Biology subjects

Zheng, J.

Publications and source records attributed to Zheng, J..

At least 289 records · Page 16Linked to original sources

bioRxiv2020

EpiGraphDB: a database and data mining platform for health data science

MotivationThe wealth of data resources on human phenotypes, risk factors, molecular traits and therapeutic interventions presents new opportunities for population health sciences. These opportunities are paralleled by a growing need for data integration, curation and mining to increase research efficiency, reduce mis-inference and ensure reproducible research. ResultsWe developed EpiGraphDB (https://epigraphdb.org/), a graph database containing an array of different biomedical and epidemiological relationships and an analytical platform to support their use in human population health data science. In addition, we present three case studies that illustrate the value of this platform. The first uses EpiGraphDB to evaluate potential pleiotropic relationships, addressing mis-inference in systematic causal analysis. In the second case study we illustrate how protein-protein interaction data offer opportunities to identify new drug targets. The final case study integrates causal inference using Mendelian randomization with relationships mined from the biomedical literature to "triangulate" evidence from different sources. AvailabilityThe EpiGraphDB platform is openly available at https://epigraphdb.org. Code for replicating case study results is available at https://github.com/MRCIEU/epigraphdb as Jupyter notebooks using the API, and https://mrcieu.github.io/epigraphdb-r using the R package. Contactyi6240.liu@bristol.ac.uk, ben.elsworth@bristol.ac.uk, Tom.Gaunt@bristol.ac.uk

bioinformatics↗

bioRxiv2020

Simultaneous Epigenetic Perturbation and Genome Imaging Reveal Distinct Roles of H3K9me3 in Chromatin Architecture and Transcription

Despite the long-observed correlation between H3K9me3, chromatin architecture and transcriptional repression, how H3K9me3 regulates genome higher-order organization and transcriptional activity in living cells remains unclear. Here we develop EpiGo (Epigenetic perturbation induced Genome organization)-KRAB to introduce H3K9me3 at hundreds of loci spanning megabases on human chromosome 19 and simultaneously track genome organization. EpiGo-KRAB is sufficient to induce de novo heterochromatin-like domain formation, which requires SETDB1, a methyltransferase of H3K9me3. Unexpectedly, EpiGo-KRAB induced heterochromatin-like domain does not result in widespread gene repression except a small set of genes with concurrent loss of H3K4me3 and H3K27ac. Ectopic H3K9me3 appears to spread in inactive regions but is largely restricted to transcriptional initiation sites in active regions. Finally, Hi-C analysis showed that EpiGo-KRAB induced to reshape existing compartments. These results reveal the role of H3K9me3 in genome organization could be partially separated from its function in gene repression.

molecular biology↗

bioRxiv2020

If the link missed：Could inflammatory skin disorders with barrier dysfunction increase the risk of COVID-19?

Since the end of 2019, COVID-19 pandemic caused by the SARS-CoV-2 emerged globally. The angiotensin-converting enzyme 2 (ACE2) on the cell surface is crucial for SARS-COV-2 entering into the cells. We use SARS-COV-2 pseudo virus and humanized ACE2 mice to mimic the possible transmitting of SARS-COV-2 through skin based on the data we found that skin ACE2 level is associated with skin pre-existing cutaneous conditions in human and mouse models and inflammatory skin disorders with barrier dysfunction increased the penetration of topical FITC conjugated spike protein into the skin. Our study indicated the possibility that the pre-existing cutaneous conditions could increase the risk for SARS-COV-2 infection. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/181297v4_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@14cef60org.highwire.dtl.DTLVardef@1f78c65org.highwire.dtl.DTLVardef@1224834org.highwire.dtl.DTLVardef@1b27475_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2020

The germline mutational process in rhesus macaque and its implications for phylogenetic dating

