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Liang, W.

Publications and source records attributed to Liang, W..

At least 55 records · Page 3Linked to original sources
bioRxiv2023

Predictive evolutionary modelling for influenza virus by site-based dynamics of mutations

A predictive evolutionary model was developed to forecast representative influenza viral strains and select vaccine strains for upcoming epidemic seasons. Influenza virus continuously evolves to escape human adaptive immunity and generates seasonal epidemics. A computational approach beth-1 that models site-wise mutation dynamics demonstrated remarkable matching of predicted strains to the circulating viruses in subsequent seasons for the influenza A(H1N1)pdm09 and A(H3N2) viruses in both retrospective and prospective validations. The method offers a promising and ready-to-use tool to facilitate vaccine strain selection for the influenza virus, achieved by capturing heterogeneous evolutionary dynamics over genome space-time and linking molecular variants to population immune response. One-Sentence SummaryA computational model predicts virus evolution and facilitates vaccine strain selection for the influenza virus

evolutionary biology↗
bioRxiv2023

Slow conduction and spatial dispersion of repolarization are intrinsic properties of cardiomyocyte electrophysiology that contribute to proarrhythmia in an iPSC model of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease; characterised by left ventricular wall thickening, cardiomyocyte disarray, and fibrosis, and is associated with arrhythmias, heart failure and sudden death. However, it is unclear to what extent the electrophysiological disturbances that lead to sudden death occur secondary to the structural changes in the myocardium, or as a result of intrinsic properties of the HCM cardiomyocyte. In this study, we used an induced pluripotent stem cell model of the Arg403Gln variant in myosin heavy chain 7 (MYH7) to study tissue level electrophysiological properties of HCM cardiomyocytes. For the first time, we show significant slowing of conduction velocity and an increase in local spatial dispersion of repolarisation - both well-established substrates for arrhythmia - in monolayers of HCM cardiomyocytes. Analysis of rhythmonome protein expression in R403Q cardiomyocytes revealed dramatically reduced connexin-43, sodium channels, and inward rectifier channels - a three-way hit that combines to reduce electrotonic coupling between HCM cardiomyocytes and slow cardiac conduction. Our data therefore represent a novel, biophysical basis for arrhythmia in HCM, that is intrinsic to cardiomyocyte electrophysiology. Later in the progression of the disease, these proarrhythmic electrical phenotypes may be accentuated by fibrosis and myocyte disarray to contribute to sudden death in HCM patients.

physiology↗
bioRxiv2023

Identification of a novel MCR-1 variant displaying low level of co-resistance to β-lactam antibiotics that uncovers a potential novel antimicrobial peptide

The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. It is accepted that MCR-1 affects bacterial fitness, and this fitness cost correlates with bacterial membrane lipid A perturbation. However, the detailed molecular mechanism remains unclear. Here, we screened out a novel MCR-1 variant, named M6, with a two-point mutation that rendered a low level of co-resistance to {beta}-lactam antibiotics. Compared to wild-type (WT) MCR-1, this variant caused severe lipid A perturbation resulting in peptidoglycan layer remodelling and thus resulted in phenotypic co-resistance to {beta}-lactams. Moreover, we found that a lipid A loading cavity is localized at the linker domain of MCR-1 and governs colistin resistance and bacterial membrane permeability, and the mutated pocket of M6 facilitates the binding affinity of lipid A. More importantly, synthetic peptides derived from M6 achieved broad-spectrum antimicrobial activity. These findings provide insights into a potential vulnerability that could be exploited in future antimicrobial drug design.

microbiology↗
bioRxiv2023

Secondary bile acid production by gut bacteria promotes Western diet-associated colorectal cancer

