Biology subjects

Gong, Q.

Publications and source records attributed to Gong, Q..

48 records · Page 3Linked to original sources

bioRxiv2022

PALMO: a comprehensive platform for analyzing longitudinal multi-omics data

Longitudinal bulk and single-cell omics data is increasingly generated for biological and clinical research but is challenging to analyze due to its many intrinsic types of variations. We present PALMO (https://github.com/aifimmunology/PALMO), a platform that contains five analytical modules to examine longitudinal bulk and single-cell multi-omics data from multiple perspectives, including decomposition of sources of variations within the data, collection of stable or variable features across timepoints and participants, identification of up- or down-regulated markers across timepoints of individual participants, and investigation on samples of same participants for possible outlier events. We tested PALMO performance on a complex longitudinal multi-omics dataset of five data modalities on the same samples and six external datasets of diverse background. Both PALMO and our longitudinal multi-omics dataset can be valuable resources to the scientific community.

immunology↗

bioRxiv2022

uniPort: a unified computational framework for single-cell data integration with optimal transport

Single-cell data integration can provide a comprehensive molecular view of cells. Here we introduce uniPort, a unified single-cell data integration framework which combines a coupled Variational Autoencoder (coupled-VAE) and Minibatch Unbalanced Optimal Transport (Minibatch-UOT). It leverages both highly variable common and dataset-specific genes for integration and is scalable to large-scale and partially overlapping datasets. uniPort jointly embeds heterogeneous single-cell multi-omics datasets into a shared latent space. It can further construct a reference atlas for online prediction across datasets. Meanwhile, uniPort provides a flexible label transfer framework to deconvolute spatial heterogeneous data using optimal transport space, instead of embedding latent space. We demonstrate the capability of uniPort by integrating a variety of datasets, including single-cell transcriptomics, chromatin accessibility and spatially resolved transcriptome data. uniPort software is available at https://github.com/caokai1073/uniPort.

bioinformatics↗

bioRxiv2021

The brown algae Saccharina japonica and Sargassum horneri exhibit species-specific responses to synergistic stress of ocean acidification and eutrophication

Ocean acidification and eutrophication are two important environmental stressors. They inevitably impact marine macroalgae, and hence the coastal ecosystem of China. Saccharina japonica, as the main culture species in China, is suffering the harmful golden tide caused by Sargassum horneri. However, it remains unclear whether the detrimental effects of S. horneri on S. japonica cultivation become more severe in future acidified and eutrophic scenario. In this study, we respectively investigated the effects of pCO2 (400 atm and 1000 atm) and nutrients (non-enriched and enriched seawater) on the growth, photosynthesis, respiration, chlorophyll contents, and tissue nitrogen of S. japonica and S. horneri. Results indicated that enrichment of nutrients contributed S. horneri to utilize HCO3-. The carbon acquisition pathway shifted from HCO3- to CO2 in S. japonica, while S. horneri remained using HCO3- regulated by nutrient enrichment. S. horneri exhibited better photosynthetic traits than S. japonica, with a higher level of net photosynthetic rate and chlorophyll contents at elevated pCO2 and enriched nutrients. Tissue nitrogen also accumulated richly in the thalli of S. horneri under higher pCO2 and nutrients. Significant enhancement in growth was only detected in S. horneri under synergistic stress. Together, S. horneri showed competitive dominance in current study. These findings suggest that increasing risk of golden tide in acidified and eutrophic ocean can most likely result in great damage to S. japonica cultivation.

