Biology subjects

Liang, Q.

Publications and source records attributed to Liang, Q..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

Hydroxycitric acid inhibits oxalate nephropathies formation through crystallization regulation and activation of the PPARα pathway

Oxalate-induced nephropathies comprise a range of kidney disorders, for which there are no efficient pharmacological treatments. Hydroxycitric acid (HCA) is a derivative of citric acid with a variety of pharmacological activities including reducing body weight and calcium salt deposition. However, the specific mechanism of inhibition of oxalate nephropathies by this compound is not well understood. In this study, we successfully applied bioinformatics-based and simulated drug molecular docking approaches to predict potential targets of HCA. Subsequently, we explored the molecular mechanisms of HCA inhibition of renal calcium oxalate (CaOx) deposition and nephrotoxicity in an oxalate-induced NRK-52E cell model and an oxalate nephropathy rat model. HCA could effectively inhibit CaOx crystal deposition and reduce crystal adhesion and oxidative damage, effectively inhibit lipid deposition caused by high oxalate, and reduce lipid nephrotoxicity. HCA is more effective than traditional stone medications in inhibiting CaOx deposition and kidney damage. Further cellular transcriptomic analysis and in vitro results showed that HCA could stably bind peroxisome proliferator-activated receptor (PPAR) and promote PPAR-RXR heterodimer formation, thus promoting the expression of downstream oxidative stress molecules (Nrf2, HO-1, SOD) and inhibiting calcium ion release and mitochondrial dysfunction, thus reducing oxalate-induced renal lipid peroxidation damage. Therefore, HCA, a novel drug with the ability to modulate lipid metabolism and inhibit CaOx formation, may be a therapeutic option for the treatment of oxalate nephropathies.

biochemistry↗

bioRxiv2022

Spatial organization of the mouse retina at single cell resolution

The visual signal processing in the retina requires the precise organization of diverse neuronal types working in concert. We performed spatial transcriptomic profiling of over 100,000 cells from the mouse retina, uncovering the spatial distribution of all major retina cell types with over 100 cell subtypes. Our data revealed that the retina is organized in a laminar structure at the major cell type and subgroup level, both of which has strong correlation with the birth order of the cell. In contrast, overall random dispersion of cells within sub-laminar layers indicates that retinal mosaics are driven by dendritic field patterning rather than neuron soma placement. Through the integration of single cell transcriptomic and spatial data, we have generated the first comprehensive spatial single cell reference atlas of the mouse retina, a resource to the community and an essential step toward gaining a comprehensive understanding of the mechanism of retinal function. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/518972v1_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@1dc0eaforg.highwire.dtl.DTLVardef@480731org.highwire.dtl.DTLVardef@d0221borg.highwire.dtl.DTLVardef@6f5894_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

A multi-omics atlas of the human retina at single-cell resolution

Cell classes in the human retina are highly heterogeneous with their abundance varying by several orders of magnitude. Although previous studies reported the profiles of the retinal cell types as the transcriptome level, there is no study regarding the open-chromatin profiles at a similar resolution. Here, we generated and integrated a multi-omics single-cell atlas of the adult human retina, including over 250K nuclei for single-nuclei RNA-seq and 137K nuclei for single-nuclei ATAC-seq. Through enrichment of rare cell types, this single cell multiome atlas is more comprehensive than previous human retina studies. Cross species comparison of the retina atlas among human, monkey, mice, and chicken revealed relatively conserved and non-conserved types. Interestingly, the overall cell heterogeneity in primate retina decreases compared to that of rodent and chicken retina. Furthermore, integrative analysis of the single cell multi-omics data identified 35k distal cis-element-gene pairs with most of these cis-elements being cell type specific. We also showed that the cis-element-gene relationship in different cell types within the same class could be highly heterogenous. Moreover, we constructed transcription factor (TF)-target regulons for over 200 TFs, partitioned the TFs into distinct co-active modules, and annotated each module based on their cell-type specificity. Taken together, we present the most comprehensive single-cell multi-omics atlas of the human retina as a valuable resource that enables systematic in-depth molecular characterization at individual cell type resolution.

