Biology subjects

Qi, G.

Publications and source records attributed to Qi, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Building an Interoperable Rare Disease Multi-omic Resource: The GREGoR Data Model and Dataset

Rare disease research and diagnosis rely on the integration of genomic and phenotypic data generated across diverse clinical sites; however, the absence of widely adopted standards for representing genomic data and associated metadata has limited data interoperability, reuse, and cross-study analysis. The Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was established to investigate challenging rare disease cases and evaluate emerging multi-omic technologies for clinical translation. To support coordinated data integration across distributed research sites, we developed a common Consortium Data Model in partnership with domain experts to standardize the capture of participant-, family-, phenotype- and assay-level metadata, with a particular emphasis on using a modular architecture to support linking of multiple data versions from multiple omic technologies to a single individual and attribution of a genetic finding to the specific technology used for its initial discovery. Adoption of the GREGoR Data Model has enabled continued generation and public release of a harmonized, analysis-ready Consortium Dataset. The most recent release includes phenotypic, family and multi-omic data from 12,292 participants in 5,029 families. Other rare disease data sharing efforts are beginning to adopt this data model which will facilitate cross consortium analyses and empower rare disease research. This work demonstrates that a collaborative, flexible, and scalable data model can enable large-scale rare disease research, facilitate cross-center data harmonization, and enable data interoperability.

genomics↗

bioRxiv2026

Morphoelectric properties of inhibitory neurons shift gradually and regardless of cell type along the depth of the cerebral cortex

How can we understand the enormous diversity of the GABAergic inhibitory neurons in the cerebral cortex? To address this question, we quantify the electrophysiological and morphological properties of inhibitory neurons across the depth of an entire cortical column in the rat barrel cortex. We find properties that shift gradually with the cortical depth of the cell bodies across all inhibitory neurons, regardless of their cell types. By isolating morphoelectric variations from their shifts along the cortical depth, we find that the same simple relationships between morphoelectric properties distinguish between the four main molecular cell types of inhibitory neurons at any cortical depth, and in both the rat barrel cortex and mouse primary visual cortex. We provide converging evidence from dense electron-microscopic reconstructions of inhibitory neurons in the mouse visual cortex, and observe comparable depth-dependent shifts in additional datasets from the mouse primary motor cortex and the middle temporal gyrus of the human cortex. Our findings indicate that two different sources of morphoelectric variations can account for the diversity of cortical inhibitory neurons. The first source is molecular cell type-specific, but cortical depth-independent. The second source is cortical depth-dependent, but affects inhibitory neurons similarly across all cell types. We propose that intrinsic developmental specification vs. extrinsic environmental modulation leads to such a decoupling of inhibitory type-specific properties from gradual shifts of these properties with cortical depth.

neuroscience↗

bioRxiv2025

CausalGRN: deciphering causal gene regulatory networks from single-cell CRISPR screens

Large-scale single-cell CRISPR screens with single-cell RNA-seq (scRNA-seq) readouts provide critical data to map causal gene regulatory networks (GRNs). However, translating the complex scRNA-seq outputs into reliable causal insights remains a major analytical challenge. Here we present CausalGRN, a scalable computational framework that infers causal GRNs and predicts cellular responses to unseen perturbations. CausalGRN first mitigates pervasive spurious partial correlations in sparse scRNA-seq data through a novel adaptive thresholding correction, enabling robust inference of an undirected graph. It then orients this graph using observed perturbation outcomes. The resulting directed GRN can be used to predict the downstream effects of novel perturbations via network propagation. Across both simulations and diverse experimental datasets, CausalGRN substantially outperforms existing approaches in network reconstruction accuracy and in predicting the effects of unseen perturbations, providing a principled bridge from perturbation data to causal gene regulation.

bioinformatics↗

bioRxiv2025

MECP2 Duplication Uncouples Mitochondrial and Purine Metabolism During neuronal maturation

