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Hu, B.

Publications and source records attributed to Hu, B..

At least 163 records · Page 9Linked to original sources

Epigenome dysregulation resulting from NSD1 mutation in head and neck squamous cell carcinoma

Epigenetic dysregulation has emerged as an important mechanism of oncogenesis. To develop targeted treatments, it is important to understand the epigenetic and transcriptomic consequences of mutations in epigenetic modifier genes. Recently, mutations in the histone methyltransferase gene NSD1 have been identified in a subset of head and neck squamous cell carcinomas (HNSCCs) - one of the most common and deadly cancers. Here, we use whole (epi)genome approaches and genome editing to dissect the downstream effects of loss of NSD1 in HNSCC. We demonstrate that NSD1 mutations are directly responsible for loss of intergenic H3K36me2 domains, followed by loss of DNA methylation, and gain of H3K27me3 in the affected genomic regions. We further show that those regions are enriched in cis-regulatory elements and that subsequent loss of H3K27ac correlates with reduced expression of their target genes. Our analysis identifies genes and pathways affected by the loss of NSD1 and paves the way to further understanding the interplay among chromatin modifications in cancer.

genomics↗

Origin and cross-species transmission of bat coronaviruses in China

Bats are presumed reservoirs of diverse coronaviruses (CoVs) including progenitors of Severe Acute Respiratory Syndrome (SARS)-CoV and SARS-CoV-2, the causative agent of COVID-19. However, the evolution and diversification of these coronaviruses remains poorly understood. We used a Bayesian statistical framework and sequence data from all known bat-CoVs (including 630 novel CoV sequences) to study their macroevolution, cross-species transmission, and dispersal in China. We find that host-switching was more frequent and across more distantly related host taxa in alpha-than beta-CoVs, and more highly constrained by phylogenetic distance for beta-CoVs. We show that inter-family and -genus switching is most common in Rhinolophidae and the genus Rhinolophus. Our analyses identify the host taxa and geographic regions that define hotspots of CoV evolutionary diversity in China that could help target bat-CoV discovery for proactive zoonotic disease surveillance. Finally, we present a phylogenetic analysis suggesting a likely origin for SARS-CoV-2 in Rhinolophus spp. bats.

evolutionary biology↗

Neuronal and glial 3D chromatin architecture illustrates cellular etiology of brain disorders

Cellular heterogeneity in the human brain obscures the identification of robust cellular regulatory networks. Here we integrated genome-wide chromosome conformation in purified neurons and glia with transcriptomic and enhancer profiles to build the gene regulatory landscape of two major cell classes in the human brain. Within glutamatergic and GABAergic neurons, we were able to link enhancers to their cognate genes via neuronal chromatin interaction profiles. These cell-type-specific regulatory landscapes were then leveraged to gain insight into the cellular etiology of several brain disorders. We found that Alzheimers disease (AD)-associated epigenetic dysregulation was linked to neurons and oligodendrocytes, whereas genetic risk factors for AD highlighted microglia as a central cell type, suggesting that different cell types may confer risk to the disease via different genetic mechanisms. Moreover, neuronal subtype-specific annotation of genetic risk factors for schizophrenia and bipolar disorder identified shared (parvalbumin-expressing interneurons) and distinct cellular etiology (upper layer neurons for bipolar and deeper layer projection neurons for schizophrenia) between these two closely related psychiatric illnesses. Collectively, these findings shed new light on cell-type-specific gene regulatory networks in brain disorders.

neuroscience↗

Evolutionary arms race between virus and host drives genetic diversity in bat SARS related coronavirus spike genes

