Deng H, Zhao Q, Liu T
… +7 more, Zhang Z, Zhu Z, Zhou Y, Peng HX, Yang W, Gao H, Zhou H
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372167
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Architected materials derive functionality from geometry, yet conventional unit cell-based design limits functional heterogeneity, geometric adaptability, and robustness to defects. Inspired by natural morphogenesis, we...Architected materials derive functionality from geometry, yet conventional unit cell-based design limits functional heterogeneity, geometric adaptability, and robustness to defects. Inspired by natural morphogenesis, we introduce RDGenCAD, a morphogenetic design framework that translates programmable growth rules into reaction-diffusion dynamics to generate self-organized, CAD-ready architectures. A database of 120,000 morphogenetic structures reveals statistically deterministic and continuous tunability of elastic properties across auxetic and conventional regimes, despite pronounced geometric irregularity. These architectures further exhibit emergent flaw insensitivity and crack deflection through stress compartmentalization, leading to synergistic gains in strength and toughness relative to regular lattices. By shifting architected material design from unit-cell tessellation to programmable morphogenetic growth, this work establishes self-organization as a generative principle for designing materials that are irregular yet predictable, heterogeneous yet "coherent," and directly manufacturable.
Romero-Vidal P, Sánchez-Navarro S, Tena E
… +1 more, Clavero M
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372166
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A recent study has provided the first direct evidence that the greater noctule bat () preys on and consume nocturnally migrating passerines in flight, using a combination of biologging, acoustic and movement monitoring,...A recent study has provided the first direct evidence that the greater noctule bat () preys on and consume nocturnally migrating passerines in flight, using a combination of biologging, acoustic and movement monitoring, and molecular analyses. This result builds upon evidence accumulated over the past two decades. The research began with the first study reporting passerine feathers in the feces of this bat species. Subsequent fecal pellet analyses revealed peaks in the consumption of migratory avian prey, which coincided with migration periods. This body of evidence culminated in the recent publication demonstrating that greater noctules capture and consume migratory birds in flight at high altitudes. Here, we show that this interaction was depicted more than four centuries ago. In the canvas Air (1611), a painting by Jan Brueghel the Elder that contains detailed representations of more than 60 bird species, the artist also included three bat species. One of them, unmistakably identified as noctule bat, is represented in flight with a small passerine in its mouth. Although the behavior portrayed does not fully match contemporary descriptions of prey handling, the specificity of this predation scene suggests some familiarity of the artist with this behavior in the greater noctule. As the digitization of art collections accelerates and analytical tools continue to advance, the value of these sources to provide valuable data-previously difficult to extract and often overlooked-and complement modern research approaches will notably increase.
Abson KL, Zijmers L, Mittell EA
… +4 more, Young EA, Postma E, Eyre-Walker A, Hadfield JD
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372165
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The capacity to adapt is essential for a population to avoid extinction in a changing world and is recognized as a global conservation priority. Adaptation requires additive (heritable) genetic variation for traits that...The capacity to adapt is essential for a population to avoid extinction in a changing world and is recognized as a global conservation priority. Adaptation requires additive (heritable) genetic variation for traits that influence survival and fecundity, but measuring this variation is difficult, particularly in species of conservation concern. Instead, molecular genetic diversity is often used to infer adaptive potential. However, previous research has cast doubt on the suitability of traditional molecular markers (allozymes and microsatellites) for this purpose given their weak relationship with heritability-a common measure of additive genetic variance. Advances in sequencing technology have since shifted focus toward nucleotide diversity and variation in functional regions, but their practicality for predicting adaptive potential remains debated. Furthermore, heritability itself is a poor proxy for adaptive potential because it depends on environmental variance. We collated 2,113 published estimates of evolvability-a measure of additive genetic variance that avoids environmental confounding-across 193 eukaryotic species, and evaluated how well evolvability is predicted by molecular diversity. We find that microsatellite and nucleotide diversity are not significantly correlated to each other, and neither predict evolvability. Nucleotide diversity explains 1.1% of interspecific differences in evolvability and doubling nucleotide diversity only corresponds to a 11.7% increase in evolvability. With theoretical work, we show that such weak associations are expected. Together, our results suggest that simple molecular measures of genetic variation are insufficient for predicting adaptive potential and reliance on these metrics risks misinforming conservation management.
