Biology subjects

Han, Y.

Publications and source records attributed to Han, Y..

At least 325 records · Page 18Linked to original sources

bioRxiv2019

A new GABAergic projection from the BNST onto accumbal parvalbumin neurons controls anxiety

The prevailing view is that parvalbumin (PV) interneurons play modulatory roles in emotional response through local medium spiny projection neurons (MSNs). Here, we show that PV activity within the nucleus accumbens shell (sNAc) is required for producing anxiety-related avoidance when mice are under anxiogenic situations; sNAcPV neurons exhibited high excitability in chronically stressed mice model, which generated excessive maladaptive avoidance behavior in an anxiogenic context. We also discovered a novel GABAergic projections from the anterior dorsal bed nuclei of stria terminalis (adBNST) to sNAcPV neurons; optogenetic activation of these afferent terminals in sNAc produced an anxiolytic effect via GABA transmission. Next, we further demonstrated that chronic stressors attenuated the inhibitory synaptic transmission at adBNSTGABA [Formula] sNAcPV synapses, which in turn explains the hyperexcitability of sNAcPV neurons on stressed models; therefore, activation of these GABAergic afferents in sNAc rescued the excessive avoidance behavior related to anxious state.\n\nOur findings reveal the coordination between BNST and NAc through an inhibitory architecture in controlling of anxiety-related response and provide a neurobiological basis for therapeutic interventions in pathological anxiety.

neuroscience↗

bioRxiv2019

Macrocyclization of an all-D linear peptide improves target affinity and imparts cellular activity: A novel stapled α-helical peptide modality

Peptide-based inhibitors hold great potential for targeted modulation of intracellular protein-protein interactions (PPIs) by leveraging vast chemical space relative to primary structure via sequence diversity as well as conformationally through varying secondary and tertiary structures. However, the development of peptide therapeutics has been hindered because of their limited conformational stability, proteolytic sensitivity and cell permeability. Several contemporary peptide design strategies address these issues to varying degrees. Strategic macrocyclization through optimally placed chemical braces such as olefinic hydrocarbon crosslinks, commonly referred to as staples, may address these issues by i) restricting conformational freedom to improve target affinities, ii) improving proteolytic resistance, and iii) enhancing cell permeability. Conversely, molecules constructed entirely from D-amino acids are hyper-resistant to proteolytic cleavage, but generally lack conformational stability and membrane permeability. Since neither approach is a complete solution, we have combined these strategies to identify the first examples of all-D -helical stapled and stitched peptides. As a template, we used a recently reported all D-linear peptide that is a potent inhibitor of the p53-Mdm2 interaction, but is devoid of cellular activity. To design both stapled and stitched all-D-peptide analogues, we used computational modelling to predict optimal staple placement. The resultant novel macrocyclic all D-peptide was determined to exhibit increased -helicity, improved target binding, complete proteolytic stability and, most notably, cellular activity.

biochemistry↗

bioRxiv2019

Large-scale Genetic Analysis Identifies 66 Novel Loci for Asthma

We carried out a genome-wide association study (GWAS) for asthma in UK Biobank, followed by a meta-analysis with results from the Trans-National Asthma Genetic Consortium (TAGC). 66 novel genomic regions were identified, bringing the number of known asthma susceptibility loci to 211. Significant gene-sex interactions were also observed where susceptibility alleles, either individually or as a function of polygenic risk scores, increased asthma risk to a greater extent in men than women. Bioinformatics analyses demonstrated that asthma-associated variants were enriched for colocalizing to regions of open chromatic in immune cells and identified candidate causal genes at 52 of the novel loci, including CD52. An anti-CD52 (-CD52) antibody mimicked the immune cell-depleting effects of an FDA-approved human -CD52 antibody and reduced allergen-induced airway hyperreactivity in mice. These results further elucidate the genetic architecture of asthma, provide evidence that the immune system plays a prominent role in its pathogenesis, and suggest that CD52 represents a potentially novel therapeutic target for treating asthma.

