Biology subjects

Peng, Q.

Publications and source records attributed to Peng, Q..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

Three-dose vaccination-induced immune responses protect against SARS-CoV-2 Omicron-BA.2

BackgroundThe ongoing outbreak of SARS-CoV-2 Omicron BA.2 infections in Hong Kong, the model city of universal masking of the world, has resulted in a major public health crisis. Although the third vaccination resulted in strong boosting of neutralization antibody, vaccine efficacy and corelates of immune protection against the major circulating Omicron BA.2 remains to be investigated. MethodsWe investigated the vaccine efficacy against the Omicron BA.2 breakthrough infection among 470 public servants who had received different SARS-CoV-2 vaccine regimens including two-dose BNT162b2 (2xBNT, n=169), three-dose BNT162b2 (3xBNT, n=170), two-dose CoronaVac (2xCorV, n=34), three-dose CoronaVac (3xCorV, n=67) and third-dose BNT162b2 following 2xCorV (2xCorV+1BNT, n=32). Humoral and cellular immune responses after three-dose vaccination were further characterized and correlated with clinical characteristics of BA.2 infection. FindingsDuring the BA.2 outbreak, 27.7% vaccinees were infected. The timely third-dose vaccination provided significant protection with lower incidence rates of breakthrough infections (2xBNT 49.2% vs 3xBNT 13.1%, p <0.0001; 2xCorV 44.1% vs 3xCoV 19.4%, p=0.003). Investigation of immune response on blood samples derived from 92 subjects in three-dose vaccination cohorts collected before the BA.2 outbreak revealed that the third-dose vaccination activated spike (S)-specific memory B cells and Omicron cross-reactive T cell responses, which correlated with reduced frequencies of breakthrough infections and disease severity rather than with types of vaccines. Moreover, the frequency of S-specific activated memory B cells was significantly lower in infected vaccinees than uninfected vaccinees before vaccine-breakthrough infection whereas IFN-{gamma}+ CD4 T cells were negatively associated with age and viral clearance time. Critically, BA.2 breakthrough infection boosted cross-reactive memory B cells with enhanced cross-neutralizing antibodies to Omicron sublineages, including BA.2.12.1 and BA.4/5, in all vaccinees tested. InterpretationOur results imply that the timely third vaccination and immune responses are likely required for vaccine-mediated protection against Omicron BA.2 pandemic. Although BA.2 conferred the highest neutralization resistance compared with variants of concern tested before the emergence of BA.2.12.1 and BA.4/5, the third dose vaccination-activated S-specific memory B cells and Omicron cross-reactive T cell responses contributed to reduced frequencies of breakthrough infection and disease severity. Neutralizing antibody potency enhanced by BA. 2 breakthrough infection with previous 3 doses of vaccines (CoronaVac or BNT162b2) may reduce the risk for infection of ongoing BA.2.12.1 and BA.4/5. FundingHong Kong Research Grants Council Collaborative Research Fund, Health and Medical Research Fund, Wellcome Trust, Shenzhen Science and Technology Program, the Health@InnoHK, Innovation and Technology Commission of Hong Kong, China, National Program on Key Research Project, Emergency Key Program of Guangzhou Laboratory, donations from the Friends of Hope Education Fund and the Hong Kong Theme-Based Research Scheme.

immunology↗

bioRxiv2022

Effects of immunomodulatory peptides derived from a soil bacterium on cecal microbiota of broilers challenged with Clostridium perfringens

Brevibacillus texasporus peptide (BT peptide) is immunomodulatory in poultry as a feed additive to substitute antibiotics. In the present study we performed 16S rRNA gene sequencing to compare development of the cecal microbial communities in Clostridium perfringens-challenged broilers fed basal diet only or with either BT peptide (48 ppm) or antibiotics mixture (20 ppm bacitracin zinc and 40 ppm colistin sulfate). 240 chicks were randomly assigned into each treatment and a total of 65 cecal samples were collected at the beginning, during seven challenge days and one week post challenge. The composition of microbial communities was clearly distinguishable over time. Treatments with challenge and the antibiotics mixture were associated with increased diversity and with higher relative abundances of Alistipes sp. CHKCI003 and Faecalibacterium and lower abundance of Escherichia coli (all p < 0.05). At the termination of the trial, the cecal microbiota in broilers supplemented with BT peptide was dominated by members of Bacteroidaceae. Predicted function analysis reveals significant enrichment of genes involved in ion-coupled transporters and sugar and biotin metabolism in the BT peptide treatment. Taken together, our results suggest that BT peptide and commonly used antibiotics have different influences on modulating the composition of cecal microbiota in broilers.

