Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceCommercial whaling devastated bowhead whale populations, and recovery has been slow and spatially heterogeneous. By reconstructing daily routes and hunting activities of more than 700 historic British and American whaling voyages, we mapped ...
Science Journals
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceTrophic interactions underpin ecosystem structure and function, yet how past species losses, evolutionary histories, and environmental variability shape macroecological patterns of food webs remains poorly understood. We present continental-...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceDespite the widely accepted hypothesis that infectious disease drives HLA diversity, specific examples are rare. We show, in an antenatal cohort in KwaZulu-Natal, South Africa, that maternal HLA-B genotype significantly impacts HIV-1 survival ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceThe differences between modern human and Neanderthal brains, as estimated from endocranial reconstructions, do not meaningfully exceed those among different modern human populations. Additionally, because cognitive ability is only very weakly ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificanceEarth experienced extreme climate swings during the Neoproterozoic epoch, including the Sturtian glaciation, when ice likely covered the planet. Explaining aspects of the geologic record and the survival of life through this event has been a ...
Proceedings of the National Academy of Sciences, Volume 123, Issue 19, May 2026. SignificancePrevious genetic studies indicate that bread wheat (Triticum aestivum L) originated approximately 8,000 y ago, with the distribution of its wild progenitor, goatgrass (Aegilops tauschii Coss.) suggesting that the South Caucasus or southwestern ...
Apparent neural encoding of future words may arise from the statistical structure of language itself, rather than from predictive computations in the brain.
Voltage-gated K<sup>+</sup> channels play central roles in human physiology, in health, and disease. A repertoire of inhibitors that are both potent and specific would, therefore, be of great value. RY785 has been described as promising in this regard, as it selectively inhibits channels in the Kv2 subfamily with high potency. Its mechanism of action has not yet been determined at the molecular level, but functional studies indicate it differs from those of less specific inhibitors, such as quaternary-ammonium compounds or aminopyridines. To examine this mechanism at the single-molecule level, we have carried out a series of all-atom molecular dynamics simulations based on the structure of the Kv2.1 channel in the ion-conducting state. The simulations demonstrate both RY785 and tetraethylammonium spontaneously enter the channel interior through the cytoplasmic gate, but with distinct effects. Tetraethylammonium binds to a site adjacent to the selectivity filter, on the pore axis, thus blocking the flow of K<sup>+</sup> ions. RY785, by contrast, binds to the channel walls, off-axis, and allows K<sup>+</sup> flow while the gate remains open. This observation indicates RY785 inhibits Kv2.1 by fostering the occlusion of the gate, through a network of hydrophobic interactions therein, explaining why it also modulates the voltage-sensing mechanism of the channel, 3 nanometers away.
The qualities of antibody (Ab) responses provided by B lymphocytes and their plasma cell (PC) descendants are crucial facets of responses to vaccines and microbes. Metabolic processes and products regulate aspects of B cell proliferation and differentiation into germinal center (GC) and PC states along with Ab diversification. However, there is little information about lymphoid-cell-intrinsic functions of enzymes that mediate ether lipid biosynthesis. Imaging mass spectrometry (IMS) results had indicated that concentrations of a number of these phospholipids were substantially enhanced in GC compared to the background average in spleens, but it was unclear if biosynthesis in B cells was a basis for this finding, or whether cell-intrinsic biosynthesis contributes to B cell physiology or Ab responses. Ether lipid biosynthesis can involve the enzyme PexRAP, encoded by the <i>Dhrs7b</i> gene. Using IMS and immunization experiments in mouse models with inducible <i>Dhrs7b</i> loss of function, we now show that B-lineage-intrinsic expression of PexRAP promotes the magnitude and affinity maturation of a serological response. Moreover, the data revealed a <i>Dhrs7b</i>-dependent increase in ether phospholipids in primary follicles with a more prominent increase in GC. Mechanistically, PexRAP impacted B cell proliferation via enhanced survival associated with controlling levels of ROS and membrane peroxidation. These findings reveal a vital role of this peroxisomal enzyme in B cell homeostasis and the physiology of humoral immunity.