Mitochondria and nucleotide metabolism are critical for cellular and developmental homeostasis, yet their potential interdependence and role in neurodevelopmental disease remain unclear. In MECP2 Duplication Syndrome (MDS), we identify a conserved correlation between mitochondrial function and purine metabolism that is disrupted across human, organoid, and mouse models. Multiomics integration reveals Complex III as the focal point of mitochondrial collapse, leading to redox stress, DNA damage, and hyperactivation of the de novo purine biosynthesis via purinosome assembly. The breakdown of mitochondria-purinosome coupling compromises genome stability, impairs radial glia proliferation, and delays neuronal maturation. By linking a defined genetic dosage imbalance to metabolic network failure, our study positions the mitochondria-purinosome coordination as a fundamental control axis for neurodevelopment and a therapeutic entry point across metabolic and neurodevelopmental disorders. Metabolic control is fundamental to cellular function, influencing energy production, signaling, epigenetic regulation, and tissue homeostasis1. Nowhere is this more critical than in the brain, where tightly regulated metabolic networks sustain high energetic demands and support neuronal development, synaptic plasticity, and circuit formation2. Disruptions in these networks are increasingly implicated across a spectrum of neurodevelopmental disorders3-5, yet their precise metabolic signatures and mechanistic contributions remain poorly understood.

neuroscience↗

bioRxiv2025

DAESC+: High-performance, integrated software for single-cell allele-specific expression data

Single-cell allele-specific expression (ASE) provides valuable insights into gene regulatory mechanisms. However, its utility is limited by the lack of dedicated computational tools. We present DAESC+, an end-to-end software package for the processing and analysis of single-cell ASE. The preprocessing module, DAESC-P, is a user-friendly bioinformatics pipeline to obtain ASE counts from multiplexed scRNA-seq data. The analysis module, DAESC-GPU, is a scalable tool for differential ASE analysis powered by graphics processing units (GPUs). We demonstrated that DAESC-P is more accurate than the existing SALSA pipeline. DAESC-GPU is dozens of times faster than our previous method (DAESC) and scalable to over a million cells. Applying DAESC+ to a subset of the OneK1K cohort, we identified 15 genes exhibiting differential regulatory patterns between naive and central memory CD4+ T cells, and 2 genes between naive and memory B cells.

bioinformatics↗

bioRxiv2025

Cis-delivering releasable IL-15 superagonist enhances antitumor immunity in cold tumors by invigorating preexisting CD25+CD8+ T cells

Antibody-mediated cis-delivery and trans-delivery both direct cytokines to tumors and have been extensively investigated in clinical trials. However, a comparative analysis of their differential effects on cytokine activity is still lacking. In this study, we initially verify that cis-delivery of cytokine demonstrates a markedly stronger antitumor effect than trans-delivery, but it also exhibits certain drawbacks, including severe toxicity, insufficient activation of CD25+CD8+ T cells, and enhanced stimulation of intratumoral regulatory T cells (Tregs). To further address these issues, we developed a conditionally releasable and cis-delivering IL-15 immunocytokine (termed PMIS), which can selectively release a free IL-15 superagonist within tumors rather than immobilizing IL-15 to PD-1+ Tregs, thereby potently stimulating CD25+CD8+ T cells. Mice treated with PMIS showed significantly reduced systemic toxicities while achieving notably stronger antitumor effects. Administered either alone or in combination with other therapies, PMIS exhibits great potential for inhibiting orthotopic cold tumor and its metastases. Mechanistically, the significant activation of the pre-existing intratumoral CD25+CD8+ T cells and the improved CD25+CD8/Treg ratio contribute to the enhanced antitumor response of PMIS. These findings underscore the indispensable role of CD25+CD8+ T cells in cis-delivering IL-15 and provide a promising strategy for overcoming resistance to therapies and effectively controlling advanced cold tumors.

immunology↗

bioRxiv2025

Compositionality of social gaze in the prefrontal-amygdala circuits

Social gaze underpins primate communication, yet the neural principles enabling its flexibility remain unknown. Each social gaze can be deconstructed into three primitives: gaze content, social state, and gaze duration. To reduce dimensionality and facilitate generalization, the brain needs to represent these primitives in an abstract format. Here we show that social gaze is governed by a compositional code built from these primitives in the brain. In male and female macaques (neural recordings in two males) engaged in real-life social gaze interaction, behavior analyses revealed that partner responses were determined by how primitives were combined, rather than by their independent sums, providing evidence for behavioral compositionality. The basolateral amygdala and the anterior cingulate gyrus represented content and state in an abstract format and orthogonally to one another, whereas the dorsomedial prefrontal and orbitofrontal cortices exhibited limited generalization. Linear mixed-selective neurons encoding both content and state in the basolateral amygdala and the anterior cingulate gyrus, but not in the other two areas, facilitated the abstraction underlying generalization. Moreover, distinct channels routed content and state information across prefrontal-amygdala circuits to minimize interference, which was mediated by linear mixed selectivity neurons. These findings identify a neural grammar for social gaze, revealing compositional computations as a principle of flexible social communication.

