Biology subjects

He, Y.

Publications and source records attributed to He, Y..

At least 577 records · Page 32Linked to original sources

bioRxiv2020

Gesture's body orientation modulates the N400 during semantic integration of gesture and visual sentence

Body orientation of gesture entails social-communicative intention, and may thus influence how gestures are perceived and comprehended together with auditory speech during face-to-face communication. To date, despite the emergence of neuroscientific literature on the role of body orientation on hand action perception, limited studies have directly investigated the role of body orientation in the interaction between gesture and language. To address this research question, we carried out an EEG experiment presenting to participants (n=21) videos of frontal and lateral hand gestures of five-seconds (e.g., raising a hand), followed by visually presented sentences that are either congruent or incongruent with the hand gesture (e.g., the mountain is high/low...). All participants underwent a semantic-probe task, judging whether a target word is related or unrelated to the gesture-speech event. EEG results suggest that, during the perception phase of hand-gestures, while both frontal and lateral gestures elicited power decrease in both the alpha (8-12Hz) and the beta (16-24Hz) bands, lateral gestures elicited reduced power decrease in the beta band when compared with frontal gestures. For sentence comprehension, at the critical word whose meaning is congruent/incongruent with the gesture, frontal gestures elicited an N400 effect for gesture-sentence incongruency. More importantly, this incongruency effect was significantly reduced for lateral gestures. The findings suggest that body orientation plays a crucial role in gesture perception, and that its inferred social-communicative intention influences gesture-sentence semantic integration in an interactive manner.

neuroscience↗

bioRxiv2020

ACTB and GAPDH proteins appear at multiple positions of SDS-PAGE and may not be suitable for serving as reference genes for the protein level determination in such techniques as Western blotting

Most human genes can produce multiple protein isoforms that should appear at multiple positions of polyacrylamide gel electrophoresis (PAGE) with sodium dodecyl sulfate (SDS), but most published results of Western blotting show only one protein. We performed SDS-PAGE of proteins from several human cell lines, isolated the proteins at the 72-, 55-, 48-, 40-, and 26-kD positions, and used liquid chromatography and tandem mass spectrometry (LC-MS/MS) to determine the protein identities. Although ACTB and GAPDH are 41.7-kD and 36-kD proteins, respectively, LC-MS/MS identified peptides of ACTB and GAPDH at all of these SDS-PAGE positions, making us wonder whether they produce some unknown protein isoforms. The NCBI (National Center for Biotechnology Information, USA) database lists only one ACTB mRNA but five GAPDH mRNAs and one non-coding RNA. The five GAPDH mRNAs encode three protein isoforms, while our bioinformatic analysis identified a 17.6-kD isoform encoded by the non-coding RNA. All LC-MS/MS-identified GAPDH peptides at all positions studied are unique, but some of the identified ACTB peptides are shared by ACTC1, ACTBL2, POTEF, POTEE, POTEI, and POTEJ. ACTC1 and ACTBL2 belong to the ACT family with great similarities to ACTB in protein sequence, whereas the four POTEs are ACTB-containing chimeric genes with the C-terminus of their proteins highly similar to ACTB. These data collectively disqualify GAPDH and ACTB from serving as the reference genes for determination of the protein level in such techniques as Western blotting, a leading role these two genes have been playing for decades in the biomedical research.

molecular biology↗

bioRxiv2020

Epitope-based peptide vaccines predicted against novel coronavirus disease caused by SARS-CoV-2

The outbreak of the 2019 novel coronavirus (SARS-CoV-2) has infected thousands of people with a large number of deaths across 26 countries. The sudden appearance of the virus leads to the limited existing therapies for SARS-CoV-2. Therefore, vaccines and antiviral medicines are in desperate need. This study took immune-informatics approaches to identify B- and T-cell epitopes for surface glycoprotein (S) of SARS-CoV-2, followed by estimating their antigenicity and interactions with the human leukocyte antigen (HLA) alleles. We identified four B cell epitopes, two MHC class-I and nine MHC class-II binding T-cell epitopes, which showed highly antigenic features. Allergenicity, toxicity and physiochemical properties analysis confirmed the specificity and selectivity of epitopes. The stability and safety of epitopes were confirmed by digestion analysis. No mutations were observed in all the selected B- and T-cell epitopes across all isolates from different locations worldwide. Epitopes were thus identified and some of them can be potential candidates for vaccine development.