During mouse development, hematopoietic stem and progenitor cells (HSPCs) originate from hemogenic endothelial cells (ECs) through a process of endothelial-to-hematopoietic transition. These HSPCs are thought to fully sustain adult hematopoiesis. However, it remains unknown whether adult ECs retain hemogenic potential. Here, we used in vivo genetic lineage tracking at population and single-cell (sc) levels, scRNA sequencing, and bone marrow (BM) transplantation to detect hemogenic ECs in adult mice. We identify and characterize BM-resident, adult <i>Cdh5</i>/VE-Cadherin<sup>+</sup> ECs that produce hematopoietic cell-progeny in vitro and in mice. These adult hemogenic ECs and their hematopoietic cell progeny give rise to hematopoietic cells following adoptive transfer into adult mice. Furthermore, blood cells generated from adult and developmental ECs comparably home to peripheral tissues, where they similarly contribute to inflammatory responses. Thus, our results identify previously unrecognized BM-derived adult hemogenic ECs that generate HSPC and functional mature blood cells.
Sensory neurons drive animal behaviors by detecting environmental stimuli and relaying information to downstream circuits. Beyond their primary roles in sensing, these neurons often form additional synaptic connections outside their main sensory modality, suggesting broader contributions to behavior modulation. Here, we uncover an unexpected role for the thermosensory neuron AFD in coupling tactile experience to locomotion modulation in <i>Caenorhabditis elegans</i>. We show that while AFD employs cyclic guanosine monophosphate (cGMP) signaling for both thermotaxis and tactile-dependent modulation, the specific molecular components of the cGMP pathway differ between these two processes. Interestingly, disrupting the dendritic sensory apparatus of AFD, which is essential for thermotaxis, does not impair tactile-based locomotion modulation, indicating that AFD can mediate tactile-dependent behavior independently of its thermosensory apparatus. In contrast, ablating the AFD neuron eliminates tactile-dependent modulation, pointing to an essential role for AFD itself, rather than its sensory dendritic endings. Further, we find tactile-dependent modulation requires the AIB interneuron, which connects AFD to touch circuits via electrical synapses. Removing innexins expressed in AFD and AIB abolishes this modulation, while re-establishing AFD–AIB connections with engineered electrical synapses restores it. Collectively, these findings uncover a previously unrecognized function of AFD beyond thermosensation, highlighting its influence on context-dependent neuroplasticity and behavioral modulation through broader circuit connectivity.
New England Journal of Medicine, Ahead of Print.
<p>by Cheol Soh, Mario Hervault, Nathan H. Chalkley, Kien Huynh, Qiang Zhang, Ergun Y. Uc, Jeremy D. W. Greenlee, Jan R. Wessel</p>
Response inhibition is an important cognitive control mechanism that enables flexible behavior by stopping inappropriate actions. Intracranial recordings across species have identified a neural circuit that implements response inhibition via the subthalamic nucleus of the basal ganglia. However, this work has been limited to simple tasks, in which unequivocal, salient “stop”-signals require the inhibition of all ongoing responses. Notably, response inhibition in the real world is substantially different. Real-world response inhibition is selective: it occurs only after specific salient signals (‘stimulus-selectivity’) and stops only specific movements while others continue (‘response-selectivity’). If and how the fronto-subthalamic system implements selective inhibition is largely unknown. Here, we recorded subthalamic local field potentials and scalp-EEG in humans performing a novel, selective inhibition task. Salient signals either required stopping all initiated responses (global inhibition), stopping only some responses (response-selective inhibition), or continuing all responses—i.e., ignoring the signal (which ensures stimulus-selectivity). All three signals initially triggered a common fronto-subthalamic inhibitory process, signified by a rapid increase in β-burst activity. During global inhibition, subthalamic β-bursting subsequently increased above baseline, persisting for over a second. During response-selective inhibition, this activity was delayed, which enabled a second bout of disinhibition and allowed appropriate responses to continue. Throughout this period, frontal cortical and subthalamic β-band activity were tightly coupled. This shows that selective inhibition is accompanied by rapid, context-dependent engagement and release of fronto-subthalamic inhibition. Moreover, subthalamic activity lasted substantially lon…
<p>by Jillian P. Lewis, Spencer V. Nyholm</p>
Eggs released in the environment are at risk from many threats. A recent study in PLOS Biology reveals that plastid-derived carotenoid crystals in sea urchin eggs benefit larval survival and trans-oceanic dispersal.
