Biology subjects

Qiu, J.

Publications and source records attributed to Qiu, J..

At least 109 records · Page 6Linked to original sources

bioRxiv2021

Screening of cell-virus, cell-cell, gene-gene interactions among kingdoms of life at single cell resolution

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) issued a significant and urgent threat to global health. The exact animal origin of SARS-CoV-2 remains obscure and understanding its host range is vital for preventing interspecies transmission. Previously, we have assessed the target cell profiles of SARS-CoV-2 in pets, livestock, poultry and wild animals. Herein, we expand this investigation to a wider range of animal species and viruses to provide a comprehensive source for large-scale screening of potential virus hosts. Single cell atlas for several mammalian species (alpaca, hamster, hedgehog, chinchilla etc.), as well as comparative atlas for lung, brain and peripheral blood mononuclear cells (PBMC) for various lineages of animals were constructed, from which we systemically analyzed the virus entry factors for 113 viruses over 20 species from mammalians, birds, reptiles, amphibians and invertebrates. Conserved cellular connectomes and regulomes were also identified, revealing the fundamental cell-cell and gene-gene cross-talks between these species. Overall, our study could help identify the potential host range and tissue tropism of SARS-CoV-2 and a diverse set of viruses and reveal the host-virus co-evolution footprints.

cell biology↗

bioRxiv2021

Previously unrecognized non-reproducible antibody-antigen interactions and their implications for diagnosis of viral infections including COVID-19

Antibody-antigen (Ab-Ag) interactions are canonically described by a model which exclusively accommodates non-interaction (0) or reproducible-interaction (RI) states, yet this model is inadequate to explain often-encountered non-reproducible signals. Here, by monitoring diverse experimental systems and confirmed COVID-19 clinical sera using a peptide microarray, we observed that non-specific interactions (NSI) comprise a substantial proportion of non-reproducible antibody-based results. This enabled our discovery and capacity to reliably identify non-reproducible Ab-Ag interactions (NRI), as well as our development of a powerful explanatory model ("0-RI-NRI-Hook four-state model") that is [mAb]-dependent, regardless of specificity, which ultimately shows that both NSI and NRI are not predictable yet certain-to-happen. In experiments using seven FDA-approved mAb drugs, we demonstrated the use of NSI counts in predicting epitope type. Beyond challenging the centrality of Ab-Ag interaction specificity data in serology and immunology, our discoveries also facilitated the rapid development of a serological test with uniquely informative COVID-19 diagnosis performance.

immunology↗

bioRxiv2021

Arabidopsis Topless-related 1 mitigates physiological damage and growth penalties of induced immunity

Transcriptional corepressors of the Topless family are important regulators of plant hormone and immunity signaling. The lack of a genome-wide profile of their chromatin associations limits understanding of transcriptional regulation in plant immune responses. Chromatin immunoprecipitation with sequencing (ChIP-seq) was performed on GFP-tagged Topless-related 1 (TPR1) expressed in Arabidopsis thaliana lines with and without constitutive immunity dependent on Enhanced Disease Susceptibility 1 (EDS1). RNA-seq profiling of pathogen-infected tpl/tpr mutants and assessments of growth and physiological parameters were employed to determine TPL/TPR roles in transcriptional immunity and defense homeostasis. TPR1 bound to promoter regions of ~1,400 genes and ~10% of the detected binding required EDS1 immunity signaling. A tpr1 tpl tpr4 (t3) mutant displayed mildly enhanced defense-related transcriptional reprogramming upon bacterial infection but not increased bacterial resistance. Bacteria or pep1 phytocytokine-challenged t3 plants exhibited, respectively, photosystem II dysfunction and exacerbated root growth inhibition. Transgenic expression of TPR1 restored the t3 physiological defects. We propose that TPR1 and TPL-family proteins function in Arabidopsis to reduce detrimental effects associated with activated transcriptional immunity.

plant biology↗

bioRxiv2021

Permeability profiling of all 13 Arabidopsis PIP aquaporins using a high throughput yeast approach