ecology↗

bioRxiv2021

Disruption of nuclear architecture as a cause of COVID-19 induced anosmia

Olfaction relies on a coordinated partnership between odorant flow and neuronal communication. Disruption in our ability to detect odors, or anosmia, has emerged as a hallmark symptom of infection with SARS-CoV-2, yet the mechanism behind this abrupt sensory deficit remains elusive. Here, using molecular evaluation of human olfactory epithelium (OE) from subjects succumbing to COVID-19 and a hamster model of SARS-CoV-2 infection, we discovered widespread downregulation of olfactory receptors (ORs) as well as key components of their signaling pathway. OR downregulation likely represents a non-cell autonomous effect, since SARS-CoV-2 detection in OSNs is extremely rare both in human and hamster OEs. A likely explanation for the reduction of OR transcription is the striking reorganization of nuclear architecture observed in the OSN lineage, which disrupts multi-chromosomal compartments regulating OR expression in humans and hamsters. Our experiments uncover a novel molecular mechanism by which a virus with a very selective tropism can elicit persistent transcriptional changes in cells that evade it, contributing to the severity of COVID-19.

neuroscience↗

bioRxiv2020

Microfluidic Device Facilitates Novel In Vitro Modeling of Human Neonatal Necrotizing Enterocolitis-on-a-Chip

Necrotizing enterocolitis (NEC) is a deadly gastrointestinal disease of premature infants characterized by an exaggerated inflammatory response, dysbiosis of the gut microbiome, decreased epithelial cell proliferation, and gut barrier disruption. Here, we describe a novel in vitro model of human neonatal small intestinal epithelium (Neonatal-Intestine-on-a-Chip) that mimics key features of intestinal physiology by utilizing a combination of premature infant intestinal enteroids co-cultured with human intestinal microvascular endothelial cells within a microfluidic device. We used our Neonatal-Intestine-on-a-Chip to recapitulate NEC pathophysiology in an in vitro model system of the premature gut inoculated with infant-derived microbiota. This model, also known as NEC-on-a-Chip, emulates the prominent features of NEC, demonstrating significant upregulation of pro-inflammatory cytokines, decreased intestinal epithelial cell markers, reduced epithelial proliferation and disrupted epithelial barrier integrity. NEC-on-a-Chip provides a novel preclinical model of NEC, which may be used as a personalized medicine approach to test new therapeutics for this devastating disease.

cell biology↗

bioRxiv2020

Large-scale Gradient Dysfunction of the Functional Connectome in Major Depression

BackgroundPatients with major depressive disorder (MDD) exhibit concurrent deficits in sensory processing and high-order cognitive functions such as self-awareness and rumination. Connectome mapping studies have suggested a principal primary-to-transmodal gradient in functional brain networks, supporting the spectrum from sensation to cognition. However, whether this principal connectome gradient is disrupted in patients with MDD and how this disruption is associated with gene expression profiles remain unclear. MethodsUsing a large cohort of resting-state functional magnetic resonance imaging data from 2,234 participants (1,150 patients with MDD and 1,084 healthy controls) recruited at 10 sites, we investigated MDD-related alterations in the principal connectome gradient. We further used Neurosynth and postmortem gene expression data to assess the cognitive functions and transcriptional profiles related to the gradient alterations in MDD, respectively. ResultsRelative to controls, patients with MDD exhibited abnormal global topography of the principal primary-to-transmodal gradient, as indicated by reduced explanation ratio, gradient range, and gradient variation (Cohens d = -0.16[~]-0.21). Focal alterations of gradient scores were mostly in the primary systems involved in sensory processing and in the transmodal systems implicated in high-order cognition. The transcriptional profiles explained 53.9% of the spatial variance in the altered gradient patterns, with the most correlated genes enriched in transsynaptic signaling and calcium ion binding. ConclusionsThese results highlight the dysfunction of the core connectome hierarchy in MDD and its linkage with gene expression profiles, providing insights into the neurobiological and molecular genetic underpinnings of sensory-cognitive deficits in this disorder.