Eggs released in the environment are at risk from many threats. This Primer discusses how plastid-like carotenoid crystals benefit larval survival and trans-oceanic dispersal in sea urchin eggs.
<p>by Giorgia Greter, Sebastian Hummel, Daria Künzli, Naomi Dünki, Niina Ruoho, Patricia Burkhardt, Suwannee Ganguillet, Milad Radiom, Claudia Moresi, Leanid Laganenka, Wolf-Dietrich Hardt, Steffen Geisel, Julien Bauland, Sebastian Jordi, Benjamin Misselwitz, Bahtiyar Yilmaz, Jonasz Słomka, Eleonora Secchi, Roman Stocker, Emma Slack, Markus Arnoldini</p>
Spatial structure can functionally determine ecological interactions and evolution of microbial communities. The gut microbiota is known to be spatially structured longitudinally along the gastrointestinal tract, but micro-scale structure in the gut lumen has not been extensively explored. Here, we show that bacteria cluster within species in the cecum of gnotobiotic mice. We find that clustering is not driven by active swimming, antibody-mediated aggregation, or factors exclusive to the host, but likely due to bacterial growth in the matrix of gut content. In samples from mice and humans, we show that upper large-intestinal content behaves as a nonNewtonian fluid that changes its viscoelastic properties under the force of gut contractions. We argue that microbial growth in the gel-like structure of cecum content can lead to micro-scale bacterial clustering, which is periodically disrupted by peristalsis-driven shear thinning and clearance. Our study shows mechanistically how spatial structure in the gut emerges through the interplay between microbial and host physiology and highlights the possibility of host control over gut microbiota distribution through gut contractions.
New England Journal of Medicine, Ahead of Print.
Acquisition of essential nutrients through diet is crucial for the survival of animals. Dietary odors might enable animals to forage for nutrient-rich diets. We asked if <i>Caenorhabditis elegans</i>, a bacterivorous nematode, uses olfactory cues to forage for essential amino acid-rich (EAA) diets. Using the native microbiota of <i>C. elegans,</i> we show that worms rely on olfaction to select leucine (EAA)-supplemented bacteria. Using gas chromatography, we find that leucine-supplemented bacteria produce isoamyl alcohol (IAA) odor in the highest abundance. Prior adaptation of worms to IAA diminishes the diet preference of worms. Several wild isolates of <i>C. elegans</i> display robust responses to IAA, emphasizing its ecological relevance. We find that foraging for a leucine-supplemented diet is mediated via the AWC olfactory neurons. Finally, we identify SNIF-1 G protein-coupled receptor in AWC neurons as a receptor for IAA and a mediator of dietary decisions in worms. Our study identifies a receptor-ligand module underpinning foraging behavior in <i>C. elegans</i>.
Vestibular hair cells (HCs) convert gravitational and head motion cues into neural signals through mechanotransduction, mediated by the hair bundle—a mechanically integrated organelle composed of stereocilia and a kinocilium. The kinocilium, a specialized form of primary cilium, remains incompletely defined in structure, molecular composition, and function. To elucidate its characteristics, we conducted single-cell RNA sequencing of adult vestibular and cochlear HCs, uncovering a selective enrichment of primary and motile cilia-associated genes in vestibular HCs, particularly those related to the axonemal repeat complex. This enrichment of orthologous axoneme-related genes was conserved in zebrafish and human vestibular HCs, indicating a shared molecular architecture. Immunostaining validated the expression of key motile cilia markers in vestibular kinocilia. Moreover, live imaging of bullfrog and mouse HCs from crista ampullaris revealed spontaneous kinociliary motion. Together, these findings define the kinocilium as a unique organelle with molecular features of primary and motile cilia and suggest its previously unknown role as an active, force-generating element within the hair bundle.