Plant aquaporins have many more functions than just transporting water. Within the diversity of plant aquaporins are isoforms capable of transporting signaling molecules, nutrients, metalloids and gases. It is established that aquaporin substrate discrimination depends on combinations of factors such as solute size, pore size and polarity, and post-translational protein modifications. But our understanding of the relationships between variation in aquaporin structures and the implications for permeability is limited. High-throughput yeast-based assays were developed to assess diverse substrate permeabilities to water, H2O2, boric acid, urea and Na+. All 13 plasma membrane intrinsic proteins (PIPs) from Arabidopsis (AtPIPs) were permeable to both water and H2O2, although their effectiveness varied, and none were permeable to urea. AtPIP2 isoforms were more permeable to water than AtPIP1s, while AtPIP1s were more efficient at transporting H2O2 with AtPIP1;3 and AtPIP1;4 being the most permeable. Among the AtPIP2s, AtPIP2;2 and AtPIP2;7 were also permeable to boric acid and Na+. Linking AtPIP substrate profiles with phylogenetics and gene expression data enabled us to align substrate preferences with known biological roles of AtPIPs and importantly guide towards unidentified roles hidden by functional redundancy at key developmental stages and within tissue types. This analysis positions us to more strategically test in planta physiological roles of AtPIPs in order to unravel their complex contributions to the transport of important substrates, and secondly, to resolve links between aquaporin protein structure, substrate discrimination, and transport efficiency. One sentence summaryYeast based high throughput assays were developed to assess the permeability of each Arabidopsis PIP aquaporin isoform to water, H2O2, boric acid, urea and sodium.

plant biology↗

bioRxiv2021

Polycomb repressive complex 2 coordinates with Sin3 histone deacetylase complex to epigenetically reprogram genome-wide expression of effectors and regulate pathogenicity in Magnaporthe oryzae

The strict suppression and reprogramming of gene expression are necessary at different development stages and/or in response to environment stimuli in eukaryotes. In Rice Magnaporthe oryzae pathosystem, effectors from pathogen are kept transcriptionally silenced in the vegetative growth stage and are highly expressed during invasive growth stage to adapt to the host environment. However, the mechanism of how such effectors are stably repressed in the vegetative stage and its roles during rice blast infection remain unclear so far. Here, we showed that all subunits of Polycomb Repressive Complex 2 are required for such repression by direct H3K27me3 occupancy and pathogenic process in M. oryzae. Suppression of polycomb-mediated H3K27me3 causes an improper induction of effectors during vegetative growth thus simulating a host environment. Notably, the addition subunit P55 not only acts as the bridge to connect with core subunits to form a complex in M. oryzae, but also recruits Sin3 histone deacetylase complex to prompt H3K27me3 occupancy for stable maintenance of transcriptional silencing of the target genes in the absence of PRC1. In contrast, during invasive growth stage, the repressed state of effectors chromatin can be partially erased during pathogenic development resulting in transcriptional activation of effectors therein. Overall, Polycomb repressive complex 2 coordinates with Sin3 histone deacetylase complex to epigenetically reprogram genome-wide expression of effectors, which act as molecular switch to memorize the host environment from vegetative to invasive growth, thus contributing to the infection of rice blast.

microbiology↗

bioRxiv2021

Chronic exercise protects against the progression of renal cyst growth and dysfunction in rats with polycystic kidney disease

IntroductionPolycystic kidney disease (PKD) is a genetic disorder characterized by the progressive enlargement of renal epithelial cysts and renal dysfunction. Previous studies have reported the beneficial effects of chronic exercise on chronic kidney disease. However, the effects of chronic exercise have not been fully examined in PKD patients or models. The effects of chronic exercise on the progression of PKD were investigated in a polycystic kidney (PCK) rat model. MethodsSix-week-old male PCK rats were divided into a sedentary group and an exercise group. The exercise group underwent forced treadmill exercise for 12 weeks (28 m/min, 60 min/day, 5 days/week). After 12 weeks, kidney function and histology were examined, protein expressions were analyzed, and signaling cascades of PKD were examined. ResultsChronic exercise reduced the excretion of urinary protein, liver-type fatty acid-binding protein, plasma creatinine, urea nitrogen, and increased plasma irisin and urinary arginine vasopressin (AVP) excretion. Chronic exercise also slowed renal cyst growth, glomerular damage, and interstitial fibrosis, and led to reduced Ki-67 expression. Chronic exercise had no effect on cAMP content but decreased the renal expression of B-Raf and reduced the phosphorylation of extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR), and S6. ConclusionChronic exercise slows renal cyst growth and damage in PCK rats, despite increasing AVP, with down-regulation of the cAMP/B-Raf/ERK and mTOR/S6 pathways in the kidney of PCK rats.

