Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceLarge observational datasets are often used in epidemiology or social sciences to identify risk factors associated with health outcomes. However, these studies can be misleading when the putative risk factor and outcome are both complex ...
Science Journals
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceFor democracy to endure, citizens must be willing to reject politicians who threaten to undermine it. Yet, whether citizens will do so in practice remains an open question. An important line of experimental research shows that citizens’ ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceAffective signals profoundly influence movement, yet the mechanisms linking motivationally relevant contexts with motor behavior remain unclear. Combining ultra-high-field (7 T) connectomics with task-based (3 T) neuroimaging, we provide ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceTonotopy maps sound frequency to location along the cochlea, but animal studies show this map shifts with sound level. In humans, level-dependent place shifts have been inferred mainly from masking and pitch measures because intracochlear ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceHow does the brain sustain effortful cognitive activity? Might subcortical valuation regions play a larger role than they are usually given credit for? Using neuroimaging with humans, we show that the amygdala and the nucleus accumbens work ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceThis study suggests that, when viewed broadly, emotional intelligence (EI) has a robust association with human flourishing (e.g., purpose, fulfillment, success in the classroom and at work, mental and physical health). Specifically, EI-...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceDevelopment requires that cells change identity in the correct order while the organism continues to grow. How multicellular animals generate and synchronize this timing information across tissues has remained unclear. We identify a molecular ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceGut bacteria exhibit extensive genetic diversity that influences microbiome function and host health. The evolutionary forces shaping this diversity—homologous recombination and horizontal gene transfer (HGT)—remain poorly understood across ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceRecent cryospheric imbalance across the Asian water towers, threatening water security for over two billion people, reflects the coupled effects of large-scale atmospheric circulation and global warming. Disentangling these effects remains ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceILC2s are essential in mucosal immunity against helminth infections and maintaining metabolic health by producing type 2 cytokines. However, they also contribute to the pathology of allergic inflammation in the lungs, intestines, and skin. ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceHuman immunoglobulin IgA occurs in diverse assemblies, mainly monomers (mIgA) and J-chain coupled dimers (dIgA). The general view is that these forms are produced at different sites, i.e., circulatory and mucosal, with mIgA assumed to ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceCell communication is essential to coordinate cellular functions within living organisms. Our study shows that three-dimensional (3D) cell shapes can directly impact contact-based Notch-Delta signaling to modify signaling range and set SOP ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026.
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026.
Polyphenolic compounds are widely explored for health benefits, including hypertension, but their active ingredients, molecular targets, and mechanisms remain poorly defined. We identify the xanthone Mangostin from <i>Garcinia mangostana</i> as a potent modulator of several potassium channels, with large-conductance K<sup>+</sup> (BK) channels as its primary target for vasorelaxation. Mangostin-activated BK channels as α subunits alone, in complexes with vascular β1 subunits, and in reconstituted BKα/β1–Ca<sub>v</sub> nanodomains. It shifted BK voltage activation to more negative potentials by antagonizing channel closure and promoting channel opening without markedly altering Ca²<sup>+</sup> sensitivity. Docking, competition, single-channel analysis, and mutagenesis localized the binding site in the pore cavity below the SF, involving gating-critical S6 residues I308, L312, and A316, and suggest that Mangostin stays bound in closed and open states. These findings establish BK channel activation as the core molecular mechanism driving Mangostin’s vascular effects and define its structural mode of action, informing nutraceutical safety assessment and BK-targeted drug design.
Organisational gradients refer to a continuous low-dimensional embedding of brain regions and can quantify core organisational principles of complex systems like the human brain. Mapping how these organisational principles are altered or refined across development and phenotypes is essential to understanding the relationship between brain and behaviour. Taking a developmental approach and leveraging longitudinal and cross-sectional data from two multi-modal neuroimaging datasets, spanning the full neurotypical-neurodivergent continuum, we charted the organisational variability of structural (610 participants, N=390 with one observation, N=163 with two observations and N=57 with three) and functional (512 participants, N=340 with one observation, N=128 with two observations and N=44 with three). Across datasets, despite differing phenotypes, we observe highly similar structural and functional gradients. These gradients, or organisational principles, are highly stable across development, with the exact same ordering across early childhood into mid-adolescence. However, there is substantial developmental change in the strength of embedding within those gradients: by modelling developmental trajectories as non-linear splines, we show that structural and functional gradients are refined across development. Specifically, structural gradients gradually contract in low-dimensional space as networks become more integrated, whilst the functional manifold expands, indexing functional specialisation. The coupling of these structural and functional gradients follows a unimodal-association axis and varies across individuals, with developmental effects concentrated in the more plastic higher-order networks. Importantly, these developmental effects on coupling, in these higher-order networks, are attenuated in the neurodivergent sample. Finally, we mapped structure-function coupling onto dimensions of psychopathology and cognition and demonstrate that dimensions of cognition, su…
CRISPR–Cas9 nucleases have transformed genome engineering, yet their application is often constrained by protospacer-adjacent motif (PAM) requirements. <i>Staphylococcus aureus</i> Cas9 (SaCas9) is particularly attractive for in vivo applications due to its compact size; however, its NNGRRT PAM limits targetable genomic sites. Here, we report KRH, a SaCas9 variant designed entirely from the wild-type enzyme through a fully computational point-mutation design workflow, UniDesign, without additional experimental optimization. As expected, KRH efficiently recognizes an expanded NNNRRT PAM and exhibits substantially enhanced editing efficiency at non-canonical PAM sites, with improvements of up to 116-fold over the wild type. KRH achieves genome- and base-editing efficiencies comparable to, or exceeding, those of the well-known evolution-derived KKH variant. Computational modeling by UniDesign provides a mechanistic explanation for the PAM relaxation observed in both KRH and KKH, with structural and energetic analyses revealing that KRH relaxes PAM specificity by fine-tuning the balance between sequence-specific interactions with PAM bases and nonspecific contacts with the DNA backbone. Beyond its practical utility, KRH demonstrates that computational design can identify a minimal set of mutations sufficient to remodel the PAM interface while preserving high nuclease activity. This approach recapitulates—and in some cases surpasses—the performance of evolution-derived variants, offering a scalable strategy for high-throughput Cas9 engineering. Overall, these results establish KRH as a blueprint for rationally engineered, PAM-relaxed nucleases and underscore the power of computational design to accelerate next-generation genome editing.
HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content
It is now recognized that mitochondria play a crucial role in tumorigenesis; however, it has become clear that tumor metabolism varies significantly between cancer types. The failure of recent clinical trials aimed at directly targeting tumor respiration through oxidative phosphorylation inhibitors underscores the critical need for further studies providing an in-depth evaluation of mitochondrial bioenergetics. Accordingly, we comprehensively assessed the bulk tumor and mitochondrial metabolic phenotype in murine HER2-driven mammary cancer tumors and benign mammary tissue. Transcriptomic and proteomic profiling revealed a broad downregulation of mitochondrial genes/proteins in tumors, including OXPHOS subunits comprising Complexes I–IV. Despite reductions in tumor mitochondrial proteins, mitochondrial respiration was several-fold higher compared to benign mammary tissue, which persisted regardless of normalization method (wet weight, total protein content, and when corrected for mitochondrial content). This upregulated respiratory capacity could not be explained by OXPHOS uncoupling, suggesting HER2 signaling regulates intrinsic mitochondrial bioenergetics. In further support, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, attenuated mitochondrial respiration in NF639 murine mammary tumor epithelial cells. Together, this data highlights that the typical correlation between mitochondrial content and respiratory capacity may not apply to all tumor types and implicates HER2-linked activation of mitochondrial respiration supporting tumorigenesis in this model.
Tuberculosis remains a global health crisis due to the resilience of <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), largely attributed to its unique cell envelope. The impermeability and structural complexity of the outer membrane of this envelope, driven by mycolic acids and glycolipids, pose significant challenges for therapeutic intervention. Here, we present the first all-atom models of an <i>Mtb</i> outer membrane using molecular dynamics simulations. We demonstrate that α-mycolic acids adopt extended conformations to stabilize bilayers, with a phase transition near 338 K that underscores their thermal resilience. Lipids in the outer leaflet, such as PDIM and PAT, induce membrane heterogeneity, migrating to the interleaflet space and reducing lipid order. The simulated mycobacterial outer membrane has ordered inner leaflets and disordered outer leaflets, which contrasts with the outer membrane of Gram-negative bacteria. These findings reveal that PDIM- and PAT-driven lipid redistribution, reduced lipid order, and asymmetric fluidity gradients enable <i>Mtb’s</i> outer membrane to resist host-derived stresses and limit antibiotic penetration, thereby promoting bacterial survival. Our work provides a foundational framework for targeting the mycobacterial outer membrane in future drug development.
Continuous flash suppression (CFS), in which a dynamic masker presented to one eye suppresses awareness of a stimulus in the other eye, is widely used to study visual subconsciousness. Although some studies report preserved high-level processing under CFS, these effects have been increasingly questioned and may partly reflect residual low-level feature processing. A key unresolved issue is how strongly neuronal responses in V1, where inputs from the two eyes first converge, are affected by CFS, and how much the remaining signals can support downstream processing. Here, we used two-photon calcium imaging to record large populations of V1 neurons in awake, fixating macaques while presenting grating stimuli under CFS. CFS strongly suppressed V1 orientation responses in an ocular-dominance-dependent manner, nearly abolishing responses in neurons preferring the masker eye or both eyes, and significantly reducing responses in neurons preferring the grating eye. Modeling analyses further indicated that V1 population activity under CFS may still support coarse orientation classification but not accurate stimulus reconstruction. These results suggest that CFS substantially degrades orientation information in V1. The residual signals may support limited low-level processing but are likely insufficient for downstream higher-level visual and cognitive tasks.