Metzger SM, Jones TC, Meier JIJ
… +6 more, Richter A, Klassen MC, Olmer R, Diegmüller N, Heimsch KC, Drosten C
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372164
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The origin of the polybasic furin cleavage site (FCS) of SARS-CoV-2 remains a central question in debates on the emergence of COVID-19. One hypothesis proposes a genetic relationship between the SARS-CoV-2 S1/S2 motif RR...The origin of the polybasic furin cleavage site (FCS) of SARS-CoV-2 remains a central question in debates on the emergence of COVID-19. One hypothesis proposes a genetic relationship between the SARS-CoV-2 S1/S2 motif RRAR and the RRVR sequence found in the mouse-adapted MERS-CoV strain MERS-MA30. Here, we combined large-scale bioinformatic analysis with experimental virology to evaluate this scenario. Analysis of over 17 million SARS-CoV-2 genomes revealed that the S:684V substitution corresponding to RRVR occurred repeatedly but only sporadically, never became phylogenetically basal, and showed limited geographic and temporal spread. Using reverse genetics, we generated SARS-CoV-2 variants encoding RRVR and demonstrated that S:684V consistently reduced viral entry efficiency and competitive fitness in multiple cell systems, including human respiratory epithelial cultures. RRVR variants did not evolve toward RRAR but instead accumulated alternative substitutions. These findings do not support an evolutionary relationship between MERS-MA30 and the SARS-CoV-2 FCS.
Dawel A, George T, Mah EY
… +4 more, Dunn JD, Sutherland CAM, Argument N, Tanaka JW
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372163
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As AI-generated faces become indistinguishable from real ones, deepfake technology poses escalating threats to information integrity and security. While algorithms can detect deepfakes, they suffer from opacity and criti...As AI-generated faces become indistinguishable from real ones, deepfake technology poses escalating threats to information integrity and security. While algorithms can detect deepfakes, they suffer from opacity and critical vulnerabilities-and training humans to identify specific visual artifacts has proven largely ineffective. Here, we introduce a fundamentally different approach that harnesses people's global impressions of faces. Building on findings that AI and human faces evoke systematically different perceptual impressions (Miller et al., 2023), we trained participants to attend to these distinguishing qualities without explicit instruction on how to use them. Using a rigorous pre-post design with untrained test faces, we demonstrate that all participants ( = 45) improved, with mean accuracy nearly doubling. High performers achieved near-perfect detection, and participants developed metacognitive insight, showing appropriate confidence calibration only after training. A test-retest control study ruled out practice effects as an explanation for training gains, and an online replication demonstrates the scalability of our approach. As the technology advances, targeting systematic biases that are inherent to generative AI, and which manifest in global features, may offer a more durable defense than approaches reliant on image artifacts alone.
McAllister RA, Stiegler AL, Chari K
… +3 more, Chari M, Bhattacharyya M, Gupta K
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372161
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Peripheral membrane proteins (PMPs) are critical mediators of signaling cascades initiated at the cell surface. Their functions depend on their innate ability to interact dynamically with membranes in response to changin...Peripheral membrane proteins (PMPs) are critical mediators of signaling cascades initiated at the cell surface. Their functions depend on their innate ability to interact dynamically with membranes in response to changing cellular conditions. This membrane recruitment may occur via high-affinity interactions with specific lipids/proteins or via transient, low-affinity interactions with the membrane. These weak and dynamic interactions, which are critical regulators of PMP function, are challenging to capture. Taking Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell activation, we demonstrate a native mass spectrometry platform to understand lipid-mediated recruitment of PMPs by directly studying it from lipid bilayers customized to target membranes. Our data demonstrate that BTK recognizes phosphatidylserine (PS) independently of phosphatidylinositol (3, 4, 5) phosphate (PIP) binding. We show that PS-bound BTK retains PIP binding via high-affinity sites, while exhibiting PIP-independent basal membrane recruitment. Biochemical assays show that this PS-mediated recruitment sensitizes BTK to PIP-mediated activation at near-physiological PIP concentrations. Thus, we propose a two-step model for BTK membrane recruitment and activation. A low-affinity interaction with high-copy number PS enables plasma membrane recruitment of BTK and increases its membrane-bound concentration. Upon B cell activation, this prerecruited, membrane-bound BTK population localizes to PIP-rich domains via electrostatic gliding along the membrane, driven by low-affinity PS and high-affinity PIP binding. This indicates a cooperative mechanism in which PS can amplify B cell signaling by increasing membrane-bound BTK levels. Our work demonstrates a general model of regulation of PH domain-containing proteins by weak protein-lipid interactions, which can be extended to other PMPs.