neuroscience↗

bioRxiv2020

Structural and biochemical mechanisms of NLRP1 inhibition by DPP9

The nucleotide-binding domain (NBD) and leucine-rich repeat (LRR)-containing receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires auto-cleavage within its FIIND domain1-7. In resting cells, the dipeptidyl peptidase DPP9 interacts with NLRP1-FIIND and together with a related enzyme DPP8, suppresses spontaneous NLRP1 activation8,9. The mechanisms of DPP8/9-mediated NLRP1 inhibition, however, remain elusive. Here we provide structural and biochemical evidence demonstrating that rat NLRP1 (rNLRP1) interacts with rDPP9 in a stepwise manner to form a 2:1 complex. An auto-inhibited rNLRP1 molecule first interacts with rDPP9 via its ZU5 domain. This 1:1 rNLRP1-rDPP9 complex then captures the UPA domain of a second rNLRP1 molecule via a UPA-interacting site on DPP9 and dimeric UPA-UPA interactions with the first rNLRP1. The 2:1 rNLRP1-rDPP9 complex prevents NLRP1 UPA-mediated higher order oligomerization and maintains NLRP1 in the auto-inhibited state. Structure-guided biochemical and functional assays show that both NLRP1-binding and its enzymatic activity are required for DPP9 to suppress NLRP1, supporting guard-type activation of the NLR. Together, our data reveal the mechanism of DPP9-mediated inhibition of NLRP1 and shed light on activation of the NLRP1 inflammasome.

immunology↗

bioRxiv2020

Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related NLR proteins, NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, the molecular mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to trigger the assembly of distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core composed of oligomerized CARD domains and the outer layer consisting of FIINDUPA rings. Biochemically, oligomerized NLRP1-CARD is sufficient to drive ASC speck formation in cultured human cells via filament formation-a process that is greatly enhanced by NLRP1-FIINDUPA, which forms ring-like oligomers in vitro. In addition, we report the cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments at 3.7 [A], which uncovers unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide unique structural insight into the mechanisms of activation for human NLRP1 and CARD8, uncovering an unexpected level of specificity in inflammasome signaling mediated by heterotypic CARD domain interactions.

immunology↗

bioRxiv2020

Transcriptional Difference between SARS-COV-2 and other Human Coronaviruses Revealed by Sub-genomic RNA Profiling

BackgroundFundamental to viral biology is identification and annotation of viral genes and their function. Determining the level of coronavirus gene expression is inherently difficult due to the positive stranded RNA genome and the identification of sub-genomic RNAs (sgRNAs) that are required for expression of most viral genes. In the COVID-19 epidemic so far, few genomic studies have looked at viral sgRNAs and none have systematically examined the sgRNA profiles of large numbers of SARS-CoV2 datasets in conjuction with data for other coronaviruses. ResultsWe developed a bioinformatic pipeline to analyze the sgRNA profiles of coronaviruses and applied it to 588 individual samples from 20 independent studies, covering more than 10 coronavirus species. Our result showed that SARS-CoV, SARS-CoV-2 and MERS-CoV each had a core sgRNA repertoire generated via a canonical mechanism. Novel sgRNAs that encode peptides with evolutionarily conserved structures were identified in several coronaviruses and were expressed in vitro and in vivo. Two novel peptides may have direct functional relevance to disease, by alluding interferon responses and disrupting IL17E (IL25) signaling. Relevant to coronavirus infectivity and transmission, we also observed that the level of Spike sgRNAs were significantly higher in-vivo than in-vitro, while the opposite held true for the Nucleocapside protein. ConclusionsOur results greatly expanded the predicted number of coronaviruses proteins and identified potential viral peptide suggested to be involved in viral virulence. These methods and findings shed new light on coronavirus biology and provides a valuable resource for future genomic studies of coronaviruses.

bioinformatics↗

bioRxiv2020

Similar gut bacterial microbiota in two fruit-feeding moth pests collected from different host species and locations