physiology↗

bioRxiv2021

SweepCluster: A SNP clustering tool for detecting gene-specific sweeps in prokaryotes

BackgroundThe gene-specific sweep is a selection process where an advantageous mutation along with the nearby neutral sites in a gene region increases the frequency in the population. It has been demonstrated to play important roles in ecological differentiation or phenotypic divergence in microbial populations. Therefore, identifying gene-specific sweeps in microorganisms will not only provide insights into the evolutionary mechanisms, but also unravel potential genetic markers associated with biological phenotypes. However, current methods were mainly developed for detecting selective sweeps in eukaryotic data of sparse genotypes and are not readily applicable to prokaryotic data. Furthermore, some challenges have not been sufficiently addressed by the methods, such as the low spatial resolution of sweep regions and lack of consideration of the spatial distribution of mutations. ResultsWe proposed a novel gene-centric and spatial-aware approach for identifying gene-specific sweeps in prokaryotes and implemented it in a python tool SweepCluster. Our method searches for gene regions with a high level of spatial clustering of pre-selected polymorphisms in genotype datasets assuming a null distribution model of neutral selection. The pre-selection of polymorphisms is based on their genetic signatures, such as elevated population subdivision, excessive linkage disequilibrium, or significant phenotype association. Performance evaluation using simulation data showed that the accuracy and sensitivity of the clustering algorithm in SweepCluster is above 90%. The application of SweepCluster in two real datasets from the bacteria Streptococcus pyogenes and Streptococcus suis showed that the impact of pre-selection was dramatic and significantly reduced the uninformative signals. We validated our method using the genotype data from Vibrio cyclitrophicus, the only available dataset of gene-specific sweeps in bacteria, and obtained a concordance rate of 78%. We noted that the concordance rate could be underestimated due to distinct reference genomes and clustering strategies. The application to the human genotype datasets showed that SweepCluster is also applicable to eukaryotic data and recovered the known sweep regions in a wide dynamic range of pre-selection parameters. ConclusionsSweepCluster is applicable to a broad category of datasets. It will be valuable for detecting gene-specific sweeps in diverse genotypic data and provide novel insights on adaptive evolution.

bioinformatics↗

bioRxiv2021

A chloride efflux transporter OsBIRG1 regulates grain size and salt tolerance in rice

Grain size is determined by the number of cells and cell size of the grain. Regulation of grain size is crucial for improving crop yield. However, the genes and underlying molecular mechanisms controlling grain size remain elusive. Here we report a member of Detoxification efflux carrier (DTX)/Multidrug and Toxic Compound Extrusion (MATE) family transporter, BIG RICE GRAIN 1 (BIRG1), negatively regulates the grain size in rice. BIRG1 is highly expressed in reproductive organs and roots. In birg1 grain, the size of the outer parenchyma layer cells of spikelet hulls is noticeably larger but the cell number is not altered compared with that in the wild-type (WT) grain. When expressed in Xenopus oocytes, BIRG1 exhibits chloride efflux activity. In line with the role of BIRG1 in mediating chloride efflux, the birg1 mutant shows reduced tolerance to salt stress under which the chloride level is toxic. Moreover, the birg1 grains contain higher level of chloride compared to WT grains when grown under normal paddy field. The birg1 roots accumulate more chloride than those of WT under saline condition. Collectively, our findings suggest that BIRG1 functions as a chloride efflux transporter regulating grain size and salt tolerance via controlling chloride homeostasis in rice.

plant biology↗

bioRxiv2021

A positive role of task-deactivated default mode network in narrative speech comprehension