genetics↗

bioRxiv2019

Map3k2-Regulated Intestinal Stromal Cells (MRISC) Define a Distinct Sub-cryptic Stem Cell Niche for Damage Induced Wnt Agonist R-spondin1 Production

Intestinal stem cell propagation and differentiation are essential for rapid repair of tissue damage in the gut. While intestinal stromal cells were recently identified as key mediators of this process, the cellular and molecular mechanisms by which this diverse population induces tissue repair remains poorly understood. Here we show that Map3k2 has a colon stromal cell specific function critically required for maintenance of Lgr5+ intestinal stem cells and protection against acute intestinal damage. This Map3k2-specific function is mediated by enhancing Wnt agonist R-spondin1 production. We further reveal a unique novel cell population, named Map3k2-regulated intestinal stromal cells (MRISC), as the primary cellular source of R-spondin1 following intestinal injury. Together, our data identify a novel intestinal stem cell niche organized by MRISC, which specifically dependent on the Map3k2-signaling pathway to augment the production of Wnt agonist R-spondin1 and promote regeneration of the acutely damaged intestine.\n\nHighlightsO_LIMap3k2 protects mice from DSS-induced colitis by promoting intestinal stem cell regeneration.\nC_LIO_LIMap3k2-MAPK pathway cross-talks with Wnt signaling pathway via upregulation of R-spondin1.\nC_LIO_LIMap3k2-Regulated Intestinal Stromal Cells (MRISC) marked by co-expression of CD90, CD34 and CD81 defines a novel colonic stem cell niche.\nC_LI

cell biology↗

bioRxiv2019

Estimating the heritability of psychological measures in the Human Connectome Project dataset

The Human Connectome Project (HCP) is a large structural and functional MRI dataset with a rich array of behavioral measures and extensive family structure. This makes it a valuable resource for investigating questions about individual differences, including questions about heritability. While its MRI data have been analyzed extensively in this regard, to our knowledge a comprehensive estimation of the heritability of the behavioral dataset has never been conducted. Using a set of behavioral measures of personality, emotion and cognition, we show that it is possible to re-identify the same individual across two testing times, and identify identical twins. Using machine-learning (univariate linear model, Ridge classifier and Random Forest model) we estimated the heritability of 37 behavioral measures and compared the results to those derived from twin correlations. Correlations between the standard heritability metric and each set of model weights ranged from 0.42 to 0.67, and questionnaire-based and task-based measures did not differ significantly in their heritability. We further derived nine latent factors from the 37 measures and repeated the heritability estimation; in this case, the correlations between the standard heritability and each set of model weights were lower, ranging from 0.15 to 0.38. One specific discrepancy arose for the general intelligence factor, which all models assigned high importance, but the standard heritability calculation did not. We present an alternative method for qualitatively estimating the heritability of the behavioral measures in the HCP as a resource for other investigators, and recommend the use of machine-learning models for estimating heritability.

genetics↗

bioRxiv2019

Transferrin plays a central role to maintain coagulation balance by interacting with clotting factors

Coagulation balance is maintained through fine-tuning interactions among clotting factors. Physiological concentrations of clotting factors are huge difference. Especially, coagulation proteases concentration (pM to nM) is much lower than their natural inactivator antithrombin III (AT-III, [~]3 M). Here we show that transferrin (normal plasma concentration [~]40 M) interacts with fibrinogen, thrombin, FXIIa and AT-III with different affinity to maintain coagulation balance. Normally, transferrin is sequestered by binding with fibrinogen (normal plasma concentration [~]10 M) with a molar ratio of 4:1. In atherosclerosis, abnormally up-regulated transferrin interacts with and potentiates thrombin/FXIIa and blocks AT-IIIs inactivation on coagulation proteases by binding to AT-III, and thus induces hypercoagulability. In mouse models, transferrin-overexpression aggravated atherosclerosis while transferrin-knockdown, anti-transferrin antibody or designed peptides interfering transferrin-thrombin/FXIIa interactions alleviated it. Collectively, these findings identify transferrin as a clotting factor and an adjuster for maintaining coagulation balance and modify the coagulation cascade.