immunology↗

bioRxiv2020

Modality-specific dysfunctional neural processing of social and non-social information in schizophrenia

Schizophrenia is characterized by marked communication dysfunctions encompassing potential impairments in the processing of social-abstract and non-social-concrete information, especially in everyday situations where multiple modalities are present in the form of speech and gesture. To date, the neurobiological basis of these deficits remains elusive. In a functional magnetic resonance imaging (fMRI) study, 17 patients with schizophrenia or schizoaffective disorder, and 18 matched controls watched videos of an actor speaking, gesturing (unimodal), and both speaking and gesturing (bimodal) about social or non-social events in a naturalistic way. Participants were asked to judge whether each video contains person-related (social) or object-related (non-social) information. When processing social-abstract content, patients showed reduced activation in the medial prefrontal cortex (mPFC) only in the gesture but not in the speech condition. For non-social-concrete content, remarkably, reduced neural activation for patients in the left postcentral gyrus and the right insula was observed only in the speech condition. Moreover, in the bimodal conditions, patients displayed improved task performance and comparable activation to controls in both social and non-social content. To conclude, patients with schizophrenia displayed modality-specific aberrant neural processing of social and non-social information, which is not present for the bimodal conditions. This finding provides novel insights into dysfunctional multimodal communication in schizophrenia, and may have potential therapeutic implications.

neuroscience↗

bioRxiv2020

Selective germline genome edited pigs and their long immune tolerance in Non Human Primates

Organ transplantation is the only curative treatment for patients with terminal organ failure, however, there is a worldwide organ shortage. Genetically modified pig organs and tissues have become an attractive and practical alternative solution for the severe organ shortage, which has been made possible by significant progress in xenotransplantation in recent years. The past several decades witnessed an expanding list of genetically engineered pigs due to technology advancements, however, the necessary combination of genetic modifications in pig for human organ xenotransplantation has not been determined. In the current study, we created a selective germline genome edited pig (SGGEP). The first triple xenoantigens (GGTA, B4GAL, and CAMH) knockout somatic cells were generated to serve as a prototype cells and then human proteins were expressed in the xenoantigen knockout cells, which include human complement system negative regulatory proteins (CD46, CD55, and CD59); human coagulation system negative regulatory proteins thrombomodulin (THBD); tissue factor pathway inhibitor (TFPI); CD39; macrophage negative regulatory proteins (human CD47); and natural killer cell negative regulatory human HLA-E. After the successful establishment of SGGEP by the nuclear tranfer, we engrafted SGGEP skin to NHP, up to 25 days graft survival without immunosuppressive drugs was observed. Because a pig skin graft does not impact the success of a subsequent allograft or autograft or vice versa, thus our SGGEP could have a great potential for clinical value to save severe and large area burn patients and the other human organ failure. Therefore, this combination of specific gene modifications is a major milestone and provides proof of concept to initiate investigator-initiated clinical trials (IITs) in severe burn patients with defined processes and governance measures in place and the other clinical application.

synthetic biology↗

bioRxiv2020

Single-cell mapping reveals new markers and functions of lymphatic endothelial cells in lymph nodes

Lymph nodes (LNs) are highly organized secondary lymphoid organs that mediate adaptive immune responses to antigens delivered via afferent lymphatic vessels. Lymphatic endothelial cells (LECs) line intranodal lymphatic sinuses and organize lymph and antigen distribution. LECs also directly regulate T cells, mediating peripheral tolerance to self-antigens, and play a major role in many diseases including cancer metastasis. However, little is known about the phenotypic and functional heterogeneity of LN LECs. Using single-cell RNA sequencing, we comprehensively defined the transcriptome of LECs in murine skin-draining LNs, and identified new markers and functions of distinct LEC subpopulations. We found that LECs residing in the subcapsular sinus have an unanticipated function in scavenging of modified LDL and also identified a specific cortical LEC subtype implicated in rapid lymphocyte egress from LNs. Our data provide new insights into the diversity of LECs in murine lymph nodes and a rich resource for future studies into the regulation of immune responses by lymph node LECs.

immunology↗

bioRxiv2020

The predictive power of the microbiome exceeds that of genome-wide association studies in the discrimination of complex human disease