genomics↗

bioRxiv2022

Integrative single cell multiomics analysis of human retina indicates a role for hierarchical transcription factors collaboration in genetic effects on gene regulation

BackgroundSystematic characterization of how genetic variation modulates gene regulation in a cell type specific context is essential for understanding complex traits. To address this question, we profiled gene expression and chromatin state of cells from healthy retinae of 20 human donors with a single-cell multiomics approach, and performed genomic sequencing. ResultsWe mapped single-cell eQTL (sc-eQTLs), single-cell caQTL (sc-caQTL), single-cell allelic specific chromatin accessibility (sc-ASCA) and single-cell allelic specific expression (sc-ASE) in major retinal cell types. By integrating these results, we identified and characterized regulatory elements and genetic variants effective on gene regulation in individual cell types. Most of the sc-eQTLs and sc-caQTLs identified show cell type specific effects, while the cis-elements containing the genetic variants with cell type specific effects tend to be accessible in multiple cell types. Furthermore, the transcription factors with binding sites perturbed by genetic variants tend to have higher expression in the cell types, where the variants have effect, than the cell types where the variants do not have effect. Finally, we identified the enriched cell types, candidate causal variants and genes, and cell type specific regulatory mechanism underlying GWAS loci. ConclusionsOverall, genetic effects on gene regulation are highly context dependent. Our results suggest that among cell types sharing a similar lineage, cell type dependent genetic effect is primarily driven by trans-factors rather than cell type specific chromatin state of cis-elements. Our findings indicate a role for hierarchical transcription factors collaboration in cell type specific effects of genetic variants on gene regulation.

genomics↗

bioRxiv2022

Identifying Patients with Cognitive Motor Dissociation Using Resting-state Temporal Stability

BackgroundUsing task-dependent neuroimaging techniques, recent studies discovered a fraction of patients with disorders of consciousness (DOC) who had no command-following behaviors but showed a clear sign of awareness, which was defined as cognitive motor dissociation (CMD). Although many efforts were made to identify the CMD, existing task-dependent approaches might fail when patients had multiple cognitive function (e.g., attention, memory) impairments, and thus lead to false-negative findings. However, recent advances in resting-state fMRI (rs-fMRI) analysis allow investigation of the dynamic change of spontaneous brain activity, which might be a powerful tool to test the patients cognitive functions, while its capacity in identifying CMD was unclear. MethodsThe rs-fMRI study included 119 participants from three independent research sites. A sliding-window approach was used to investigate the dynamic functional connectivity of the brain in two aspects: the global and regional temporal stability, which measures how stable the brain functional architecture is across time. The temporal stability was compared in the first dataset (36/16 DOC/controls), and then a Support Vector Machine (SVM) classifier was built to discriminate DOC patients from controls. Furthermore, the generalizability of the SVM classifier was tested in the second independent dataset (35/21 DOC/controls). Finally, the SVM classifier was applied to the third independent dataset where patients underwent an rs-fMRI and brain-computer interface assessment (4/7 CMD/potential non-CMD), to test its performance in identifying CMD. ResultsOur results showed that the global and regional temporal stability were impaired in DOC patients, especially in regions from the cingulo-opercular task control, default mode, fronto-parietal task control, and salience network. Using the temporal stability as features, the SVM model not only showed a good performance in the first dataset (accuracy = 90 %), but a good generalizability in the second dataset (accuracy = 82 %). Most importantly, the SVM model generalized well in identifying CMD in the third dataset (accuracy = 91 %). ConclusionThe current findings suggested that rs-fMRI could be a potential tool to assist in diagnosing CMD. Furthermore, the temporal stability investigated in this study also contributed to a deeper understanding of the neural mechanism of the consciousness.

