Biology subjects

Xie, H.

Publications and source records attributed to Xie, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Heterogeneous Graph Contrastive Learning for Drug-Gene-Disease Motif Prediction

Drug repurposing and target discovery offer critical strategies for advancing therapeutic development by uncovering the potential biological pathways and novel associations among drugs, genes, and diseases. However, experimental discovery remains expensive and time-consuming, which limits the scalability of large-scale studies. In addition, existing computational approaches often struggle to effectively integrate heterogeneous biomedical data, capture the complex higher-order topological signatures of biological interactomes, and generalize to unseen entities. Here, we present HANAMI (Heterogeneous grAph coNtrastive leArning for drug-gene-disease Motif predIction), a multi-view deep graph learning framework designed to model complex interactions among drugs, genes, and diseases. HANAMI integrates diverse heterogeneous biomedical knowledge, including chemical structures, genomic sequences, and clinical phenotypes, and leverages relation-aware topology encoding, structure-aware aggregation, and contrastive learning to enable accurate motif prediction with biological context from the network. Systematic evaluation on benchmark datasets shows that HANAMI achieves up to 6% improvements over existing state-of-the-art methods in predicting drug-gene-disease motifs. The framework further demonstrates strong inductive generalization, maintaining an [~]18% performance advantage in zero-shot settings involving previously unseen entities. Beyond predictive performance, HANAMI effectively prioritizes drug-disease relationships investigated in Phase II or III trials while identifying candidate genes that suggest plausible mechanistic links. Together, HANAMI provides a computational framework for interpreting complex biomedical interactions, offering a scalable foundation to accelerate drug repurposing and therapeutic innovation.

bioinformatics↗

bioRxiv2026

Discovery and Optimization of Imidazothiazole Carboxamides as Novel Anti-Tuberculosis Agents

Screening of the open-access CRESTdb small-molecule library identified the imidazothiazole carboxamide sCQG200 (1) as an initial hit, with activity against H37Rv and Erdman Mycobacterium tuberculosis strains in cholesterol-containing medium (MIC90= 6.88 uM and 4.48 uM, respectively) and against intracellular Mtb (EC50= 3.80 uM). sCQG200 retained activity against drug-resistant Mtb strains, including clinical MDR/XDR isolates. SAR optimization led to analogs 21 and 24 with substantially improved antimycobacterial potency. Mouse pharmacokinetic studies following oral and intravenous administration showed 62.1% and 29.5% oral bioavailability for 21 and 24, respectively. This structurally differentiated chemotype provides a promising starting point for further optimization as antitubercular agent.

microbiology↗

bioRxiv2026

Discovery and Structure Activity Relationship Optimization of a Novel Rv1625c Agonist Chemotype with Antitubercular Activity

Rv1625c/Cya has emerged as a promising target for the development of treatment-shortening therapies for tuberculosis. Screening of an Enamine compound library identified sBQQ004 as an initial hit, and rapid hit optimization led to compound 1, which was subsequently confirmed as an Rv1625c/Cya agonist. Structure activity relationship studies identified lead compound 25 with potent activity against Mycobacterium tuberculosis H37Rv under cholesterol-dependent growth conditions (MIC = 0.27 uM) and strong intramacrophage activity (EC50 = 0.079 uM). Compounds 1 and 25 showed oral bioavailabilities of 84.5% and 51.9% in mice, respectively. Repeat BID dosing of compound 1 resulted in a dose- and time-dependent decrease in systemic exposure. Despite this pharmacokinetic limitation, the potency and overall profile of this chemotype encouraged continued optimization.

microbiology↗

bioRxiv2026

Microbiota-pathogen interactions after host death:a potential determinant of pathogen evolution