neuroscience↗

bioRxiv2025

Early transcriptional signatures of MeCP2 positive and negative cells in Rett syndrome

Rett syndrome (RTT) is an X-linked neurological disorder caused by MECP2 mutations. Like other X-linked disorders, RTT patients have sex-specific differences in clinical presentation due to distinct cellular environments, where females have [~]50% of cells expressing either a mutant or wild-type copy of MECP2 (mosaic) and males have 100% of cells expressing a mutant MECP2 (non-mosaic). Typical RTT females have a short window of normal early development until [~]6-18 months, followed by regression and progressive decline, whereas neonatal encephalopathy is more likely in RTT males. How these sex-specific differences in cellular context contribute molecularly to RTT pathogenesis, particularly in the presymptomatic stages of RTT females, remains poorly understood. Here, we profiled the hippocampal transcriptomes of female (Mecp2+/-) and male (Mecp2-/y) RTT mice at early timepoints using both bulk and single-nucleus RNA-seq, including sorted MeCP2 positive (MeCP2+) and MeCP2 negative (MeCP2-) neurons in female mice. We identified a core disease signature consisting of 12 genes consistently dysregulated only in MeCP2-cells across RTT models. Moreover, we uncovered non-cell-autonomous effects exclusively in female MeCP2+ excitatory neurons, but not inhibitory neurons, suggesting excitatory circuits are more vulnerable early in the mosaic RTT environment. The single-nuclei data also revealed that a previously underappreciated MeCP2-interneuron subtype had the most transcriptional dysregulation in both male and female RTT hippocampi. Together, these data highlight the different effects of MeCP2 loss on excitatory and inhibitory circuits between the mosaic and non-mosaic environment that appear early in RTT pathogenesis.

neuroscience↗

bioRxiv2024

Transport-Related Effects on Intrinsic and Synaptic Properties of Human Cortical Neurons: A Comparative Study

Transporting human brain tissue from the operating theater to an off-site laboratory may affect sample integrity for electrophysiological studies. This study investigated how a 30-40 minute transport influenced the intrinsic, synaptic, and morphological properties of human cortical neurons. Electrophysiological recordings were performed on Layer 2/3 (L2/3 pyramidal cells and fast-spiking (FS) interneurons from human cortical slices (n = 200 neurons from 32 surgeries), comparing on-site recordings at RWTH Aachen University Hospital and off-site at Research Centre Juelich. Action potential firing patterns remained largely preserved across both recording sites, but several differences were observed. Off-site recorded pyramidal cells showed a slightly depolarized resting membrane potential and a significantly lower rheobase current. In off-site recorded FS interneurons, we found a narrower action potential half-width and an increased amplitude, suggesting altered ion channel kinetics and/or neuromodulatory environment. Additionally, a significant reduction in large rhythmic depolarizations (LRDs) and the amplitudes of excitatory postsynaptic potentials (EPSPs) in off-site recorded FS interneurons indicated an impaired synaptic efficacy. The dendritic spine densities in apical oblique and apical tuft dendrites of off-site recorded pyramidal cells were also reduced. These findings emphasize the need for optimized transport conditions to preserve synaptic integrity, network properties, and neuronal morphology. Standardized protocols are crucial for ensuring reliable and reproducible results in studies of human cortical microcircuits. Significance StatementThis study demonstrates that transporting live human brain tissue for neuronal recordings significantly impacts the intrinsic, synaptic, and network properties of cortical neurons. By comparing on-site and off-site recordings, we found that even a brief transportation (30-40 minutes) induces increased neuronal excitability, reduced synaptic efficacy, and diminished network events such as LRDs. These alterations are likely due to the mechanical stress and washout of critical neuromodulators, which compromise tissue integrity and neuronal function. The findings underscore the necessity for optimizing transport protocols to preserve synaptic and network integrity, ensuring reliable and reproducible results in human brain research. Ultimately, this work advances our understanding of cortical microcircuitry and informs best practices for handling human brain tissue in experimental settings.