Western diet is an important risk factor for the development of sporadic colorectal cancer (CRC). Dietary fat stimulates bile acid (BA) production by the host and their conversion to secondary BAs by 7-dehydroxylating (7DH+) bacteria, but causal proof of their tumor-promoting effects in vivo is lacking. To address this, we performed feeding studies in a genetically engineered pig model of CRC combined with multi-omics analyses and gnotobiotic mouse studies. Western diet worsened the disease phenotype in APC1311/+ pigs. This was accompanied by microbiota changes, increased levels of the secondary bile acid deoxycholic acid (DCA), and higher colonic epithelial cell proliferation. The latter was counteracted by using the BA-scavenging drug colestyramine. Metagenomic analysis across multiple cohorts revealed higher occurrence of bai (BA inducible) operons from Clostridium scindens and close relatives in stool of CRC subjects (n = 1,034). Using two gnotobiotic mouse models of CRC, we demonstrate that colonization with 7DH+ bacteria (C. scindens or Extibacter muris) increased colonic tumor loads. This work provides clear evidence for the causal role of microbiome-derived DCA production in CRC under detrimental dietary conditions, opening avenues for future preventive strategies.

microbiology↗
bioRxiv2023

The Small GTPase Rab7 Regulates Release of Mitochondria in Extracellular Vesicles in Response to Lysosomal Dysfunction

Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.

physiology↗
bioRxiv2023

How random is the review outcome? A systematic study of the impact of external factors on eLife peer review

The advance of science rests on a robust peer review process. However whether or not a paper is accepted can depend on random external factors--e.g. the timing of the submission, the matching of editors and reviewers--that are beyond the quality of the work. This article systematically investigates the impact of these random factors independent of the papers quality on peer review outcomes in a major biomedical journal, eLife. We analyzed all of the submissions to eLife between 2016 to 2018, with 23,190 total submissions. We examined the effects of random factors at each decision point in the review process, from the gatekeeping senior editors who may desk-reject papers to review editors and reviewers who recommend the final outcome. Our results suggest that the peer-review process in eLife is robust overall and that random external factors have relatively little quantifiable bias.

bioinformatics↗
bioRxiv2022

Evidence suggesting creatine as a new central neurotransmitter: presence in synaptic vesicles, release upon stimulation, effects on cortical neurons and uptake into synaptosomes and synaptic vesicles

The discovery of a new neurotransmitter, especially one in the central nervous system (CNS), is both important and difficult. We have been searching for new neurotransmitters for 12 years. We detected creatine (Cr) in synaptic vesicles (SVs), at a level lower than glutamate (Glu) and gamma-aminobutyric acid (GABA) but higher than acetylcholine (ACh) and 5-hydroxytryptamine (5-HT). SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (AGAT, a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability (ID) in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in SLC6A8 and AGAT mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP dependent manner. Our biochemical, chemical, genetic and electrophysiological results are consistent with the possibility of Cr as a neurotransmitter, though not yet reaching the level of proof for the now classic transmitters. Our novel approach to discover neurotransmitters is to begin with analysis of contents in SVs before defining their function and physiology.

neuroscience↗
bioRxiv2022

Spatial Evolution of Information Dynamics in the Primary Motor Cortex During Reach

The primary motor cortex (M1) is known to be spatially organized in terms of muscles and body parts, notwithstanding some overlap. However, the classical view is largely static, neglecting potential representational changes on a fast time scale. To address potential representational dynamics, we probed the mutual information between M1 signals recorded across the cortical sheet and electromyography (EMG) activity from a set of muscles while a macaque monkey performed planar reaches. Here, we demonstrated that the spatial organization of the M1 encoding was in fact quite dynamic throughout the course of a reaching movement such that a given cortical site maximally encoded different muscles at different times. Despite these rapid representational changes, a proximal-to-distal gradient of the upper limb representation was preserved particularly close to movement onset. Representation was most stable close to movement onset, with characteristic topographic maps, possibly serving functional needs. This study bridges the important gap between flexible motor encoding and static motor maps, emphasizing the importance of considering space and time together in motor representation studies.