<p>by Tyler J. Carrier, Andrés Rufino-Navarro, Thorben Knoop, Urska Repnik, Andrés Mauricio Caraballo-Rodríguez, David M. Needham, Corinna Bang, Sören Franzenburg, Marc Bramkamp, Willi Rath, Arne Biastoch, José Carlos Hernández, Ute Hentschel</p>
Development in the sea has long been thought to be a nutritional gamble that disproportionately ends in starvation. Here, we support the premise that components of plastids appear to be incorporated into sea urchin eggs and that these, in turn, benefit development. We find chromoplast-derived carotenoid crystals and chromoplast-specific metabolites inside the eggs of the sea urchin <i>Arbacia lixula</i>. We find evidence of plastid DNA in the eggs of 11 other sea urchins, with diatoms being the primary source and taxonomic richness of these plastid taxa directly related to egg size. The light-dependent activity of these chromoplast components influences phytohormone and lipid metabolism as well as offspring development, morphological plasticity, and survival. Offspring that benefit from these chromoplast components are predicted to disperse further, over larger geographic areas, and use a wider range of currents, including those that cross ocean basins. Data presented here challenge the long-held belief that components of non-metazoan organelles are unable to enter the germline and be passed between generations. We hypothesize that sea urchins manipulate plastids solely for their self-interest with the result of this process being a novel and adaptive form of maternal provisioning.
The process of publishing a research article in a scientific journal inevitably involves revising the original version of the article to respond to the concerns raised by peer reviewers. In this article we describe a course module that introduces MSc students at Utrecht University in the Netherlands to this part of the publication process. During the module the students and an invited speaker actively discuss the revision process for a recent article by the speaker. Feedback from students and speakers on the module – which could be readily transferred to other courses in the life and biomedical sciences – has been largely positive.
<p>by Chun-Jie Liu, Chao Zhang, Wei Feng, Gaoxiang Huang, Xiaopeng Zou, Wenlu Wei, Donghui Zhang</p>
Cilia dysfunction is implicated in a range of disorders. Here, we present CiliaKB, a manually curated knowledge base that serves as a one-stop platform for researchers to rapidly access mechanistic data and mine for translational clues about cilia.
Cilia dysfunction is implicated in a range of disorders. This Community Page presents CiliaKB, a manually curated knowledge base that serves as a one-stop platform for researchers to rapidly access mechanistic data and mine for translational clues about cilia.
<p>by Zhixuan Zhao, Dong-Ping Wang, Xin Zhang, Yuan Gao, Hexin Xu, Xinyu Teng, Cheng Shen, Jirui Chen, Jinru Zhang, Chang-Run Guo, Motoyuki Hattori</p>
P2X receptors are ATP-gated cation channels, and the P2X3 subtype plays crucial roles in peripheral sensory neurons, including in chronic pain and chronic cough. Accordingly, P2X3 receptors have attracted substantial interest as a therapeutic target. Gefapixant, a negative allosteric modulator (NAM) of P2X3 receptors, has been approved in some countries for the treatment of chronic cough; however, its limited selectivity for P2X3 homomers over P2X2/P2X3 heteromers is associated with taste disturbance as a prominent adverse effect. These limitations have motivated the development of next-generation NAMs with improved subtype selectivity, but their subtype-specific allosteric inhibition mechanisms are unclear. Here, we report the cryo-EM structure of the human P2X3 receptor in complex with ATP and the P2X3-selective next-generation NAM sivopixant, an investigational drug. Sivopixant binds to an allosteric site at the portal of the central pocket in the extracellular domain, and structure-based mutational analysis by electrophysiology identifies key residues required for sivopixant-dependent inhibition of human P2X3 receptors. Structural comparisons across P2X subtypes, together with patch-clamp analyses of gain-of-function mutants that confer sensitivity to two investigational drugs, sivopixant and camlipixant, provided a broadly applicable structural framework for subtype selectivity. Furthermore, structural comparisons with apo and ATP-bound open states of P2X3 receptors, together with molecular dynamics simulations, revealed that sivopixant expands the upper-body domain to suppress the lower-body movements required for channel activation, thereby preventing channel opening even in the presence of ATP.
