates orientation selectivity, and center-surround antagonism shapes band-pass spatial frequency tuning. At the microcircuit level, B/K WACs receive excitation driven by one contrast polarity (e.g., “ON”) and glycinergic inhibition driven by the opposite polarity (e.g., “OFF”). However, this “crossover” inhibition is not essential for generating orientation selectivity. A minimal biophysical model reproduced compartmentalized pooling from feedforward excitatory inputs combined with a substantial increase in the specific membrane resistance between somatic and dendritic compartments. Collectively, our results reveal the biophysical mechanism for generating orientation selectivity in dendrites of B/K WACs, enriching our understanding of the diverse strategies employed throughout the visual system to detect orientation.

GPT-4o mini: Non-social science research article

Pharmacological inhibition of HIF2 protects against bone loss in an experimental model of estrogen deficiency

Giulia Lanzolla, Elena Sabini, Katherine Beigel, Mohd Parvez Khan, Xiaowei Sherry Liu, Dian Wang, Brittany Laslow, Deanne Taylor, Teresita Bellido, Amato Giaccia, Ernestina Schipani

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Estrogen deficiency, which is linked to various pathological conditions such as primary ovarian insufficiency and postmenopausal osteoporosis, disrupts the delicate balance between bone formation and resorption. This imbalance leads to bone loss and an increased risk of fractures, primarily due to a significant reduction in trabecular bone mass. Trabecular osteoblasts, the cells responsible for bone formation within the trabecular compartment, originate from skeletal progenitors located in the bone marrow. The microenvironment of the bone marrow contains hypoxic (low oxygen) regions, and the hypoxia-inducible factor-2α (HIF2) plays a crucial role in cellular responses to these low-oxygen conditions. This study demonstrates that the loss of HIF2 in skeletal progenitors and their derivatives during development enhances trabecular bone mass by promoting bone formation. More importantly, PT2399, a small molecule that specifically inhibits HIF2, effectively prevents trabecular bone loss in ovariectomized adult mice, a model for estrogen-deficient bone loss. Both the genetic and pharmacological approaches result in an increase in osteoblast number, which is linked to the expansion of the pool of skeletal progenitor cells. This expansion either by loss or inhibition of HIF2 uncovers a pivotal mechanism for increasing osteoblast numbers and bone formation, resulting in greater trabecular bone mass.

GPT-4o mini: Non-social science research article

Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes

Michael J. Topper, Joseph W. Guarnieri, Jeffrey A. Haltom, Amy Chadburn, Henry Cope, Justin Frere, Julia An, Alain Borczuk, Saloni Sinha, JangKeun Kim, Jiwoon Park, Daniel Butler, Cem Meydan, Jonathan Foox, Yaron Bram, Stephanie A. Richard, Nusrat J. Epsi, Brian Agan, Josh G. Chenoweth, Mark P. Simons, David Tribble, Timothy Burgess, Clifton Dalgard, Mark T. Heise, Nathaniel J. Moorman, Victoria K. Baxter, Emily A. Madden, Sharon A. Taft-Benz, Elizabeth J. Anderson, Wes A. Sanders, Rebekah J. Dickmander, Katherine Beigel, Gabrielle A. Widjaja, Kevin A. Janssen, Timothy Lie, Deborah G. Murdock, Alessia Angelin, Yentli E. Soto Albrecht, Arnold Z. Olali, Zimu Cen, Joseph Dybas, Waldemar Priebe, Mark R. Emmett, Sonja M. Best, Maya Kelsey Johnson, Nidia S. Trovao, Kevin B. Clark, Victoria Zaksas, Robert Meller, Peter Grabham, Jonathan C. Schisler, Pedro M. Moraes-Vieira, Simon Pollett, Christopher E. Mason, Eve Syrkin Wurtele, Deanne Taylor, Robert E. Schwartz, Afshin Beheshti, Douglas C. Wallace, Stephen B. Baylin

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Lethal COVID-19 outcomes are attributed to classic cytokine storm. We revisit this using RNA sequencing of nasopharyngeal and 40 autopsy samples from patients dying of SARS-CoV-2. Subsets of the 100 top-upregulated genes in nasal swabs are upregulated in the heart, lung, kidney, and liver, but not mediastinal lymph nodes. Twenty-two of these are “noncanonical” immune genes, which we link to components of the renin-angiotensin-activation-system that manifest as increased fibrin deposition, leaky vessels, thrombotic tendency, PANoptosis, and mitochondrial dysfunction. Immunohistochemistry of mediastinal lymph nodes reveals altered architecture, excess collagen deposition, and pathogenic fibroblast infiltration. Many of the above findings are paralleled in animal models of SARS-CoV-2 infection and human peripheral blood mononuclear and whole blood samples from individuals with early and later SARS-CoV-2 variants. We then redefine cytokine storm in lethal COVID-19 as driven by upstream immune gene and mitochondrial signaling producing downstream RAAS (renin-angiotensin-aldosterone system) overactivation and organ damage, including compromised mediastinal lymph node function.

GPT-4o mini: Non-social science research article

Using the phenotype differences model to identify genetic effects in samples of partially genotyped sibling pairs

Sam Trejo, Klint Kanopka

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The identification of causal relationships between specific genes and social, behavioral, and health outcomes is challenging due to environmental confounding from population stratification and dynastic genetic effects. Existing methods to eliminate environmental confounding leverage random genetic variation resulting from recombination and require within-family dyadic genetic data (i.e., parent–child and/or sibling pairs), meaning they can only be applied in relatively small and selected samples. We introduce the phenotype differences model and provide derivations showing that it—under plausible assumptions—provides consistent (and, in certain cases, unbiased) estimates of genetic effects using just a single individual’s genotype. Then, leveraging distinct samples of fully and partially genotyped sibling pairs in the Wisconsin Longitudinal Study, we use polygenic indices and phenotypic data for 24 different traits to empirically validate the phenotype differences model. Finally, we utilize the model to test the effects of 40 polygenic indices on lifespan. After a 10% false discovery rate correction, we find that polygenic indices for three traits—body mass index, self-rated health, chronic obstructive pulmonary disease—have a statistically significant effect on an individual’s lifespan.

GPT-4o mini: Non-social science research article

Molecular insights into the interaction between a disordered protein and a folded RNA

Rishav Mitra, Emery T. Usher, Selin Dedeoğlu, Matthew J. Crotteau, Olivia A. Fraser, Neela H. Yennawar, Varun V. Gadkari, Brandon T. Ruotolo, Alex S. Holehouse, Loïc Salmon, Scott A. Showalter, James C. A. Bardwell

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Intrinsically disordered protein regions (IDRs) are well established as contributors to intermolecular interactions and the formation of biomolecular condensates. In particular, RNA-binding proteins (RBPs) often harbor IDRs in addition to folded RNA-binding domains that contribute to RBP function. To understand the dynamic interactions of an IDR–RNA complex, we characterized the RNA-binding features of a small (68 residues), positively charged IDR-containing protein, Small ERDK-Rich Factor (SERF). At high concentrations, SERF and RNA undergo charge-driven associative phase separation to form a protein- and RNA-rich dense phase. A key advantage of this model system is that this threshold for demixing is sufficiently high that we could use solution-state biophysical methods to interrogate the stoichiometric complexes of SERF with RNA in the one-phase regime. Herein, we describe our comprehensive characterization of SERF alone and in complex with a small fragment of the HIV-1 Trans-Activation Response (TAR) RNA with complementary biophysical methods and molecular simulations. We find that this binding event is not accompanied by the acquisition of structure by either molecule; however, we see evidence for a modest global compaction of the SERF ensemble when bound to RNA. This behavior likely reflects attenuated charge repulsion within SERF via binding to the polyanionic RNA and provides a rationale for the higher-order assembly of SERF in the context of RNA. We envision that the SERF–RNA system will lower the barrier to accessing the details that support IDR–RNA interactions and likewise deepen our understanding of the role of IDR–RNA contacts in complex formation and liquid–liquid phase separation.

GPT-4o mini: Non-social science research article

Inhibition of zDHHC7-driven protein S-palmitoylation prevents cognitive deficits in an experimental model of Alzheimer’s disease

Francesca Natale, Matteo Spinelli, Marco Rinaudo, Walter Gulisano, Ida Nifo Sarrapochiello, Giuseppe Aceto, Daniela Puzzo, Salvatore Fusco, Claudio Grassi

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Protein post-translational modifications (PTM) play a crucial role in the modulation of synaptic function and their alterations are involved in the onset and progression of neurodegenerative disorders. S-palmitoylation is a PTM catalyzed by zinc finger DHHC domain containing (zDHHC) S-acyltransferases that affects both localization and activity of proteins regulating synaptic plasticity and amyloid-β (Aβ) metabolism. Here, we found significant increases of both zDHHC7 expression and protein S-palmitoylation in hippocampi of both 3×Tg-AD mice and post-mortem Alzheimer’s disease (AD) patients. Chronic intranasal administration of the S-palmitoylation inhibitor 2-bromopalmitate counteracted synaptic plasticity and cognitive deficits, reduced the Aβ deposition in the hippocampus and extended the lifespan of both male and female 3×Tg-AD mice. Moreover, hippocampal silencing of zDHHC7 prevented the onset of cognitive deficits in the same experimental model. We also identified a FoxO1-mediated epigenetic mechanism inducing zDHHC7 expression, which was triggered by brain insulin resistance in 3×Tg-AD mice. Finally, in hippocampi of AD patients S-palmitoylation levels of Beta-Secretase 1 were associated with Aβ 1 to 42 load and they inversely correlated with Mini Mental State Examination scores. Our data reveal a key role of both zDHHC7 overexpression and protein hyperpalmitoylation in the onset and progression of AD-related alterations of synaptic plasticity and memory.

GPT-4o mini: Non-social science research article

Force balance of opposing diffusive motors generates polarity-sorted microtubule patterns

Clothilde Utzschneider, Bhagyanath Suresh, Alfredo Sciortino, Jérémie Gaillard, Alexandre Schaeffer, Sudipta Pattanayak, Jean-François Joanny, Laurent Blanchoin, Manuel Théry

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The internal organization of cells is largely determined by the architecture and orientation of the microtubule network. Microtubules serve as polar tracks for the selective transport of specific molecular motors toward either their plus or minus ends. How both motors reciprocally move microtubules and organize the network’s arrangement and polarity is unknown. Here, we combined experiments on reconstituted systems and theory to study the interaction of microtubules with both plus- and minus-end directed motors bound to a fluid membrane. Depending on motor concentrations, the system could lead either to the constant transport of microtubules or to their alignment, stacking, and immobilization in regular bands that separate motors into domains of opposite polarities. In bands, microtubules shared the same polarity and segregated the two opposing motors accordingly. These regular patterns resulted from the balance of forces produced by the two motors as they walked in opposite directions along microtubules. The system was maintained in a dynamic steady state in which the directional transport of microtubule-bound motors compensates for the random diffusion of lipid-bound motors. The size of motor domains depended on their respective concentrations. The constant flow of motors allowed the system to respond to variations in motor concentrations by moving microtubules to adapt to the new force balance. The polar sorting and linear arrangement of microtubules associated with the segregation of motors of opposite polarity are typical of cellular architectures, which these data may help to better understand.

GPT-4o mini: Non-social science research article

MR1 presents vitamin B6–related compounds for recognition by MR1-reactive T cells

Mitchell P. McInerney, Wael Awad, Michael N. T. Souter, Yang Kang, Carl J. H. Wang, Kean Chan Yew Poa, Mohamed R. Abdelaal, Ngoc H. Le, Chloe M. Shepherd, Conor McNeice, Lucy J. Meehan, Adam G. Nelson, Jeremy M. Raynes, Jeffrey Y. W. Mak, James McCluskey, Zhenjun Chen, Ching-Seng Ang, David P. Fairlie, Jérôme Le Nours, Patricia T. Illing, Jamie Rossjohn, Anthony W. Purcell

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The major histocompatibility complex class I related protein (MR1) presents microbially derived vitamin B2 precursors to mucosal-associated invariant T (MAIT) cells. MR1 can also present other metabolites to activate MR1-restricted T cells expressing more diverse T cell receptors (TCRs), some with anti-tumor reactivity. However, knowledge of the range of the antigen(s) that can activate diverse MR1-reactive T cells remains incomplete. Here, we identify pyridoxal (vitamin B6) as a naturally presented MR1 ligand using unbiased mass spectrometry analyses of MR1-bound metabolites. Pyridoxal, and the related compound, pyridoxal 5-phosphate bound to MR1 and enabled cell surface upregulation of wild type MR1*01 and MR1 expressing the Arg9His polymorphism associated with the MR1*04 allotype in a manner dependent on Lys43-mediated Schiff-base formation. Crystal structures of MR1*01 in complex with pyridoxal and pyridoxal 5-phosphate showed how these ligands were accommodated within the A-pocket of MR1. T cell lines transduced with the 7.G5 TCR, which has reported “pan-cancer” specificity, were specifically activated by pyridoxal presented by antigen-presenting cells expressing MR1*01 and MR1 allotypes bearing the less common Arg9His polymorphism. 7.G5 T cells also recognized, to a lesser extent, pyridoxal 5-phosphate and, importantly, recognition of both vitamers was blocked by an anti-MR1 antibody. 7.G5 TCR reactivity toward pyridoxal was enhanced when presented by the Arg9His polymorphism-bearing MR1 allotypes. Vitamin B6, and vitamers thereof, have been associated with various cancers, and here we describe a link between this ligand, MR1, and its allomorphs, and the pan-cancer 7.G5 TCR. This work identifies an MR1 ligand that can activate a diverse MR1-restricted TCR.

GPT-4o mini: Non-social science research article

Structural basis for the synergetic neutralization of hepatitis E virus by antibody–antibody interaction

Minghua Zheng, Lizhi Zhou, Yang Huang, Xiao Zhang, Zihao Yu, Chengyu Yang, Yuanzhi Chen, Dong Ying, Hong Wang, Zhenqin Chen, Chang Liu, Zimin Tang, Siling Wang, Kaihang Wang, Kaixiang Yang, Yanqing Lin, Tingting Li, Qingbing Zheng, Zizheng Zheng, Jun Zhang, Hai Yu, Shaowei Li, Ying Gu, Ningshao Xia

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Neutralizing antibodies (nAbs) play a crucial role in virology, antibody drug development, and vaccine research. In this study, we investigated the synergistic effect of two hepatitis E virus (HEV) nAbs, 8H3, and 8C11, which have exhibited enhanced neutralizing activity in a rhesus monkey model. We presented crystal structures of 8H3 Fab alone and a triple complex of 8C11 Fab and 8H3 Fab simultaneously binding to the HEV E2s protein (8C11:E2s:8H3). Through structural analysis, we identified critical binding sites and fully elucidated the binding footprints of nAb 8H3 in the 8C11:E2s:8H3 complex using site-directed mutagenesis, pinpointing Ile 529, Glu 549, Lys 554, and Ser 566 in the E2s domain, and K66H, S67H, D88H in the 8C11 heavy chain. Interestingly, the synergetic enhancement of 8C11 to 8H3 converted to an antagonistic effect when 8C11 bound to E2s with pretreatment of 8H3, indicating a unidirectional synergistic effect associated with the sequence of antibody involvement. We demonstrated this phenomenon through structural comparisons of E2s:8C11 vs. 8C11:E2s:8H3 crystal structures and molecular dynamics simulations, found that Ile 529 played a key role in the synergistic interplay between these two nAbs. The two-antibody combination showed a more potent antibody-imposed physical disruption mechanism and enhanced coneutralization in an authentic HEV-based cell model. Our study suggests a strategy for synergistic antibody cocktail design with antibody–antibody side-by-side interaction.

GPT-4o mini: Non-social science research article

Continental freshwater discharge influences sea surface salinity variability near world’s megadeltas

Fahad K. Khadim, Augusto Getirana, Rajat Bindlish, Nishan Kumar Biswas, Wanshu Nie, Timothy M. Lahmers, Sujay V. Kumar

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Sea surface salinity ( SSS ) is a key parameter in the thermohaline circulation of global oceans. Near the megadeltas, inland streamflow through large catchments plays a crucial role in mediating salinity. While some regional studies have investigated how SSS is impacted through water cycle and climate components, a global scale quantification of inland streamflow contribution on SSS variability is lacking. Here, we utilized remote sensing and observation-driven datasets to quantify the statistical associations between SSS and streamflow ( Q basin ) at 48 megadeltas worldwide. This study uncovers a robust negative association between Q basin and SSS , with correlation coefficients R less than - 0.6 for seasonal data found in 26 of the 48 megadeltas, and less than - 0.4 for deseasoned data in 21 megadeltas. The anticorrelation relationship is more pronounced in large deltas, particularly near tropical climates and in river-influenced deltas. The study also underscores the significant roles of climate, morphological, and anthropogenic stratification in impacting the natural influence of freshwater discharge on SSS . By highlighting the interconnected impacts of alterations in terrestrial water cycle upstream and SSS , this work contributes to enhancing our understanding of global ocean and climate circulation patterns and in tackling environmental issues pertaining to marine ecosystems.

GPT-4o mini: Non-social science research article

Uncovering the mechanical secrets of the squirting cucumber

Finn Box, Derek E. Moulton, Dominic Vella, Yuvraj Bhagotra, Tristan Lowe, Alain Goriely, Chris J. Thorogood

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Rapid movement is rare in the plant kingdom, but a prerequisite for ballistic seed dispersal. A particularly dramatic example of rapid motion in plants is the squirting cucumber ( Ecballium elaterium ) which launches its seeds explosively via a high-pressure jet. Despite intriguing scientists for centuries, the exact mechanism of seed dispersal and its effect on subsequent generations remain poorly understood. Here, through a combination of experimentation, high-speed videography, quantitative image analysis, and mathematical modeling, we develop a full mechanical description of the process. We quantify the turgor pressure driving ballistic ejection, and uncover key mechanical interactions between the fruit and stem both prior to and during seed ejection, including the unique feature that fluid is redistributed from fruit to stem prior to ejection, a developmental event that goes against the paradigm of rapid seed ejection but which is of key importance in successful dispersal for Ecballium . Combining modeling elements, we quantify and simulate the ballistic trajectories of seeds, which are dispersed over distances greater than 2,000 times their length. We demonstrate how together these mechanical features contribute to a nearly uniform distribution of seeds away from the parent plant. Parametric variation of key developmental events in the modeling framework indicates how a suite of adaptive features in combination drives the spatial distribution of offspring over consecutive generations, and suggests that ballistic seed dispersal has a stabilizing effect on population dynamics by reducing intraspecific competition.

GPT-4o mini: Non-social science research article

Genetic risk factors for Mesoamerican nephropathy

David J. Friedman, Dominick A. Leone, Juan José Amador, Joseph Kupferman, Lauren J. Francey, Damaris Lopez-Pilarte, Jorge Lau, Iris Delgado, W. Katherine Yih, Alejandro Salinas, Minxian Wang, Giulio Genovese, Shrijal Shah, Jessica Kelly, Calum F. Tattersfield, Nathan H. Raines, Magaly Amador, Leny Dias, Achilleas Pitsillides, Oriana Ramirez-Rubio, Alda G. Amador, Marissa Cortopassi, Katie M. Applebaum, Seth L. Alper, Alex S. Banks, Michael D. McClean, Jessica H. Leibler, Madeleine K. Scammell, Josée Dupuis, Daniel R. Brooks

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Mesoamerican nephropathy (MeN) is a progressive kidney disease found on the Pacific coast of Central America primarily in young male agricultural workers without typical kidney disease risk factors. While it is generally accepted that environmental exposures contribute to MeN, we hypothesized that there was also an important genetic component. We performed a genome-wide association study comparing individuals with MeN versus individuals with normal kidney function. We found that Native American ancestry was strongly associated with increased risk of MeN. We also identified candidate variants in the OPCML gene, which encodes a protein that binds opioid receptors, that were associated with ~sixfold reduced odds of MeN (allele frequency 0.029 in controls and 0.005 in cases, OR = 0.16; P = 4 × 10 −8 ). Sugarcane workers with the protective OPCML variants had markedly increased urine osmolality suggesting greater ability to defend against hypovolemia. Experiments with Opcml knock-out mice revealed roles for OPCML in fluid balance and temperature regulation consistent with our findings in humans. Our data suggest that heritable differential sensitivity to heat stress and dehydration contributes to high rates of kidney disease in Central America.

GPT-4o mini: Non-social science research article

CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum

Jung-Mi Choi, Rakshya Acharya, Hye Lim Cha, Kwang-Wook Lee, Jewoo Seo, Esther Yang, Hyun Kim, Jong Hyuk Yoon, Da-Young Chang, Sung-Soo Kim, Sang Jeong Kim, Lutz Birnbaumer, Haeyoung Suh-Kim

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GNAO1 encodes the alpha subunit of the heterotrimeric Go protein. Despite being the most abundant G protein at synapses, the role of Go in the brain remains unclear, primarily because of the high mortality associated with developmental and epileptic encephalopathy (DEE) 17 in Gnao1 mutated animals. Here, we conducted proteomic analyses with a brain synaptosomal fraction to investigate the Go-interactome and then generated a non-DEE model using Gli1 CreERT2 mice to selectively knockout (KO) the presynaptic Gαo within cerebellum. Our findings revealed that Gαo interacts with multiple proteins involved in neurotransmitter release, as well as cannabinoid receptor type 1 (CB1R), a key Gi/o-coupled receptor in presynaptic terminals. In Gnao1 KO mice, synapse formation was reduced in the cerebellum with a concomitant reduction in depolarization-induced suppression of excitation, a manifestation of CB1R-mediated synaptic plasticity found in the cerebellum. These mice displayed motor deficits in rotarod, grip strength, gait, and beam balance tests. Our results suggest that Go plays a critical role in regulating neurotransmitter releases at the presynaptic terminals and its absence in the entire brain may contribute to DEE pathogenesis. This study also provides valuable insights into the signaling pathways in the brain from a Go-dependent perspective.

GPT-4o mini: Non-social science research article

Universal moiré buckling of freestanding 2D bilayers

Jin Wang, Erio Tosatti

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The physics of membranes, a classic subject, acquires new momentum from two-dimensional (2D) materials multilayers. This work reports the surprising results emerged during a theoretical study of equilibrium geometry of bilayers as freestanding membranes. While ordinary membranes are prone to buckle around compressive impurities, we predict that all 2D material freestanding bilayers universally undergo, even if impurity-free, a spontaneous out-of-plane buckling. The moiré network nodes here play the role of internal impurities, the dislocations that join them giving rise to a stress pattern, purely shear in homobilayers and mixed compressive/shear in heterobilayers. That intrinsic stress is, theory and simulations show, generally capable to cause all freestanding 2D bilayers to undergo distortive bucklings with large amplitudes and a rich predicted phase transition scenario. Realistic simulations predict quantitative parameters expected for these phenomena as expected in heterobilayers such as graphene/hBN, WS 2 / WSe 2 heterobilayers, and for twisted homobilayers such as graphene, hBN, MoS 2 . Buckling then entails a variety of predicted consequences. Mechanically, a critical drop of bending stiffness is expected at all buckling transitions. Thermally, the average buckling corrugation decreases with temperature, with buckling-unbuckling phase transitions expected in some cases, and the buckled state often persisting even above room temperature. Buckling will be suppressed by deposition on hard attractive substrates, and survives in reduced form on soft ones. Frictional, electronic, and other associated phenomena are also highlighted. The universality and richness of these predicted phenomena strongly encourages an experimental search, which is possible but still missing.

GPT-4o mini: Non-social science research article

Correction for Ravanfar et al., Tryptophan extends the life of cytochrome P450

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GPT-4o mini: Non-social science research article

Correction for Porwal et al., Comparing methods for statistical inference with model uncertainty

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GPT-4o mini: Non-social science research article

Dynamic tuning of neural stability for cognitive control

Muyuan Xu, Takayuki Hosokawa, Ken-Ichiro Tsutsui, Kazuyuki Aihara

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The brain is thought to execute cognitive control by actively maintaining and flexibly updating patterns of neural activity that represent goals and rules. However, while actively maintaining patterns of activity requires robustness against noise and distractors, updating the activity requires sensitivity to task-relevant inputs. How these conflicting demands can be reconciled in a single neural system remains unclear. Here, we study the prefrontal cortex of monkeys maintaining a covert rule and integrating sensory inputs toward a choice. Following the onset of neural responses, sensory integration evolves with a 70 ms delay. Using a stability analysis and a recurrent neural network model trained to perform the task, we show that this delay enables a transient, system-level destabilization, opening a temporal window to selectively incorporate new information. This mechanism allows robustness and sensitivity to coexist in a neural system and hierarchically updates patterns of neural activity, providing a general framework for cognitive control. Furthermore, it reveals a learned, explicit rule representation, suggesting a reconciliation between the symbolic and connectionist approaches for building intelligent machines.