Over the past decade, studies of the human genome and microbiome have deepened our understanding of the connections between human genes, environments, microbes, and disease. For example, the sheer number of indicators of the microbiome and human genetic common variants associated with disease has been immense, but clinical utility has been elusive. Here, we compared the predictive capabilities of the human microbiome versus human genomic common variants across 13 common diseases. We concluded that microbiomic indicators outperform human genetics in predicting host phenotype (overall Microbiome-Association-Study [MAS] area under the curve [AUC] = 0.79 [SE = 0.03], overall Genome-Wide-Association-Study [GWAS] AUC = 0.67 [SE = 0.02]). Our results, while preliminary and focused on a subset of the totality of disease, demonstrate the relative predictive ability of the microbiome, indicating that it may outperform human genetics in discriminating human disease cases and controls. They additionally motivate the need for population-level microbiome sequencing resources, akin to the UK Biobank, to further improve and reproduce metagenomic models of disease.

bioinformatics↗

bioRxiv2019

The mechanosensitive Piezo1 orchestrating angiogenesis is essential in bone fracture repair

Mechanical ion channel protein Piezo1 play vital roles in angiogenesis which has been proved to be high importance in varieties of biological processes. Bone formation in the fracture repair requires oxygen and nutrients from new blood vessels generated from fractured lesion. Understanding the underlying mechanisms linking angiogenesis and bone formation must be of great value for improved fracture healing. Here we employed mice with genetically modified endothelial specific depletion of Piezo1 channels to explore the hypothesis that Piezo1 is vital to the initiation of fracture healing. In this study, we demonstrated that Piezo1 expression and wide distribution along the bone and impaired endothelial Piezo1 channels result in derangements in bone fracture repair. Intriguingly, the calcium activated proteolytic caplain activity severely disrupted during vascularization, precluded osteoblast maturation and mineralization and subsequently the phosphorylated PI3K-AKT reduction. Furthermore, Piezo1 endothelial disruption impaired Notch signaling in bone union. These data collectively suggest that Piezo1 channels serve as a basis for clinical strategies to improve bone regeneration and treat delayed or nonunion in bone fracture.

systems biology↗

bioRxiv2019

A big-data approach to understanding metabolic rate and response to obesity in laboratory mice

Maintaining a healthy body weight requires an exquisite balance between energy intake and energy expenditure. In humans and in laboratory mice these factors are experimentally measured by powerful and sensitive indirect calorimetry devices. To understand the genetic and environmental factors that contribute to the regulation of body weight, an important first step is to establish the normal range of metabolic values and primary sources contributing to variability in results. Here we examine indirect calorimetry results from two experimental mouse projects, the Mouse Metabolic Phenotyping Centers and International Mouse Phenotyping Consortium to develop insights into large-scale trends in mammalian metabolism. Analysis of nearly 10,000 wildtype mice revealed that the largest experimental variances are consequences of institutional site. This institutional effect on variation eclipsed those of housing temperature, body mass, locomotor activity, sex, or season. We do not find support for the claim that female mice have greater metabolic variation than male mice. An analysis of these factors shows a normal distribution for energy expenditure in the phenotypic analysis of 2,246 knockout strains and establishes a reference for the magnitude of metabolic changes. Using this framework, we examine knockout strains with known metabolic phenotypes. We compare these effects with common environmental challenges including age, and exercise. We further examine the distribution of metabolic phenotypes exhibited by knockout strains of genes corresponding to GWAS obesity susceptibility loci. Based on these findings, we provide suggestions for how best to design and conduct energy balance experiments in rodents, as well as how to analyze and report data from these studies. These recommendations will move us closer to the goal of a centralized physiological repository to foster transparency, rigor and reproducibility in metabolic physiology experimentation.

physiology↗

bioRxiv2019

Poly-Exposure and Poly-Genomic Scores Implicate Prominent Roles of Non-Genetic and Demographic Factors in Four Common Diseases in the UK

