Science Journals

<p>by Yan Xu, Wenbo Zeng, Guodian Xiong, Zhenhua Zheng, Jingwen Wang</p> Ticks transmit numerous viruses that pose significant threats to human and animal health, however, the molecular interactions between ticks and viruses remain poorly understood. Using Langat virus (LGTV)—a surrogate for tick-borne encephalitis virus (TBEV), we show that the JAK/STAT pathway promotes viral infection in <i>Haemaphysalis longicornis</i>. Rather than directly interacting with viral proteins, this proviral effect is mediated by a low-density lipoprotein receptor-related protein (LRP), whose expression is regulated by STAT. Silencing <i>LRP</i> in <i>H. longicornis</i> reduced LGTV infection, while ectopic expression of <i>LRP</i> enhanced it. Unlike its mammalian counterparts, <i>H. longicornis</i> LRP lacks a transmembrane domain and localizes intracellularly. Functionally, LRP promotes lipophagy, leading to lipid droplets breakdown and providing energy to support viral replication. Together, these findings reveal a non-canonical mechanism by which the JAK/STAT pathway facilitates LGTV replication through STAT-dependent regulation of an atypical, intracellular LRP that drives lipophagy.

<p>by Paul Knabl, June F. Ordoñez, Juan Daniel Montenegro Cabrera, Daniel Abed-Navandi, Roland Halbauer, Oliver Link, Tim Wollesen, Grigory Genikhovich</p> In Bilateria with centralized nervous systems (e.g., in vertebrates or arthropods), the minimum of the BMP signaling activity gradient defines the position of the central nervous system. BMP-dependent patterning of the secondary body axis is ancestral for Bilateria and possibly also for the bilaterian sister clade Cnidaria. However, the variety of levels of centralization of the nervous systems in Bilateria—from diffuse to fully centralized—as well as the lack of centralization of the nervous system in Cnidaria, suggest that BMP signaling cannot be perceived as a universally “anti-neural” signal. Here we use transgenic reporter lines in the anthozoan cnidarian <i>Nematostella</i> to show that BMP signaling is active in distinct neuronal populations. Moreover, attenuation of BMP signaling followed by RNA-Seq shows that BMP signaling is a positive regulator of many neuronal genes, including the top-tier neural progenitor marker <i>soxB(2)</i>. Furthermore, we analyze BMP signaling activity in the cubozoan jellyfish <i>Tripedalia</i> and the scyphozoan jellyfish <i>Stomolophus</i> and prove that BMP signaling in parts of the diffuse nervous system is not an anthozoan but an ancestral cnidarian feature, shared by anthozoans and medusozoans. Finally, we show that the highly centralized ventral nervous system of the nonmodel spiralian, the chaetognath <i>Spadella</i>, forms out of paired BMP signaling-positive domains on the lateral sides of the embryo. Together, our data suggest that one of the ancestral roles of BMP signaling may have been in promoting neurogenesis. We propose that the “anti-neural” function of BMP signaling in vertebrates and arthropods is a consequence of its global role in the dorsoventral patterning of the ectoderm.

<p>by Katlyn Todd, Olivia Schneider, Joshua M. Lawrence, Josefina L. Aronoff, Bartosz Witek, Valerie Velázquez-Colón, Verónica Santana-Ufret, Nicole L. Anderson, Krista Gunter, Moraima Noda, Ryan F. Relich, Lifan Zeng, Dominique H. Limoli, Christopher Whidbey, Jay Vornhagen</p> <i>Pseudomonas aeruginosa</i> and <i>Klebsiella pneumoniae</i> are gram-negative opportunistic pathogens that frequently colonize the human body and are major causes of infection. These bacteria are often co-isolated in polymicrobial urinary tract and lung infections, the latter of which is associated with increased disease severity and worse clinical outcomes. Despite their overlapping niches and clinical relevance, little is known about how these two pathogens interact and how those interactions influence human health. Given the growing recognition that microbial interactions are key drivers of disease, we investigated how <i>P. aeruginosa</i> and <i>K. pneumoniae</i> influence one another. We discovered an antagonistic interaction in which <i>P. aeruginosa</i> restricts the growth of <i>K. pneumoniae</i>. This inhibition is driven by phenazine production in <i>P. aeruginosa</i>, specifically the secondary metabolites pyocyanin and pyorubin, which are both necessary and sufficient to suppress <i>K. pneumoniae</i> growth. Using a diverse set of clinical isolates, we found that this antagonism is strain-dependent. Both the susceptibility of <i>K. pneumoniae</i> to phenazines and the ability of <i>P. aeruginosa</i> to restrict <i>K. pneumoniae</i> growth varies between strains. Moreover, the necessity of phenazine production is specific to the site of infection. Together, these findings demonstrate that strain background and environmental context are critical determinants of pathogen interactions. These findings reveal that both strain background and environmental redox conditions govern the ecological rules of pathogen interaction, providing a framework for predicting outcomes.

