Biology subjects

Wang, Q.

Publications and source records attributed to Wang, Q..

At least 217 records · Page 12Linked to original sources

bioRxiv2025

Lipocalins are versatile regulators of development and stress response in mosses

Major physiological and developmental innovations, such as stress tolerance strategies and three-dimensional growth, are key to land plant adaptation and evolution, but their genetic basis remains to be fully understood. Although lipocalins are known for their role to optimize adaptation and development in animals, they are heavily understudied in plants. Here we show that lipocalins in the moss Physcomitrium patens are versatile regulators of miscellaneous key physiological and developmental processes. Phylogenetics analyses revealed three major groups of plant lipocalins, including a newly identified group that is restricted to seedless plants. The temperature-induced lipocalin gene in P. patens (PpTIL) is functionally conserved with flowering plants in response to various abiotic stresses (e.g., heat, cold, salt, and dehydration). We demonstrate that PpTIL not only regulates protonemal development and the transition from two-dimensional to three-dimensional growth, but also affects many other processes such as lipid transport and metabolism, auxin biosynthesis and transport, and chlorophyll catabolism. These findings provide major insights into the role of lipocalins in land plant evolution.

evolutionary biology↗

bioRxiv2025

Alpha modulation of spiking activity across multiple brain regions in mice performing a tactile selective detection task

Many cognitive and sensory processes are characterized by strong relationships between the timing of neuronal spiking and the phase of ongoing local field potential oscillations. The coupling of neuronal spiking in neocortex to the phase of alpha oscillations (8-12 Hz) has been well studied in nonhuman primates but remains largely unexplored in other mammals. How this alpha modulation of spiking differs between brain areas and cell types, as well as its role in sensory processing and decision making, are not well understood. We used Neuropixels 1.0 probes to chronically record neural activity from somatosensory cortex, prefrontal cortex, striatum, and amygdala in mice performing a whisker-based selective detection task. We observed strong spontaneous alpha modulation of single-neuron spiking activity during inter-trial intervals while mice performed the task. The prevalence and strength of alpha phase modulation differed significantly across regions and between cell types. Phase modulated neurons exhibited stronger responses to both go and no-go stimuli, as well as stronger motor- and reward-related changes in firing rate, than their unmodulated counterparts. The increased responsiveness of phase modulated neurons suggests they are innervated by more diverse populations. Alpha modulation of neuronal spiking during baseline activity also correlated with task performance. In particular, many neurons exhibited strong alpha modulation before correct trials, but not before incorrect trials. These data suggest that dysregulation of spiking activity with respect to alpha oscillations may characterize lapses in attention.

neuroscience↗

bioRxiv2025

Electrokinetic detection of single-molecule phosphorylation

Current single-molecule fluorescence experiments lack direct sensitivity to molecular phosphorylation state. We show that electrokinetic properties measured with an anti-Brownian trap resolve the number of phosphorylated sites on individual biomolecules and can monitor phosphorylation cycles with single kinase turn overs. As an application, we directly visualize the rate limiting step in the kinase catalytic cycle.

biophysics↗

bioRxiv2025

Le Petit Prince (LPP) Multi-talker: Naturalistic 7T fMRI and EEG Dataset

Prior neuroimaging datasets using naturalistic listening paradigms have predominantly focused on single-talker scenarios. While these studies have been invaluable for advancing our understanding of speech and language processing in the brain, they do not capture the complexities of real-world multi-talker environments. Here, we introduce the "Le Petit Prince (LPP) Multi-talker Dataset", a high-quality, naturalistic neuroimaging dataset featuring 40 minutes of electroencephalogram (EEG) and 7T functional magnetic resonance imaging (fMRI) recordings from 26 native Mandarin Chinese speakers as they listened to both single-talker and multi-talker speech streams. Validation analyses conducted on both EEG and fMRI data demonstrate the datasets high quality and robustness. Additionally, the dataset includes detailed transcriptions and prosodic and linguistic annotations of the speech stimuli, enabling fine-grained analyses of neural responses to specific linguistic and acoustic features. The LPP Multi-talker Dataset is well-suited for addressing a wide range of research questions in cognitive neuroscience, including selective attention, auditory stream segregation, and working memory processes in naturalistic listening contexts.

neuroscience↗

bioRxiv2025

Splanchnic and pelvic spinal afferent pathways relay sensory information from the mouse colorectum into distinct brainstem circuits.