T cells expressing the γδ T cell receptor (TCR) develop in a stepwise process initiating at the αβ/γδ T cell branch point, followed by maturation and acquisition of effector functions, including the ability to produce interleukin-17 (IL-17) as γδT17 cells. Previous studies linked TCR signal strength and fate choices to the transcriptional regulator HEB (<i>Tcf12</i>) and its antagonist, Id3, but how these factors regulate different stages of γδ T cell development has not been determined. We found that immature fetal γδTCR<sup>+</sup> cells from conditional <i>Tcf12</i> knockout (HEB cKO) mice were defective in activating the γδT17 program at an early stage, whereas <i>Id3</i>-deficient (Id3-KO) mice displayed a partial block in γδT17 maturation and a defect in IL-17 production. We also found that HEB cKO mice failed to upregulate <i>Id3</i> during γδT17 development, whereas HEB overexpression elevated the levels of <i>Id3</i> in collaboration with TCR signaling. Moreover, Egr2 and HEB were bound to several of the same regulatory sites on the <i>Id3</i> gene locus in the context of early T cell development. Therefore, our findings reveal an interlinked sequence of events during which HEB and TCR signaling synergize to upregulate <i>Id3</i>, which enables maturation and acquisition of the γδT17 effector program.
Motor skill learning is a complex and gradual process that involves the cortex and basal ganglia, both crucial for the acquisition and long-term retention of skills. The cerebellum, which rapidly learns to adjust the movement, connects to the motor cortex and the striatum primarily via the ventral and intralaminar thalamus, respectively. Here, we evaluated the contribution of cerebellar neurons projecting to these thalamic nuclei in a skilled locomotion task in mice. Using a targeted chemogenetic inhibition that preserves the motor abilities, we found that cerebellar nuclei neurons projecting to the intralaminar thalamus contribute to learning and expression, while cerebellar nuclei neurons projecting to the ventral thalamus contribute to offline consolidation. Asymptotic performance, however, required each type of neurons. Thus, our results show that cerebellar neurons belonging to two parallel cerebello-thalamic pathways play distinct, but complementary, roles functioning on different timescales and both necessary for motor skill learning.
Adipose tissues exhibit a remarkable capacity to expand, regress, and remodel in response to energy status. The cellular mechanisms underlying adipose remodelling are central to metabolic health. Hypertrophic remodelling – characterised by the enlargement of existing adipocytes – is associated with insulin resistance, type 2 diabetes, and cardiovascular disease. In contrast, hyperplastic remodelling – in which new adipocytes are generated – is linked to improved metabolic outcomes. Despite its clinical importance, the regulation of hypertrophic and hyperplastic adipose morphology remains poorly understood. Here, we integrate human transcriptomic data with a quantitative CRISPR-imaging platform in zebrafish to identify regulators of adipose morphology. We developed an image-based phenotyping pipeline that captures lipid droplet size, number, and spatial patterning, and applied generalised additive modelling to quantify hyperplastic versus hypertrophic morphology signatures. Using this platform, we conducted an F0 CRISPR screen targeting 25 candidate genes and identified three that induced hypertrophic morphology (<i>txnipa</i>, <i>mmp14b,</i> and <i>foxp1b</i>) and an additional candidate that altered total adiposity (<i>kazna</i>). For functional validation, we generated stable loss-of-function alleles for both zebrafish foxp1 paralogues. Spatial analysis along the anterior-posterior axis revealed that <i>foxp1b</i> mutants display developmental hypertrophy but profoundly blunted adaptive responses to high-fat diet (~68% reduction across all spatial zones), while <i>foxp1a</i> mutants show normal baseline morphology but disrupted spatial patterning of diet-induced hypertrophy. Together, these findings establish a scalable CRISPR-imaging platform for in vivo genetic screening of adipose morphology and reveal distinct roles for Foxp1 paralogues in developmental patterning and adaptive responses to dietary challenge in adipose tissue.