Biology subjects

Jin, H.

Publications and source records attributed to Jin, H..

At least 145 records · Page 8Linked to original sources

bioRxiv2020

An infectivity-enhancing site on the SARS-CoV-2 spike protein is targeted by COVID-19 patient antibodies

SARS-CoV-2 infection causes severe symptoms in a subset of patients, suggesting the presence of certain unknown risk factors. Although antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike have been shown prevent SARS-CoV-2 infection, the effects of antibodies against other spike protein domains are largely unknown. Here, we screened a series of anti-spike monoclonal antibodies from COVID-19 patients, and found that some of antibodies against the N-terminal domain (NTD) dramatically enhanced the binding capacity of the spike protein to ACE2, and thus increased SARS-CoV2 infectivity. Surprisingly, mutational analysis revealed that all the infectivity-enhancing antibodies recognized a specific site on the surface of the NTD. The antibodies against this infectivity-enhancing site were detected in all samples of hospitalized COVID-19 patients in the study. However, the ratio of infectivity-enhancing antibodies to neutralizing antibodies differed among patients. Furthermore, the antibodies against the infectivity-enhancing site were detected in 3 out of 48 uninfected donors, albeit at low levels. These findings suggest that the production of antibodies against SARS-CoV-2 infectivity-enhancing site could be considered as a possible exacerbating factors for COVID-19 and that a spike protein lacking such antibody epitopes may be required for safe vaccine development, especially for individuals with pre-existing enhancing antibodies.

microbiology↗

bioRxiv2020

Characterization of Nonmotor Symptoms in the MitoPark Mouse Model of Parkinson's Disease

Mitochondrial dysfunction has been implicated as a key player in the pathogenesis of Parkinsons disease (PD). The MitoPark mouse, a transgenic mitochondrial impairment model developed by specific inactivation of TFAM in dopaminergic neurons, spontaneously exhibits progressive motor deficits and neurodegeneration, recapitulating several features of PD. Since non-motor symptoms are now recognized as important features of the prodromal stage of PD, we monitored the clinically relevant motor and nonmotor symptoms from ages 8-24 wks in MitoPark mice and their littermate controls. As expected, motor deficits in MitoPark mice began around 12-14 wks and became severe by 16-24 wks. Interestingly, male MitoPark mice showed spatial memory deficits before female mice, beginning at 8 wks and becoming most severe at 16 wks, as determined by Morris water maze. When compared to age-matched control mice, MitoPark mice exhibited olfactory deficits in novel and social scent tests as early as 10-12 wks. MitoPark mice between 16-24 wks spent more time immobile in forced swim and tail suspension tests, and made fewer entries into open arms of the elevated plus maze, indicating a depressive and anxiety-like phenotype, respectively. Importantly, depressive behavior as determined by immobility in forced swim test was reversible by antidepressant treatment with desipramine. Collectively, our results indicate that MitoPark mice progressively exhibit deficits in cognitive learning and memory, olfactory discrimination, and anxiety-and depression-like behaviors. Thus, MitoPark mice can serve as an invaluable model for studying motor and non-motor symptoms in addition to studying pathology in PD.

neuroscience↗

bioRxiv2020

CircRNA may not be "circular"

Circular RNA (circRNA) is a novel regulatory non-coding RNA and participates in diverse physiological and pathological processes. However, the structures and molecular mechanisms of circRNAs remain unclear. In this study, we took advantage of circRNA array and bioinformatics analysis and found lots of internal complementary base-pairing sequences (ICBPS) existed in plenty of circRNAs, especially in extremely long circRNAs (el-circRNAs, > 5,000 nt). The result indicated that circRNA may not be a simple circular structure. In addition, we put forward the hypothesis of "open-close effect " in the transition for specific circRNA from normal state to morbid state. Taken together, our results not only expand the knowledge of circRNAs, but also highlight the potential molecular mechanism of circRNAs.

molecular biology↗

bioRxiv2020

Parietal cell-Specific SLC26A9 Deletion induces spontaneous Gastric Carcinogenesis in Mice