This study aimed to identify where the sensory information relayed by the two spinal afferent pathways innervating the distal colon and rectum (colorectum), the splanchnic and pelvic spinal afferent pathways, integrates within the brainstem. Localised injections of transneuronal viral tracer (herpes simplex virus H129 strain expressing EGFP (H129-EGFP)) into the distal colon was used to assess the brainstem structures receiving ascending input from the colorectum. H129-EGFP+ cells were distributed in structures involved in ascending sensory relay, descending pain modulation and autonomic regulation in the medulla from 96 hours and in pontine and caudal midbrain 120 hours after inoculation. In a separate cohort of mice, in vivo noxious colorectal distension (CRD) followed by brainstem immunolabelling for phosphorylated MAP kinase ERK 1/2 (pERK) showed that many of the structures in which H129-EGFP+ labelling was observed were relevant to colorectal sensory processing. Surgical removal of dorsal root ganglia (DRG) containing cell bodies of splanchnic colorectal afferent neurons, significantly reduced CRD evoked neuronal activation within the caudal ventrolateral medulla, rostral ventromedial medulla and the lateral parabrachial nuclei. Whilst, removal of DRG containing cell bodies of pelvic colorectal afferent neurons significantly reduced CRD evoked neuronal activation within the rostral ventromedial medulla, lateral parabrachial nuclei, the locus coeruleus, Barringtons nucleus and periaqueductal gray. Collectively, this study showed that the two spinal afferent pathways innervating the colorectum differentially shape colorectal processing within the brainstem and provides new insight into their unique roles to mediating visceromotor responses and defecation associated with colorectal nociception.

neuroscience↗

bioRxiv2025

mTOR regulates Wnt signaling to promote tension-mediated lens vesicle closure

Lens vesicle closure is a pivotal event in ocular morphogenesis, and its disruption underlies Peters anomaly, a leading congenital cause of corneal opacity. Here, we elucidate a mechanistic hierarchy in which mTOR-Wnt signaling orchestrates cytoskeletal tension to drive this process. Conditional ablation of mTOR in the lens ectoderm induces aberrant corneal-lenticular stalk formation and transdifferentiation of the ciliary margin into neural retina. mTOR inhibition suppresses Wnt3 expression, and Wnt3 displayed a similar lens stalk phenotype, positioning mTOR as an upstream regulator of Wnt ligand production. Complete ablation of lens-derived Wnt ligands via deletion of the Wnt transporter Wls exacerbates developmental defects, triggering anterior lens herniation and ciliary margin development failure. Disruption of {beta}-catenin-mediated Wnt signaling or dual deletion of Wnt co-receptors Lrp5/6 in lens ectoderm similarly prevents vesicle closure, recapitulating lens herniation. Strikingly, Rac1 deletion rescues corneal-lenticular stalk phenotypes in mTOR, Wls, and {beta}-catenin mutants, directly linking Wnt effectors to cytoskeletal remodeling. Our findings establish an mTOR-Wnt-Rac1 signaling axis as the core regulator of cytoskeletal tension required for lens vesicle closure.

developmental biology↗

bioRxiv2025

A distinctive subset of microglia positioned at the paraventricular zone are dedicated to cleaning the cerebrospinal fluid

The interconnected ventricles in the central nervous system are filled with cerebrospinal fluid (CSF) which serves multifaceted roles including bring away metabolic wastes. However, whether there is an inherent "dislodging" mechanism, in addition to CSF drainage and reabsorption, at play for the removal of microparticles in the CSF is unclear. In this study, we identified a subset of microglia distributed in close proximity to the ependymal wall of ventricles. They differed from parenchymal microglia in morphology, behaviors and transcriptomes. In particular, the paraventricular microglia extended transependymal dendrites into the lumen of ventricles and were proficient in sequestering and phagocytosing intraventricular exogenous particles when present. A specific removal of the paraventricular microglia led to an acute ventriculomegaly due to an increased colloid osmotic pressure in the CSF resulting from protein accumulation. Thus, we identified the paraventricular microglia as specific guardians in monitoring and cleaning the CSF.

