Biology subjects

Zhang, M.

Publications and source records attributed to Zhang, M..

At least 649 records · Page 36Linked to original sources

bioRxiv2020

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

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

cancer biology↗

bioRxiv2020

Telmisartan potentiates insulin secretion via ion channels, independent of the AT1 receptor and PPARγ

Angiotensin II type 1 receptor blockers (ARBs), as antihypertensive drugs, have drawn attention for their benefits to individuals with diabetes and prediabetes. However, the effects of ARBs on insulin secretion remain unclear. Here, we investigated the insulinotropic effects of ARBs (telmisartan, valsartan, and irbesartan) and the underlying electrophysiological mechanism in rat islets. We found that only telmisartan among the three ARBs exhibited an insulin secretagogue role. Distinct from other ARBs, telmisartan exerted effects on ion channels including voltage-gated potassium (Kv) channels and voltage-gated Ca2+ channels to promote extracellular Ca2+ influx, thereby potentiating insulin secretion in a glucose-dependent manner. We observed that the peroxisome proliferator-activated receptor {gamma} pathway was not involved in these telmisartan-induced effects. Furthermore, we identified that telmisartan at least directly inhibited Kv2.1 channel through construction of a Chinese hamster ovary cell line with Kv2.1 channel overexpression. Acute exposure of type 2 diabetes model (db/db) mice to a telmisartan dose equivalent to therapeutic doses in humans resulted in lower blood glucose and increased plasma insulin concentration in the oral glucose tolerance test. We further observed the telmisartan-induced insulinotropic and electrophysiological effects on pathological pancreatic islets isolated from db/db mice. Collectively, our results establish an important function of telmisartan distinct from other ARBs in the treatment of diabetes.

cell biology↗

bioRxiv2020

CECR2 Drives Breast Cancer Metastasis by Suppressing Macrophage Inflammatory Responses

Epigenetic and transcriptional changes are critical for metastasis, the major cause of cancer-related deaths. Metastatic tumor cells escape immune surveillance more efficiently than tumor cells in the primary sites, but the mechanisms controlling their immune evasion are poorly understood. We found that distal metastases are more immune inert with increased M2 macrophages compared to their matched primary tumors. Acetyl-lysine reader CECR2 is an epigenetic regulator upregulated in metastases and positively associated with M2 macrophages. CECR2 specifically promotes breast cancer metastasis in multiple mouse models, with more profound effect in the immunocompetent setting. Mechanistically, NF-{kappa}B family member RELA recruits CECR2 to activate CSF1 and CXCL1, which are critical for macrophage-mediated immunosuppression at the metastatic sites. Furthermore, pharmacological inhibition of CECR2 bromodomain impedes NF-{kappa}B-mediated immune suppression by macrophages and inhibits breast cancer metastasis. These results reveal novel therapeutic strategies to treat metastatic breast cancer. Statement of SignificanceComparison of matched primary breast tumors and distal metastases show that metastases are more immune inert with increased tumor promoting macrophages. Depletion or pharmacological inhibition of CECR2 inhibits breast cancer metastasis by suppressing macrophage inflammatory responses, nominating CECR2 as a promising therapeutic target for cancer metastasis.

cancer biology↗

bioRxiv2020

Inflammation mediates lung cancer-induced increase in the epidermal green autofluorescence of mice

Skins autofluorescence (AF) holds great promise for non-invasive diagnosis of diseases. Our previous study has indicated that keratin-based skins AF holds great promise to become a novel biomarker for diagnosis of multiple major diseases, including lung cancer, acute ischemic stroke, Parkinsons diseases, stable coronary artery disease and myocardial infarction. It is critical to investigate the mechanisms underlying the increased skins AF of the patients. Our previous study has shown that development of lung cancer can induce increased skins green AF of mice, while the mechanisms underlying the increased AF have remained unclear. We hypothesized that the inflammation in the mice with lung cancer is causative to the increased AF. Our study found that the anti-inflammation drug indomethacin virtually abolished the lung cancer-induced increase in the skins green AF. We further found that the AF was originated from the epidermis of the mice. Our findings have provided critical information for understanding the mechanisms underlying the lung cancer-induced increase in the epidermal green AF, indicating that at least for lung cancer, the disease-induced increase in the skins AF mainly results from increased inflammation in the body.