Previous study showed that Slc26a9 loss impairs parietal cell function and survival. We investigated whether Slc26a9 loss causes spontaneous gastric carcinogenesis in mice and plays a role in the development and progression in human gastric cancer (GC). Gastric histopathology and potential molecular mechanism were explored in Slc26a9 knockout mice and wild-type littermates as well as Slc26a9fl/fl/Atp4b-Cre and Slc26a9fl/fl mice from 8 days to 18 months by histological and immunohistochemical analyses, quantitative PCR, in situ hybridization, and RNA microarray analysis, respectively. We demonstrated that loss of parietal cell expression of Slc26a9 is the key event to induce spontaneous gastric carcinogenesis in mice, and clarified the sequence of events leading to malignant transformation, including Slc26a9 deficiency in parietal cells resulted in dysregulated differentiation of stem cells in an inflammatory environment, activated Wnt signaling pathway to induce gastric epithelia cell hyperproliferation and apoptosis inhibition, as well as spontaneous epithelial to mesenchymal transition-induced cancer stem cell phenotypes. Downregulation of SLC26A9 correlated with GC patients short survival. Graphical AbstractLoss of parietal cell expression of Slc26a9 is the key event to induce spontaneous gastric carcinogenesis in transgenic mice. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/316398v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@33a2dcorg.highwire.dtl.DTLVardef@94ce8org.highwire.dtl.DTLVardef@9851eforg.highwire.dtl.DTLVardef@2b5fc3_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Munc13 binds and recruits SNAP25 to chaperone SNARE complex assembly

Synaptic vesicle fusion is mediated by membrane-bridging complexes formed by SNARE proteins - VAMP2 on the vesicle and Syntaxin-1/SNAP25 on the pre-synaptic membrane. Accumulating evidence suggest that chaperones Munc18-1 and Munc13-1 co-operatively catalyze SNARE assembly via an intermediate template complex containing Syntaxin-1 and VAMP2. How SNAP25 is chaperoned into this nascent complex remains a mystery. Here we report that Munc13-1 recruits SNAP25 to initiate the ternary SNARE complex assembly by direct binding, as judged by bulk FRET spectroscopy and single-molecule optical tweezer studies. Detailed structure-function analyses show that the binding is mediated by the Munc13-1 MUN domain and is specific for the SNAP25 linker region that connects the two SNARE motifs. Consequently, freely diffusing SNAP25 molecules on phospholipid bilayers are concentrated and presumably bound in ~1:1 stoichiometry by the self-assembled Munc13-1 nanoclusters. Our data suggests that Munc13-1s capacity to bind all three synaptic SNARE proteins likely underlie its chaperone function.

neuroscience↗

bioRxiv2020

Probiotic consumption relieved human stress and anxiety symptoms via modulating the gut microbiota and neuroactive potential

Stress has been shown to disturb the balance of human intestinal microbiota and subsequently cause mental health problems, such as anxiety and depression. The gut microbial communities are able to synthesize and/or consume various neuroactive metabolites, and preliminary human studies have also demonstrated the ability of probiotics to modulate the levels of neurotransmitter. However, the study and interpretation of the biological significance of microbial neuroactive compounds have been hindered by the lack of dedicated reference databases and corresponding human intestinal microbiota reference genomes. Our previous study showed that ingesting the probiotic strain, Lactobacillus (L.) plantarum P-8, for 12 weeks could alleviate stress and anxiety of stressed adults. The current study was a follow-up work aiming to further elucidate mechanisms behind the observed beneficial effects by performing deep analysis of the fecal metagenomes of the probiotic (n = 43) and placebo (n = 36) groups. Comparing with the probiotic group, the gut microbiomes of the placebo group showed significantly higher Bray-Curtis dissimilarity between weeks 0 and 12 (p < 0.05). Comparing with week 0, the Shannon diversity index of the placebo group decreased significantly at week 12 (t-test; p < 0.05), but such decrease was non-significant for the probiotic group. Additionally, the fecal metagenomes of the probiotic group showed significant increases in the species-level genome bins (SGBs) of Bifidobacterium adolescent, Bifidobacterium longum, and Fecalibacterium prausnitzii increased, while decreases in the SGBs of Roseburia faeci and Fusicatenibacter saccharivorans. Furthermore, the 12-week probiotic supplementation enhanced the diversity of neurotransmitter-synthesizing and/or -consuming SGBs, and the levels of some predicted microbial neuroactive metabolites (short chain fatty acids, gamma-aminobutyric acid, arachidonic acid, and sphingomyelin et.al). In conclusion, this study revealed the potential mechanism of probiotics in alleviating stress and anxiety via the gut-brain axis. The modulation of the intestinal microbiota by probiotics is an attractive strategy for managing stress and anxiety.