immunology↗

bioRxiv2025

Kidney cortex macrophages prevent the formation of mineral stones by reabsorbing phosphate from the urine

Resident macrophages are important in maintaining tissue homeostasis by meeting specialized physiological demands and mitigating the unique stresses each tissue endures. In the kidney, urine is formed in a process of glomerular filtration and tubular reabsorption. Supersaturation of mineral solutes such as calcium phosphate poses a persistent challenge to the kidney; if left unchecked, kidneys stones form, which will cause tubular obstruction and even kidney failure. However, cellular mechanisms of preventing kidney stone formation remain incompletely understood. In this study, we found that resident macrophages in kidney cortex distinguishably expressed phosphate transporter SLC34A1. These cells extend transtubular protrusions and were capable of reabsorbing phosphate from the urine through the SLC34A1, a function previously only attributed to tubular epithelial cells. Depletion of Slc34a1 from kidney cortex macrophages led to increased urinary phosphate excretion, disrupting body phosphorus balance. More importantly, loss of macrophage-mediated phosphate reabsorption from the urine resulted in a drastic over-deposition of calcium phosphate microcrystals in kidney tubules, particularly in the late proximal tubules of inner cortex where intratubular calcium concentration is high. This also accelerated mineral stone formation. Exposure to mineral crystals stimulated cortex macrophages to upregulate SLC34A1 expression, a response mechanistically driven by lysosomal disruption. As such, cortex macrophages employed phosphate reabsorption as a proactive strategy to prevent mineral stone formation.

immunology↗

bioRxiv2025

Optimized antibody with W32I mutation enhances antiviral efficacy against influenza

The influenza virus has caused a global pandemic with significant morbidity and mortality, highlighting the need to optimize antibodies for improved antiviral efficacy. The 3E1 antibody effectively neutralizes influenza subtypes H1 and H5 by inhibiting acid-induced conformational changes of hemagglutinin (HA). This study aimed to optimize the antibodys bioactivity by modifying amino acid residues, resulting in single-point mutants (3E1-L [W32I], 3E1-H [F103I]) and a double mutant (3E1-H+L [F103I, W32I]). The binding affinity, neutralizing activity, and antiviral mechanisms of the mutants were evaluated. Notably, the 3E1-L mutant showed significantly enhanced antiviral activity against H1N1 and H3N2 compared to wild-type 3E1, inhibiting both viral entry and release. The prophylactic and therapeutic efficacy of the 3E1-L mutant was validated. Molecular dynamics simulations of the 3E1-L/HA complex showed that the W32I mutation reduces steric hindrance between tryptophan at position 32 and the complementarity-determining region (CDR) L1 loop of HA. In conclusion, the W32I substitution enhances the antiviral activity of wild-type 3E1, making the optimization of 3E1-L a promising strategy for developing more effective influenza therapies.

immunology↗

bioRxiv2025

Role of Age in Mediating the Association Between the Vaginal Microbiota and Preterm Birth

The vaginal microbiota plays a crucial role in vaginal health and pregnancy outcomes. However, the influence of maternal characteristics, especially age, on the relationship between the vaginal microbiota and preterm birth is poorly understood. This study quantifies the effects of race, maternal age, and gestational age on vaginal microbiota composition. Our results demonstrate stronger associations between preterm birth and a less optimal vaginal microbiota in White and Asian women compared to Black or African American women. The microbiota difference between preterm and term births was more pronounced in older reproductive-age women, with Lactobacillus species increasing with age only in term births. Additionally, lower alpha diversity was observed in term pregnancies compared to preterm during both early and late pregnancy, particularly in women aged above 25 years. These findings highlight the mediating role of age in the relationship between the vaginal microbiota and preterm birth.

microbiology↗

bioRxiv2025

Nipah virus matrix protein utilizes cortical actin to stabilize the virus assembly sites and promote budding