Understanding the rate and pattern of germline mutations is of fundamental importance for understanding evolutionary processes. Here we analyzed 19 parent-offspring trios of rhesus macaques (Macaca mulatta) at high sequencing coverage of ca. 76X per individual, and estimated an average rate of 0.77 x 10-8 de novo mutations per site per generation (95 % CI: 0.69 x 10-8 - 0.85 x 10-8). By phasing 50 % of the mutations to parental origins, we found that the mutation rate is positively correlated with the paternal age. The paternal lineage contributed an average of 81 % of the de novo mutations, with a trend of an increasing male contribution for older fathers. About 3.5 % of de novo mutations were shared between siblings, with no parental bias, suggesting that they arose from early development (postzygotic) stages. Finally, the divergence times between closely related primates calculated based on the yearly mutation rate of rhesus macaque generally reconcile with divergence estimated with molecular clock methods, except for the Cercopithecidae/Hominoidea molecular divergence dated at 52 Mya using our new estimate of the yearly mutation rate.

evolutionary biology↗

bioRxiv2020

The ribbon-helix-helix domain proteins CdrS and CdrL regulate cell division in archaea

Precise control of the cell cycle is central to the physiology of all cells. In prior work we demonstrated that archaeal cells maintain a constant size; however, the regulatory mechanisms underlying the cell cycle remain unexplored in this domain of life. Here we use genetics, functional genomics, and quantitative imaging to identify and characterize the novel CdrSL gene regulatory network in a model species of archaea. We demonstrate the central role of these ribbon-helix-helix family transcription factors in the regulation of cell division through specific transcriptional control of the gene encoding FtsZ2, a putative tubulin homolog. Using time lapse fluorescence microscopy in live cells cultivated in microfluidics devices, we further demonstrate that FtsZ2 is required for cell division but not elongation. The cdrS-ftsZ2 locus is highly conserved throughout the archaeal domain, and the central function of CdrS in regulating cell division is conserved across hypersaline adapted archaea. We propose that the CdrSL-FtsZ2 transcriptional network coordinates cell division timing with cell growth in archaea. ImportanceHealthy cell growth and division are critical for individual organism survival and species long-term viability. However, it remains unknown how cells of the domain Archaea maintain a healthy cell cycle. Understanding archaeal cell cycle is of paramount evolutionary importance given that an archaeal cell was the host of the endosymbiotic event that gave rise to eukaryotes. Here we identify and characterize novel molecular players needed for regulating cell division in archaea. These molecules dictate the timing of cell septation, but are dispensable for growth between divisions. Timing is accomplished through transcriptional control of the cell division ring. Our results shed light on mechanisms underlying the archaeal cell cycle, which has thus far remained elusive.

microbiology↗

bioRxiv2020

ScRNA-seq discover cell cluster change under OAB: ACE2 expression reveal possible alternation of 2019-nCoV infectious pathway

ObjectivePrevious study indicated that bladder cells which express ACE2 were a potential infection route of 2019-nCov. This study observed some differences of bladder cell cluster and their ACE2 expression between OAB mice and healthy mice, indicating the change of infectious possibility and pathway under overactive bladder (OAB) circumstance. Material and methodPubic dataset acquisition was used to get ACE2 expression in normal human bladder and mice bladder (GSE129845). We built up over OAB model and studied the impact on cell typing and ACE2 expression. By way of using single-cell RNA sequencing (scRNA-seq) technique, bladder cell clustering and ACE2 expression in various cell types were measured respectively. ResultIn pubic database (healthy human and mice bladder), ACE2 expression in humans and mice is concentrated in bladder epithelial cells. The disappearance of umbrella cells, a component of bladder epithelial, was found in our OAB model. In the two mouse bladder samples, ACE2 expression of epithelial cells is 34.1%, also the highest of all cell types. ConclusionThe disappearance of umbrella cell may alternate the infection pathway of 2019-nCov and relate to the onset and progression of OAB.

cell biology↗

bioRxiv2020

BtToxin_Digger: a comprehensive and high-throughput pipeline for mining toxin protein genes from Bacillus thuringiensis