neuroscience↗

bioRxiv2022

Trends in self-citation rates in neuroscience literature

Citation metrics influence academic reputation and career trajectories. Recent works have highlighted flaws in citation practices in the Neurosciences, such as the under-citation of women. However, self-citation rates--or how much authors cite themselves--have not yet been comprehensively investigated in the Neurosciences. This work characterizes self-citation rates in basic, translational, and clinical Neuroscience literature by collating 100,347 articles from 63 journals between the years 2000-2020. In analyzing over five million citations, we demonstrate four key findings: 1) increasing self-citation rates of Last Authors relative to First Authors, 2) lower self-citation rates in low- and middle-income countries, 3) gender differences in self-citation stemming from differences in the number of previously published papers, and 4) variations in self-citation rates by field. Our characterization of self-citation provides insight into citation practices that shape the perceived influence of authors in the Neurosciences, which in turn may impact what type of scientific research is done and who gets the opportunity to do it.

neuroscience↗

bioRxiv2022

A view of the pan-genome of domesticated cowpea (Vigna unguiculata Walp.)

Cowpea, Vigna unguiculata L. Walp., is a diploid warm-season legume of critical importance as both food and fodder in sub-Saharan Africa. This species is also grown in Northern Africa, Europe, Latin America, North America, and East to Southeast Asia. To capture the genomic diversity of domesticates of this important legume, de novo genome assemblies were produced for representatives of six sub-populations of cultivated cowpea identified previously from genotyping of several hundred diverse accessions. In the most complete assembly (IT97K-499-35), 26,026 core and 4,963 noncore genes were identified, with 35,436 pan genes when considering all seven accessions. GO-terms associated with response to stress and defense response were highly enriched among the noncore genes, while core genes were enriched in terms related to transcription factor activity, and transport and metabolic processes. Over 5 million SNPs relative to each assembly and over 40 structural variants >1 Mb in size were identified by comparing genomes. Vu10 was the chromosome with the highest frequency of SNPs, and Vu04 had the most structural variants. Noncore genes harbor a larger proportion of potentially disruptive variants than core genes, including missense, stop gain, and frameshift mutations; this suggests that noncore genes substantially contribute to diversity within domesticated cowpea. Article SummaryThis study reports annotated genome assemblies of six cowpea accessions. Together with the previously reported annotated genome of IT97K-499-35, these constitute a pan-genome resource representing six subpopulations of domesticated cowpea. Annotations include genes, variant calls for SNPs and short indels, larger presence or absence variants, and inversions. Noncore genes are enriched for loci involved in stress response and harbor many genic variants with potential effects on coding sequence.

genomics↗

bioRxiv2022

Characterizing transition cells in developmental processes from scRNA-seq data

Multi-cellular organism development involves orchestrated gene regulations of different cell types and cell states. Single-cell RNA-Seq, enable simultaneous observation of cells in various states, making it possible to study the underlying molecular mechanisms. However, most of the analytical methods do not make full use of the dynamics captured. Here, we model single-cell RNA-seq data obtained from a developmental process as a function of gene regulatory network using stochastic differential equations (SDEs). Based on dynamical systems theory, we showed that pair-wise gene expression correlation coefficients can accurately infer cell state transitions and validated it using mouse muscle cell regeneration scRNA-seq data. We then applied our analytical framework to the PDAC (Pancreatic ductal adenocarcinoma) mouse model scRNA-seq data. Through transition cells found in the pancreatic preinvasive lesions scRNA-seq data, we can better explain the heterogeneity and predict distinct cell fate even at early tumorigenesis stage. This suggests that the biomarkers identified by transition cells can be potentially used for diagnosis, prognosis and therapeutics of diseases.

bioinformatics↗

bioRxiv2022

Decoding The Nuclear Genome of The Human Pathogen Babesia duncani Shed Light on its Virulence, Drug Susceptibility and Evolution among Apicomplexa