microbiology↗

bioRxiv2022

An elite broadly neutralizing antibody protects SARS-CoV-2 Omicron variant challenge

The strikingly high transmissibility and antibody evasion of SARS-CoV-2 Omicron variant have posted great challenges on the efficacy of current vaccines and antibody immunotherapy.Here, we screened 34 BNT162b2-vaccinees and cloned a public broadly neutralizing antibody (bNAb) ZCB11 from an elite vaccinee. ZCB11 neutralized all authentic SARS-CoV-2 variants of concern (VOCs), including Omicron and OmicronR346K with potent IC50 concentrations of 36.8 and 11.7 ng/mL, respectively. Functional analysis demonstrated that ZCB11 targeted viral receptor-binding domain (RBD) and competed strongly with ZB8, a known RBD-specific class II NAb. Pseudovirus-based mapping of 57 naturally occurred single mutations or deletions revealed that only S371L resulted in 11-fold neutralization resistance, but this phenotype was not observed in the Omicron variant. Furthermore,prophylactic ZCB11 administration protected lung infection against both the circulating pandemic Delta and Omicron variants in golden Syrian hamsters. These results demonstrated that vaccine-induced ZCB11 is a promising bNAb for immunotherapy against pandemic SARS-CoV-2 VOCs.

immunology↗

bioRxiv2022

Neuronal cell-type and circuit basis for visual predictive processing

Bayesian Brain theory suggests brain utilises predictive processing framework to interpret the noisy world1-11. Predictive processing is essential to perception, action, cognition and psychiatric disease12, but underlying neural circuit mechanisms remain undelineated. Here we show the neuronal cell-type and circuit basis for visual predictive processing in awake, head-fixed mice during self-initiated running. Preceding running, vasoactive intestinal peptide (VIP)-expressing inhibitory interneurons (INs) in primary visual cortex (V1) are robustly activated in absence of structured visual stimuli. This pre-running activation is mediated via distal top-down projections from frontal, parietal and retrosplenial areas known for motion planning, but not local excitatory inputs associated with the bottom-up pathway. Somatostatin (SST) INs show pre-running suppression and post-running activation, indicating a VIP-SST motif. Differential VIP-SST peri-running dynamics anisotropically suppress neighbouring pyramidal (Pyr) neurons, preadapting Pyr neurons to the incoming running. Our data delineate key neuron types and circuit elements of predictive processing brain employs in action and perception. One Sentence SummaryVIP-SST-Pyr microcircuit in visual predictive processing during voluntary running

neuroscience↗

bioRxiv2021

The P2Y2 Nucleotide Receptor Mediates Monocyte Tissue Factor Expression and Endotoxemia Death in Mice

Recently we reported that in human coronary artery endothelial cells, activation of the P2Y2 receptor (P2Y2R) induces up-regulation of tissue factor (TF), a vital initiator of the coagulation cascade. However, others have shown that monocyte TF is more critical than endothelial TF in provoking a pro-thrombotic state. Thus, we aimed to study whether monocytes express the P2Y2R, its role in controlling TF expression, and its relevance in vivo. RT-PCR and receptor activity assays revealed that among the eight P2Y nucleotide receptors, the P2Y2 subtype was selectively and functionally expressed in human monocytic THP-1 cells and primary monocytes. Stimulation of the cells by ATP or UTP dramatically increased TF protein expression, which was abolished by AR-C118925, a selective P2Y2R antagonist, or by siRNA silencing the P2Y2R. In addition, UTP or ATP treatment induced a rapid accumulation of TF mRNA preceded with an increased TF pre-mRNA, indicating enhanced TF gene transcription. In addition, stimulation of the monocyte P2Y2R significantly activated ERK1/2, JNK, p38, and Akt, along with their downstream transcription factors including c-Jun, c-Fos, and ATF-2, whereas blocking these pathways respectively, all significantly suppressed P2Y2R-mediated TF expression. Furthermore, we found that LPS triggered ATP release and TF expression, the latter of which was suppressed by apyrase or P2Y2R blockage. Importantly, P2Y2R-null mice were more resistant than wild-type mice in response to a lethal dose of LPS, accompanied by much less TF expression in bone marrow cells. These findings demonstrate for the first time that the P2Y2R mediates TF expression in human monocytes through mechanisms involving ERK1/2, JNK, p38, and AKT, and that P2Y2R deletion protects the mice from endotoxemia-induced TF expression and death, highlighting monocyte P2Y2R may be a new drug target for the prevention and/or treatment of relevant thrombotic disease.