<p>by Hangyu Liao, Jun Yang, Lei Cai, Luhao Chi, Chunming Wang, Yuyan Xu, Juncheng Xie, Kunling Chen, Jingyuan Pei, Zesheng Jiang, Mingxin Pan, Liang Zhao</p> Crosstalk between hepatocellular carcinoma (HCC) and the tumor microenvironment (TME) is pivotal for the initiation and management of HCC. The infiltration and function of natural killer (NK) cells in the TME are frequently hindered. However, it is unclear whether a crucial regulatory factor originating from HCC cells directly modulates NK cell activity to evade immune surveillance. In this study, we found that mannose-binding lectin 2 (MBL2) expression was markedly decreased in HCC and positively correlated with HCC prognosis. MBL2 inhibited the proliferation and migration of HCC cells intracellularly. Human and murine co-culture systems of HCC and NK cells were established to demonstrate that secreted MBL2 recruited and activated NK cells in the TME, particularly upregulating the infiltration of NKp46⁺ NK cells. Furthermore, secreted MBL2 promoted the production of IL-13 and IL-25 by NK cells, resulting in a decrease in exhausted cytotoxic T lymphocytes. Mechanistically, MBL2 interacts with the integrin β1 receptor, activating the FAK/AKT pathway and increasing PD-L1 expression on NK cells. Our discovery identifies MBL2 as an NK cell–activating cytokine, initiating the integrin β1/FAK/AKT pathway in NK cells and reshaping an immune-activated microenvironment of HCC. Strategies to up-regulate MBL2 may enhance the anti-PD-L1 immunotherapy efficacy and serve as a potential therapeutic approach for HCC.

<p>by Alejandro Vasquez-Rifo, Denis Susorov, Emily H. Sholi, Gabriel Demo, Yasaman Jami, Jihui Sha, James A. Wohlschlegel, Andrei Korostelev, Victor Ambros</p> <i>Pseudomonas aeruginosa</i> employs host translation inhibition as a virulence-enhancing strategy. We previously showed that the bacterium induces cleavage of <i>Caenorhabditis elegans</i> large ribosomal RNA at helix 69 (H69), part of a central intersubunit bridge and the ribosomal decoding center. In this study, we demonstrate that a previously uncharacterized ribonuclease, Ribocin, is necessary and sufficient for H69 cleavage. Recombinant Ribocin cuts H69 in worm and mammalian ribosomes, indicating that H69 cleavage by <i>P. aeruginosa</i> is phylogenetically conserved. In worms, mammalian cells, and rabbit reticulocyte lysates, H69 cleavage results in translation inhibition. Furthermore, Ribocin contributes to bacterial virulence toward <i>C. elegans</i>, triggers a major host response to translation inhibition, and operates in parallel with Exotoxin A-mediated translation inhibition. These findings unveil the first known nuclease that cleaves eukaryotic ribosomes at H69 and expand the understanding of host translation-inhibition by establishing targeted rRNA cleavage as a mechanism of host attack.

