Communications Biology最新文献

The ability to move within a given environment necessitates constant regulation of sensory and motor functions. However, intricacies of sensory-motor integration via intercortical signal correlation remain to be fully elucidated. In this study, we dissociated internally driven cortical dominance from original signals by removing the influence of behavior variables during locomotion on motorized treadmill, wheel, and disk. There were no significant differences in either original or internally driven activity across the cortex of mice during walking based on the type of track. However, the spatial pattern of internally driven cortical connectivity depended on the track type. Especially, internally driven functional connectivity during sustained locomotion on the treadmill significantly decreased only in the medial M2 regions. Thus, the maintenance of stable locomotion on a linear runway is indicative of successful internal sensory-motor integration, which is achieved through inhibitory control of M2. Our findings demonstrate that the spatial patterns of cortical functional connectivity during locomotion are altered by the gait kinematics following physical rotation of the track. Furthermore, we suggest that understanding of health and disorder related to locomotion in environmental contexts requires the consideration of internally driven activity and functional connectivity across the widefield cortex.

Potyviruses are the largest group of plant positive-sense single-stranded RNA viruses and represent a major economic burden worldwide. Their coat protein (CP) forms a filamentous, flexible capsid around the genomic RNA. However, information is still lacking on the mechanisms of virion assembly, disassembly and stability, which is central to understanding virus biology and control. Here, we investigate the role of CP in these processes using structural, biochemical and biophysical studies of five potyviral CPs from three phylogenetic clades combined with bioinformatics and in planta experiments. Our results suggest that, while potyviruses have a conserved virion structure, the amino acids forming the CP-CP and CP-RNA interactions leading to this structure are species-specific. We show that the species-specific CP sequence also determines the architecture of RNA-free virus-like particles (VLPs) and the degree of their structural polymorphism. We identify the residues that determine this specificity at distinct S1-S4 interaction sites. In contrast, a highly conserved charged amino acid triad at the CP-CP interface is essential for the stability of virions and RNA-free VLPs. These results contribute to understanding the molecular mechanism of potyviral virion assembly and highlight the significance of the amino acid sequence of selected CPs in potential biotechnological or biomedical applications.

Extensive evidence links gut microbiota to the pathogenesis of major depressive disorder (MDD), yet the specific microbial species involved remain unclear. Here, we identify distinct roles of three Bacteroides species-B. uniformis, B. vulgatus, and B. thetaiotaomicron-in depression. B. uniformis increases susceptibility to depression in mice, significantly enhances Th17 cell differentiation in vivo and in vitro, and upregulates hippocampal IL-17A level. However, treatment with SR1001, a Th17 cell inhibitor, alleviates B. uniformis-induced depressive-like behaviors. Conversely, B. thetaiotaomicron and B. vulgatus attenuate depressive behaviors in mice, significantly suppresse the differentiation of Th1 and Th17 cells in vivo, and reduce the levels of hippocampal cytokines, including IL-17A, IFN-γ, and TNF-α. Clinical analyses reveal increased Th1 and Th17 cells in MDD patients, correlating with depression severity. B. uniformis is enriched in MDD fecal samples and positively associated with Th17 levels, whereas B. thetaiotaomicron showes an inverse correlation. Mechanistically, targeted metabolomic shows that B. uniformis reduces butyric acid and cholesterol sulfate, whereas B. thetaiotaomicron increases butyric acid, propionic acid, and biotin, all of which are linked to Th1 and Th17 regulation. These findings highlight the role of Bacteroides species in depression via a gut-Th1/Th17 cells-brain axis, providing mechanistic insights and ideas for therapeutic strategies.

Identifying the mutant genes that are selected during carcinogenesis is key to identifying candidates for intervention and understanding the processes that promote transformation. Here we applied two selection metrics to study the dynamics of mutational selection in a mouse model of ultraviolet light driven skin carcinogenesis in which multiple synchronous tumors develop in each animal. Sequencing normal skin and tumors over a time course revealed two genetic routes to squamous carcinoma. Nonsynonymous Trp53 mutants were positively selected in both epidermis and tumors and present in 90% of tumors. The remaining tumors carried other oncogenic mutants, including activating Kras mutations. However, other positively selected mutant genes lost their competitive advantage in heavily mutated epidermis and in tumors. We found ten mutant genes under negative selection in normal skin, one of which was also negatively selected in tumors. In addition one gene was negatively selected in tumors but not normal skin. We conclude that analysing selection in normal tissue alongside tumors may resolve the dynamics of selection in carcinogenesis and refine the identification of cancer drivers.

Flexible motor control is essential for navigating complex, unpredictable environments. Although movement execution is often associated with stereotyped patterns of neural and muscular activation, the degree to which these patterns are conserved versus flexibly reorganized to meet task demands across diverse contextual changes has not been well characterized. Here we recorded head and body kinematics alongside muscle activity in rhesus monkeys during head stabilization-crucial for maintaining gaze and balance-while walking on a treadmill at various speeds, and during overground locomotion in the presence or absence of enhanced autonomic arousal. Dimensionality reduction analyses revealed a flexible control strategy during treadmill walking: a stable activation structure that scaled with speed. In contrast, overground walking evoked heightened muscle engagement and more substantial changes in organization. This pattern largely persisted even during elevated arousal, with larger pupil size linked to stronger but structurally preserved muscle recruitment. Together these findings demonstrate that the brain dynamically adapts motor coordination to context even for automatic behaviors, underscoring the need to examine control strategies in a wide range of conditions.