pharmacology and toxicology↗

bioRxiv2021

Vaccine-breakthrough infection by the SARS-CoV-2 Omicron variant elicits broadly cross-reactive immune responses

Highly transmissible SARS-CoV-2 Omicron variant has posted a new crisis for COVID-19 pandemic control. Within a month, Omicron is dominating over Delta variant in several countries probably due to immune evasion. It remains unclear whether vaccine-induced memory responses can be recalled by Omicron infection. Here, we investigated host immune responses in the first vaccine-breakthrough case of Omicron infection in Hong Kong. We found that the breakthrough infection rapidly recruited potent cross-reactive broad neutralizing antibodies (bNAbs) against current VOCs, including Alpha, Beta, Gamma, Delta and Omicron, from unmeasurable IC50 values to mean 1:2929 at around 9-12 days, which were higher than the mean peak IC50 values of BioNTech-vaccinees. Cross-reactive spike- and nucleocapsid-specific CD4 and CD8 T cell responses were detected. Similar results were also obtained in the second vaccine-breakthrough case of Omicron infection. Our preliminary findings may have timely implications to booster vaccine optimization and preventive strategies of pandemic control.

immunology↗

bioRxiv2021

Waning immune responses against SARS-CoV-2 among vaccinees in Hong Kong

BackgroundNearly 4 billion doses of the BioNTech-mRNA and Sinovac-inactivated vaccines have been administrated globally, yet different vaccine-induced immunity against SARS-CoV-2 variants of concern (VOCs) remain incompletely investigated. MethodsWe compare the immunogenicity and durability of these two vaccines among fully vaccinated Hong Kong people. FindingsStandard BioNTech and Sinovac vaccinations were tolerated and induced neutralizing antibody (NAb) (100% and 85.7%) and spike-specific CD4 T cell responses (96.7% and 82.1%), respectively. The geometric mean NAb IC50 and median frequencies of reactive CD4 subsets were consistently lower among Sinovac-vaccinees than BioNTech-vaccinees. Against VOCs, NAb response rate and geometric mean IC50 against B1.351 and B.1.617.2 were significantly lower for Sinovac (14.3%, 15 and 50%, 23.2) than BioNTech (79.4%, 107 and 94.1%, 131). Three months after vaccinations, NAbs to VOCs dropped near to detection limit, along with waning memory T cell responses, mainly among Sinovac-vaccinees. InterpretationOur results indicate that Sinovac-vaccinees may face higher risk to pandemic VOCs breakthrough infection. FundingThis study was supported by the Hong Kong Research Grants Council Collaborative Research Fund (C7156-20GF to Z.C and C1134-20GF); the National Program on Key Research Project of China (Grant 2020YFC0860600, 2020YFA0707500 and 2020YFA0707504); Shenzhen Science and Technology Program (JSGG20200225151410198 and JCYJ20210324131610027); HKU Development Fund and LKS Faculty of Medicine Matching Fund to AIDS Institute; Hong Kong Innovation and Technology Fund, Innovation and Technology Commission and generous donation from the Friends of Hope Education Fund. Z.C.s team was also partly supported by the Theme-Based Research Scheme (T11-706/18-N).

immunology↗

bioRxiv2021

Dihydroartemisinin broke immune evasion through YAP1/JAK1/STAT1, 3 pathways to enhance anti-PD-1 therapy in hepatocellular carcinoma