neuroscience↗
bioRxiv2022

Complexes Formed by Mixing Tumor-derived Extracellular Vesicles with Polymeric Surfactants for Personalized Therapeutic Vaccine

The personalized therapeutic vaccine is an ideal weapon to eliminate tumors. However, the core steps of manufacturing personalized cancer vaccines are identifying tumor-specific antigens (TSAs, also called neoantigens) and HLA epitope prediction, which is time-consuming and labor-intense. Tumor-derived extracellular vesicles (TEVs) are alternative sources of neoantigens. However, the immunosuppressive nature of TEVs limits their application in such immunotherapy. In this study, we present a new strategy to maintain neoantigens in TEVs and diminish the immunosuppression by deconstructing the structure of TEVs with polymeric surfactant polyethylene glycol-phosphatidylethanolamine (PEG-PE). Together with adjuvant MPLA, the newly formed micelle-like complexes compose a therapeutic vaccine (MLC-V). Results show that MLC-V is capable of eliciting neoantigen-specific T-cell responses, restoring TEV-induced immunosuppression, and preventing lung metastasis of murine melanoma. MLC-V also exhibits outstanding anti-tumor efficacy in multiple tumor models. MLC-V can be used as a personalized therapeutic vaccine in a mimetic pre-clinical MC38 model and the anti-tumor effect of MLC-V was synergistically enhanced by PD-1 mAb. Taken together, the present study demonstrates a time-saving, low-cost, and simplified strategy to produce personalized therapeutic vaccines based on MLC-V platform technology.

immunology↗
bioRxiv2022

Vascular endothelial growth factor A contributes to the increasing of mammalian respiratory epithelial permeability induced by Pasteurella multocida infection

Infections with Pasteurella multocida can cause significant zoonotic respiratory problems in both humans and animals. In vivo tests in mouse infection models were used to investigate the mechanisms of respiratory epithelial barrier dysfunction during respiratory bacterial infection with these pathogens. Results revealed that P. multocida infection significantly increased epithelial permeability and increased expression of vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) in murine tracheae and lungs. In murine lung epithelial cell (MLE-12) models, P. multocida infection decreased the expression of tight junctions (ZO-1) and adherens junctions ({beta}-catenin, E-cadherin), but induced the activation of the hypoxia-inducible factor-1 (HIF-1) and VEGFA signaling. When expression of HIF-1 is suppressed, the induction of VEGFA and ZO-1expression by P. multocida infection is decreased. We also found that intervention of HIF-1 and VEGFA signaling affected infection outcomes caused by respiratory bacteria in mouse models. Most importantly, we demonstrated that P. multocida infection increased permeability of human respiratory epithelial cells and this process was associated with the activation of the HIF-1 and VEGFA signaling and likely contributes to the pathogenesis of P. multocida in humans. ImportanceMammalian respiratory epithelium forms the first line of defense against infections with Pasteurella multocida, an important zoonotic respiratory pathogen. In this study, we found P. multocida infection increased respiratory epithelial permeability and promoted the induction of the hypoxia-HIF-1-VEGFA axis in both mouse and murine cell models. Similar findings were also demonstrated in human respiratory epithelial cells. The results from this study gain important knowledge about the pathogenesis of P. multocida causing infections in both animals and humans.

microbiology↗
bioRxiv2022

Importance of Glutamine in Synaptic Vesicles Revealed by Functional Studies of SLC6A17 and Its Mutations Pathogenic for Intellectual Disability

Human mutations in the gene encoding the solute carrier (SLC) 6A17 caused intellectual disability (ID). The physiological role of SLC6A17 and pathogenesis of Slc6a17-based-ID were both unclear. Here we report learning deficits in SLC6A17 knockout and point mutants. Biochemistry, proteomics and electron microscopy (EM) support SLC6A17 protein localization in synaptic vesicles (SVs). Chemical analysis of SVs by liquid chromatography coupled to mass spectrometry (LC-MS) revealed glutamine (Gln) in SVs containing SLC6A17. Virally mediated overexpression of SLC6A17 increased Gln in SVs. Either genetic or virally mediated targeting of SLC6A17 reduced Gln in SVs. One ID mutation caused SLC6A17 mislocalization while the other caused defective Gln transport. Multidisciplinary approaches with 7 types of genetically modified mice have shown Gln as an endogenous substrate of SLC 6A17, uncovered Gln as a new molecule in SVs, established the necessary and sufficient roles of SLC6A17 in Gln transport into SVs, and suggested SV Gln decrease as the key pathogenetic mechanism in human ID.