Dotan E, Lyubman I, Ehrlich M
… +3 more, Bacharach E, Pupko T, Belinkov Y
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372160
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Deciphering protein function is fundamental to advancements in medicine and biotechnology. However, conventional experimental characterization remains resource-intensive. Public large language models (LLMs), though profi...Deciphering protein function is fundamental to advancements in medicine and biotechnology. However, conventional experimental characterization remains resource-intensive. Public large language models (LLMs), though proficient in natural language processing, often fail to accurately interpret and predict the functional and structural properties of proteins, limiting their utility in bioinformatics. To address this gap, we introduce BetaDescribe, designed to generate detailed and rich textual descriptions of proteins, including their function, catalytic activity, involvement in specific metabolic pathways, subcellular localizations, and the presence of specific domains. The trained BetaDescribe model receives protein sequences as input and outputs a textual description of these properties. BetaDescribe starting point was the LLAMA2 model, which was trained on trillions of tokens. Our model was next trained on datasets containing both biological and English text, which allowed the incorporation of biological knowledge. In addition to the description generator, BetaDescribe comprises multiple validator models and a judge, which together enable accurate ranking of alternative generated descriptions. We demonstrate the utility of BetaDescribe by providing descriptions for proteins that share little to no sequence similarity to proteins with functional descriptions in public datasets. Using in silico mutagenesis, we further show that BetaDescribe relies on functionally important regions, as part of its prediction, suggesting that the model identifies regions of importance for the protein functionality without needing homologous sequence. BetaDescribe offers a powerful tool to explore protein functionality, augmenting existing approaches such as annotation transfer based on sequence or structure similarity.
Dutta D, Kim Y, Ho CY
… +4 more, Seidman JG, Seidman CE, Craig R, Padrón R
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372158
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Hypertrophic cardiomyopathy (HCM) variants in genes encoding the myosin heavy chain (MHC) (), myosin light chains ( and ), and cardiac myosin binding protein-C (cMyBP-C, ) lead to cardiac hypertrophy, with abnormal contr...Hypertrophic cardiomyopathy (HCM) variants in genes encoding the myosin heavy chain (MHC) (), myosin light chains ( and ), and cardiac myosin binding protein-C (cMyBP-C, ) lead to cardiac hypertrophy, with abnormal contractility, relaxation, and energy consumption. Here, we defined the structural consequences of pathogenic and benign missense variants in these genes by mapping 233 variants (, n = 175; , n = 41; , n = 12; , n = 5) onto a cryo-EM-based atomic model of the human cardiac thick filament. We identified HCM variants residing in 30 molecular interfaces of the complex thick filament interactome, including the two main interfaces of the myosin interacting-heads motif (IHM), and interfaces involving the MHC, essential and regulatory light chains, and cMyBP-C. None of the 21 variants classified as benign were within interfaces. We demonstrated earlier disease onset and adverse outcomes in HCM patients with pathogenic variants within vs. outside of molecular interfaces, emphasizing their importance in normal thick filament function and improving risk stratification of patients.