Understanding evolution of human pathogens requires looking beyond the effects of recent interventions. To study malaria parasites prior to widespread drug selection, Plasmodium falciparum genomes were sequenced from the oldest population-based set of archived research samples yet identified, placental blood collected in the Gambia between 1966 and 1971. High-quality data were obtained from 54 infected samples, showing that genomic complexity within infections was high, most infections were genetically unrelated, and no drug resistance alleles were detected. Strong signatures of positive selection are clearly seen at multiple loci throughout the genome, most of which encode surface proteins that bind erythrocytes and are targets of acquired antibody responses. Comparison of population samples obtained over a following period of almost 50 years revealed major directional allele frequency changes at several loci apart from drug resistance genes. Exceptional changes over this time are seen at gdv1 that regulates the rate of parasite sexual conversion required for transmission, and at the unlinked Pfsa1 and Pfsa3 loci previously associated with infection of individuals with sickle-cell trait. Other affected loci encode surface and transporter proteins warranting targeted functional analyses. This identification of key long-term adaptations is important for understanding and managing future evolution of malaria parasites.

Visual perception appears largely stable in time. However, psychophysical studies have revealed that low frequency (0.5 - 7 Hz) oscillatory dynamics can modulate perception and have been linked to various cognitive states and functions. Neither the contribution of waves around 5 Hz (theta or alpha-like) to cortical activity nor their impact during aberrant brain states have been resolved at high spatiotemporal scales. Here, using cortex-wide population voltage imaging in awake mice, we found that bouts of 5-Hz oscillations in the visual cortex are accompanied by similar oscillations in the retrosplenial cortex, occurring both spontaneously and evoked by visual stimulation. Injection of psychotropic 5-HT2AR agonist induced a significant increase in spontaneous 5-Hz oscillations, and also increased the power, occurrence probability and temporal persistence of visually evoked 5-Hz oscillations. This modulation of 5-Hz oscillations in both cortical areas indicates a strengthening of top-down control of perception, supporting an underlying mechanism of perceptual filling and visual hallucinations.

Desert ungulates, such as Camelus bactrianus and Hippotraginae antelopes, exhibit extraordinary adaptation to extreme environment. Deciphering these genetic adaptations is critical for understanding evolutionary resilience under climate change. Here, we generate a chromosome-level genome for domestic Bactrian camel and integrate comparative genomics analyses to uncover genomic adaptation in arid-desert ungulates. We find elevated molecular evolution rates with intensified positive selection among desert-adapted lineages. Convergent positively selected genes are mainly involved in energy metabolism, and ion transport and homeostasis. In addition, we identify further evidence reveals numerous parallel amino acid substitution genes associated with lipid/sterol metabolism, particularly cholesterol biosynthesis. Cross-species metabolomics reveal lower steroid-lipid levels in fasting camel serum, suggesting that genetic adaptation promotes metabolic trade-offs for desert survival. INSIG1 involved in cholesterol biosynthesis process emerge as a key candidate. Functional validation reveals that the INSIG1 mutation enhances lipid synthesis in energy-rich hepatocytes and promotes lipolysis during fasting in genome-edited male mice. Altogether, these findings highlight lipid/sterol plasticity as a cornerstone of desert adaptation, providing insights into breeding drought-resistant livestock and advancing therapeutic strategies for human metabolic disorders.

Breast cancer ranks highest globally in terms of both incidence and mortality rates among female malignancies. Elucidating the molecular mechanisms driving breast cancer initiation and progression, as well as identifying novel therapeutic agents, remains a critical unmet medical need. This study aimed to identify FDA-approved CYP4Z1 inhibitors with anti-breast cancer activity through a drug repurposing strategy, thereby providing preclinical evidence for potential clinical adjuvant therapies. Fluvastatin was identified as a concentration-dependent CYP4Z1 inhibitor through molecular docking and site-directed mutagenesis studies, binding to critical residues Lys109, Pro444, and Arg450 in the enzyme's active site. Functional studies demonstrated that Fluvastatin significantly attenuated cancer stem cell properties, migratory/invasive capacities, and epithelial-mesenchymal transition in breast cancer cell lines. In vivo experiments revealed that fluvastatin suppressed primary tumor growth and lung metastasis in xenograft models, while delaying mammary tumorigenesis in PyMT-MMTV-CYP4Z1 transgenic mice. Notably, this effect was less pronounced in PyMT-MMTV wild-type controls. This study establishes Fluvastatin as a novel CYP4Z1-targeted therapeutic candidate for breast cancer, providing preclinical validation for its potential use in combination therapies.

Focal adhesions (FAs) are mechanosensitive structures that mediate force transmission between cells and the extracellular matrix. While Traction Force Microscopy (TFM) quantifies cellular tractions exerted on deformable substrates, Förster Resonance Energy Transfer (FRET)-based tension probes, such as vinculin tension sensors, measure molecular-scale forces within FA proteins. Despite their potential synergy, these methods have rarely been combined to explore the interplay between molecular tension and cellular tractions. Here, we introduce a framework integrating TFM and FRET-based vinculin tension sensors to investigate FA mechanics across scales. At cell level, tractions and vinculin tension increased with substrate stiffness. At FA level, vinculin tension correlated solely with vinculin density, while tractions scaled with FA area, orientation, total vinculin content and vinculin density. Direct comparison of tractions to vinculin tension revealed a complex, heterogenous relationship between these forces, possibly linked to diverse cell and FA maturation states. Sub-FA analysis revealed conserved spatial patterns, with both tension and traction increasing towards the cell periphery. This multiscale approach provides an integrated workflow for studying focal adhesion forces, helping to bridge the gap between vinculin tension and cellular tractions.