During the lifetime of many animals, the microbiota fulfills multiple functions. After death of their hosts, these microbes contribute to cadaver decomposition, with implications for forensics, fossilization and soil nutrient and microbial community dynamics. Here, we draw attention to the possibility that host microbiota can also influence the evolution of pathogen lifestyles. We hypothesized that competition between microbiota and pathogens after host death can reduce benefits to pathogens of killing and decomposing their host. To test this hypothesis, we conducted infection experiments in which we injected the entomopathogenic bacteria Pseudomonas entomophila into Tenebrio molitor larvae. Our results show that bacterial proliferation after pathogen-induced host death occurs in larvae with strongly reduced microbiota, but not in larvae with intact gut microbiota. Strikingly, we found that gut microbiota can suppress the proliferation of an about 100 times larger pathogen population. In addition, we identified a microbiota member that might have mediated competitive suppression of pathogen proliferation after host death. Taken together, our results support our hypothesis that decomposing host microbiota can effectively compete with pathogens, thereby reducing the fitness of pathogens that kill and then exploit dead hosts. Based on a reanalysis of an existing theoretical model, we conclude that the host microbiota can facilitate the evolution of more benign pathogens that are less likely to kill their host for cadaver exploitation. Thus, our findings highlight the potentially important but so far unexplored possibility that pathogen-microbiota interactions in dead hosts can affect living hosts by influencing the evolution of pathogens lifestyles.

microbiology↗

bioRxiv2026

Resolving the Deep Sleep Dual Indeterminacy Problem: Context-Dependent Slow-Wave Activity Modeling Predicts Neurobehavioral Fatigue Where Clinical Sleep Modeling Fails

Deep sleep is widely considered to be the most recuperative component of sleep restoration. Accordingly, a positive relationship between naturally occurring deep sleep and function (e.g., cognitive performance) is often assumed. However, this assumption warrants closer examination--particularly given the rise of sleep tracking that emphasizes traditional sleep metrics and their implied predictive value. We present evidence that while clinical deep sleep scoring provides no predictive value, slow-wave activity (SWA) exhibits a paradoxical association with both improved and worsened neurobehavioral fatigue following sleep deprivation. Specifically, we found that SWA-based models account for approximately 50-60% of the inter-individual variance in recovery from sleep deprivation. Remarkably, when regressed against recovery from sleep deprivation, SWA during the baseline sleep night showed a negative association (normalized {beta} = (-)0.5, p = 0.001) while in the same model SWA during the subsequent wakefulness period showed an opposite positive association (normalized {beta} = 0.5, p = 0.001). Furthermore, although the group-averaged SWA while behaviorally awake increased with impairment across the sleep deprivation period, individual-level data revealed an inverse relationship: individuals more resilient to sleep deprivation exhibited greater SWA in-between mental test sessions and less corresponding impairment during wakefulness suggestive of a protective effect. These findings identify a Deep Sleep Dual Indeterminacy Problem -- simultaneous measurement and causal indeterminacy -- that explains why clinical sleep staging fails as a functional biomarker across a wide range of outcomes, and provide a principled framework for next-generation sleep metrics grounded in continuous electrophysiology and temporal modeling.

physiology↗

bioRxiv2026

Efficient Reprogramming of the Epiblast Enables the Generation of Cloned Mice

Somatic cell nuclear transfer (SCNT) can generate viable mammals despite pervasive epigenetic abnormalities in cloned embryos, yet the mechanism underlying this paradox remains unclear. Here we show, using single-cell transcriptomics, that efficient reprogramming occurs exclusively in the epiblast (EPI), but the not primitive endoderm (PrE) of late mouse SCNT blastocysts. Integrating this with previous findings of trophectoderm (TE) aberration, we propose the EPI as the sole effectively reprogrammed lineage. By innovatively employing a Lego-like multi-lineage embryonic aggregation approach, where the extra-embryonic lineages were replaced with fertilization-derived counterparts, we demonstrated that SCNT-derived EPI inherently possesses full-term developmental potential nearly identical to that of fertilized EPI (20.5% vs. 21.8% birth rate), functionally confirming its effective reprogramming. Our study uncovers a lineage-specific asymmetric reprogramming mode where the EPI specifically achieves effective reprogramming, thereby constituting the deterministic basis for cloned animal generation. This work also provides a versatile strategy for investigating lineage potency and function.

developmental biology↗

bioRxiv2026

Minimum inoculum of resistance assay for evaluating for anti-toxoplasmosis compounds that target phenyl alanine tRNA synthetase

