bioRxiv : the preprint server for biology最新文献

Pulmonary Arterial Hypertension (PAH) is a rare vascular disorder characterized by elevated pressure in pulmonary arteries, eventually leading to right ventricular failure. Approximately 50% of pediatric disease and 20% of adult disease can be linked to a genetic mutation, with nearly 70% of these cases involving mutations in the bone morphogenetic protein receptor type 2 (BMPR2) locus. Investigations using rodent models have made significant advances in our understanding of BMPR2 signaling; however, limited data exist regarding the onset and course of PAH, and etiologies for phenotypic expression in these patients remain unknown. In this work, we describe the development of a novel ovine model of heritable PAH. Because homozygous disruption of BMPR2 is embryonic lethal, we developed heterozygous BMPR2 sheep by using a PAM-disrupting synonymous single stranded oligodeoxyribonucleotide alongside a single guide RNA and Cas9 mediated gene editing strategy. The resulting BMPR2(+/-) lambs demonstrated cardiac and pulmonary vascular pathology that are consistent with BMPR2 mutation-driven PAH observed in humans. Given the genetic and physiological similarities of BMPR2(+/-) sheep to humans with heritable PAH, this large animal model will serve as a vital platform for mechanistic molecular studies and will provide a much-needed pre-clinical model for extensive treatment evaluations.

Human and nonhuman primates rely heavily on vision to actively explore and navigate their environment. Although primate visual cortex has been studied extensively in head-fixed animals, little is known about how the primate visual system supports natural, active vision in freely moving animals. Here, we address this gap in the primary visual cortex (V1) by leveraging a head-mounted eye-tracking system while simultaneously recording the activity of ensembles of single V1 neurons in freely moving marmosets. Our results reveal that primate neural activity is tightly driven by visual input and organized by the temporal structure of natural gaze behavior, and these gaze-related responses are largely abolished in the absence of visual input. We further show that distinct phases of gaze movement, i.e. rapid redirection (gaze shift) and subsequent stabilization (fixation), engage separable suppression and enhancement of the V1 responses. The enhancement during fixation was clearly linked to visual input. These findings define the dynamics in V1 that link natural gaze behavior and stimulus-driven responses in freely moving primates. The work opens a previously inaccessible but fundamental regime of primate vision and establishes freely moving paradigms as a foundation for understanding real-world visual processing during ethologically relevant behaviors.

Group A Streptococcus (GAS) infections can lead to neuropsychiatric sequelae in children, yet the mechanisms driving post infectious brain pathology remain poorly defined. In a mouse disease model, Th17 lymphocytes induce microglial activation, blood brain barrier (BBB) dysfunction, and neural circuit impairment; however, the transcriptional programs underlying these effects, and the specific Th17 derived cytokines involved are unclear. Using mouse genetics, single cell RNA sequencing, and spatial transcriptomics, we show that GAS infections induce inflammatory gene programs in microglia and brain endothelial cells (BECs), accompanied by downregulation of BBB associated transcripts in BECs. Spatial transcriptomic analyses reveal that GAS-responsive microglia are enriched near infiltrating T cells. Several chemokines upregulated in microglia following GAS infection in mice are elevated in sera from affected patients. Conditional ablation of GMCSF in CD4 T cells partially attenuates microglial chemokine gene expression, but does not restore BBB integrity. Neutralization of IL17A partially rescues BBB transcriptional changes in BECs and reduces microglial chemokine expression; however, compensatory peripheral immune responses associated with persistent infection exacerbate BBB disruption. In contrast, microglia/macrophage-specific deletion of IL17 receptor A partially rescues BBB deficits following GAS infection. Together, these findings identify IL17A / IL17RA signaling in microglia as a critical driver of BBB dysfunction after GAS infections.