The efficacy of anti-PD-1 therapy is not as expected in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) was overexpressed and activated in HCC. This study aimed to investigate the potential mechanism and inhibitor of YAP1 on immune evasion, and promote anti-PD-1 therapy in HCC. Here, we showed that dihydroartemisinin (DHA), an FDA approved drug, directly suppressed YAP1 expression, leading to break immune evasion in liver tumor niche, characterized by decreased PD-L1 in liver tumor cells and increased CD8+ T cell infiltration. Mechanismly, YAP1 is not only directly related to PD-L1, but also involved in activating the JAK1/STAT1, 3 pathways. Moreover, Yap1 knockout elevated CD4+ and CD8+ T cells in liver tumor niche of Yap1LKO mice. Consistently, verteporfin, YAP1 inhibitor, decreased TGF-{beta} in liver tumor niche and exhausted CD8+ T cells in spleen. Furthermore, DHA combined with anti-PD-1 treatment promoted CD4+ T cell infiltration in the spleen and CD8+ T cells in tumor tissues. Thus, we provide a new combined therapeutic strategy for anti-PD-1 with DHA, a potent YAP1 inhibitor, in HCC.

cancer biology↗

bioRxiv2021

FastQTLmapping: an ultra-fast package for mQTL-like analysis

SummaryHere we describe fastQTLmapping, a C++ package that is computationally efficient not only for mQTL-like analysis but as a generic solver also for conducting exhaustive linear regressions involving extraordinarily large numbers of dependent and explanatory variables allowing for covariates. Compared to the state-of-the-art MatrixEQTL, fastQTLmapping was an order of magnitude faster with much lower peak memory usage. In a large dataset consisting of 3,500 individuals, 8 million SNPs, 0.8 million CpGs and 20 covariates, fastQTLmapping completed the mQTL analysis in 7 hours with 230GB peak memory usage. Availability and ImplementationFastQTLmapping is implemented in C++ and released under a GPL license. FastQTLmapping can be downloaded from https://github.com/TianTTL/xQTLmapping. Contactliufan@big.ac.cn

bioinformatics↗

bioRxiv2021

Nasal prevention of SARS-CoV-2 infection by intranasal influenza-based boost vaccination

BackgroundVaccines in emergency use are efficacious against COVID-19, yet vaccine-induced prevention against nasal SARS-CoV-2 infection remains suboptimal. MethodsSince mucosal immunity is critical for nasal prevention, we investigated an intramuscular PD1-based receptor-binding domain (RBD) DNA vaccine (PD1-RBD-DNA) and intranasal live attenuated influenza-based vaccines (LAIV-CA4-RBD and LAIV-HK68-RBD) against SARS-CoV-2. FindingsSubstantially higher systemic and mucosal immune responses, including bronchoalveolar lavage IgA/IgG and lung polyfunctional memory CD8 T cells, were induced by the heterologous PD1-RBD-DNA/LAIV-HK68-RBD as compared with other regimens. When vaccinated animals were challenged at the memory phase, prevention of robust SARS-CoV-2 infection in nasal turbinate was achieved primarily by the heterologous regimen besides consistent protection in lungs. The regimen-induced antibodies cross-neutralized variants of concerns. Furthermore, LAIV-CA4-RBD could boost the BioNTech vaccine for improved mucosal immunity. InterpretationOur results demonstrated that intranasal influenza-based boost vaccination is required for inducing mucosal and systemic immunity for effective SARS-CoV-2 prevention in both upper and lower respiratory systems. FundingThis study was supported by the Research Grants Council Collaborative Research Fund (C7156-20G, C1134-20G and C5110-20G), General Research Fund (17107019) and Health and Medical Research Fund (19181052 and 19181012) in Hong Kong; Outbreak Response to Novel Coronavirus (COVID-19) by the Coalition for Epidemic Preparedness Innovations; Shenzhen Science and Technology Program (JSGG20200225151410198); the Health@InnoHK, Innovation and Technology Commission of Hong Kong; and National Program on Key Research Project of China (2020YFC0860600, 2020YFA0707500 and 2020YFA0707504); and donations from the Friends of Hope Education Fund. Z.C.s team was also partly supported by the Theme-Based Research Scheme (T11-706/18-N).