neuroscience↗
bioRxiv2022

Herb-paths, a network and statistical model to explore health-beneficial effects of herbs and herbal constituents

Predictions on bioactivities of herbs and herbal compounds could greatly aid drug development, but require integration of available information on herb and compound effects from various databases. We present Herb-paths, an integrated network connecting information on health-beneficial effects of herbs and herbal constituents. The statistical models included in Herb-paths allow for the calculation of the association strength of herbal (constituents) with health-beneficial effects, for both known and novel effects, and give insight into the major bioactive compounds and molecular mechanisms driving the effects. Herb-paths predictions were tested and validated using a case-study of Panax notoginseng and its derived medicinal extract of Panaxatriol saponins (PTS), used in traditional Chinese medicine to treat stroke and other cardiovascular and cerebrovascular thromboembolic (CCT) disorders. Results showed that Herb-paths predicted known and novel associations between PTS/Notoginseng and CCT phenotypes and diseases, including stroke. Predicted novel associations, such as MoyaMoya disease, are promising putative leads for treatment with PTS/Notoginseng, to be tested in further studies.

bioinformatics↗
bioRxiv2022

Acetylation of a fungal effector that translocates host PR1 facilitates virulence

Pathogens utilize a panoply of effectors to manipulate plant defense. However, despite their importance, relatively little is actually known about regulation of these virulence factors. Here, we show that the effector FolSvp1, secreted from fungal pathogen Fusarium oxysporum f. sp. lycopersici (Fol) directly binds and translocates the tomato pathogenesis-related protein1, SlPR1, from the apoplast outside the plasma membrane to the host nucleus via its nuclear localization signal. Relocation of SlPR1 abolishes generation of the defense signaling peptide, CAPE1, from its C-terminus, and as a consequence, facilitates pathogen invasion of plants. The action of FolSvp1 requires covalent modification by acetylation for full virulence in host tomato tissues. The modification is catalyzed by the Fol FolArd1 lysine acetyltransferase prior to secretion. Addition of an acetyl group to one residue, K167, prevents ubiquitination-dependent degradation of FolSvp1 in both Fol and plant cells with different mechanisms, allowing it to function normally in fungal invasion. Either inactivation of FolSvp1 or removal of the acetyl group on K167 leads to impaired pathogenicity of Fol. These findings indicate that acetylation can regulate the stability of effectors of fungal plant pathogens with impact on virulence.

microbiology↗
bioRxiv2022

Age-related seroprevalence trajectories of seasonal coronaviruses in children

Four seasonal coronaviruses, including HCoV-NL63 and HCoV-229E, HCoV-OC43 and HCoV-HKU1 cause approximately 15-30% of common colds in adults. However, the frequency and timing of early infection with four seasonal coronaviruses in the infant are still not well studied. Here, we evaluated the serological response to four seasonal coronaviruses in 1886 children under 18-year-old to construct the viral infection rates. The antibody levels were also determined from the plasma samples of 485 pairs postpartum women and their newborn babies. This passive immunity waned at one year after birth and the resurgence of the IgGs were found thereafter with the increase of the age. Taken together, our results show the age-related seroprevalence trajectories of seasonal coronaviruses in children and provide useful information for deciding vaccine strategy for coronaviruses in the future.

immunology↗
bioRxiv2022

Organs-on-a-Chip Database (OOCDB): A Comprehensive, Systematic and Real-time Organs-on-a-chip Database