During speech comprehension, as listeners need to keep tracking the external audio streams, the default mode network (DMN) is often de-activated and anticorrelated with task-positive networks. Such a pattern has been interpreted as the suppression of the DMN to support externally-oriented cognitive processes. Taking a "two-brain" approach, the current study demonstrated that, despite exhibiting deactivation and anticorrelated with the language network and executive control network, the DMN was not suppressed but played an active role in spoken narrative comprehension. This was evidenced by significant listener-speaker neural couplings in both the posterior and anterior DMN and the positive correlation between the coupling strength and listeners speech comprehension. Moreover, we demonstrated that the functionality of posterior DMN depended on its interaction with the executive control network, rather than its level of activation. Finally, Dynamic Causal Modeling together with the two-brain results indicates the language and executive control networks, the anterior DMN, and the posterior DMN occupied the bottom, intermediate and top layers of a hierarchical system, respectively. These results suggest that the DMN may primarily serve as an internally-oriented system that cooperates with the externally-oriented networks, which may allow the transformation of external acoustic signals into internal mental representations during language comprehension.

neuroscience↗

bioRxiv2021

PredictProtein - Predicting Protein Structure and Function for 29 Years

Since 1992 PredictProtein (https://predictprotein.org) is a one-stop online resource for protein sequence analysis with its main site hosted at the Luxembourg Centre for Systems Biomedicine (LCSB) and queried monthly by over 3,000 users in 2020. PredictProtein was the first Internet server for protein predictions. It pioneered combining evolutionary information and machine learning. Given a protein sequence as input, the server outputs multiple sequence alignments, predictions of protein structure in 1D and 2D (secondary structure, solvent accessibility, transmembrane segments, disordered regions, protein flexibility, and disulfide bridges) and predictions of protein function (functional effects of sequence variation or point mutations, Gene Ontology (GO) terms, subcellular localization, and protein-, RNA-, and DNA binding). PredictProteins infrastructure has moved to the LCSB increasing throughput; the use of MMseqs2 sequence search reduced runtime five-fold; user interface elements improved usability, and new prediction methods were added. PredictProtein recently included predictions from deep learning embeddings (GO and secondary structure) and a method for the prediction of proteins and residues binding DNA, RNA, or other proteins. PredictProtein.org aspires to provide reliable predictions to computational and experimental biologists alike. All scripts and methods are freely available for offline execution in high-throughput settings. AvailabilityFreely accessible webserver PredictProtein.org; Source and docker images: github.com/rostlab

bioinformatics↗

bioRxiv2021

Direct activation of endothelial cells by SARS-CoV-2 nucleocapsid protein is blocked by Simvastatin

Emerging evidence suggests that endothelial activation plays a central role in the pathogenesis of acute respiratory distress syndrome (ARDS) and multi-organ failure in patients with COVID-19. However, the molecular mechanisms underlying endothelial activation in COVID-19 patients remain unclear. In this study, the SARS-CoV-2 viral proteins that potently activate human endothelial cells were screened to elucidate the molecular mechanisms involved with endothelial activation. It was found that nucleocapsid protein (NP) of SARS-CoV-2 significantly activated human endothelial cells through TLR2/NF-{kappa}B and MAPK signaling pathways. Moreover, by screening a natural microbial compound library containing 154 natural compounds, simvastatin was identified as a potent inhibitor of NP-induced endothelial activation. Remarkablely, though the protein sequences of N proteins from coronaviruses are highly conserved, only NP from SARS-CoV-2 induced endothelial activation. The NPs from other coronaviruses such as SARS-CoV, MERS-CoV, HUB1-CoV and influenza virus H1N1 did not affect endothelial activation. These findings are well consistent with the results from clinical investigations showing broad endotheliitis and organ injury in severe COVID-19 patients. In conclusion, the study provides insights on SARS-CoV-2-induced vasculopathy and coagulopathy, and suggests that simvastatin, an FDA-approved lipid-lowering drug, may benefit to prevent the pathogenesis and improve the outcome of COVID-19 patients.

immunology↗

bioRxiv2021

Identification and Evaluation of a Panel of Strong Constitutive Promoters in Listeria monocytogenes for Improving the Expression of Foreign Antigens