immunology↗

bioRxiv2021

Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice

ObjectiveMetformin exhibits therapeutic potential in behavioural deficits induced by methamphetamine (METH) in rats. Emerging studies suggest gut microbiota may impact psychiatric symptoms, but there is no direct evidence supporting metformins participation in the pathophysiology of withdrawal symptoms via modulation of gut microbiota. MehodsIn order to define the functional contributions by gut microbiota and metformin to the behavioural deficits during METH withdrawal, we utilized a combination of fecal microbiota transplantation (FMT), high-throughput sequencing, and untargeted metabolomics technologies. ResultsFirst, METH addicts exhibited higher diversity and distinct microbial structures compared to heathy controls. In particular, the relative abundance of Rikenellaceae was positively correlated with the severity of anxiety and depression. Second, both human-to-mouse and mouse-to-mouse FMTs confirmed that METH-altered-microbiota transplantation is sufficient to promote anxiety and depression-like behaviours in recipient germ-free mice, and these behavioural disturbances could be ameliorated by metformin. In-depth analysis revealed that METH significantly altered the bacterial composition and structure as well as relative abundance of several bacterial taxa and metabolites, including Rikenellaceae and inosine, respectively, whereas add-on metformin could remodel these alterations. Finally, the inosine complementation successfully restored METH-induced anxiety and depression-like behaviours in mice. DiscussionThis study demonstrates that METH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model. The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota-derived metabolites, highlighting the role of the gut microbiota in substance use disorders and the pathophysiology of withdrawal symptoms. Study HighlightsO_ST_ABSWhat is known?C_ST_ABSO_LIThere are no targeted therapies for substance withdrawal syndrome, but there is considerable evidence that withdrawal-associated psychiatric manifestations contribute to the poor adherence to rehabilitation treatment as well as the relapse rates. C_LIO_LIMetformin has shown its therapeutic potential against METH-induced neurobehavioural changes and neurodegeneration in rats through CREB/BDNF and Akt/GSK3 signaling pathways in the anxiety-related brain nuclei. C_LI What is new here?O_LIMETH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model. C_LIO_LIThe therapeutic effects of metformin on psychiatric manifestations are associated with microbiota derived metabolites. C_LIO_LIInosine complementation could restore METH withdrawal-induced anxiety and depression-like behaviours. C_LI

animal behavior and cognition↗

bioRxiv2021

Transient nuclear deformation primes epigenetic state and promotes cell reprogramming

Cell reprogramming has wide applications in tissue regeneration, disease modeling and personalized medicine, but low reprogramming efficiency remains a challenge. In addition to biochemical cues, biophysical factors can modulate the epigenetic state and a variety of cell functions. However, how biophysical factors help overcome the epigenetic barrier for cell reprogramming are not well understood. Here we utilized microfluidic channels to induce a transient deformation of the cell nucleus, which caused the disassembly of the nuclear lamina and a downregulation of DNA methylation and histone (H3K9) for 12-24 hours. These global decreases of heterochromatin marks at the early stage of cell reprogramming strikingly enhanced the conversion of fibroblasts into neurons and induced pluripotent stem cells. Consistently, inhibition of DNA methylation and H3K9 methylation partially mimicked the effects of mechanical squeezing on iN reprogramming efficiency. Knocking down lamin A had similar effects to squeezing on enhancing the reprogramming efficiency. Based on these findings, we developed a scalable microfluidic system that enabled a continuous cell processing to effectively prime the epigenetic state for cell reprogramming, demonstrating the potential of mechano-biotechnology for cell engineering.