The Chinese horseshoe bat (Rhinolophus sinicus), reservoir host of severe acute respiratory syndrome coronavirus (SARS-CoV), carries many bat SARS-related CoVs (SARSr-CoVs) with high genetic diversity, particularly in the spike gene. Despite these variations, some bat SARSr-CoVs can utilize the orthologs of human SARS-CoV receptor, angiotensin-converting enzyme 2 (ACE2), for entry. It is speculated that the interaction between bat ACE2 and SARSr-CoV spike proteins drives diversity. Here, we have identified a series of R. sinicus ACE2 variants with some polymorphic sites involved in the interaction with the SARS-CoV spike protein. Pseudoviruses or SARSr-CoVs carrying different spike proteins showed different infection efficiency in cells transiently expressing bat ACE2 variants. Consistent results were observed by binding affinity assays between SARS- and SARSr-CoV spike proteins and receptor molecules from bats and humans. All tested bat SARSr-CoV spike proteins had a higher binding affinity to human ACE2 than to bat ACE2, although they showed a 10-fold lower binding affinity to human ACE2 compared with their SARS-CoV counterpart. Structure modeling revealed that the difference in binding affinity between spike and ACE2 might be caused by the alteration of some key residues in the interface of these two molecules. Molecular evolution analysis indicates that these residues were under strong positive selection. These results suggest that the SARSr-CoV spike protein and R. sinicus ACE2 may have coevolved over time and experienced selection pressure from each other, triggering the evolutionary arms race dynamics. It further proves that R. sinicus is the natural host of SARSr-CoVs. ImportanceEvolutionary arms race dynamics shape the diversity of viruses and their receptors. Identification of key residues which are involved in interspecies transmission is important to predict potential pathogen spillover from wildlife to humans. Previously, we have identified genetically diverse SARSr-CoV in Chinese horseshoe bats. Here, we show the highly polymorphic ACE2 in Chinese horseshoe bat populations. These ACE2 variants support SARS- and SARSr-CoV infection but with different binding affinity to different spike proteins. The higher binding affinity of SARSr-CoV spike to human ACE2 suggests that these viruses have the capacity of spillover to humans. The positive selection of residues at the interface between ACE2 and SARSr-CoV spike protein suggests a long-term and ongoing coevolutionary dynamics between them. Continued surveillance of this group of viruses in bats is necessary for the prevention of the next SARS-like disease.

microbiology↗

Closure motif-mediated state changes of the HORMA protein ASY1

Meiotic HORMA domain-containing proteins (HORMADs) are key components of the chromosome axis and play an essential role in meiosis in many organisms. The meiotic HORMADs, including yeast Hop1, mouse HORMAD1 and HORMAD2, and Arabidopsis ASY1, assemble along chromosomes at early prophase and the closure motif at their C-termini has been hypothesized to be instrumental for this step by promoting HORMAD oligomerization. In late prophase, ASY1 and its homologs are progressively removed from synapsed chromosomes promoting chromosome synapsis and recombination. The conserved AAA+ ATPase PCH2/TRIP13 has been intensively studied for its role in removing HORMADs from synapsed chromosomes. In contrast, not much is known about how HORMADs are loaded onto chromosomes. Here, we reveal that the PCH2-mediated dissociation of the HORMA domain of ASY1 from its closure motif is important for the nuclear targeting and subsequent chromosomal loading of ASY1. This indicates that the promotion of ASY1 to an unlocked state is a prerequisite for its nuclear localization and chromosomal assembly. Likewise, we find that the closure motif is also necessary for the removal of ASY1 by PCH2 later in prophase. Our work results in a grand unified model for PCH2 and HORMADs function in meiosis.

cell biology↗

Neuroimaging Correlates of Emotional Response-Inhibition Discriminate Between Young Depressed Adults With and Without Sub-threshold Bipolar Symptoms

BackgroundA significant number of subjects with major depression (MDD) exhibit subthreshold mania symptoms (MDD+). This study investigated, for the first time, using emotional inhibition tasks, whether the neurobiology of MDD+ subjects is more akin to bipolar disorder depression (BDD) or to MDD subjects without any subthreshold bipolar symptoms (MDD-). MethodThis study included 118 medication-free young adult subjects (16 - 30 yrs.): 20 BDD, 28 MDD+, 41 MDD-, and 29 HC subjects. Participants underwent fMRI during emotional and non-emotional Go/No-go tasks during which they responded for Go stimuli and inhibited response for happy, fear, emotional (happy + fear) and non-emotional (gender) faces No-go stimuli. Linear mixed effects (LME) analysis for group effects and Gaussian Process Classifier (GPC) analyses was conducted. ResultsMDD- group compared to both the BDD and MDD+ groups, exhibited significantly lower activation in parietal, temporal and frontal regions (cluster-wise corrected p <0.05) for emotional inhibition conditions vs. non-emotional condition. No significant differences were found between BDD and MDD+ groups. GPC classification of emotional vs non-emotional response-inhibition activation pattern showed good discrimination between BDD and MDD- subjects (AUC: 0.70; balanced accuracy: 70% (p = 0.006)) as well as MDD+ and MDD- subjects (AUC: 0.72; balanced accuracy: 67% (p = 0.015)) but less efficient discrimination between BDD and MDD+ groups (AUC: 0.68; balanced accuracy: 61% (p = 0.091)). Notably, classification of the MDD- group was weighted for left amygdala activation pattern. ConclusionUsing an fMRI emotional Go-Nogo task, MDD- subjects can be discriminated from BDD subjects and MDD+.

