Biology subjects

Gao, X.

Publications and source records attributed to Gao, X..

At least 289 records · Page 16Linked to original sources

bioRxiv2020

NERO: A Biomedical Named-entity (Recognition) Ontology with a Large, Annotated Corpus Reveals Meaningful Associations Through Text Embedding

Machine reading is essential for unlocking valuable knowledge contained in the millions of existing biomedical documents. Over the last two decades 1,2, the most dramatic advances in machine-reading have followed in the wake of critical corpus development3. Large, well-annotated corpora have been associated with punctuated advances in machine reading methodology and automated knowledge extraction systems in the same way that ImageNet 4 was fundamental for developing machine vision techniques. This study contributes six components to an advanced, named-entity analysis tool for biomedicine: (a) a new, Named-Entity Recognition Ontology (NERO) developed specifically for describing entities in biomedical texts, which accounts for diverse levels of ambiguity, bridging the scientific sublanguages of molecular biology, genetics, biochemistry, and medicine; (b) detailed guidelines for human experts annotating hundreds of named-entity classes; (c) pictographs for all named entities, to simplify the burden of annotation for curators; (d) an original, annotated corpus comprising 35,865 sentences, which encapsulate 190,679 named entities and 43,438 events connecting two or more entities; (e) validated, off-the-shelf, named-entity recognition automated extraction, and; (f) embedding models that demonstrate the promise of biomedical associations embedded within this corpus.

systems biology↗

bioRxiv2020

Duple extinguishment of COVID-19: single compound synergized inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokines in vitro/vivo

We firstly disclose single compound yields better therapeutic outcome than Remdesivir in COVID-19 hamster treatments as it is armed with direct inhibition viral replication and intrinsic suppression inflammatory cytokines expression. Crystal data reveals that Au (I), released from Au22Glutathione18 (GA), covalently binds thiolate of Cys145 of SARS-CoV-2 Mpro. GA directly decreases SARS-CoV-2 viral replication (EC50: ~0.24 M) and intrinsically down-regulates NF{kappa}B pathway therefore significantly inhibiting expression of inflammatory cytokines in cells. The lung viral load and inflammatory cytokines in GA-treated COVID-19 transgenic mice are found to be significantly lower than that of control mice. When COVID-19 golden hamsters are treated by GA, the lung inflammatory cytokines levels are significantly lower than that of Remdesivir while their lung viral load are decreased to same level. The pathological results show that GA treatment significantly reduce lung inflammatory injuries when compared to that of Remdesivir-treated COVID-19 golden hamsters. One Sentence SummaryWe found that gold cluster molecule directly inhibits SARS-CoV-2 replication and intrinsically suppresses inflammatory cytokines expression in COVID-19 transgenic mouse and golden hamster model, gold cluster providing a better lung injury protection than Remdesivir in COVID-19 golden hamsters via intranasally dropping administration.

microbiology↗

bioRxiv2020

WSB1 Regulates c-Myc Expression Through β-catenin Signaling and Forms a Feedforward Circuit Promoting the Development of Cancer.

The dysregulation of transcription factors is widely associated with tumorigenesis. As the most well-defined transcription factor in multiple types of cancer, c-Myc can directly transform cells by transactivating various downstream genes. Given that there is no effective way to directly inhibit c-Myc, c-Myc targeting strategies based on its regulatory mechanism hold great potential for cancer therapy. In this study, we found that WSB1, a direct target gene of c-Myc, can positively regulate c-Myc expression, which forms a feedforward circuit promoting cancer development. Luciferase-based promoter activity assays and RNA sequencing results confirmed that WSB1 promoted c-Myc expression through the {beta}-catenin pathway. Mechanistically, WSB1 affected {beta}-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor {beta}-TRCP recruitment, which inhibited the ubiquitination of {beta}-catenin and subsequently transactivated c-Myc. Of interest, the promoting effect of WSB1 on c-Myc was independent of its E3 ligase activity. Moreover, co-expression of WSB1 and c-Myc strongly enhanced the initiation and progression of tumours both in vitro and in vivo. Thus, our findings revealed a novel mechanism involved in tumorigenesis in which the WSB1/c-Myc feedforward circuit played an essential role, highlighting a potential c-Myc intervention strategy in cancer treatment.

molecular biology↗

bioRxiv2020

A proof of concept for neutralizing antibody-guided vaccine design against SARS-CoV-2