neuroscience↗

bioRxiv2024

Estrus-Tracking Cortical Neurons Integrate Social cues and Reproductive states to Adaptively Control Sexually Dimorphic Sociosexual Behaviors

Female sociosexual behaviors, essential for survival and reproduction, are adaptively modulated by ovarian hormones. However, the neural mechanisms integrating internal hormonal states with external social cues to guide these behaviors remain poorly understood. Here we identified primary estrous-sensitive Cacna1h-expressing medial prefrontal (mPFCCacna1h+) neurons that orchestrate adaptive sociosexual behaviors. Bidirectional manipulation of mPFCCacna1h+ neurons drives opposite-sex-directed behavioral shifts between estrus and diestrus females. In males, these neurons serve opposite functions compared to estrus females, mediating sexually dimorphic effects via anterior hypothalamic outputs. Miniscope imaging reveals mixed-representation of self-estrous states and social target sex in distinct mPFCCacna1h+ subpopulations, with biased-encoding of opposite-sex social cues in estrus females and males. Mechanistically, ovarian hormone-driven upregulation of Cacna1h-encoded T-type calcium channels underlies estrus-specific activity changes and sexual-dimorphic function of mPFCCacna1h+ neurons. These findings uncover a prefrontal circuit that integrates internal hormonal states and target-sex information to exert sexually bivalent top-down control over adaptive social behaviors.

neuroscience↗

bioRxiv2024

FOXP2-immunoreactive, corticothalamic pyramidal cells in neocortical layers 6a and 6b are tightly regulated by neuromodulatory systems

The FOXP2/Foxp2 gene is involved in fine motor control in many vertebrate species; in humans, it is one of the candidate genes thought to play a prominent role in language production. Several studies suggest that in the neocortex, Foxp2 is exclusively expressed in a subset of corticothalamic (CT) pyramidal cells (PCs) in layer 6 (L6). However, the morphological and intrinsic electrophysiological, synaptic and neuromodulatory properties of Foxp2-expressing L6 PCs remain largely unknown. Here we systematically characterise these properties for FOXP2-positive (FOXP2+) PCs across L6 in the rat somatosensory cortex. We find that L6 FOXP2+ PCs are distinct in all of these properties from those of L6 FOXP2-negative (FOXP2-) neuronal cell types. We show that L6 FOXP2+ PCs project exclusively to thalamus. In upper L6 (L6a), FOXP2+ PCs innervate either the first-order thalamus or both first and higher-order thalamic nuclei. FOXP2+ PCs in deep L6 (L6b) project almost exclusively to higher-order thalamus. Synaptic connections established by L6a and L6b FOXP2+ PCs exhibit low synaptic release probability, whereas L6 corticocortical PCs have a high release probability. Both L6a and L6b FOXP2+ PCs respond strongly to acetylcholine (ACh), which in the absence of TTX results in firing of action potential (AP) trains. Notably, L6b but not L6a FOXP2- PCs are highly sensitive to ACh. In addition, L6b FOXP2+ PCs close to the white matter border show strong responses to dopamine that develop into prolonged AP firing. Our data suggest that FOXP2 is a marker for CT PCs in L6 that are strongly controlled by neurotransmitters such as ACh and dopamine. These findings are in line with a pivotal role for both L6a and L6b CT PCs as modulators of thalamic activity.

neuroscience↗

bioRxiv2024

Linking Altered Neuronal and Synaptic Properties to Nicotinic Receptor Alpha5 Subunit Gene Dysfunction: A Translational Investigation in Rat mPFC and Human Cortical Layer 6