Organs-on-a-Chip is a microfluidic microphysiological system that uses microfluidic technology to make high-resolution and real-time imaging analysis on the structure and function of living human cells at the level of tissue and organ in vitro. Compared with the traditional two-dimensional cell culture model and animal model, organs-on-a-chip technology can simulate the pathological and toxicological interactions between different organs or tissues more closely and reflect the collaborative response of multiple organs to drugs. Although lots of organs-on-a-chip-related literature have been published, none of current databases have achieved all the following functionalities yet: searching, downloading and analyzing data and results from literature of organs-on-a-chip. To address this need, we established a database named organs-on-a-chip database (OOCDB), as a platform to integrate information related to organs-on-a-chip from various sources: literature, patents, microarray and transcriptome sequencing raw data, many open access data of organs-on-a-chip and organoids, as well as the data generated in our lab. OOCDB comprises dozens of sub databases and analysis tools and each sub database contains a number of data related to organs-on-a-chip, aiming to provide a comprehensive, systematic and convenient search engine for researchers. In addition, it provides functions such as mathematical modeling, three-dimensional model and citation map to meet the needs of researchers and to promote the development of organs-on-a-chip. The organs-on-a-chip database can be visited at http://www.organchip.cn.

bioinformatics↗
bioRxiv2022

A translational swine model for Crohn`s disease

Crohns Disease (CD) is incurable, and represents a lifelong burden for patients and its incidence is increasing worldwide. A key contributing factor is a dysregulated immune response. Here we report the generation of genome edited pigs with a deletion of the transcript-destabilizing AU-rich element (ARE) and a constitutive decay element (CDE) in the TNF gene which recapitulate major characteristics of human CD, including ulcerative transmural ileocolitis, increased abundance of proinflammatory cytokines, evidence for impaired integrity of the intestinal epithelial cell barrier, immune cell infiltration, and dysbiotic microbial communities. This physiologically relevant CD model enables human-scale and long-term studies to assess diagnostic, nutritional or microbial interventions, filling the gap for translating findings into the clinic.

bioengineering↗
bioRxiv2022

Sex differences in the nasal microbiome of healthy young adults

Respiratory diseases impose an immense health burden worldwide. Epidemiological studies have revealed extensive disparities in the incidence and severity of respiratory tract infections (RTIs) between males and females. It is recently hypothesized that there might also be a nasal microbiome axis contributing to the observed sex disparities, but without evidence. In this work, we study the nasal microbiome of healthy young adults in, as of today, the largest cohort based on deep shot-gun metagenomic sequencing. We mainly focus on the bacteriome, but also integrate the mycobiome to get a more holistic perspective. De novo assembly is performed to catalog the nasal bacterial colonizers/residents, which also identify and therefore account for uncharacterized components of the community. The bacteriome is then profiled based on the non-redundant metagenome-assembled genomes (MAGs) catalog constructed therefrom. Unsupervised clustering reveals clearly separable structural patterns in the nasal microbiome between the two sexes. Following this link, we systematically evaluate sex differences for the first time and reveal extensive sex-specific features in the nasal microbiome composition. More importantly, through network analyses, we capture markedly higher ecological stability and antagonistic potentials in the nasal microbiome of females than that of males. The analysis of the keystone bacteria of the communities reveal that the sex-dependent evolutionary characteristics might have contributed to this difference. HighlightsThe non-redundant nasal bacterial MAGs catalog constructed from ultra-deeply sequenced metagenomic data provides a valuable resource. Integrating nasal bacteriome and mycobiome data provides a more holistic perspective for the understudied human nasal microbiome. Unsupervised clustering helps uncover extensive sex differences in the nasal microbiome compositions. Network analyses capture markedly higher ecological stability and antagonistic potentials in the nasal microbiome of females than that of males. Sex-dependent genetic evolutionary forces play a role in the shaping of keystones in the nasal microbial community.

microbiology↗