Mutations and transient conformational movements of receptor binding domain (RBD) that make neutralizing epitopes momentarily unavailable, present immune escape routes to SARS-CoV-2. To mitigate viral escape, we developed a cocktail of neutralizing antibodies (NAbs) targeting epitopes located on different domains of spike (S) protein. Screening of a library of monoclonal antibodies generated from peripheral blood mononuclear cells of COVID-19 convalescent patients yielded potent NAbs, targeting N-terminal domain (NTD) and RBD domain of S, effective at nM concentrations. Remarkably, combination of RBD-targeting NAbs and NTD-binding NAb, FC05, dramatically enhanced the neutralization potency in cell-based assays and animal model. Results of competitive SPR assays and cryo-EM structures of Fabs bound to S unveil determinants of immunogenicity. Combinations of immunogens, identified in NTD and RBD of S, when immunized in rabbits elicited potent protective immune responses against SARS-CoV-2. These results provide a proof-of-concept for neutralization-based immunogen design targeting SARS-CoV-2 NTD and RBD. One sentence summaryImmunogens identified in the NTD and RBD of the SARS-CoV-2 spike protein using a cocktail of non-competing NAbs when injected in rabbits elicited a potent protective immune response against SARS-CoV-2.

microbiology↗

bioRxiv2020

Identification and Characterization of a Residual Host Cell Protein Hexosaminidase B Associated with N-glycan Degradation During the Stability Study of a Therapeutic Recombinant Monoclonal Antibody Product

Host cell proteins (HCPs) are process-related impurities derived from host organisms, which need to be controlled to ensure adequate product quality and safety. In this study, product quality attributes were tracked for several mAbs under the intended storage and accelerated stability conditions. One product quality attribute not expected to be stability indicating is the N-glycan heterogeneity profile. However, significant N-glycan degradation was observed for one mAbs under accelerated and stressed stability conditions. The root cause for this instability was attributed to Hexosaminidase B (HEXB), an enzyme known to remove terminal N-acetylglucosamine (GlcNAc). HEXB was identified by liquid chromatography-mass spectrometry (LC-MS) based proteomics approach to be enriched in the impacted stability batches from mAb-1. Subsequently, enzymatic and targeted multiple reaction monitoring (MRM) MS assays were developed to support process and product characterization. A potential interaction between HEXB and mAb-1 was initially observed from the analysis of process intermediates by proteomics among several mAbs and later supported by computational modeling. An improved bioprocess was developed to significantly reduce HEXB levels in the final drug substance. A risk assessment was conducted by evaluating the in silico immunogenicity risk and the impact on product quality. To the best of our knowledge, HEXB is the first residual HCP reported to have impact on the glycan profile of a formulated drug product. The combination of different analytical tools, mass spectrometry and computational modeling provide a general strategy on how to study residual HCP for biotherapeutics development.

biochemistry↗

bioRxiv2020

Reduction of neuronal activity mediated by blood-vessel regression in the brain

The brain vasculature supplies neurons with glucose and oxygen, but little is known about how vascular plasticity contributes to brain function. Using longitudinal in vivo imaging, we reported that a substantial proportion of blood vessels in the adult brain sporadically occluded and regressed. Their regression proceeded through sequential stages of blood-flow occlusion, endothelial cell collapse, relocation or loss of pericytes, and retraction of glial endfeet. Regressing vessels were found to be widespread in mouse, monkey and human brains. Both brief occlusions of the middle cerebral artery and lipopolysaccharide-mediated inflammation induced an increase of vessel regression. Blockage of leukocyte adhesion to endothelial cells alleviated LPS-induced vessel regression. We further revealed that blood vessel regression caused a reduction of neuronal activity due to a dysfunction in mitochondrial metabolism and glutamate production. Our results elucidate the mechanism of vessel regression and its role in neuronal function in the adult brain.

neuroscience↗

bioRxiv2020

The Pancreatic Tumor Microenvironment Buffers Redox Imbalance Imposed by Disrupted Mitochondrial Metabolism

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) restricts vascularization and, consequently, access to blood-derived nutrients and oxygen, which impacts tumor growth. Intracellular redox imbalance is another restraint on cellular proliferation, yet it is unknown if the TME contributes to the maintenance of redox homeostasis in PDA cells. Here, we demonstrate that the loss of mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2), a component in the malate-aspartate shuttle, disturbs redox homeostasis and halts proliferation of PDA cells in vitro. In contrast, GOT2 inhibition has no effect on in vivo tumor growth or tumorigenesis in an autochthonous model. We propose that this discrepancy is explained by heterocellular pyruvate exchange from the TME, including from cancer associated fibroblasts. More broadly, pyruvate similarly confers resistance to inhibitors of mitochondrial respiration. Genetic or pharmacologic inhibition of pyruvate uptake or metabolism abrogated pyruvate-mediated alleviation of reductive stress from NADH buildup. In sum, this work describes a potential resistance mechanism mediated by metabolic crosstalk within the pancreatic TME. These findings have important implications for metabolic treatment strategies since several mitochondrial inhibitors are currently in clinical trials for PDA and other cancers.