biophysics↗

bioRxiv2021

From musk to body odor: decoding olfaction through genetic variation

The olfactory system combines input from multiple receptor types to represent odor information, but there are few explicit examples relating olfactory receptor (OR) activity patterns to odor perception. To uncover these relationships, we performed genome-wide scans on odor-perception phenotypes for ten odors in 1003 Han Chinese and validated results for six of these odors in an ethnically diverse population (n=364). In both populations, we replicated three previously reported associations ({beta}-ionone/OR5A, androstenone/OR7D4, cis-3-hexen-1-ol/OR2J3 LD-band), suggesting that olfactory phenotype/genotype studies are robust across populations. Two novel associations between an OR and odor perception contribute to our understanding of olfactory coding. First, we found a SNP in OR51B2 that associated with trans-3-methyl-2-hexenoic acid, a key component of human underarm odor. Second, we found two linked SNPs associated with the musk Galaxolide in a novel musk receptor, OR4D6, which is also the first OR shown to drive specific anosmia to a musk compound. We also found that the derived alleles of the SNPs reportedly associated with odor perception tend to reduce odor intensity, supporting the hypothesis that the primate olfactory gene repertoire has degenerated over time. This study provides information about coding for human body odor, and gives us insight into broader mechanisms of olfactory coding, such as how differential OR activation can converge on a similar percept.

genetics↗

bioRxiv2021

Rice NIN-LIKE PROTEIN 3 plays a significant role in nitrogen use efficiency and grain yield under nitrate-sufficient conditions

Nitrogen (N) is an essential macronutrient for crop growth and yield, but excessive application of N fertilizer has caused serious environmental pollution and greatly increased the cost of agricultural production. One of the effective and economical solutions to this dilemma is to improve the N use efficiency (NUE) of crops. Although some components involved in regulating NUE have been identified, the underlying molecular mechanism remains largely elusive in rice. Here we report that the OsNLP3 (NIN-like protein 3) is an important regulator in NUE and grain yield under nitrate-sufficient conditions. Both NUE and grain yield were significantly improved by enhanced OsNLP3 expression in the field, but reduced in osnlp3 mutants. The expression of OsNLP3 responds to both nitrate and ammonium, while OsNLP3 nuclear retention is only induced by nitrate, not by ammonium. OsNLP3 regulates the expression of a set of genes involved in N transport and assimilation by directly binding to the nitrate-responsive cis-element in the promoters of these genes. Our study demonstrates that OsNLP3 is significant for the regulation of NUE and grain yield, particularly in nitrate-rich conditions, thus providing a candidate for improving NUE and grain yield in rice.

plant biology↗

bioRxiv2021

SAILER: Scalable and Accurate Invariant Representation Learning for Single-Cell ATAC-Seq Processing and Integration

MotivationSingle-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) provides new opportunities to dissect epigenomic heterogeneity and elucidate transcriptional regulatory mechanisms. However, computational modelling of scATAC-seq data is challenging due to its high dimension, extreme sparsity, complex dependencies, and high sensitivity to confounding factors from various sources. ResultsHere we propose a new deep generative model framework, named SAILER, for analysing scATAC-seq data. SAILER aims to learn a low-dimensional nonlinear latent representation of each cell that defines its intrinsic chromatin state, invariant to extrinsic confounding factors like read depth and batch effects. SAILER adopts the conventional encoder-decoder framework to learn the latent representation but imposes additional constraints to ensure the independence of the learned representations from the confounding factors. Experimental results on both simulated and real scATAC-seq datasets demonstrate that SAILER learns better and biologically more meaningful representations of cells than other methods. Its noise-free cell embeddings bring in significant benefits in downstream analyses: Clustering and imputation based on SAILER result in 6.9% and 18.5% improvements over existing methods, respectively. Moreover, because no matrix factorization is involved, SAILER can easily scale to process millions of cells. We implemented SAILER into a software package, freely available to all for large-scale scATAC-seq data analysis. AvailabilityThe software is publicly available at https://github.com/uci-cbcl/SAILER Contactjingz31@uci.edu and xhx@uci.edu