GPT-4o mini: Non-social science research article

Global hinge sites of proteins as target sites for drug binding

Haotian Zhang, Mert Gur, Ivet Bahar

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Hinge sites of proteins play a key role in mediating conformational mechanics. Among them, those involved in the most collective modes of motion, also called global hinges, are of particular interest, as they support cooperative rearrangements that are often functional. Yet, the utility of targeting global hinges for modulating function remains to be established. We present here a systematic study of a series of proteins resolved in drug-bound forms to examine the probabilistic occurrence of spatial overlaps between hinge sites and drug-binding pockets. Our analysis reveals a high propensity of drug binding to hinge sites compared to random. Notably, one-third of currently approved drugs are colocalized with hinge sites. These mechanosensitive sites are predictable by simple models such as the Gaussian Network Model. Their targeting thus emerges as a viable strategy for developing a new class of drugs that would exploit and modulate the target proteins’ intrinsic dynamics, and potentially alleviate drug-resistance when used in combination with orthosteric or allosteric drugs.

GPT-4o mini: Non-social science research article

Global emergence of regional heatwave hotspots outpaces climate model simulations

Kai Kornhuber, Samuel Bartusek, Richard Seager, Hans Joachim Schellnhuber, Mingfang Ting

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Multiple recent record-shattering weather events raise questions about the adequacy of climate models to effectively predict and prepare for unprecedented climate impacts on human life, infrastructure, and ecosystems. Here, we show that extreme heat in several regions globally is increasing significantly and faster in magnitude than what state-of-the-art climate models have predicted under present warming even after accounting for their regional summer background warming. Across all global land area, models underestimate positive trends exceeding 0.5 °C per decade in widening of the upper tail of extreme surface temperature distributions by a factor of four compared to reanalysis data and exhibit a lower fraction of significantly increasing trends overall. To a lesser degree, models also underestimate observed strong trends of contraction of the upper tails in some areas, while moderate trends are well reproduced in a global perspective. Our results highlight the need to better understand and model the drivers of extreme heat and to rapidly mitigate greenhouse gas emissions to avoid further harm from unexpected weather events.

GPT-4o mini: Non-social science research article

Structural basis of chiral wrap and T-segment capture by Escherichia coli DNA gyrase

Elizabeth Michalczyk, Zuzanna Pakosz-Stępień, Jonathon D. Liston, Olivia Gittins, Marta Pabis, Jonathan G. Heddle, Dmitry Ghilarov

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Type II topoisomerase DNA gyrase transduces the energy of ATP hydrolysis into the negative supercoiling of DNA. The postulated catalytic mechanism involves stabilization of a chiral DNA loop followed by the passage of the T-segment through the temporarily cleaved G-segment resulting in sign inversion. The molecular basis for this is poorly understood as the chiral loop has never been directly observed. We have obtained high-resolution cryoEM structures of Escherichia coli gyrase with chirally wrapped 217 bp DNA with and without the fluoroquinolone moxifloxacin (MFX). Each structure constrains a positively supercoiled figure-of-eight DNA loop stabilized by a GyrA β-pinwheel domain which has the structure of a flat disc. By comparing the catalytic site of the native drug-free and MFX-bound gyrase structures both of which contain a single metal ion, we demonstrate that the enzyme is observed in a native precatalytic state. Our data imply that T-segment trapping is not dependent on the dimerization of the ATPase domains which appears to only be possible after strand passage has taken place.

GPT-4o mini: Non-social science research article

PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity

Grigor Varuzhanyan, Chia-Chun Chen, Jack Freeland, Tian He, Wendy Tran, Kai Song, Liang Wang, Donghui Cheng, Shili Xu, Gabriella A. Dibernardo, Favour N. Esedebe, Vipul Bhatia, Mingqi Han, Evan R. Abt, Jung Wook Park, Sanaz Memarzadeh, David B. Shackelford, John K. Lee, Thomas G. Graeber, Orian S. Shirihai, Owen N. Witte

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Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers composed of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1α), a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNCs. PGC-1α correlated tightly with increased expression of the lineage marker Achaete-scute homolog 1, (ASCL1) through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. Conversely, PGC-1α overexpression enhanced OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting metabolic vulnerabilities in SCNCs across different tissues.

GPT-4o mini: Non-social science research article

ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis

Hyunbae Kim, Qi Chen, Donghong Ju, Neeraja Purandare, Xuequn Chen, Lobelia Samavati, Li Li, Ren Zhang, Lawrence I. Grossman, Kezhong Zhang

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The Mitochondrial Unfolded Protein Response (UPR mt ), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPR mt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPR mt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor α (PPARα), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPR mt transcriptional regulators, independent of the ER-originated UPR (UPR ER ) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPR mt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.

GPT-4o mini: Non-social science research article

Caenorhabditis elegans inositol hexaphosphate pathways couple to RNA interference and pathogen defense

Wenjing Xu, Yifan Sun, Peter Breen, Gary Ruvkun, Kai Mao

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RNA interference (RNAi) is an evolutionarily conserved pathway that defends against viral infections in diverse organisms. Caenorhabditis elegans mutations that enhance RNAi have revealed pathways that may regulate antiviral defense. A genetic screen for C. elegans mutations that fail to up-regulate a defense response reporter transgene detected mutations that enhance RNAi to silence this reporter gene in the inositol polyphosphate multikinase impk-1 , the synMuv B gene lin-15B, and the pathogen defense response gene pals-22 . Using other assays for enhanced RNAi, we found that the impk-1 alleles and an ippk-1 gene inactivation of a later step in inositol hexaphosphate (IP 6 ) synthesis, and the lin-15B and pals-22 alleles enhance RNAi. IP 6 has been known for decades to bind and stabilize human adenosine deaminase that acts on RNA (ADAR) as well as the paralog tRNA editing ADAT. We show that the C. elegans IP 6 pathway is also required for mRNA and tRNA editing. Thus, a deficiency in two axes of RNA editing enhances the already potent C. elegans RNAi antiviral defense, suggesting adenosine to inosine RNA editing may normally moderate this siRNA antiviral defense pathway. The C. elegans IP 6 -deficient mutants are synthetic lethal with a set of enhanced RNAi mutants that act in the polyploid hypodermis to regulate collagen secretion and signaling from that tissue, implicating IP 6 signaling especially in this tissue. This enhanced antiviral RNAi response uses the C. elegans RIG-I-like receptor DRH-1 to activate the unfolded protein response (UPR). The production of primary siRNAs, rather than secondary siRNAs, contributes to this activation of the UPR through XBP-1 signaling. The gon-14 and pal-17 mutants that also emerged from this screen act in the mitochondrial defense pathway rather than by enhancing RNAi.

GPT-4o mini: Non-social science research article

Cis-regulatory elements driving motor neuron-selective viral payload expression within the mammalian spinal cord

M. Aurel Nagy, Spencer Price, Kristina Wang, Stanley Gill, Erika Ren, Lorna Jayne, Victoria Pajak, Sarah Deighan, Bin Liu, Xiaodong Lu, Aissatou Diallo, Shih-Ching Lo, Robin Kleiman, Christopher Henderson, Junghae Suh, Eric C. Griffith, Michael E. Greenberg, Sinisa Hrvatin

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Spinal motor neuron (MN) dysfunction is the cause of a number of clinically significant movement disorders. Despite the recent approval of gene therapeutics targeting these MN-related disorders, there are no viral delivery mechanisms that achieve MN-restricted transgene expression. In this study, chromatin accessibility profiling of genetically defined mouse MNs was used to identify candidate cis-regulatory elements (CREs) capable of driving MN-selective gene expression. Subsequent testing of these candidates identified two CREs that confer MN-selective gene expression in the spinal cord as well as reduced off-target expression in dorsal root ganglia. Within one of these candidate elements, we identified a compact core transcription factor (TF)-binding region that drives MN-selective gene expression. Finally, we demonstrated that selective spinal cord expression driven by this mouse CRE is preserved in non-human primates. These findings suggest that cell-type-selective viral reagents in which cell-type-selective CREs drive restricted gene expression will be valuable research tools in mice and other mammalian species, with potentially significant therapeutic value in humans.

GPT-4o mini: Non-social science research article

Species-wide inventory of Arabidopsis thaliana organellar variation reveals ample phenotypic variation for photosynthetic performance

Tom P. J. M. Theeuwen, Raúl Y. Wijfjes, Delfi Dorussen, Aaron W. Lawson, Jorrit Lind, Kaining Jin, Janhenk Boekeloo, Dillian Tijink, David Hall, Corrie Hanhart, Frank F. M. Becker, Fred A. van Eeuwijk, David M. Kramer, Erik Wijnker, Jeremy Harbinson, Maarten Koornneef, Mark G. M. Aarts

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Efforts to improve photosynthetic performance are increasingly employing natural genetic variation. However, genetic variation in the organellar genomes (plasmotypes) is often disregarded due to the difficulty of studying the plasmotypes and the lack of evidence that this is a worthwhile investment. Here, we systematically phenotyped plasmotype diversity using Arabidopsis thaliana as a model species. A reanalysis of whole-genome resequencing data of 1,541 representative accessions shows that the genetic diversity among the mitochondrial genomes is eight times lower than among the chloroplast genomes. Plasmotype diversity of the accessions divides the species into two major phylogenetic clusters, within which highly divergent subclusters are distinguished. We combined plasmotypes from 60 A. thaliana accessions with the nuclear genomes (nucleotypes) of four A. thaliana accessions to create a panel of 232 cytonuclear genotypes (cybrids). The cybrid plants were grown in a range of different light and temperature conditions and phenotyped using high-throughput phenotyping platforms. Analysis of the phenotypes showed that several plasmotypes alone or in interaction with the nucleotypes have significant effects on photosynthesis and that the effects are highly dependent on the environment. Moreover, we introduce Plasmotype Association Studies (PAS) as a method to reveal plasmotypic effects. Within A. thaliana, several organellar variants can influence photosynthetic phenotypes, which emphasizes the valuable role this variation has on improving photosynthetic performance. The increasing feasibility of producing cybrids in various species calls for further research into how these phenotypes may support breeding goals in crop species.

GPT-4o mini: Non-social science research article

Diversification of pectoral control through motor pool extension

Ruth Gutjahr, Maximilian S. Bothe, Thorin Jonsson, Boris P. Chagnaud

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Flexible control of pectoral appendages enables motor behaviors of vastly different strength, speed, and amplitude, as in a human playing the piano or throwing a ball. Such control necessitates a fine-tuned, coordinated activation of motoneurons, which is facilitated by spatially ordered motoneuron pools in mammals. While differently sized neurons are known to contribute to different strengths of pectoral movements, it remains unclear how these pectoral motor pools are organized in less complex pectoral systems as those of teleost fish. We show how pectoral motor control can be extended to increase the speed- and amplitude-range of motor behaviors by investigating anatomical and physiological features of pectoral motoneurons and the motor pools they form in freshwater hatchet fish, well-known for their pectoral aerial escape response. Through the differentiation of one motor pool, the pectoral motor network of hatchet fish acquired additional flexibility to enable specific control of vastly different amplitudes, velocities, and strengths. Similar neuronal organization patterns have been described for controlling fast, intermediate, and slow axial muscles in zebrafish and in tetrapod motor systems controlling pectoral limbs. We show that hatchet fish share organizational principles of their pectoral motor pools with those found in other motor networks in both teleosts and tetrapods. Our data thus suggest that principles of spatial and physiological differentiation of motor pools associated with different pectoral muscles and behaviors might be deeply homologous between actinopterygian and sarcopterygian vertebrates.

GPT-4o mini: Non-social science research article

Metamorphism in a wet Martian middle crust

Richard Palin, Jon Wade, Brendan Dyck

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GPT-4o mini: Non-social science research article

Correction for Chiang et al., Intercellular friction and motility drive orientational order in cell monolayers

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GPT-4o mini: Non-social science research article

In This Issue

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GPT-4o mini: Non-social science research article

TMPRSS2-mediated SARS-CoV-2 uptake boosts innate immune activation, enhances cytopathology, and drives convergent virus evolution

Bingqian Qu, Csaba Miskey, André Gömer, Robin D. V. Kleinert, Sara Calvo Ibanez, Regina Eberle, Aileen Ebenig, Dylan Postmus, Maximilian K. Nocke, Maike Herrmann, Tabitha K. Itotia, Simon T. Herrmann, Natalie Heinen, Sebastian Höck, Florian D. Hastert, Christine von Rhein, Christoph Schürmann, Xue Li, Ger van Zandbergen, Marek Widera, Sandra Ciesek, Barbara S. Schnierle, Alexander W. Tarr, Eike Steinmann, Christine Goffinet, Stephanie Pfaender, Jacomina Krijnse Locker, Michael D. Mühlebach, Daniel Todt, Richard J. P. Brown

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The accessory protease transmembrane protease serine 2 (TMPRSS2) enhances severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uptake into ACE2-expressing cells, although how increased entry impacts downstream viral and host processes remains unclear. To investigate this in more detail, we performed infection assays in engineered cells promoting ACE2-mediated entry with and without TMPRSS2 coexpression. Electron microscopy and inhibitor experiments indicated TMPRSS2-mediated cell entry was associated with increased virion internalization into endosomes, and partially dependent upon clathrin-mediated endocytosis. TMPRSS2 increased panvariant uptake efficiency and enhanced early rates of virus replication, transcription, and secretion, with variant-specific profiles observed. On the host side, transcriptional profiling confirmed the magnitude of infection-induced antiviral and proinflammatory responses were linked to uptake efficiency, with TMPRSS2-assisted entry boosting early antiviral responses. In addition, TMPRSS2-enhanced infections increased rates of cytopathology, apoptosis, and necrosis and modulated virus secretion kinetics in a variant-specific manner. On the virus side, convergent signatures of cell-uptake-dependent innate immune induction were recorded in viral genomes, manifesting as switches in dominant coupled Nsp3 residues whose frequencies were correlated to the magnitude of the cellular response to infection. Experimentally, we demonstrated that selected Nsp3 mutations conferred enhanced interferon antagonism. More broadly, we show that TMPRSS2 orthologues from evolutionarily diverse mammals facilitate panvariant enhancement of cell uptake. In summary, our study uncovers previously unreported associations, linking cell entry efficiency to innate immune activation kinetics, cell death rates, virus secretion dynamics, and convergent selection of viral mutations. These data expand our understanding of TMPRSS2’s role in the SARS-CoV-2 life cycle and confirm its broader significance in zoonotic reservoirs and animal models.

GPT-4o mini: Non-social science research article

Identification of a depupylation regulator for an essential enzyme in Mycobacterium tuberculosis

Shoshanna C. Kahne, Jin Hee Yoo, James Chen, Kehilwe Nakedi, Lakshminarayan M. Iyer, Gregory Putzel, Nora M. Samhadaneh, Alejandro Pironti, L. Aravind, Damian C. Ekiert, Gira Bhabha, Kyu Y. Rhee, K. Heran Darwin

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In Mycobacterium tuberculosis (Mtb) , proteins that are posttranslationally modified with a prokaryotic ubiquitin-like protein (Pup) can be degraded by bacterial proteasomes. A single Pup-ligase and depupylase shape the pupylome, but the mechanisms regulating their substrate specificity are incompletely understood. Here, we identified a depupylation regulator, a protein called CoaX, through its copurification with the depupylase Dop. CoaX is a pseudopantothenate kinase that showed evidence of binding to pantothenate, an essential nutrient Mtb synthesizes, but not its phosphorylation. In a ∆ coaX mutant, pantothenate synthesis enzymes including PanB, a substrate of the Pup-proteasome system (PPS), were more abundant than in the parental strain. In vitro, CoaX specifically accelerated depupylation of Pup~PanB, while addition of pantothenate inhibited this reaction. In culture, media supplementation with pantothenate decreased PanB levels, which required CoaX. Collectively, we propose CoaX regulates PanB abundance in response to pantothenate levels by modulating its vulnerability to proteolysis by Mtb proteasomes.

GPT-4o mini: Non-social science research article

Wet–dry cycles cause nucleic acid monomers to polymerize into long chains

Xiaowei Song, Povilas Simonis, David Deamer, Richard N. Zare

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The key first step in the oligomerization of monomers is to find an initiator, which is usually done by thermolysis or photolysis. We present a markedly different approach that initiates acid-catalyzed polymerization at the surface of water films or water droplets, which is the reactive phase during a wet–dry cycle in freshwater hot springs associated with subaerial volcanic landmasses. We apply this method to the oligomerization of different nucleic acids, a topic relevant to how it might be possible to go from simple nucleic acid monomers to long-chain polymers, a key step in forming the building blocks of life. It has long been known that dehydration at elevated temperatures can drive the synthesis of ester and peptide bonds, but this reaction has typically been carried out by incubating dry monomers at elevated temperatures. We report that single or multiple cycles of wetting and drying link mononucleotides by forming phosphodiester bonds. Mass spectrometric analysis reveals uridine monophosphate oligomers up to 53 nucleotides, with an abundance of 35 and 43 nt in length. Long-chain oligomers are also observed for thymidine monophosphate, adenosine monophosphate, and deoxyadenosine monophosphate after exposure to a few wet–dry cycles. Nanopore sequencing confirms that long linear chains are formed. Enzyme digestion shows that the linkage is the phosphodiester bond, which is further confirmed by 31 P NMR and Fourier transform infrared spectroscopy. This suggests that nucleic acid oligomers were likely to be present on early Earth in a steady state of synthesis and hydrolysis.

GPT-4o mini: Non-social science research article

Permeability–selectivity trade-off for a universal leaky channel inspired by mobula filters

Xinyu Mao, Irmgard Bischofberger, Anette E. Hosoi

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Mobula rays have evolved leaf-shaped filter structures to separate food particles from seawater, which function similarly to industrial cross-flow filters. Unlike cross-flow filtration, where permeability and selectivity are rationally designed following trade-off analyses, the driving forces underlying the evolution of mobula filter geometry have remained elusive. To bridge the principles of cross-flow and mobula filtration, we establish a universal framework for the permeability–selectivity trade-off in a leaky channel inspired by mobula filters, where permeability and selectivity are characterized by the pore-scale leaking rate and the cut-off particle size, respectively. Beyond the classic pore-flow regime in cross-flow filtration, we reveal transition and vortex regimes pertinent to mobula filtration. Combining theory, physical experiments, and simulations, we present distinct features of water permeability and particle selectivity across the three regimes. In particular, we identify an unreported 1/2-scaling law for the leaking rate in the vortex regime. We conclude by demonstrating that mobula filters strike an elegant balance between permeability and selectivity, which enables mobula rays to simultaneously satisfy biological requirements for breathing and filter feeding. By integrating cross-flow and mobula filtration into a universal framework, our findings provide fundamental insights into the physical constraints and evolutionary pressures associated with biological filtration geometries and lay the foundation for developing mobula-inspired filtration in industry.

GPT-4o mini: Non-social science research article

Long-term stability of productivity increases with tree diversity in Canadian forests

Xiaxia Ding, Peter B. Reich, Masumi Hisano, Han Y. H. Chen

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The temporal stability of forest productivity is a key ecosystem function and an essential service to humanity. Plot-scale tree diversity experiments with observations over 10 to 11 y indicate that tree diversity increases stability under various environmental changes. However, it remains unknown whether these small-scale experimental findings are relevant to the longer-term stability of natural forests. Using 7,500 natural forest plots across much of Canada, monitored over three to four decades on average, we provide strong evidence that higher temporal stability (defined as the mean productivity divided by its SD over time) is consistently associated with greater tree functional, phylogenetic, and taxonomic diversity across all lengths of observations. Specifically, increasing functional diversity from its minimum to maximum values increases stability, mean productivity, and the temporal SD of productivity by 14%, 36%, and 28%, respectively. Our results highlight that the promotion of functionally, phylogenetically, and/or taxonomically diverse forests could enhance the long-term productivity and stability of natural forests.

GPT-4o mini: Non-social science research article

Phase separation of planetary ices explains nondipolar magnetic fields of Uranus and Neptune

Burkhard Militzer

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The Voyager spacecraft discovered that the ice giants Uranus and Neptune have nondipolar magnetic fields, defying expectations that a thick interior layer of planetary ices would generate strong dipolar fields. Stanley and Bloxham showed that nondipolar fields emerge if the magnetic field is only generated in a thin outer layer. However, the origin and composition of this dynamo active layer has so far remained elusive. Here, we show with ab initio computer simulations that a mixture of H 2 O, CH 4 , and NH 3 will phase separate under the pressure–temperature condition in the interiors of Uranus and Neptune, forming a H 2 O-dominated fluid in the upper mantle and a CH 4 -NH 3 mixture below. We further demonstrate that with increasing pressure, the CH 4 -NH 3 mixture becomes increasingly hydrogen depleted as it assumes the state of a polymeric C-N-H fluid. Since the amount of hydrogen loss increases with pressure, we propose that the C-N-H fluid forms a stably stratified layer. The magnetic fields are primarily generated in an upper layer that is H 2 O-rich, homogeneous, convective, and electrically conducting. Under these assumptions, we construct ensembles of models for the interiors of Uranus and Neptune with the Concentric MacLaurin Spheroid method. We demonstrate that the phase separation of the solar-type H 2 O-CH 4 -NH 3 mixture leads to models that match the observed gravity field and to layer thicknesses that are compatible with magnetic field measurements.

GPT-4o mini: Non-social science research article

Adaptive expression of phage auxiliary metabolic genes in paddy soils and their contribution toward global carbon sequestration

Dong Zhu, Shu-Yue Liu, Ming-Ming Sun, Xing-Yun Yi, Gui-Lan Duan, Mao Ye, Michael R. Gillings, Yong-Guan Zhu

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Habitats with intermittent flooding, such as paddy soils, are crucial reservoirs in the global carbon pool; however, the effect of phage–host interactions on the biogeochemical cycling of carbon in paddy soils remains unclear. Hence, this study applied multiomics and global datasets integrated with validation experiments to investigate phage–host community interactions and the potential of phages to impact carbon sequestration in paddy soils. The results demonstrated that paddy soil phages harbor a diverse and abundant repertoire of auxiliary metabolic genes (AMGs) associated with carbon fixation, comprising 23.7% of the identified AMGs. The successful annotation of protein structures and promoters further suggested an elevated expression potential of these genes within their bacterial hosts. Moreover, environmental stressors, such as heavy metal contamination, cause genetic variation in paddy phages and up-regulate the expression of carbon fixation AMGs, as demonstrated by the significant enrichment of related metabolites ( P < 0.05). Notably, the findings indicate that lysogenic phages infecting carbon-fixing hosts increased by 10.7% under heavy metal stress. In addition, in situ isotopic labeling experiments induced by mitomycin-C revealed that by increasing heavy metal concentrations, 13 CO 2 emissions from the treatment with added lysogenic phage decreased by approximately 17.9%. In contrast, 13 C-labeled microbial biomass carbon content increased by an average of 35.4% compared to the control. These results suggest that paddy soil phages prominently influence the global carbon cycle, particularly under global change conditions. This research enhances our understanding of phage–host cooperation in driving carbon sequestration in paddy soils amid evolving environmental conditions.

GPT-4o mini: Non-social science research article

Mutation-based mechanism and evolution of the potent multidrug efflux pump RE-CmeABC in Campylobacter

Lei Dai, Zuowei Wu, Orhan Sahin, Shaohua Zhao, Edward W. Yu, Qijing Zhang

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The resistance-nodulation-cell division (RND) superfamily of multidrug efflux systems are important players in mediating antibiotic resistance in gram-negative pathogens. Campylobacter jejuni , a major enteric pathogen, utilizes an RND-type transporter system, CmeABC, as the primary mechanism for extrusion of various antibiotics. Recently, a functionally potent variant of CmeABC (named RE-CmeABC) emerged in clinical Campylobacter isolates, conferring enhanced resistance to multiple antibiotic classes. Despite the clinical importance of RE-CmeABC, the molecular mechanisms for its functional gain and its evolutionary trajectory remain unknown. Here, we demonstrated that amino acid substitutions in RE-CmeB (inner membrane transporter), but not in RE-CmeA (periplasmic protein) and RE-CmeC (outer membrane protein), in conjunction with a nucleotide mutation in the promoter region of the efflux operon, are responsible for the functional gain of the multidrug efflux system. We also showed that RE- cmeABC is emerging globally and distributed in genetically diverse C. jejuni strains, suggesting its possible spread by horizontal gene transfer. Notably, many of RE- cmeABC harboring isolates were associated with the human host including strains from large disease outbreaks, indicating the clinical relevance and significance of RE-CmeABC. Evolutionary analysis indicated that RE- cmeB likely originated from Campylobacter coli , but its expansion mainly occurred in C. jejuni, possibly driven by antibiotic selection pressure. Additionally, RE- cmeB , but not RE- cmeA and RE- cmeC , experienced a selective sweep and was progressing to be fixed during evolution. Together, these results identify a mutation-based mechanism for functional gain in RE-CmeABC and reveal the key role of RE-CmeB in facilitating Campylobacter adaptation to antibiotic selection.