<p>by Fuchun Zhou, Sivakumar Periasamy, Nathaniel D. Jackson, Wan Sze Cheng, Ruben Soto Acosta, Aarti Tripathi, Kritika Kedarinath, Philipp A. Ilinykh, Chengjin Ye, Shailendra Chauhan, German Nudelman, Elena Zaslavsky, Haiping Hao, Steven G. Widen, Luis Martinez-Sobrido, Stuart C. Sealfon, Alexander Bukreyev</p> Several SARS-CoV-2 proteins have been shown to counteract the host innate immune response, mostly using in vitro protein expression, which may not fully reflect their role in the context of viral infection. In addition, while each viral protein was characterized in a different experimental system, its relative contribution to immunosuppression remains unclear. Here we used a SARS-CoV-2 bacterial artificial chromosome with <i>en passant</i> mutagenesis to recover a panel of 12 infectious recombinant SARS-CoV-2 viruses, each with mutations in either NSP1, NSP2, NSP3, NSP6, NSP12, NSP13, NSP14, NSP15, NSP16, ORF3a, ORF6, or ORF8. We used the interferon-stimulated response element (ISRE)-driven luciferase assay in 293T-ACE2/TMPRSS2 cells to test the panel, demonstrating that mutations in many proteins, especially in NSP1 and NSP15, increased the type I interferon response relative to the parental wild-type virus. RNA-seq analysis of mutant-virus infected Calu-3 cells showed that the mutations in NSP1 or NSP15 lead to higher expression of multiple genes involved in innate immune response, cytokine-mediated signaling, and regulation of lymphocyte proliferation. Furthermore, mutations in either NSP1 or NSP15 resulted in a greater maturation of human monocyte-derived dendritic cells in vitro. Infection of K18 hACE2 transgenic mice with either NSP1 or NSP15 mutated viruses demonstrated attenuated respiratory tract replication. Analysis of lung immune cells from infected mice by single-cell RNA-seq identified 15 populations of major myeloid and lymphoid cells with changes in the pattern of their activation associated with viral infection. The effects of mutations …

<p>by Siqi Liu, Flávio Silva Costa, Dario Riccardo Valenzano</p> Host-associated microbiomes are compositionally stable across most of the life span, yet undergo consistent and marked deterioration during aging, a phenomenon linked to metabolic dysfunction and disease. What drives this late-life collapse remains poorly understood, in part because the mechanisms by which hosts actively construct and maintain the microbial niche during adulthood remain incompletely characterized. This Unsolved Mystery integrates evidence from immunology and ecosystem ecology to investigate the role of immunosenescence in age-associated dysbiosis, raising the possibility of interventions that restore immune surveillance capacity alongside ecologically informed microbiome management, rather than targeting community composition in isolation.

<p>by Anthony M. Bonacolta, Tristan Kravitz, Rocío Mozo, Lydia J. Baker, Rachael M. Heuer, Martin Grosell, Javier del Campo</p> Marine fish play a significant yet understudied role in the oceanic carbon cycle through the production of magnesium-rich calcium carbonate (CaCO₃) precipitates known as ichthyocarbonates. These deposits form in the gut of marine teleost fish in response to salinity, serving as part of their osmoregulation strategy. Through this, marine fish may contribute as much as 9.04 Pg of CaCO₃ per year in global new carbonate production, being equivalent to or potentially higher than the production by coccolithophores and pelagic foraminifera. Despite their ecological relevance, the biological mechanisms driving ichthyocarbonate precipitation remain to be fully resolved. Intriguingly, bacteria are consistently found in intimate association with ichthyocarbonate precipitates. Given the widespread capacity of prokaryotes to mediate CaCO₃ precipitation, this association points to a previously unexplored microbial contribution to the process. To investigate the potential role of bacteria in ichthyocarbonate production, we subjected Gulf toadfish (<i>Opsanus beta</i>) to salinity treatments common to their native range and known to elicit changes in CaCO₃ precipitation. To assess the respective contributions of the host and its microbiota to ichthyocarbonate formation in the gut, we characterized the microbiome across the toadfish gut and performed meta-transcriptomic analysis. Across the toadfish gut, we identify a high abundance of vibrios associated with ichthyocarbonates with the metabolic potential for CaCO₃ precipitation. Specifically, we observe the expression of the transcriptional activator of urease (<i>ureR</i>) by <i>Photobacterium damselae</i> subsp<i>. damselae,</i> which can induce the precipitation of CaCO₃ via the production of bicarbonate. We demonstrate that CaCO₃ precipitation …