cancer biology↗

bioRxiv2020

PI3K inhibition reverses migratory direction of single cells but not cell groups in electric field

Motile cells migrate directionally in the electric field in a process known as galvanotaxis. Galvanotaxis is important in wound healing, development, cell division, and nerve growth. Different cell types migrate in opposite directions in electric fields, to either cathode, or anode, and the same cell can switch the directionality depending on chemical conditions. We previously reported that individual fish keratocyte cells sense electric fields and migrate to the cathode, while inhibition of PI3K reverses single cells to the anode. Many physiological processes rely on collective, not individual, cell migration, so here we report on directional migration of cohesive cell groups in electric fields. Uninhibited cell groups of any size move to the cathode, with speed decreasing and directionality increasing with the group size. Surprisingly, large groups of PI3K-inhibited cells move to the cathode, in the direction opposite to that of individual cells, which move to the anode, while such small groups are not persistently directional. In the large groups, cells velocities are distributed unevenly: the fastest cells are at the front of the uninhibited groups, but at the middle and rear of the PI3K-inhibited groups. Our results are most consistent with the hypothesis, supported by the computational model, that cells inside and at the edge of the groups interpret directional signals differently. Namely, cells in the group interior are directed to the cathode independently of their chemical state. Meanwhile, edge cells behave like the individual cells: they are directed to the cathode/anode in uninhibited/PI3K-inhibited groups, respectively. As a result, all cells drive uninhibited groups to the cathode, but a mechanical tug-of-war between the inner and edge cells directs large PI3K-inhibited groups with cell majority in the interior to the cathode, while rendering small groups non-directional. Significance statementMotile cells migrate directionally in electric fields. This behavior - galvanotaxis - is important in many physiological phenomena. Individual fish keratocytes migrate to the cathode, while inhibition of PI3K reverses single cells to the anode. Uninhibited cell groups move to the cathode. Surprisingly, large groups of PI3K-inhibited cells also move to the cathode, in the direction opposite to that of individual cells. The fastest cells are at the front of the uninhibited groups, but at the middle and rear of the PI3K-inhibited groups. We posit that inner and edge cells interpret directional signals differently, and that a tug-of-war between the edge and inner cells directs the cell groups. These results shed light on general principles of collective cell migration.

biophysics↗

bioRxiv2020

Impaired learning and memory ability induced by a bilaterally hippocampal injection of streptozotocin in mice: involved with the adaptive changes of synaptic plasticity

BackgroundAlzheimers disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, psychiatric symptoms and behavioral disorders, resulting in disability and loss of self-sufficiency. ObjectiveTo establish an AD mice model, investigate the behavioral performance, and explore the potential mechanism. MethodsStreptozotocin (STZ, 3 mg/kg) was microinjected bilaterally into the dorsal hippocampus of C57BL /6 mice to establish the AD model. Behavioral changes (anhedonia and despair, balance and motor coordination, locomotion, and learning and memory) were examined and the serum concentrations of insulin and nesfatin-1 were measured by ELISA. The activation of hippocampal microglia was assessed by immunohistochemistry and the protein expression of several molecular associated with the regulation of synaptic plasticity in the hippocampus and the prefrontal cortex (PFC) was detected via western blotting. ResultsThe STZ model mice showed a slower bodyweight gain and higher serum concentration of insulin and nesfatin-1. Although there was no significant difference between groups with regard to the ability of balance and motor coordination, the model mice presented a decline of spontaneous movement and exploratory behavior, together with an impairment of learning and memory ability. Increased activated microglia was aggregated in the hippocampal dentate gyrus of model mice. Moreover, the protein expression of NMDAR2A, NMDAR2B, SynGAP, PSD95, BDNF, and p-{beta}-catenin/{beta}-catenin were remarkably decreased in the hippocampus and the PFC of model mice, and the expression of p-GSK-3{beta} (ser9)/GSK-3{beta} were reduced in the hippocampus. ConclusionA bilateral hippocampal microinjection of STZ could successfully duplicate an AD mice model, as indicated by the impaired learning and memory and the alternated synaptic plasticity, together with the hyperactive inflammatory response in the hippocampus and the imbalanced abundance of serum insulin and nesfatin-1. Apart from these, the mechanism might be associated with the imbalanced expression of the key proteins of Wnt signaling pathway in the hippocampus and the PFC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/235481v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@181c9a9org.highwire.dtl.DTLVardef@1deaa4forg.highwire.dtl.DTLVardef@17f3f09org.highwire.dtl.DTLVardef@1037c21_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Genetically Determined Strength of Natural Killer Cells is Enhanced by Adaptive HLA class I Admixture in East Asians