While polygenic risk scores (PRSs) have been shown to identify a small number of individuals with increased clinical risk for several common diseases, non-genetic factors that change during a lifetime, such as lifestyle, employment, diet, and pollution, have a larger role in clinical prediction. We analyzed data from 459,613 participants of the UK Biobank to investigate the independent and combined roles of demographics (e.g., sex and age), 96 environmental exposures, and common genetic variants in atrial fibrillation, coronary artery disease, inflammatory bowel disease, and type 2 diabetes. We develop an additive modelling approach to estimate and validate a poly-exposure score (PXS) that goes beyond consideration of a handful of factors such as smoking and pollution. PXS is able to identify groups with high prevalence of the four common disease comparable to, if not better, than the PRS. Type 2 diabetes has the largest discrepancy in PXS and PRS performance, defined as the maximum area under the receiver-operator curve (AUC) (PXS AUC of 0.828 [0.821-0.836], PRS AUC of 0.711 [0.702-0.720]). Most importantly, we show that PXS identifies individuals that have low genetic risk but high overall risk for disease. While PRS is useful for screening genetically exceptional individuals in a time-invariant way, broader consideration of multiple non-genetic and modifiable factors is required to fully translate risk scores to the bedside for precision medicine. All results and the PXS calculator can be found in our web application http://apps.chiragjpgroup.org/pxs/.

bioinformatics↗

bioRxiv2019

A Multimodal and Integrated Approach to Interrogate Human Kidney Biopsies with Rigor and Reproducibility: The Kidney Precision Medicine Project

Comprehensive and spatially mapped molecular atlases of organs at a cellular level are a critical resource to gain insights into pathogenic mechanisms and personalized therapies for diseases. The Kidney Precision Medicine Project (KPMP) is an endeavor to generate 3-dimensional (3D) molecular atlases of healthy and diseased kidney biopsies using multiple state-of-the-art OMICS and imaging technologies across several institutions. Obtaining rigorous and reproducible results from disparate methods and at different sites to interrogate biomolecules at a single cell level or in 3D space is a significant challenge that can be a futile exercise if not well controlled. We describe a "follow the tissue" pipeline for generating a reliable and authentic single cell/region 3D molecular atlas of human adult kidney. Our approach emphasizes quality assurance, quality control, validation and harmonization across different OMICS and imaging technologies from sample procurement, processing, storage, shipping to data generation, analysis and sharing. We established benchmarks for quality control, rigor, reproducibility and feasibility across multiple technologies through a pilot experiment using common source tissue that was processed and analyzed at different institutions and different technologies. A peer review system was established to critically review quality control measures and the reproducibility of data generated by each technology before being approved to interrogate clinical biopsy specimens. The process established economizes the use of valuable biopsy tissue for multi-OMICS and imaging analysis with stringent quality control to ensure rigor and reproducibility of results and serves as a model for precision medicine projects across laboratories, institutions and consortia.

scientific communication and education↗

bioRxiv2019

MicroRNA-148a Regulates Low-Density Lipoprotein Metabolism by Repressing the (Pro)renin Receptor

High plasma LDL cholesterol (LDL-c) concentration is a major risk factor for atherosclerosis. Hepatic LDLR regulates LDL metabolism, and thereby plasma LDL-c concentration. Recently, we identified the (pro)renin receptor [(P)RR] as a novel regulator of LDL metabolism, which regulates LDLR degradation and hence its protein abundance and activity. In silicon analysis suggests that the (P)RR is a target of miR-148a. In this study we determined whether miR-148a could regulate LDL metabolism by regulating (P)RR expression in HepG2 and Huh7 cells. We found that miR-148a suppressed (P)RR expression by binding to the 3-untranslated regions (3-UTR) of (P)RR mRNA. Mutating the binding sites for miR-148a in the 3-UTR of (P)RR mRNA abolished the inhibitory effects of miR-148a on (P)RR expression. In line with our recent findings, reduced (P)RR expression resulted in decreased cellular LDL uptake, likely as a consequence of decreased LDLR protein abundance. Overexpressing the (P)RR prevented miR-148a-induced reduction in LDLR abundance and cellular LDL uptake. Our study supports a new concept that miR-148a is a regulator of (P)RR expression. By reducing (P)RR abundance, miR-148a decreases LDLR protein abundance and consequently cellular LDL uptake.