biophysics↗

bioRxiv2020

Shoot-derived miR2111 controls legume root and nodule development

Legumes control their nodule numbers through the Autoregulation Of Nodulation (AON). Rhizobia infection stimulates the production of root-derived CLE peptide hormones that are translocated to the shoot where they regulate a new signal. We used soybean to demonstrate that this shoot-derived signal is miR2111, which is transported via phloem to the root where it targets transcripts of Too Much Love (TML), a negative regulator of nodulation. Shoot perception of rhizobia-induced CLE peptides suppresses miR2111 expression, resulting in TML accumulation in roots and subsequent inhibition of nodule organogenesis. Feeding synthetic mature miR2111 via the petiole increased nodule numbers per plant. Likewise, elevating miR2111 availability by over-expression promoted nodulation, while target mimicry of TML induced the opposite effect on nodule development in wild-type plants and alleviated the supernodulating and stunted root growth phenotypes of AON-defective mutants. Additionally, in non-nodulating wild-type plants, ectopic expression of miR2111 significantly enhanced lateral root emergence with a decrease in lateral root length and average root diameter. In contrast, hairy roots constitutively expressing the target mimic construct exhibited reduced lateral root density. Overall, these findings demonstrate that miR2111 is both the critical shoot-to-root factor that positively regulates root nodule development, and also acts to shape root system architecture via orchestrating the degree of root branching, as well as the length and thickness of lateral roots.

plant biology↗

bioRxiv2020

Modeling SARS-CoV-2 infection in vitro with a human intestine-on-chip device

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) has given rise to a global pandemic. The gastrointestinal symptoms of some COVID-19 patients are underestimated. There is an urgent need to develop physiologically relevant model that can accurately reflect human response to viral infection. Here, we report the creation of a biomimetic human intestine infection model on a chip system that allows to recapitulate the intestinal injury and immune response induced by SARS-CoV-2, for the first time. The microengineered intestine-on-chip device contains human intestinal epithelium (co-cultured human intestinal epithelial Caco-2 cells and mucin secreting HT-29 cells) lined in upper channel and vascular endothelium (human umbilical vein endothelial cells, HUVECs) in a parallel lower channel under fluidic flow condition, sandwiched by a porous PDMS membrane coated with extracellular matrix (ECM). At day 3 post-infection of SARS-CoV-2, the intestine epithelium showed high susceptibility to viral infection and obvious morphological changes with destruction of intestinal villus, dispersed distribution of mucus secreting cells and reduced expression of tight junction (E-cadherin), indicating the destruction of mucous layer and the integrity of intestinal barrier caused by virus. Moreover, the endothelium exhibited abnormal cell morphology with disrupted expression of adherent junction protein (VE-cadherin). Transcriptional analysis revealed the abnormal RNA and protein metabolism, as well as activated immune responses in both epithelial and endothelial cells after viral infection (e.g., up-regulated cytokine genes, TNF signaling and NF-kappa B signaling-related genes). This bioengineered in vitro model system can mirror the human relevant pathophysiology and response to viral infection at the organ level, which is not possible in existing in vitro culture systems. It may provide a promising tool to accelerate our understanding of COVID-19 and devising novel therapies.

bioengineering↗

bioRxiv2020

Engineered Trimeric ACE2 Binds and Locks "Three-up" Spike Protein to Potently Inhibit SARS-CoVs and Mutants

SARS-CoV-2 enters cells via ACE-2, which binds the spike protein with moderate affinity. Despite a constant background mutational rate, the virus must retain binding with ACE2 for infectivity, providing a conserved constraint for SARS-CoV-2 inhibitors. To prevent mutational escape of SARS-CoV-2 and to prepare for future related coronavirus outbreaks, we engineered a de novo trimeric ACE2 (T-ACE2) protein scaffold that binds the trimeric spike protein with extremely high affinity (KD < 1 pM), while retaining ACE2 native sequence. T-ACE2 potently inhibits all tested pseudotyped viruses including SARS-CoV-2, SARS-CoV, eight naturally occurring SARS-CoV-2 mutants, two SARSr-CoVs as well as authentic SARS-CoV-2. The cryo-EM structure reveals that T-ACE2 can induce the transit of spike protein to "three-up" RBD conformation upon binding. T-ACE2 thus represents a promising class of broadly neutralizing proteins against SARS-CoVs and mutants.

bioengineering↗

bioRxiv2020

Deep learning and alignment of spatially-resolved whole transcriptomes of single cells in the mouse brain with Tangram