Babesia species are tick-transmitted apicomplexan pathogens and the causative agents of babesiosis, a malaria-like disease of major medical and veterinary importance. Of the different species of Babesia reported so far, Babesia duncani causes severe to lethal infection in patients. Despite the highly virulent nature of this parasite and the risk it may pose as an emerging pathogen, little is known about its biology, metabolic requirements, and pathogenesis. B. duncani is unique among apicomplexan parasites that infect red blood cells in that it can be continuously cultured in vitro in human erythrocytes but can also infect mice leading to fulminant babesiosis infection and death. Here we have taken advantage of the recent advances in the propagation of this parasite in vitro and in vivo to conduct detailed molecular, genomic and transcriptomic analyses and to gain insights into its biology. We report the assembly, 3D structure, and annotation of the nuclear genome of this parasite as well as its transcriptomic profile and an atlas of its metabolism during its intraerythrocytic life cycle. Detailed examination of the B. duncani genome and comparative genomic analyses identified new classes of candidate virulence factors, suitable antigens for diagnosis of active infection, and several attractive drug targets. Translational analyses and efficacy studies identified highly potent inhibitors of B. duncani thus enriching the pipeline of small molecules that could be developed as effective therapies for the treatment of human babesiosis.

microbiology↗

bioRxiv2022

Broadly neutralizing and protective nanobodies against diverse sarbecoviruses

As SARS-CoV-2 Omicron and other variants of concern continue spreading around the world, development of antibodies and vaccines to confer broad and protective activity is a global priority. Here, we report on the identification of a special group of nanobodies from immunized alpaca with exceptional breadth and potency against diverse sarbecoviruses including SARS-CoV-1, Omicron BA.1, and BA.2. Crystal structure analysis of one representative nanobody, 3-2A2-4, revealed a highly conserved epitope between the cryptic and the outer face of the receptor binding domain (RBD). The epitope is readily accessible regardless of RBD in "up" or "down" conformation and distinctive from the receptor ACE2 binding site. Passive delivery of 3-2A2-4 protected K18-hACE2 mice from infection of authentic SARS-CoV-2 Delta and Omicron. This group of nanobodies and the epitope identified should provide invaluable reference for the development of next generation antibody therapies and vaccines against wide varieties of SARS-CoV-2 infection and beyond.

immunology↗

bioRxiv2022

Comparative miRNA Transcriptomics of Mouse and Macaque Reveals Cytoskeleton is An Inhibitor for C. neoformans Invasion into Brain

Cryptococcal meningoencephalitis is an emerging infection shifted from primarily ART-naive to being ART-experienced HIV/AIDS patients, COVID-19 patients and also in immune competent individuals, mainly caused by the human opportunistic pathogen Cryptococcus neoformans, yet mechanisms of the brain or CNS dissemination remain to elucidate, which is the deadest process for the disease. Meanwhile, illustrations of clinically relevant responses in cryptococcosis were limited, as the low availabilities of clinical samples. In this study, macaque and mouse infection models were employed and miRNA-mRNA transcriptomes were performed and combined, which revealed cytoskeleton, a major feather in HIV/AIDS patients, was a centric pathway regulated in both two infection models. Notably, assays of clinical immune cells confirmed an enhanced "Trojan Horse" in HIV/AIDS patients, which can be shut down by cytoskeleton inhibitors. Furthermore, we identified a novel enhancer for macrophage "Trojan Horse", myocilin, and an enhanced fungal burden was achieved in brains of MYOC transgenic mice. Taking together, this study reveals fundamental roles of cytoskeleton and MYOC in blocking fungal CNS dissemination, which not only helps to understand the high prevalence of cryptococcal meningitis in HIV/AIDS, but also facilitates the development of novel drugs for therapies of meningoencephalitis caused by C. neoformans and other pathogenic microorganisms.

microbiology↗

bioRxiv2021

Tomato SlBES1.8 influences leaf morphogenesis by mediating gibberellin metabolism and signaling

