Biology subjects

Chen, M. X.

Publications and source records attributed to Chen, M. X..

12 recordsLinked to original sources

bioRxiv2026

Integrated Proteo-Metabolomics of Urinary Extracellular Vesicles Reveals Early Molecular Divergence and Temporal Pathogenesis of Sepsis-Associated AKI

BackgroundSepsis-associated acute kidney injury (S-AKI) is a major contributor to morbidity and mortality in critically ill patients. However, the molecular mechanisms underlying its temporal progression remain poorly understood because conventional biomarkers primarily reflect renal dysfunction rather than disease pathogenesis. Urinary extracellular vesicles (uEVs), which carry kidney-derived molecular cargo, provide a promising platform for monitoring renal-specific biological alterations during disease progression. MethodsWe conducted a longitudinal multi-omics study of uEVs collected from 81 patients with sepsis, including 48 patients with S-AKI and 33 sepsis-only controls. Patients were randomly assigned to a discovery cohort (n = 52) and an independent validation cohort (n = 29). Urine samples were collected at Day 1, Day 4, and Day 8 after AKI diagnosis. High-resolution proteomic and metabolomic profiling was performed to characterize temporal molecular alterations. Enriched pathways identified in the discovery cohort were evaluated in the validation cohort using pathway-level concordance analysis. ResultsComparative analysis between S-AKI and sepsis-only patients identified distinct stage-specific molecular alterations throughout disease progression. At the early stage (Day 1), validated pathways included complement and coagulation cascades, ferroptosis, HIF-1 signaling, sphingolipid metabolism, and arachidonic acid metabolism, highlighting coordinated inflammatory, hypoxic, and lipid metabolic responses. During the mid-stage (Day 4), persistent activation of complement and coagulation cascades, ferroptosis, and HIF-1 signaling was accompanied by metabolic reprogramming involving alanine, aspartate and glutamate metabolism and tyrosine metabolism. Although limited sample availability reduced statistical power at Day 8, phenylalanine metabolism remained validated in the metabolomic analysis, suggesting persistent metabolic dysregulation during late-stage disease progression. ConclusionsThis study provides the first longitudinal, independently validated multi-omics characterization of human uEVs in S-AKI. By integrating proteomic and metabolomic profiling, we reveal the temporal evolution of renal-specific molecular pathways from early inflammatory and hypoxic responses to subsequent metabolic reprogramming. These findings establish uEV-based multi-omics as a promising strategy for molecular phenotyping of S-AKI beyond conventional clinical biomarkers and provide a valuable resource for future biomarker discovery and therapeutic target identification.

biochemistry↗

bioRxiv2026

Learning temporal structure engages hippocampus and guides value-based behaviour

The ability to learn and exploit structured relationships between events is fundamental to adaptive behaviour and episodic-like memory, yet the neural mechanisms that support such learning remain poorly understood. Progress has been limited by the difficulty of dissociating relational structure from sensory cues, value, and motor output in experimentally tractable tasks. Here we introduce a temporally structured olfactory task for mice that isolates relational structure from cue identity and reward statistics. Mice rapidly learned to use the ordered relationship between two sequentially presented odours to predict outcome. Because individual odours were equally associated with reward across contexts, their predictive value depended entirely on their relationship to preceding cues. Behavioural analyses and reinforcement learning models revealed a gradual shift to the use of structured representations as learning progressed. Dopamine activity in the nucleus accumbens reflected this transition. Over learning, identical sensory inputs became associated with opposite predicted outcomes depending only on their temporal position, consistent with dopamine prediction errors reflecting latent task structure rather than cue identity. Trial-by-trial variability in dopamine dynamics was quantitatively captured by the same models that described behavioural strategy, linking dopamine prediction errors directly to these learned structural representations. Finally, using a matched control task that preserved sensory input and reward statistics while eliminating structure, we found that learning and using temporal structure selectively increased ventral hippocampal activity. Together, these results establish a minimal, non-spatial paradigm for studying structural learning in mice, link behavioural representations to dopamine signalling, and show that isolating relational structure from sensory and reward confounds selectively recruits hippocampal circuitry long theorised to support it.

neuroscience↗

bioRxiv2026

Prenatal stress interacts with embryonic loss of Fgfr2 to increase locomotor hyperactivity in mice