Charting a biological atlas of an organ, such as the brain, requires us to spatially-resolve whole transcriptomes of single cells, and to relate such cellular features to the histological and anatomical scales. Single-cell and single-nucleus RNA-Seq (sc/snRNA-seq) can map cells comprehensively5,6, but relating those to their histological and anatomical positions in the context of an organs common coordinate framework remains a major challenge and barrier to the construction of a cell atlas7-10. Conversely, Spatial Transcriptomics allows for in-situ measurements11-13 at the histological level, but at lower spatial resolution and with limited sensitivity. Targeted in situ technologies1-3 solve both issues, but are limited in gene throughput which impedes profiling of the entire transcriptome. Finally, as samples are collected for profiling, their registration to anatomical atlases often require human supervision, which is a major obstacle to build pipelines at scale. Here, we demonstrate spatial mapping of cells, histology, and anatomy in the somatomotor area and the visual area of the healthy adult mouse brain. We devise Tangram, a method that aligns snRNA-seq data to various forms of spatial data collected from the same brain region, including MERFISH1, STARmap2, smFISH3, and Spatial Transcriptomics4 (Visium), as well as histological images and public atlases. Tangram can map any type of sc/snRNA-seq data, including multi-modal data such as SHARE-seq data5, which we used to reveal spatial patterns of chromatin accessibility. We equipped Tangram with a deep learning computer vision pipeline, which allows for automatic identification of anatomical annotations on histological images of mouse brain. By doing so, Tangram reconstructs a genome-wide, anatomically-integrated, spatial map of the visual and somatomotor area with [~]30,000 genes at single-cell resolution, revealing spatial gene expression and chromatin accessibility patterning beyond current limitation of in-situ technologies.

genomics↗

bioRxiv2020

The global landscape of SARS-CoV-2 genomes, variants, and haplotypes in 2019nCoVR

On 22 January 2020, the National Genomics Data Center (NGDC), part of the China National Center for Bioinformation (CNCB), created the 2019 Novel Coronavirus Resource (2019nCoVR), an open-access SARS-CoV-2 information resource. 2019nCoVR features a comprehensive integration of sequence and clinical information for all publicly available SARS-CoV-2 isolates, which are manually curated with value-added annotations and quality evaluated by our in-house automated pipeline. Of particular note, 2019nCoVR performs systematic analyses to generate a dynamic landscape of SARS-CoV-2 genomic variations at a global scale. It provides all identified variants and detailed statistics for each virus isolate, and congregates the quality score, functional annotation, and population frequency for each variant. It also generates visualization of the spatiotemporal change for each variant and yields historical viral haplotype network maps for the course of the outbreak from all complete and high-quality genomes. Moreover, 2019nCoVR provides a full collection of SARS-CoV-2 relevant literature on COVID-19 (Coronavirus Disease 2019), including published papers from PubMed as well as preprints from services such as bioRxiv and medRxiv through Europe PMC. Furthermore, by linking with relevant databases in CNCB-NGDC, 2019nCoVR offers data submission services for raw sequence reads and assembled genomes, and data sharing with National Center for Biotechnology Information. Collectively, all SARS-CoV-2 genome sequences, variants, haplotypes and literature are updated daily to provide timely information, making 2019nCoVR a valuable resource for the global research community. 2019nCoVR is accessible at https://bigd.big.ac.cn/ncov/.

genomics↗

bioRxiv2020

Compositional Variability and Mutation Spectra of Monophyletic SARS-CoV-2 Clades

COVID-19 and its causative pathogen SARS-CoV-2 have rushed the world into a staggering pandemic in a few months and a global fight against both is still going on. Here, we describe an analysis procedure where genome composition and its variables are related, through the genetic code, to molecular mechanisms based on understanding of RNA replication and its feedback loop from mutation to viral proteome sequence fraternity including effective sites on replicase-transcriptase complex. Our analysis starts with primary sequence information and identity-based phylogeny based on 22,051 SARS-CoV-2 genome sequences and evaluation of sequence variation patterns as mutation spectrum and its 12 permutations among organized clades tailored to two key mechanisms: strand-biased and function-associated mutations. Our findings include: (1) The most dominant mutation is C-to-U permutation whose abundant second-codon-position counts alter amino acid composition toward higher molecular weight and lower hydrophobicity albeit assumed most slightly deleterious. (2) The second abundance group includes: three negative-strand mutations U-to-C, A-to-G, G-to-A and a positive-strand mutation G-to-U generated through an identical mechanism as C-to-U. (3) A clade-associated and biased mutation trend is found attributable to elevated level of the negative-sense strand synthesis. (4) Within-clade permutation variation is very informative for associating non-synonymous mutations and viral proteome changes. These findings demand a bioinformatics platform where emerging mutations are mapped on to mostly subtle but fast-adjusting viral proteomes and transcriptomes to provide biological and clinical information after logical convergence for effective pharmaceutical and diagnostic applications. Such thoughts and actions are in desperate need, especially in the middle of the War against COVID-19.