BackgroundGenetic variation in the 5 nicotinic acetylcholine receptor (nAChR) subunit of mice results in behavioral deficits linked to the prefrontal cortex (PFC). A Single Nucleotide Polymorphisms (SNP) in CHRNA5 imparts a partial loss of function to the 5 subunit-containing (5*) nAChRs and have been demonstrated to be associated with psychiatric disorders in humans, including schizophrenia, nicotine dependence, cocaine and alcohol addiction. MethodsWe performed single cell-electrophysiology combined with morphological reconstructions on layer 6 (L6) excitatory neurons in the medial PFC (mPFC) of wild type (WT) rats (n = 25), rats carrying the human coding polymorphism rs16969968 in Chrna5 (n = 11) and 5 knockout (KO) rats (n = 28). Neuronal and synaptic properties were compared among three rat genotypes. Galantamine was applied to identified L6 neuron populations to specifically boost the nicotinic responses mediated by 5*nAChRs in the rat mPFC and human neocortex (n = 6 patients). ResultsCompared with neurons in WT rats, L6 regular spiking (RS) neurons in the 5KO group exhibited altered electrophysiological properties, while those in 5SNP rats remained unchanged. L6 RS neurons in mPFC of 5SNP and 5KO rats differed from WT rats in dendritic morphology, spine density and spontaneous synaptic activity. Galantamine acted as a positive allosteric modulator of 5*nAChRs in RS but not burst spiking (BS) neurons in both rat and human cortical L6. ConclusionOur findings suggest that dysfunction in the 5 subunit gene leads to aberrant neuronal and synaptic properties, shedding light on the underlying mechanisms of cognitive deficits observed in human populations carrying 5SNPs. They highlight a potential pharmacological target for restoring the relevant behavioral output.

neuroscience↗

bioRxiv2023

A Layered Microcircuit Model of Somatosensory Cortex with Three Interneuron Types and Cell-Type-Specific Short-Term Plasticity

Three major types of GABAergic interneurons, parvalbumin- (PV), somatostatin- (SOM) and vasoactive intestinal peptide-expressing (VIP) cells, play critical but distinct roles in the cortical microcircuitry. Their specific electrophysiology and connectivity shape their inhibitory functions. To study the network dynamics and signal processing specific to these cell types in the cerebral cortex, we developed a multi-layer model incorporating biologically realistic interneuron parameters from rodent somatosensory cortex. The model is fitted to in vivo data on cell-type-specific population firing rates. With a protocol of cell-type-specific stimulation, network responses when activating different neuron types are examined. The model reproduces the experimentally observed inhibitory effects of PV and SOM cells and disinhibitory effect of VIP cells on excitatory cells. We further create a version of the model incorporating cell-type-specific short-term synaptic plasticity (STP). While the ongoing activity with and without STP is similar, STP modulates the responses of Exc, SOM, and VIP cells to cell-type-specific stimulation, presumably by changing the dominant inhibitory pathways. With slight adjustments, the model also reproduces sensory responses of specific interneuron types recorded in vivo. Our model provides predictions on network dynamics involving cell-type-specific short-term plasticity and can serve to explore the computational roles of inhibitory interneurons in sensory functions.

neuroscience↗

bioRxiv2023

Modulation of Giant Depolarizing Potentials (GDPs) in Human Large Basket Cells by Norepinephrine and Acetylcholine

Rhythmic brain activity has been implicated in many brain functions and it is sensible to neuromodulation, but so far very few studies have investigated this activity on the cellular level in vitro in human tissue samples. In this study we revealed and characterized a novel rhythmic network activity in human neocortex. Intracellular patch-clamp recordings showed that giant depolarizing potentials (GDPs) were frequently found in human cortical neurons. GDPs appeared in a low frequency band ([~] 0.3 Hz) similar to that described for slow oscillations in vivo and displayed large amplitudes and long decay times. Under the same experimental conditions, no rhythmic activity was found in L2/3 of the rat neocortex. GDPs were predominantly observed in a subset of L2/3 interneurons considered to be large basket cells based on previously described morphological features. In addition, GDPs are highly sensitive to norepinephrine (NE) and acetylcholine (ACh), two neuromodulators known to modulate low frequency oscillations. NE increased the frequency of the GDPs by enhancing {beta}-adrenergic receptor activity while ACh decreased GDP frequency through M4 muscarinic receptor-activation. Multi-electrode array (MEA) recordings demonstrated that NE promoted synchronous oscillatory network activity while the application of ACh led to a desynchronization of neuronal activity. Our data indicate that the human neocortex is more prone to generate slow wave activity, which was reflected by more pronounced GDPs in L2/3 large basket cells. The distinct modulation of GDPs and slow wave activity by NE and ACh exerts a specific modulatory control over the human neocortex.