<p>by Nomiki Koutsoumpari, Johannes Algermissen, Siti Nurbaya Yaakub, Hanneke EM den Ouden, Nadege Bault, Elsa Fouragnan</p>
Pavlovian biases reflect how evolutionarily hard-wired tendencies—automatic approach toward reward cues and withdrawal from threat cues—can interfere with flexible, goal-directed action. Such biases arise through three mechanisms: (a) anticipated rewards energize action while anticipated punishments suppress it (response bias), (b) agents learn differently from actions than from inactions (learning bias), and (c) reward/punishment cues themselves drive repetitive behavior, independent of outcomes (perseveration bias). The neural origin of these biases is unclear. Past evidence suggests dorsal anterior cingulate cortex (dACC) and anterior insula (aIns) as part of a “reset network” that rapidly responds to salient information and might contribute to these biases. We used transcranial ultrasonic stimulation (TUS) in 29 healthy participants to interfere with neural activity in these regions and test their causal role in a within-subject, counter-balanced design across three sessions (sham, TUS-dACC, TUS-aIns). Computational modeling revealed a functional differentiation of both regions in Pavlovian biases: while TUS to either region did not affect the response bias, TUS to the aIns decreased people’s learning bias, while TUS to dACC increased participants’ perseveration bias. Although the dACC and aIns are part of the same network and often co-activate during decision-making tasks, TUS interference reveals their distinct roles: the dACC mediates cue-dependent persistence while the aIns is critical for inferring whether outcomes are self-caused.
<p>by A. J. Campbell, Meredith Shephard, Abigail P. Paulos, Matthew D. Pauly, Michelle N. Vu, Chloe Stenkamp-Strahm, Kaitlyn Bushfield, Betsy Hunter-Binns, Orlando Sablon, Emily E. Bendall, William J. Fitzimmons, Kayla Brizuela, Grace E. Quirk, Nirmal Kumar, Brian McCluskey, Nishit Shetty, Linsey C. Marr, Jenna J. Guthmiller, Jefferson J. S. Santos, Scott E. Hensley, Edith S. Marshall, Kevin Abernathy, Adam S. Lauring, Blaine T. Melody, Marlene K. Wolfe, Jason Lombard, Seema S. Lakdawala</p>
Transmission routes of highly pathogenic H5N1 between cows or to humans remain unclear due to limited data from affected dairy farms. We performed air, farm wastewater, and milk sampling on 14 H5N1-positive dairy farms across two different California regions. Infectious virus was detected in the air in milking parlors and in wastewater streams, while viral RNA was found in exhaled breath of cows. Sequence analysis of infectious H5N1 virus from air and wastewater samples on one farm revealed viral variants relevant for potential human susceptibility. Longitudinal analysis of milk from the individual quarters of cows revealed a high prevalence of subclinical H5N1-positive cows. Additionally, a heterogeneous distribution of infected quarters that maintained a consistent pattern over time was observed, inconsistent with shared milking equipment serving as the sole transmission mode. The presence of subclinically infected cows was further supported by detection of antibodies in the milk of animals that exhibited no clinical signs during the H5N1 outbreak on one farm. Our data highlight additional sources and potential modes of H5N1 transmission on dairy farms.
<p>by Laura C. Ristow, Emma E. Blackburn, Andrew J. Jezewski, Xiaorong Lin, Damian J. Krysan</p>
<i>Cryptococcus neoformans</i> is an environmental pathogen that remodels its cellular physiology to survive within mammals and, in susceptible hosts, cause life-threatening meningoencephalitis. Of the many distinctions between the external environment and mammalian tissues, CO<sub>2</sub> concentration in the host is two orders of magnitude higher than in the environment and represents a critical stress for <i>C. neoformans</i>. <i>C. neoformans</i> strains that do not replicate at host CO<sub>2</sub> concentrations are less virulent in mouse models of infection, further supporting CO<sub>2</sub> tolerance as a virulence trait. To further understand the genetic determinants of <i>C. neoformans</i> CO<sub>2</sub> tolerance, we performed a near genome-wide screen for deletion mutants with altered CO<sub>2</sub> fitness using a competitive growth assay. A total of 301 of 4,692 deletion mutants showed altered CO<sub>2</sub> tolerance (245 reduced fitness; 56 increased fitness) demonstrating the global effect of host CO<sub>2</sub> on <i>C. neoformans</i> physiology. Based on this data set as well as a metabolomic analysis of <i>C. neoformans</i> adaptation to host CO<sub>2</sub>, we show that remodeling of central carbon metabolism, oxidative stress buffering, and membrane homeostasis represent an integrated response to CO<sub>2</sub> stress that is mediated in part by the TOR-Ypk1 signaling axis. We propose that CO<sub>2</sub>-induced capsule formation leads to reduced cellular glucose which, in turn, triggers remodeling of central carbon metabolism toward utilization of alternative carbon sources and increased mitochondrial respiration/reactive oxygen generation. Thus, these data provide a near genome-wide profile of the genetic determinants <i>of C. neoformans</i> CO<sub>2</sub> tolerance as well as a model for how this important environmental human fungal pathogen a…
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceThis study advances theories of violence by bridging sociology and social psychology to show how social cognitions shaped by past violence exposure persist and influence behavior in new contexts. By identifying specific social cognitions ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceMicrohomology-mediated tandem duplications (MTDs) are a conserved mechanism driving genomic variation across species. MTDs evolve primarily under neutral dynamics, with purifying selection preferentially depleting them from coding regions. The ...