microbiology↗

bioRxiv2020

Hemodynamic responses link individual differences in informational masking to the vicinity of superior temporal gyrus

Suppressing unwanted background sound is crucial for aural communication. A particularly disruptive type of background sound, informational masking (IM), often interferes in social settings. However, IM mechanisms are incompletely understood. At present, IM is identified operationally: when a target should be audible, based on suprathreshold target/masker energy ratios, yet cannot be heard because perceptually similar background sound interferes. Here, functional near infrared spectroscopy recordings show that task-evoked blood oxygenation changes near the superior temporal gyrus (STG) covary with behavioral speech detection performance for high-IM but not low-IM background sound, suggesting that the STG is part of an IM-dependent network. Moreover, listeners who are more vulnerable to IM show increased hemodynamic recruitment near STG. In contrast, task-evoked responses near another auditory region of cortex, the caudal inferior frontal sulcus (cIFS), do not predict behavioral sensitivity, suggesting that the cIFS belongs to an IM-independent network. Results are consistent with the idea that cortical gating shapes individual vulnerability to IM.

neuroscience↗

bioRxiv2020

Tumor Immunity Microenvironment-based classifications of bladder cancer for enhancing cancer immunotherapy

BackgroundBladder cancer is composed by a mass of heterogenetic characteristics, immunotherapy is a potential way to save the life of bladder cancer patients, but only benefit to about 20% patients. Methods and materialsA total of 4003 bladder cancer patients from 19 cohorts was enrolled in this study, collecting the clinical information and mRNA expression profile. The unsupervised non-negative matrix factorization (NMF) and nearest template prediction (NTP) algorithm was used to divide the patients to immune activated, immune exhausted and non-immune class. Verified gene sets of signatures were used to illustrate the characteristic of immunophenotypes. Clinical and genetic features were compared in different immunophenotypes. ResultsWe identified the immune class and non-immune classes in from TCGA-BLCA cohort. The 150 top different expression genes between these two classes was extracted as the input profile for the reappearing of the classification in the other 19 cohorts. As to the activated and exhausted subgroups, a stromal activation signature was conducted by NTP algorithm. Patients in the immune classes shown the highly enriched signatures of immunocytes, while the exhausted subgroup also shown an increased signature of TITR, WNT/TGF-{beta}, TGF-{beta}1 activated, and C-ECM signatures. Patients in the immune activated shown a lower CNA burden, better overall survival, and favorable response to anti-PD-1 therapy. ConclusionWe defined and validated a novel classifier among the 4003 bladder cancer patients. Anti-PD-1 immunotherapy could benefit more for the patients belong to immune activated subgroup, while ICB therapy plus TGF-{beta} inhibitor or EP300 inhibitor might be more effectiveness for patients in immune exhausted subgroup.

immunology↗

bioRxiv2020

Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency

Metazoan cells only utilize a small subset of the potential DNA replication origins to duplicate the whole genome in each cell cycle. Origin choice is linked to cell growth, differentiation, and replication stress. Despite various genetic and epigenetic signatures are found to be related with active origins, it remains elusive how the selection of origins is determined. The classic Rosette model proposes that the origins clustered in a chromatin domain are preferentially and simultaneously fired, but direct imaging evidence has been lacking due to insufficient spatial resolution. Here, we applied dual-color stochastic optical reconstruction microscopy (STORM) super-resolution imaging to map the spatial distribution of origins within individual topologically associating domains (TADs). We found that multiple replication origins initiate separately at the spatial boundary of a TAD at the beginning of the S phase, in contrary to the Rosette model. Intriguingly, while both active and dormant origins are distributed homogeneously in the TAD during the G1 phase, active origins relocate to the TAD periphery before entering the S phase. We proved that such origin relocalization is dependent on both transcription and CTCF-mediated chromatin structure. Further, we observed that the replication machinery protein PCNA forms immobile clusters around the TADs at the G1/S transition, which explains why origins at the TAD periphery are preferentially fired. Thus, we propose a "Chromatin Re-organization Induced Selective Initiation" (CRISI) model that the transcription-coupled chromatin structural re-organization determines the selection of replication origins, which transcends the scope of specific genetic and epigenetic signatures for origin efficiency. Our in situ super-resolution imaging unveiled coordination among DNA replication, transcription, and chromatin organization inside individual TADs, providing new insights into the biological functions of sub-domain chromatin structural dynamics.