Toxoplasma gondii is a globally important intracellular parasite, and treatment regimens are limited by the failure of drugs to target latent tissue cysts. Developing new candidates for treatment also needs to address the potential for resistance to arise. Here, we developed a Minimum Inoculum for Resistance (MIR) assay as a quantitative metric for evaluating inhibitors of T. gondii. The MIR assay, adapted from assays used in malaria drug discovery, measures the frequency for pre-existing resistance alleles by exposing different sized parasite populations to drug pressure. We profiled a series of bicyclic pyrrolidone analogs that inhibit phenylalanine tRNA synthetase (PheRS). We demonstrate that these inhibitors require higher inocula to lead to parasite resistance (up to > 108 parasites) in comparison with an inhibitor of DNA synthesis, and that MIR values vary across inhibitors with closely related chemical structures. Clonal analysis of resistant parasites emerging from MIR assays revealed both new and previously identified resistance conferring mutations in TgPheRS, and structural modeling revealed their potential impact the enzyme active site. The MIR assay provides a functional benchmark to compare new and existing inhibitors, allowing for rational prioritization of lead compounds with a high genetic barrier to resistance.

microbiology↗

bioRxiv2026

Lineage-specific tprK diversification and Treponema pallidum transmission dynamics in Buenos Aires, Argentina

BackgroundSyphilis rates are rising globally, with increases in congenital syphilis in South America particularly concerning. The characterization of contemporary South American Treponema pallidum (Tp) strains is crucial to syphilis vaccine development, yet few genomic epidemiology studies have focused on this region. Here, we performed whole genome sequencing (WGS) of Tp from Buenos Aires, Argentina, as well as deep sequencing of the hypervariable tprK locus, which is critical to Tp immune evasion. MethodsPeople with primary, secondary, or congenital syphilis were enrolled at two clinics in Buenos Aires between October 2018 and January 2023, including individuals associated with intra-household transmission. Hybrid capture WGS was performed and a core genome phylogeny generated. K-mer-based methods using full-length tprK PacBio long reads were used to uncover differences in diversity and detect Tp transmission. FindingsTp genomes were recovered from 70 individuals in Buenos Aires and primarily belonged to globally dominant SS14 sublineage-1 and Nichols sublineage-8, as did Tp from Brazil (n=8). Peruvian samples (n=3) all belonged to sublineage-1. Two individuals from Argentina had co-infections with Nichols- and SS14-lineage strains. Macrolide resistance via A2058G occurred in 27/70 (38.6%) samples. Across 56 samples, tprK allelic diversity was significantly increased in secondary syphilis, oral lesions, and SS14-lineage strains compared to primary syphilis, anogenital lesions, and Nichols-lineage strains, respectively. Increased diversity in SS14-lineage strains is driven by an enhanced repertoire of V7-specific donor sequences. tprK sequences from intra-household transmissions were more similar than unrelated samples with identical core genomes. InterpretationTp circulating in South America is closely related to dominant global sublineages. Increased tprK diversity in the SS14 lineage may influence Tps ability to escape host immunity. tprK profiling is a promising tool to elucidate syphilis transmission networks. This study underscores the utility of genomics to yield insights into Tp pathogenesis. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAlthough whole genome sequencing (WGS) and genomic epidemiology have contributed to an understanding of the global diversity of Treponema pallidum (Tp), very few strains from South America have been sequenced to date. On January 6th, 2026, we performed a PubMed search including terms "syphilis genomic epidemiology", "South America", "Treponema pallidum", and "Argentina". We excluded studies of ancient Tp samples found in South American archeological sites. A single Tp sample from Argentina was originally sequenced in 2016 and included in subsequent analyses of global diversity. Nine Peruvian samples were previously sequenced in a study of global diversity on six continents. Thirty-three samples from Cali, Colombia were predominantly SS14-lineage and genotypic macrolide resistance was found in half of strains. Additionally, studies of Tp in Buenos Aires using a multi-locus sequence typing approach have shown circulation of strains belonging to both Nichols and SS14 lineages, with an increasing rate of macrolide resistance over time. Five previous studies have examined tprK in clinical specimens and consistently shown increased tprK diversity in specimens associated with secondary syphilis compared to primary syphilis lesions. One study has shown that loss of tprK donor cassettes is associated with reduced tprK diversity, consistent with results from in vitro experiments. A single study has shown that tprK sequence content is more similar in samples with a suspected epidemiologic link, though no prior studies have looked at tprK diversity in the context of known syphilis transmission events. Added value of this studyThis study is the first to use WGS to comprehensively examine Tp transmission in a large South American city, yielding 96 samples from 70 individuals. We also add the first contemporary Tp genomes from Brazil. In contrast to findings from England, Australia, and other high-income countries, no Tp sublineages are associated with demographic groups or sexual networks in Buenos Aires. Two of seventy patients were co-infected with both Nichols- and SS14-lineage strains, showing the previously unappreciated frequency of conditions that permit inter-strain recombination-driven diversification of Tp. This study also reveals novel aspects of Tp pathogenesis, including lineage-specific differences in tprK diversity. We also develop methods for the analysis of tprK relatedness between samples and demonstrate that tprK sequences are more similar in samples from individuals within intra-household syphilis transmission chains compared to those from epidemiologically unrelated individuals. Implications of all the available evidenceTp strains circulating in Buenos Aires are genetically similar to those circulating worldwide and in Brazil and Peru but are noteworthy for the low (but rising) rate of macrolide resistance. Lineage-specific patterns of tprK antigenic variation could result in differences between Nichols- and SS14-lineage strains interactions with the host immune system. Finally, we show that tprK profiling holds promise to identify samples from within a syphilis transmission chain and could play an important role in public health.