GPT-4o mini: Non-social science research article

Genetic evidence against involvement of TRPC proteins in SOCE, ROCE, and CRAC channel function

Sebastian Susperreguy, Megumi Yamashita, Chan-il Choi, Yanhong Liao, Lauranell H. Burch, Terry L. Blankenship, Erika Hayes, Thomas Sliwa, Yingpei Zhang, Dagoberto Grenet, Mitzie Walker, Nicholas W. Plummer, Joel Abramowitz, Jean Pierre Kinet, Karina Formoso, Brandon E. Johnson, Andrea Fleig, Lori Hazlehurst, Reinhold Penner, Marc Freichel, Veit Flockerzi, Murali Prakriya, Lutz Birnbaumer

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Using genetically engineered mice and cell lines derived from genetically engineered mice we show that depletion of ER delimited Ca 2+ stores activates heteromeric Ca 2+ entry (SOCE) channels formed obligatorily, but not exclusively by Orai1 molecules. Comparison of Orai-dependent Ca 2+ entries revealed Orai1 to be dominant when compared to Orai2 and Orai3. Unexpectedly, we found that store-depletion-activated Ca 2+ entry does not depend obligatorily on functionally intact TRPC molecules, as SOCE monitored with the Fura2 Ca 2+ reporter dye is unaffected in cells in which all seven TRPC coding genes have been structurally and functionally inactivated. Unexpectedly as well, we found that TRPC-independent Gq-coupled receptor-operated Ca 2+ entry (ROCE) also depends on Orai1. Biophysical measurements of Ca 2+ release activated Ca 2+ currents (Icrac) are likewise unaffected by ablation of all seven TRPC genes. We refer to mice and cells carrying the seven-fold disruption of TRPC genes as TRPC heptaKO mice and cells. TRPC heptaKO mice are fertile allowing the creation of a new homozygous inbred strain.

GPT-4o mini: Non-social science research article

Emergent collective behavior evolves more rapidly than individual behavior among acorn ant species

Grant Navid Doering, Matthew M. Prebus, Sachin Suresh, Jordan N. Greer, Reilly Bowden, Timothy A. Linksvayer

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Emergence is a fundamental concept in biology and other disciplines, but whether emergent phenotypes evolve similarly to nonemergent phenotypes is unclear. The hypothesized process of emergent evolution posits that evolutionary change in at least some collective behaviors will differ from evolutionary change in the corresponding intrinsic behaviors of isolated individuals. As a result, collective behavior might evolve more rapidly and diversify more between populations compared to individual behavior. To test whether collective behavior evolves emergently, we conducted a large comparative study using 22 ant species and gathered over 1,500 behavioral rhythm time series from hundreds of colonies and isolated individuals, totaling over 1.5 y of behavioral data. We show that analogous traits measured at individual and collective levels exhibit distinct evolutionary patterns. The estimated rates of phenotypic evolution for the rhythmicity of activity in ant colonies were faster than the evolutionary rates of the same behavior measured in isolated individual ants, and total variation across species in collective behavior was higher than variation in individual behavior. We hypothesize that more rapid evolution and higher variation is a widespread feature of emergent phenotypes relative to lower-level phenotypes across complex biological systems.

GPT-4o mini: Non-social science research article

Insulin-inspired peptides may open new pathways to treat Alzheimer’s disease

Mie Kristensen

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GPT-4o mini: Non-social science research article

Cyanobacteria from marine oxygen-deficient zones encode both form I and form II Rubiscos

Alexander L. Jaffe, Kaitlin Harrison, Renée Z. Wang, Leah J. Taylor-Kearney, Navami Jain, Noam Prywes, Patrick M. Shih, Jodi Young, Gabrielle Rocap, Anne E. Dekas

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Cyanobacteria are highly abundant in the marine photic zone and primary drivers of the conversion of inorganic carbon into biomass. To date, all studied cyanobacterial lineages encode carbon fixation machinery relying upon form I Rubiscos within a CO 2 -concentrating carboxysome. Here, we report that the uncultivated anoxic marine zone (AMZ) IB lineage of Prochlorococcus from pelagic oxygen-deficient zones (ODZs) harbors both form I and form II Rubiscos, the latter of which are typically noncarboxysomal and possess biochemical properties tuned toward low-oxygen environments. We demonstrate that these cyanobacterial form II enzymes are functional in vitro and were likely acquired from proteobacteria. Metagenomic analysis reveals that AMZ IB are essentially restricted to ODZs in the Eastern Pacific, suggesting that form II acquisition may confer an advantage under low-O 2 conditions. AMZ IB populations express both forms of Rubisco in situ, with the highest form II expression at depths where oxygen and light are low, possibly as a mechanism to increase the efficiency of photoautotrophy under energy limitation. Our findings expand the diversity of carbon fixation configurations in the microbial world and may have implications for carbon sequestration in natural and engineered systems.

GPT-4o mini: Non-social science research article

Connecting the dots: Presentation of EBV antigens on HLA class II risk alleles connects the two main risk factors of multiple sclerosis

Tobias V. Lanz, William H. Robinson

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GPT-4o mini: Non-social science research article

Metagenomic study of lake microbial mats reveals protease-inhibiting antiviral peptides from a core microbiome member

Chandrashekhar Padhi, Christopher M. Field, Clarissa C. Forneris, Dominik Olszewski, Amy E. Fraley, Ioana Sandu, Thomas A. Scott, Jakob Farnung, Hans-Joachim Ruscheweyh, Ananta Narayan Panda, Annette Oxenius, Urs F. Greber, Jeffrey W. Bode, Shinichi Sunagawa, Vishakha Raina, Mrutyunjay Suar, Jörn Piel

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In contrast to the large body of work on bioactive natural products from individually cultivated bacteria, the chemistry of environmental microbial communities remains largely elusive. Here, we present a comprehensive bioinformatic and functional study on a complex and interaction-rich ecosystem, algal-bacterial (microbial) mats of Lake Chilika in India, Asia’s largest brackish water body. We report the bacterial compositional dynamics over the mat life cycle, >1,300 reconstructed environmental genomes harboring >2,200 biosynthetic gene clusters (BGCs), the successful cultivation of a widespread core microbiome member belonging to the genus Rheinheimera , heterologous reconstitution of two silent Rheinheimera biosynthetic pathways, and new compounds with potent protease inhibitory and antiviral activities. The identified substances, posttranslationally modified peptides from the graspetide and spliceotide families, were targeted among the large BGC diversity by applying a strategy focusing on recurring multi-BGC loci identified in diverse samples, suggesting their presence in successful colonizers. In addition to providing broad insights into the biosynthetic potential of a poorly studied community from sampling to bioactive substances, the study highlights the potential of ribosomally synthesized and posttranslationally modified peptides as a large, underexplored resource for antiviral drug discovery.

GPT-4o mini: Non-social science research article

Action similarity warps visual feature space in working memory

Caterina Trentin, Luigi Falanga, Jannik Jeske, Christian N.L. Olivers, Heleen A. Slagter

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Visual working memory (VWM) retains representations of past visual information for future action. Yet to date, most studies have approached VWM as just serving perception beyond the immediate. Whether and how prospective actions shape information in VWM remains largely unknown, in part because typical experimental setups limit behavior to simple button presses. In two experiments (one preregistered), using a novel interactive VWM task, we show that the similarity of the actions that we intend to perform on memory items adaptively distorts their representation. Participants memorized the orientation of two bars, after which they were informed as to which manual actions they should reproduce these orientations with in a memory recall test. We observed that perceptually similar items were remembered as more distinct when paired with different action plans versus the same action plan. A control experiment showed that this action-induced effect reflects a true change in the visual representation rather than a motor bias. These findings demonstrate that VWM representations are flexibly adapted to guide specific overt actions and provide evidence that action plans can retrospectively warp sensory feature space in VWM.

GPT-4o mini: Non-social science research article

AgRP neurons mediate activity-dependent development of oxytocin connectivity and autonomic regulation

Jessica E. Biddinger, Amanda E. T. Elson, Payam A. Fathi, Serena R. Sweet, Katsuhiko Nishimori, Julio E. Ayala, Richard B. Simerly

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During postnatal life, leptin specifies neuronal inputs to the paraventricular nucleus of the hypothalamus (PVH) and activates agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus. Activity-dependent developmental mechanisms impact refinement of sensory circuits, but whether leptin-mediated postnatal neuronal activity specifies hypothalamic neural projections is largely unexplored. Here, we used chemogenetics to manipulate the activity of AgRP neurons during a discrete postnatal critical period and evaluated the development of AgRP inputs to the PVH and descending efferent outflow to the dorsal vagal complex (DVC). In leptin-deficient mice, targeting of AgRP neuronal outgrowth to PVH oxytocin neurons was reduced, and despite the lack of leptin receptors found on oxytocin neurons in the PVH, oxytocin-containing connections to the DVC were also impaired. Activation of AgRP neurons during early postnatal life not only normalized AgRP inputs to the PVH but also oxytocin outputs to the DVC in leptin-deficient mice. Blocking AgRP neuron activity during the same postnatal period reduced the density of AgRP inputs to the PVH of wild type mice, as well as the density of oxytocin-containing DVC fibers, and these innervation deficits were associated with dysregulated autonomic function. These findings suggest that leptin-mediated AgRP neuronal activity is required for the development of PVH connectivity and represents a unique activity-dependent mechanism for specification of neural pathways involved in the hypothalamic integration of autonomic responses.

GPT-4o mini: Non-social science research article

Nanoscale dynamics of Dynamin 1 helices reveals squeeze-twist deformation mode critical for membrane fission

Yuliang Zhang, Javier Vera Lillo, Mahmoud Shaaban Mohamed Abdelrasoul, Yaqing Wang, Pedro Arrasate, Vadim A. Frolov, Aleksandr Noy

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Dynamin 1 (Dyn1) GTPase, a principal driver of membrane fission during synaptic endocytosis, self-assembles into short mechanoactive helices cleaving the necks of endocytic vesicles. While structural information about Dyn1 helix is abundant, little is known about the nanoscale dynamics of the helical scaffolding at the moment of fission, complicating mechanistic understanding of Dyn1 action. To address the role of the helix dynamics in fission, we used High-Speed Atomic Force Microscopy (HS-AFM) and fluorescence microscopy to track and compare the spatiotemporal characteristics of the helices formed by wild-type Dyn1 and its K44A mutant impaired in GTP hydrolysis on minimal lipid membrane templates. In the absence of nucleotide, membrane-bound WT Dyn1 and K44A Dyn1 self-assembled into tubular protein scaffolding of similar diameter encaging the lipid bilayer. In both cases, the GTP addition caused scaffold constriction coupled with formation of 20 to 30 nm nanogaps in the protein coverage. While both proteins reached scaffold diameters characteristic for membrane superconstriction causing fission, the fission was detected only with WT Dyn1. We associated the fission activity with the dynamic evolution of the nanogaps: K44A Dyn1 gaps were static, while WT Dyn1 gaps actively evolved via repetitive nonaxisymmetric constriction-bending deformations caused by localized GTP hydrolysis. Modeling of the deformations implicated filament twist as an additional deformation mode which combines with superconstriction to facilitate membrane fission. Our results thus show that the dynamics of the Dyn1 helical scaffold goes beyond radial constriction and involves nonaxisymmetric deformations, where filament twist emerges as a critical driver of membrane fission.

GPT-4o mini: Non-social science research article

Molecular architecture of synaptic vesicles

Uljana Kravčenko, Max Ruwolt, Jana Kroll, Artsemi Yushkevich, Martina Zenkner, Julia Ruta, Rowaa Lotfy, Erich E. Wanker, Christian Rosenmund, Fan Liu, Mikhail Kudryashev

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Synaptic vesicles (SVs) store and transport neurotransmitters to the presynaptic active zone for release by exocytosis. After release, SV proteins and excess membrane are recycled via endocytosis, and new SVs can be formed in a clathrin-dependent manner. This process maintains complex molecular composition of SVs through multiple recycling rounds. Previous studies explored the molecular composition of SVs through proteomic analysis and fluorescent microscopy, proposing a model for an average SV ( 1 ). However, the structural heterogeneity and molecular architecture of individual SVs are not well described. Here, we used cryoelectron tomography to visualize molecular details of SVs isolated from mouse brains and inside cultured neurons. We describe several classes of small proteins on the SV surface and long proteinaceous densities inside SVs. We identified V-ATPases, determined a structure using subtomogram averaging, and showed them forming a complex with the membrane-embedded protein synaptophysin (Syp). Our bioluminescence assay revealed pairwise interactions between vesicle-associated membrane protein 2 and Syp and V-ATPase Voe1 domains. Interestingly, V-ATPases were randomly distributed on the surface of SVs irrespective of vesicle size. A subpopulation of isolated vesicles and vesicles inside neurons contained a partially assembled clathrin coat with an icosahedral symmetry. We observed V-ATPases under clathrin cages in several isolated clathrin-coated vesicles (CCVs). Additionally, from isolated SV preparations and within hippocampal neurons we identified clathrin baskets without vesicles. We determined their and CCVs preferential location in proximity to the cell membrane. Our analysis advances the understanding of individual SVs' diversity and their molecular architecture.

GPT-4o mini: Non-social science research article

Proteome-wide bioinformatic annotation and functional validation of the monotopic phosphoglycosyl transferase superfamily

Theo Durand, Greg J. Dodge, Roxanne P. Siuda, Hugh R. Higinbotham, Christine A. Arbour, Soumi Ghosh, Karen N. Allen, Barbara Imperiali

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Phosphoglycosyl transferases (PGTs) are membrane proteins that initiate glycoconjugate biosynthesis by transferring a phospho-sugar moiety from a soluble nucleoside diphosphate sugar to a membrane-embedded polyprenol phosphate acceptor. The centrality of PGTs in complex glycan assembly and the current lack of functional information make these enzymes high-value targets for biochemical investigation. In particular, the small monotopic PGT family is exclusively bacterial and represents the minimal functional unit of the monotopic PGT superfamily. Here, we combine a sequence similarity network analysis with a generalizable, luminescence-based activity assay to probe the substrate specificity of this family of monoPGTs in the bacterial cell-membrane fraction. This strategy allows us to identify specificity on a far more significant scale than previously achievable and correlate preferred substrate specificities with predicted structural differences within the conserved monoPGT fold. Finally, we present the proof-of-concept for a small-scale inhibitor screen (eight nucleoside analogs) with four monoPGTs of diverse substrate specificity, thus building a foundation for future inhibitor discovery initiatives.

GPT-4o mini: Non-social science research article

Dissecting neurofilament tail sequence-phosphorylation-structure relationships with multicomponent reconstituted protein brushes

Erika A. Ding, Takashi J. Yokokura, Rui Wang, Sanjay Kumar

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Neurofilaments (NFs) are multisubunit, bottlebrush-shaped intermediate filaments abundant in the axonal cytoskeleton. Each NF subunit contains a long intrinsically disordered tail domain, which protrudes from the NF core to form a “brush” surrounding each NF. Precisely how the tails’ variable charge patterns and repetitive phosphorylation sites mediate their conformation within the brush remains an open question in axonal biology. We address this problem by grafting recombinant NF tail protein constructs NF-Light, -Medium, and -Heavy (NFL, NFM, and NFH) to surfaces, yielding protein brushes of defined stoichiometry that can be phosphorylated in vitro. Atomic force microscopy measurements reveal that brush height depends on composition monotonically but not always linearly for binary NFL:NFM or NFL:NFH systems, and that NFM-based brushes are highly extended, while brushes incorporating the much larger NFH are surprisingly compact even after multisite phosphorylation. Complementary self-consistent field theory (SCFT) predicts multilayer brush morphologies for NFM and phosphorylated NFH brushes. Further experiments and SCFT analysis with designed mutants reveal that N-terminal negative charges in the NFH tail repel phosphorylated residues to generate the multilayer morphology, while the C-terminal charge-neutral region contributes to multilayer brush morphology but not total brush height. Charge-shuffled NFM variants show that charge segregation promotes brush collapse near physiological ionic strengths. Collectively, this study supports a role for NFM in establishing a dynamic range for NF brush conformation, lending insight into previous in vitro and in vivo findings. More broadly, this work establishes a platform for dissecting contributions of disordered protein sequence to conformation at interfaces.

GPT-4o mini: Non-social science research article

Staggered immunization with mRNA vaccines encoding SARS-CoV-2 polymerase or spike antigens broadens the T cell epitope repertoire

Evan R. Abt, Alex K. Lam, Miyako Noguchi, Khalid Rashid, Jami McLaughlin, Pu-Lin Teng, Wendy Tran, Donghui Cheng, Pavlo A. Nesterenko, Zhiyuan Mao, Amanda L. Creech, Giselle Burton Sojo, Arjit Vijey Jeyachandran, Ying K. Tam, Jill E. Henley, Lucio Comai, Norbert Pardi, Vaithilingaraja Arumugaswami, Owen N. Witte, Caius G. Radu, Ting-Ting Wu

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Combining a T cell-targeting mRNA vaccine encoding the conserved SARS-CoV-2 RNA-dependent RNA polymerase, RdRp, with a Spike-encoding mRNA vaccine may offer an additional pathway toward COVID-19 protection. Here, we show that a nucleoside-modified RdRp mRNA vaccine raises robust and durable CD8+ T cell responses in mice. Immunization drives a CD8+ T cell response enriched toward a specific RdRp epitope. Unexpectedly, coadministration of mRNA vaccines encoding RdRp or the Spike Receptor Binding Domain (RBD) dampens RBD-specific immune responses. Contralateral administration reduces the suppression of RBD-specific T cell responses while type I interferon signaling blockade restores RBD-specific antibodies. A staggered immunization strategy maintains both RBD vaccine-mediated antibody and T cell responses as well as protection against lethal SARS-CoV-2 challenge in human ACE2 transgenic mice. In HLA-A2.1 transgenic mice, the RdRp vaccine elicits CD8+ T cell responses against HLA-A*02:01-restricted epitopes recognized by human donor T cells. These results highlight RdRp as a candidate antigen for COVID-19 vaccines. The findings also offer insights into crafting effective multivalent mRNA vaccines to broaden CD8+ T cell responses against SARS-CoV-2 and potentially other viruses with pandemic potential.

GPT-4o mini: Non-social science research article

PBLD enhances antiviral innate immunity by promoting the p53–USP4–MAVS signaling axis

Fengyun Chu, Peili Hou, Hongchao Zhu, Yan Gao, Xiaomeng Wang, Wenqi He, Juan Ren, Min Li, Yu Liu, Daniel Chang He, Hongmei Wang, Yuwei Gao, Hongbin He

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Phenazine biosynthesis-like domain-containing protein (PBLD) has been reported to be involved in the development of many cancers. However, whether PBLD regulates innate immune responses and viral replication is unclear. In this study, although it was found that the activity of PBLD extends to other PRRs, we focused on the RLR pathway activated via the p53–USP4–MAVS axis in response to virus infections. We found that PBLD deubiquitinates and stabilizes MAVS through ubiquitin-specific protease 4 (USP4) to promote antiviral innate immunity. Mechanistically, PBLD activates the transcription of USP4 via the upregulation of p53. USP4, which is a MAVS-interacting protein, substantially stabilizes the MAVS protein by deconjugating K48-linked ubiquitination chains from the MAVS protein at Lys461 during RNA virus infection. Most intriguingly, RNA virus-infected primary macrophages (peritoneal macrophages, PMs, and bone marrow–derived macrophages, BMDMs) and internal organ cells (lung and liver) from PBLD-deficient mice suppress the IFN-I response and promote viral replication. Notably, PBLD-deficient mice are more susceptible to RNA virus infection than their wild-type littermates. Our findings highlight a unique function of PBLD in antiviral innate immunity through the p53–USP4–MAVS signaling, providing a preliminary basis for research on PBLD as a target molecule for treating RNA virus infection.

GPT-4o mini: Non-social science research article

Early disruption of the CREB pathway drives dendritic morphological alterations in FTD/ALS cortical neurons

Michelle Jean Gregoire, Riccardo Sirtori, Liviana Donatelli, Emily Morgan Potts, Alicia Collins, Danielo Zamor, Natallia Katenka, Claudia Fallini

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Synaptic loss and dendritic degeneration are common pathologies in several neurodegenerative diseases characterized by progressive cognitive and/or motor decline, such as Alzheimer’s disease (AD) and frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). An essential regulator of neuronal health, the cAMP-dependent transcription factor CREB positively regulates synaptic growth, learning, and memory. Phosphorylation of CREB by protein kinase A (PKA) and other cellular kinases promotes neuronal survival and maturation via transcriptional activation of a wide range of downstream target genes. CREB pathway dysfunction has been strongly implicated in AD pathogenesis, and recent data suggest that impaired CREB activation may contribute to disease phenotypes in FTD/ALS as well. However, the mechanisms behind reduced CREB activity in FTD/ALS pathology are not clear. In this study, we found that cortical-like neurons derived from iPSC lines carrying the hexanucleotide repeat expansion in the C9ORF72 gene, a common genetic cause of FTD/ALS, displayed a diminished activation of CREB, resulting in decreased dendritic and synaptic health. Importantly, we determined such impairments to be mechanistically linked to an imbalance in the ratio of regulatory and catalytic subunits of the CREB activator PKA and to be conserved in C9-ALS patient’s postmortem tissue. Modulation of cAMP upstream of this impairment allowed for a rescue of CREB activity and an amelioration of dendritic morphology and synaptic protein levels. Our data elucidate the mechanism behind early CREB pathway dysfunction and discern a feasible therapeutic target for the treatment of FTD/ALS and possibly other neurodegenerative diseases.

GPT-4o mini: Non-social science research article

Synthesizing ordered polar patterns in nonpolar SrTiO 3 nanofilms via wrinkle-induced flexoelectricity

Hongxing Shang, Tang Sheng, Huiting Dong, Yihan Wu, Qianqian Ma, Xin Zhang, Lingtong Lv, Hongyu Cao, Feng Deng, Xu Liang, Shuling Hu, Shengping Shen

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Ordered polar structures in oxide nanofilms play a pivotal role in the development of nanoelectronic applications. Hitherto, ordered polar structures have been restricted to a limited number of ferroelectric materials, and there is no effective scheme to induce and manipulate ordered polar patterns in centrosymmetric nonpolar nanofilms due to the absence of spontaneous symmetry breaking. Here, we circumvent these limitations by utilizing the wrinkle-induced strain gradient modulation associated with flexoelectricity as a general means of inducing and manipulating ordered polar patterns in nonpolar nanofilms. Leveraging the surface instability caused by strain mismatch between oxide nanofilms and pre-strained compliant substrate, we successfully fabricate striped SrTiO 3 wrinkles, where well-ordered strain gradients and corresponding periodic polar patterns are readily achieved. Through in-situ piezoresponse force microscopy experiments, we show that the generated polar patterns can be manipulated by varying strain boundaries. Furthermore, the atomistic resolution images and first-principles calculations reveal that such wrinkle-induced ordered polar patterns primarily emerge from the flexoelectric coupling between the local polarization and strain gradients. These findings provide implications for manipulating polar structures by strain gradient and flexoelectric engineering, which in turn enable the realization of nontrivial polar structures in a broader range of materials.