Several families of enveloped viruses assemble and bud from the host cell plasma membranes (PM), including paramyxoviruses. Nipah virus (NiV) is a deadly zoonotic paramyxovirus causing yearly outbreaks in Southeast Asia with >75% mortality. NiV encodes matrix proteins (M) that drive assembly and budding. NiV-M forms dimers and interacts with membrane lipids in the host cells PM for budding. Using single-molecule localization microscopy and single-particle tracking, we show that the host F-actin maintains the nanoscale organization of NiV assembly sites at the PM. This F-actin-dependent integrity of NiV assembly sites is observed at the membrane retention stage after the assembly process is complete, rather than during the recruitment of NiV-M molecules to these sites. NiV-M interacts with actin via its C-terminal domain. We also show that the actin-branching factor, Arp2/3 complex, promotes virus-like-particle production. Meanwhile, inhibiting Arp2/3 disfavors the PM retention of NiV assembly sites and NiV-M-mediated generation of membrane protrusions, but does not affect the assembly rate. This suggests that Arp2/3-nucleated actin polymerization and branching are critical for maintaining NiV-M assembly sites at the PM, allowing it to facilitate membrane protrusion generation for virus budding. Our findings support the following model: NiV-M interacts with F-actin through its C-terminus to remain at the host PM after assembly completion. This F-actin-dependent retention is promoted by the Arp2/3-driven actin branching and polymerization, which also drives the formation of NiV-M-induced membrane protrusions necessary for virus budding. SignificanceNipah virus (NiV) is a deadly paramyxovirus capable of animal-animal and animal-human transmissions. To produce a NiV particle, the NiV matrix protein (M) must create an assembly site by binding to the surface of an infected cell and pushing the cell membrane outward for virus budding. To do so, the NiV matrix protein must co-opt or overcome an actin network underneath the cell membrane. We provide single-molecule evidence that M interacts with the actin cytoskeleton for membrane retention but not recruitment of M to existing assembly sites. This process is promoted by the Arp2/3-driven actin branching and polymerization. Our findings suggest the role of actin remodeling in NiV budding and identify a druggable site at the C-terminus of NiV-M.

microbiology↗

bioRxiv2025

TransBrain: A computational framework for translating brain-wide phenotypes between humans and mice

Despite remarkable advances in whole-brain imaging technologies, the lack of quantitative approaches to bridge rodent preclinical and human studies remains a critical challenge. Here we present TransBrain, a computational framework enabling bidirectional translation of brain-wide phenotypes between humans and mice. TransBrain improves human-mouse homology mapping accuracy through: (1) a novel detached region-specific deep neural network trained on integrated multi-modal human transcriptomics to improve cortical correspondence (89.5% improvement over the original transcriptome), which revealed two evolutionarily conserved gradients explaining >50% of cortical organizational variance, and (2) random walk-based graph representation learning to construct a unified cross-species latent space incorporating anatomical hierarchies and structural connectivity. We demonstrated TransBrains utility through three cross-species applications: quantitative assessment of resting-state brain organizational features, inferring human cognitive functions from mouse optogenetic circuits, and translating molecular insights from mouse models to individual-level mechanisms in autism. TransBrain enables quantitative cross-species comparison and mechanistic investigation of both normal and pathological brain functions.

neuroscience↗

bioRxiv2025

Follicular mural granulosa cells stockpile glycogen to fuel corpus luteum pre-vascularization

The corpus luteum (CL) arises from the luteinization of follicular granulosa cells (GCs) and theca cells, marked by rapid progesterone elevation and angiogenesis. Intriguingly, angiogenesis lags behind progesterone elevation, creating an avascular phase during which luteal cells must fuel intensive steroidogenesis without perfusion. How the avascular CL meets this energetic demand remains a mystery. Here, we reveal a novel cellular adaptive mechanism-GC energy storage (GCES)-that resolves this enigma. We demonstrate that upon luteinization initiation, GCs enter a metabolically quiescent state yet enhance glucose uptake via SLC2A1, converting the glucose into glycogen through the hCG (LH)-MAPK-RUNX1-Insulin signaling axis. Catabolism of this glycogen reserve supplies the energy required for the avascular CL, ensuring normal luteogenesis. GCES is evolutionarily conserved across species. Genetic or pharmacological disruption of GCES or glycogenolysis induces luteal insufficiency, whereas timely glucose administration enhances GCES, improving luteal function and optimize reproductive outcome in both mouse and ovine models. In human study, orally intake of glucose post-hCG significantly augments GCES and enhances progesterone production in women. These results advance luteal physiology by uncovering a universal reproductive principle with direct clinical implications.

developmental biology↗

bioRxiv2025

Yeast DNA Polymerase δ Proofreading Nuclease Suppresses Translesion Synthesis and Facilitates Recombination in DNA Lesion Bypass.