<p>by Richard X. Zhou, Matthew K. Higgins</p> The scavenger receptor CD163 detoxifies free hemoglobin released on erythrocyte lysis to prevent oxidative damage. The best understood route for hemoglobin detoxification involves the formation of haptoglobin-hemoglobin complexes that bind CD163 and are internalized into macrophages, resulting in hemoglobin degradation. However, during conditions such as sickle cell anemia or malaria, haptoglobin is depleted. CD163 can then act as a lower-affinity receptor for free hemoglobin. Previous studies revealed that CD163 forms a multimeric "base," which presents "arms" that form a binding site for haptoglobin-hemoglobin. In this study, we use cryogenic electron microscopy to reveal how human CD163 binds hemoglobin tetramers in a process that, unlike haptoglobin-hemoglobin uptake, requires a full trimeric CD163 assembly to achieve sufficient binding. We reveal how flexibility at the calcium-mediated base, combined with a hinge between receptor domains 2 and 3, allows the arms to wrap around diverse ligands. This brings together multiple small binding surfaces from different domains to form cradles for different ligands. These adaptations allow the scavenger receptor to be promiscuous, protecting us from oxidative damage caused by hemoglobin release in various pathological conditions.

<p>by Omer Revah, Fred Wolf, Michael J. Gutnick, Andreas Neef</p> Sixty years after the concept of population coding in neuronal networks was introduced, we still lack a comprehensive understanding of its performance limits and the role of neuronal physiology. Here, we use dynamic gain analysis in a general model of population coding and demonstrate that disparate parameters of neurons and populations determine how accurately they can encode information. These are cell number, cell size, and the correlation time of the background noise. We experimentally test and confirm these predictions on neurons of excitatory populations in the mouse barrel cortex. Surprisingly, dendrite size and background correlations are precisely matched with the number of neurons in layer 4, such that even a single thalamocortical spike at the input is reliably reflected in the population output. However, this encoding performance can be modulated by the channels that mediate M-current, suggesting that coding in layer 4 may vary as a function of brain state.

<p>by Karin Modig, Marcus Ebeling</p> A common misconception is that increasing longevity reflects slower aging. Instead, most longevity gain comes from medical advances that allow survival with disease, rather than changes to the biology of aging itself, challenging how we study aging and health. Modern medicine has transformed not only how long we live, but also how we age, with more people surviving to old age with chronic disease. This Perspective examines how aging, health, and care should be redefined to reflect these increasingly complex later lives.

<p>by Jiaqi Zhang, Licong Huang, Shuhui Wang, Jingwen Ding, Yuping Yang, Chenhui Li, Ping Zhao, Qian Li, Fei Yan</p> Photothermal therapy (PTT) serves as a complementary strategy to conventional cancer treatments. Indocyanine green (ICG) is the only U.S. Food and Drug Administration (FDA)-approved photothermal agent. However, its clinical application is hindered by poor stability, short blood half-life, and lack of tumor targeting. Herein, we developed biosynthetic gas vesicles (GVs) covalently conjugated with ICG (ICG-GVs) for remotely controlled, visibly acoustic delivery of ICG to tumors in a subcutaneous xenograft model of MB49 murine bladder cancer in C57BL/6 mice. The resulting ICG-GVs exhibit uniform morphology (~200 nm) with an ICG loading rate of 58%, good colloidal stability, and enable trimodal imaging (ultrasound, near-infrared fluorescence, and photoacoustic) for real-time visualization of delivery. Pharmacokinetic analysis revealed that ICG-GVs significantly prolong ICG circulation half-life and increase AUC. Ultrasound-triggered GV cavitation enhanced intratumoral ICG delivery, achieving tumor temperatures >60 °C upon laser irradiation, leading to complete tumor regression and prolonged survival without detectable toxicity. This study provides a clinically translatable strategy for precise and effective ICG-based PTT.

<p>by Jeff Boucher, Shihab Shamma, Yves Boubenec</p> Decisions are driven by perception, but also by non-perceptual factors. It remains an open question, however, whether frontal brain regions involved in perceptual decision-making tend to uniquely reflect the perception of an animal, or the final choice of action driven by perceptual and non-perceptual factors. Using functional ultrasound imaging (fUSI), we investigated how the premotor cortex (PMC) in ferrets represents stimuli in a Go/NoGo auditory categorization task, varying the difficulty in order to manipulate the rates of perceptual errors relative to non-perceptual errors. We found that on Easy error trials, where error in perception was less likely, PMC activity was similar to correct answers for the same stimulus category. In contrast, on Difficult error trials, PMC activity more closely reflected the choice the animal made, being similar to correct answers for the opposite category. These results together are consistent with PMC activity reflecting the reward-predictive perceptual category. Perceptual errors could be refined further by assessing licking patterns, but licking patterns alone did not explain the effect. This study advances our understanding of the functional role of the frontal cortex in decision-making, suggesting that the PMC integrates sensory inputs to guide behavior based on perceptual information, rather than motivational information.