molecular biology↗

bioRxiv2019

GmPTF1 Modifies Root Architecture Responses to Phosphate Starvation in Soybean

Though root architecture modifications may be critically important for improving phosphorus (P) efficiency in crops, the regulatory mechanisms triggering these changes remain unclear. In this study, we demonstrate that genotypic variation in GmEXPB2 expression is strongly correlated with root elongation and P acquisition efficiency, and enhancing its transcription significantly improves soybean yield in the field. Promoter deletion analysis was performed using six 5 truncation fragments (P1-P6) of GmEXPB2 fused with the GUS reporter gene in transgenic hairy roots, which revealed that the P1 segment containing 3 E-box elements significantly enhances induction of gene expression in response to phosphate (Pi) starvation. Further experimentation demonstrated that GmPTF1, a bHLH transcription factor, is the regulatory factor responsible for the induction of GmEXPB2 expression in response to Pi starvation. In short, Pi starvation induced expression of GmPTF1, with the GmPTF1 product not only directly binding the E-box motif in the P1 region of the GmEXPB2 promoter, but also activating GUS expression in a dosage dependent manner. Further work with soybean transgenic composite plants showed that, altering GmPTF1 expression significantly impacted GmEXPB2 transcription, and thereby affected root growth, biomass and P uptake. Taken together, this work identifies a novel regulatory factor, GmPTF1, involved in changing soybean root architecture through regulation the expression of GmEXPB2. These findings contribute to understanding the molecular basis of root architecture modifications in response to P deficiency, and, in the process, suggest candidate genes and a promoter region to target for improving soybean yield through molecular breeding of P efficiency. One Sentence SummaryThe bHLH transcription factor GmPTF1 regulates the expression of {beta}-expansin gene GmEXPB2 to modify root architecture, and thus promote phosphate acquisition, and biomass in soybean.

physiology↗

bioRxiv2019

PHYTOCHROME INTERACTING FACTORs trigger environmentally responsive chromatin dynamics

The pivotal interplay between light receptors and PHYTOCHROME INTERACTING FACTORs (PIFs) serves as an essential regulatory hub that perceives and integrates environmental cues into the plants transcriptional networks. A critical control component of environmentally-responsive gene networks is the histone variant H2A.Z which provides transcriptional plasticity and prevents undesired gene activation. However, the functional relationship between PIF transcription factors and H2A.Z is only poorly understood. Here, we describe a genomic approach that utilizes the rapid and reversible light-mediated manipulation of PIF7 activity to visualize PIF7 DNA binding and H2A.Z occupancy kinetics. Strikingly, PIFs shape the H2A.Z landscape in a light quality-dependent manner. In addition, we observed that PIFs initiate H2A.Z eviction through direct interaction with EIN6 ENHANCER (EEN), a subunit of INO80 chromatin remodeling complex. These studies uncover a previously unknown PIF-INO80 regulatory module controlling plant growth in response to rapid environmental changes.\n\nOne-sentence summaryA PIF-INO80 module controls light quality-dependent H2A.Z dynamics.

genomics↗

bioRxiv2019

A complex structure of arrestin-2 bound to a G protein-coupled receptor

Arrestins comprise a family of signal regulators of G-protein-coupled receptors (GPCRs), which include arrestins 1 to 4. While arrestins 1 and 4 are visual arrestins dedicated to rhodopsin, arrestins 2 and 3 (Arr2 and Arr3) are {beta}-arrestins known to regulate many nonvisual GPCRs. The dynamic and promiscuous coupling of Arr2 to nonvisual GPCRs has posed technical challenges to tackle the basis of arrestin binding to GPCRs. Here we report the structure of Arr2 in complex with neurotensin receptor 1 (NTSR1), which reveals an overall assembly that is strikingly different from the visual arrestin-rhodopsin complex by a 90{degrees} rotation of Arr2 relative to the receptor. In this new configuration, intracellular loop 3 (ICL3) and transmembrane helix 6 (TM6) of the receptor are oriented toward the N-terminal domain of the arrestin, making it possible for GPCRs that lack the C-terminal tail to couple Arr2 through their ICL3. Molecular dynamics simulation and crosslinking data further support the assembly of the Arr2-NTSR1 complex. Sequence analysis and homology modeling suggest that the Arr2-NTSR1 complex structure may provide an alternative template for modeling arrestin-GPCR interactions.

biophysics↗

bioRxiv2019

Predicting the fMRI signal fluctuation with echo-state neural networks trained on vascular network dynamics

