Biology subjects

ZHANG, X.

Publications and source records attributed to ZHANG, X..

16 recordsLinked to original sources

bioRxiv2026

Cooperative Peripheral CB1 Inhibition by Extracellular Antibody Binding and Orthosteric Antagonism

The cannabinoid receptor CB1 is an important therapeutic target for obesity and metabolic disorders, yet centrally acting CB1 antagonists are limited by neuropsychiatric side effects. Although the anti-CB1 antibody Nimacimab has advanced to Phase 2 clinical trials for metabolic disorders, the molecular mechanisms underlying peripheral CB1 inhibition remain poorly understood. Here, we report cryo-EM structures of human CB1 bound to Nimacimab alone and in complex with the orthosteric antagonists Rimonabant and JD5037. Unlike previously characterized inhibitory GPCR antibodies that block ligand access through steric occlusion or directly engage orthosteric sites, Nimacimab functions through extracellular allosteric inhibition by stabilizing an inactive-like extracellular architecture of CB1. Antibody binding restricts extracellular conformational dynamics and allosterically stabilizes inactive-state signaling microswitches. Importantly, extracellular antibody engagement is structurally compatible with orthosteric antagonism and cooperatively enhances CB1 inhibition. Structural analysis further reveals how JD5037 remodels the extracellular vestibule to achieve peripheral-selective antagonism. Together, these findings establish extracellular allosteric inhibition as a distinct mechanism of GPCR regulation and provide a structural framework for the development of peripherally selective CB1 therapeutics.

pharmacology and toxicology↗

bioRxiv2026

Easy-Multiome enables joint profiling of gene expression and chromatin accessibility in single cells

Gene expression and chromatin accessibility provide complementary insights into the regulatory mechanisms that define cell states. Although methods for jointly profiling these modalities exist, plant applications remain limited because of complex workflows, inconsistent performance, and prohibitive costs. Here, we present easy-Multiome, a streamlined single-cell multiomic workflow that integrates a single in situ reverse transcription step into the standard droplet-based scATAC-seq protocol. Using easy-Multiome, we profiled more than 20,000 nuclei from maize seedlings generating paired gene expression and chromatin accessibility data, with approximately 90% of nuclei containing both high-quality RNA and chromatin accessibility profiles. The resulting transcriptome data resolved 16 clusters corresponding to nine major maize seedling cell types and enabled direct characterization of cell-type-specific chromatin accessibility from the same nuclei. Furthermore, easy-Multiome simultaneously captured cell-type-specific transcription factor expression and the accessibility of their cognate DNA-binding motifs, providing direct links between transcriptional programs and regulatory landscapes. Together, these results demonstrate that easy-Multiome enables robust and efficient joint profiling of plant gene expression and chromatin accessibility while requiring only minimal modifications to existing droplet-based scATAC-seq workflows.

genomics↗

bioRxiv2026

A genetically defined midbrain-pontine circuit gates vocal communication

Vocal communication is selectively expressed in social and emotional contexts1-3, suggesting the presence of neural substrates that gate the conversion of internal states into vocal motor output. Although the periaqueductal gray (PAG) is known to be essential for vocalization4-6, the genetic identity and circuit logic of the neurons that initiate and shape vocal signals remain unclear. Here, we identify a genetically defined population of somatostatin-expressing neurons in the lateral and ventrolateral PAG (l/vlPAGSST) that functions as a premotor gate for ultrasonic vocalizations in mice. In vivo calcium imaging shows that l/vlPAGSST neurons are selectively recruited around vocal onset. Manipulating l/vlPAGSST neuron activity bidirectionally regulates vocal output: activation prolongs call duration by coordinating respiratory, laryngeal, and orofacial motor programs, whereas silencing suppresses courtship vocalizations. Projection-specific manipulations further demonstrate that descending glutamatergic, but not neuropeptidergic, output from l/vlPAGSST neurons to the dorsal pontine tegmentum is sufficient to drive vocal production. Together, these findings define a genetically specified midbrain-pontine circuit that gates vocal communication and provides prospective access for linking internal conditions to vocal expressions.

neuroscience↗

bioRxiv2025

Lineage-specific evolution of regulatory landscapes in polyploid plant and its diploid progenitors