<p>by Jiazheng Quan, Xibao Zhao, Shaoying Chen, Hongrui Li, Wei Chen, Qianqian Di, Xunwei Li, Jiajing Zhao, Han Wu, Jin Chen, Yue Xiao, Zherui Wu, Weilin Chen</p> RIG-I and STING are critical for mediating the RIG-I and cGAS-STING signaling pathways that guard against viral infection. Here, we report that ubiquitin-specific peptidase 39 (USP39) positively regulates the RIG-I and cGAS-STING pathways to induce antiviral innate immunity in vitro and in vivo. The USP39 deficiency impaired the antiviral immune response of macrophages, leading to low type I IFNs expression, and high RNA and (e.g., VSV, H1N1 PR8) DNA virus (e.g., HSV-1) replication<i>.</i> Moreover, USP39-deficient mice were more sensitive to VSV or HSV-1 infection than control mice. Conversely, USP39 overexpression promoted the antiviral immune response. Mechanistically, we found that USP39 regulates RIG-I protein expression by promoting pre-RIG-I mRNA splicing and maturation. In addition, we also revealed that USP39 interacts with and stabilizes STING protein by deubiquitinating K48-linked polyubiquitin of STING at K288. These data show that USP39 positively regulates RNA and DNA-virus-induced RIG-I and cGAS-STING signaling, respectively, by promoting post-transcriptional control of RIG-I and stabilization of STING. These data provide new insights and potential therapeutic targets to control viral infections.

<p>by Clayton Baker, Victor A. Ansere, Cossette I. Sanqui, Bérénice A. Benayoun</p> Aging has effects on the immune system that are similar in men and women, but also reshapes their immune systems in unique, sex-specific ways. These sex-specific patterns of immune aging influence disease susceptibility, vaccine effectiveness, cancer survival, and responses to pharmacological therapies, and have direct implications for preventive medicine and clinical care. However, these differences in susceptibilities and responses are rarely considered in research, clinical trials, or treatment guidelines. By integrating knowledge of sex-specific immune aging with real-world outcomes from vaccines, cancer immunotherapy, and pharmacovigilance studies, this Essay argues that accounting for both sex and age is essential to advance personalized medicine.

<p>by Ying-Jun Dong, Kun Xi, Ya-Zhi Zhang, Jian-Heng Xue, Dan-Dan Shen, Shao-Kun Zang, Ruozhu Zhao, Hai Qi, Chunyou Mao, Wei-Wei Wang, Yan Zhang</p> G protein-coupled receptor 174 (GPR174), a key modulator of autoimmune responses, maintains immune homeostasis through distinct G protein signaling pathways, particularly G_s and G_i. Although the structural mechanism of lysophosphatidylserine (LysoPS)-activated GPR174 in the G_s pathway has been characterized, how hydration-mediated interactions influence GPR174 activation and signaling selectivity remains unclear. Here, we determined high-resolution cryo-electron microscopy (cryo-EM) structures of LysoPS-activated human GPR174 bound to G_s (2.0 Å) and G_i (3.4 Å), revealing a continuous hydration-mediated signal transduction network that bridges the sodium-binding pocket, the NPxxY and DRY motifs, and the G protein-binding interface. This network stabilizes the active-state conformation of GPR174 and dynamically reshapes the intracellular cavity, thereby enabling differential engagement of G_s and G_i. Molecular dynamics simulations and functional assays demonstrated that the hydration network is essential for receptor activation and selectively modulates G protein coupling. To evaluate its conservation, we performed sequence alignments and structural analyses across class A GPCRs, defining three hydration cavities: the conserved water cavity (CWC), the junctional water cavity (JWC), and the extended water cavity (EWC), whose hydration is determined by residue properties at position 5.58. Together, our study reveals a hydration-driven molecular mechanism that underlies the activation of GPR174 and its dual G protein selectivity. These findings advance the understanding of hydration-mediated signaling in GPR174 and provide a framework for investigating water-mediated regulation across class A GPCRs.