neuroscience↗

Sessile bacterium unlocks ability of surface motility through mutualistic interspecies interaction

In addition to their common planktonic lifestyle, bacteria frequently live in surface-associated habitats. Surface motility is essential for exploring these habitats for food sources. However, many bacteria are found on surfaces, even though they lack features required for migrating along surfaces. How these canonical non-motile bacteria adapt to the environmental fluctuations on surfaces remains unknown. Recently, several cases of interspecies interaction were reported that induce surface motility of non-motile bacteria either by using hitchhiking strategies or through social spreading mechanisms. Here, we report a previously unknown mechanism for interaction-dependent surface motility of the canonical non-motile bacterium, Dietzia sp. DQ12-45-1b, which is induced by interaction with a dimorphic prosthecate bacterium, Glycocaulis alkaliphilus 6B-8T. Dietzia cells exhibits "sliding"-like motility in an area where the strain Glycocaulis cells was pre-colonized with a sufficient density. Furthermore, we show that biosurfactants play a critical role in inducing the surface motility of Dietzia cells. Our analysis also demonstrates that Dietzia degrade n-alkanes and provide Glycocaulis with the resulting metabolites for survival, which in turn enabled directional migration of Dietzia towards nutrients in the environment. Such interaction-dependent migration was also found between Dietzia and Glycocaulis strains isolated from other habitats, suggesting that this mutualistic relationship ubiquitously occurs in natural environments. In conclusion, we propose a novel model for such a win-win strategy, whereby non-motile bacteria pay metabolites to dimorphic prosthecate bacteria in return for migrating to reach environments otherwise inaccessible. We propose that this mechanism represents a common strategy for canonically non-motile bacteria living on a surface. ImportanceCell motility provides a selective advantage for bacteria searching for nutrients. While a large body of evidence exists for how motile bacteria migrate on surface by virtue of different ways of motility, fewer studies concerned about how canonical non-motile bacteria adapted to those surface-associated habitats. Recent reports have proposed that interactions with other bacteria trigger the movement of those sessile bacteria. However, these interactions are limited to hitchhiking or social spreading modes. Here, we characterized a previously unknown interaction mode between Dietzia and Glycocaulis. This interaction differs from previously described modes, thus advance our limited understanding of how sessile bacteria move on surfaces. We propose that this interaction mode represents a win-win strategy for both strains, and this mode might be widely distributed across diverse environments. These novel insights should greatly assist in understanding the mechanisms responsible for the cellular interplay between microbes in complex microbiomes.

microbiology↗

Multiscale three-dimensional pathology findings of COVID-19 diseased lung using high-resolution cleared tissue microscopy

The study of pulmonary samples from individuals who have died as a direct result of COVID-19 infection is vital to our understanding of the pathogenesis of this disease. Histopathologic studies of lung tissue from autopsy of patients with COVID-19 specific mortality are only just emerging. All existing reports have relied on traditional 2-dimensional slide-based histological methods for specimen preparation. However, emerging methods for high-resolution, massively multiscale imaging of tissue microstructure using fluorescence labeling and tissue clearing methods enable the acquisition of tissue histology in 3-dimensions, that could open new insights into the nature of SARS-Cov-2 infection and COVID-19 disease processes. In this article, we present the first 3-dimensional images of lung autopsy tissues taken from a COVID-19 patient, including 3D "virtual histology" of cubic-millimeter volumes of the diseased lung, providing unique insights into disease processes contributing to mortality that could inform frontline treatment decisions.