neuroscience↗

bioRxiv2022

Uncovering context-specific genetic-regulation of gene expression from single-cell RNA-sequencing using latent-factor models

Genetic regulation of gene expression is a complex process, with genetic effects known to vary across cellular contexts such as cell types and environmental conditions. We developed SURGE, a method for unsupervised discovery of context-specific expression quantitative trait loci (eQTLs) from single-cell transcriptomic data. This allows discovery of the contexts or cell types modulating genetic regulation without prior knowledge. Applied to peripheral blood single-cell eQTL data, SURGE contexts capture continuous representations of distinct cell types and groupings of biologically related cell types. We demonstrate the disease-relevance of SURGE context-specific eQTLs using colocalization analysis and stratified LD-score regression.

bioinformatics↗

bioRxiv2022

Study of Pinelliae Rhizoma hepatotoxicity based on complex network algorithm improvement

Important protein identification methods based on centrality have reached a high level of accuracy. However, there is a need to improve centrality algorithms because they currently consider the nature of protein-protein interaction (PPI) network topology but not protein properties. To improve the centrality algorithm, we introduce the weighted PageRank algorithm, which represents node importance, and the protein interaction combined_score, which represents PPI network edge importance in the STRING database to construct a weighted PPI network. We constructed yeast protein networks for simulations to validate the improved algorithm. Finally, we studied the hepatotoxicity of Pinelliae Rhizoma by applying the PageRank and Edge Clustering (PEC) algorithm. Our study shows that the PageRank and Edge Clustering algorithm can pre-screen important targets and has superior accuracy, sensitivity, and specificity to other centrality algorithms.

pharmacology and toxicology↗

bioRxiv2022

Single-cell allele-specific expression analysis reveals dynamic and cell-type-specific regulatory effects

Allele-specific expression, which measures the expression of two alleles of a gene in a diploid individual, is a powerful signal to study cis-regulatory effects. Comparing ASE across conditions, or differential ASE, can reveal context-specific gene regulation. Recently, single-cell RNA sequencing (scRNA-seq) has allowed the measurement of ASE at the resolution of individual cells, but there is a lack of statistical methods to analyze such data. We develop DAESC, a statistical method for differential ASE analysis across any condition of interest using scRNA-seq data from multiple individuals. DAESC includes a baseline model based on beta-binomial regression with random effects accounting for multiple cells from the same individual (DAESC-BB), and an extended mixture model that incorporates implicit haplotype phasing (DAESC-Mix). We demonstrate through simulations that DAESC accurately captures differential ASE effects in a wide range of scenarios. Application to scRNA-seq data from 105 induced pluripotent stem cell lines identifies 657 genes that are dynamically regulated during endoderm differentiation. A second application identifies several genes that are differentially regulated in pancreatic endocrine cells between type 2 diabetes patients and controls. In conclusion, DAESC is a powerful method for single-cell differential ASE analysis and can facilitate the discovery of context-specific regulatory effects.

genomics↗

bioRxiv2022

Genome-Wide Large-Scale Multi-Trait Analysis Characterizes Global Patterns of Pleiotropy and Unique Trait-Specific Variants

Genome-wide association studies (GWAS) have found widespread evidence of pleiotropy, but characterization of global patterns of pleiotropy remain highly incomplete due to insufficient power of current approaches. We develop fastASSET, an extension of the method ASSET, to allow computationally efficient detection of variant-level pleiotropic association across a large number of traits. We analyze GWAS summary statistics of 116 complex traits of diverse types collected from the NIH GRASP repository and a number of other large GWAS consortia. We identify a total of 2,293 independent loci at the genome-wide significance level and found that the lead variants in nearly all of these loci ([~]99%) to be associated with to two or more (median = 6) traits. Further, the estimated degree of pleiotropy for the detected variants strongly predicted their degree of pleiotropy across a much larger number of traits (K=4,114) in the UK Biobank Study. Follow-up analyses of 21 unique trait-specific variants suggest that they are often linked to the expression in trait-related tissues for a small number of genes, some of which are well known to be involved in relevant biological processes. Our findings provide deeper insight into the nature of complex trait pleiotropy and leads to, for the first time, identification of highly unique trait-specific susceptibility variants.

genetics↗