Attention-deficit/hyperactivity disorder (ADHD) is a developmental psychiatric disorder associated with a complex interplay of genetic and environmental risk factors. We have shown embryonic dorsal forebrain loss in mice of fibroblast growth factor receptor 2 (Fgfr2), which has a critical role in normal brain development, results in ADHD-relevant phenotypes: increased locomotion and sociability, and impaired working memory postnatally. How such genetic vulnerabilities interact with environmental exposures to translationally model human ADHD risk remains unclear. Here, we pair the embryonic hGFAP-cre Fgfr2 conditional knockout (Fgfr2 cKO) mouse model with prenatal repetitive restraint stress, modeling an environmental factor associated with ADHD risk, to assess adult offspring behaviors and dopamine transporter (DAT) levels. Offspring of prenatally stressed, Fgfr2 cKO mice show increased locomotion (80% compared to non-stressed, Fgfr2 cKO animals). Prenatal stress led to a trend increase in impulsivity and trend decrease in working memory but did not affect sociability. There were no interactions with Fgfr2 cKO observed in these behaviors. Neurobiologically, prenatal stress led to a trend decrease in medial frontal cortex DAT, but these changes did not correlate with behavior. Taken together, our findings implicate prenatal stress as a potential contributor to gene-environment interactions for ADHD risk, supporting its use in translational animal models of childhood psychiatric disorders.

neuroscience↗

bioRxiv2025

Psychiatric risk implications of adolescent exposure to environmental insecticides: a systematic review of rodent studies

Adolescence is a sensitive period of neurodevelopment marked by remodeling of brain circuits that support cognitive development and emotion and behavior regulation. These maturation processes heighten psychiatric vulnerability to environmental exposures, including to toxicants such as insecticides. Epidemiological studies show widespread adolescent insecticide exposure and increasingly link this with psychiatric outcomes, yet underlying neural mechanisms remain poorly understood. Preclinical studies can clarify these associations and identify insecticide-induced mechanisms that may disrupt neurodevelopment and produce consequent long-term behavioral outcomes. Here, we performed a systematic review of rodent studies following PRISMA guidelines. 50 original articles met inclusion criteria, examining neurotoxic outcomes following insecticide exposure during adolescence (postnatal days 21-60). Outcomes were categorized into four domains: neurocognitive, neuropsychiatric, neurobiological, and general neurotoxicity. Risk of bias was assessed using the SYRCLE Risk of Bias tool. Across studies, insecticide exposure during adolescence led to learning and memory impairments and tended to increase depression relevant behaviors, alter locomotor activity, and produce general neurotoxic effects. Mechanistic findings highlighted disruptions in cholinergic and monoaminergic signaling, oxidative stress, neuroimmune changes, and cell death and other neurodegenerative processes. Together, these findings indicate adolescent insecticide exposure disrupts multiple neural systems with behavioral consequences relevant to adolescent development and psychiatric risk. Future research should model real-world exposures (e.g. dose, timing) to better inform translational understanding of adolescent psychiatric vulnerability. Because many life-long neuropsychiatric disorders emerge in adolescence, identifying how modifiable environmental exposures shape risk offers an opportunity for prevention and intervention strategies to alter the course of disease across the lifespan.

neuroscience↗

bioRxiv2025

Overnight circuit remodelling drives juvenile alloparental care

Parental care is critical for the survival of altricial young and is mediated by neural circuits that are well characterised in adult rodents. Although adults can exhibit caregiving even before becoming parents, the developmental origins of this so-called alloparental behaviour remain unclear. Here, we show that alloparental behaviour in mice emerges abruptly between postnatal day (P)14 and 15, independently of prior social experience. This behavioural transition coincides with the onset of pup-specific activity in galanin-expressing medial preoptic area (MPOAGal) neurons, which are essential for parental behaviour in adulthood. Chemogenetic silencing of MPOAGal neurons abolishes caregiving in juveniles, suggesting that similar circuits control parenting across life stages. Viral trans-synaptic tracing and whole-cell recordings reveal extensive input remodelling of MPOAGal neurons between P14 and 15, marking a rapid transition from a highly connected, immature network to a sparser, adult-like circuit configuration. We identify microglia as key mediators of this process, as their ablation prevents both synaptic reorganisation and the emergence of alloparenting. Together, these findings uncover a previously unrecognised, microglia-dependent developmental switch that enables caregiving in juveniles through rapid circuit reconfiguration.

neuroscience↗

bioRxiv2025

A Clinically Aligned Murine Model of Electroconvulsive Stimulation Reverses Social Aversion and Displays Fear Memory Impairment After Chronic Social Defeat Stress

