Biology subjects

Sheng, X.

Publications and source records attributed to Sheng, X..

47 records · Page 3Linked to original sources

bioRxiv2020

Circuit-free, optoelectronic sensing of electrodermal activities based on photon recycling of a micro-LED

Conventional epidermal electronics integrate multiple power harvesting, signal amplification and data transmission components for wireless biophysical and biochemical signal detection. This paper reports the real-time electrodermal activities can be optically captured using a microscale light-emitting diode (micro-LED), eliminating the need for complicated sensing circuit. Owing to its strong photon-recycling effects, the micro-LEDs photoluminescence (PL) emission exhibits a superlinear dependence on the external resistance. Taking advantage of this unique mechanism, the galvanic skin response (GSR) of a human subject is optically monitored, and it demonstrates that such an optoelectronic sensing technique outperforms a traditional tethered, electrically based GSR sensing circuit, in terms of its footprint, accuracy and sensitivity. This presented optoelectronic sensing approach could establish promising routes to advanced biological sensors.

bioengineering↗

bioRxiv2020

Rapid adaptation of SARS-CoV-2 in BALB/c mice: Novel mouse model for vaccine efficacy

Coronavirus disease 2019 (COVID-19) threatens global public health and economy. In order to develop safe and effective vaccines, suitable animal models must be established. Here we report the rapid adaption of SARS-CoV-2 in BALB/c mice, based on which a convenient, economical and effective animal model was developed. Specifically, we found that mouse-adapted SARS-CoV-2 at passage 6 (MACSp6) efficiently infected both aged and young wild-type BALB/c mice, resulting in moderate pneumonia as well as inflammatory responses. The elevated infectivity of MACSp6 in mice could be attributed to the substitution of a key residue (N501Y) in the receptorbinding domain (RBD). Using this novel animal model, we further evaluated the in vivo protective efficacy of an RBD-based SARS-CoV-2 subunit vaccine, which elicited highly potent neutralizing antibodies and conferred full protection against SARS-CoV-2 MACSp6 challenge. This novel mouse model is convenient and effective in evaluating the in vivo protective efficacy of SARS-CoV-2 vaccine. SummaryThis study describes a unique mouse model for SARS-CoV-2 infection and confirms protective efficacy of a SARS-CoV-2 RBD subunit vaccine.

microbiology↗

bioRxiv2020

Ratio of the interferon-γ signature to the immunosuppression signature predicts anti-PD-1 therapy response in melanoma

Immune checkpoint inhibitor (ICI) treatments produce clinical benefit in many patients. However, better pretreatment predictive biomarkers for ICI are still needed to help match individual patients to the treatment most likely to be of benefit. Existing gene expression profiling (GEP)-based biomarkers for ICI are primarily focused on measuring a T cell-inflamed tumour microenvironment that contributes positively to the response to ICI. Here, we identified an immunosuppression signature (IMS) through analysing RNA sequencing data from a combined discovery cohort (n = 120) consisting of three publicly available melanoma datasets. Using the ratio of an established IFN-{gamma} signature and IMS led to consistently better prediction of the ICI therapy outcome compared to a collection of nine published GEP signatures from the literature on a newly generated internal validation cohort (n = 55) and three published datasets of metastatic melanoma treated with anti-PD-1 (n = 48) and anti-CTLA-4 (n = 42) as well as in patients with gastric cancer treated with antiPD-1 (n = 45), demonstrating the potential utility of IMS as a predictive/prognostic biomarker that complements existing GEP signatures for immunotherapy.

immunology↗

bioRxiv2020

Renal tubule Cpt1a overexpression mitigates kidney fibrosis by restoring mitochondrial homeostasis

Chronic kidney disease (CKD) remains a major epidemiological, clinical and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) suffer a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine if FAO gain-of-function (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1 A (CPT1A) in TECs. Cpt1a knock-in (CPT1A KI) mice subjected to three different models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy-FAN and adenine induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted pro-inflammatory response and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restituted oxidative metabolism and mitochondrial number and enhanced bioenergetics increasing palmitate oxidation and ATP levels, changes also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients evidenced decreased CPT1 levels and increased accumulation of short and middle chain acyl-carnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD. Graphical abstractOverexpression of CPT1A impedes tubular epithelial renal cell dedifferentiation and a pro-fibrotic phenotype by restoring mitochondrial metabolic bioenergetics. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

biochemistry↗

bioRxiv2020

A wireless, implantable optoelectrochemical probe for optogenetic stimulation and dopamine detection