Modeling nonlinear, multiscale, and transiently chaotic biological processes remains a major challenge in computational biology. Traditional deep learning models, while powerful, require large datasets and lack mechanistic interpretability, limiting their effectiveness for time-resolved biological systems. Reservoir computing (RC) offers a promising alternative by leveraging the rich transient dynamics of fixed nonlinear systems, yet standard RC architectures struggle with high-dimensional biological data and complex temporal regimes. Here, we introduce Dynamical System Machine Learning (DynML), a multiplexed reservoir framework designed to model gene-expression dynamics in systems such as liver regeneration and textit{Drosophila} embryogenesis. DynML encodes biological signals using heterogeneous Lorenz reservoirs and employs a single global readout to capture stage-dependent dynamics with high predictive accuracy. We further show that reservoir topological entropy quantitatively predicts model performance, linking dynamical richness to biological forecasting accuracy. Beyond biological time-series modeling, we demonstrate the generality of DynML on the MNIST handwritten digit classification task using a Rossler-based chaotic reservoir, showing that fixed dynamical cores with linear readouts can also support high-dimensional static classification. Overall, DynML provides a scalable, interpretable, and computationally efficient framework that unifies biological time-series modeling and conventional machine-learning tasks within a single dynamical systems paradigm.

Initiation and resolution of inflammation are required to restore homeostasis. While neutrophils are classically viewed as short-lived effector cells that initiate inflammation, accumulating evidence suggests they can also contribute to resolution processes. Here, we identify neutrophil state characterized by long in vivo half-life, mitochondrial fitness, and reduced inflammatory output. Using myeloid- and neutrophil-restricted sphingosine 1-phosphate receptor-1 (S1PR1) overexpression mouse models (S1PR1hi), we show that elevated S1PR1 signaling is associated with redistribution of neutrophils from the bone marrow to peripheral tissues under steady-state conditions, without inducing overt inflammation or tissue injury. S1PR1hi neutrophils exhibit reduced turnover in vivo, increased mitochondrial membrane potential and oxidative phosphorylation, and transcriptional programs linked to survival and dampened inflammatory signaling. Despite reduced oxidative burst, these neutrophils retain phagocytic capacity and antibacterial activity. In a model of influenza A virus infection, enhanced neutrophil-intrinsic S1PR1 signaling correlates with reduced lung injury, decreased inflammatory output, and improved survival. Together, these findings support a model in which S1PR1 tunes neutrophil persistence and inflammatory potential, thereby shaping immune responses during infection and tissue repair.

Mammalian phosphatidylserine synthase-1 and -2 synthesize phosphatidylserine (PS) by replacing the headgroup of either phosphatidylcholine (PC, PTDSS1) or phosphatidylethanolamine (PE, PTDSS2) with a serine. We determined structures of PTDSS2 from Equus caballus in complex with either PE or serine substrates to resolutions of 2.8-3.2 Å. The structures define substrate binding sites and reveal that the phosphate group of PE is coordinated by two Ca2+. In addition, we found that PTDSS2 has significant phospholipase D (PLD) activity in the absence of serine, which was not reported previously, and that Ca2+ is required for the PLD activity. These discoveries enrich our knowledge in the mechanism of mammalian PTDSS.

The mechanisms by which latent HIV-1 reservoirs persist during antiretroviral therapy is incompletely understood. Here, we derive a model system to measure clonal expansion and viral latency in which populations of human memory CD4+ T cells, each bearing a single transcriptionally active HIV-1 provirus are engrafted into immunodeficient mice. Over ~2 months in vivo, clonal expansion and the establishment of latency occurred in subsets of engrafted infected cells. Clonal expansion in vivo was driven by T-cell receptor identity, but not by proviral insertional mutagenesis. The integration sites of proviruses that became latent in vivo were enriched on chromosome 19, in intergenic and centromeric satellite regions, and genes whose expression is atypically low. Pre-existing repressive epigenetic features were associated with latency for subsets of proviruses. Our findings suggest a confluency of genomic and epigenomic factors predispose certain genomic locations, including ZNF genes, to host proviruses that constitute the latent reservoir.