Yang R, Yang H, Davydenko A
… +5 more, Mawaldi Z, Kormos R, Myerscough D, Wu Y, DeGrado WF
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372157
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It has been hypothesized that while random sequences are unlikely to fold into proteins of the length of globular proteins, repeated random sequences are more likely to adopt stably folded structures, with implications f...It has been hypothesized that while random sequences are unlikely to fold into proteins of the length of globular proteins, repeated random sequences are more likely to adopt stably folded structures, with implications for molecular evolution. We used structure prediction methods to determine the foldability of approximately 120-residue sequences composed of 5- to 60-residue random repeats. With repeats of less than 30-residues, sequences were frequently discovered (1 to 12%) that fold with high confidence. For less than 60-residue repeats, we frequently observe β-solenoids, similar to those seen in natural proteins. We observe solenoids stabilized by apolar packing as well as ones stabilized by polar interactions with Ca in the core of the structure as in natural Repeats in ToXin (RTX) domains. Helical bundles were observed with high frequency when insertions or deletions were included between blocks of repeating sequences. We also observed a new supersecondary structure consisting of a tightly wound α-helical screw and experimentally confirmed its stability and structure by circular dichroism (CD) spectroscopy and X-ray crystallography. Thus, structure predictors can discover structures that are well out of the distribution of the data upon which they were trained. Beyond 40-residue repeat lengths, very few sequences were predicted to fold. The small number of structures we observed was representative of well-established major classes of tertiary structures; greater sampling would be needed to discover novel structures from a random distribution. These studies illuminate dark matter regions of protein structure space and support previous predictions that proteins evolved through the assortment of shorter peptide sequences.
Rouxel R, Lüttig J, Jones MR
… +1 more, Zigmantas D
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372156
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Understanding the remarkable quantum efficiency of solar energy collection in phototrophic bacteria requires a clear description of the functional connectivity between the individual complexes comprising the photosynthet...Understanding the remarkable quantum efficiency of solar energy collection in phototrophic bacteria requires a clear description of the functional connectivity between the individual complexes comprising the photosynthetic apparatus. While significant progress has been made since the 1980s in understanding energy transfer dynamics within isolated complexes, information about intercomplex processes in intact cells is still sparse. One reason is the great complexity of intact systems that leads to highly congested spectra, especially at room temperature. Two-dimensional electronic spectroscopy (2DES) is a method that is well suited to discriminating between different subsystems and disentangling their responses, since the excitation energy is resolved along the "second dimension" of the spectra. However, 2DES on intact photosynthetic systems such as whole bacterial cells is challenging due to the high scattering properties of such samples. With a 2DES setup designed to reduce scattering, we were able to overcome these limitations. Here, we present physiological temperature measurements on intact cells of the purple photosynthetic bacterium , which enabled us to fully map the energy transfer processes in an intact photosynthetic unit with femtosecond resolution, from the initial light-harvesting steps in the antenna complexes LH2 and LH1 through to arrival of the excitation to the reaction center. In particular, we observe the appearance of a clear signature of charge separation in the reaction center as a strong electrochromic band-shift signal. Through a global analysis approach, we extract the effective time constants for all these processes and expand the existing picture of how bacterial light harvesting works in vivo.
Cao J, Liu S, Su C
… +5 more, Wang L, Li Z, Qi J, Wang P, Gao GF
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372155
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Migratory birds are the natural reservoir of influenza A virus (IAV), but their role as a carrier of SARS-CoV-2 remains unclear. Here, we report the identification of three almost full-length viral genome sequences of SA...Migratory birds are the natural reservoir of influenza A virus (IAV), but their role as a carrier of SARS-CoV-2 remains unclear. Here, we report the identification of three almost full-length viral genome sequences of SARS-CoV-2 variants of concern (VOCs) in Tundra swans. These sequences are named hCoV-19/Tundra swan/Jiangxi/IMCAS_M1/2021 (IMCAS_M1), hCoV-19/Tundra swan/Jiangxi /IMCAS_M2/2021 (IMCAS_M2), and hCoV-19/Tundra swan/Jiangxi/IMCAS_M3/2021 (IMCAS_M3). IMCAS_M1 and IMCAS_M3 have the same mutations as the Beta VOC (K417N, E484K, and N501Y) in the receptor-binding domain (RBD) of the viral spike (S) protein, whereas IMCAS_M2 shares the same mutations as the Gamma VOC (K417T, E484K, and N501Y) in the RBD with all three showing their distinct mutations in the genomes. Virus receptor angiotensin-converting enzyme 2 (ACE2) proteins from both Tundra swan (tsACE2) and Black swan (bsACE2) can bind to the RBDs of all three viruses and the Alpha VOC, but not to RBD of the prototype (PT) virus. The polar contacts and hydrophobic interactions revealed by cryo-electron microscopy (cryo-EM) structures of the RBD-ACE2 complex, play key roles in virus-receptor engagement. Furthermore, HeLa cells expressing bsACE2 and tsACE2 proteins could be transduced by pseudotyped SARS-CoV-2 variants (Alpha, Beta, and Gamma) but not PT SARS-CoV-2. In addition, we obtained one partial genome of MERS-CoV named Bar-headed goose/Tibet/IMCAS_M4/2022 (IMCAS_M4) with 20,180 bp (~70.0% coverage). Our findings highlight the importance of migratory birds as potential carrier of both SARS-CoV-2 and MERS-CoV, thereby posing potential threat to public health.