SummaryBacillus thuringiensis (Bt) which is a spore-forming gram-positive bacterium, has been used as the most successful microbial pesticide for decades. Its toxin genes (cry) have been successfully used for the development of GM crops against pests. We have previously developed a web-based insecticidal gene mining tool BtToxin_scanner, which has been proved to be the most important method for mining cry genes from Bt genome sequences. To facilitate efficiently mining major toxin genes and novel virulence factors from large-scale Bt genomic data, we re-design this tool with a new workflow. Here we present BtToxin_Digger, a comprehensive, high-throughput, and easy-to-use Bt toxin mining tool. It runs fast and can get rich, accurate, and useful results for downstream analysis and experiment designs. Moreover, it can also be used to mine other targeting genes from large-scale genome and metagenome data with the addition of other query sequences.Availability and Implementation The BtToxin_Digger codes and instructions are freely available at https://github.com/BMBGenomics/BtToxin_Digger. A web server of BtToxin_Digger can be found at http://bcam.hzau.edu.cn/BtToxin_Digger.Contact jszheng{at}mail.hzau.edu.cn; m98sun{at}mail.hzau.edu.cn.Competing Interest StatementThe authors have declared no competing interest.View Full Text

bioinformatics↗

bioRxiv2020

Light-Sheet Fluorescence Imaging Charts the Gastrula Origin of Vascular Endothelial Cells in Early Zebrafish Embryos

It remains challenging to construct a complete cell lineage map of the origin of vascular endothelial cells in any vertebrate embryo. Here, we report the application of in toto light-sheet fluorescence imaging of embryos to tracing the origin of vascular endothelial cells (ECs) at single-cell resolution in zebrafish. We first adapted a previously-reported method to mount embryos and light-sheet imaging, created an alignment, fusion, and extraction all-in-one software (AFEIO) for processing big data, and performed quantitative analysis of cell lineage relationships using commercially-available Imaris software. Our data revealed that vascular ECs originated from broad regions of the gastrula along the dorsal-ventral and anterior-posterior axes, of which the dorsal-anterior cells contributed to cerebral ECs, the dorsal-lateral cells to anterior trunk ECs, and the ventral-lateral cells to posterior trunk and tail ECs. Therefore, this work, to our knowledge, charts the first comprehensive map of the gastrula origin of vascular ECs in zebrafish, and has potential applications for studying the origin of any embryonic organs in zebrafish and other model organisms.

developmental biology↗

bioRxiv2020

Targeted Genome Mining Discovery of the Ramoplanin Congener Chersinamycin from the Dynemicin-Producer Micromonospora chersina DSM 44154.

The availability of genome sequence data combined with bioinformatic genome mining has accelerated the identification of biosynthetic gene clusters (BGCs). Ramoplanins and enduracidins are lipodepsipeptides produced by Actinoplanes ramoplaninifer ATCC 33076 and Streptomyces fungicidicus B-5477, respectively, that exhibit excellent in vitro activity against a broad spectrum of Gram-positive pathogens. To explore if ramoplanin/enduracidin-like BGCs exist within genomes of organisms sequenced to date, we devised a targeted genome mining strategy that employed structure-activity relationships to identify conserved, essential biosynthesis genes from the ramoplanin and enduracidin BGCs. Five microorganisms were found to contain ramoplanin-like BGCs: the enediyne antibiotic producer Micromonospora chersina strain DSM 44151(dynemycin); the glycopeptide antibiotic producers Amycolatopsis orientalis strain B-37 (norvancomycin), Amycolatopsis orientalis strain DSM 40040 (vancomycin), and Amycolatopsis balhimycina FH1894 strain DSM 44591 (balhimycin); and Streptomyces sp. TLI_053. A single compound from fermentation of M. chersina was purified to homogeneity and found to possess good antibiotic activity against several Gram-positive bacterial test strains (1-2 g/mL), comparing favorably to ramoplanin family members. We named this compound chersinamycin and elucidated its covalent structure, which differs distinctly from ramoplanins and enduracidins. Further, the chersinamycin BGC was validated through insertional gene inactivation using CRISPR-Cas9 gene editing. In addition to the information gained by comparing and contrasting the sequence and organization of these five new BGCs, the amenability of M. chersina to genetic manipulation provides a much-needed tool to investigate the fundamental aspects of lipodepsipeptide biosynthesis and to facilitate metabolic engineering efforts for the production of novel antibiotics capable of combating antibiotic-resistant infections.