Attenuated Listeria monocytogenes (L. monocytogenes) could be used as a vaccine vector for immunotherapy of tumors or pathogens. However, the lack of reliable promoters limits its ability to express foreign antigens. In this work, 21 promoters from L. monocytogenes were identified by RNA-seq analysis under two conditions of pH 7.4 and pH 5.5. Based on the constructed fluorescence report system, 7 constitutive promoters showed higher strength than that of Phelp, a previously reported strong promoter. Further, the selected 5 constitutive promoters also showed high activity in the production of UreB, a widely used antigen against Helicobacter pylori (H. pylori). In particular, a well-characterized constitutive promoter P18, which performed best in both fluorescence intensity and UreB production, was proved to be highly active in vitro and in vivo. In summary, we provide a useful promoter library for Listeria species and offer a reference for constitutive promoter mining in other organisms. Key pointsO_LI21 promoters from L. monocytogenes were identified by RNA-seq. C_LIO_LIFluorescent tracer of L. monocytogenes (P18) was performed in vitro and in vivo. C_LIO_LIA well-characterized constitutive promoter P18 could improve the expression level of a foreign antigen UreB in L. monocytogenes C_LI

microbiology↗

bioRxiv2021

Embedding of exogenous B cell epitopes on the surface of UreB structure generates a broadly reactive antibody response against Helicobacter pylori

Since Helicobacter pylori (H. pylori) resistance to antibiotic regimens is increased, vaccination is becoming an increasingly important alternative therapy to control H. pylori infection. UreB, FlaA, AlpB, SabA, and HpaA proteins of H. pylori were previously proved to be used as candidate vaccine antigens. Here, we developed an engineered antigen based on a recombinant chimeric protein containing a structural scaffold from UreB and B cell epitopes from FlaA, AlpB, SabA, and HpaA. The multi-epitope chimeric antigen, named MECU, could generate a broadly reactive antibody response including antigen-specific antibodies and neutralizing antibodies against H. pylori urease and adhesins. Moreover, therapeutic immunization with MECU could reduce H. pylori colonization in the stomach and protect the stomach in BALB/c mice. This study not only provides a promising immunotherapy to control H. pylori infection, but also offers a reference for antigen engineering against other pathogens.

immunology↗

bioRxiv2021

The SARS-CoV-2 transcriptome and the dynamics of the S gene furin cleavage site in primary human airway epithelia

The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused the devastating ongoing coronavirus disease-2019 (COVID-19) pandemic which poses a great threat to global public health. The spike (S) polypeptide of SARS-CoV-2 consists of the S1 and S2 subunits and is processed by cellular proteases at the S1/S2 boundary. The inclusion of the 4 amino acids (PRRA) at the S1/S2 boundary forms a furin cleavage site (FCS), 682RRAR{downarrow}S686, distinguishing SARS-CoV-2 from its closest relative, the SARS-CoV. Various deletions surrounding the FCS have been identified in patients. When SARS-CoV-2 propagated in Vero cells, the virus acquired various deletions surrounding the FCS. In the present study, we studied the viral transcriptome in SARS-CoV-2 infected primary human airway epithelia (HAE) cultured at an air-liquid interface (ALI) with an emphasis on the viral genome stability at the S1/S2 boundary using RNA-seq. While we found overall the viral transcriptome is similar to that generated from infected Vero cells, we identified a high percentage of mutated viral genome and transcripts in HAE-ALI. Two highly frequent deletions were found at the S1/S2 boundary of the S gene: one is a deletion of 12 amino acids, 678TNSPRRAR{downarrow}SVAS689, which contains the FCS, another is a deletion of 5 amino acids, 675QTQTN679, which is two amino acids upstream of the FCS. Further studies on the dynamics of the FCS deletions in apically released virions revealed that the selective pressure for the FCS maintains the S gene stability in HAE-ALI but with exceptions, in which the FCS deletions are remained at a high rate. Thus, our study presents evidence for the role of unique properties of human airway epithelia in the dynamics of the FCS region during infection of human airways, which is donor-dependent.