Physical and chemical technologies have been continuously progressing advances of neuroscience research. The development of research tools for closed-loop control and monitoring neural activities in behaving animals is highly desirable. In this paper, we introduce a wirelessly operated, miniaturized microprobe system for optical interrogation and neurochemical sensing in the deep brain. Via epitaxial liftoff and transfer printing, microscale light emitting diodes (micro-LEDs) as light sources, and poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) coated diamond films as electrochemical sensors are vertically assembled to form implantable optoelectrochemical probes, for real-time optogenetic stimulation and dopamine detection capabilities. A customized, lightweight circuit module is employed for untethered, remote signal control and data acquisition. Injected into the ventral tegmental area (VTA) of freely behaving mice, in vivo experiments clearly demonstrate the utilities of the multifunctional optoelectrochemical microprobe system for optogenetic interference of place preferences and detection of dopamine release. The presented options for material and device integrations provide a practical route to simultaneous optical control and electrochemical sensing of complex nervous systems.

bioengineering↗

bioRxiv2019

Rapidly cycling stem cells regenerate the intestine independent of Lgr5high cells

The +4 cells in intestinal crypts are DNA damage-resistant and contribute to regeneration. However, their exact identity and the mechanism underlying +4 cell-mediated regeneration remain unclear. Using lineage tracing, we show that cells marked by an Msi1 reporter (Msi1+) are enriched at the +4 position in intestinal crypts and exhibit DNA damage resistance. Single-cell RNA sequencing reveals that the Msi1+ cells are heterogeneous with the majority being intestinal stem cells (ISCs). The DNA damage-resistant subpopulation of Msi1+ cells is characterized by low-to-negative Lgr5 expression and is more rapidly cycling than Lgr5high radio-sensitive crypt base columnar stem cells (CBCs); they enable fast repopulation of the intestinal epithelium independent of CBCs that are largely depleted after irradiation. Furthermore, relative to CBCs, Msi1+ cells preferentially produce Paneth cells during homeostasis and upon radiation repair. Together, we demonstrate that the DNA damage-resistant Msi1+ cells are rapidly cycling ISCs that maintain and regenerate the intestinal epithelium.

cell biology↗

bioRxiv2019

Population specific reference panels are crucial for the genetic analyses of Native Hawai’ians: an example of the CREBRF locus

Statistical imputation applied to genome-wide array data is the most cost-effective approach to complete the catalog of genetic variation in a study population. However, imputed genotypes in underrepresented populations incur greater inaccuracies due to ascertainment bias and a lack of representation among reference individuals,, further contributing to the obstacles to study these populations. Here we examined the consequences due to the lack of representation by genotyping a functionally important, Polynesian-specific variant, rs373863828, in the CREBRF gene, in a large number of self-reported Native Hawaiians (N=3,693) from the Multiethnic Cohort. We found the derived allele of rs373863828 was significantly associated with several adiposity traits with large effects (e.g. 0.214 s.d., or approximately 1.28 kg/m2, per allele, in BMI as the most significant; P = 7.5x10-5). Due to the current absence of Polynesian representation in publicly accessible reference sequences, rs373863828 or any of its proxies could not be tested through imputation using these existing resources. Moreover, the association signals at this Polynesian-specific variant could not be captured by alternative approaches, such as admixture mapping. In contrast, highly accurate imputation can be achieved even if a small number (<200) of Polynesian reference individuals were available. By constructing an internal set of Polynesian reference individuals, we were able to increase sample size for analysis up to 3,936 individuals, and improved the statistical evidence of association (e.g. p = 1.5x10-7, 3x10-6, and 1.4x10-4 for BMI, hip circumference, and T2D, respectively). Taken together, our results suggest the alarming possibility that lack of representation in reference panels would inhibit discovery of functionally important, population-specific loci such as CREBRF. Yet, they could be easily detected and prioritized with improved representation of diverse populations in sequencing studies.

genetics↗

bioRxiv2019

Genome-wide association analyses identify variants in IRF4 associated with Acute Myeloid Leukemia and Myelodysplastic Syndrome susceptibility

The role of common genetic variation in susceptibility to acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS), a group of rare clonal hematologic disorders characterized by dysplastic hematopoiesis and high mortality, remains unclear. We performed AML and MDS genome-wide association studies (GWAS) in the DISCOVeRY-BMT cohorts (2309 cases and 2814 controls). Association analysis based on subsets (ASSET) was used to conduct a summary statistics SNP-based analysis of MDS and AML subtypes. For each AML and MDS case and control we used PrediXcan to estimate the component of gene expression determined by their genetic profile and correlate this imputed gene expression level with risk of developing disease in a transcriptome-wide association study (TWAS). ASSET identified an increased risk for de novo AML and MDS (OR=1.38, 95% CI, 1.26-1.51, Pmeta=2.8x10-12) in patients carrying the T allele at rs12203592 in Interferon Regulatory Factor 4 (IRF4), a transcription factor which regulates myeloid and lymphoid hematopoietic differentiation. Our TWAS analyses showed increased IRF4 gene expression is associated with increased risk of de novo AML and MDS (OR=3.90, 95% CI, 2.36-6.44, Pmeta =1.0x10-7). The identification of IRF4 by both GWAS and TWAS contributes valuable insight on the role of genetic variation in AML and MDS susceptibility.