neuroscience↗

bioRxiv2020

Characterization of the gut DNA and RNA viromes in a cohort of Chinese residents and visiting Pakistanis

BackgroundTrillions of viruses inhabit the gastrointestinal tract. Some of them have been well-studied on their roles in infection and human health, but the majority remain unsurveyed. It has been established that the composition of the gut virome is highly variable based on the changes of diet, physical state, and environmental factors. However, the effect of host genetic factors, e.g. ethnic origin, on the gut virome is rarely investigated. Methods and ResultsHere, we characterized and compared the gut virome in a cohort of local Chinese residents and visiting Pakistani individuals, each group containing 24 healthy adults and 6 children. Using metagenomic shotgun sequencing and assembly of fecal samples, a huge number of viral operational taxonomic units (vOTUs) were identified for profiling the DNA and RNA viromes. National background contributed a primary variation to individuals gut virome. Compared with the Chinese adults, the Pakistan adults showed higher macrodiversity and different compositional and functional structures in their DNA virome and lower diversity and altered composition in their RNA virome. The virome variations of Pakistan children were inherited from the that of the adults but also tended to share similar characteristics with the Chinese cohort. We also analyzed and compared the bacterial microbiome between two cohorts and further revealed numerous connections between virus and bacterial host. Statistically, the gut DNA and RNA viromes were covariant to some extent (p<0.001), and they both influenced the holistic bacterial composition and vice versa. ConclusionsThis study provides an overview of gut viral community in Chinese and visiting Pakistanis and proposes a considerable role of ethnic origin in shaping the virome.

microbiology↗

bioRxiv2020

Prediction of Direct Carbon Emissions of Chinese Provincial Residents under Artificial Neural Networks in Deep Learning Environment

It is aimed to deepen the understanding of the consumption carbon emissions of Chinese provinces, establish an accurate and feasible carbon emission prediction model, develop an urban low-carbon economy, and ensure the sustainable development of Chinese cities. Through the national statistical data information, based on the artificial neural network model, mathematical statistics and deep learning methods are used to learn and analyze the carbon emission data of various provinces in China from 1999 to 2019. The neural network toolbox in Matlab is used to program separately to realize the prediction of carbon emissions by different neural network models. After comparing and analyzing the accuracy and prediction performance, the optimal model for the prediction effect is selected. Finally, based on ArcGIS Engine (Arc Geographic Information Science Engine) and C#.NET platform, the call to Matlab neural network toolbox is realized. The selected model is embedded in the prediction system to complete the development of the entire system. The results show that the carbon emissions of residents in the north are distinctly higher than those in the south. Also, with the passage of time, the rate of carbon emissions continues to accelerate. Compared with other models, Elman neural network has higher accuracy and smaller error in carbon emission prediction. Compared to BP (Back Propagation) neural network, the accuracy is improved by 55.93%, and the prediction performance is improved by 19.48%. The prediction results show that China is expected to reach the peak of carbon emissions from 2027 to 2032. This investigation will provide a theoretical basis to control and plan carbon emissions from Chinese urban residents.

ecology↗

bioRxiv2020

Molecular Functions of Conserved Developmentally-Regulated GTP-Binding Protein Drg1 in Translation