GPT-4o mini: Non-social science research article

Flexible bioelectronic systems with large-scale temperature sensor arrays for monitoring and treatments of localized wound inflammation

Junhan Liu, Zhongzheng Li, Mubai Sun, Lianjie Zhou, Xiaojun Wu, Yifei Lu, Yuting Shao, Chang Liu, Ningge Huang, Bofan Hu, Zhongyuan Wu, Chunyu You, Lizhu Li, Ming Wang, Ling Tao, Zengfeng Di, Xing Sheng, Yongfeng Mei, Enming Song

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Continuous monitoring and closed-loop therapy of soft wound tissues is of particular interest in biomedical research and clinical practices. An important focus is on the development of implantable bioelectronics that can measure time-dependent temperature distribution related to localized inflammation over large areas of wound and offer in situ treatment. Existing approaches such as thermometers/thermocouples provide limited spatial resolution, inapplicable to a wearable/implantable format. Here, we report a conformal, scalable device package that integrates a flexible amorphous silicon–based temperature sensor array and drug-loaded hydrogel for the healing process. This system can enable the spatial temperature mapping at submillimeter resolution and high sensitivity of 0.1 °C, for dynamically localizing the inflammation regions associated with temperature change, automatically followed with heat-triggered drug delivery from hydrogel triggered by wearable infrared light-emitting-diodes. We establish the operational principles experimentally and computationally and evaluate system functionalities with a wide range of targets including live animal models and human subjects. As an example of medical utility, this system can yield closed-loop monitoring/treatments by tracking of temperature distribution over wound areas of live rats, in designs that can be integrated with automated wireless control. These findings create broad utilities of these platforms for clinical diagnosis and advanced therapy for wound healthcare.

GPT-4o mini: Non-social science research article

The fork protection complex generates DNA topological stress–induced DNA damage while ensuring full and faithful genome duplication

Andrea Keszthelyi, Sahar Mansoubi, Alex Whale, Jonathan Houseley, Jonathan Baxter

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The fork protection complex (FPC), composed of Mrc1, Tof1, and Csm3, supports rapid and stable DNA replication. Here, we show that FPC activity also introduces DNA damage by increasing DNA topological stress during replication. Mrc1 action increases DNA topological stress during plasmid replication, while Mrc1 or Tof1 activity causes replication stress and DNA damage within topologically constrained regions. We show that the recruitment of Top1 to the fork by Tof1 suppresses the DNA damage generated in these loci. While FPC activity introduces some DNA damage due to increased topological stress, the FPC is also necessary to prevent DNA damage in long replicons across the genome, indicating that the FPC is required for complete and faithful genome duplication. We conclude that FPC regulation must balance ensuring full genome duplication through rapid replication with minimizing the consequential DNA topological stress–induced DNA damage caused by rapid replication through constrained regions.

GPT-4o mini: Non-social science research article

Constitutive opening of the Kv7.2 pore activation gate causes KCNQ2 -developmental encephalopathy

Mario Nappi, Giulio Alberini, Alessandro Berselli, Agnese Roscioni, Maria Virginia Soldovieri, Ilenio Servettini, Vincenzo Barrese, Sarah Weckhuysen, Ting-Gee Annie Chiu, Ingrid E. Scheffer, Fabio Benfenati, Luca Maragliano, Francesco Miceli, Maurizio Taglialatela

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Pathogenic variants in KCNQ2 encoding Kv7.2 voltage-gated potassium channel subunits cause developmental encephalopathies ( KCNQ2 -encephalopathies), both with and without epilepsy. We herein describe the clinical, in vitro, and in silico features of two encephalopathy-causing variants (A317T, L318V) in Kv7.2 affecting two consecutive residues in the S 6 activation gate that undergoes large structural rearrangements during pore opening; the disease-causing A356T variant in KCNQ3 , paralogous to the A317T variant in KCNQ2 , was also investigated. Currents through KCNQ2 mutant channels displayed increased density, hyperpolarizing shifts in activation gating, faster activation and slower deactivation kinetics, and resistance to changes in the cellular concentrations of phosphatidylinositol 4,5-bisphosphate (PIP 2 ), a critical regulator of Kv7 channel function; all these features are consistent with a strong gain-of-function effect. An increase in the probability of single-channel opening, with no change in membrane abundance or single-channel conductance, was responsible for the observed gain-of-function effects. All-atom molecular dynamics simulations revealed that the mutations widened the inner pore gate and stabilized a constitutively open channel configuration in the closed state, with minimal effects on the open conformation. Thus, mutation-induced stabilization of the inner pore gate open configuration is a molecular pathogenetic mechanism for KCNQ2 -related encephalopathies.

GPT-4o mini: Non-social science research article

A widespread family of ribosomal peptide metallophores involved in bacterial adaptation to metal stress

Laura Leprevost, Sophie Jünger, Guy Lippens, Céline Guillaume, Giuseppe Sicoli, Lydie Oliveira, Enrico Falcone, Emiliano de Santis, Alex Rivera-Millot, Gabriel Billon, Francesco Stellato, Céline Henry, Rudy Antoine, Séverine Zirah, Svetlana Dubiley, Yanyan Li, Françoise Jacob-Dubuisson

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Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a structurally diverse group of natural products that bacteria employ in their survival strategies. Herein, we characterized the structure, the biosynthetic pathway, and the mode of action of a RiPP family called bufferins. With thousands of homologous biosynthetic gene clusters throughout the bacterial phylogenetic tree, bufferins form by far the largest family of RiPPs modified by multinuclear nonheme iron-dependent oxidases (MNIO, DUF692 family). Using Caulobacter vibrioides bufferins as a model, we showed that the conserved Cys residues of their precursors are transformed into 5-thiooxazoles, further expanding the reaction range of MNIO enzymes. This rare modification is installed in conjunction with a partner protein of the DUF2063 family. Bufferin precursors are rare examples of bacterial RiPPs found to feature an N-terminal Sec signal peptide allowing them to be exported by the ubiquitous Sec pathway. We reveal that bufferins are involved in copper homeostasis, and their metal-binding propensity requires the thiooxazole heterocycles. Bufferins enhance bacterial growth under copper stress by complexing excess metal ions. Our study thus describes a large family of RiPP metallophores and unveils a widespread but overlooked metal homeostasis mechanism in bacteria.

GPT-4o mini: Non-social science research article

Profile of Susan Goldin-Meadow

Sandeep Ravindran

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GPT-4o mini: Non-social science research article

Interstitial telomeric sequences promote gross chromosomal rearrangement via multiple mechanisms

Fernando R. Rosas Bringas, Ziqing Yin, Yue Yao, Jonathan Boudeman, Sandra Ollivaud, Michael Chang

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Telomeric DNA sequences are difficult to replicate. Replication forks frequently pause or stall at telomeres, which can lead to telomere truncation and dysfunction. In addition to being at chromosome ends, telomere repeats are also present at internal locations within chromosomes, known as interstitial telomeric sequences (ITSs). These sequences are unstable and prone to triggering gross chromosomal rearrangements (GCRs). In this study, we quantitatively examined the effect of ITSs on the GCR rate in Saccharomyces cerevisiae using a genetic assay. We find that the GCR rate increases exponentially with ITS length. This increase can be attributed to the telomere repeat binding protein Rap1 impeding DNA replication and a bias of repairing DNA breaks at or distal to the ITS via de novo telomere addition. Additionally, we performed a genome-wide screen for genes that modulate the rate of ITS-induced GCRs. We find that mutation of core components of the DNA replication machinery leads to an increase in GCRs, but many mutants known to increase the GCR rate in the absence of an ITS do not significantly affect the GCR rate when an ITS is present. We also identified genes that promote the formation of ITS-induced GCRs, including genes with roles in telomere maintenance, nucleotide excision repair, and transcription. Our work thus uncovers multiple mechanisms by which an ITS promotes GCR.

GPT-4o mini: Non-social science research article

Medium-density amorphous ice unveils shear rate as a new dimension in water’s phase diagram

Ingrid de Almeida Ribeiro, Debdas Dhabal, Rajat Kumar, Suvo Banik, Subramanian K. R. S. Sankaranarayanan, Valeria Molinero

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Recent experiments revealed a new amorphous ice phase, medium-density amorphous ice (MDA), formed by ball-milling ice I h at 77 K [Rosu-Finsen et al. , Science 379 , 474–478 (2023)]. MDA has density between that of low-density amorphous (LDA) and high-density amorphous (HDA) ices, adding to the complexity of water’s phase diagram, known for its glass polyamorphism and two-state thermodynamics. The nature of MDA and its relation to other amorphous ices and liquid water remain unsolved. Here, we use molecular simulations under controlled pressure and shear rate at 77 K to produce and investigate MDA. We find that MDA formed at constant shear rate is a steady-state nonequilibrium shear-driven amorphous ice (SDA), that can be produced by shearing ice I h , LDA, or HDA. Our results suggest that MDA could be obtained by ball-milling water glasses without crystallization interference. Increasing the shear rate at ambient pressure produces SDAs with densities ranging from LDA to HDA, revealing shear rate as a new thermodynamic variable in the nonequilibrium phase diagram of water. Indeed, shearing provides access to amorphous states inaccessible by controlling pressure and temperature alone. SDAs produced with shearing rates as high as 10 6 s −1 sample the same region of the potential energy landscape than hyperquenched glasses with identical density, pressure, and temperature. Intriguingly, SDAs obtained by shearing at ~10 8 s −1 have density, enthalpy, and structure indistinguishable from those of water “instantaneously” quenched from room temperature to 77 K over 10 ps, making them good approximants for the “true glass” of ambient liquid water.

GPT-4o mini: Non-social science research article

CO 2 protects cells from iron-Fenton oxidative DNA damage in Escherichia coli and humans

Aaron M. Fleming, Justin C. Dingman, Cynthia J. Burrows

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While hydroxyl radical is commonly named as the Fenton product responsible for DNA and RNA damage in cells, here we demonstrate that the cellular reaction generates carbonate radical anion due to physiological bicarbonate levels. In human and Escherichia coli models, their transcriptomes were analyzed by RNA direct nanopore sequencing of ribosomal RNA and chromatography coupled to electrochemical detection to quantify oxidation products in order to follow the bicarbonate dependency in H 2 O 2 -induced oxidation. These transcriptomic studies identified physiologically relevant levels of bicarbonate focused oxidation on the guanine base favorably yielding 8-oxo-7,8-dihydroguanine (OG). In human cells, the bicarbonate-dependent oxidation was further analyzed in the metabolome by mass spectrometry, and a glycosylase-dependent qPCR assay to quantify oxidation sites in telomeres. These analyses further identify guanine as the site of oxidation when bicarbonate is present upon H 2 O 2 exposure. Labile iron as the catalyst for forming carbonate radical anion was demonstrated by repeating the bicarbonate-dependent oxidations in cells experiencing ferroptosis, which had a >fivefold increase in redox-active iron, to find enhanced overall guanine-specific oxidation when bicarbonate was present. The complete profiling of nucleic acid oxidation in the genome, transcriptome, and metabolome supports the conclusion that a cellular Fe(II)-carbonate complex redirects the Fenton reaction to yield carbonate radical anion. Focusing H 2 O 2 -induced oxidative modification on one pathway is consistent with the highly evolved base excision repair suite of enzymes to locate G-oxidation sites for repair and gene regulation in response to oxidative stress.

GPT-4o mini: Non-social science research article

BCL2 regulates antibacterial autophagy in the intestinal epithelium

Yun Li, Shai Bel, Jamaal L. Benjamin, Kelly A. Ruhn, Brian Hassell, Cassie L. Behrendt, Zheng Kuang, Lora V. Hooper

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Autophagy is a key innate immune defense mechanism in intestinal epithelial cells. Bacterial invasion of epithelial cells activates antibacterial autophagy through a process that requires the innate immune adaptor protein MYD88, yet how MYD88 signaling connects to the autophagy machinery is unknown. Here, we show that the mouse intestinal pathogen Salmonella enterica Serovar Typhimurium ( Salmonella Typhimurium) triggers MYD88 signaling that regulates binding of the anti-autophagy factor B cell lymphoma 2 (BCL2) to the essential autophagy protein Beclin1 (BECN1) in small intestinal enterocytes, a key epithelial cell lineage. Salmonella infection activated the kinase c-Jun N-terminal protein kinase 1 (JNK1) downstream of MYD88. JNK1 induced enterocyte BCL2 phosphorylation, promoting dissociation of the inhibitory BCL2–BECN1 complex and releasing BECN1 to initiate autophagy. Mice with BCL2 phosphorylation site mutations that prevent BCL2–BECN1 dissociation showed increased Salmonella invasion of enterocytes and dissemination to extraintestinal sites. These findings reveal that BCL2 links MYD88 signaling to enterocyte autophagy initiation, providing mechanistic insight into how invading bacteria trigger autophagy in the intestinal epithelium.

GPT-4o mini: Non-social science research article

Rigidity transition of a highly compressible granular medium

Samuel Poincloux, Kazumasa A. Takeuchi

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A wide range of disordered materials, from biological to geological assemblies, feature discrete elements undergoing large shape changes. How significant geometrical variations at the microscopic scale affect the response of the assembly, in particular rigidity transitions, is an ongoing challenge in soft matter physics. However, the lack of a model granular-like experimental system featuring large and versatile particle deformability impedes advances. Here, we explore the oscillatory shear response of a sponge-like granular assembly composed of highly compressible elastic rings. We highlight a progressive rigidity transition, switching from a yielded phase to a solid one by increasing density or decreasing shear amplitude. The rearranging yielded state consists of crystal clusters separated by melted regions; in contrast, the solid state remains amorphous and absorbs all imposed shear elastically. We rationalize this transition by uncovering an effective, attractive shear force between rings that emerges from a friction-geometry interplay. If friction is sufficiently high, the extent of the contacts between rings, captured analytically by elementary geometry, controls the rigidity transition.

GPT-4o mini: Non-social science research article

Correction for Johnson et al., L-type Ca 2+ channel blockers promote vascular remodeling through activation of STIM proteins

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GPT-4o mini: Non-social science research article

Reply to Fine et al. and Rippon: Significant sex differences in accelerated cortical thinning associated with the COVID-19 lockdowns

Neva M. Corrigan, Ariel Rokem, Patricia K. Kuhl

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GPT-4o mini: Non-social science research article

AtFH5 recruits and transports the arabinogalactan protein AGP23 to maintain the tip growth of pollen tube

Jiang Li, Ligang Fan, Ting Yang, Puzhi Zhang, Huaqiang Ruan, Yihao Li, Ting Wang, Yi Zhang, Fanfan Zhang, Haiyun Ren

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Actin cytoskeleton drives the targeted transport of cell wall components to sustain the tip growth of pollen tubes for double fertilization; however, the underlying mechanism remains largely unknown. Arabidopsis formin 5 (AtFH5), an actin-nucleating protein, localizes at secretory vesicles and mediates actin polymerization-based vesicle trafficking in pollen. Here, we demonstrate that AtFH5 determines the recruitment and transport of cell wall components in AtFH5-labeled vesicles during the tip growth of pollen tubes. Through a screen of interacting proteins of AtFH5, we identify many cell wall–related proteins, with arabinogalactan protein 23 (AGP23) occupying the highest frequency. AtFH5 interacts with AGP23 via its N-terminal extracellular domain (ECD) and jointly regulate the pollen germination and tube growth process. Further observations reveal that AGP23 co-localizes with AtFH5 at moving vesicles, germination sites, and pollen tube tips, suggesting that AGP23 is delivered by AtFH5-labeled vesicles. Deletion of the ECD of AtFH5 interrupts the dynamic localization and cell-wall connection of AGP23 in pollen grains and tubes. Cytological and genetic evidence shows that AGP23 and AtFH5 work in the same pathway to modulate cell wall composition. Together, our data uncover a role of formin in directing the sorting and deposition of cell wall components via secretory vesicle trafficking during pollen germination and tube growth.

GPT-4o mini: Non-social science research article

Recurrent DNA nicks drive massive expansions of (GAA) n repeats

Liangzi Li, W. Shem Scott, Alexandra N. Khristich, Jillian F. Armenia, Sergei M. Mirkin

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Over 50 hereditary degenerative disorders are caused by expansions of short tandem DNA repeats (STRs). (GAA) n repeat expansions are responsible for Friedreich’s ataxia as well as late-onset cerebellar ataxias (LOCAs). Thus, the mechanisms of (GAA) n repeat expansions attract broad scientific attention. To investigate the role of DNA nicks in this process, we utilized a CRISPR-Cas9 nickase system to introduce targeted nicks adjacent to the (GAA) n repeat tract. We found that DNA nicks 5′ of the (GAA) 100 run led to a dramatic increase in both the rate and scale of its expansion in dividing cells. Strikingly, they also promoted large-scale expansions of carrier- and large normal-size (GAA) n repeats, recreating, in a model system, the expansion events that occur in human pedigrees. DNA nicks 3′ of the (GAA) 100 repeat led to a smaller but significant increase in the expansion rate as well. Our genetic analysis implies that in dividing cells, conversion of nicks into double-strand breaks (DSBs) during DNA replication followed by DSB or fork repair leads to repeat expansions. Finally, we showed that 5′ GAA-strand nicks increase expansion frequency in nondividing yeast cells, albeit to a lesser extent than in dividing cells.

GPT-4o mini: Non-social science research article

Electrochemical cofactor recycling of bacterial microcompartments

Markus Sutter, Lisa M. Utschig, Jens Niklas, Sathi Paul, Darren N. Kahan, Sayan Gupta, Oleg G. Poluektov, Bryan H. Ferlez, Nicholas M. Tefft, Michaela A. TerAvest, David P. Hickey, Josh V. Vermaas, Corie Y. Ralston, Cheryl A. Kerfeld

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Bacterial microcompartments (BMCs) are prokaryotic organelles that consist of a protein shell which sequesters metabolic reactions in its interior. While most of the substrates and products are relatively small and can permeate the shell, many of the encapsulated enzymes require cofactors that must be regenerated inside. We have analyzed the occurrence of an enzyme previously assigned as a cobalamin (vitamin B 12 ) reductase and, curiously, found it in many unrelated BMC types that do not employ B 12 cofactors. We propose Nicotinamide adenine dinucleotide (NAD+) regeneration as the function of this enzyme and name it Metabolosome Nicotinamide Adenine Dinucleotide Hydrogen (NADH) dehydrogenase (MNdh). Its partner shell protein BMC-T SE (tandem domain BMC shell protein of the single layer type for electron transfer) assists in passing the generated electrons to the outside. We support this hypothesis with bioinformatic analysis, functional assays, Electron Paramagnetic Resonance spectroscopy, protein voltammetry, and structural modeling verified with X-ray footprinting. This finding represents a paradigm for the BMC field, identifying a new, widely occurring route for cofactor recycling and a new function for the shell as separating redox environments.

GPT-4o mini: Non-social science research article

Correction for Shahriar et al., Targeted recruitment of immune effector cells for rapid eradication of influenza virus infections

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GPT-4o mini: Non-social science research article

Hominin brain size increase has emerged from within-species encephalization

Thomas A. Püschel, Samuel L. Nicholson, Joanna Baker, Robert A. Barton, Chris Venditti

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The fact that rapid brain size increase was clearly a key aspect of human evolution has prompted many studies focusing on this phenomenon, and many suggestions as to the underlying evolutionary patterns and processes. No study to date has however separated out the contributions of change through time within vs. between hominin species while simultaneously incorporating effects of body size. Using a phylogenetic approach never applied before to paleoanthropological data, we show that relative brain size increase across ~7 My of hominin evolution arose from increases within individual species which account for an observed overall increase in relative brain size. Variation among species in brain size after accounting for this effect is associated with body mass differences but not time. In addition, our analysis also reveals that the within-species trend escalated in more recent lineages, implying an overall pattern of accelerating relative brain size increase through time.

Impression management in research reporting: When effects are not really as pronounced as claimed

Gina Rippon

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Childhood exposure to coethnics increases naturalization

Mathias Kruse

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In Europe, the tendency among immigrants and descendants to seek out and interact with other coethnics has raised concern for their integration as it can reduce contact with the ethnic majority. Though policymakers implement large-scale integration programs to counteract these trends, it remains empirically and theoretically ambiguous whether exposure to coethnic peers impedes integration, and causal evidence is more limited for the growing population of migrant children. In this article, I use high-quality Danish administrative panel data over 28 y to investigate whether the ethnic composition experienced in childhood among immigrants and descendants with a non-EU background affects a core behavioral indicator of integration: naturalization. To isolate the causal effect of the childhood ethnic composition, I use the quasi-experimental assignment of siblings into different school grades in the same school. I find that being exposed to coethnic peers in the school grade increases the probability of naturalizing later in life. The main explanation is that exposure to some coethnic peers improves academic skills which are positively correlated with citizenship acquisition. These findings demonstrate the causal importance of non-EU migrant children’s social environment for their later integration into the national community showing that the modest presence of coethnic peers can be a precondition for, not a barrier to, integration.

The July 2024 Trump assassination attempt was followed by lower in-group support for partisan violence and increased group unity

Derek E. Holliday, Yphtach Lelkes, Sean J. Westwood

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The attempted assassination of Donald Trump led to widespread concern that the event would escalate political violence between U.S. partisans. While some politicians pleaded for Americans to unite against political violence and “turn down the temperature” on partisan hostility, others continued to engage in inflammatory rhetoric and blame. Using a national survey in the field at the time of the assassination attempt, we take the temperature of America’s partisans before and after the event. We exploit the natural variation induced by the assassination attempt and large daily survey coverage (preattempt: 3,572; postattempt: 703; and 690 in a panel) in the days before and after the attempt to estimate the causal effects of extreme partisan violence on measures of partisan animosity and identity. Using panel and cross-sectional interrupted time series analysis, we find no evidence that the event increased tensions or support for retaliatory violence in the immediate aftermath. On the contrary, Republicans, including MAGA Republicans, became significantly less supportive of partisan violence against Democrats. Republicans also did not become more hostile toward Democrats; instead, their attachment to their own party significantly increased. Democrats experienced no change in attitudes. While nearly a third of Americans have no positive feelings toward the other party, and a supermajority have negative feelings, this animosity was not exacerbated by an extreme but salient instance of partisan violence. Despite the ills of modern political conflict, extreme partisan violence did not cause an immediate upsurge in support for violence.

Neural responses to social rejection reflect dissociable learning about relational value and reward

Begüm G. Babür, Yuan Chang Leong, Chelsey X. Pan, Leor M. Hackel

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Social rejection hurts, but it can also be informative: Through experiences of acceptance and rejection, people identify partners interested in connecting with them and choose which ties to cement or to sever. What is it that people actually learn from rejection? In social interactions, people can learn from two kinds of information. First, people generally learn from rewarding outcomes, which may include concrete opportunities for interaction. Second, people track the “relational value” others ascribe to them—an internal model of how much others value them. Here, we used computational neuroimaging to dissociate these forms of learning. Participants repeatedly tried to match with others in a social game. Feedback revealed whether they successfully matched (a rewarding outcome) and how much the other person wanted to play with them (relational value). A Bayesian cognitive model revealed that participants chose partners who provided rewarding outcomes and partners who valued them. Whereas learning from outcomes was linked to brain regions involved in reward-based reinforcement, learning about relational value was linked to brain regions previously associated with social rejection. These findings identify precise computations underlying brain responses to rejection and support a neurocomputational model of social affiliation in which people build an internal model of relational value and learn from rewarding outcomes.

Uncertainty of adolescent brain maturation sex difference claims

Cordelia Fine, Liz Cope, Lucienne Elliott, Chloe A. Matthews, Madison Muscat, Christine Polowyj, Harvey L. Warren

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Cognitive reflection is a distinct and measurable trait

Andrew Meyer, Yigal Attali, Maya Bar-Hillel, Shane Frederick, Daniel Kahneman

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We report the findings of an adversarial collaboration examining whether the cognitive reflection test (CRT) measures anything beyond mathematical aptitude and, if so, whether its incremental predictive validity can be attributed to reflection, per se. We found that an 8-item CRT has greater predictive validity than an 8-item Mathematical Aptitude Test (MAT) consisting of comparably difficult items which lack dominant intuitive lures. Further, the incremental predictive validity stems from the CRT’s measurement of reflection, which we show using both structural equation models and a dual-response paradigm that helps distinguish susceptibility to intuitions from inadequate mathematical aptitude.

Beyond a binary theorizing of prosociality

Chen Shen, Zhixue He, Hao Guo, Shuyue Hu, Jun Tanimoto, Lei Shi, Petter Holme

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Stylized experiments, the public goods game and its variants thereof, have taught us the peculiar reproducible fact that humans tend to cooperate (or contribute to shared resources) more than expected from economically rational assumptions. There have been two competing explanations for this phenomenon: Either cooperating is an innate human trait (the prosocial preference hypothesis) or a transitory effect while learning the game (the confused learner hypothesis). We use large-scale experimental data in the two-player version of the public goods game—the prisoner’s dilemma—from an experimental design to distinguish between these two hypotheses. By monitoring the effects of zealots (persistently cooperating bots) and varying the participants’ awareness of them, we find a considerably more complex scenario than previously reported. People indeed have a prosocial bias, but not to the degree that they always forego taking action to increase their profit. While our findings end the simplistic theorizing of prosociality, an observed positive, cooperative response to zealots has actionable policy implications.