Cis-regulatory elements are specific DNA sequences that control gene expression in a spatiotemporal manner, and variation within these elements represents a major source of phenotypic diversity and evolutionary innovation. Nevertheless, how regulatory elements evolve and shape gene expression remains poorly understood, particularly in plants. The well-resolved phylogeny of allopolyploid peanut (Arachis hypogaea) and its diploid progenitors, A. duranensis and A. ipaensis, provides an ideal system to investigate the regulatory evolution at a lineage-specific level. By integrating comparative analyses of sequence similarity, chromatin accessibility, histone modifications, conserved noncoding sequences (CNSs), and gene expression, we reconstructed the evolutionary trajectories of Accessible Chromatin Regions (ACRs), where regulatory elements typically reside, and revealed their distinct contributions to homeolog expression bias, unequal expressions between homeologs. Most ACRs exhibited high sequence similarity, comparable chromatin accessibility, and conserved states for H3K4me3, H3K56ac, and H3K36me3, indicating regulatory stability after hybridization and polyploidization. However, a subset of novel ACRs emerged de novo from previously non-regulatory regions or through sequence mutations in preexisting ACRs, arising at different rates and evolutionary stages. Notably, even highly sequence-conserved ACRs exhibited substantial variation in chromatin accessibility, consistent with CNS composition differences and minor sequence variation, although causal relationships remain to be demonstrated. Our analyses further revealed a complex spectrum of CNS dynamics across the diploid-polyploid framework. Overall, our study provides empirical insights into the fine-scale evolution of plant regulatory landscapes and complements previous large-scale comparisons across distant lineages.

evolutionary biology↗

bioRxiv2025

Structure based discovery of antipsychotic-like TAAR1 agonists

Schizophrenia is a severe mental illness whose current treatments primarily target dopamine and serotonin receptors. These drugs often cause side effects and vary in effectiveness across patients. The trace amine-associated receptor 1 (TAAR1), which modulates monoamine signaling, has emerged as a promising alternative target. To discover new TAAR1 ligands, we computationally docked 65 million molecules against the active state of TAAR1 and experimentally tested 55 of those highly ranked. Fourteen molecules active against TAAR1 with potencies ranging from mid-nanomolar to micromolar, all as agonists. This high functional selectivity may reflect the compact conformation adopted by the activated TAAR1 orthosteric site. While this was favorable for agonist prioritization, simulations suggest that it can be over-optimized for initial hit rates at the expense of subsequent affinity maturation. Here, hit optimization yielded nanomolar agonists whose docking-predicted poses were confirmed by cryo-EM. Three agonists had high brain exposure and potencies apparently better than the investigational drug ulotaront and sufficient for behavioral studies. All three potently normalized amphetamine-induced pre-pulse inhibition in mice, a model for schizophrenia, without catalepsy, a common side effect of traditional antipsychotics.

biochemistry↗

bioRxiv2025

Systematic Metaproteomics Mapping Reveals Functional and Ecological Landscapes of Human Gut Microbiota Responses to Therapeutic Drugs

Therapeutic compounds exert impacts on gut microbiota; however, how they affect the community functional ecology, especially as reflected at the protein level, remains largely unexplored. In this study, we systematically map metaproteomic responses of ex vivo human gut microbiota to 312 compounds, generating 4.6 million microbial protein responses, available as an interactive resource (https://shiny.imetalab.ca/MPR_Viz/). Protein-level analyses identify significant metaproteomic shifts induced by 47 compounds, with neuropharmaceuticals as the sole drug class significantly enriched among these hits. Further analyses on the community level reveal a tri-stability pattern in microbial composition and the emergence of three distinct functional states, based on a functional beta-diversity metric. Notably, neuropharmaceuticals cause particularly strong effects on the microbiomes, lowering the proteome-level functional redundancy and raising the level of antimicrobial resistance proteins, ultimately pushing the microbiome into an alternative functional state. Preliminary validation suggests that enhancing functional redundancy may contribute to maintaining microbiota resilience against neuropharmaceutical-induced antimicrobial resistance. Overall, this work establishes a comprehensive view of how drugs influence gut microbiome function and ecology at the protein level, proposes a landscape-based framework for interpreting community resilience, and highlights the need to consider protein-level and ecological responses in the evaluation of therapeutic interventions.

microbiology↗

bioRxiv2024

Attention field as a cognitive-behavioral marker for demarcating internet- but not smoking-addiction from reward