microbiology↗

bioRxiv2026

From cognitive abstraction to adaptive behavior: neural bases of concept learning in autistic adolescents

BACKGROUNDLearned knowledge does not consistently generalize to new contexts in autistic individuals, limiting potential for adapting to real-world demands. This challenge is hypothesized to stem from difficulties with forming abstract representations, potentially arising from perceptual processing that favors local details over the gestalt. We tested the prediction that generalization would be primarily based on exemplar-specific representations in autistic youth using computational modelling coupled with neuroimaging. METHODSSixty-four autistic adolescents without intellectual disability (69% males; ages 14-18 years) completed a category generalization task during functional magnetic resonance imaging at two time points. Computational models estimated abstract (prototype-based) and specific (exemplar-based) representations and underlying neural correlates. We further examined associations with adaptive functioning and moderation by autistic traits. RESULTSContrary to predictions, we observed a consistent prototype-dominant majority, a subgroup who generalized without consistent representational reliance, and a small minority who failed to acquire category structure. Prototypes were represented in bilateral ventromedial prefrontal cortex (VMPFC), inferior parietal lobule (IPL), right frontal pole, and right lateral occipital cortex, while exemplars were represented in bilateral cuneus. Better generalization predicted better real-world adaptive functioning. Moreover, greater prototype-related activation in left IPL predicted better adaptive functioning in participants with higher autistic traits. CONCLUSIONSThese findings challenge the prevailing view that concept learning in autism relies primarily on hyper-specific perceptual processing, identify meaningful variability in representational strategies, and reveal neural pathways through which abstract representation may support real-world adaptive behavior.

neuroscience↗

bioRxiv2026

Organic Components Modulate the Morphology of Respirable Aerovirology Relevant Aerosols

Airborne transmission of pathogens occurs via aerosol particles, whose morphology provides insights into the microenvironments that pathogens experience. Aerosol morphology includes particle size, shape, phase state, and chemical homogeneity, yet systematic studies remain limited. Here, we characterized model bioaerosol morphologies generated from (1) NaCl-organic two-component mixtures, (2) common cell culture media, and (3) artificial respiratory fluids. Particles were collected using a virtual impactor and Andersen cascade impactor and analyzed by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). Results show that organic components modulate the morphology: dipalmitoylphosphatidylcholine (DPPC) promotes organic-inorganic phase separation while proteins prohibit formation of large crystals and leads to better mixing among components. At 30% RH with a drying period of 10 seconds, most aerosols appeared desiccated, though NaCl-glucose, DMEM-complete-media and artificial saliva with mucin remained semi-solid or gel-like. Among all formulations examined EMEM-complete-media and artificial saliva (non mucin) show a size-dependent morphology. Our study demonstrates how chemical composition and size alters surrogate bioaerosol phase (semi-solid or solid) and morphology and provides new insights into the microenvironment of aerosol particles for aerovirology investigations.