genomics↗

bioRxiv2020

Generation of nonhuman primate retinitis pigmentosa model by in situ knockout of RHO in rhesus macaque retina

Retinitis pigmentosa (RP) is a form of inherited retinal degenerative disease that ultimately involves the macula, which is present in primates but not in the rodents. Therefore, creating nonhuman primate (NHP) models of RP is of critical importance to study its mechanism of pathogenesis and to evaluate potential therapeutic options in the future. Here we applied adeno-associated virus (AAV)-delivered CRISPR/SaCas9 technology to knockout the RHO gene in the retinae of the adult rhesus macaque (Macaca mulatta) to investigate the hypothesis whether non-germline mutation of the RHO gene is sufficient to recapitulate RP. Through a series of studies, we were able to demonstrate successful somatic editing of the RHO gene and reduced RHO protein expression. More importantly, the mutant macaque retinae displayed clinical RP phenotypes, including photoreceptor degeneration, retinal thinning, abnormal rod subcellular structures, and reduced photoresponse. Therefore, we suggest somatic editing of the RHO gene is able to phenocopy RP, and the reduced time span in generating NHP mutant accelerates RP research and expands the utility of NHP model for human disease study.

neuroscience↗

bioRxiv2020

Drug Screening with Zebrafish Visual Behavior Identifies Carvedilol as a Potential Treatment for Retinitis Pigmentosa

Retinitis Pigmentosa (RP) is an incurable inherited retinal degeneration affecting approximately 1 in 4,000 individuals globally. The goal of this work was to identify drugs that can help patients suffering from the disease. To accomplish this, we screened drugs on a zebrafish RP model. This model expresses a truncated human rhodopsin transgene (Tg(rho:Hsa.RH1_Q344X)) causing significant rod degeneration by 7 days post-fertilization (dpf). Consequently, the larvae displayed a deficit in visual motor response (VMR) under scotopic condition. The diminished VMR was leveraged to screen an ENZO SCREEN-WELL(R) REDOX library since oxidative stress is postulated to play a role in RP progression. Our screening identified a beta-blocker, carvedilol, that ameliorated the deficient VMR of the RP larvae and increased their rod number. Carvedilol can act directly on rods as it affected the adrenergic pathway in a rod-like human Y79 cell line. Since carvedilol is an FDA-approved drug, our findings suggest that carvedilol can potentially be repurposed to treat RP patients. Summary StatementThis paper presents the utilization of zebrafish visual behavior, a novel paradigm to screen and identify drugs to treat retinitis pigmentosa, an incurable retinal-degenerative disease.

neuroscience↗

bioRxiv2020

Berberine alleviates adiposity and cardiac dysfunction in offspring exposed to gestational diabetes mellitus