Attentional effect (AE), attention profile (AP), and attention field (AF) have been studied extensively, however, their roles in addiction and demarcating addiction from rewards remain unclear. Using a modified Posner-paradigm with two types of pre-rewarded-cues (addiction-related and addiction-unrelated) and four groups (smoking-dependents, internet-dependents, and respective HCs), we found that both AEs and APs were independent of either cue type or group, while AFs were interactively modulated by the two. AFs of addiction-related cues were narrower than those of addiction-unrelated cues for internet-dependents, but not for either smoking-dependents or HCs; AFs of internet-dependents (not smoking-dependents) were narrower than those of HCs for addiction-related cues, but not for addiction-unrelated cues. Significantly, internet-dependents reduced AFs can be simulated by the divisive-normalization computation, both of which closely tracked their addictive severities. Our findings identify a cognitive-behavioral marker for demarcating internet-addiction from rewarding, arguing against the notion that internet-addiction, or, more generally, non-substance-addiction, is ill-posed.

neuroscience↗

bioRxiv2024

Spatially global effects of feature-based attention in functional subdivisions of human subcortical nuclei

Attention can prioritize the processing of non-spatial features throughout the visual field. While human subcortical nuclei are known to play important roles in spatial attention, the subcortical mechanisms of feature-based attention remain elusive. Using high-resolution 7T fMRI, we investigated the spatially global effects of color-based attention in functional subdivisions of human subcortical nuclei. Paying attention to a color matching the unattended stimulus across the visual field selectively modulated BOLD signals in the parvocellular (P) layers of the lateral geniculate nucleus (LGN) of the thalamus, enhancing the response to the unattended stimulus while reducing the response to the attended stimulus. The spatially global effects of color-based attention were also found in the deeper layers of the superior colliculus (SC), early visual cortices, and the intraparietal sulcus (IPS) of the parietal lobe. Effective connectivity analyses further revealed enhanced feedforward and feedback connectivity between LGN and V1, along with top-down modulation from IPS through the SC and ventral pulvinar. Finally, attended color can be decoded from multi-voxel response patterns in frontoparietal regions. These findings demonstrate that color-based attention selectively modulates color processing in P subdivisions of the LGN of the thalamus throughout the visual field, controlled by top-down signals from the parietal cortex through the SC and pulvinar. HighlightsO_LIColor-based attention selectively modulates parvocellular activity in the LGN throughout the visual field. C_LIO_LISpatially global effect of feature-based attention significantly modulates activity in the deeper layers of the SC. C_LIO_LIFeature-based attention enhances both feedforward and feedback connectivity between the LGN and V1. C_LIO_LITop-down signals from IPS through the SC and pulvinar controls feature-based attention. C_LI

neuroscience↗

bioRxiv2024

Center-surround inhibition by expectation: a neuro-computational account

Expectation is beneficial for adaptive behavior through quickly deducing plausible interpretations of information. The profile and underlying neural computations of this process, however, remain unclear. When participants expected a grating with a specific orientation, we found a center-surround inhibition profile in orientation space, which was independent from attentional modulations by task-relevance. Using computational modeling, we showed that this center-surround inhibition could be reproduced by either a sharpening of tuning curves of expected orientation or a shift of tuning curves of unexpected orientations. Intriguingly, these two computations were further supported by orientation-adjustment and orientation-discrimination experiments. Finally, the ablation studies in convolutional neural networks revealed that predictive coding feedback played a critical role in the center-surround inhibition in expectation. Altogether, our study reveals for the first time that expectation results in both enhancement and suppression, optimizing plausible interpretations during perception by enhancing expected and attenuating similar but irrelevant and potentially interfering representations.

neuroscience↗

bioRxiv2024

Multilevel proteomic profiling of colorectal adenocarcinoma cell differentiation to characterize an intestinal epithelial model