<p>by Kaisar Ahmad Lone, Amit Mahendra Karole, Geethanjali Ravindran, Shweta Tyagi</p> Trimethylation of histone 3 lysine 4 (H3K4me3) is a mark of active transcription, and its regulatory role in RNA polymerase II-mediated transcription has been well-studied. However, if and how this mark regulates RNA polymerase I (RNA Pol I) is not known. Here, we used customized genome assemblies for rDNA to demonstrate that KMT2A and KMT2F bind to entire rDNA loci. The binding of these enzymes was mirrored by the binding of H3K4me2 and H3K4me3 marks. Using biochemical assays, we demonstrate the interaction of KMT2-specific subunits with RNA Pol I transcriptional machinery. Our findings reveal KMT2F as the primary KMT depositing the H3K4me3 on rDNA. Loss of H3K4me3 adversely affects the epigenetic landscape and leads to repression of the rDNA locus. Mechanistically, using mammalian cells as a model system, we demonstrate that KMT2F promotes the formation of the pre-initiation complex by RNA Pol I. Our findings highlight the thus far undiscovered role of H3K4me3 in the transcriptional initiation of rDNA genes.

<p>by Rong Bi, Jan Grohn, Patricia L. Lockwood, Miriam C. Klein-Flügge, Lilian Weber</p> Humans show remarkable flexibility in adapting their behaviour to constantly changing environments. This flexibility relies on the ability to regulate motivation in response to changing motivational demands. Typically, the amount of effort required to achieve a certain goal is not precisely signalled by the environment but needs to be learnt from experience. By contrast, prior work examining motivated choices has usually directly instructed effort requirements. It therefore remains unclear how healthy individuals estimate and flexibly regulate effort and how they might achieve this in dynamically changing environments. In the current study, we examine how effort learning is shaped by different types of environmental uncertainty when motivational requirements are not explicitly instructed. Analogous to tasks in the reward learning domain, we designed a novel effort learning task that systematically manipulated two key sources of uncertainty: volatility and noise. Participants were asked to exert effort by squeezing hand-held dynamometers. We characterised effort learning across different stages of the effort production process (e.g., initiation of effort production, effort expectation, error-driven adjustment), which allowed us to capture the dynamics underlying effort estimation and regulation over time. Our findings reveal that humans are able to learn effort requirements by integrating both effort priors and sensorimotor feedback. We further show that effort learning is modulated by environmental statistics, with slower force initiation, weaker priors, slower learning, and faster within-trial force adjustments in high noise environments, but slower learning and slower within-trial force adjustments in high volatility environments. In summary, when effort information is not instructed, different sources of uncertainty about an action’s required effort are integrated into pa…

<p>by Sean P. Heighton, Jérôme Murienne, Mukesh Thakur, Alain Didier Missoup, Wirdateti Wirdateti, Chabi Sylvestre Djagoun, Sery Bi Gonedelé, Gabriel Ngua Ayecaba, Brice Roxan Momboua, Flobert Njiokou, Anne-Lise Chaber, Helen C. Nash, Barbora Černá Bolfíková, Sylvain Dufour, Guy T. Gembu, Ayodeji Olayemi, Jordi Salmona, Amaia Iribar, Yves Cuenot, Philippe Gaubert</p> Pangolins have become emblematic of the global wildlife trade crisis due to intense trafficking for consumption and traditional medicine. Coupled with habitat loss, the illicit trade in pangolins has severely threatened wild populations. Genetic identification of distinct pangolin populations is an imperative step toward guiding effective and informed conservation management. These populations can serve as a reference for assigning seized individuals to their geographic origins, and thus tracing trafficking networks. However, pangolin population genetics studies have been hindered by limited sampling of geo-referenced individuals, largely due to the species’ elusive nature. To address this, we developed a tailored gene-capture approach targeting 671 loci totaling 627 kb with high evolutionary and adaptive value across all eight pangolin species. We optimized the approach for low-quality DNA, including samples from museum collections and wildlife trade, such as bushmeat and scale seizures. We reassessed range-wide population delineations for the three most traded species, the white-bellied (<i>Phataginus tricuspis</i>), Sunda (<i>Manis javanica</i>), and Chinese (<i>M. pentadactyla</i>) pangolins, highlighting the need for biogeographically consistent lineage nomenclature and spatially aware analyses to support coherent conservation planning. The unprecedented geo-referenced DNA database for the three species yielded snapshot insights into pangolin trafficking hotspots and trade dynamics of both domestic markets and global trade seizures, the former providing novel insights into bushmeat trade. Domes…