molecular biology↗

bioRxiv2019

Iron-deficiency and estrogen are associated with ischemic stroke by up-regulating transferrin to induce hypercoagulability

In the accompanying manuscript, transferrin has been demonstrated to maintain coagulation balance by interacting with clotting factors, suggesting that elevated transferrin causes thromboembolic diseases and factors up-regulating transferrin is associated with thrombosis. Here we show that transferrin and transferrin-thrombin/FXIIa complexes are elevated in plasma and cerebrospinal fluid of ischemic stroke (IS) patients with iron-deficiency anemia (IDA) history, IDA patients and venous thromboembolism patients using combined oral contraceptives (CC) as well as ID mice, suggesting an association of transferrin up-regulation with ID and CC. ID and estrogen up-regulated transferrin through hypoxia and estrogen response elements located at transferrin gene enhancer and promoter region, respectively. ID, exogenous transferrin/estrogen administration or transferrin over-expression promoted hypercoagulability and aggravated IS, while anti-transferrin antibody, transferrin knockdown or designed peptide inhibitors interfering transferrin-thrombin/FXIIa interaction exerted anti-IS effects in vivo. Collectively, the results reveal that factors (i.e., ID and CC) up-regulating transferrin are risk factors of thromboembolic diseases.

biochemistry↗

bioRxiv2019

Transitions in brain-network level information processing dynamics are driven by alterations in neural gain

A key component of the flexibility and complexity of the brain is its ability to dynamically adapt its functional network structure between integrated and segregated brain states depending on the demands of different cognitive tasks. Integrated states are prevalent when performing tasks of high complexity, such as maintaining items in working memory, consistent with models of a global workspace architecture. Recent work has suggested that the balance between integration and segregation is under the control of ascending neuromodulatory systems, such as the noradrenergic system. In a previous large-scale nonlinear oscillator model of neuronal network dynamics, we showed that manipulating neural gain led to a critical transition in phase synchrony that was associated with a shift from segregated to integrated topology, thus confirming our original prediction. In this study, we advance these results by demonstrating that the gain-mediated phase transition is characterized by a shift in the underlying dynamics of neural information processing. Specifically, the dynamics of the subcritical (segregated) regime are dominated by information storage, whereas the supercritical (integrated) regime is associated with increased information transfer (measured via transfer entropy). Operating near to the critical regime with respect to modulating neural gain would thus appear to provide computational advantages, offering flexibility in the information processing that can be performed with only subtle changes in gain control. Our results thus link studies of whole-brain network topology and the ascending arousal system with information processing dynamics, and suggest that the constraints imposed by the ascending arousal system constrain low-dimensional modes of information processing within the brain.\n\nAuthor summaryHigher brain function relies on a dynamic balance between functional integration and segregation. Previous work has shown that this balance is mediated in part by alterations in neural gain, which are thought to relate to projections from ascending neuromodulatory nuclei, such as the locus coeruleus. Here, we extend this work by demonstrating that the modulation of neural gain alters the information processing dynamics of the neural components of a biophysical neural model. Specifically, we find that low levels of neural gain are characterized by high Active Information Storage, whereas higher levels of neural gain are associated with an increase in inter-regional Transfer Entropy. Our results suggest that the modulation of neural gain via the ascending arousal system may fundamentally alter the information processing mode of the brain, which in turn has important implications for understanding the biophysical basis of cognition.

neuroscience↗

bioRxiv2019

LAmbDA: Label Ambiguous Domain Adaption Dataset Integration Reduces Batch Effects and Improves Subtype Detection