Translesion synthesis (TLS) employs specialized polymerases to incorporate nucleotides opposite DNA lesions, allowing replication to continue temporarily without repairing the lesions, while sacrificing replication fidelity (1). TLS depends on a ubiquitin molecule attached to the clamp PCNA at residue Lys164 (2, 3); the precise biochemical and molecular basis how PCNA modification stimulates TLS is still elusive (4-10). In this study, we discovered that DNA polymerase {delta} (Pol {delta}) 3 to 5 "proofreading" exonuclease degrades nascent TLS synthesis opposite pyrimidine dimers and inhibits TLS on both leading and lagging strands. Rad18 E3 ligase and PCNA ubiquitylation become dispensable for TLS when Pol {delta} exonuclease is inactive. Biochemical reconstitution showed that the major UV lesion bypass polymerase Rad30 is intrinsically inefficient at bypassing thymidine dimers and requires multiple turnovers. Pol {delta} exonuclease impedes Rad30 activity both catalytically and non-catalytically during and post-lesion bypass. Importantly, PCNA and PCNA ubiquitylation enhance processivity of Rad30 after thymidine dimer bypass, a critical step for further DNA synthesis extension and overcoming Pol {delta} inhibition. Our study reveals a new paradigm how PCNA ubiquitylation facilitates TLS and the new role of Pol {delta} nuclease in lesion bypass pathway choice and replication fidelity at fork-blocking DNA lesions.

genetics↗

bioRxiv2025

Distinct CD8+ T-cell types Associated with COVID-19 Severity in Unvaccinated HLA-A2+ Patients

Although emerging data have revealed the critical role of memory CD8+ T cells in preventing and controlling SARS-CoV-2 infection, virus-specific CD8+ T-cell responses against SARS-CoV-2 and its memory and innate-like subsets in unvaccinated COVID-19 patients with various disease manifestations in an HLA-restricted fashion remain to be understood. Here, we show the strong association of protective cellular immunity with mild COVID-19 and unique cell types against SARS-CoV-2 virus in an HLA-A2 restricted manner. ELISpot assays reveal that SARS-CoV-2-specific CD8+ T-cell responses in mild COVID-19 patients are significantly higher than in severe patients, whereas neutralizing antibody responses against SARS-CoV-2 virus significantly correlate with disease severity. Single-cell analyses of HLA-A2-restricted CD8+ T cells, which recognize highly conserved immunodominant SARS-CoV-2-specific epitopes, demonstrate divergent profiles in unvaccinated patients with mild versus severe disease. CD8+ T-cell types including cytotoxic KLRB1+ CD8 cells with innate-like T-cell signatures, IFNGhiID3hi memory cells and IL7R+ proliferative stem cell-like memory cells are preferentially observed in mild COVID-19, whereas distinct terminally-differentiated T-cell subsets are predominantly detected in severe COVID-19: highly activated FASLhi T-cell subsets and early-terminated or dysfunctional IL4R+ GATA3+ stem cell-like memory T-cell subset. In conclusion, our findings suggest that unique and contrasting SARS-CoV-2-specific CD8+ T-cell profiles may dictate COVID-19 severity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/632164v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@154796corg.highwire.dtl.DTLVardef@efca24org.highwire.dtl.DTLVardef@c01b9corg.highwire.dtl.DTLVardef@54ad83_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO SARS-CoV-2 epitope-specific CD8+ T-cell subtypes associated with mild or severe COVID-19 patients. Potent memory CD8+ T-cell subtypes with gene signature in mild COVID-19 patients (upper) and dysfunctional CD8+ T-cell subtypes with gene signature in severe COVID-19 patients (lower). C_FIG