Human natural killer (NK) cells are essential for controlling infection, cancer and fetal development. NK cell functions are modulated by interactions between polymorphic inhibitory killer cell immunoglobulin-like receptors (KIR) and polymorphic HLA-A, -B and -C ligands expressed on tissue cells. All HLA-C alleles encode a KIR ligand and contribute to reproduction and immunity. In contrast, only some HLA-A and -B alleles encode KIR ligands and they focus on immunity. By high-resolution analysis of KIR and HLA-A, -B and -C genes, we show that the Chinese Southern Han are significantly enriched for interactions between inhibitory KIR and HLA-A and -B. This enrichment has had substantial input through population admixture with neighboring populations, who contributed HLA class I haplotypes expressing the KIR ligands B*46:01 and B*58:01, which subsequently rose to high frequency by natural selection. Consequently, over 80% of Southern Han HLA haplotypes encode more than one KIR ligand. Complementing the high number of KIR ligands, the Chinese Southern Han KIR locus combines a high frequency of genes expressing potent inhibitory KIR, with a low frequency of those expressing activating KIR. The Southern Han centromeric KIR region encodes strong, conserved, inhibitory HLA-C specific receptors, and the telomeric region provides a high number and diversity of inhibitory HLA-A and -B specific receptors. In all these characteristics, the Southern Han represent other East Asians, whose NK cell repertoires are thus enhanced in quantity, diversity and effector strength, likely through natural selection for resistance to endemic viral infections.

immunology↗

bioRxiv2020

Selective Nanotherapeutic Targeting of the Neutrophil Subset Mediating Inflammatory Injury

Inflammatory tissue injury such as acute lung injury (ALI) is a disorder that leads to respiratory failure, a major cause of morbidity and mortality worldwide. Excessive neutrophil influx is a critical pathogenic factor in the development of ALI. Here, we identify the subset of neutrophils that is responsible for ALI and lethality in polymicrobial sepsis. The pro-inflammatory neutrophil subpopulation was characterized by its unique ability to endocytose albumin nanoparticles (ANP), upregulation of pro-inflammatory cytokines and chemokines as well as the excessive production of reactive oxygen species (ROS) in models of endotoxemia and septicemia. ANP delivery of the drug piceatannol, a spleen tyrosine kinase (Syk) inhibitor, to the susceptible subset of neutrophils, prevented ALI and mortality in mice subjected to polymicrobial infection. Targeted inhibition of Syk in ANP-susceptible neutrophils had no detrimental effect on neutrophil-dependent host defense because the subset of ANPlow neutrophils effectively controlled polymicrobial infection. The results show that neutrophil heterogeneity can be leveraged therapeutically to prevent ALI without compromising host defense.Competing Interest StatementABM, AS, KB have interests in the biotechnology company Nano Biotherapeutics Inc.View Full Text

immunology↗

bioRxiv2020

In Vitro efficacy comparison of linezolid, tedizolid, sutezolid and delpazolid against rapid growing Mycobacteria isolated in Beijing, China