Numerous gut microbes are associated with insects, but their composition remains largely unknown for many insect groups, along with factors influencing their composition. Here, we compared gut bacterial microbiota of two co-occurring agricultural pests, the peach fruit moth (PFM) and the oriental fruit moth (OFM), collected from different orchards and host plant species. Gut microbiota of both species was mainly composed of bacteria from Proteobacteria, followed by Firmicutes. The two species shared bacteria from the genera Pseudomonas, Gluconobacter, Acetobacter, and Pantoea, although endosymbiotic Wolbachia was the most abundant genus in PFM and Lactobacillus was the most abundant in OFM. PFM tended to have lower diversity and richness of gut microbiota than OFM; however, only some of the comparisons were statistically significant. Orchards can influence gut microbiota in terms of richness, particularly for PFM, but not so much for diversity parameters. Functional prediction of gut microbiota showed that the top pathways are amino acid metabolism, translation, and membrane transport in both species, but their abundance varied between the two moth species. These results show that two fruit moths share many features of gut microbiota, and the bacterial species are relatively stable within moth species even when they use different host plants. Our study suggests that fruit-feeding behavior may play a role in shaping gut microbiota of the two fruit moths, which may provide microbial targets for pest control. ImportanceUnderstanding the associated microbes with insects can point to new targets for pest control. Here we compared bacterial community in the gut of two co-occurring agricultural pests, the peach fruit moth (PFM) and the oriental fruit moth (OFM), collected from different orchards and host plant species. We found that the bacterial genera Pseudomonas, Gluconobacter, Acetobacter, and Pantoea are abundant and shared in two moths. The composition of the bacterial species is relatively stable within moth species even when they use different host plants, indicating that the gut microbiota community in the PFM and OFM is likely to be related to their fruit-feeding behavior. The findings have implications for developing novel pest control approaches by targeting gut microbes associated with the two moths.

microbiology↗

bioRxiv2019

Reproducibility of functional brain alterations in major depressive disorder: evidence from a multisite resting-state functional MRI study with 1,434 individuals

Resting-state functional MRI (R-fMRI) studies have demonstrated widespread alterations in brain function in patients with major depressive disorder (MDD). However, a clear and consistent conclusion regarding a repeatable pattern of MDD-relevant alterations is still limited due to the scarcity of large-sample, multisite datasets. Here, we address this issue by including a large R-fMRI dataset with 1,434 participants (709 patients with MDD and 725 healthy controls) from five centers in China. Individual functional activity maps that represent very local to long-range connections are computed using the amplitude of low-frequency fluctuations, regional homogeneity and distance-related functional connectivity strength. The reproducibility analyses involve different statistical strategies, global signal regression, across-center consistency, clinical variables, and sample size. We observed significant hypoactivity in the orbitofrontal, sensorimotor, and visual cortices and hyperactivity in the frontoparietal cortices in MDD patients compared to the controls. These alterations are not affected by different statistical analysis strategies, global signal regression and medication status and are generally reproducible across centers. However, these between-group differences are partially influenced by the episode status and the age of disease onset in patients, and the brain-clinical variable relationship exhibits poor cross-center reproducibility. Bootstrap analyses reveal that at least 400 subjects in each group are required to replicate significant alterations (an extent threshold of P<.05 and a height threshold of P<.001) at 50% reproducibility. Together, these results highlight reproducible patterns of functional alterations in MDD and relevant influencing factors, which provides crucial guidance for future neuroimaging studies of this disorder.

neuroscience↗

bioRxiv2018

MITA couples with PI3K to regulate actin reorganization during BCR activation

As an adaptor protein, MITA has been extensively studied in innate immunity. However, its role in adaptive immunity as well as its underlying mechanism are not completely understood. We used MITA KO mice to study the effect of MITA deficiency on B cell development and differentiation, BCR signaling during BCR activation and humoral immune response. We found that MITA deficiency promotes the differentiation of marginal zone B cells, which is linked to the lupus-like autoimmune disease that develops in MITA KO mice. MITA is involved in BCR activation and negatively regulates the activation of CD19 and Btk and positively regulates the activation of SHIP. Interestingly, we found that the activation of WASP and accumulation of F-actin is enhanced in MITA KO B cells upon stimulation. Mechanistically, we found that MITA uses PI3K mediated by the CD19-Btk axis as a central hub to control the actin remodeling that, in turn, offers feedback to BCR signaling. Overall, our study has provided a new mechanism on how MITA regulates BCR signaling via feedback from actin reorganization, which may contribute to the effects of MITA on the humoral immune response.

immunology↗