biochemistry↗

bioRxiv2025

Topological data analysis reveals rigid brain-state dynamics during self-viewing in trait rumination

Rumination--repetitive, negatively valenced, self-focused thought--is a maladaptive cognitive style linked to emotional dysregulation and psychiatric risk. To investigate its neural underpinnings in a naturalistic context, we developed an fMRI paradigm in which participants observed and reflected on videos of their own past group-based problem-solving sessions, a naturalistic self-relevant context rarely examined in fMRI studies. Thirty-two adults (mean age = 30.4 {+/-} 5.4 years; 13 F) were recorded during collaborative design-thinking tasks in triads. In a subsequent scanning session, each participant viewed two self-relevant team videos and one control team video, followed by a structured reflection period. We assessed trait rumination using the Rumination-Reflection Questionnaire (RRQ) and applied Topological Data Analysis (TDA) via the Mapper algorithm to model individual-level whole-brain dynamics during the task. Mapper shape graphs captured temporal transitions between brain states, allowing us to quantify the similarity of timepoints across the session. Individuals with higher trait rumination showed significantly higher temporal similarity, indicating reduced brain-state variability, during self-relevant conditions (r = 0.46, p = 0.018). This effect was not observed during the control condition. These findings suggest that rumination is associated with rigid brain dynamics during self-observation and evaluative processing. Traditional GLM and inter-subject correlation (ISC) analyses confirmed task engagement of key self-referential and social-evaluative regions, while Mapper revealed dynamic features not captured by static or group-averaged methods. Together, these findings demonstrate that trait rumination is associated with rigid large-scale brain dynamics during self-relevant cognition and highlight the value of combining naturalistic paradigms with topological approaches to capture behaviorally meaningful signatures. Significance StatementRumination--repetitive, self-focused thought--is a core cognitive feature of depression and anxiety. However, the neural dynamics underlying this mental inflexibility remain poorly understood, especially during ecologically valid, self-relevant experiences. Using topological data analysis and a naturalistic self-reflection fMRI paradigm, we identify a novel neural marker: individuals with higher rumination traits exhibit reduced flexibility in brain state transitions when watching videos of themselves. This signature is uniquely captured by Mapper, a data-driven geometric framework, and not detected by traditional neuroimaging methods. Our findings offer a new window into how maladaptive thought patterns manifest in brain dynamics, paving the way for personalized diagnostics and interventions in mood disorders.

neuroscience↗

bioRxiv2025

Lymphotoxin-driven cancer cell eradication by tumoricidal CD8+ tumor-infiltrating lymphocytes

Tumor-infiltrating lymphocyte (TIL) therapy is FDA-approved for patients with treatment-resistant advanced melanoma, but the TIL subpopulations critical for tumor eradication remains incompletely understood. Using patient-derived TIL-melanoma co-cultures, we identified and characterized a novel subset of CD8+ TIL, capable of class I HLA-independent cancer cell lysis. The lymphotoxin {beta} receptor (LT{beta}R) and interferon (IFN) sensing pathways were nominated as key determinants of TIL-mediated cancer cell killing from a whole-genome, loss-of-function CRISPR screen. Validation studies confirmed that dual LT{beta}R and IFN sensing is necessary and sufficient for cancer cell lysis, and that expanded CD8+ TIL express high lymphotoxin {beta} (LTB) and upregulate lymphotoxin (LTA) upon coculture with cancer cells. Leveraging paired scRNA-seq and scTCR-seq data, we confirmed that enrichment of LTB+CD8+ T cells is associated with clinical response to TIL, and that LTB+CD8+ TIL are expanded from putative neoantigen-reactive, LTBlo CD8+ T cells in resected tumors. SignificanceWe have uncovered a previously unrecognized mechanism of TIL-mediated tumor eradication, providing mechanistic insights into the role of LTBR/IFN signaling in TIL-mediated cancer cell killing, and potentially offering insights into novel strategies to isolate, enrich, and expand tumoricidal TIL or augment specific TIL functions to enhance tumor control.