Conserved developmentally-regulated GTP-binding (Drg) proteins and their binding partner Dfrp proteins are known to be important for embryonic development, cellular growth control, differentiation and proliferation. Here, we report that the yeast Drg1/Dfrp1 ortholog, Rbg1/Tma46, facilitates translational initiation, elongation and termination via suppressing prolonged ribosome pausing. Consistent with the genome-wide observations, Rbg1 reverses the growth defect resulting from translation stalling and stabilizes mRNAs against no-go decay. Furthermore, we provide a cryoEM structure of the 80S ribosome bound with Rbg1/Tma46 that reveals the molecular interactions responsible for Rbg1/Tma46 function. The Rbg1 subunit binds to the GTPase association center of the ribosome and the A-tRNA, and the N-terminal zinc finger domain of Tma46 subunit binds to the 40S, establishing an interaction critical for the complex ribosomal association. Our results answer the fundamental question on how a paused ribosome resumes translation and show that Drg1/Dfrp1 proteins play a critical role in ensuring orderly translation.

biophysics↗

bioRxiv2020

KDM6B promotes oncogenic CDK4/6-pRB-E2F pathway via maintaining enhancer activation in high-risk neuroblastoma

The H3K27me2/me3 histone demethylase KDM6B is over-expressed in neuroblastoma and is essential to neuroblastoma cell survival. While the KDM6B inhibitor, GSK-J4, has shown activity in in vitro and in vivo preclinical models, the mechanism of action remains poorly defined. We demonstrate that genetic and pharmacologic inhibition of KDM6B downregulates the pRB-E2F transcriptome and MYCN expression. Chemical genetic analyses show that high expression of the E2F transcriptome is positively correlated with sensitivity of cancer cells to GSK-J4. Mechanistically, inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and GSK-J4. A gene signature targeted by KDM6B inhibition is associated with poor survival of patients with neuroblastoma regardless of the MYCN status. These data indicate that KDM6B activity promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.

cancer biology↗

bioRxiv2020

Atom Identifiers Generated by a Graph Coloring Method Enable Compound Harmonization Across Metabolic Databases

Metabolic flux analysis requires both a reliable metabolic model and metabolic profiles in characterizing metabolic reprogramming. Advances in analytic methodologies enable production of high-quality metabolomics datasets capturing isotopic flux. However, useful metabolic models can be difficult to derive due to the lack of relatively complete atom-resolved metabolic networks for a variety of organisms, including human. Here, we developed a graph coloring method that creates unique identifiers for each atom in a compound facilitating construction of an atom-resolved metabolic network. What is more, this method is guaranteed to generate the same identifier for symmetric atoms, enabling automatic identification of possible additional mappings caused by molecular symmetry. Furthermore, a compound coloring identifier derived from the corresponding atom coloring identifiers can be used for compound harmonization across various metabolic network databases, which is an essential first step in network integration. With the compound coloring identifiers, 8865 correspondences between KEGG and MetaCyc compounds are detected, with 5451 of them confirmed by other identifiers provided by the two databases. In addition, we found that the Enzyme Commission numbers (EC) of reactions can be used to validate possible correspondence pairs, with 1848 unconfirmed pairs validated by commonality in reaction ECs. Moreover, we were able to detect various issues and errors with compound representation in KEGG and MetaCyc databases by compound coloring identifiers, demonstrating the usefulness of this methodology for database curation.Competing Interest StatementThe authors have declared no competing interest.View Full Text

systems biology↗

bioRxiv2020

Mps2 links Csm4 and Mps3 to form a telomere-associated LINC complex in budding yeast