bioinformatics↗

bioRxiv2020

Coupling between slow-waves and sharp-wave ripples organizes distributed neural activity during sleep in humans

Hippocampal-dependent memory consolidation during sleep is hypothesized to depend on the synchronization of distributed neuronal ensembles, organized by the hippocampal sharp-wave ripples (SWRs, 80-150 Hz) and subcortical/cortical slow-waves (0.5-4 Hz). However, the precise role of SWR-slow-wave interactions in synchronizing subcortical/cortical neuronal activity is unclear. Here, we leverage intracranial electrophysiological recordings from the human hippocampus, amygdala, temporal and frontal cortices, to examine activity modulation and cross-regional coordination during SWRs. Hippocampal SWRs are associated with widespread modulation of high frequency activity (HFA; 70-200 Hz) a measure of local neuronal activation. This peri-SWR HFA modulation is predicted by the coupling between hippocampal SWRs and local subcortical/cortical slow-waves. Finally, local cortical slow-wave phase offsets during SWRs predicted functional connectivity between the frontal and temporal cortex. These findings suggest a selection mechanism wherein hippocampal SWR and cortical slow-wave synchronization governs the transient engagement of distributed neuronal populations supporting hippocampal-dependent memory consolidation.

neuroscience↗

bioRxiv2020

Chemogenetic manipulation of microglia inhibits neuroinflammation and neuropathic pain in mice

Microglia play an important role in the central sensitization and chronic pain. However, a direct connection between microglial function and the development of neuropathic pain in vivo remains incompletely understood. To address this issue, we applied chemogenetic approach by using CX3CR1creER/+:R26LSL-hM4Di/+ transgenic mice to enable expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (Gi DREADD) exclusively in microglia. We found that microglial Gi DREADD activation inhibited spinal nerve transection (SNT)-induced microglial reactivity as well as chronic pain initiation and maintenance. Gi DREADD activation downregulated the transcription factor interferon regulatory factor 8 (IRF8) and its downstream target pro-inflammatory cytokine interleukin 1 beta (IL-1{beta}). Using in vivo spinal cord recording, we found that activation of microglial Gi DREADD attenuated synaptic transmission following SNT. Our results demonstrate that microglial Gi DREADD reduces neuroinflammation, synaptic function and neuropathic pain after peripheral nerve injury. Thus, chemogenetic approaches provide a potential opportunity for interrogating microglial function and neuropathic pain treatment.

neuroscience↗

bioRxiv2020

The effects of YKL-40 on angiogenic potential of HUVECs are partly mediated by syndecan-4