The natural resistance of rapid growth Mycobacterium (RGM) against multiple antibiotics renders the treatment of caused infections less successful and time consuming. Therefore, new effective agents are urgently needed. The aim of this study was to evaluate the in vitro susceptibility of 115 isolates, constituting different RGM species, against four oxazolidinones i.e. delpazolid, sutezolid, tedizolid and linezolid. Additionally, 32 reference strains of different RGM species were also tested. The four oxazolidinones exhibited potent in vitro activity against the recruited RGM reference strains, 24 out of 32 RGM species had MICs [≤] 8 g/mL against all four oxazolidinones whereas tedizolid and delpazolid generally presented lower MICs than linezolid or sutezolid. Tedizolid showed the strongest activity against clinical isolates of M. abscessus with MIC50=1g/mL and MIC90=2g/mL. MIC values for tedizolid were usually 4- to 8-fold less than the MICs of linezolid for M. abscessus subsp. abscessus. The MIC distributions of sutezolid and linezolid were similar, while delpazolid showed 2-fold lower MIC as compared with linezolid. Linezolid was not active against most of the tested M. fortuitum isolates, 22 out of the 25 M. fortuitum were resistant against linezolid. However, delpazolid exhibited better antimicrobial activity against these isolates with 4-fold lower MIC values, in contrast with linezolid. In addition, the protein alignment of RplC and RplD and structure based analysis showed that there may be no correlation between oxazolidinones resistance and mutations in rplC, rplD and 23 srRNAgenes in tested RGM. This study showed tedizolid harbors the strongest inhibitory activity against M. abscessus in vitro, while delpazolid presented the best activity against M. fortuitum, which provided important insights on the potential clinical application of oxazolidinones to treat RGM infections.

microbiology↗

bioRxiv2020

Integrated metabolic modeling, culturing and transcriptomics explains enhanced virulence of V. cholerae during co-infection with ETEC

Gene essentiality is altered during polymicrobial infections. Nevertheless, most studies rely on single-species infections to assess pathogen gene essentiality. Here, we use genome-scale metabolic models to explore the effect of co-infection of the diarrheagenic pathogen Vibrio cholerae (V. cholerae) with another enteric pathogen, enterotoxigenic E. coli (ETEC). Model predictions showed that V. cholerae metabolic capabilities were increased due to ample cross-feeding opportunities enabled by ETEC. This is in line with increased severity of cholera symptoms known to occur in patients with dual-infections by the two pathogens. In vitro co-culture systems confirmed that V. cholerae growth is enhanced in co-cultures relative to single-cultures. Further, expression levels of several V. cholerae metabolic genes were significantly perturbed as shown by dual RNAseq analysis of its co-cultures with different ETEC strains. A decrease in ETEC growth was also observed, probably mediated by non-metabolic factors. Single gene essentiality analysis predicted conditionally-independent genes that are essential for the pathogen’s growth in both single- and co-infection scenarios. Our results reveal growth differences that are of relevance to drug targeting and efficiency in polymicrobial infections.Importance Most studies proposing new strategies to manage and treat infections have been largely focused on identifying druggable targets that can inhibit a pathogen’s growth when it is the single cause of infection. In vivo, however, infections can be caused by multiple species. This is important to take into account when attempting to develop or use current antibacterials since their efficacy can change significantly between single and co-infections. In this study, we used genome-scale metabolic models (GEMs) to interrogate the growth capabilities of Vibrio cholerae (V. cholerae) in single and co-infections with enterotoxigenic E. coli (ETEC), which co-occur in large fraction of diarrheagenic patients. Co-infection model predictions showed that V. cholerae growth capabilities are enhanced in presence of ETEC relative to V. cholerae single-infection, through cross-fed metabolites made available to V. cholerae by ETEC. In vitro, co-cultures of the two enteric pathogens further confirmed model predictions showing an increased growth of V. cholerae in co-culture relative to V. cholerae single-cultures while ETEC growth was suppressed. Dual RNAseq analysis of the co-cultures also confirmed that the transcriptome of V. cholerae is distinct during co-infection compared to single infection scenarios where processes related to metabolism were significantly perturbed. Further, in silico gene-knock out simulations uncovered discrepancies in gene essentiality for V. cholerae growth between single and co-infections. Integrative model-guided analysis thus identified druggable targets that would be critical for V. cholerae growth in both single and co-infections, thus designing inhibitors against those targets would provide a broader spectrum coverage against cholera infections.View Full Text

systems biology↗

bioRxiv2020

An enormous Paris polyphylla genome sheds light on genome size evolution and polyphyllin biogenesis

The monocot family Melanthiaceae with varying genome sizes in a range of 230-fold is an ideal model to study the genome size fluctuation in plants. Its family member Paris genus demonstrates an evolutionary trend of bearing huge genomes characterized by an average c-value of 49.22 pg. Here, we report a 70.18 Gb genome assembly out of the 82.55 Gb genome of Paris polyphylla var. yunnanensis (PPY), which represents the biggest sequenced genome to date. We annotate 69.53% repetitive sequences in this genome and 62.50% of which are long-terminal repeat (LTR) transposable elements. Further evolution analysis indicates that the giant genome likely results from the joint effect of common and species-specific expansion of different LTR superfamilies, which might contribute to the environment adaptation after speciation. Moreover, we identify the candidate pathway genes for the biogenesis of polyphyllins, the PPY-specific medicinal saponins, by complementary approaches including genome mining, comprehensive analysis of 31 next-generation RNA-seq data and 55.23 Gb single-molecule circular consensus sequencing (CCS) RNA-seq reads, and correlation of the transcriptome and phytochemical data of five different tissues at four growth stages. This study not only provides significant insights into plant genome size evolution, but also paves the way for the following polyphyllin synthetic biology.