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372154
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From hunting to financial planning, many decisions are made under risk and alongside social partners whose decisions and outcomes are coupled with our own. Joint decision-making can create challenges, such as navigating...From hunting to financial planning, many decisions are made under risk and alongside social partners whose decisions and outcomes are coupled with our own. Joint decision-making can create challenges, such as navigating conflicting risk preferences, evaluating each other's actions, and deciding whether to compromise. Yet when and why people compromise, how they evaluate each other's responsibilities during joint decision-making, and the computational and psychological underpinnings of these processes remain unclear. We introduce a dyadic foraging paradigm designed to capture diverse risk preferences, where two participants jointly choose between locations that yield rewards but carry risks and evaluate each other's responsibility for shared outcomes. Across two studies (exploratory N = 250, confirmatory N = 514), people tended to compromise rather than counteract their partner, especially under diverging risk preferences and when compromise was reciprocated. Computationally, compromise was explained by a reinforcement learning model showing that individuals integrate their preferences with that of their partner. Responsibility attributions exhibited egocentric biases-with participants claiming more credit for wins than blame for losses-and these biases were associated with individual differences in compromise behavior. The interplay between individual differences in risk and responsibility attribution further shaped coordination patterns. Finally, we show that compromising improved performance for risk-averse individuals, increased desirability as a social partner, and led to more favorable responsibility attributions, suggesting multiple benefits of compromising. By linking decisions about risk-reward trade-offs to metacognitive judgments about responsibility, our study reveals the social and cognitive processes underlying compromise in risky foraging and, more broadly, in collaborative contexts with conflicting preferences.
Dong Y, Rahaman SM, Zhu W
… +10 more, Inutsuka A, Ono D, Tanaka R, Matsuzaki T, Shibata E, Isobe M, Izawa S, Yamanaka A, Yamada K, Mizoguchi H
Proc Natl Acad Sci U S A
· 2026 Jul · PMID 42372152
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Orexin neurons regulate physiological functions, such as energy homeostasis, wakefulness, and motivated behaviors. However, studies linking orexin neuron activity to behavior via selectively activating/inactivating these...Orexin neurons regulate physiological functions, such as energy homeostasis, wakefulness, and motivated behaviors. However, studies linking orexin neuron activity to behavior via selectively activating/inactivating these inputs in a temporally controlled manner in rats are scarce. Here, we examined the role that orexin neurons play in motivated behavior in transgenic rats using cell type-specific fiber photometry and optogenetic manipulation. Using chemogenetics, we found that motivation for a reward increased when orexin neurons were activated. Furthermore, during motivated behavior, orexin neuron activity changed dynamically: Activity increased during reward prediction and decreased after reward receipt. When an unexpected event occurred (i.e., not obtaining an expected reward), increased orexin activity was sustained. Notably, orexin activity strengthened with increasing effort. Optogenetic inhibition of orexin neuron activation during reward prediction and treatment with an orexin 1-receptor antagonist reduced reward-seeking behavior. Therefore, orexin is crucial for linking predicted expectations with motivated behavior. Moreover, optimization of orexin activity is necessary to overcome difficulties during motivated behaviors.