cancer biology↗

bioRxiv2025

Spatiotemporal control of PIWI compartmentalization by mitochondrial scaffolds defines pachytene piRNA pathway organization

Pachytene piRNAs are the least understood class of piRNAs in the mammalian male germ line. During meiosis, their biogenesis occurs near mitochondrial outer membrane in germ granules known as intermitochondrial cement (IMC). However, how mitochondrial factors regulate the trafficking of PIWI proteins into and out of the IMC remain poorly understood. Here we show that the cytoplasmic PIWI proteins MILI and MIWI are recruited for pachytene piRNA biogenesis via distinct mitochondrial membrane proteins. Loss of the mitochondrial scaffold protein ASZ1 during meiosis in mice disrupts multiple downstream biogenesis steps, leading to misregulation of MILI and MIWI, failure of IMC formation, and a near-complete loss of mature pachytene piRNAs. Strikingly, despite the drastic depletion of pachytene piRNAs, LINE1 transposon silencing remains unaffected. We identify three classes of pachytene piRNA pathway components that coordinate piRNA production and compartmentalization. Our findings reveal that chromatoid body precursors serve as a central hub for the accumulation of pachytene PIWI-piRNA complexes, thus establishing a connection between IMC-based biogenesis and downstream piRNA function.

developmental biology↗

bioRxiv2025

In Situ Structure Determination of a Membrane Protein in Native Cellular Membranes by Proton-Detected Solid-State NMR

Determining the structure of membrane proteins within their native cellular membranes remains a substantial challenge in structural biology. In this study, we present a proton-detected solid-state NMR (ssNMR) approach, combined with an optimized random partial protonation (RAP) labeling strategy, to determine the high-resolution structure of the large-conductance mechanosensitive channel (MscL) directly within native E.coli membranes (backbone RMSD = 1.9 [A]). Our approach effectively suppresses background protein signals and achieves high spectral resolution and sensitivity at moderate MAS frequencies (40-60 kHz) by differentially tuning amide and side-chain protonation levels. Using advanced recoupling schemes, we obtained chemical shift assignments of side-chain protons by 3D hCCH spectra and 1H-1H distance restraints from a series of 3D hNHH spectra. With 10% protonation in side-chains, the 1H signals displayed linewidths of approximately 50Hz, facilitating the extraction of 49 long-range distance restraints between amide and side-chain protons, which are crucial for structural convergence. Ambiguities in the assignment of weak signals corresponding to distance restraints were resolved by integrating 3D hNHH experimental data with CS-Rosetta structural modeling. The resulting structure reveals a well-defined pentameric assembly, with transmembrane helix packing consistent with that observed in detergent environments. This study demonstrates significant sensitivity advantages of 1H-detected over 13C-detected in situ ssNMR methods, highlighting the potential of 1H-detected ssNMR for the structure determination of a broad range of membrane proteins in native membranes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=59 SRC="FIGDIR/small/685061v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1c2638dorg.highwire.dtl.DTLVardef@115e4d6org.highwire.dtl.DTLVardef@62c20forg.highwire.dtl.DTLVardef@1b29f67_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2025

Symmetric brain-liver circuits mediate lateralized regulation of hepatic glucose output

Neural lateralization is well recognized in the control of contralateral somatic movement, yet its relevance to visceral organ regulation remains poorly understood. This study aimed to determine whether the central nervous system exerts lateralized control over hepatic glucose metabolism and to localize the site of peripheral sympathetic crossover to the liver. Pseudorabies virus (PRV) tracing revealed bilateral projections from the lateral paragigantocellular nucleus (LPGi) with preferential innervation of the contralateral hepatic lobes. Unilateral LPGi activation elevated systemic glucose by enhancing glycogenolysis and gluconeogenesis specifically in contralateral lobes, whereas bilateral activation produced additive effects. Following unilateral hepatic denervation, contralateral LPGi activation induced metabolic compensation in the remaining innervated lobes, characterized by increased norepinephrine release, glucose production, and glycogen depletion. Whole-mount tissue clearing and dual viral tracing localized the sympathetic crossover to the porta hepatis. Developmental analysis showed that lobar-specific innervation along the vasculature emerges by postnatal week 2. These findings demonstrate that the brainstem can exert lobe-specific, lateralized control of hepatic glucose metabolism via bilaterally projecting brain - liver sympathetic pathways. This contralateral regulation arises from a peripheral decussation at the porta hepatis, and the compensatory activation observed after denervation reveals an intrinsic neuroadaptive mechanism that helps safeguard systemic glucose homeostasis. HighlightsO_LIBrain-liver sympathetic projections exhibit predominant contralateral innervation C_LIO_LIUnilateral LPGi activation drives glucose production in contralateral hepatic lobes C_LIO_LIUnilateral denervation augments contralateral LPGi-mediated metabolic compensation C_LIO_LISympathetic crossover to the liver localizes at the porta hepatis C_LI