ObjectiveYKL-40, a secreted glycoprotein, has a role in promoting tumor angiogenesis through syndecan-1 receptor. As one of the members of syndecans family, syndecan-4 is also an important mediator for tube formation. However, the effects of YKL-40 on migration and tube formation of human umbilical vein cells (HUVECs) mediated by syndecan-4 receptor are unknown. MethodsHUVECs were transfected with lentivirus encoding syndecan-4 short hairpin (sh) RNA (lenti-synd4 shRNA) and the efficiency of transfection was measured using reverse transcription quantitative real time polymerase chain reaction (qRT-PCR) and flow cytometry. The effects of recombinant protein of YKL-40 on migration and angiogenesis of HUVECs adjusted by syndecan-4 were determined by wound healing and tube formation assay. The expression of protein kinase C (PKC) and extracellular signal regulated kinases (ERKs) 1 and 2 (ERK1/2) in HUVECs was measured using western blotting. ResultsTransfection of lenti-synd4 shRNA significantly decreased the membrane protein expression of syndecan-4 in HUVECs. HUVECs transfected with lenti-synd4 shRNA remarkably inhibited the migration and tube formation of endothelial cells stimulated by recombinant protein of YKL-40. The levels of PKC and ratio of p-ERK1/2 to ERK1/2 in HUVECs were also down-regulated by silencing syndecan-4. ConclusionThe effects of YKL-40-induced on migration and tube formation of HUVECs may partly be inhibited by knock-downing syndecan-4 through suppressing PKC and ERK1/2 signaling pathways.

molecular biology↗

bioRxiv2020

Potential host range of multiple SARS-like coronaviruses and an improved ACE2-Fc variant that is potent against both SARS-CoV-2 and SARS-CoV-1

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a currently uncontrolled pandemic and the etiological agent of coronavirus disease 2019 (COVID-19). It is important to study the host range of SARS-CoV-2 because some domestic species might harbor the virus and transmit it back to humans. In addition, insight into the ability of SARS-CoV-2 and SARS-like viruses to utilize animal orthologs of the SARS-CoV-2 receptor ACE2 might provide structural insight into improving ACE2-based viral entry inhibitors. Here we show that ACE2 orthologs of a wide range of domestic and wild animals support entry of SARS-CoV-2, as well as that of SARS-CoV-1, bat coronavirus RaTG13, and a coronavirus isolated from pangolins. Some of these species, including camels, cattle, horses, goats, sheep, pigs, cats, and rabbits may serve as potential intermediate hosts for new human transmission, and rabbits in particular may serve as a useful experimental model of COVID-19. We show that SARS-CoV-2 and SARS-CoV-1 entry could be potently blocked by recombinant IgG Fc-fusion proteins of viral spike protein receptor-binding domains (RBD-Fc) and soluble ACE2 (ACE2-Fc). Moreover, an ACE2-Fc variant, which carries a D30E mutation and has ACE2 truncated at its residue 740 but not 615, outperforms all the other ACE2-Fc variants on blocking entry of both viruses. Our data suggest that RBD-Fc and ACE2-Fc could be used to treat and prevent infection of SARS-CoV-2 and any new viral variants that emerge over the course of the pandemic.

microbiology↗

bioRxiv2020

Assessment of a weak mode of bacterial adhesion by applying an electric field

Microbial attachment to surfaces is ubiquitous in nature. Most species of bacteria attach and adhere to surfaces via special appendages such as pili and fimbriae, the roles of which have been extensively studied. Here we report an experiment on pilus-less mutants of Caulobacter crescentus weakly attached to a plastic surface and subjected to an electric field parallel to the surface. We find that some individual cells transiently but repeatedly adhere to the surface in a stick-slip fashion in the presence of an electric field. Even while transiently detached, these bacteria move significantly slower than the unattached ones in the same field of view undergoing electrophoretic motion. We refer this behavior of repeated and transient attachment as "quasi-attachment". The speed of the quasi-attached bacteria exhibits large variations, frequently dropping close to zero for short intervals of time. This study suggests applying electric field as a useful method to investigate bacteria-surface interaction, which is significant in broader contexts such as infection and environmental control. SignificanceInteraction between bacteria and surfaces occur widely in nature, including those in industrial, environmental, and medical settings. It is therefore important to understand various mechanisms and factors that affect numerous forms of bacterium-surface interaction, particularly those resulting in adhesion or attachment, be they strong or weak, permanent or transient. This work takes a unique approach to identify a transient and reversible mode of bacterial attachment to a solid surface, by applying an electric field to exert a force for detachment. The force thus exerted proves to reach the amplitude required to detach bacteria of a pilus-less strain that weakly attach to a plastic surface. The method may be applied broadly to investigate bacteria-surface interaction.