Emergent advancements on the intestinal microbiome for human health and disease treatment necessitates well-defined intestinal cellular models to study and rapidly assess host, microbiome, and drug interactions. This study characterized molecular alterations during Caco-2 cell differentiation, an epithelial intestinal model, using quantitative multi-omic approaches. We demonstrated that both spontaneous and medium-induced cellular differentiations displayed similar protein and pathway changes, including the down-regulation of proteins related to translation and proliferation, and up-regulation of proteins related to cell adhesion, molecule binding and metabolic pathways. Acetyl-proteomics revealed decreased histone acetylation and increased acetylation in proteins associated with mitochondria functions in differentiated cells. Butyrate-containing differentiation medium accelerates differentiation, with earlier up-regulation of proteins related to differentiation and host-microbiome interactions. These results emphasize the controlled progression of Caco-2 differentiation toward a specialized intestinal epithelial-like cell. This further enhances their characterization, establishing their suitability for facilitating the effective evaluation of risk and quality in microbiome-directed therapeutics.

systems biology↗

bioRxiv2022

Category-induced global effects of feature-based attention in human visual system

Global effects of FBA are generally limited to stimuli sharing the same or similar features, as hypothesized in the "feature-similarity gain model". Visual perception, however, often reflects categories acquired via experience; whether the global-FBA effect can be induced by the categorized features remains unclear. Here human subjects were trained to classify motion-directions into two discrete categories and performed a classical motion-based attention task. We found a category-induced global-FBA effect in both the MT+ and frontoparietal areas, where attention to a motion-direction globally spread to unattended motion-directions within the same category, but not to those in a different category. Effective connectivity analysis showed that the category-induced global-FBA effect in MT+ was derived by feedback from the IFJ. Altogether, our results reveal for the first time a category-induced global-FBA effect and identify a source for this effect in human prefrontal cortex, implying that FBA is of greater ecological significance than previously thought.

neuroscience↗

bioRxiv2022

A graph representation of gapped patterns in phage sequences for graph convolutional network

Genome sequencing technologies reveal a huge amount of genomic sequences. Neural network-based methods can be prime candidates for retrieving insights from these sequences because of their applicability to large and diverse datasets.However, the highly variable lengths of nucleic acid sequences severely impair the presentation of sequences as input to the neural network. Genetic variations further complicate tasks that involve sequence comparison or alignment. Here, we propose a graph representation of nucleic acid sequences called gapped pattern graphs. These graphs can be transformed through a Graph Convolutional Network to form lower-dimensional embeddings for downstream tasks. On the basis of the gapped pattern graphs, we implemented a neural network model and demonstrated its performance in studying phage sequences. We compared our model with equivalent models based on other forms of input in performing four tasks related to nucleic acid sequences--phage and ICE discrimination, phage integration site prediction, lifestyle prediction, and host prediction. Other state-of-the-art tools were also compared, where available. Our method consistently outperformed all the other methods in various metrics on all four tasks. In addition, our model was able to identify distinct gapped pattern signatures from the sequences.

bioinformatics↗

bioRxiv2022

RapidAIM 2.0: a high-throughput assay to study functional response of human gut microbiome to xenobiotics

Our gut microbiome functions like an organ, having its own set of functions and roles which can be modulated by various types of xenobiotic and biotic components. High-throughput screening approaches that are established based on in vitro or ex vivo cell, tissue or organ models greatly accelerate drug discovery and our understanding of biological and pathological processes within these systems. There was a lack of a high-throughput compatible functional screening approach of the gut microbiome until we recently developed the RapidAIM (Rapid Assay of Individual Microbiome). RapidAIM combines an optimized culturing model, which maintains the taxonomic and functional profiles of the human gut microbiome in vitro, and a high-throughput metaproteomics workflow to gain deep functional insights into microbiome responses. This protocol describes the most recently optimized 2.0 version of RapidAIM, consisting of extensive details on stool sample collection, biobanking, in vitro culturing and stimulation, microbiome sample processing, and metaproteomics measurement and data analysis. To demonstrate the typical outcome of the protocol, we show an example of using RapidAIM 2.0 to evaluate the effect of prebiotic kestose on ex vivo individual human gut microbiomes biobanked with five different workflows; we also show that kestose had consistent functional effects across individuals and can be used as positive control in the assay.

microbiology↗

bioRxiv2021

A survey of Chinese pig farms and human healthcare isolates reveals separate human and animal MRSA populations