The linker of the nucleoskeleton and cytoskeleton (LINC) protein complex is composed of a pair of transmembrane proteins: the KASH-domain protein localized to the outer nuclear membrane and the SUN-domain protein to the inner nuclear membrane. In budding yeast, the sole SUN-domain protein, Mps3, is thought to pair with either Csm4 or Mps2, two KASH-like proteins, to form two separate LINC complexes. Here we show that Mps2 mediates the interaction between Csm4 and Mps3 to form a heterotrimeric telomere-associated LINC (t-LINC) in budding yeast meiosis. Mps2 binds to Csm4 and Mps3, and all three are localized to the telomere. Telomeric localization of Csm4 depends on both Mps2 and Mps3; in contrast, Mps2s localization depends on Mps3 but not Csm4. Mps2-mediated t-LINC regulates telomere movement and meiotic recombination. By ectopically expressing CSM4 in vegetative yeast cells, we reconstitute the heterotrimeric t-LINC and demonstrate its ability to tether telomeres. Our findings therefore reveal the heterotrimeric composition of t-LINC in budding yeast and have implications for understanding LINC variant formation.

cell biology↗

bioRxiv2020

Natural variation identifies a Pxy gene controlling root vascular organization and formation of nodules and lateral roots in Lotus japonicus

Forward and reverse genetics using the model legumes Lotus japonicus and Medicago truncatula have been instrumental for identifying the essential genes governing legume-rhizobial symbiosis. However, little is known about the effects of intraspecific variation on symbiotic signaling. The Lotus accessions Gifu and MG20 show differentiated phenotypic responses to the Mesorhizobium loti exoU mutant that produces truncated exopolysaccharides. Using Quantitative Trait Locus sequencing (QTL-seq), we identify the Pxy gene as a component of this differential exoU response. Lotus Pxy encodes a leucine-rich-repeat kinase similar to Arabidopsis PXY, which regulates stem vascular development. We show that Lotus pxy insertion mutants display defects in root vascular organization, as well as lateral root and nodule formation. Our work links Pxy to de novo organogenesis in the root, highlights the genetic overlap between regulation of lateral root and nodule formation, and demonstrates that specific natural variants of Pxy differentially affect nodulation signaling.

plant biology↗

bioRxiv2020

The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression program

MiDAC is a recently identified histone deacetylase (HDAC) complex. While other HDAC complexes have been implicated in neurogenesis, the physiological role of MiDAC remains unknown. Here, we show that MiDAC constitutes an important regulator of neural differentiation. We demonstrate that MiDAC functions as a modulator of a neurodevelopmental gene expression program and binds to important regulators of neurite outgrowth. On the one hand, MiDAC upregulates gene expression by mediating the removal of H4K20ac on the promoters and enhancers of pro-neural genes such as those encoding the secreted ligands SLIT3 and NETRIN1 (NTN1). Conversely, MiDAC inhibits gene expression by reducing H3K27ac on promoter-proximal and -distal elements of negative regulators of neurogenesis. Furthermore, loss of MiDAC results in neurite outgrowth defects that can be rescued by supplementation with SLIT3 and/or NTN1. These findings indicate a crucial role for MiDAC in regulating the ligands of the SLIT3 and NTN1 signaling axes to ensure the proper integrity of neurite development.

molecular biology↗

bioRxiv2020

Mechanosensation Mediates Long-Range Spatial Decision-Making in an Aneural Organism

The unicellular protist Physarum polycephalum is an important emerging model for understanding how aneural organisms process information toward adaptive behavior. Here, we reveal that Physarum can use mechanosensation to reliably make decisions about distant objects its environment, preferentially growing in the direction of heavier, substrate-deforming but chemically-inert masses. This long-range mass-sensing is abolished by gentle rhythmic mechanical disruption, changing substrate stiffness, or addition of a mechanosensitive transient receptor potential channel inhibitor. Computational modeling revealed that Physarum may perform this calculation by sensing the fraction of its growth perimeter that is distorted above a threshold strain - a fundamentally novel method of mechanosensation. Together, these data identify a surprising behavioral preference relying on biomechanical features and not nutritional content, and characterize a new example of an aneural organism that exploits physics to make decisions about growth and form. HighlightsO_LIThe aneural Physarum makes behavioral decisions by control of its morphology C_LIO_LIIt has a preference for larger masses, which it can detect at long range C_LIO_LIThis effect is mediated by mechanosensing, not requiring chemical attractants C_LIO_LIMachine learning reveals that it surveys environment and makes decision in < 4 hours C_LIO_LIA biophysical model reveals how its pulsations enable long-distance mapping of environmental features C_LI

animal behavior and cognition↗

bioRxiv2020

TRIBE editing reveals specific mRNA targets of eIF4E-BP in Drosophila and in mammals