microbiology↗

bioRxiv2020

Severe and multifaceted systemic immunosuppression caused by experimental cancers of the central nervous system requires release of non-steroid soluble mediators

Immunosuppression of unknown etiology is a hallmark feature of glioblastoma (GBM) and is characterized by decreased CD4 T cell counts and down regulation of MHC class II expression on peripheral blood monocytes in patients. This immunosuppression is a critical barrier to the successful development of immunotherapies for GBM. We recapitulated the immunosuppression observed in GBM patients in the C57BL/6 mouse and investigated the etiology of low CD4 T cell counts. We determined that thymic involution was a hallmark feature of immunosuppression in three distinct models of CNS cancer, including mice harboring GL261 glioma, B16 melanoma, and in a spontaneous model of Diffuse Intrinsic Pontine Glioma (DIPG). In addition to thymic involution, we determined that tumor growth in the brain induced significant splenic involution, reductions in peripheral T cells, reduced MHC class II expression on hematopoietic cells, and a modest increase in bone marrow resident CD4 T cells with a naive phenotype. Using parabiosis we report that thymic involution, declines in peripheral T cell counts, and reduced MHC class II expression levels were mediated through circulating blood-derived factors. Conversely, T cell sequestration in the bone marrow was not governed through circulating factors. Serum isolated from glioma-bearing mice potently inhibited proliferation and functions of T cells both in vitro and in vivo. Interestingly, the factor responsible for immunosuppression in serum is nonsteroidal and of high molecular weight. Through further analysis of neurological disease models, we determined that the aforementioned immunosuppression was not unique to cancer itself, but rather occurs in response to CNS injury. Noncancerous acute neurological insults also induced significant thymic involution and rendered serum immunosuppressive. Both thymic involution and serum-derived immunosuppression were reversible upon clearance of brain insults. These findings demonstrate that CNS cancers cause multifaceted immunosuppression and pinpoint circulating factors as a target of intervention to restore immunity. Short SummaryCNS cancers and other brain-injuries suppress immunity through release of non-steroid soluble factors that disrupt immune homeostasis and dampen responses of the peripheral immune system. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/006825v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@14e90c2org.highwire.dtl.DTLVardef@101de5corg.highwire.dtl.DTLVardef@1ad8534org.highwire.dtl.DTLVardef@1041fef_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

immunology↗

bioRxiv2020

Single cell RNA-seq analysis reveals compartment-specific heterogeneity and plasticity of microglia

Microglia are heterogeneous and ubiquitous CNS-resident macrophages that maintain homeostasis of neural tissues and protect them from pathogen attacks. Yet, their differentiation in different compartments remains elusive. We performed single cell RNA-seq (scRNA-seq) analysis to compare the transcriptomes of microglia in adult mouse (C57/Bl) brains and spinal cords to identify microglial subtypes in these CNS compartments. Cortical microglia from 2-month mice consisted of a predominant population of the homeostatic subtype (HOM-M) and a small population (4%) of the inflammatory subtype (IFLAM-M), while spinal microglia consisted of 55% HOM-M and 45% IFLAM-M subtype. Comparison of cortical and spinal microglia at 2, 4 and 8 months revealed consistently a higher composition of the IFLAM-M subtype in the spinal cord. At 8-month, cortical microglia differentiated a small new subtype with interferon response phenotypes (INF-M), while spinal microglia polarized toward a proinflammatory phenotype, as indicated by the increase of microglia expressing IL-1{beta}. To further characterize the differential plasticity of cortical and spinal microglial heterogeneity, we determined the microglial transcriptomes from HIV-1 gp 120 transgenic (Tg) mice, a model of HIV-associated neurological disorders. Compared with wild-type (Wt) cortical microglia, the gp120Tg cortical microglia had three new subtypes, with signatures of interferon I response (INF-M), cell proliferation (PLF-M), and myelination or demyelination (MYE-M) respectively; while INF-M and PLF-M subtypes presented at all ages, the MYE-M only at 4-month. In contrast, only the INF-M subtype was observed in the spinal microglia from 2- and 4-month gp120tg mice. Bioinformatic analysis of regulated molecular pathways of individual microglial subtypes indicated that gp120 more severely impaired the biological function of microglia in cortices than in the spinal cord. The results collectively reveal differential heterogeneity and plasticity of cortical and spinal microglia, and suggest functional differentiation of microglia in different CNS compartments.