Resting-state functional MRI (rs-fMRI) studies have revealed specific low-frequency hemodynamic signal fluctuations (<0.1 Hz) in the brain, which could be related to oscillations in neural activity through several mechanisms. Although the vascular origin of the fMRI signal is well established, the neural correlates of global rs-fMRI signal fluctuations are difficult to separate from other confounding sources. Recently, we reported that single-vessel fMRI slow oscillations are directly coupled to brain state changes. Here, we used an echo-state network (ESN) to predict the future temporal evolution of the rs-fMRI slow oscillatory feature from both rodent and human brains. rs-fMRI signals from individual blood vessels that were strongly correlated with neural calcium oscillations were used to train an ESN to predict brain state-specific rs-fMRI signal fluctuations. The ESN-based prediction model was also applied to recordings from the Human Connectome Project (HCP), which classified variance-independent brain states based on global fluctuations of rs-fMRI features. The ESN revealed brain states with global synchrony and decoupled internal correlations within the default-mode network.

neuroscience↗

bioRxiv2019

Cryo-electron microscopy structure of a nucleosome-bound SWI/SNF chromatin remodeling complex

The multi-subunit chromatin remodeling complex SWI/SNF1-3 is highly conserved from yeast to humans and plays critical roles in various cellular processes including transcription and DNA damage repair4, 5. It uses the energy from ATP hydrolysis to remodel chromatin structure by sliding and evicting the histone octamer6-10, creating DNA regions that become accessible to other essential protein complexes. However, our mechanistic understanding of the chromatin remodeling activity is largely hindered by the lack of a high-resolution structure of any complex from this family. Here we report the first structure of SWI/SNF from the yeast S. cerevisiae bound to a nucleosome at near atomic resolution determined by cryo-electron microscopy (cryo-EM). In the structure, the Arp module is sandwiched between the ATPase and the Body module of the complex, with the Snf2 HSA domain connecting all modules. The HSA domain also extends into the Body and anchors at the opposite side of the complex. The Body contains an assembly scaffold composed of conserved subunits Snf12 (SMARCD/BAF60), Snf5 (SMARCB1/BAF47/ INI1) and an asymmetric dimer of Swi3 (SMARCC/BAF155/170). Another conserved subunit Swi1 (ARID1/BAF250) folds into an Armadillo (ARM) repeat domain that resides in the core of the SWI/SNF Body, acting as a molecular hub. In addition to the interaction between Snf2 and the nucleosome, we also observed interactions between the conserved Snf5 subunit and the histones at the acidic patch, which could serve as an anchor point during active DNA translocation. Our structure allows us to map and rationalize a subset of cancer-related mutations in the human SWI/SNF complex and propose a model of how SWI/SNF recognizes and remodels the +1 nucleosome to generate nucleosome-depleted regions during gene activation11-13.

molecular biology↗

bioRxiv2019

Paralytic, the Drosophila voltage-gated sodium channel, regulates proliferation of neural progenitors

Proliferating cells, typically considered \"non-excitable,\" nevertheless exhibit regulation by bioelectrical signals. Notably, voltage-gated sodium channels (VGSC) that are crucial for neuronal excitability, are also found in progenitors and upregulated in cancer. Here, we identify a role for VGSC in proliferation of Drosophila neuroblast (NB) lineages within the central nervous system. Loss of paralytic (para), the sole gene that encodes Drosophila VGSC, reduces neuroblast progeny cell number. The type II neuroblast lineages, featuring a transit-amplifying intermediate neural progenitors (INP) population similar to that found in the developing human cortex, are particularly sensitive to para manipulation. Following a series of asymmetric divisions, INPs normally exit the cell cycle through a final symmetric division. Our data suggests that loss of para induces apoptosis in this population, whereas overexpression leads to an increase in INPs and overall neuroblast progeny cell numbers. These effects are cell autonomous and depend on Para channel activity. Reduction of Para not only affects normal NB development, but also strongly suppresses brain tumor mass, implicating a role for Para in cancer progression. To our knowledge, our studies are the first to identify a role for VGSC in neural progenitor proliferation. Elucidating the contribution of VGSC in proliferation will advance our understanding of bioelectric signaling within development and disease states.

developmental biology↗