genomics↗

bioRxiv2019

Stromal ISLR promotes intestinal regeneration and cancer by suppressing epithelial Hippo signaling

The YAP signaling activation in epithelial cells is essential for intestinal regeneration and tumorigenesis. However, the molecular mechanism linking stromal signals to YAP-mediated intestinal regeneration and tumorigenesis is poorly defined. Here we report a stroma-epithelia YAP signaling axis essential for stromal cells to modulate epithelial cell growth during intestinal regeneration and tumorigenesis. Specifically, upon inflammation and in cancer, an oncogenic transcription factor ETS1 in stromal cells induces expression of a secreted protein ISLR that can directly binds to a transmembrane protocadherin FAT1 on the surface of epithelial cells. This binding suppressed the Hippo signaling by disrupting MST1-FAT1 association, resulting in YAP signaling activation. Deletion of Islr in stromal cells in mice markedly impaired intestinal regeneration, and suppressed tumorigenesis in the colon. Moreover, the expression of stromal cell-specific ISLR and ETS1 significantly increased in inflamed mucosa of human IBD patients and in human colorectal adenocarcinoma, accounting for the epithelial YAP hyperactivation. Collectively, our findings uncovered a molecular mechanism governing signals for communication between stroma and epithelium during tissue regeneration and tumorigenesis.

cancer biology↗

bioRxiv2017

An evidence-based approach to globally assess the covariate-dependent effect of MTHFR SNP rs1801133 on plasma homocysteine: a systematic review and meta-analysis

BackgroundThe single nucleotide polymorphism (SNP) of the gene Methylenetetrahydrofolate Reductase (MTHFR) C677T (or rs1801133) is the most established genetic factor that increases plasma total homocysteine (tHcy) and consequently results in hyperhomocysteinemia. Yet given the limited penetrance of this genetic variant, it is necessary to individually predict the risk of hyperhomocysteinemia for a rs1801133 carrier.\n\nObjectiveWe hypothesized that variability of this genetic risk is largely due to the presence of factors (covariates) that serve as effect modifiers and/or confounders, such as folic acid (FA) intake, and aimed to assess this risk in the complex context of these covariates.\n\nDesignWe systematically extracted from published studies the data of tHcy, rs1801133, and any previously reported rs1801133 covariates. The resulting meta-dataset was first used to analyze the covariates modifying effect by meta regression and other statistical means. Subsequently, we stratified tHcy data by the rs1801133 genotypes and analyzed under each genotype the variability of the risk resulted from the covariates confounding.\n\nResultsThe dataset contains data of 36 rs1801133 covariates that were collected from 114,448 subjects and 249 qualified studies, among which 6 covariates (sex, age, race, FA intake, smoking, and alcohol consumption) are the most frequently informed and therefore included for statistical analysis. The effect of rs1801133 on tHcy exhibits significant variability that can be attributed to effect modification and, to a larger degree, confounding by these covariates. Via statistical modeling, we predicted the covariate-dependent risk of tHcy elevation and hyperhomocysteinemia in a systematic manner.\n\nConclusionswe demonstrated an evidence-based approach that globally assesses the covariate-dependent effect of rs1801133 on tHcy. The results should assist clinicians in interpreting the rs1801133 data from genetic testing for their patients. Such information is also important for the public that increasingly receives genetic data from commercial services without interpretation of its clinical relevance.

genetics↗

bioRxiv2017

Deubiquitylation and stabilization of p21 by USP11 is critical for cell cycle progression and DNA damage responses

p21WAF1/CIP1 is a broad-acting cyclin-dependent kinase inhibitor. Its stability is essential for proper cell cycle progression and cell fate decision. Ubiquitylation by the multiple E3 ubiquitin ligases complex is the major regulatory mechanism of p21, which induces p21 degradation. However, it is unclear whether ubiquitylated p21 can be recycled. In this study, we report USP11 as a deubiquitylase of p21. In the nucleus, USP11 binds to p21, catalyzes the removal of polyubiquitin chains conjugated onto p21 and stabilizes p21 protein. As a result, USP11 reverses p21 polyubiquitylation and degradation mediated by SCFSKP2, CRL4CDT2 and APC/CCDT20 in a cell cycle-independent manner. Loss of USP11 causes the destabilization of p21 and induces the G1/S transition in unperturbed cells. Furthermore, p21 accumulation mediated by DNA damage is completely abolished in cells depleted of USP11, which results in abrogation of the G2 checkpoint and induction of apoptosis. Functionally, USP11-mediated stabilization of p21 inhibits cell proliferation and tumorigenesis in vivo. These findings reveal an important mechanism by which p21 can be stabilized by direct deubiquitylation and pinpoint a crucial role of the USP11-p21 axis in regulating cell cycle progression and DNA damage responses.

cell biology↗