Cultural tightness and resilience against environmental shocks in nonindustrial societies

Denis Tverskoi, Carol R. Ember, Michele J. Gelfand, Eric C. Jones, Ian Skoggard, Louise Toutée, Sergey Gavrilets

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With climate change intensifying, building resilience against climate-related shocks is now a global imperative. Historically, many societies have faced natural hazards, with some adapting through specific social and cultural practices. Understanding these responses is key to developing modern sustainability strategies. Here, we address this issue by developing a mathematical model explicitly accounting for various environmental shock dimensions, cooperative activities common in nonindustrial societies, and decision-making based on material factors as well as personal values and social norms. Our results suggest that cultural looseness can be vital for effectively responding to mild, slow-onset shocks, leading to moderate cooperation and minimal cultural change. Conversely, coping with severe shocks requires an intermediate level of cultural tightness, fostering significant cultural transformation and high cooperation. While tight societies struggle with new shocks, they may handle regular, severe, fast-onset shocks better than do loose societies. Our research enhances understanding of environmental impacts on cooperation, cultural tightness, and social resilience, and highlights cultural adaptations useful in addressing current environmental challenges like global warming, floods, tornadoes, and soil degradation.

Nebulized vasopressin penetrates CSF and improves social cognition without inducing aggression in a rhesus monkey model of autism

Catherine F. Talbot, Ozge Oztan, Sierra M. V. Simmons, Callum Trainor, Lesly C. Ceniceros, Duyen K. K. Nguyen, Laura A. Del Rosso, Joseph P. Garner, John P. Capitanio, Karen J. Parker

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Low cerebrospinal (CSF) arginine vasopressin (AVP) concentration is a biomarker of social impairment in low-social monkeys and children with autism, suggesting that AVP administration may improve primate social functioning. However, AVP administration also increases aggression, at least in “neurotypical” animals with intact AVP signaling. Here, we tested the effects of a voluntary drug administration method in low-social male rhesus monkeys with high autistic-like trait burden. Monkeys received nebulized AVP or placebo, using a within-subjects design. Study 1 (N = 8) investigated the effects of AVP administration on social cognition in two tests comparing responses to social versus nonsocial stimuli. Test 1: Placebo-administered monkeys lacked face recognition memory, whereas face recognition memory was “rescued” following AVP administration. In contrast, object recognition memory was intact and did not differ between administration conditions. Test 2: Placebo-administered monkeys did not respond to conspecific social communication cues, whereas following AVP administration, they reciprocated affiliative communication cues with species-typical affiliative responses. Importantly, AVP administration did not increase aggressive responses to conspecific aggressive or affiliative overtures. Study 2 (N = 4) evaluated the pharmacokinetics of this administration method. Following AVP nebulization, we observed a linear increase in cisternal CSF AVP levels, and a quadratic rise and fall in blood AVP levels. These findings indicate that nebulized AVP likely penetrates the central nervous system, selectively promotes species-typical responses to social information, and does not induce aggression in low-social individuals. Nebulized AVP therefore may hold promise for managing similar social symptoms in people with autism, particularly in very young or lower functioning individuals.

Social learning with complex contagion

Hiroaki Chiba-Okabe, Joshua B. Plotkin

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Traditional models of social learning by imitation are based on simple contagion—where an individual may imitate a more successful neighbor following a single interaction. But real-world contagion processes are often complex, meaning that multiple exposures may be required before an individual considers changing their type. We introduce a framework that combines the concepts of simple payoff-biased imitation with complex contagion, to describe how social behaviors spread through a population. We formulate this model as a discrete time and state stochastic process in a finite population, and we derive its continuum limit as an ordinary differential equation that generalizes the replicator equation, a widely used dynamical model in evolutionary game theory. When applied to linear frequency-dependent games, social learning with complex contagion produces qualitatively different outcomes than traditional imitation dynamics: it can shift the Prisoner’s Dilemma from a unique all-defector equilibrium to either a stable mixture of cooperators and defectors in the population, or a bistable system; it changes the Snowdrift game from a single to a bistable equilibrium; and it can alter the Coordination game from bistability at the boundaries to two internal equilibria. The long-term outcome depends on the balance between the complexity of the contagion process and the strength of selection that biases imitation toward more successful types. Our analysis intercalates the fields of evolutionary game theory with complex contagions, and it provides a synthetic framework to describe more realistic forms of behavioral change in social systems.

Could ChatGPT get an engineering degree? Evaluating higher education vulnerability to AI assistants

Beatriz Borges, Negar Foroutan, Deniz Bayazit, Anna Sotnikova, Syrielle Montariol, Tanya Nazaretzky, Mohammadreza Banaei, Alireza Sakhaeirad, Philippe Servant, Seyed Parsa Neshaei, Jibril Frej, Angelika Romanou, Gail Weiss, Sepideh Mamooler, Zeming Chen, Simin Fan, Silin Gao, Mete Ismayilzada, Debjit Paul, Philippe Schwaller, Sacha Friedli, Patrick Jermann, Tanja Käser, Antoine Bosselut, character(0), character(0)

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AI assistants, such as ChatGPT, are being increasingly used by students in higher education institutions. While these tools provide opportunities for improved teaching and education, they also pose significant challenges for assessment and learning outcomes. We conceptualize these challenges through the lens of vulnerability, the potential for university assessments and learning outcomes to be impacted by student use of generative AI. We investigate the potential scale of this vulnerability by measuring the degree to which AI assistants can complete assessment questions in standard university-level Science, Technology, Engineering, and Mathematics (STEM) courses. Specifically, we compile a dataset of textual assessment questions from 50 courses at the École polytechnique fédérale de Lausanne (EPFL) and evaluate whether two AI assistants, GPT-3.5 and GPT-4 can adequately answer these questions. We use eight prompting strategies to produce responses and find that GPT-4 answers an average of 65.8% of questions correctly, and can even produce the correct answer across at least one prompting strategy for 85.1% of questions. When grouping courses in our dataset by degree program, these systems already pass the nonproject assessments of large numbers of core courses in various degree programs, posing risks to higher education accreditation that will be amplified as these models improve. Our results call for revising program-level assessment design in higher education in light of advances in generative AI.

Science

GPT-4o mini: Non-social science research article

Footprint evidence for locomotor diversity and shared habitats among early Pleistocene hominins

Kevin G. Hatala, Neil T. Roach, Anna K. Behrensmeyer, Peter L. Falkingham, Stephen M. Gatesy, Erin Marie Williams-Hatala, Craig S. Feibel, Ibrae Dalacha, Martin Kirinya, Ezekiel Linga, Richard Loki, Apolo Alkoro, Longaye, Malmalo Longaye, Emmanuel Lonyericho, Iyole Loyapan, Nyiber Nakudo, Cyprian Nyete, Louise N. Leakey

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For much of the Pliocene and Pleistocene, multiple hominin species coexisted in the same regions of eastern and southern Africa. Due to the limitations of the skeletal fossil record, questions regarding their interspecific interactions remain unanswered. We report the discovery of footprints (~1.5 million years old) from Koobi Fora, Kenya, that provide the first evidence of two different patterns of Pleistocene hominin bipedalism appearing on the same footprint surface. New analyses show that this is observed repeatedly across multiple contemporaneous sites in the eastern Turkana Basin. These data indicate a sympatric relationship between Homo erectus and Paranthropus boisei , suggesting that lake margin habitats were important to both species and highlighting the possible influence of varying levels of coexistence, competition, and niche partitioning in human evolution.

GPT-4o mini: Non-social science research article

Decadal oscillations in the ocean’s largest oxygen-deficient zone

N. N. Duprey, A. D. Foreman, J. D. Carriquiry, C. D. Charles, S. C. Sanchez, H. Vonhof, F. Rubach, R. Rabenstein, M. Rohr, H. Reyes-Bonilla, D. Marconi, D. M. Sigman, G. H. Haug, A. Martínez-García

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The impact of global warming on the ocean’s oxygen-deficient zones (ODZs) is uncertain, partly because of a lack of data on past changes. We report monthly resolved records of coral skeleton–bound nitrogen isotopes (CS-δ 15 N) to reconstruct denitrification in the Eastern Tropical North Pacific (ETNP) ODZ over the last 80 years. The data indicate strong decadal variation in ETNP denitrification, with maxima during the cool North Pacific phase of Pacific Decadal Variability. The maxima in denitrification (and thus oxygen deficiency) were likely due to stronger upwelling that enhanced productivity leading to greater oxygen demand in the thermocline. Prior findings of multidecadal-to-centennial ODZ trends were likely biased by this variability. ODZ evolution over the next century will depend on how global warming interacts with the decadal oscillations.

GPT-4o mini: Non-social science research article

A panoramic view of cell population dynamics in mammalian aging

Zehao Zhang, Chloe Schaefer, Weirong Jiang, Ziyu Lu, Jasper Lee, Andras Sziraki, Abdulraouf Abdulraouf, Brittney Wick, Maximilian Haeussler, Zhuoyan Li, Gesmira Molla, Rahul Satija, Wei Zhou, Junyue Cao

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To elucidate aging-associated cellular population dynamics, we present PanSci , a single-cell transcriptome atlas profiling over 20 million cells from 623 mouse tissues across different life stages, sexes, and genotypes. This comprehensive dataset reveals more than 3,000 unique cellular states and over 200 aging-associated cell populations. Our panoramic analysis uncovered organ-, lineage-, and sex-specific shifts of cellular dynamics during lifespan progression. Moreover, we identify both systematic and organ-specific alterations in immune cell populations associated with aging. We further explored the regulatory roles of the immune system on aging and pinpointed specific age-related cell population expansions that are lymphocyte dependent. Our “cell-omics” strategy enhances comprehension of cellular aging and lays the groundwork for exploring the complex cellular regulatory networks in aging and aging-associated diseases.

GPT-4o mini: Non-social science research article

Natural selection could determine whether Acropora corals persist under expected climate change

Liam Lachs, Yves-Marie Bozec, John C. Bythell, Simon D. Donner, Holly K. East, Alasdair J. Edwards, Yimnang Golbuu, Marine Gouezo, James R. Guest, Adriana Humanes, Cynthia Riginos, Peter J. Mumby

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Marine heatwaves are intensifying under climate change, exposing populations of reef-building corals to mass mortality and intense selective pressure. It remains unknown whether adaptation can keep pace with warming and maintain reef functioning. We have developed an eco-evolutionary metapopulation model for Acropora , an ecologically important yet highly threatened coral taxon. We find that although corals have some adaptation capacity, they will suffer severe heatwave-induced declines over the coming decades. For a future where emissions lead to ~3°C of global warming, natural selection could allow populations to persist, albeit in severely depleted states with elevated extinction risk and potential loss of ecosystem functioning. Yet, for thermally sensitive coral populations to thrive post-2050 demands rapid reductions of greenhouse gas emissions that limit global warming to 2°C.

GPT-4o mini: Non-social science research article

Magnetically programmed diffractive robotics

Conrad L. Smart, Tanner G. Pearson, Zexi Liang, Melody X. Lim, Mohamed I. Abdelrahman, Francesco Monticone, Itai Cohen, Paul L. McEuen

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Microscopic robots with features comparable with the wavelength of light offer new ways of probing the microscopic world and controlling light at the microscale. We introduce a new class of magnetically controlled microscopic robots (microbots) that operate at the visible-light diffraction limit, which we term diffractive robots. We combined nanometer-thick mechanical membranes, programmable nanomagnets, and diffractive optical elements to create untethered microbots small enough to diffract visible light and flexible enough to undergo complex reconfigurations in millitesla-scale magnetic fields. We demonstrated their applications, including subdiffractive imaging by using a variant of structured illumination microscopy, tunable diffractive optical elements for beam steering and focusing, and force sensing with piconewton sensitivity.

GPT-4o mini: Non-social science research article

Chemically induced proximity reveals a Piezo-dependent meiotic checkpoint at the oocyte nuclear envelope

Chenshu Liu, Abby F. Dernburg

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Sexual reproduction relies on robust quality control during meiosis. Assembly of the synaptonemal complex between homologous chromosomes (synapsis) regulates meiotic recombination and is crucial for accurate chromosome segregation in most eukaryotes. Synapsis defects can trigger cell cycle delays and, in some cases, apoptosis. We developed and deployed a chemically induced proximity system to identify key elements of this quality control pathway in Caenorhabditis elegans . Persistence of the polo-like kinase PLK-2 at pairing centers—specialized chromosome regions that interact with the nuclear envelope—induced apoptosis of oocytes in response to phosphorylation and destabilization of the nuclear lamina. Unexpectedly, the Piezo1/PEZO-1 channel localized to the nuclear envelope and was required to transduce this signal to promote apoptosis in maturing oocytes.

GPT-4o mini: Non-social science research article

Mechanically strong yet metabolizable supramolecular plastics by desalting upon phase separation

Yiren Cheng, Eiji Hirano, Hao Wang, Motonobu Kuwayama, E. W. Meijer, Hubiao Huang, Takuzo Aida

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Plastics that can metabolize in oceans are highly sought for a sustainable future. In this work, we report the noncovalent synthesis of unprecedented plastics that are mechanically strong yet metabolizable under biologically relevant conditions owing to their dissociative nature with electrolytes. Salt-bridging sodium hexametaphosphate with di- or tritopic guanidinium sulfate in water forms a cross-linked supramolecular network, which is stable unless electrolytes are resupplied. This unusual stability is caused by a liquid-liquid phase separation that expels sodium sulfate, generated upon salt bridging, into a water-rich phase. Drying the remaining condensed liquid phase yields glassy plastics that are thermally reshapable, such as thermoplastics, and usable even in aqueous media with hydrophobic parylene C coating. This approach can be extended to polysaccharide-based supramolecular plastics that are applicable for three-dimensional printing.

GPT-4o mini: Non-social science research article

Platelet factor 4–induced T H 1-T reg polarization suppresses antitumor immunity

Ayumi Kuratani, Masaaki Okamoto, Kazuki Kishida, Daisuke Okuzaki, Miwa Sasai, Shimon Sakaguchi, Hisashi Arase, Masahiro Yamamoto

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The tumor microenvironment (TME) contains a number of immune-suppressive cells such as T helper 1–polarized regulatory T cells (T H 1-T reg cells). However, little is known about the mechanism behind the abundant presence of T H 1-T reg cells in the TME. We demonstrate that selective depletion of arginase I (Arg1)–expressing tumor-associated macrophages (Arg1 + TAMs) inhibits tumor growth and concurrently reduces the ratio of T H 1-T reg cells in the TME. Arg1 + TAMs secrete the chemokine platelet factor 4 (PF4), which reinforces interferon-γ (IFN-γ)–induced T reg cell polarization into T H 1-T reg cells in a manner dependent on CXCR3 and the IFN-γ receptor. Both genetic PF4 inactivation and PF4 neutralization hinder T H 1-T reg cell accumulation in the TME and reduce tumor growth. Collectively, our study highlights the importance of Arg1 + TAM–produced PF4 for high T H 1-T reg cell levels in the TME to suppress antitumor immunity.

GPT-4o mini: Non-social science research article

Direct hearing measurements in a baleen whale suggest ultrasonic sensitivity

Dorian S. Houser, Petter H. Kvadsheim, Lars Kleivane, Jason Mulsow, Rolf A. Ølberg, Craig A. Harms, Jonas Teilmann, James J. Finneran

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Predicting and mitigating the impacts of anthropogenic ocean noise on marine animals is hindered by a lack of information on hearing in these species. We established a catch-and-release program to temporarily hold adolescent minke whales ( Balaenoptera acutorostrata ) for hearing tests during their summer migration. In 2023, two minke whales provided measures of the auditory brainstem response and data on the frequency range of their hearing. Results show that minke whales are sensitive to sound frequencies as high as 45 to 90 kilohertz. These tests provide information on the types of anthropogenic noise that could affect minke whales and potentially, other related baleen whale species.

GPT-4o mini: Non-social science research article

Specific tRNAs promote mRNA decay by recruiting the CCR4-NOT complex to translating ribosomes

Xiaoqiang Zhu, Victor Emmanuel Cruz, He Zhang, Jan P. Erzberger, Joshua T. Mendell

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The CCR4-NOT complex is a major regulator of eukaryotic messenger RNA (mRNA) stability. Slow decoding during translation promotes association of CCR4-NOT with ribosomes, accelerating mRNA degradation. We applied selective ribosome profiling to further investigate the determinants of CCR4-NOT recruitment to ribosomes in mammalian cells. This revealed that specific arginine codons in the P-site are strong signals for ribosomal recruitment of human CNOT3, a CCR4-NOT subunit. Cryo–electron microscopy and transfer RNA (tRNA) mutagenesis demonstrated that the D-arms of select arginine tRNAs interact with CNOT3 and promote its recruitment whereas other tRNA D-arms sterically clash with CNOT3. These effects link codon content to mRNA stability. Thus, in addition to their canonical decoding function, tRNAs directly engage regulatory complexes during translation, a mechanism we term P-site tRNA-mediated mRNA decay.

GPT-4o mini: Non-social science research article

Chloronitramide anion is a decomposition product of inorganic chloramines

Julian L. Fairey, Juliana R. Laszakovits, Huong T. Pham, Thien D. Do, Samuel D. Hodges, Kristopher McNeill, David G. Wahman

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Inorganic chloramines are commonly used drinking water disinfectants intended to safeguard public health and curb regulated disinfection by-product formation. However, inorganic chloramines themselves produce by-products that are poorly characterized. We report chloronitramide anion (Cl–N–NO 2 − ) as a previously unidentified end product of inorganic chloramine decomposition. Analysis of chloraminated US drinking waters found Cl–N–NO 2 − in all samples tested ( n = 40), with a median concentration of 23 micrograms per liter and first and third quartiles of 1.3 and 92 micrograms per liter, respectively. Cl–N–NO 2 − warrants occurrence and toxicity studies in chloraminated water systems that serve more than 113 million people in the US alone.

GPT-4o mini: Non-social science research article

NREM sleep improves behavioral performance by desynchronizing cortical circuits

Natasha Kharas, Mircea I. Chelaru, Sarah Eagleman, Arun Parajuli, Valentin Dragoi

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Sleep improves cognitive performance, yet little is known about the neural mechanisms of this improvement. We performed multielectrode recording in macaque visual and dorsolateral prefrontal cortex while animals performed a visual discrimination task before and after non–rapid eye movement (NREM) sleep. Although sleep induces synchronized fluctuations in population activity across cortical areas, the post-sleep population activity became more desynchronized relative to the pre-sleep state. The changes after sleep were correlated with an increase in information encoded in population activity in each area and improved behavioral performance. Electrically stimulating visual cortex at 4 hertz emulated the beneficial effects of sleep on network and perceptual performance. A large-scale neural network model indicated that asymmetric depression of local intracortical synapses is consistent with the observed changes in neural activity after sleep.

GPT-4o mini: Non-social science research article

Nature of metal-support interaction for metal catalysts on oxide supports

Tairan Wang, Jianyu Hu, Runhai Ouyang, Yutao Wang, Yi Huang, Sulei Hu, Wei-Xue Li

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The metal-support interaction is one of the most important pillars in heterogeneous catalysis, but developing a fundamental theory has been challenging because of the intricate interfaces. Based on experimental ‎data, interpretable machine learning, theoretical derivation, and first-principles simulations, we established a ‎general theory of metal-oxide interactions grounded in ‎metal-metal and metal-oxygen interactions. The theory applies to metal nanoparticles and atoms on oxide supports and oxide films on metal supports. We found that for late-transition metal catalysts, metal-metal interactions dominated the oxide support effects and suboxide encapsulation over metal nanoparticles. A principle of strong metal-metal interactions for encapsulation occurrence is formulated and substantiated by extensive ‎experiments including 10 metals and 16 ‎oxides. The valuable insights revealed on (strong) metal-support interaction advance the interfacial design of supported metal catalysts.

GPT-4o mini: Non-social science research article

Surface restructuring and predictive design of heterogeneous catalysts

Franklin Tao, Miquel Salmeron

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Heterogeneous catalysts, which often consist of metal nanoparticles loaded on supports such as metal oxides, can undergo several types of restructuring under reaction and catalytic conditions. Advanced characterizations now allow the surface structure of a catalyst in a gas phase to be determined to some extent. Metal nanoparticles may experience changes in shape, surface structure and composition, and atomic packing in response to the pressure of a reactant or product gas, temperature, and reaction between the catalyst surface and gas. Metal oxide supports can partially or fully encapsulate metal nanoparticles, altering their electronic structure and reactivity. Restructuring is a main approach to creating active catalytic sites. The rational design of catalysts must anticipate that such restructurings can occur under reaction or catalytic conditions and gain knowledge of how they occur. It is expected that computational studies can predict such restructurings and that advanced synthesis may be used to prepare pristine catalysts with enhanced resistance to restructurings.

GPT-4o mini: Non-social science research article

Reconstruction of the human amylase locus reveals ancient duplications seeding modern-day variation

Feyza Yilmaz, Charikleia Karageorgiou, Kwondo Kim, Petar Pajic, Kendra Scheer, character(0), Christine R. Beck, Ann-Marie Torregrossa, Charles Lee, Omer Gokcumen, Peter A. Audano, Olanrewaju Austine-Orimoloye, Christine R. Beck, Evan E. Eichler, Pille Hallast, William T. Harvey, Alex R. Hastie, Kendra Hoekzema, Sarah Hunt, Jan O. Korbel, Jennifer Kordosky, Charles Lee, Alexandra P. Lewis, Tobias Marschall, Katherine M. Munson, Andy Pang, Feyza Yilmaz

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Previous studies suggested that the copy number of the human salivary amylase gene, AMY1 , correlates with starch-rich diets. However, evolutionary analyses are hampered by the absence of accurate, sequence-resolved haplotype variation maps. We identified 30 structurally distinct haplotypes at nucleotide resolution among 98 present-day humans, revealing that the coding sequences of AMY1 copies are evolving under negative selection. Genomic analyses of these haplotypes in archaic hominins and ancient human genomes suggest that a common three-copy haplotype, dating as far back as 800,000 years ago, has seeded rapidly evolving rearrangements through recurrent nonallelic homologous recombination. Additionally, haplotypes with more than three AMY1 copies have significantly increased in frequency among European farmers over the past 4000 years, potentially as an adaptive response to increased starch digestion.

GPT-4o mini: Non-social science research article

Whole-brain spatial transcriptional analysis at cellular resolution

Shigeaki Kanatani, Judith C. Kreutzmann, Yue Li, Zoe West, Lea Lydolph Larsen, Danai Vougesi Nikou, Ilse Eidhof, Abigail Walton, Songbai Zhang, Leslie Rubio Rodríguez-Kirby, Jacob Lercke Skytte, Casper Gravesen Salinas, Kimiharu Takamatsu, Xiaofei Li, Daisuke H. Tanaka, Dagmara Kaczynska, Keishiro Fukumoto, Razieh Karamzadeh, Yujiao Xiang, Naofumi Uesaka, Tsutomu Tanabe, Mikael Adner, Johan Hartman, Ayako Miyakawa, Erik Sundström, Gonçalo Castelo-Branco, Urmas Roostalu, Jacob Hecksher-Sørensen, Per Uhlén

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Recent advances in RNA analysis have deepened our understanding of cellular states in biological tissues. However, a substantial gap remains in integrating RNA expression data with spatial context across organs, primarily owing to the challenges associated with RNA detection within intact tissue volumes. Here, we developed Tris buffer–mediated retention of in situ hybridization chain reaction signal in cleared organs (TRISCO), an effective tissue-clearing method designed for whole-brain spatial three-dimensional (3D) RNA imaging. TRISCO resolved several crucial issues, including the preservation of RNA integrity, achieving uniform RNA labeling, and enhancing tissue transparency. We tested TRISCO using a broad range of cell-identity markers, noncoding and activity-dependent RNAs, within diverse organs of varying sizes and species. TRISCO thus emerges as a powerful tool for single-cell, whole-brain, 3D imaging that enables comprehensive transcriptional spatial analysis across the entire brain.