immunology↗

bioRxiv2025

OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies

Optineurin (OPTN) is a crucial component of the homeostatic pathway, playing a pivotal role in regulating a number of essential signaling pathways including NF-{kappa}B, interferon, autophagy, and vesicular trafficking. The dysfunction of OPTN has been implicated in the pathogenesis of several diseases, such as primary open angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia, and Pagets disease of bone. Interestingly, mutations in OPTN are implicated as gain-of-function in glaucoma pathology and loss-of-function in ALS. However, the role of loss-of-function OPTN in glaucoma pathology remains unclear. Here, we demonstrate that OPTN dysfunction contributes to chronic neuroinflammation, leading to sustained RGC death, which may represent a shared pathological mechanism in both normal tension glaucoma (NTG) and high-tension glaucoma (HTG). Retinal conditioned OPTN knockout contributes to short-term astrogliosis and long-term microglia activation, with the propagation of microglia activation spreading to the optic nerve. Moreover, OPTN loss of function does not further exacerbate RGC death in the ocular hypertension mouse model induced by viscobead injection. Combined with the downregulation of OPTN in glaucoma patients, we have revealed an IOP-independent mechanism of glaucoma pathogenesis. Furthermore, we found that OPTN-driven NPY upregulation may suppress the CHOP-associated neurodegeneration. Our findings reveal a neuroprotective role for the OPTN-NPY signaling pathway, and its dysfunction promotes RGC loss in glaucoma pathology. The OPTN-NPY-mediated neuroinflammatory pathway provides a potential therapy for IOP-resistant glaucoma and highlights a druggable target for CHOP-associated neurodegeneration.

neuroscience↗

bioRxiv2025

Non-mutated human tau stimulates Alzheimer's disease-relevant neurodegeneration in a microglia-dependent manner

The accumulation of abnormal, non-mutated tau protein is a key pathological hallmark of Alzheimers disease (AD). Despite its strong association with disease progression, the mechanisms by which tau drives neurodegeneration in the brain remain poorly understood. Here, we selectively expressed non-mutated or mutated human microtubule-associated protein tau (hMAPT) in neurons across the brain and observed neurodegeneration in the hippocampus, especially associated with non-mutated human tau. Single-nuclei RNA sequencing confirmed a selective loss of hippocampal excitatory neurons by the wild-type tau and revealed the upregulation of neurodegeneration-related pathways in the affected populations. The accumulation of phosphorylated tau was accompanied by cellular stress in neurons and reactive gliosis in multiple brain regions. Notably, the lifelong absence of microglia significantly and differentially influenced the extent of neurodegeneration in the hippocampus and thalamus. Therefore, our study established an AD-relevant tauopathy mouse model, elucidated both neuron-intrinsic and neuron-extrinsic responses, and highlighted critical and complex roles of microglia in modulating tau-driven neurodegeneration.

neuroscience↗

bioRxiv2025

A cytoskeletal scaffold promotes motile cilia assembly by regulating transition-zone integrity

Motile cilia are eukaryotic organelles with essential chemo- and mechano-sensing functions across evolution, from single cell organisms to humans. Motile cilia of the mammalian nervous, respiratory and reproductive systems are characterized by unique motility proteins to generate fluid flow essential for transporting metabolites and removing mucus. The molecular mechanism of motile cilia biogenesis remains unknown. Here, we use mouse genetics, single-molecule motility assays, proteomics, high-resolution imaging, and in situ cryo-tomography to identify mammalian KIF27, a motor protein of the Kinesin-4 family and homologue of the Hedgehog pathway regulator COS2/KIF7, as a key regulator of motile cilia assembly. We show that KIF27 promotes the integrity of the transition zone, a diffusion barrier situated at the cilium base. Loss of KIF27 causes specific and profound defects in axonemal structure and disrupts cilia beating, which collectively lead to organismal phenotypes that recapitulate primary ciliary dyskinesia. We show that the motile properties of KIF27 are dispensable for its function in motile cilia biogenesis. Instead, KIF27 acts as a microtubule scaffold to regulate the transition zone architecture and enable correct ciliary incorporation of motility-generating proteins. Given that KIF27 homologues exist in different evolutionarily lineages, we propose that the ancestral activities of KIF27/KIF7 kinesins were to form a microtubule-associated scaffold for protein-protein interactions pertinent to cilia formation and signaling. The transition-zone associated KIF27 activities may represent a general building principle for motile cilia assembly in diverse species and cell types.

developmental biology↗