bioinformatics↗

bioRxiv2020

Structural basis of SARS-CoV-2 polymerase inhibition by Favipiravir

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed into an unprecedented global pandemic. Nucleoside analogues, such as Remdesivir and Favipiravir, can serve as the first-line broad-spectrum antiviral drugs against the newly emerging viral diseases. Recent clinical trials of these two drugs for SARS-CoV-2 treatment revealed antiviral efficacies as well as side effects with different extents1-4. As a pyrazine derivative, Favipiravir could be incorporated into the viral RNA products by mimicking both adenine and guanine nucleotides, which may further lead to mutations in progeny RNA copies due to the non-conserved base-pairing capacity5. Here, we determined the cryo-EM structure of Favipiravir bound to the replicating polymerase complex of SARS-CoV-2 in the pre-catalytic state. This structure provides a missing snapshot for visualizing the catalysis dynamics of coronavirus polymerase, and reveals an unexpected base-pairing pattern between Favipiravir and pyrimidine residues which may explain its capacity for mimicking both adenine and guanine nucleotides. These findings shed lights on the mechanism of coronavirus polymerase catalysis and provide a rational basis for developing antiviral drugs to combat the SARS-CoV-2 pandemic.

microbiology↗

bioRxiv2020

Functional Evidence for Biased Inhibition of G protein Signaling by YM-254890 in Human Coronary Artery Endothelial Cells

Small molecular chemicals targeting individual subtype of G proteins including Gs, Gi/o and Gq has been lacking, except for pertussis toxin being an established selective peptide inhibitor of the Gi/o protein. Recently, a cyclic depsipeptide compound YM-254890 isolated from culture broth of Chromobacterium sp. was reported as a selective inhibitor for the Gq protein by blocking GDP exchange of GTP on the subunit of Gq complex. However, functional selectivity of YM-254890 towards various G proteins was not fully characterized, primarily due to its restricted availability before 2017. Here, using human coronary artery endothelial cells as a model, we performed a systemic pharmacological evaluation on the functional selectivity of YM-254890 on multiple G protein-mediated receptor signaling. First, we confirmed that YM-254890, at 30 nM, abolished UTP-activated P2Y2 receptor-mediated Ca2+ signaling and ERK1/2 phosphorylation, indicating its potent inhibition on the Gq protein. However, we unexpectedly found that YM-254890 also significantly suppressed cAMP elevation and ERK1/2 phosphorylation induced by multiple Gs-coupled receptors including {beta}2-adrenegic, adenosine A2 and PGI2 receptors. Surprisingly, although YM-254890 had no impact on CXCR4/Gi/o protein-mediated suppression of cAMP production, it abolished ERK1/2 activation. Further, no cellular toxicity was observed for YM-254890, and it neither affected A23187- or thapsigargin-induced Ca2+ signaling, nor forskolin-induced cAMP elevation and growth factor-induced MAPK signaling. We conclude that YM-254890 is not a selective inhibitor for Gq protein; instead, it acts as a broad spectrum inhibitor for Gq and Gs proteins and exhibits a biased inhibition on Gi/o signaling, without affecting non-GPCR-mediated cellular signaling.

pharmacology and toxicology↗

bioRxiv2020

Neuroanatomical underpinning of diffusion kurtosis measurements in the cerebral cortex of healthy macaque brains

PurposeTo investigate the neuroanatomical underpinning of healthy macaque brain cortical microstructure measured by diffusion kurtosis imaging (DKI) which characterizes non-Gaussian water diffusion. MethodsHigh-resolution DKI was acquired from 6 postmortem macaque brains. Neurofilament density (ND) was quantified based on structure tensor from neurofilament histological images of a different macaque brain sample. After alignment of DKI-derived mean kurtosis (MK) maps to the histological images, MK and histology-based ND were measured at corresponding regions of interests characterized by distinguished cortical MK values in the prefrontal/precentral-postcentral and temporal cortices. Pearson correlation was performed to test significant correlation between these cortical MK and ND measurements. ResultsHeterogeneity of cortical MK across different cortical regions was revealed, with significantly and consistently higher MK measurements in the prefrontal/precentral-postcentral cortex compared to those in the temporal cortex across all 6 scanned macaque brains. Corresponding higher ND measurements in the prefrontal/precentral-postcentral cortex than in the temporal cortex were also found. The heterogeneity of cortical MK is associated with heterogeneity of histology-based ND measurements, with significant correlation between cortical MK and corresponding ND measurements (P <0.005). ConclusionThese findings suggested that DKI-derived MK can potentially be an effective noninvasive biomarker quantifying underlying neuroanatomical complexity inside the cerebral cortical mantle for clinical and neuroscientific research.

neuroscience↗