GPT-4o mini: Non-social science research article

Amidination of ligands for chemical and field-effect passivation stabilizes perovskite solar cells

Yi Yang, Hao Chen, Cheng Liu, Jian Xu, Chuying Huang, Christos D. Malliakas, Haoyue Wan, Abdulaziz S. R. Bati, Zaiwei Wang, Robert P. Reynolds, Isaiah W. Gilley, Shuta Kitade, Taylor E. Wiggins, Stefan Zeiske, Selengesuren Suragtkhuu, Munkhbayar Batmunkh, Lin X. Chen, Bin Chen, Mercouri G. Kanatzidis, Edward H. Sargent

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Surface passivation has driven the rapid increase in the power conversion efficiency (PCE) of perovskite solar cells (PSCs). However, state-of-the-art surface passivation techniques rely on ammonium ligands that suffer deprotonation under light and thermal stress. We developed a library of amidinium ligands, of interest for their resonance effect–enhanced N–H bonds that may resist deprotonation, to increase the thermal stability of passivation layers on perovskite surfaces. This strategy resulted in a >10-fold reduction in the ligand deprotonation equilibrium constant and a twofold increase in the maintenance of photoluminescence quantum yield after aging at 85°C under illumination in air. Implementing this approach, we achieved a certified quasi–steady-state PCE of 26.3% for inverted PSCs; and we report retention of ≥90% PCE after 1100 hours of continuous 1-sun maximum power point operation at 85°C.

GPT-4o mini: Non-social science research article

Ship collision risk threatens whales across the world’s oceans

Anna C. Nisi, Heather Welch, Stephanie Brodie, Callie Leiphardt, Rachel Rhodes, Elliott L. Hazen, Jessica V. Redfern, Trevor A. Branch, Andre S. Barreto, John Calambokidis, Tyler Clavelle, Lauren Dares, Asha de Vos, Shane Gero, Jennifer A. Jackson, Robert D. Kenney, David Kroodsma, Russell Leaper, Douglas J. McCauley, Sue E. Moore, Ekaterina Ovsyanikova, Simone Panigada, Chloe V. Robinson, Tim White, Jono Wilson, Briana Abrahms

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After the near-complete cessation of commercial whaling, ship collisions have emerged as a primary threat to large whales, but knowledge of collision risk is lacking across most of the world’s oceans. We compiled a dataset of 435,000 whale locations to generate global distribution models for four globally ranging species. We then combined >35 billion positions from 176,000 ships to produce a global estimate of whale-ship collision risk. Shipping occurs across 92% of whale ranges, and <7% of risk hotspots contain management strategies to reduce collisions. Full coverage of hotspots could be achieved by expanding management over only 2.6% of the ocean’s surface. These inferences support the continued recovery of large whales against the backdrop of a rapidly growing shipping industry.

GPT-4o mini: Non-social science research article

Hidden state inference requires abstract contextual representations in the ventral hippocampus

Karyna Mishchanchuk, Gabrielle Gregoriou, Albert Qü, Alizée Kastler, Quentin J. M. Huys, Linda Wilbrecht, Andrew F. MacAskill

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The ability to use subjective, latent contextual representations to influence decision-making is crucial for everyday life. The hippocampus is hypothesized to bind together otherwise abstract combinations of stimuli to represent such latent contexts, to support the process of hidden state inference. Yet evidence for a role of the hippocampus in hidden state inference remains limited. We found that the ventral hippocampus is required for mice to perform hidden state inference during a two-armed bandit task. Hippocampal neurons differentiate the two abstract contexts required for this strategy in a manner similar to the differentiation of spatial locations, and their activity is essential for appropriate dopamine dynamics. These findings offer insight into how latent contextual information is used to optimize decisions, and they emphasize a key role for the hippocampus in hidden state inference.

GPT-4o mini: Non-social science research article

Population connectivity shapes the distribution and complexity of chimpanzee cumulative culture

Cassandra Gunasekaram, Federico Battiston, Onkar Sadekar, Cecilia Padilla-Iglesias, Maria A. van Noordwijk, Reinhard Furrer, Andrea Manica, Jaume Bertranpetit, Andrew Whiten, Carel P. van Schaik, Lucio Vinicius, Andrea Bamberg Migliano

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Although cumulative culture is a hallmark of hominin evolution, its origins can be traced back to our common ancestor with chimpanzees. Here, we investigated the evolutionary origins of chimpanzee cumulative culture and why it remained incipient. To trace cultural transmission among the four chimpanzee subspecies, we compared population networks based on genetic markers of recent migration and shared cultural traits. We show that limited levels of group connectivity favored the emergence of a few instances of cumulative culture in chimpanzees. As in humans, cultural complexification likely happened in steps, with transmission between populations, incremental changes, and repurposing of technologies. We propose that divergence in social patterns led to increased mobility between groups in the genus Homo , resulting in irreversible dependence on cultural exchange and complexification.

Science abstract < 200 char.: Not a research article

EPA braces for change under Trump

Erik Stokstad

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Industry looks forward to looser rules, and agency scientists may face pressure

Science abstract < 200 char.: Not a research article

Prospect of RFK Jr. at HHS alarms biomedical community

Jocelyn Kaiser, Meredith Wadman

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Robert F. Kennedy Jr. has vowed to scrutinize proven vaccines and slash staff at research and regulatory agencies

Science abstract < 200 char.: Not a research article

In Science Journals

Sacha Vignieri, Peter Stern, Phil Szuromi, Mattia Maroso, Yury Suleymanov, Hannah M. Isles, Priscilla N. Kelly, L. Bryan Ray, Di Jiang, Michael A. Funk, Corinne Simonti, Leslie K. Ferrarelli, Orla Smith

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Highlights from the Science family of journals

Science abstract < 200 char.: Not a research article

In Other Journals

Jesse Smith, Di Jiang, Madeleine Seale, Mattia Maroso, Sacha Vignieri, Brad Wible, Jake S. Yeston

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Editors’ selections from the current scientific literature

Science abstract < 200 char.: Not a research article

The chloramine dilemma

Daniel L. McCurry

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A decades-long drinking-water disinfection mystery ends with a potentially toxic surprise

Science abstract < 200 char.: Not a research article

Ferroptosis—disease perils and therapeutic promise

Ashley R. Brown, Tal Hirschhorn, Brent R. Stockwell

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Mechanisms of iron-dependent cell death reveal potential new targets for disease treatment

Science abstract < 200 char.: Not a research article

News at a glance

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Science abstract < 200 char.: Not a research article

An institution-level analysis of gender gaps in STEM over time

Joseph R. Cimpian, Jo R. King

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Gender gaps in engineering and computer science narrow at math-selective schools and widen in others

Science abstract < 200 char.: Not a research article

Preserve Petra and Bedouin rights in Jordan

Hussam Hussein, Olivia Mason

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Science abstract < 200 char.: Not a research article

Nature’s gift economies The Serviceberry: Abundance and Reciprocity in the Natural World Robin Wall Kimmerer Scribner, 2024. 128 pp.

Jessica Hernandez

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An Indigenous botanist finds lessons in gratitude in the serviceberry

Science abstract < 200 char.: Not a research article

Canada should curtail research ties with China, lawmakers say

Brian Owens

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Canada should curtail research ties with China, lawmakers say

Science abstract < 200 char.: Not a research article

Portraits of the Universe Hidden in the Heavens Jason Steffen Princeton University Press, 2024. 272 pp. Pillars of Creation Richard Panek Little, Brown, 2024. 256 pp.

Jennifer Carson

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A pair of books celebrate the discoveries made by two major space telescope programs

Science abstract < 200 char.: Not a research article

Shades of blue

Ignacio Amigo

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Blue zones, supposed havens of longevity, have become a global brand. But skeptics think they rest on shaky science

Science abstract < 200 char.: Not a research article

Macrophage modulation of tumor immunity

Peter Savage

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Macrophages deliver polarizing messages to promote immune suppression in tumors

Science abstract < 200 char.: Not a research article

Culture in humans and other animals

Peter J. Richerson, Robert T. Boyd

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Migration provides evidence for cumulative cultural evolution in chimpanzees

Science abstract < 200 char.: Not a research article

China’s hunger for minerals spurs massive geology survey

Richard Stone

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$1 billion SinoProbe II will map the depths with drill rigs and instrument arrays

Science abstract < 200 char.: Not a research article

Open-access journal eLife to lose ‘impact factor’

Jeffrey Brainard

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Web of Science index pulls metric because of the publisher’s unusual peer-review model

Science abstract < 200 char.: Not a research article

Connection, not perfection

Ahalya Suresh

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Science abstract < 200 char.: Not a research article

Small wetlands: Critical to flood management

Bo Yang, Xiaohui Yuan, Fei Tang, Dichen Liu

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Scientists as political advocates

Agustín Fuentes

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Science, both teaching and doing, is under attack. The recent US presidential election of a person and platform with anti-science bias exemplifies this. The study of climate processes and patterns and the role of human activities in these phenomena are at the heart of multiple global crises, and yet the scientific results , and the scientists presenting them, are attacked constantly . The dissemination of knowledge on health involving reproduction and human sexuality is increasingly marked for attack (in Russia , Uganda , and the USA ), and researchers in these areas are often the target of extensive political pressure . The massive attack on the science and the scientists behind vaccines, pathogen transmission, and public health during the COVID-19 pandemic and beyond is well documented , as are attacks on basic science education and the practice of science (for example, in Hungary and the USA ). Even in the arena of biodiversity conservation, there is growing politicization of the data and political targeting of the scientists producing it. According to the US-based National Association of Biology Teachers (NABT), climate change, reproduction, vaccines, and other evidence-based scientific topics are being deemed “controversial” by school boards and state officials and are being removed from state-approved teaching resources across the country. Core research on health, climate, human biology, and biodiversity is being undermined by private foundations, governments, and anti-science ideologues.

Trust edges up—slightly

H. Holden Thorp

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The Pew Research Center survey on trust in science and researchers is eagerly awaited every year by science policy experts and communicators. This year’s results, released last week, give a small, but meaningful, reason to be optimistic: Trust in scientists, which took a substantial hit during the pandemic, is starting to recover. The survey, conducted in October 2024 with 9593 adults across the United States, estimates that 76% of Americans now have a great deal or fair amount of confidence in scientists to act in the public’s best interests. That’s a modest uptick from 73% last year and a hopeful sign that the page may be turning on some of the pandemic-era skepticism. Although the increase is barely outside the margin of error, it may mark the end of a troubling 3-year decline. However, the data reveal a persistent problem—a considerable portion of the public continues to harbor negative views of scientists’ personal qualities, particularly their communication skills. This reality should be worrisome to the scientific community and drive a collective conversation about rebuilding public confidence.

Science Advances

GPT-4o mini: Non-social science research article

The human social cognitive network contains multiple regions within the amygdala

Donnisa Edmonds, Joseph J. Salvo, Nathan Anderson, Maya Lakshman, Qiaohan Yang, Kendrick Kay, Christina Zelano, Rodrigo M. Braga

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Reasoning about someone’s thoughts and intentions—i.e., forming a “theory of mind”—is a core aspect of social cognition and relies on association areas of the brain that have expanded disproportionately in the human lineage. We recently showed that these association zones comprise parallel distributed networks that, despite occupying adjacent and interdigitated regions, serve dissociable functions. One network is selectively recruited by social cognitive processes. What circuit properties differentiate these parallel networks? Here, we show that social cognitive association areas are intrinsically and selectively connected to anterior regions of the medial temporal lobe that are implicated in emotional learning and social behaviors, including the amygdala at or near the basolateral complex and medial nucleus. The results suggest that social cognitive functions emerge through coordinated activity between internal circuits of the amygdala and a broader distributed association network, and indicate the medial nucleus may play an important role in social cognition in humans.

GPT-4o mini: Non-social science research article

Four SpsP neurons are an integrating sleep regulation hub in Drosophila

Xihuimin Dai, Jasmine Quynh Le, Dingbang Ma, Michael Rosbash

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Sleep is essential and highly conserved, yet its regulatory mechanisms remain largely unknown. To identify sleep drive neurons, we imaged Drosophila brains with calcium-modulated photoactivatable ratiometric integrator (CaMPARI). The results indicate that the activity of the protocerebral bridge (PB) correlates with sleep drive. We further identified a key three-layer PB circuit, EPG-SpsP-PEcG, in which the four SpsP neurons in the PB respond to ellipsoid body (EB) signals from EPG neurons and send signals back to the EB through PEcG neurons. This circuit is strengthened by sleep deprivation, indicating a plasticity response to sleep drive. SpsP neurons also receive inputs from the sensorimotor brain region, suggesting that they may encode sleep drive by integrating sensorimotor and navigation cues. Together, our experiments show that the four SpsP neurons and their sleep regulatory circuit play an important and dynamic role in sleep regulation.

GPT-4o mini: Non-social science research article

Effectively tuning the quantum Griffiths phase by controllable quantum fluctuations

Beilin Wang, Guopei Ying, Linhai Guo, Zhiyong Lin, Haiwen Liu, Changgan Zeng

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Quantum Griffiths phase (QGP), marked by a quantum Griffiths singularity with a divergent effective critical exponent, has garnered considerable attention in the realm of superconductivity. However, the ability to control QGP remains elusive. Here, we demonstrate that QGP at the LaAlO 3 /KTaO 3 (110) interface can be efficiently modulated by the orientation of applied magnetic field: With a perpendicular field, an anomalous QGP emerges in the low-temperature regime, characterized by a decreasing critical field as temperature lowers; conversely, with a parallel field, a normal QGP arises, where the critical field increases with decreasing temperature. Such opposite characteristics stem from the controllable quantum fluctuations and conductivity corrections under distinct magnetic field orientations. Furthermore, we show the effective tuning of the phase boundary by electrostatic gating, attributed to the gate-controlled quantum fluctuations. These findings not only demonstrate how to experimentally manipulate QGP but also provide a comprehensive understanding of how quantum fluctuations can effectively modulate QGP.

GPT-4o mini: Non-social science research article

Electrically silent mutants unravel the mechanism of binding−gating coupling in Cys-loop receptors

Nicole E. Godellas, Gisela D. Cymes, Claudio Grosman

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The transduction of extracellular chemical signals into intracellular events relies on the communication between neighboring domains of membrane receptors. In the particular case of Cys-loop receptor channels, five short stretches of amino acids, one per subunit, link the extracellular and transmembrane domains in such a way that the ion permeability of the latter and the affinity for neurotransmitters of the former become tied to each other. Here, using direct functional approaches, we set out to understand the molecular bases of this crucial interdependence through the characterization of total loss-of-current mutations at the interface between domains. Our results indicate that domain−domain proximity plays a previously unnoticed critical role inasmuch as inserting a single residue in each linker rendered the two domains independent of each other. In marked contrast, loss-of-current mutations that leave the linkers’ length unaltered did not compromise the interdomain coupling, but rather, seemed to cause agonist-bound closed receptors to desensitize without appreciably opening.

GPT-4o mini: Non-social science research article

A general temperature-guided language model to design proteins of enhanced stability and activity

Fan Jiang, Mingchen Li, Jiajun Dong, Yuanxi Yu, Xinyu Sun, Banghao Wu, Jin Huang, Liqi Kang, Yufeng Pei, Liang Zhang, Shaojie Wang, Wenxue Xu, Jingyao Xin, Wanli Ouyang, Guisheng Fan, Lirong Zheng, Yang Tan, Zhiqiang Hu, Yi Xiong, Yan Feng, Guangyu Yang, Qian Liu, Jie Song, Jia Liu, Liang Hong, Pan Tan

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Designing protein mutants with both high stability and activity is a critical yet challenging task in protein engineering. Here, we introduce PRIME, a deep learning model, which can suggest protein mutants with improved stability and activity without any prior experimental mutagenesis data for the specified protein. Leveraging temperature-aware language modeling, PRIME demonstrated superior predictive ability compared to current state-of-the-art models on the public mutagenesis dataset across 283 protein assays. Furthermore, we validated PRIME’s predictions on five proteins, examining the impact of the top 30 to 45 single-site mutations on various protein properties, including thermal stability, antigen-antibody binding affinity, and the ability to polymerize nonnatural nucleic acid or resilience to extreme alkaline conditions. More than 30% of PRIME-recommended mutants exhibited superior performance compared to their premutation counterparts across all proteins and desired properties. We developed an efficient and effective method based on PRIME to rapidly obtain multisite mutants with enhanced activity and stability. Hence, PRIME demonstrates broad applicability in protein engineering.

GPT-4o mini: Non-social science research article

Late Archaic large-scale fisheries in the wetlands of the pre-Columbian Maya Lowlands

Eleanor Harrison-Buck, Samantha M. Krause, Marieka Brouwer Burg, Mark Willis, Angelina Perrotti, Katie Bailey

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Multiproxy data collected from the largest inland wetland in Belize, Central America, demonstrate the presence of large-scale pre-Columbian fish-trapping facilities built by Late Archaic hunter-gatherer-fishers, which continued to be used by their Maya descendants during Formative times (approximately 2000 BCE to 200 CE). This is the earliest large-scale Archaic fish-trapping facility recorded in ancient Mesoamerica. We suggest that such landscape-scale intensification may have been a response to long-term climate disturbance recorded between 2200 and 1900 BCE. Agricultural intensification after 2000 BCE has been credited for supporting the rise of pre-Columbian civilizations in Formative Mesoamerica, but we suggest that some groups relied more heavily on the mass harvesting of aquatic resources. We argue that such early intensification of aquatic food production offered a high value subsistence strategy that was instrumental in the emergence of Formative period sedentarism and the development of complexity among pre-Columbian civilizations like the Maya.

GPT-4o mini: Non-social science research article

CalDAG-GEFI acts as a guanine nucleotide exchange factor for LRRK2 to regulate LRRK2 function and neurodegeneration

Qinfang Liu, Bingxu Huang, Noah Guy Lewis Guiberson, Shifan Chen, Dong Zhu, Gang Ma, Xin-Ming Ma, Jill R. Crittenden, Jianzhong Yu, Ann M. Graybiel, Ted M. Dawson, Valina L. Dawson, Yulan Xiong

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Mutations in LRRK2 are the most common genetic cause of Parkinson’s disease (PD). LRRK2 protein contains two enzymatic domains: a GTPase (Roc-COR) and a kinase domain. Disease-causing mutations are found in both domains. Now, studies have focused largely on LRRK2 kinase activity, while attention to its GTPase function is limited. LRRK2 is a guanine nucleotide–binding protein, but the mechanism of direct regulation of its GTPase activity remains unclear and its physiological GEF is not known. Here, we identified CalDAG-GEFI (CDGI) as a physiological GEF for LRRK2. CDGI interacts with LRRK2 and increases its GDP to GTP exchange activity. CDGI modulates LRRK2 cellular functions and LRRK2-induced neurodegeneration in both LRRK2 Drosophila and mouse models. Together, this study identified the physiological GEF for LRRK2 and provides strong evidence that LRRK2 GTPase is regulated by GAPs and GEFs. The LRRK2 GTPase, GAP, or GEF activities have the potential to serve as therapeutic targets, which is distinct from the direct LRRK2 kinase inhibition.

GPT-4o mini: Non-social science research article

Bridging activity gaps between batch and flow reactor configurations in the electroreduction of carbon dioxide

Qiwen Sun, Linke Fu, Xiaoxia Chang, Bingjun Xu

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To date, the understanding of various modes of CO 2 mass transport remains incomplete, impeding the transfer of catalysts identified in the more accessible electrochemical batch cells to high-performance flow cells. In this work, we demonstrate that the meniscus region formed between the electrode and the convex liquid level due to the electrowetting of the catalyst plays a vital role in the CO 2 RR in batch cells. CO 2 RR in the meniscus region in batch cells exhibits similar performance with that in flow cells, and the performance disparity between these two configurations largely disappears when conducting CO 2 RR primarily in the meniscus region. An assembled double-sided gas diffusion electrode with a gas channel is developed to maximize the meniscus-like region, achieving a CO 2 RR partial current density of 640 mA/cm 2 geo on commercial Cu in the KHCO 3 electrolyte. This performance represents the highest CO 2 RR activity in neutral buffered media.

GPT-4o mini: Non-social science research article

Hormone response elements for the thyroid receptor-α include specific distal 5′-flanking DNA

David P. Lohry, Taylor A. Stevens, Tongye Shen, Elias J. Fernandez

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Optimal gene transcription is achieved through precise interactions between transcription factors and their DNA binding sites. We provide evidence that conserved distally located 5′-flanking sequences interact directly with the intrinsically disordered amino-terminal region of the thyroid receptor-α (TRα) to control transcriptional activity. Simulated modeling and dynamics with multiple ChIP-seq–derived sequences consistently reveal specific lysine/arginine–DNA minor groove interactions. The impact of these interactions is to distort DNA structural conformations, and these are also revealed with atomic force microscopy. The importance of the 5′-flanking DNA is further emphasized with reporter gene assays and comparisons with canonical response elements. Overall, the study reveals the inadequacy of current definitions of the DNA hormone response element (HRE) and suggests that future descriptions of the HRE include the conserved distal DNA sequences. The broad impact of this study is further underscored by the common occurrence of Lys/Arg-rich motifs within the intrinsically disordered regions of nuclear receptors.

GPT-4o mini: Non-social science research article

Identification of VISTA regulators in macrophages mediating cancer cell survival

Abdalla M. Abdrabou, Sharif U. Ahmed, Mengqi Jonathan Fan, Bill T. V. Duong, Kangfu Chen, Pei-Ying Lo, Julia M. Mayes, Fatemeh Esmaeili, Amin GhavamiNejad, Hossein Zargartalebi, Randy Singh Atwal, Sichun Lin, Stephane Angers, Shana O. Kelley

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Numerous human cancers have exhibited the ability to elude immune checkpoint blockade (ICB) therapies. This type of resistance can be mediated by immune-suppressive macrophages that limit antitumor immunity in the tumor microenvironment (TME). Here, we elucidate a strategy to shift macrophages into a proinflammatory state that down-regulates V domain immunoglobulin suppressor of T cell activation (VISTA) via inhibiting AhR and IRAK1. We used a high-throughput microfluidic platform combined with a genome-wide CRISPR knockout screen to identify regulators of VISTA levels. Functional characterization showed that the knockdown of these hits diminished VISTA surface levels on macrophages and sustained an antitumor phenotype. Furthermore, targeting of both AhR and IRAK1 in mouse models overcame resistance to ICB treatment. Tumor immunophenotyping indicated that infiltration of cytotoxic CD8 + cells, natural killer cells, and antitumor macrophages was substantially increased in treated mice. Collectively, AhR and IRAK1 are implicated as regulators of VISTA that coordinate a multifaceted barrier to antitumor immune responses.

GPT-4o mini: Non-social science research article

Zircon trace element evidence for early hydrothermal activity on Mars

Jack Gillespie, Aaron J. Cavosie, Denis Fougerouse, Cristiana L. Ciobanu, William D. A. Rickard, David W. Saxey, Gretchen K. Benedix, Phil A. Bland

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Finding direct evidence for hydrous fluids on early Mars is of interest for understanding the origin of water on rocky planets, surface processes, and conditions essential for habitability, but it is challenging to obtain from martian meteorites. Micro- to nanoscale microscopy of a unique impact-shocked zircon from the regolith breccia meteorite NWA7034 reveals textural and chemical indicators of hydrothermal conditions on Mars during crystallization 4.45 billion years ago. Element distribution maps show sharp alternating zoning defined by marked enrichments of non-formula elements, such as Fe, Al, and Na, and ubiquitous nanoscale magnetite inclusions. The zoning and inclusions are similar to those reported in terrestrial zircon crystallizing in the presence of aqueous fluid and are here interpreted as primary features recording zircon growth from exsolved hydrous fluids at ~4.45 billion years. The unique record of crustal processes preserved in this grain survived early impact bombardment and provides previously unidentified petrological evidence for a wet pre-Noachian martian crust.

GPT-4o mini: Non-social science research article

Functional anatomy of the subthalamic nucleus and the pathophysiology of cardinal features of Parkinson’s disease unraveled by focused ultrasound ablation

Rafael Rodriguez-Rojas, Jorge U. Máñez-Miró, José A. Pineda-Pardo, Marta del Álamo, Raúl Martínez-Fernández, José A. Obeso

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The subthalamic nucleus (STN) modulates basal ganglia output and plays a fundamental role in the pathophysiology of Parkinson’s disease (PD). Blockade/ablation of the STN improves motor signs in PD. We assessed the topography of focused ultrasound subthalamotomy ( n = 39) by voxel-based lesion-symptom mapping to identify statistically validated brain voxels with the optimal effect against each cardinal feature and their respective cortical connectivity patterns by diffusion-weighted tractography. Bradykinesia and rigidity amelioration were associated with ablation of the rostral motor STN subregion connected to the supplementary motor and premotor cortices, whereas antitremor effect was explained by lesioning the posterolateral STN projection to the primary motor cortex. These findings were corroborated prospectively in another PD cohort ( n = 12). This work concurs with recent deep brain stimulation findings that suggest different corticosubthalamic circuits underlying each PD cardinal feature. Our results provide sound evidence in humans of segregated anatomy of subthalamic-cortical connections and their distinct role in PD pathophysiology and normal motor control.