Leaf morphogenetic activity determines its shape diversity. However, our knowledge to the regulatory mechanism in maintaining leaf morphogenetic capacity is still limited. In tomato, gibberellin (GA) negatively regulates leaf complexity by shortening the morphogenetic window. We here reported a tomato BRI1-EMS-SUPPRESSOR 1 (BES1) transcription factor, SlBES1.8, that promoted the simplification of leaf pattern in a similar manner as GA functions. Enhanced level of SlBES1.8 dramatically decreased the sensibility of tomato to GA whereas increased the sensibility to the GA biosynthesis inhibitor, PAC. In line with the phenotypic observation, the endogenous bioactive GA contents were increased in OE-SlBES1.8 lines, which certainly promoted the degradation of the GA signaling negative regulator, SlDELLA. Moreover, transcriptomic analysis uncovered a set of overlapping genomic targets of SlBES1.8 and GA, and most of them were regulated in the same way. Expression studies showed the repression of SlBES1.8 to the transcriptions of two GA deactivated genes, SlGA2ox2 and SlGA2ox6, and one GA receptor, SlGID1b-1. Further experiments confirmed the direct regulation of SlBES1.8 to their promoters. On the other hand, SlDELLA physically interacted with SlBES1.8 and further inhibited its transcriptional regulation activity by abolishing SlBES1.8-DNA binding. Conclusively, by mediating GA deactivation and signaling, SlBES1.8 greatly influenced tomato leaf morphogenesis. HighlightThe BRI1-EMS-SUPPRESSOR 1 (BES1) family protein SlBES1.8 promotes leaf simplification by inhibiting gibberellin deactivation and physically interacting with DELLA protein in tomato.

plant biology↗

bioRxiv2021

Ancient genomes redate the extinction of Sussemionus, a subgenus of Equus, to late Holocene

The exceptionally-rich fossil record available for the equid family has provided textbook examples of macroevolutionary changes. Horses, asses and zebras represent three extant subgenus of Equus lineage, while the Sussemionus subgenus is another remarkable Equus lineage ranging from North America to Ethiopia in Pleistocene. We sequenced 26 archaeological specimens from northern China in Holocene showing morphological features reminiscent of Equus ovodovi, a species representative of Sussemionus, and further confirmed them as this species by genetic analyses. Thus, we present the first high-quality complete genome of the Sussemionus that we sequenced to 12.0x depth-of-coverage and demonstrate that it survived until [~]3,500 years ago, despite the continued demographic collapse during the Last Glacial Maximum and the great human expansion in East Asia. We also confirmed the Equus phylogenetic tree, and found Sussemionus diverged from the ancestor of non-caballine equids [~]2.3-2.7 Million years ago and admixture events could have taken place between them. Our works suggest the small genetic diversity but not the enhanced inbreeding mainly limited the chances of survival of the species, and illustrates how ancient DNA can inform on extinction dynamics and the long-term resilience of species surviving in cryptic population pockets.

genomics↗

bioRxiv2021

Stratified Test Accurately Identifies Differentially Expressed Genes Under Batch Effects in Single-Cell Data

Analyzing single-cell sequencing data from large cohorts is challenging. Discrepancies across experiments and differences among participants often lead to omissions and false discoveries in differentially expressed genes. We find that the Van Elteren test, a stratified version of the widely used Wilcoxon rank-sum test, elegantly mitigates the problem. We also modified the common language effect size to supplement this test, further improving its utility. On both simulated and real patient data we show the ability of Van Elteren test to control for false positives and false negatives. A comprehensive assessment using receiver operating characteristic (ROC) curve shows that Van Elteren test achieves higher sensitivity and specificity on simulated datasets, compared with nine state-of-the-art differential expression analysis methods. The effect size also estimates the differences between cell types more accurately.

bioinformatics↗

bioRxiv2021

The First High-Quality Reference Genome of Sika Deer Provides Insights for High-Tannin Adaptation

Sika deer are known to prefer oak leaves, which are rich in tannins and toxic to most mammals; however, the genetic mechanisms underlying their unique ability to adapt to living in the jungle are still unclear. In identifying the mechanism responsible for the tolerance of a highly toxic diet, we have made a major advancement in the elucidation of the genomics of sika deer. We generated the first high-quality, chromosome-level genome assembly of sika deer and measured the correlation between tannin intake and RNA expression in 15 tissues through 180 experiments. Comparative genome analyses showed that the UGT and CYP gene families are functionally involved in the adaptation of sika deer to high-tannin food, especially the expansion of UGT genes in a subfamily. The first chromosome-level assembly and genetic characterization of the tolerance toa highly toxic diet suggest that the sika deer genome will serve as an essential resource for understanding evolutionary events and tannin adaptation. Our study provides a paradigm of comparative expressive genomics that can be applied to the study of unique biological features in non-model animals.