<p>by The PLOS Biology Staff </p>

<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, CO₂ 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 CO₂ concentrations are less virulent in mouse models of infection, further supporting CO₂ tolerance as a virulence trait. To further understand the genetic determinants of <i>C. neoformans</i> CO₂ tolerance, we performed a near genome-wide screen for deletion mutants with altered CO₂ fitness using a competitive growth assay. A total of 301 of 4,692 deletion mutants showed altered CO₂ tolerance (245 reduced fitness; 56 increased fitness) demonstrating the global effect of host CO₂ 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 CO₂, we show that remodeling of central carbon metabolism, oxidative stress buffering, and membrane homeostasis represent an integrated response to CO₂ stress that is mediated in part by the TOR-Ypk1 signaling axis. We propose that CO₂-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> CO₂ tolerance as well as a model for how this important environmental human fungal pathogen a…

<p>by Xiaojia Zhu, Rui Bi, Haotian Yan, Qiyu Wang, Lin Li, Hongli Li, Long-Bao Lv, Cirong Liu, Yong-Gang Yao</p> The tree shrew (<i>Tupaia belangeri</i>), phylogenetically proximal to primates, serves as a critical model for evolutionary neurobiology and disease mechanisms. High-resolution MRI provides a unique opportunity to refine its neuroanatomical architecture and facilitate cross-species comparisons. Here, we present a comprehensive, ultra-high-resolution (9.4T) MRI atlas of the tree shrew brain, integrating structural and diffusion imaging to resolve fine-scale anatomical features and whole-brain connectivity gradients. Our comparative analysis characterizes the tree shrew as a distinct evolutionary mosaic: the cerebellum exhibits pronounced volumetric expansion and connectivity gradients recapitulating those of primates, whereas the hippocampus retains rodent-like architectural scaling yet preserves evolutionarily conserved longitudinal functional axes. Moving beyond these regional adaptations, we uncovered a universal organizational principle: geometry–gradient coupling (GGC)—the fundamental constraint of brain shape on functional organization. By systematically linking geometric eigenmodes to connectivity gradients across diverse species (from mice to humans), we demonstrate that despite dramatic morphological divergence, the spatial alignment between brain geometry and functional organization remains evolutionarily invariant. Collectively, these results establish the tree shrew as a pivotal phylogenetic bridge and provide a neuroanatomical benchmark for deciphering the interplay between structural diversity and universal biophysical constraints.

<p>by Damian Koevoet, Dirk Van Moorselaar, Edward Awh, Stefan Van der Stigchel</p> Visual selection is often conceptualized as emerging from goal-, stimulus- and history-driven processes within spatial priority maps. Although extensive work detailed the interplay between goal- and stimulus-driven selection, it is largely unknown how goal- and history-driven processes jointly drive selection. While persistent neural firing likely underlies goal-driven selection, it is generally assumed that activity-silent mechanisms effectuate history-driven selection. Due to these different underlying neural mechanisms, simultaneously tracking goal- and history-driven influences neurally has proven difficult. We here employed EEG decoding techniques to simultaneously track and compare goal- and history-driven influences on search. We first established a history-driven signal: Neural decoding closely tracked the target location from the preceding trial. We further demonstrated simultaneous, distinct neural representations of the current and preceding target locations. Strikingly, even when participants attended an upcoming target location before search could commence, prior target locations were reactivated. Our results show that past experiences are reactivated in an inflexible fashion, and do so even when prior targets are completely task-irrelevant. Together, we demonstrate that goal- and history-driven selection are neurally distinct, and reveal that both influences are represented in parallel.