GPT-4o mini: Non-social science research article

Hemochromatosis neural archetype reveals iron disruption in motor circuits

Robert Loughnan, Jonathan Ahern, Mary Boyle, Terry L. Jernigan, Donald J. Hagler, John R. Iversen, Oleksandr Frei, Diana M. Smith, Ole Andreassen, Noah Zaitlen, Leo Sugrue, Wesley K. Thompson, Anders Dale, Andrew J. Schork, Chun Chieh Fan

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Our understanding of brain iron regulation and its disruption in disease is limited. Excess iron affects motor circuitry, contributing to Parkinson’s disease (PD) risk. The molecular mechanisms regulating central iron levels, beyond a few well-known genes controlling peripheral iron, remain unclear. We generated scores based on the archetypal brain iron accumulation observed in magnetic resonance imaging scans of individuals with excessive dietary iron absorption and hemochromatosis risk. Genome-wide analysis revealed that this score is highly heritable, identifying loci associated with iron homeostasis, and driven by peripheral iron levels. Our score predicted gait abnormalities and showed a U-shaped relationship with PD risk, identifying individuals with threefold increased risk. These results establish a hormetic relationship between brain iron and PD risk, where central iron levels are strongly determined by genetics via peripheral iron. This framework combining forward and reverse genetics is a powerful study design to understand genomic drivers underlying high dimensional phenotypes.

GPT-4o mini: Non-social science research article

Monoamine transporter ubiquitination and inward-open conformation synergistically maximize transporter endocytosis

Tatiana Sorkina, Tarique Bagalkot, Mary Hongying Cheng, Daryl A. Guthrie, Amy Hauck Newman, Simon C. Watkins, Alexander Sorkin

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Monoamine transporters function in neuronal membranes to control extracellular concentrations of their substrates. Cell-surface expression of transporters is regulated by substrates and intracellular signaling, but the underlying mechanisms remain unclear. Here, we found that substrates of the dopamine transporter (DAT), amphetamine and dopamine, synergize with protein kinase C (PKC)–dependent DAT ubiquitination to markedly elevate clathrin-mediated endocytosis of DAT, which is accompanied by DAT movement out of plasma membrane protrusions with a negative curvature. Disruption of the outward-open (OO) DAT conformation or its stabilization in the inward-open (IO) conformation recapitulates substrate effects on DAT endocytosis. Amphetamine strongly increases PKC-dependent endocytosis of norepinephrine transporter (NET) but not of serotonin transporter (SERT), correlating with a substantially weaker ubiquitination of SERT compared to NET. We propose a “shape-transition” model whereby shifting from convex-shaped OO conformers to IO conformers minimizes retention of transporters in negatively curved membranes, which facilitates their PKC-dependent ubiquitination and recruitment to positively invaginated clathrin-coated membranes, driving robust transporter endocytosis.

GPT-4o mini: Non-social science research article

Fine-scale Southern California Moho structure uncovered with distributed acoustic sensing

James Atterholt, Zhongwen Zhan

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Moho topography yields insights into the evolution of the lithosphere and the strength of the lower crust. The Moho reflected phase (PmP) samples this key boundary and may be used in concert with the first arriving P phase to infer crustal thickness. The densely sampled station coverage of distributed acoustic sensing arrays allows for the observation of PmP at fine-scale intervals over many kilometers with individual events. We use PmP recorded by a 100-km-long fiber that traverses a path between Ridgecrest, CA and Barstow, CA to explore Moho variability in Southern California. With hundreds of well-recorded events, we verify that PmP is observable and develop a technique to identify and pick P-PmP differential times with high confidence. We use these observations to constrain Moho depth throughout Southern California, and we find that short-wavelength variability in crustal thickness is abundant, with sharp changes across the Garlock Fault and Coso Volcanic Field.

GPT-4o mini: Non-social science research article

Catalytic kinetic resolution of helical polycyclic phenols via an organocatalyzed enantioselective dearomative amination reaction

Anqi Chu, Boyan Zhu, Xiaoyong Zhang, Hanwen Zhu, Jingying Zhang, Xihong Liu

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Despite the considerable potential applications for helically chiral molecules across various sectors, their catalytic asymmetric synthesis remains nascent and has seen very limited advancement compared to that of central and axial chiral compounds, primarily owing to the scarcity of available starting materials and the immense challenges associated with achieving stereochemical control. Herein, we report an innovative approach to the facile synthesis and catalytic kinetic resolution of uniquely structured and stereochemically complex helical polycyclic phenols by using a steric hindrance–regulated enantioselective dearomative amination reaction. The distinguished aspects of this method include the exceptional stability of the dearomatized products and impressive versatility of the recovered substrates in the construction of enantioenriched helical frameworks. This work showcases that the strategic incorporation of appropriate steric groups near the reaction site of an electron-rich aromatic compound can indeed enable an interrupted Friedel-Crafts reaction, thus opening an alternate avenue for the study of dearomatization in nonfunctionalized arenes.

GPT-4o mini: Non-social science research article

Reductive deaminative cross-coupling of alkyl bistriflimides enabled by electrocatalysis

Xiangzhang Tao, Wooseok Lee, Zhimin Xu, Hui Shu, Qing Wang, Shengyang Ni, Yi Pan, Sungwoo Hong, Yi Wang

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We present a versatile nickel-electrocatalytic deaminative cross-coupling platform for the efficient construction of C(sp 3 )–C(sp 3 ) and C(sp 3 )–C(sp 2 ) bonds from readily available alkyl bistriflimides. This methodology involves the assembly of two leaving groups on alkyl amines to form alkyl bistriflimides, followed by their effective coupling with a wide range of alkyl halides, alkyl pseudohalides, aryl halides, and alkenyl halides under electrochemical reductive conditions. Moreover, the successful application of electrochemical reductive relay cross-coupling and transition metal–free cross-electrophile coupling further demonstrates the versatility of alkyl bistriflimides as valuable building blocks in organic synthesis. Combined control experiments and density functional theory calculations provide insights into the reaction pathway and the crucial role of iodide in the catalytic process.

GPT-4o mini: Non-social science research article

Enhanced dual-mode imaging: Superior photoacoustic and ultrasound endoscopy in live pigs using a transparent ultrasound transducer

Jaewoo Kim, Dasom Heo, Seonghee Cho, Mingyu Ha, Jeongwoo Park, Joongho Ahn, Minsu Kim, Donggyu Kim, Da Hyun Jung, Hyung Ham Kim, Hee Man Kim, Chulhong Kim

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Dual-mode photoacoustic/ultrasound endoscopy (ePAUS) is a promising tool for preclinical and clinical interventions. To be clinically useful, ePAUS must deliver high-performance ultrasound imaging comparable to commercial systems and maintain high photoacoustic imaging performance at long working distances. This requires a transducer with an intact physical aperture and coaxial alignment of acoustic and optical beams within the probe, a challenging integration task. We present a high-performance ePAUS probe with a miniaturized, optically transparent ultrasonic transducer (TUT) called ePAUS-TUT. The 1.8-mm-diameter probe, fitting into standard endoscopic channels, aligns acoustic and optical beams efficiently, achieving commercial-level ultrasound and high-resolution photoacoustic imaging over long distances. These imaging capabilities were validated through in vivo imaging of a rat’s rectum and a pig’s esophagus. The ePAUS-TUT system substantially enhances feasibility and potential for clinical applications.

GPT-4o mini: Non-social science research article

Structural characterization and AlphaFold modeling of human T cell receptor recognition of NRAS cancer neoantigens

Daichao Wu, Rui Yin, Guodong Chen, Helder V. Ribeiro-Filho, Melyssa Cheung, Paul F. Robbins, Roy A. Mariuzza, Brian G. Pierce

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T cell receptors (TCRs) that recognize cancer neoantigens are important for anticancer immune responses and immunotherapy. Understanding the structural basis of TCR recognition of neoantigens provides insights into their exquisite specificity and can enable design of optimized TCRs. We determined crystal structures of a human TCR in complex with NRAS Q61K and Q61R neoantigen peptides and HLA-A1 major histocompatibility complex (MHC), revealing the molecular underpinnings for dual recognition and specificity versus wild-type NRAS peptide. We then used multiple versions of AlphaFold to model the corresponding complex structures, given the challenge of immune recognition for such methods. One implementation of AlphaFold2 (TCRmodel2) with additional sampling was able to generate accurate models of the complexes, while AlphaFold3 also showed strong performance, although success was lower for other complexes. This study provides insights into TCR recognition of a shared cancer neoantigen as well as the utility and practical considerations for using AlphaFold to model TCR-peptide-MHC complexes.

GPT-4o mini: Non-social science research article

Submillimeter fiber robots capable of decoupled macro-micro motion for endoluminal manipulation

Cheng Zhou, Zheng Xu, Zecai Lin, Xiaotong Qin, Jingyuan Xia, Xiaojie Ai, Chuqian Lou, Ziyi Huang, Shaoping Huang, Huanghua Liu, Yun Zou, Weidong Chen, Guang-Zhong Yang, Anzhu Gao

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Endoluminal and endocavitary intervention via natural orifices of the body is an emerging trend in medicine, further underpinning the future of early intervention and precision surgery. This motivates the development of small continuum robots to navigate freely in confined and tortuous environment. The trade-off between a large range of motion and high precision with concomitant actuation cross-talk poses a major challenge. Here, we present a submillimeter-scale fiber robot (~1 mm) capable of decoupled macro and micro manipulations for intervention and operation. The thin optical fibers, working both as mechanical tendons and light waveguides, can be pulled/pushed to actuate the macro tendon-driven continuum robot and transmit light to actuate the liquid crystal elastomer–based micro built-in light-driven parallel robot. The combination of the decoupled macro and micro motions can accomplish accurate cross-scale motion from several millimeters down to tens of micrometers. In vivo animal studies are performed to demonstrate its positioning accuracy of precise micro operations in endoluminal or endocavitary intervention.

GPT-4o mini: Non-social science research article

Structural basis for the reaction cycle and transport mechanism of human Na + -sulfate cotransporter NaS1 (SLC13A1)

Xudong Chen, Youqi Zhang, Jian Yin, Chang Liu, Min Xie, Yixue Wang, Meiying Chen, Rui Zhang, Xinyi Yuan, De Li, Xiangmei Chen, Xin Gao, Guangyan Cai, Sensen Zhang, Boda Zhou, Maojun Yang

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Sulfate (SO 4 2− ) is a pivotal inorganic anion with essential roles in mammalian physiology. NaS1, a member of solute carrier 13 family and divalent anion/sodium symporter family, functions as a Na + -sulfate cotransporter, facilitating sulfate (re)absorption across renal proximal tubule and small intestine epithelia. While previous studies have linked several human disorders to mutations in the NaS1 gene, its transport mechanism remains unclear. Here, we report the cryo–electron microscopy structures of five distinct conformations of the human NaS1 at resolutions of 2.7 to 3.3 angstroms, revealing the substrates recognition mechanism and the conformational change of NaS1 during the Na + -sulfate cotransport cycle. Our studies delineate the molecular basis of the detailed dynamic transport cycle of NaS1. These findings advance the current understanding of the Na + -sulfate cotransport mechanism, human sulfate (re)absorption, and the implications of disease-associated NaS1 mutations.

GPT-4o mini: Non-social science research article

A universal strategy for decoupling stiffness and extensibility of polymer networks

Baiqiang Huang, Shifeng Nian, Li-Heng Cai

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Since the invention of polymer networks such as cross-linked natural rubber in the 19th century, it has been a dogma that stiffer networks are less stretchable. We report a universal strategy for decoupling the stiffness and extensibility of single-network elastomers. Instead of using linear polymers as network strands, we use foldable bottlebrush polymers, which feature a collapsed backbone grafted with many linear side chains. Upon elongation, the collapsed backbone unfolds to release stored length, enabling remarkable extensibility. By contrast, the network elastic modulus is inversely proportional to network strand mass and is determined by the side chains. We validate this concept by creating single-network elastomers with nearly constant Young’s modulus (30 kilopascals) while increasing tensile breaking strain by 40-fold, from 20 to 800%. We show that this strategy applies to networks of different polymer species and topologies. Our discovery opens an avenue for developing polymeric materials with extraordinary mechanical properties.

GPT-4o mini: Non-social science research article

TCF1 dosage determines cell fate during T cell development

Anjali Verma, Bridget Aylward, Fei Ma, Cheryl A. Sherman, Laura Chopp, Susan Shinton, Roshni Roy, Shawn Fahl, Alejandra Contreras, Byron Koenitzer, Parirokh Awasthi, Krystyna Mazan-Mamczarz, Supriyo De, Noah Ollikainen, Xiang Qiu, Remy Bosselut, Ranjan Sen, David L. Wiest, Jyoti Misra Sen

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Loss-of-function studies have shown that transcription factor T cell factor-1 (TCF1), encoded by the Tcf7 gene, is essential for T cell development in the thymus. We discovered that the Tcf7 expression level is regulated by E box DNA binding proteins, independent of Notch, and regulates αβ and γδ T cell development. Systematic interrogation of the five E protein binding elements (EPE1–5) in the Tcf7 enhancer region showed lineage-specific utilization. Specifically, loss-of-function analysis revealed that only EPE3 plays a critical role in supporting αβ T cell development, while EPE1, 3, and 5 regulate the γδ T cell maturation and functional cell fate decision. The importance of EPE3 in supporting both lineages may stem from its unique capacity to interact with the Tcf7 transcriptional start site. Together, these studies demonstrate that the precise dosage of TCF1 expression mediated by distinct EPEs generates a balanced output of T cells from the thymus.

GPT-4o mini: Non-social science research article

The multifunctional use of an aqueous battery for a high capacity jellyfish robot

Xu Liu, Shuo Jin, Yiqi Shao, Sofia Kuperman, Autumn Pratt, Duhan Zhang, Jacqueline Lo, Yong Lak Joo, Amir D. Gat, Lynden A. Archer, Robert F. Shepherd

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The batteries that power untethered underwater vehicles (UUVs) serve a single purpose: to provide energy to electronics and motors; the more energy required, the bigger the robot must be to accommodate space for more energy storage. By choosing batteries composed primarily of liquid media [e.g., redox flow batteries (RFBs)], the increased weight can be better distributed for improved capacity with reduced inertial moment. Here, we formed an RFB into the shape of a jellyfish, using two redox chemistries and architectures: (i) a secondary ZnBr 2 battery and (ii) a hybrid primary/secondary ZnI 2 battery. A UUV was able to be powered solely by RFBs with increased volumetric ( Q ~ 11 ampere-hours per liter) and areal (108 milliampere-hours per square centimeter) energy density, resulting in a long operational lifetime ( T ~ 1.5 hours) for UUVs composed of primarily electrochemically energy-dense liquid (~90% of the robot’s weight).

GPT-4o mini: Non-social science research article

The Hox protein Antennapedia orchestrates Drosophila adult flight muscle development

Gabriela Poliacikova, Aïcha Aouane, Nathalie Caruso, Nicolas Brouilly, Corinne Maurel-Zaffran, Yacine Graba, Andrew J. Saurin

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Muscle development and diversity require a large number of spatially and temporally regulated events controlled by transcription factors (TFs). Drosophila has long stood as a model to study myogenesis due to the highly conserved key TFs involved at all stages of muscle development. While many studies focused on the diversification of Drosophila larval musculature, how distinct adult muscle types are generated is much less characterized. Here, we identify an essential regulator of Drosophila thoracic flight muscle development, the Hox TF Antennapedia (Antp). Correcting a long-standing belief that flight muscle development occurs without the input of Hox TFs, we show that Antp intervenes at several stages of flight muscle development, from the establishment of the progenitor pool in the embryo to myoblast differentiation in the early pupa. Furthermore, the precisely regulated clearance of Hox in the developing flight muscle fibers is required to allow for fibrillar muscle fate diversification, setting these muscles apart from all other adult tubular muscle types.

GPT-4o mini: Non-social science research article

Recent emergence of Arctic atlantification dominated by climate warming

Qiang Wang, Qi Shu, Fan Wang

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The Arctic Ocean’s Eurasian Basin underwent notable atlantification during the 2010s, characterized by warming of the Atlantic Water layer and increased upper ocean salinity. Despite profound implications for the Arctic climate system and marine ecosystems, the primary drivers of this process remain debated. One hypothesis suggested that alternating phases of the atmospheric Arctic Dipole may have mitigated recent atlantification. Here, we use high-resolution model simulations to disentangle the main contributors to atlantification in the Arctic basin. We show that the decline in Arctic sea ice was the dominant driver, while wind variability associated with the Arctic Dipole played a minor role, contributing slightly rather than mitigating the process. The positive phase of the Arctic Oscillation also made a relatively small contribution. Although recent changes in atmospheric circulation over the Greenland Sea tended to reduce warm water inflow through the Fram Strait, this cooling effect on the Arctic Atlantic Water layer was outweighed by the warming induced by sea ice decline.

GPT-4o mini: Non-social science research article

Multifunctional hydrogel electronics for closed-loop antiepileptic treatment

Jin Qu, Kai Xie, Shu Chen, Xingdao He, Yuan Wang, Matthew Chamberlin, Xi Zhao, Guangyu Zhu, Chenjie Xu, Peng Shi

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Closed-loop strategies offer advanced therapeutic potential through intelligent disease management. Here, we develop a hydrogel-based, single-component, organic electronic device for closed-loop neurotherapy. Fabricated out of conductive hydrogels, the device consists of a flexible array of microneedle electrodes, each of which can be individually addressed to perform electrical recording and control chemical release with sophisticated spatiotemporal control, thus pioneering a smart antiseizure therapeutic system by combining electrical and pharmacological interventions. The recorded neural signal acts as the trigger for a voltage-driven drug release in detected pathological conditions predicted by real-time electrophysiology analysis. When implanted into epileptic animals, the device enables autonomous antiseizure management, where the dosing of antiepileptic drug is controlled in a time-sensitive, region-selective, and dose-adaptive manner, allowing the inhibition of seizure outbursts through the delivery of just-necessary drug dosages. The side effects are minimized with dosages three orders of magnitude lower than the usage in approaches simulating existing clinical treatments.

GPT-4o mini: Non-social science research article

Multiplex digital profiling of DNA methylation heterogeneity for sensitive and cost-effective cancer detection in low-volume liquid biopsies

Yang Zhao, Christine M. O’Keefe, Jiumei Hu, Conor M. Allan, Weiwen Cui, Hanran Lei, Allyson Chiu, Kuangwen Hsieh, Sonali C. Joyce, James G. Herman, Thomas R. Pisanic, Tza-Huei Wang

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Molecular alterations in cancerous tissues exhibit intercellular genetic and epigenetic heterogeneity, complicating the performance of diagnostic assays, particularly for early cancer detection. Conventional liquid biopsy methods have limited sensitivity and/or ability to assess epigenetic heterogeneity of rare epiallelic variants cost-effectively. We report an approach, named REM-DREAMing (Ratiometric-Encoded Multiplex Discrimination of Rare EpiAlleles by Melt), which leverages a digital microfluidic platform that incorporates a ratiometric fluorescence multiplex detection scheme and precise digital high-resolution melt analysis to enable low-cost, parallelized analysis of heterogeneous methylation patterns on a molecule-by-molecule basis for the detection of cancer in liquid biopsies. We applied the platform to simultaneously assess intermolecular epigenetic heterogeneity in five methylation biomarkers for improved, blood-based screening for early-stage non–small cell lung cancer. In a cohort of 48 low-volume liquid biopsy specimens from patients with indeterminant pulmonary nodules, we show that assessment of intermolecular methylation density distributions can notably improve the performance of multigene methylation biomarker panels for the early detection of cancer.

GPT-4o mini: Non-social science research article

mRNA compartmentalization via multimodule DNA nanostructure assembly augments the immunogenicity and efficacy of cancer mRNA vaccine

Xiaocui Guo, Mengyu Guo, Rong Cai, Mingdi Hu, Le Rao, Wen Su, He Liu, Fene Gao, Xiaoyu Zhang, Jing Liu, Chunying Chen

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Messenger RNA (mRNA) vaccine has fueled a great hope for cancer immunotherapy. However, low immunogenicity, caused by inefficient mRNA expression and weak immune stimulation, hampers the efficacy of mRNA vaccines. Here, we present an mRNA compartmentalization–based cancer vaccine, comprising a multimodule DNA nanostructure (MMDNS)–assembled compartment for efficient mRNA translation via in situ localizing mRNA concentration and relevant reaction molecules. The MMDNS is constructed via programmable DNA hybridization chain reaction (HCR)–based strategy, with integrating antigen-coded mRNA, CpG oligodeoxynucleotides (ODNs), acidic-responsive DNA sequence, and dendritic cells targeting aptamer. MMDNS undergoes in situ assembly in acidic lysosomes to form a micro-sized aggregate, inducing an enhanced CpG ODN adjuvant efficacy. Subsequently, the aggregates escape into cytoplasm, providing a moderate compartment which supports the efficient translation of spatially proximal mRNA transcripts via localizing relevant reaction molecules. The mRNA compartmentalization–based vaccine boosts a strong immune response and effectively inhibits tumor growth and metastasis, offering a robust strategy for cancer immunotherapy.

GPT-4o mini: Non-social science research article

Sudden death of quantum advantage in correlation generations

Weixiao Sun, Fuchuan Wei, Yuguo Shao, Zhaohui Wei

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Quantum noise is one of the most profound obstacles to implementing large-scale quantum algorithms and schemes. In particular, the dynamical process by which quantum noise, varying in strength from 0 to critical levels, affects and destroys quantum advantage has not been well understood. Meanwhile, correlation generation serves as a precious theoretical model for information processing tasks, where quantum advantage can be precisely quantified. In this study, we show that this model provides valuable insights into the understanding of this dynamical process. We prove that, as the strength of quantum noise continuously increases from 0, the quantum advantage diminishes gradually and eventually vanishes. Unexpectedly, in some cases, we observe the phenomenon of a sudden death of quantum advantage: When the noise strength exceeds a certain threshold, the quantum advantage abruptly disappears from a substantial level. This phenomenon, once again, reveals the tremendous impact of noise on quantum information processing tasks.

GPT-4o mini: Non-social science research article

Marine emissions of methanethiol increase aerosol cooling in the Southern Ocean

Charel Wohl, Julián Villamayor, Martí Galí, Anoop S. Mahajan, Rafael P. Fernández, Carlos A. Cuevas, Adriana Bossolasco, Qinyi Li, Anthony J. Kettle, Tara Williams, Roland Sarda-Esteve, Valérie Gros, Rafel Simó, Alfonso Saiz-Lopez

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Ocean-emitted dimethyl sulfide (DMS) is a major source of climate-cooling aerosols. However, most of the marine biogenic sulfur cycling is not routed to DMS but to methanethiol (MeSH), another volatile whose reactivity has hitherto hampered measurements. Therefore, the global emissions and climate impact of MeSH remain unexplored. We compiled a database of seawater MeSH concentrations, identified their statistical predictors, and produced monthly fields of global marine MeSH emissions adding to DMS emissions. Implemented into a global chemistry-climate model, MeSH emissions increase the sulfate aerosol burden by 30 to 70% over the Southern Ocean and enhance the aerosol cooling effect while depleting atmospheric oxidants and increasing DMS lifetime and transport. Accounting for MeSH emissions reduces the radiative bias of current climate models in this climatically relevant region.