genomics↗

bioRxiv2020

ORF3a mediated-incomplete autophagy facilitates SARS-CoV-2 replication

SARS-CoV-2 is the causative agent for the COVID-19 pandemic and there is an urgent need to understand the cellular response to SARS-CoV-2 infection. Beclin-1 is an essential scaffold autophagy protein that forms two distinct subcomplexes with modulators Atg14 and UVRAG, responsible for autophagosome formation and maturation, respectively. In the present study, we found that SARS-CoV-2 infection triggers an incomplete autophagy response, elevated autophagosome formation but impaired autophagosome maturation, and declined autophagy by genetic knockout of essential autophagic genes reduces SARS-CoV-2 replication efficiency. By screening 28 viral proteins of SARS-CoV-2, we demonstrated that expression of ORF3a alone is sufficient to induce incomplete autophagy. Mechanistically, SARS-CoV-2 ORF3a interacts with autophagy regulator UVRAG to facilitate Beclin-1-Vps34-Atg14 complex but selectively inhibit Beclin-1-Vps34-UVRAG complex. Interestingly, although SARS-CoV ORF3a shares 72.7% amino acid identity with the SARS-CoV-2 ORF3a, the former had no effect on cellular autophagy response. Thus, our findings provide the mechanistic evidence of possible takeover of host autophagy machinery by ORF3a to facilitate SARS-CoV-2 replication and raises the possibility of targeting the autophagic pathway for the treatment of COVID-19.

microbiology↗

bioRxiv2020

BacAnt: the combination annotation server of antibiotic resistance gene, insertion sequences, integron, transposable elements for bacterial DNA sequences

Whole genome sequencing (WGS) of bacteria has become a routine method in diagnostic laboratories. One of the clinically most useful advantages of WGS is the ability to predict antimicrobial resistance genes (ARGs) and mobile genetic elements (MGEs) in bacterial sequences. This allows comprehensive investigations of such genetic features but can also be used for epidemiological studies. A plethora of software programs have been developed for the detailed annotation of bacterial DNA sequences, such as RAST (Rapid Annotation using Subsystem Technology), Resfinder, ISfinder, INTEGRALL and The Transposon Registry. Unfortunately, to this day, a reliable annotation tool of the combination of ARGs and MGEs is not available, and the generation of genbank files requires much manual input. Here, we present a new webserver which allows the annotation of ARGs, integrons, and transposable elements at the same time. The pipeline generates genbank files automatically, which are compatible with easyfig for comparative genomic analysis. Our BacAnt code and standalone software package are available at https://github.com/xthua/bacant with an accompanying web application at http://bacant.net. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/284273v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@262a07org.highwire.dtl.DTLVardef@1914001org.highwire.dtl.DTLVardef@101089corg.highwire.dtl.DTLVardef@dc5807_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2020

GardeninA confers neuroprotection against environmental toxin in a Drosophila model of Parkinson's disease

Parkinson’s disease (PD) is an age-associated neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons from the midbrain. Epidemiological studies have implicated exposures to environmental toxins like the herbicide, paraquat (PQ) as major contributors to PD etiology in both mammalian and invertebrate models. We have employed a PQ-induced PD model in Drosophila as an inexpensive in vivo platform to screen therapeutics from natural products. We have identified the polymethoxyflavonoid, GardeninA, with neuroprotective potential against PQ-induced parkinsonian symptoms involving reduced survival, mobility defects, and loss of dopaminergic neurons. GardeninA-mediated neuroprotection is not solely dependent on its antioxidant activities but also involves modulation of the neuroinflammatory and cellular death responses. Furthermore, we have successfully detected GardeninA bioavailability in the fly heads after oral administration using ultra-performance liquid chromatography and mass spectrometry. Our findings reveal a molecular mechanistic insight into GardeninA-mediated neuroprotection against environmental toxin-induced PD pathogenesis for novel therapeutic intervention.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pharmacology and toxicology↗