Electroconvulsive therapy (ECT) is the most effective treatment for patients with major depression, bipolar depression, mania, catatonia, and schizophrenia. Nonetheless, the mechanisms underlying its therapeutic effects largely remain unknown. While previous preclinical studies have noted a role for neurotropic signaling, neurogenesis, and alterations in monoamine neurotransmitter systems, these models were largely conducted using procedures that deviate from clinical practice. Therefore, we sought to develop a clinically relevant murine model of ECT, referred to as electroconvulsive stimulation (ECS) in animals, which more closely aligns with current clinical approaches to better explore its mechanisms. Using the well-established chronic social defeat stress (CSDS) paradigm, known to negatively impact reward processes, we investigated whether the behavioral changes after CSDS could be reversed following a clinically related course of ECS. Additionally, we observed induction of plasticity-related genes in the nucleus accumbens (NAcc) and amygdala, regions responsible for reward and fear-related memory, respectively. Lastly, we investigated ECS-related changes in the NAcc with bulk RNA-sequencing. Pathway analysis demonstrated cellular changes primarily involved in neuroplasticity and regulating cell migration and differentiation. Therefore, utilizing our novel and clinically relevant model of ECS, we have begun to elucidate mechanisms that contribute to ECTs therapeutic outcomes by examining murine behavior and RNA from brain regions associated with stress-induced states that model anxiety and depression and the effects of ECS.

neuroscience↗

bioRxiv2024

Integration of hunger and hormonal state gates infant-directed aggression

Social behaviour is profoundly shaped by internal physiological states. While significant progress has been made in understanding how individual states such as hunger, stress, or arousal modulate behaviour, animals experience multiple states at any given time. The neural mechanisms that integrate such orthogonal states--and how this integration affects behaviour--remain poorly understood. Here we report how hunger and estrous state converge on neurons in the medial preoptic area (MPOA) to shape infant-directed behaviour. We find that hunger promotes pup-directed aggression in normally non-aggressive virgin female mice. This behavioural switch occurs through inhibition of MPOA neurons, driven by the release of neuropeptide Y (NPY) from Agouti-related peptide-expressing neurons in the arcuate nucleus (ArcAgRP neurons). The propensity for hunger-induced aggression is set by reproductive state, with MPOA neurons detecting changes in progesterone (P4) to estradiol (E2) ratio across the estrous cycle. Hunger and estrous state converge on HCN (hyperpolarization-activated cyclic nucleotide-gated) channels, which sets the baseline activity and excitability of MPOA neurons. Using micro-endoscopic imaging, we confirm these findings in vivo, revealing that MPOA neurons encode a state for pup-directed aggression. This work thus provides a mechanistic understanding of how multiple physiological states are integrated to flexibly control social behaviour.

neuroscience↗

bioRxiv2024

A Mechanically Resilient Soft Hydrogel Improves Drug Delivery for Treating Post-Traumatic Osteoarthritis in Physically Active Joints

Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in early post-traumatic osteoarthritis (PTOA) when symptoms are minimal and patients are physically active. DMOAD delivery systems therefore must withstand repeated mechanical loading without affecting the drug release kinetics. Although soft materials are preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt drug release. Here, we report a mechanically resilient soft hydrogel that rapidly self-heals under conditions resembling human running while maintaining sustained release of the cathepsin-K inhibitor L-006235 used as a proof-of-concept DMOAD. Notably, this hydrogel outperformed a previously reported hydrogel designed for intra-articular drug delivery, used as a control in our study, which neither recovered nor maintained drug release under mechanical loading. Upon injection into mouse knee joints, the hydrogel showed consistent release kinetics of the encapsulated agent in both treadmill-running and non-running mice. In a mouse model of aggressive PTOA exacerbated by treadmill running, L-006235 hydrogel markedly reduced cartilage degeneration. To our knowledge, this is the first hydrogel proven to withstand human running conditions and enable sustained DMOAD delivery in physically active joints, and the first study demonstrating reduced disease progression in a severe PTOA model under rigorous physical activity, highlighting the hydrogels potential for PTOA treatment in active patients.

bioengineering↗

bioRxiv2024

A Lipidomics-Based Method to Eliminate Negative Urine Culture in General Population

Urinary tract infections (UTIs) pose a significant challenge to human health. Accurate and timely detection remains pivotal for effective intervention. Current urine culture techniques, while essential, often encounter challenges where urinalysis yields positive results, but subsequent culture testing produces a negative result. This highlights potential discrepancies between the two methods and emphasizes the need for improved correlation in urinary tract infection (UTI) detection. Employing advanced lipidomics techniques, we deployed the fast lipid analysis technique (FLAT) on a clinical cohort suspected of having UTIs. Lipid fingerprinting by MALDI-TOF MS, directly from urine samples without ex vivo growth, correctly identified the common uropathogens within a 1-hour timeframe when compared to urine culture. FLAT analysis also identified urine samples without culturable pathogens (negative UTIs) with 99% agreement, whereas urinalysis showed 37% agreement with the gold standard urine culture. In 402 urine samples suspected for UTI from out-patients, FLAT assay rapidly ruled out negative urines without the need for culture in 77% of all cases. The potential impact of this innovative lipidomic-based approach extends beyond conventional diagnostic limitations, offering new avenues for early detection and targeted management of urinary tract infections. This research marks a paradigm shift in urine culture methodology, paving the way for improved clinical outcomes and public health interventions.