neuroscience↗

bioRxiv2025

Dynamic Meta-Networking Identifies Distinct Network Correlates of Positive and Negative Formal Thought Disorder in Schizophrenia

Formal thought disorder (FTD) is a core symptom of schizophrenia, yet the neural network mechanisms underlying this phenotype remain poorly understood. In this study, we applied a dynamic meta-networking framework, which captures temporally recurring functional network states, to investigate alterations in the language and executive control networks and their associations with positive and negative FTD. Resting-state fMRI data were collected from three independent cohorts: a discovery cohort comprising 150 first-episode, drug-naive patients with schizophrenia and 175 healthy controls (HCs); a replication cohort including 183 first-episode, drug-naive patients and 109 HCs; and a third cohort consisting of 71 patients who had received two weeks of antipsychotic treatment and 71 HCs. Meta-networking analysis identified four distinct resting-state meta-states within both the language and executive control networks. Connectivity-behavior correlation analyses and machine-learning regression models revealed that positive FTD was associated with aberrant connectivity across specific meta-states in both networks. In contrast, negative FTD was linked exclusively to dysfunction within two meta-states of the executive control network. Notably, these polarity-specific, multi-state connectivity disruptions normalized following short-term antipsychotic treatment, highlighting their potential as clinically relevant neuroimaging biomarkers.

neuroscience↗

bioRxiv2025

Convergent molecular evolution of viviparity across squamate reptiles

The molecular mechanisms underlying convergent phenotypic innovations across the tree of life are largely unknown. Viviparity (live-bearing) is a complex reproductive mode transition having more than 100 independent origins in squamate reptiles, making it an ideal model to understand the molecular basis of evolutionary innovations. Here we used 141 squamate genomes, including 42 viviparous species and representing more than 18 independent evolutionary transitions to viviparity, to search for convergent molecular signals in 14,096 protein coding genes. We show that convergent positive selection associated with viviparity at the gene-level and amino acid substitutions at the site-level are widespread in squamates, but there is no universal convergence across all viviparous clades. The chance of molecular convergence associated with viviparity is negatively correlated with genetic distance between species. Nevertheless, convergent genes are shared across independent origins of viviparity even spanning deep divergence times, and these genes are enriched in viviparity-related biological processes, including placental development, nutrient transport, and immune response to external organisms. Our result demonstrates that molecular convergence in the evolution of complex traits decreases in likelihood with evolutionary time, but when it occurs is more likely through changes in different genes of similar functional pathway rather than changes in the same genes.

evolutionary biology↗

bioRxiv2025

Early Brain Functional Connectivity Changes Induced by Antidepressants and Placebo

Major depressive disorder (MDD) is a common and debilitating condition with limited treatment precision. While brain imaging has linked neural features to MDD diagnosis and treatment response, the underlying circuits and their early modulation by treatment remain unclear. To examine changes in functional connectivity within the first two weeks of treatment, we analyzed two independent cohorts of MDD patients receiving antidepressants or placebo. Across patients, a visual-precuneus-thalamus network showed increased functional connectivity regardless of treatment arm or clinical outcome. Placebo response involved attention and striatal systems, while drug-specific effects were localized to the amygdala, mid-cingulate, orbitofrontal cortex, and cerebellum, emerging only in a subset of medicated patients. Notably, the responses of those without drug-specific changes can be predicted with a placebo response prediction model. These early functional connectivity changes reveal common and distinct mechanisms of treatment effects, offering insights that could inform more personalized interventions for MDD.

neuroscience↗