There has been increasing concern that the overuse of antibiotics in livestock farming is contributing to the burden of antimicrobial resistance in people. Farmed animals in Europe and North America, particularly pigs, provide a reservoir for livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA, ST398) found in people. This study was designed to investigate the contribution of MRSA from Chinese pig farms to human infection and carriage.A collection of 603 S. aureus were isolated from 55 pig farms and 4 hospitals (MRSA= 285, 198; MSSA= 50, 70) in central China, a high pig farming density area, during 2017-2018. CC9 MRSA accounting for 93% of all farm MRSA isolates, while no was found in hospitals. ST398 isolates were found on three farms (n = 23) and three hospitals (n = 12). None of the ST398 from this study belong to the livestock clade of the LA-MRSA commonly found in Europe and North America. The hospital ST398 MRSA isolates formed a clade that was clearly separate from the farm ST398 MRSA and MSSA isolates, and all possessed human immune evasion cluster genes which were absent from all the pig farm ST398 isolates. Despite the presence of high levels of MRSA found on Chinese pig farms we found no evidence of them spilling over to the human population. Nevertheless, the ST398 MRSA obtained from human samples appear to be part of a widely distributed lineage in China. And the new animal adapted ST398 lineage that emerged in China should also be alarmed. ImportanceWe disclosed the fact that although the high MRSA positive rate in Chinese hospitals and pig farms should be alarmed, they might be two separate issues. The new CC398 clades we identified highlight that the host adaption of the MRSA lineage is kept changing. These results suggest that continued surveillance of MRSA in livestock is necessary. We found that the pig farm MRSA isolates had unique antimicrobial resistance genes while most of the hospital MRSA isolates had human immune evasion cluster genes. These features could be used to distinguish the pig farm associated S. aureus in clinical laboratories. The policies of reducing antimicrobials use in livestock were implemented in China since 2020. Our study described the situation of MRSA populations in pig farms and hospitals in Central China before 2020, which provides a potential opportunity for future studies to evaluate the effects of the policies.

microbiology↗

bioRxiv2021

An awareness-dependent saliency map in the human visual system

The bottom-up contribution to the allocation of exogenous attention is a saliency map. However, how the saliency map is distributed when multiple salient stimuli are presented simultaneously and how this distribution interacts with awareness remain unclear. These questions were addressed here using visible and invisible stimuli that consisting of two salient foregrounds: the high one served as the target and the low one served as the distractor, which did or did not interfere the target saliency, indicating a gradient or winner-take-all manner, respectively. By combining psychophysics, fMRI, and effective connectivity analysis, we found that the saliency map was distributed as a gradient or winner-take-all manner with and without awareness, respectively. Crucially, we further revealed that the gradient manner was derived by feedback from pIPS, whereas the winner-take-all manner was constructed in V1. Together, our findings indicate an awareness-dependent saliency map and reconcile previous, seemingly contradictory findings on the saliency map.

neuroscience↗

bioRxiv2019

Physical activity reduces colorectal cancer risk independent of BMI - A two-sample Mendelian randomisation study

BackgroundEvidence from observational studies suggests a protective role for physical activity (PA) against colorectal cancer (CRC) risk. However, it has yet to be established a causal relationship. We conducted a two-sample Mendelian randomisation (MR) study to examine causality between physical activity and CRC risk.\n\nMethodsWe used common genetic variants associated with self-reported and accelerometer-based physical activity as instrumental variables (IVs) in this MR study. The IVs were derived from the largest available genome-wide association study (GWAS) of physical activity, namely UK Biobank. We analysed the effect of the IVs for physical activity in a large CRC GWAS that included 31 197 cases and 61 770 controls. We applied inverse variance weighted (IVW) method as the main analysis method.\n\nResultsOur results demonstrate a protective effect between accelerometer-based physical activity and CRC risk (the outlier-adjusted ORIVW was 0.92 per one standard deviation (SD) increase of accelerometer-base physical activity [95% CI: 0.87-0.98, P: 0.01]). The effect between self-reported physical activity and CRC risk was not statistically significant but was also supportive of an inverse association (the outlier-adjusted ORIVW was 0.61 per 1 SD increase of moderate-to-vigorous physical activity [95%CI: 0.36-1.06, P: 0.08]).\n\nConclusionsThe findings of this large MR study show for the first time that objectively measured physical activity is causally implicated in reducing CRC risk. The limitations of the study are that it is based on only two genetic instruments and that it has limited power, despite the study size. Nonetheless, at a population level, these findings provide strong reinforcing evidence to support public health policy measures that encourage exercise, even in obese individuals.

genetics↗