microbiology↗

bioRxiv2020

Collagen induced inflammations

Collagen-induced arthritis (CIA) mouse model is currently the most widely used and reliable autoimmune model to study rheumatoid arthritis. In this model, we used bovine type II collagen (CII) and complete Freunds adjuvant (CFA) or incomplete Freunds adjuvant (IFA) to form emulsifier, and mice were injected intradermal to induce autoimmune arthritis (CIA). In this model, we ground bovine collagen type II (CII) with complete Freunds adjuvant (CFA) or incomplete Freunds adjuvant (IFA) to form emulsifiers, and intradermal injection in mice induced autoimmune arthritis (CIA). This article describes the mouse, CFA strains, key emulsification, anesthesia, and injection immune techniques, as well as the incidence, date of onset, score, pathological results of arthritis. The total time for preparation of reagents and immunization of 20 mice was about 2-2.5 hours. In this protocol, we induced a high incidence of CIA with DBA/1J in genetically susceptible mice and assessed the severity and pathology of the disease, at the same time we found that CII also can induced enteritis, including ileitis and colitis. The initial symptoms of arthritis appear in the 24-26 days of the experiment, that is, 3-5 days after the second immunization, the peak period of inflammation was 30-36 days, the arthritis incidence about 90-100%, at the same time, the incidence of enteritis and arthritis were the same, small intestinal inflammation was more severe, but the duration was short; while the colonic inflammation was mild, and the duration was longer than enteritis, we named it collagen induced inflammations (CIIs).

immunology↗

bioRxiv2020

Large-scale Gradient Dysfunction of the Functional Connectome in Major Depression

BackgroundPatients with major depressive disorder (MDD) exhibit concurrent deficits in sensory processing and high-order cognitive functions such as self-awareness and rumination. Connectome mapping studies have suggested a principal primary-to-transmodal gradient in functional brain networks, supporting the spectrum from sensation to cognition. However, whether this principal connectome gradient is disrupted in patients with MDD and how this disruption is associated with gene expression profiles remain unclear. MethodsUsing a large cohort of resting-state functional magnetic resonance imaging data from 2,234 participants (1,150 patients with MDD and 1,084 healthy controls) recruited at 10 sites, we investigated MDD-related alterations in the principal connectome gradient. We further used Neurosynth and postmortem gene expression data to assess the cognitive functions and transcriptional profiles related to the gradient alterations in MDD, respectively. ResultsRelative to controls, patients with MDD exhibited abnormal global topography of the principal primary-to-transmodal gradient, as indicated by reduced explanation ratio, gradient range, and gradient variation (Cohens d = -0.16[~]-0.21). Focal alterations of gradient scores were mostly in the primary systems involved in sensory processing and in the transmodal systems implicated in high-order cognition. The transcriptional profiles explained 53.9% of the spatial variance in the altered gradient patterns, with the most correlated genes enriched in transsynaptic signaling and calcium ion binding. ConclusionsThese results highlight the dysfunction of the core connectome hierarchy in MDD and its linkage with gene expression profiles, providing insights into the neurobiological and molecular genetic underpinnings of sensory-cognitive deficits in this disorder.

neuroscience↗

bioRxiv2020

Blocking of EGFR Signaling is a Latent Strategy for the Improvement of Prognosis of HPV Induced Cancer