GPT-4o mini: Non-social science research article

Inflammatory cytokines disrupt astrocyte exosomal HepaCAM-mediated protection against neuronal excitotoxicity in the SOD1G93A ALS model

Shijie Jin, Yang Tian, Jonathan Hacker, Xuan Chen, Marcela Bertolio, Caroline Reynolds, Rachel Jarvis, Jingwen Hu, Vanessa Promes, Dilara Halim, Fen-Biao Gao, Yongjie Yang

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Astrocyte secreted signals substantially affect disease pathology in neurodegenerative diseases. It remains little understood about how proinflammatory cytokines, such as interleukin-1α/tumor necrosis factor–α/C1q (ITC), often elevated in neurodegenerative diseases, alter astrocyte-secreted signals and their effects in disease pathogenesis. By selectively isolating astrocyte exosomes (A-Exo.) and employing cell type–specific exosome reporter mice, our current study showed that ITC cytokines significantly reduced A-Exo. secretion and decreased spreading of focally labeled A-Exo. in diseased SOD1G93A mice. Our results also found that A-Exo. were minimally associated with misfolded SOD1 and elicited no toxicity to mouse spinal and human iPSC–derived motor neurons. In contrast, A-Exo. were neuroprotective against excitotoxicity, which was completely diminished by ITC cytokines and partially abolished by SOD1G93A expression. Subsequent proteomic characterization of A-Exo. and genetic analysis identified that surface expression of glial-specific HepaCAM preferentially mediates A-Exo’s axon protection effect. Together, our study defines a cytokine-induced loss-of-function mechanism of A-Exo. in protecting neurons from excitotoxicity in amyotrophic lateral sclerosis.

GPT-4o mini: Non-social science research article

Synergistic coordination of diphosphine with primary and tertiary phosphorus centers: Ultrastable icosidodecahedral Ag 30 nanoclusters with metallic aromaticity

Xu-Yang Ding, Chengkai Zhang, Lin-Xi Shi, Jin-Yun Wang, Xin Yang, Li-Yi Zhang, Di Sun, Zhong-Ning Chen

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As versatile ligands with extraordinary coordination capabilities, RPH 2 (R = alkyl or aryl) are rarely used in constructing metal nanoclusters due to their volatility, toxicity, spontaneous flammability, and susceptibility to oxidation. In this work, we designed a primary and tertiary phosphorus-bound diphosphine chelator (2-Ph 2 PC 6 H 4 PH 2 ) to create ultrastable silver nanoclusters with metallic aromaticity. By controlling the deprotonation rate of 2-Ph 2 PC 6 H 4 PH 2 and adjusting the templates, we successfully synthesized two near-infrared emissive nanoclusters, Ag30 and Ag32 , which have analogous icosidodecahedral Ag 30 shells with an I h symmetry. Deprotonated ligand (2-Ph 2 P α C 6 H 4 P β 2− ) exhibits a coordination mode of μ 5 -η 1 (P β ),η 2 (P α ,P β ), which endows a unique metallic aromaticity to Ag30 and Ag32 . The solution-processed organic light-emitting diodes based on Ag30 achieve an external quantum efficiency of 15.1%, representing the breakthrough in application of silver nanoclusters to near-infrared–emitting devices. This work represents a special ligand system for synthesizing ligand-protected coinage metal nanoclusters and opens up horizons of creating nanoclusters with distinct geometries and metal aromaticity.

GPT-4o mini: Non-social science research article

The competing controls of glaciers, precipitation, and vegetation on high-mountain fluvial sediment yields

Dongfeng Li, Ting Zhang, Desmond E. Walling, Stuart Lane, Bodo Bookhagen, Shang Tian, Irina Overeem, Jaia Syvitski, Albert J. Kettner, Edward Park, Michèle Koppes, Rafael J. P. Schmitt, Weiling Sun, Jinren Ni, Todd A. Ehlers

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Investigating erosion and river sediment yield in high-mountain areas is crucial for understanding landscape and biogeochemical responses to environmental change. We compile data on contemporary fluvial suspended sediment yield (SSY) and 12 environmental proxies from 151 rivers in High Mountain Asia surrounding the Tibetan Plateau. We demonstrate that glaciers exert a first-order control on fluvial SSYs, with high precipitation nonlinearly amplifying their role, especially in high–glacier cover basins. We find a bidirectional response to vegetation’s influence on SSY in the Eastern Tibetan Plateau and Tien Shan and identify that the two interacting factors of precipitation and vegetation cover explain 54% of the variability in SSY, reflecting the divergent roles of vegetation in promoting biogenic-weathering versus slope stabilization across bioclimatic zones. The competing interactions between glaciers, ecosystems, and climate in delivering suspended sediment have important implications for predicting carbon and nutrient exports and water quality in response to future climate change.

GPT-4o mini: Non-social science research article

Projections from subfornical organ to bed nucleus of the stria terminalis modulate inflammation-induced anxiety-like behaviors in mice

Jinlin Zhang, Chuantong Xie, Peiyao Xu, Qiuping Tong, Lei Xiao, Jing Zhong

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Peripheral inflammation is closely related to the pathogenesis of sickness behaviors and psychiatric disorders such as anxiety and depression. The circumventricular organs (CVOs) are important brain sites to perceive peripheral inflammatory signals, but few studies have reported their role in inflammation-induced anxiety or depression. Using a mouse model of lipopolysaccharide (LPS)–induced inflammation, we identified a previously unreported role of the subfornical organ (SFO), one of the CVOs, in combating inflammation-induced anxiety. LPS treatment induced anxiety-like and sickness behaviors in mice. Although both the SFO and the organum vasculosum of the lamina terminalis (a CVO) neurons were activated after LPS treatment, only manipulating SFO neurons modulated LPS-induced anxiety-like behaviors. Activating or inhibiting SFO neurons alleviated or aggravated LPS-induced anxiety-like behaviors. In addition, SFO exerted this effect through glutamatergic projections to the bed nucleus of the stria terminalis. Manipulating SFO neurons did not affect LPS-induced sickness behaviors. Thus, we uncovered an active role of SFO neurons in counteracting peripheral inflammation-induced anxiety.

GPT-4o mini: Non-social science research article

The antiviral JNJ-A07 significantly reduces dengue virus transmission by Aedes aegypti mosquitoes when delivered via blood-feeding

Ana L. Rosales-Rosas, Sara Goossens, Winston Chiu, Atreyee Majumder, Alina Soto, Serge Masyn, Bart Stoops, Lanjiao Wang, Suzanne J. F. Kaptein, Olivia Goethals, Leen Delang

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Dengue virus (DENV) is the most widespread mosquito-borne virus worldwide, but no antiviral therapies are available yet. The pan-serotype DENV inhibitor JNJ-A07 has shown potent activity in a mouse model. It remains unknown whether an antiviral drug ingested by mosquitoes could inhibit virus replication and thus reduce transmission to other hosts. Here, we investigated the antiviral activity of JNJ-A07 when administered in the blood meal to Aedes aegypti mosquitoes. JNJ-A07 blocked DENV-2 transmission by the mosquitoes in both pre-exposure and post-exposure settings. In addition, JNJ-A07 remained in the mosquito bodies for 7 days after blood meal. Reductions of DENV systemic infection in the mosquitoes suggested a potential for decreased proportions of DENV outbreaks in a simulated environment when the mosquitoes ingested JNJ-A07 via the blood meal.

GPT-4o mini: Non-social science research article

Cesarean delivery and blood DNA methylation at birth and childhood: Meta-analysis in the Pregnancy and Childhood Epigenetics Consortium

Siwen Wang, Emma Casey, Joanne Sordillo, Sofía Aguilar-Lacasaña, Fernanda Morales Berstein, Richard J. Biedrzycki, Sonia Brescianini, Su Chen, Amy Hough, Elena Isaevska, Woo Jin Kim, Marion Lecorguillé, Sebastian Shaobo Li, Christian M. Page, Jaehyun Park, Stefan Röder, Kristina Salontaji, Gillian Santorelli, Yidan Sun, Sungho Won, Eric Zillich, Lea Zillich, Isabella Annesi-Maesano, S. Hasan Arshad, Mariona Bustamante, Charlotte A. M. Cecil, Hannah R. Elliott, Susan Ewart, Janine F. Felix, Luigi Gagliardi, Siri E. Håberg, Gunda Herberth, Barbara Heude, John W. Holloway, Anke Huels, Wilfried Karmaus, Gerard H. Koppelman, Stephanie J. London, Sunni L. Mumford, Lorenza Nisticò, Maja Popovic, Franca Rusconi, Enrique F. Schisterman, Dan J. Stein, Tabea Send, Henning Tiemeier, Judith M. Vonk, Martine Vrijheid, Joseph Leo Wiemels, Stephanie H. Witt, John Wright, Edwina H. Yeung, Heather J. Zar, Ana C. Zenclussen, Hongmei Zhang, Jorge E. Chavarro, Marie-France Hivert

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Children born via cesarean delivery have a higher risk of metabolic, immunological, and neurodevelopmental disorders compared to those born via vaginal delivery, although mechanisms remain unclear. We conducted a meta-analysis of epigenome-wide association studies to examine the associations between delivery mode and blood DNA methylation at birth and its persistence in early childhood. Participants were from 19 pregnancy cohorts (9833 term newborns) and 6 pediatric cohorts (2429 children aged 6 to 10 years). We identified six CpGs in cord blood associated with cesarean delivery (effect size range: 0.4 to 0.7%, P < 1.0 × 10 −7 ): MAP2K2 (cg19423175), LIM2 (cg01500140), CNP (cg13917614), BLM (cg18247172), RASA3 (cg22348356), and RUNX3 (cg20674490), independent of cell proportions and other confounders. In childhood, none of these CpGs were associated with cesarean delivery, and no additional CpGs were identified. Delivery mode was associated with cell proportions at birth but not in childhood. Further research is needed to elucidate cesarean delivery’s molecular influence on offspring health.

GPT-4o mini: Non-social science research article

Acoustic virtual 3D scaffold for direct-interacting tumor organoid–immune cell coculture systems

Han Shan, Maike Chen, Shuang Zhao, Xiongwei Wei, Mingde Zheng, Yixin Li, Qibo Lin, Zixi Jiang, Ziyan Chen, Chunlong Fei, Zhaoxi Li, Zeyu Chen, Xiang Chen

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Three-dimensional (3D) cell culture has revolutionized life sciences, particularly in organoid technologies. Traditional bioscaffold materials, however, complicate the detachment of tumor organoids and hamper the routine use of organoid–immune cell cocultures. Here, we show an acoustic virtual 3D scaffold (AV-Scaf) method to achieve 3D tumor organoid culture, enabling a direct-interacting tumor organoid–immune cell coculture system. The self-organization process of tumor cells is facilitated by a vortex acoustic field, which enables the cell bioassembly and ion channel activation. This approach can significantly enhance the influx of calcium ions, thereby accelerating intercellular interactions of cellular assemblies. We established scaffold-free melanoma and breast cancer organoids using AV-Scaf and cocultured melanoma organoids with T cells. We found that our coculture system resulted in a high activation state of T cells, characterized by notable up-regulation of granzyme B (2.82 to 17.5%) and interferon-γ (1.36 to 16%). AV-Scaf offers an efficient method for tumor organoid–immune cell studies, advancing cancer research and immunotherapy development.

GPT-4o mini: Non-social science research article

Single-cell multi-omics sequencing uncovers region-specific plasticity of glioblastoma for complementary therapeutic targeting

Xin Wang, Qian Sun, Tianbin Liu, Haoran Lu, Xuyi Lin, Weiwen Wang, Yang Liu, Yunting Huang, Guodong Huang, Haixi Sun, Qianxue Chen, Junmin Wang, Daofeng Tian, Fan’en Yuan, Longqi Liu, Bo Wang, Ying Gu, Baohui Liu, Liang Chen

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Glioblastoma (GBM) cells are highly heterogeneous and invasive, leading to treatment resistance and relapse. However, the molecular regulation in and distal to tumors remains elusive. Here, we collected paired tissues from the tumor core (TC) and peritumoral brain (PTB) for integrated snRNA-seq and snATAC-seq analyses. Tumor cells infiltrating PTB from TC behave more like oligodendrocyte progenitor cells than astrocytes at the transcriptome level. Dual-omics analyses further suggest that the distal regulatory regions in the tumor genome and specific transcription factors are potential determinants of regional heterogeneity. Notably, while activator protein 1 (AP-1) is active in all GBM states, its activity declines from TC to PTB, with another transcription factor, BACH1, showing the opposite trend. Combined inhibition of AP-1 and BACH1 more efficiently attenuates the tumor progression in mice and prolongs survival than either single-target treatment. Together, our work reveals marked molecular alterations of infiltrated GBM cells and a synergy of combination therapy targeting intratumor heterogeneity in and distal to GBM.

GPT-4o mini: Non-social science research article

High-order direct modulation terahertz communications with a wideband time-coding metachip modulator

Lan Wang, Jun Yan Dai, Ke Seng Ding, Hong Xin Zeng, Qiang Cheng, Zi Qiang Yang, Ya Xin Zhang, Tie Jun Cui

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Terahertz communication technology based on on-off keying (OOK) direct modulation is vital for sixth-generation communication systems, especially in short-distance and high-rate applications. However, low-order OOK modulation often leads to suboptimal anti-interference capabilities and a heightened demodulation threshold. Here, we propose a high-order direct modulation terahertz communication framework using a wideband time-coding metachip modulator. The modulator leverages the electromagnetic resonance properties within the metaunit structure, with control enabled by gallium arsenide Schottky diodes. By manipulating the timing of voltage pulses applied to these diodes, the equivalent electromagnetic resonance distributions can be precisely regulated in the time domain. This enables independent and accurate control over the amplitude and phase of terahertz harmonics. Leveraging this technique, three high-order modulation schemes—quadrature phase-shift keying, 16-phase-shift keying, and 16-quadrature amplitude modulation— are achieved in a direct modulation and direct detection system, demonstrating the real-time image transmission. The proposed method offers an important way to develop integrated and low-complexity terahertz wireless communication systems.

GPT-4o mini: Non-social science research article

Progression of ocean interior acidification over the industrial era

Jens D. Müller, Nicolas Gruber

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Ocean acidification driven by the uptake of anthropogenic CO 2 represents a major threat to ocean ecosystems, yet little is known about its progression beneath the surface. Here, we reconstruct the history of ocean interior acidification over the industrial era on the basis of observation-based estimates of the accumulation of anthropogenic carbon. Across the top 100 meters and from 1800 to 2014, the saturation state of aragonite (Ω arag ) and pH = −log[H + ] decreased by more than 0.6 and 0.1, respectively, with nearly 50% of the progression occurring over the past 20 years. While the magnitude of the Ω arag change decreases uniformly with depth, the magnitude of the [H + ] increase exhibits a distinct maximum in the upper thermocline. Since 1800, the saturation horizon (Ω arag = 1) shoaled by more than 200 meters, approaching the euphotic zone in several regions, especially in the Southern Ocean, and exposing many organisms to corrosive conditions.

GPT-4o mini: Non-social science research article

Genomic heterogeneity and ploidy identify patients with intrinsic resistance to PD-1 blockade in metastatic melanoma

Giuseppe Tarantino, Cora A. Ricker, Annette Wang, William Ge, Tyler J. Aprati, Amy Y. Huang, Shariq Madha, Jiajia Chen, Yingxiao Shi, Marc Glettig, Catherine H. Feng, Dennie T. Frederick, Samuel Freeman, Marta M. Holovatska, Michael P. Manos, Lisa Zimmer, Alexander Rösch, Anne Zaremba, Elisabeth Livingstone, Jacob C. Jameson, Soroush Saghafian, Andrew Lee, Karena Zhao, Luc G.T. Morris, Brendan Reardon, Jihye Park, Haitham A. Elmarakeby, Bastian Schilling, Anita Giobbie-Hurder, Natalie I. Vokes, Elizabeth I. Buchbinder, Keith T. Flaherty, Rizwan Haq, Catherine J. Wu, Genevieve M. Boland, F. Stephen Hodi, Eliezer M. Van Allen, Dirk Schadendorf, David Liu

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The introduction of immune checkpoint blockade (ICB) has markedly improved outcomes for advanced melanoma. However, many patients develop resistance through unknown mechanisms. While combination ICB has improved response rate and progression-free survival, it substantially increases toxicity. Biomarkers to distinguish patients who would benefit from combination therapy versus aPD-1 remain elusive. We analyzed whole-exome sequencing of pretreatment tumors from four cohorts ( n = 140) of ICB-naïve patients treated with aPD-1. High genomic heterogeneity and low ploidy robustly identified patients intrinsically resistant to aPD-1. To establish clinically actionable predictions, we optimized and validated a predictive model using ploidy and heterogeneity to confidently identify (90% PPV) patients with intrinsic resistance to and worse survival on aPD-1. We further observed that three of seven (43%) patients predicted to be intrinsically resistant to single-agent PD-1 ICB responded to combination ICB, suggesting that these patients may benefit disproportionately from combination ICB. These findings highlight the importance of heterogeneity and ploidy, nominating an approach toward clinical actionability.

GPT-4o mini: Non-social science research article

EZH2 directly methylates PARP1 and regulates its activity in cancer

Qingshu Meng, Jiangchuan Shen, Yanan Ren, Qi Liu, Rui Wang, Qiaqia Li, Weihua Jiang, Quan Wang, Yixiang Zhang, Jonathan C. Trinidad, Xiaotong Lu, Tingyou Wang, Yanqiang Li, Chaehyun Yum, Yang Yi, Yongyong Yang, Dongyu Zhao, Clair Harris, Sundeep Kalantry, Kaifu Chen, Rendong Yang, Hengyao Niu, Qi Cao

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DNA repair dysregulation is a key driver of cancer development. Understanding the molecular mechanisms underlying DNA repair dysregulation in cancer cells is crucial for cancer development and therapies. Here, we report that enhancer of zeste homolog 2 (EZH2) directly methylates poly(adenosine diphosphate–ribose) polymerase-1 (PARP-1), an essential enzyme involved in DNA repair, and regulates its activity. Functionally, EZH2-catalyzed methylation represses PARP1 catalytic activity, down-regulates the recruitment of x-ray repair cross-complementing group-1 to DNA lesions and its associated DNA damage repair; on the other hand, it protects the cells from nicotinamide adenine dinucleotide overconsumption upon DNA damage formation. Meanwhile, EZH2-mediated methylation regulates PARP1 transcriptional and oncogenic activity, at least in part, through impairing PARP1-E2F1 interaction and E2F1 transcription factor activity. EZH2 and PARP1 inhibitors synergistically suppress prostate cancer growth. Collectively, our findings uncover an insight of EZH2 functions in fine-tuning PARP1 activity during DNA damage repair and cancer progression, which provides a rationale for combinational targeting EZH2 and PARP1 in cancer.

GPT-4o mini: Non-social science research article

Rhodium-catalyzed atropodivergent hydroamination of alkynes by leveraging two potential enantiodetermining steps

Ruijie Mi, Rongkai Wu, Jierui Jing, Fen Wang, Xiao-Xi Li, Xin Hong, Xingwei Li

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A pair of enantiomers is known to have different biological activities. Two catalysts with opposite chirality are nearly always required to deliver both enantiomeric products. In this work, chiral rhodium(III) cyclopentadienyl complexes are repurposed as efficient catalysts for enantiodivergent and atroposelective hydroamination of sterically hindered alkynes. Products with opposite chirality have been both obtained using the same or closely analogous chiral catalyst in good efficiency and excellent enantioselectivity, and the enantiodivergence was mainly enabled by an achiral carboxylic acid and its silver salt. Mechanistic studies revealed the origin of the enantiodivergence ascribable to the switch of the enantiodetermining step (alkyne insertion versus protonolysis) under acid control, which constitutes a previously unidentified working mode of enantiodivergence by leveraging two elementary steps.

GPT-4o mini: Non-social science research article

Load sharing and accumulated bond fracture in ion-irradiated carbon mat for energy dissipation

Kailu Xiao, Xianqian Wu, Zhen Sang, Vivek Subramanian, Edwin L. Thomas

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Multiwalled carbon nanotube (MWNT) aerogel mats were irradiated with carbon ions to explore the effect of irradiation-induced sp 3 bonds and sp 2 bond defects on ultrahigh strain rate mechanical properties. Energy dissipation was measured using a microprojectile impact test. Specific penetration energy E p * increased strongly with irradiation with a maximum E p * of ~26 megajoules per kilogram, over 200% higher than the previous best energy-absorbing material of pristine MWNT mats and at least an order of magnitude higher than any other material tested at the microscale. Perforation morphologies observed by electron microscopy show that a much larger network region is deformed due to sp 3 bond enhanced load sharing within and between tubes, while defects introduced by the radiation induce more bond, shell, and tube damage leading to strongly enhanced energy dissipation.

Socio-Economic Review

Nothing really matters: evaluating demand-side moderators of age discrimination in hiring

Axana Dalle, Louis Lippens, Stijn Baert

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As age discrimination hampers the OECD’s ambition to extend the working population, an efficient anti-discrimination policy targeted at the right employers is critical. Therefore, the context in which age discrimination is most prevalent must be identified. In this study, we thoroughly review the current theoretical arguments and empirical findings regarding moderators of age discrimination in different demand-side domains (i.e. decision-maker, vacancy, occupation, organization and sector). Our review demonstrates that the current literature is highly fragmented and often lacks field-experimental evidence, raising concerns about its internal and external validity. To address this gap, we conducted a correspondence experiment and systematically linked the resulting data to external data sources. In so doing, we were able to study the priorly determined demand-side moderators within a single multi-level analysis and simultaneously control multiple correlations between potential moderators and discrimination estimates. Having done so, we found no empirical support for any of these moderators.

Power and inequality: determinants of income inequality in rich capitalist democracies, 1960 to 2019

Jordan Rosenblum, Lane Kenworthy, Mikael Nygård

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We explore the link between the distribution of power and income inequality in rich capitalist democracies since 1960. We advance understanding of the impact of government ideology, a key indicator of the distribution of power, in two ways. First, previous research has tended to focus on government ideology at the country level. We make use of party manifesto data to introduce a novel global ideology measure that captures a global shift rightward since 1980, often referred to as the rise of neoliberalism. Second, for country-level party ideology, we use party manifesto data to capture changes over time. We find that this time-varying operationalization of party ideology is more strongly linked to income inequality than the standard expert-survey operationalization that assumes party ideology remains constant. In line with theoretical expectations derived from prior research, our findings show that a more rightward distribution of power at both the country and the global level is associated with increased income inequality within countries.

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Available journal tags

AJPS: American Journal of Political Science

APSR: American Political Science Review

AnnuRev: Annual Review of Political Science

BJPOL: British Journal of Political Science

CPS: Comparative Political Studies

CMP: Comparative Politics

ElectStud: Electoral Studies

EJPR: European Journal of Political Research

IO: International Organization

IS: International Security

ISQ: International Studies Quarterly

JCR: Journal of Conflict Resolution

JEPS: Journal of Experimental Political Science

JPR: Journal of Peace Research

JTP: Journal of Theoretical Politics

LSQ: Legislative Studies Quarterly

PP: Party Politics

PA: Political Analysis

PolBehav: Political Behavior

PolGeo: Political Geography

PolPsyc: Political Psychology

PSRM: Political Science Research and Methods

PS: PS: Political Science & Politics

PubChoice: Public Choice

POQ: Public Opinion Quarterly

QJPS: Quarterly Journal of Political Science

RAP: Research & Politics

JOP: The Journal of Politics

WEP: West European Politics

WP: World Politics

APP: American Economic Journal: Applied Economics

POL: American Economic Journal: Economic Policy

AER: American Economic Review

AnnuRev: Annual Review of Economics

ECTA: Econometrica

EJ: Economic Journal

EconPolicy: Economic Policy

EER: European Economic Review

JEconom: Journal of Econometrics

JEL: Journal of Economic Literature

JEP: Journal of Economic Perspectives

JPE: Journal of Political Economy

JPubEcon: Journal of Public Economics

JEEA: Journal of the European Economic Association

REStat: Review of Economics and Statistics

QJE: The Quarterly Journal of Economics

REStud: The Review of Economic Studies

ASR: American Sociological Review

AnnuRev: Annual Review of Sociology

ES: European Societies

ESR: European Sociological Review

SocForces: Social Forces

SociolMethodsRes: Sociological Methods & Research

AAPSS: Annals of the American Academy of Political and Social Science

Nat: Nature

NatHumBehav: Nature Human Behaviour

PNAS: Proceedings of the National Academy of Sciences

Sci: Science

SciAdv: Science Advances

SER: Socio-Economic Review

CMS: Comparative Migration Studies

ERS: Ethnic and Racial Studies

IntMigr: International Migration

IMR: International Migration Review

JEMS: Journal of Ethnic and Migration Studies

JRS: Journal of Refugee Studies

PSP: Population Space and Place

Available bunde tags

@TOP: APSR, AER, ASR

@IR: ISQ, WP, IO, JCR, JPR, IS

@MET: PA, JEconom, ECTA, SociolMethodsRes