The most robust risk factor for type 2 diabetes in childhood is prior exposure to diabetes during gestation. Currently, there are few evidence-based strategies to attenuate the of risk of metabolic syndrome in offspring exposed to gestational diabetes mellitus (GDM). Berberine (BBR) is an isoquinoline alkaloid extracted from Chinese herbs and exhibits glucose lowering properties. It has been used safely for centuries in humans. Our objective was to determine whether BBR treatment improves health outcomes in the mouse offspring of GDM dams. Dams were fed either a lean low-fat diet (Lean, LF,10% kcal fat) or a GDM-inducing high-fat/high sucrose diet (GDM, HF, 45% kcal fat) prior to breeding and throughout pregnancy. The resulting Lean and GDM-exposed offspring were randomly assigned a LF, HF or HF diet containing BBR (160 mg/kg/d) for 12 weeks. We determined that BBR treatment significantly reduced body weight ([~]20%), % body fat ([~]40%) and gonadal fat pad mass ([~]60%) compared to HF-fed GDM offspring. Furthermore, BBR treatment of HF-fed GDM offspring normalized insulin levels in the plasma and isolated pancreatic islets. Differences in food consumption did not contribute to altered body composition in BBR treated mice, as levels remained similar between experimental groups. Alternatively, BBR-treatment was associated with increased whole-body oxygen consumption (VO2), activity and heat production. Additionally, we determined that HF-fed GDM offspring developed a cardiomyopathy, characterized by increased isovolumetric contraction ([~]150%, IVCT), relaxation time ([~]70%, IVRT), elevated cardiac triglyceride ([~]120%) and reduced mitochondrial function (30%, spare capacity) compared to LF fed Lean controls. BBR treatment normalized heart function, reduced triglyceride levels and maintained mitochondrial function. Our data supports BBR as a potential pharmacotherapeutic approach to improve health outcomes in individuals exposed to GDM. Key Points SummaryO_LIGestational diabetes mellitus is a common metabolic complication of pregnancy which is increasing worldwide due to the prevalence of obesity. C_LIO_LIIt is known that individuals exposed to gestational diabetes have elevated risk of developing metabolic syndrome however there are few evidence-based strategies which provide protection. C_LIO_LIBerberine is a natural compound found in Chinese herbs which has been safely used for centuries to treat type 2 diabetes mellitus. C_LIO_LIWe determined that berberine treatment of offspring exposed to gestational diabetes attenuated weight gain, reduced insulin levels and normalized both heart and pancreatic function. C_LIO_LIOur data supports berberine as a potential pharmacotherapeutic approach to improve health outcomes in individuals exposed to gestational diabetes. C_LI

physiology↗

bioRxiv2020

Association of gut microbiota with cerebral cortex and cerebrovascular abnormality in human mild traumatic brain injury

Key roles of the gut-brain axis in brain injury development have been suggested in various mouse models; however, little is known about its functional significance in human mild traumatic brain injury (TBI). Here, we decipher this axis by profiling the gut microbiota in 98 acute mild TBI patients and 62 matched controls, and subgroup of them also measured circulating mediators and applied neuroimaging. Mild TBI patients had increased -diversity and different overall microbial compositions compared with controls. 25-microbial genus classifiers distinguish patients from controls with an area under the receiver operating characteristic curve (AUC) of 0.889, while adding serum mediators and neuroimaging features further improved performance even in a small sample size (AUC = 0.969). Numerous correlations existed between gut bacteria, aberrant cortical thickness and cerebrovascular injury. Co-occurrence network analysis revealed two unique gut-brain axes in patients: 1) altered intestinal Lachnospiraceae_NK4A136_group and Eubacterium_ruminantium_group-increased serum GDNF-subcallosal hypertrophy and cerebrovascular injury; 2) decreased intestinal Eubacterium_xylanophilum_group-upregulated IL-6-thinned anterior insula. Our findings provide a new integrated mechanistic understanding and diagnostic model of mild TBI.

microbiology↗

bioRxiv2020

A human disease model of SARS-CoV-2-induced lung injury and immune responses with a microengineered organ chip

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that seriously endangers human health. There is an urgent need to build physiological relevant human models for deep understanding the complex organ-level disease processes and facilitating effective therapeutics for COVID-19. Here, we first report the use of microengineered alveolus chip to create a human disease model of lung injury and immune responses induced by native SARS-CoV-2 at organ-level. This biomimetic system is able to reconstitute the key features of human alveolar-capillary barrier by co-culture of alveolar epithelial and microvascular endothelial cells under microfluidic flow. The epithelial cells on chip showed higher susceptibility to SARS-CoV-2 infection than endothelial cells identified by viral spike protein expression. Transcriptional analysis showed distinct responses of two cell types to SARS-CoV-2 infection, including activated type I interferon (IFN-I) signaling pathway in epithelium and activated JAK-STAT signaling pathway in endothelium. Notably, in the presence of circulating immune cells, a series of alveolar pathological changes were observed, including the detachment of endothelial cells, recruitment of immune cells, and increased production of inflammatory cytokines (IL-6, IL-8, IL-1{beta} and TNF-). These new findings revealed a crucial role of immune cells in mediating lung injury and exacerbated inflammation. Treatment with antiviral compound remdesivir could suppress viral copy and alleviate the disruption of alveolar barrier integrity induced by viral infection. This bioengineered human organ chip system can closely mirror human-relevant lung pathogenesis and immune responses to SARS-CoV-2 infection, not possible by other in vitro models, which provides a promising and alternative platform for COVID-19 research and preclinical trials.

bioengineering↗