Human papillomavirus (HPV) is a dsDNA virus and its high-risk subtypes increase cancer risks. Yet, the mechanism of HPV infection and pathogenesis still remain unclear. Therefore, understanding the molecular mechanisms, and the pathogenesis of HPV are crucial in the prevention of HPV related cancers. In this study, we analyzed cervix squamous cell carcinoma (CESC) and head and neck carcinoma (HNSC) combined data to investigate various HPV induced cancer common feature. We showed that epidermal growth factor receptor (EGFR) was downregulated in HPV positive (HPV+) cancer, and that HPV+ cancer patients exhibited better prognosis than HPV negative (HPV-) cancer patients. Our study also showed that TP53 mutation rate is lower in HPV+ cancer than in HPV- cancer and that TP53 can be modulated by HPV E7 protein. However, there was no significant difference in the expression of wildtype TP53 in both groups. Subsequently, we constructed HPV-human interaction network and found that EGFR is a critical factor. From the network, we also noticed that EGFR is regulated by HPV E7 protein and hsa-miR-944. Moreover, while phosphorylated EGFR is associated with a worse prognosis, EGFR total express level is not significantly correlated with prognosis. This indicates that EGFR activation will induce a worse outcome in HPV+ cancer patients. Further enrichment analysis showed that EGFR downstream pathway and cancer relative pathway are diversely activated in HPV+ cancer and HPV- cancer. In summary, HPV E7 protein downregulates EGFR that downregulates phosphorylated EGFR and inhibit EGFR related pathways which in turn and consequently induce better prognosis. ImportanceAlthough HPV infection has been studied in various cancer types, there are only limited studies that have focused on the common effect of HPV related cancer. Consequently, this study focused on CESC and HNSC, two cancer types with high HPV infection proportion in cohort, thereby, intending to dig out the common effects and mechanisms of HPV+ cancers. Unlike some virus-human interaction prediction studies, the P-HIPSter database provides virus-human protein interaction based on protein structure prediction. Through this data, our interaction network was able to uncover previously unnoticed protein interactions. Our finding revealed that HPV infection caused various gene expression differences, and a great amount of which interact with EGFR, a cancer related gene. Therefore, since EGFR is associated with HPV+ cancer patients survival, some FDA proved EGFR inhibitors would be potential anti-HPV drugs.

microbiology↗

bioRxiv2020

Insulin potentiates the synchronous firing of arcuate nucleus Kiss1 neurons that protects against diet-induced obesity

Kisspeptin (Kiss1) neurons are essential for reproduction, but their role in the control of energy balance and other homeostatic functions remains unclear. High frequency firing of hypothalamic arcuate Kiss1 (Kiss1ARH) neurons releases kisspeptin into the median eminence, and neurokinin B (NKB) and dynorphin onto neighboring Kiss1ARH neurons to generate a slow excitatory postsynaptic potential (EPSP) mediated by TRPC5 channels that entrains intermittent, synchronous firing of Kiss1ARH neurons. High frequency optogenetic stimulation of Kiss1ARH neurons releases glutamate to excite the anorexigenic proopiomelanocortin (POMC) neurons and inhibit the orexigenic neuropeptide Y/agouti-related peptide (AgRP) neurons via metabotropic glutamate receptors. At the molecular level, the endoplasmic reticulum calcium-sensing protein stromal interaction molecule 1 (STIM1) is critically involved in the regulation of neuronal Ca2+ signaling and neuronal excitability through its interaction with plasma membrane calcium (e.g., TRPC) channels. 17{beta}-estradiol (E2) downregulates Stim1 mRNA expression in female arcuate neurons. Therefore, we hypothesized that deletion of Stim1 in Kiss1ARH neurons would increase neuronal excitability and their synchronous firing, which ultimately would affect energy homeostasis. Using optogenetics in combination with whole-cell recording and GCaMP6 imaging in slices, we discovered that the deletion of Stim1 in Kiss1 neurons significantly increased the amplitude of the slow EPSP and augmented synchronous [Ca2+]i oscillations in Kiss1ARH neurons. Deletion of Stim1 in Kiss1ARH neurons amplified the actions of NKB and protected ovariectomized female mice from developing obesity and glucose intolerance with high-fat dieting. Therefore, STIM1 appears to play a critical role in regulating synchronous firing of Kiss1ARH neurons, which ultimately affects energy homeostasis. Significance StatementHypothalamic arcuate kisspeptin (Kiss1ARH) neurons are essential for stimulating the pulsatile release of gonadotropin releasing hormone (GnRH) and maintaining fertility. However, Kiss1ARH neurons appear to be a key player in coordinating energy balance with reproduction. The regulation of calcium channels and hence calcium signaling is critically dependent on the endoplasmic reticulum calcium-sensing protein stromal interaction molecule 1 (STIM1), which interacts with the plasma membrane calcium channels. We have conditionally deleted Stim1 in Kiss1ARH neurons and found that it significantly increased the excitability of Kiss1ARH neurons and protected ovariectomized female mice from developing obesity and glucose intolerance with high-fat dieting.

neuroscience↗