microbiology↗

bioRxiv2023

Metabolic Reprogramming of the Neovascular Niche Promotes Regenerative Angiogenesis in Proliferative Retinopathy

Healthy blood vessels supply neurons to preserve metabolic function. In blinding ischemic proliferative retinopathies (PRs), pathological neovascular tufts often emerge in lieu of needed physiological neuroretina revascularization. We show that metabolic shifts in the neurovascular niche define this angiogenic dichotomy between healthy and diseased blood vessel growth. Fatty acid oxidation (FAO) metabolites accumulated in human and murine retinopathy samples. Neovascular tufts with a distinct single-cell transcriptional signature highly expressed FAO enzymes. The deletion of Sirt3, an FAO regulator, shifted the neurovascular niche metabolism from FAO to glycolysis and suppressed tuft formation. This metabolic transition increased Vegf expression in astrocytes and reprogrammed pathological EC to a physiological phenotype, hastening vascular regeneration of the ischemic retina. Our findings identify SIRT3 as a metabolic switch in the neurovascular niche, offering a new therapeutic target for optimizing ischemic tissue revascularization. HighlightsO_LIPathological EC favor FAO over glycolysis. C_LIO_LIUnique signature for pathological EC found in proliferative retinopathy model. C_LIO_LISirt3 deletion shifts astrocytes and EC metabolism from FAO to glycolysis. C_LIO_LIMetabolic reprogramming of the vascular niche enhances physiological revascularization. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/566898v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@70020eorg.highwire.dtl.DTLVardef@19719acorg.highwire.dtl.DTLVardef@1168ddeorg.highwire.dtl.DTLVardef@1bc25e0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Endothelial FABP4 constitutes the majority of basal circulating hormone levels and regulates lipolysis-driven insulin secretion

Fatty acid binding protein 4 (FABP4) is a lipid chaperone secreted from adipocytes upon stimulation of lipolysis. Circulating FABP4 levels strongly correlate with body mass index and obesity-related pathologies in experimental models and humans. While adipocytes have been presumed to be the major source of hormonal FABP4, this question has not been addressed definitively in vivo. We generated mice with FABP4 deletion in cells known to express the gene; adipocytes (Adipo-KO), endothelial cells (Endo-KO), myeloid cells (Myeloid-KO), and the whole body (Total-KO) to examine the contribution of these cell types to basal and stimulated plasma FABP4 levels. Unexpectedly, baseline plasma FABP4 was only reduced by [~]25% in Adipo-KO mice, whereas Endo-KO mice showed [~]75% decreases compared to wildtype controls. In contrast, Adipo-KO mice exhibited [~]62% reduction in FABP4 responses to lipolysis, while there was minimal reduction in Endo-KO mice, indicating that adipocytes are the main FABP4 source in lipolysis. We did not detect any myeloid cell contribution to circulating FABP4. Surprisingly, despite the nearly intact FABP4 responses, Endo-KO mice showed blunted lipolysis-induced insulin secretion, identical to Total-KO mice. We conclude that the endothelium is the major source of baseline hormonal FABP4 and is required for the insulin response to lipolysis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/511807v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1b2d566org.highwire.dtl.DTLVardef@1d82083org.highwire.dtl.DTLVardef@3e9726org.highwire.dtl.DTLVardef@1357648_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2021

Molecular and cellular adaptations in hippocampal parvalbumin neurons mediate behavioral responses to chronic social stress

Parvalbumin-expressing interneurons (PV neurons) maintain inhibitory control of local circuits implicated in behavioral responses to environmental stressors. However, the roles of molecular and cellular adaptations in PV neurons in stress susceptibility or resilience have not been clearly established. Here, we show behavioral outcomes of chronic social defeat stress (CSDS) are mediated by differential neuronal activity and gene expression in hippocampal PV neurons in mice. Using in vivo electrophysiology and chemogenetics, we find increased PV neuronal activity in the ventral dentate gyrus is required and sufficient for behavioral susceptibility to CSDS. PV neuron-selective translational profiling indicates mitochondrial oxidative phosphorylation is the most significantly altered pathway in stress-susceptible versus resilient mice. Among differentially expressed genes associated with stress-susceptibility and resilience, we find Ahnak, an endogenous regulator of L-type calcium channels which are implicated in the regulation of mitochondrial function and gene expression. Notably, Ahnak deletion in PV neurons impedes behavioral susceptibility to CSDS. Altogether, these findings indicate behavioral effects of chronic stress can be controlled by selective modulation of PV neuronal activity or a regulator of L-type calcium signaling in PV neurons.

neuroscience↗