plant biology↗

bioRxiv2020

Integrative Molecular Characterization of Sarcomatoid and Rhabdoid Renal Cell Carcinoma Reveals Determinants of Poor Prognosis and Response to Immune Checkpoint Inhibitors

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors1-3, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings shed light on the molecular drivers of aggressivity and responsiveness to immune checkpoint inhibitors of S/R RCC tumors.

cancer biology↗

bioRxiv2020

Molecules inhibit the enzyme activity of 3-chymotrypsin-like cysteine protease of SARS-CoV-2 virus

SARS-CoV-2 has emerged as a world public health threat. Herein, we report that the clinical approved auranofin could perfectly inhibit the activity of 3-chymotrypsin-like cysteine protease (Mpro or 3CLpro) of SARS-CoV-2. Gold cluster could significantly inhibit 3CLpro of SARS-COV-2. Phenyl isothiocyanate and Vitamin K3 could well suppress the activity of 3CLpro. For Mpro inhibition, IC50 of auranofin, Vitamin K3, phenyl isothiocyanate, gold cluster are about 0.51M, 7.96M, 10.13M, 1.61M, respectively. These compounds may be with potentials for treatment SARS-CoV-2 virus replication. Especially for FDA approved auranofin, it is an anti-inflammation drug in clinic, thus it may with strong potential to inhibit virus replication and suppress the inflammation damage in COVID-19 patients. Gold cluster is with better safety index and well anti-inflammation in vitro/vivo, therefore it is with potential to inhibit virus replication and suppress the inflammation damage caused by COVID-19 virus. As Au(I) ion is active metabolism specie derived from gold compounds or gold clusters in vivo, further computational studies revealed Au ion could tightly bind thiol group of Cys145 residue of 3CLpro thus inhibit enzyme activity. Also, phenyl isothiocyanate and Vitamin K3 may interact with thiol group of Cys145 via Michael addition reaction, molecular dynamic (MD) theory studied are applied to confirmed these small molecules are stable in the pocket and inhibit Mpro activity.

biochemistry↗

bioRxiv2020

Atypical B cells are a normal component of immune responses to vaccination and infection in humans

The full diversity of the circulating human B cell compartment is unknown. Flow cytometry analysis suggests that in addition to naive and memory B cells, there exists a population of CD11c+, CD27- CD21- "atypical" B cells, that are associated with chronic or recurrent infection and autoimmunity. We used single cell RNA-seq approaches to examine the diversity of both antigen-specific B cells and total B cells in healthy subjects and individuals naturally-exposed to recurrent malaria infections. This analysis revealed two B cell lineages: a classical lineage of activated and resting memory B cells, and an atypical-like lineage. Surprisingly, the atypical lineage was common in both malaria exposed individuals and non-exposed healthy controls. Using barcoded antibodies in conjunction with our transcriptomic data, we found that atypical lineage cells in healthy individuals lack many atypical B markers and thus represent an undercounted cryptic population. We further determined using antigen specific probes that atypical cells can be induced by primary vaccination in humans and can be recalled upon boosting. Collectively these data suggest that atypical cells are not necessarily pathogenic but can be a normal component of B responses to antigen.

immunology↗

bioRxiv2020

Binding of the SARS-CoV-2 Spike Protein to Glycans

The pandemic of SARS-CoV-2 has caused a high number of deaths in the world. To combat it, it is necessary to develop a better understanding of how the virus infects host cells. Infection normally starts with the attachment of the virus to cell-surface glycans like heparan sulfate (HS) and sialic acid-containing oligosaccharides. In this study, we examined and compared the binding of the subunits and spike (S) proteins of SARS-CoV-2 and SARS-CoV, MERS-CoV to these glycans. Our results revealed that the S proteins and subunits can bind to HS in a sulfation-dependent manner, the length of HS is not a critical factor for the binding, and no binding with sialic acid residues was detected. Overall, this work suggests that HS binding may be a general mechanism for the attachment of these coronaviruses to host cells, and supports the potential importance of HS in infection and in the development of antiviral agents against these viruses.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biochemistry↗