pathology↗

Immunity-and-Matrix-Regulatory Cells Derived from Human Embryonic Stem Cells Safely and Effectively Treat Mouse Lung Injury and Fibrosis

Lung injury and fibrosis represent the most significant outcomes of severe and acute lung disorders, including COVID-19. However, there are still no effective drugs to treat lung injury and fibrosis. In this study, we report the generation of clinical-grade human embryonic stem cells (hESCs)-derived immunity- and matrix-regulatory cells (IMRCs) produced under good manufacturing practice (GMP) requirements, that can treat lung injury and fibrosis in vivo. We generate IMRCs by sequentially differentiating hESCs with serum-free reagents. IMRCs possess a unique gene expression profile distinct from umbilical cord mesenchymal stem cells (UCMSCs), such as higher levels of proliferative, immunomodulatory and anti-fibrotic genes. Moreover, intravenous delivery of IMRCs inhibits both pulmonary inflammation and fibrosis in mouse models of lung injury, and significantly improves the survival rate of the recipient mice in a dose-dependent manner, likely through paracrine regulatory mechanisms. IMRCs are superior to both primary UCMSCs and FDA-approved pirfenidone, with an excellent efficacy and safety profile in mice and monkeys. In light of public health crises involving pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), our findings suggest that IMRCs are ready for clinical trials on lung disorders.

cell biology↗

Pen-strep influence macrophage mechanical property and mechano-response to microenvironment

Penicillin-streptomycin (Pen-strep) is a common antibiotic used to prevent bacterial infection in cell culture and clinical treatment. Current research found pen-strep increased macrophage modulus but limited influence on cell adhesion. Phalloidin statin image indicates pen-strep mediate cell morphology on different extracellular matrix coated surface. The roundness analyzes further illustrated pen-strep promote cell spread on PDMS rubber, type I collagen, laminin, poly amino acid, poly-RGD peptides. Finally, YAP-1 and TAZ upregulation and {beta}1 integrin downregulation may be the causes of cell elasticity and mechano-response to extracellular matrix (ECM) change.

biophysics↗

Chandelier cell anatomy and function reveal a variably distributed but common signal

The activity and connectivity of inhibitory cells has a profound impact on the operation of neuronal networks. While the average connectivity of many inhibitory cell types has been characterized, we still lack an understanding of how individual interneurons distribute their synapses onto their targets and how heterogeneous the inhibition is onto different individual excitatory neurons. Here, we use large-scale volumetric electron microscopy (EM) and functional imaging to address this question for chandelier cells in layer 2/3 of mouse visual cortex. Using dense morphological reconstructions from EM, we mapped the complete chandelier input onto 153 pyramidal neurons. We find that the number of input synapses is highly variable across the population, but the variability is correlated with structural features of the target neuron: soma depth, soma size, and the number of perisomatic synapses received. Functionally, we found that chandelier cell activity in vivo was highly correlated and tracks pupil diameter, a proxy for arousal state. We propose that chandelier cells provide a global signal whose strength is individually adjusted for each target neuron. This approach, combining comprehensive structural analysis with functional recordings of identified cell types, will be a powerful tool to uncover the wiring rules across the diversity of cortical cell types.

neuroscience↗

Social interaction influences innate color preference of zebrafish shoals

The color discrimination can confer survival advantages by helping animals to find nutritious food and shelter and to avoid predator. Zebrafish as a social species, data on innate color preference in shoals remain controversial and there are limited data for this organism. Here we showed that, when given a choice among two color combinations (R-Y, R-G, Y-G, B-G, B-R, B-Y), shoals of zebrafish exhibited a complex pattern of color preference and the order of RYGB preference was R>Y>G, B>G. By contrast, the individual zebrafish showed marked changes, completely losing their preference for all the tested color combinations. To investigate the role of shoaling behavior in color preference, we selected a D1-receptor antagonist (SCH23390), which could disrupt social preference and decrease social interaction in zebrafish. Interestingly, the shoals that were treated by SCH23390 showed no color preference for all color combinations. Our findings indicate that social interaction is involved in color-driven behavior in zebrafish, and reveal the possible mechanisms that the dopaminergic system may contribute to innate color preference in shoals of zebrafish. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY Graphical Abstract C_FIG_DISPLAY