Galectin-3 (Gal3) is one of the most pro-inflammatory proteins and a biomarker of inflammatory diseases and cancer. Previous studies showed that Gal3 binds to αv and β1 integrins but it is unclear how Gal3 binds to integrins. Here, we show that Gal3 bound to soluble αvβ3 and αIIbβ3 integrins in 1 mM Mn2+ in cell-free conditions in a glycan-independent manner. Docking simulation predicts that Gal3 binds to the classical RGD-binding site (site 1) of αvβ3, but the predicted Gal3-binding site does not include galactose-binding site. RGDfV or eptifibatide inhibited Gal3 binding to αvβ3 and αIIbβ3, respectively, but lactose, pan-galectin inhibitor, did not inhibit Gal3 binding to integrins. Point mutations of the predicted site 1 binding interface of Gal3 effectively inhibited Gal3 binding to site 1. Site 2 is involved in pro-inflammatory signaling (e.g., TNF and IL-6 secretion) and we previously showed that pro-inflammatory cytokines (e.g., CCL5 and TNF) bind to site 2 and allosteric integrin activation. Docking simulation predicts that Gal3 binds to site 2 of αvβ3 and α5β1. We found that Gal3 induced allosteric activation of soluble integrins αvβ3, αIIbβ3, and α5β1 in 1 mM Ca2+ in cell-free conditions. Point mutations in the predicted site 2-binding interface inhibited Gal3-induced integrin activation, suggesting that Gal3 binding to site 2 is required for Gal3-induced integrin activation. Known anti-inflammatory agents, Ivermectin, NRG1, and FGF1 inhibited integrin activation induced by Gal3 in αvβ3 and αIIbβ3. These findings suggest that Gal3 binding to site 2 may be a potential mechanism of pro-inflammatory and pro-thrombotic action of Gal3.

White matter (WM) has traditionally been considered structurally important but functionally inert in fMRI research. However, growing evidence indicates that WM exhibits meaningful BOLD fluctuations and participates in functional connectivity. Here, we investigate alterations in WM functional network connectivity (FNC) across the Alzheimers disease (AD) spectrum using resting-state fMRI data from the Alzheimers Disease Neuroimaging Initiative (ADNI 415 cognitively normal (CN), 283 mild cognitive impairment (MCI), 91 AD). We applied a guided independent component analysis (ICA) approach based on a combined multiscale template including 202 intrinsic connectivity networks (ICNs; 97 WM, 105 gray matter (GM)) to estimate subject-specific timecourses and compute static FNC (sFNC). Group differences in WMWM, GMGM, and WMGM connectivity (ADCN, ADMCI, MCICN) were assessed using two-sample t-tests with covariates for age, sex, and motion, with false discovery rate correction. Results showed robust alterations in WMWM and WMGM connectivity in AD, particularly involving WM subcortical, frontal, sensorimotor, and occipitotemporal networks. Several WMGM interactions with cerebellar and hippocampal GM networks were also disrupted, including reduced GMcerebellar:WMfrontal coupling and increased GMhippocampal to WMfrontal connectivity. Notably, MCI already showed WMGM dysconnectivity relative to CN, suggesting that functional disruption of WM circuits emerges prior to overt dementia. These findings provide converging evidence that WM functional connectivity is both measurable and selectively altered across the AD continuum. Our findings support WM sFNC as a complementary candidate biomarker to GM-based measures for staging and monitoring AD. This is, to our knowledge, the first large-scale ADNI study to jointly model WM and GM intrinsic connectivity networks and quantify WMGM dysconnectivity across CN, MCI, and AD.

Springtails execute millisecond-scale escape jumps with a single appendage, the furca, on soil, snow, leaf litter, and water. Across 15 taxonomic families (n=552 individuals), relative furca length is bimodal. High-speed video and confocal imaging show that in some long-furca springtails, the resilin-rich manubrium-dens joint behaves as a compliant hinge. It bends during push-off to prolong contact, suppress pitch, and bias takeoff forward, whereas rigid joints drive backward launches with rapid body rotation. We translate this mechanism to a 20-mm, 84-mg jumping robot with an elastic robo-furca hinge. This flexible hinge reduces body rotation by ~90% on flat ground compared to rigid-hinge designs, while maintaining takeoff speed on gravel, springboards, leaves, and pine needles, enabling passive, terrain-adaptable launches for power-limited insect-scale robots without onboard sensing or active control.