4E-BP (eIF4E-BP) represses translation initiation by binding to the 5cap-binding protein eIF4E and inhibiting its activity. Although 4E-BP has been shown to be important in growth control, stress response, cancer, neuronal activity and mammalian circadian rhythms, it is not understood how it preferentially represses a subset of mRNAs. We successfully used hyperTRIBE (Targets of RNA-binding proteins identified by editing) to identify in vivo 4E-BP mRNA targets in both Drosophila and mammals under conditions known to activate 4E-BP. The protein associates with specific mRNAs, and ribosome profiling data show that mTOR inhibition changes the translational efficiency of 4E-BP TRIBE targets compared to non-targets. In both systems, these targets have specific motifs and are enriched in translation-related pathways, which correlate well with the known activity of 4E-BP and suggest that it modulates the binding specificity of eIF4E and contributes to mTOR translational specificity.

molecular biology↗

bioRxiv2020

An alternative miRISC targeting a coding mutation site in FOXL2 links to granulosa cell tumor

Recent evidence suggests that animal microRNAs (miRNAs) can target coding sequences (CDSs); however, the pathophysiological importance of such targeting remains unknown. Here, we show that a somatic heterozygous missense mutation (c.402C>G; p.C134W) in FOXL2, a feature shared by virtually all adult-type granulosa cell tumors (AGCTs), introduces a target site for miR-1236, which induces haploinsufficiency of the tumor-suppressor FOXL2. This miR-1236-mediated selective degradation of the variant FOXL2 mRNA is preferentially conducted by a distinct miRNA-loaded RNA-induced silencing complex (miRISC) directed by the Argonaute3 (AGO3) and DHX9 proteins. In both patients and mouse model of AGCT, the inversely regulated variant FOXL2 abundance with the miR-1236 levels was highly correlated with malignant features of AGCT. Our study provides a molecular basis for understanding the conserved FOXL2 CDS mutation-mediated etiology of AGCT, revealing the existence of a previously unidentified mechanism of miRNA-targeting disease-associated mutations in the CDS by forming a non-canonical miRISC.

cancer biology↗

bioRxiv2020

Epigenetic engineering of yeast reveals dynamic molecular adaptation to methylation stress and genetic modulators of specific DNMT3 family members

Cytosine methylation is a ubiquitous modification in mammalian DNA generated and maintained by several DNA methyltransferases (DNMTs) with partially overlapping functions and genomic targets. To systematically dissect the factors specifying each DNMTs activity, we engineered combinatorial knock-in of human DNMT genes in Komagataella phaffii, a yeast species lacking endogenous DNA methylation. Time-course expression measurements captured dynamic network-level adaptation of cells to DNMT3B1-induced DNA methylation stress and showed that coordinately modulating the availability of S-adenosyl methionine (SAM), the essential metabolite for DNMT-catalyzed methylation, is an evolutionarily conserved epigenetic stress response, also implicated in several human diseases. Convolutional neural networks trained on genome-wide CpG-methylation data learned distinct sequence preferences of DNMT3 family members. A simulated annealing interpretation method resolved these preferences into individual flanking nucleotides and periodic poly(A) tracts that rotationally position highly methylated cytosines relative to phased nucleosomes. Furthermore, the nucleosome repeat length defined the spatial unit of methylation spreading. Gene methylation patterns were similar to those in mammals, and hypo- and hypermethylation were predictive of increased and decreased transcription relative to control, respectively, in the absence of mammalian readers of DNA methylation. Introducing controlled epigenetic perturbations in yeast thus enabled characterization of fundamental genomic features directing specific DNMT3 proteins.

genomics↗