animal behavior and cognition↗

Adaptation supports short-term memory in a visual change detection task

The maintenance of short-term memories is critical for survival in a dynamically changing world. Previous studies suggest that this memory can be stored in the form of persistent neural activity or using a synaptic mechanism, such as with short-term plasticity. Here, we compare the predictions of these two mechanisms to neural and behavioral measurements in a visual change detection task. Mice were trained to respond to changes in a repeated sequence of natural images while neural activity was recorded using two-photon calcium imaging. We also trained two types of artificial neural networks on the same change detection task as the mice. Following fixed pre-processing using a pretrained convolutional neural network, either a recurrent neural network (RNN) or a feedforward neural network with short-term synaptic depression (STPNet) was trained to the same level of performance as the mice. While both networks are able to learn the task, the STPNet model contains units whose activity are more similar to the in vivo data and produces errors which are more similar to the mice. When images are omitted, an unexpected perturbation which was absent during training, mice often do not respond to the omission but are more likely to respond to the subsequent image. Unlike the RNN model, STPNet also produces a similar pattern of behavior. These results suggest that simple neural adaptation mechanisms may serve as an important bottom-up memory signal in this task, which can be used by downstream areas in the decision-making process. Author SummaryAnimals have to adapt to environments with rich dynamics and maintain multiple types of memories. In this study, we focus on a visual change detection task in mice which requires short-term memory. Learning which features need to be maintained in short-term memory can be realized in a recurrent neural network by changing connections in the network, resulting in memory maintenance through persistent activity. However, in biological networks, a large diversity of time-dependent intrinsic mechanisms are also available. As an alternative to persistent neural activity, we find that learning to make use of internal adapting dynamics better matches both the observed neural activity and behavior of animals in this simple task. The presence of a large diversity of temporal traces could be one of the reasons for the diversity of cells observed. We believe that both learning to keep representations of relevant stimuli in persistent activity and learning to make use of intrinsic time-dependent mechanisms exist, and their relative use will be dependent on the exact task.

neuroscience↗

Meta-analysis of the effects of sleep deprivation on depression in patients and animals

ObjectiveResearch on the antidepressant effects of sleep deprivation (SD) is lagging and has not produced completely uniform results in humans and animals. The present study aimed to reassess the effect of SD on patients and animals by meta-analysis based on updated research. MethodsWe searched PubMed, Embase and Cochrane Library for articles since the first relevant literature published up to June 10th, 2019. Data on sample characteristics, features of SD, and tests for depression were extracted. ResultsFourteen articles were included, eight on humans and six on animals. We found that when the duration of SD in patients was 7-14 days, it reflected antidepression [-1.52 (-2.07, -0.97); I2=19.6%]. In animals, the results of sucrose consumption experiments showed that SD has depressogenic effects [-1.06 (-1.63, -0.49); I2=81.1%], while the results of forced swimming experiments showed that SD treated depression [-1.17 (-2.19, -0.16); I2=80.1%], regardless of the duration of sleep deprivation. ConclusionSD can be an effective antidepressant measure when the duration is 7-14 days in patients. In animal studies, SD has shown more antidepressant effects when measured by forced swimming experiments, whereas using sucrose consumption tests had the effect of worsening depression.

neuroscience↗

Suppression of Inflammation Delays Hair Cell Regeneration and Functional Recovery Following Lateral Line Damage in Zebrafish Larvae

BackgroundHuman cochlear hair cells cannot spontaneously regenerate after loss. In contrast, those in fish and amphibians have a remarkable ability to regenerate after damaged. Previous studies focus on signaling mechanisms of hair cell regeneration, such as Wnt and Notch signals but seldom on the fact that the beginning of regeneration is accompanied by a large number of inflammatory responses. The detailed role of this inflammation in hair cell regeneration is still unknown. In addition, there is no appropriate behavioral method to quantitatively evaluate the functional recovery of lateral line hair cells after regeneration. ResultsIn this study, we found that when inflammation was suppressed, the regeneration of lateral line hair cells and the recovery of the rheotaxis of the larvae were significantly delayed. Calcium imaging showed that the function of the neuromasts in the inflammation-inhibited group was weaker than that in the non-inflammation-inhibited group at the Early Stage of regeneration, and returned to normal at the Late Stage. Calcium imaging also revealed the cause of the mismatch between the function and quantity during regeneration. ConclusionsOur results, meanwhile, suggest that suppressing inflammation delays hair cell regeneration and functional recovery when hair cells are damaged. This study may provide a new knowledge for how to promote hair cell regeneration and functional recovery in adult mammals.