neuroscience↗

bioRxiv2020

Artesunate interacts with Vitamin D receptor to reverse mouse model of sepsis-induced immunosuppression via enhancing autophagy

Background and PurposeImmunosuppression is the predominant cause of mortality for sepsis due to failure to eradicate invading pathogens. Unfortunately, no effective and specific drugs capable of reversing immunosuppression are available for clinical use. Increasing evidence implicates vitamin D receptor (VDR) involved in sepsis-induced immunosuppression. Herein, artesunate (AS) was discovered to reverse sepsis-induced immunosuppression and its molecular mechanism is investigated. Experimental ApproachEffect of artesunate on sepsis-induced immunosuppression was investigated in mice and in vitro. VDR was predicted to be an interacted candidate of AS by bioinformatics predict, then identified using PCR and immunoblotting. VDR, ATG16L1 and NF-{kappa}B p65 were modified to investigate the alteration of ASs effect on pro-inflammatory cytokines release, bacteria clearance and autophagy activities in sepsis-induced immunosuppression. Key ResultsAS significantly reduced the mortality of cecal ligation and puncture (CLP)-induced sepsis immunosuppression mice challenged with Pseudomonas Aeruginosa, and enhanced proinflammatory cytokines release and bacterial clearance to reverse sepsis-induced immunosuppression in vivo and in vitro. Mechanically, AS interacted with VDR thereby inhibited the nuclear translocation of VDR, then influencing ATG16L1 transcription and subsequent autophagy activity. In addition, AS inhibited physical interaction between VDR and NF-{kappa}B p65 in LPS tolerance macrophages, then promoted nuclear translocation of NF-{kappa}B p65, which activated the transcription of NF-{kappa}B p65 target genes such as pro-inflammatory cytokines. Conclusion and ImplicationsOur findings provide an evidence that AS interacted with VDR to reverse sepsis-induced immunosuppression in an autophagy and NF-{kappa}B dependent way, highlighting a novel approach for sepsis treatment and drug repurposing of AS in the future.

pharmacology and toxicology↗

bioRxiv2020

Polyploidization enhancing genetic recombination of the ancestral diploid genome in the evolution of hexaploid wheat

Allopolyploidy increases its evolutionary potential by fixing heterosis and the advantage of gene redundancy. Allelic combinations generated from genetic recombination potentially provide many variations to the selection pools for evolution. May there be any relationship between allopolyploidization and genetic recombination? To study the impact of polyploidy on genetic recombination, we selected wheat as a model and simulated its evolution pathway of allopolyploidy by developing synthetic hexaploid wheat. The change of homologous chromosome recombination were investigated on their diploid DD and tetraploid AABB genomes after their allohexaploidization, respectively. The genetic recombination of the ancestral diploid genome of Aegilops tauschii was enhanced significantly more than 2 folds after their hexaploidization. Hexaploidization enhancing genetic recombination of the ancestral diploid D genome was firstly reported to be a new way to increase evolutionary potential of wheat, which is beneficial for wheat to conquer their narrow origination of D genome, quickly spread and make it a major crop of the world. Finally, re-synthetizing hexaploid wheat using diverse Ae. tauschii species with tetraploid wheat can be considered as a pleiotropic strategy to speed adaptive evolution of bread wheat in breeding processes by increasing both gene allele types and genetic recombination variations.

evolutionary biology↗