neuroscience↗

Proteomic cellular signatures of kinase inhibitor-induced cardiotoxicity: Mount Sinai DToxS LINCS Center Dataset

The Drug Toxicity Signature Generation Center (DToxS) at the Icahn School of Medicine at Mount Sinai is one of the centers of the NIH Library of Integrated Network-Based Cellular Signatures (LINCS) program. A key aim of DToxS is to generate both proteomic and transcriptomic signatures that can predict adverse effects, especially cardiotoxicity, of kinase inhibitors approved by the Food and Drug Administration. Towards this goal, high throughput shot-gun proteomics experiments (317 cell line/drug combinations + 64 control lysates) have been conducted at the Center for Advanced Proteomics Research at Rutgers University - New Jersey Medical School. Using computational network analyses, these proteomic data can be integrated with transcriptomic signatures generated in tandem to identify cellular signatures of cardiotoxicity that may predict kinase inhibitor-induced toxicity and possible mitigation. Both raw and processed proteomics data have been carefully screened for quality and made publicly available via the PRIDE database. As such, this broad protein kinase inhibitor-stimulated cardiomyocyte proteomic data and signature set is valuable for the prediction of drug toxicities. Links to: Metadata Tables O_TBL View this table: org.highwire.dtl.DTLVardef@1cda9f8org.highwire.dtl.DTLVardef@1520e05org.highwire.dtl.DTLVardef@16a35borg.highwire.dtl.DTLVardef@3ee6e7org.highwire.dtl.DTLVardef@1a98664_HPS_FORMAT_FIGEXP M_TBL C_TBL

pharmacology and toxicology↗

Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin

Since the SARS outbreak 18 years ago, a large number of severe acute respiratory syndrome related coronaviruses (SARSr-CoV) have been discovered in their natural reservoir host, bats1-4. Previous studies indicated that some of those bat SARSr-CoVs have the potential to infect humans5-7. Here we report the identification and characterization of a novel coronavirus (nCoV-2019) which caused an epidemic of acute respiratory syndrome in humans, in Wuhan, China. The epidemic, started from December 12th, 2019, has caused 198 laboratory confirmed infections with three fatal cases by January 20th, 2020. Full-length genome sequences were obtained from five patients at the early stage of the outbreak. They are almost identical to each other and share 79.5% sequence identify to SARS-CoV. Furthermore, it was found that nCoV-2019 is 96% identical at the whole genome level to a bat coronavirus. The pairwise protein sequence analysis of seven conserved non-structural proteins show that this virus belongs to the species of SARSr-CoV. The nCoV-2019 virus was then isolated from the bronchoalveolar lavage fluid of a critically ill patient, which can be neutralized by sera from several patients. Importantly, we have confirmed that this novel CoV uses the same cell entry receptor, ACE2, as SARS-CoV.

microbiology↗

A survey of spiking activity reveals a functional hierarchy of mouse corticothalamic visual areas

The mammalian visual system, from retina to neocortex, has been extensively studied at both anatomical and functional levels. Anatomy indicates the cortico-thalamic system is hierarchical, but characterization of cellular-level functional interactions across multiple levels of this hierarchy is lacking, partially due to the challenge of simultaneously recording activity across numerous regions. Here, we describe a large, open dataset (part of the Allen Brain Observatory) that surveys spiking from units in six cortical and two thalamic regions responding to a battery of visual stimuli. Using spike cross-correlation analysis, we find that inter-area functional connectivity mirrors the anatomical hierarchy from the Allen Mouse Brain Connectivity Atlas. Classical functional measures of hierarchy, including visual response latency, receptive field size, phase-locking to a drifting grating stimulus, and autocorrelation timescale are all correlated with the anatomical hierarchy. Moreover, recordings during a visual task support the behavioral relevance of hierarchical processing. Overall, this dataset and the hierarchy we describe provide a foundation for understanding coding and dynamics in the mouse cortico-thalamic visual system.

neuroscience↗