MotivationRapid advances in single cell RNA sequencing have produced more granular subtypes of cells in multiple tissues from different species. There exists a need to develop rigorous methods that can i) model multiple datasets with ambiguous labels across species and studies and ii) remove systematic biases across datasets and species. ResultsWe developed a species- and dataset-independent transfer learning framework (LAmbDA) to train models on multiple datasets and applied our framework on scRNA-seq experiments. These models mapped corresponding cell types between datasets with inconsistent labels while simultaneously reducing batch effects. We achieved high accuracy in labeling cellular subtypes (weighted accuracy pancreas: 91%, brain: 78%) using LAmbDA Random Forest. LAmbDA Feedforward 1 Layer Neural Network achieved higher weighted accuracy in labeling cellular subtypes than CaSTLe or MetaNeighbor in brain (48%, 32%, 20% respectively). Furthermore, LAmbDA Feedforward 1 Layer Neural Network was the only method to correctly predict ambiguous cellular subtype labels in both pancreas and brain compared to CaSTLe and MetaNeighbor. LAmbDA is model- and dataset-independent and generalizable to diverse data types representing an advance in biocomputing. Availability: github.com/tsteelejohnson91/LAmbDA Contact: kunhuang@iu.edu, jizhan@iu.edu

bioinformatics↗

bioRxiv2018

Nationwide population genetic screening improves outcomes of newborn screening for hearing loss in China

PurposeConcurrent newborn hearing and genetic screening has been reported, but its benefits have not been statistically proven due to limited sample sizes and outcome data. To fill this gap, we analyzed outcomes of a large number of newborns with genetic screening results.\n\nMethodsNewborns in China were screened for 20 hearing-loss-related genetic variants from 2012-2017. Genetic results were categorized as positive, at-risk, inconclusive, or negative. Hearing screening results, risk factors, and up-to-date hearing status were followed-up via phone interviews.\n\nResultsWe completed genetic screening on one million newborns and followed up 12,778. We found that a positive genetic result significantly indicated a higher positive predictive value of the initial hearing screening (60% vs. 5.0%, P<0.001) and a lower rate of loss-to-follow-up (5% vs. 22%, P<0.001) than an inconclusive one. Importantly, 42% of subjects in the positive group with reported or presymptomatic hearing loss were \"missed\" by conventional hearing screening. Furthermore, genetic screening identified 0.23% of subjects predisposed to preventable ototoxicity.\n\nConclusionOur results demonstrate that limited genetic screening identified additional cases, reduced loss-to-follow-up, and informed families of ototoxicity risks, providing convincing evidence to support integrating genetic screening into universal newborn hearing screening programs.

genetics↗

bioRxiv2018

Pre-implantation genetic diagnosis for a family with Usher syndrome through targeted sequencing and haplotype analysis

ObjectiveOur objective was to investigate the applicability of targeted capture massively parallel sequencing in developing personalized pre-implantation genetic diagnosis (PGD) assay.\n\nMethodsOne couple at risk of transmitting Usher Syndrome to their offspring was recruited to this study. The genomics DNA (gDNA) was extracted from the peripheral blood and underwent in vitro fertilization (IVF)-PGD. Prenatal molecular diagnosis was performed in the 20th week of gestation and the chromosomal anomaly was analyzed.\n\nResultsCustomized capture probe targeted at USH2A gene and 350kb flanking region were designed for PGD. Eleven blastocysts were biopsied and amplified by using multiple displacement amplification (MDA) and capture sequencing. A HMM-based haplotype analysis was performed to deduce embryos genotype by using SNPs identified in each sample. Four embryos were diagnosed as free of fathers rare mutation, two were transferred and one achieved a successful pregnancy. The fetal genotype was confirmed by Sanger sequencing of fetal genomic DNA obtained by amniocentesis. The PGD and prenatal diagnosis results were further confirmed by the molecular diagnosis of the babys genomic DNA sample. The auditory test showed that the hearing was normal.\n\nConclusionTargeted capture massively parallel sequencing (MPS) is an effective and convenient strategy to develop customized PGD assay.\n\nKey pointsGenetic counseling session was conducted with a family having Usher patient who was molecularly diagnosed, and a healthy baby was born with the help of successful PGD assay. This is of vast importance in management plans since it is the first report of PGD in Usher syndrome based on targeted capture MPS.

genetics↗

bioRxiv2018

Cingulate dependent social risk assessment in rats

Social transmission of distress has been conceived of as a one-way phenomenon in which an observer catches the emotions of another. Here we use a paradigm in which an observer rat witnesses another receive electro-shocks. Bayesian model comparison and Granger causality argue against this one-way vision in favor of bidirectional information transfer: how the observer reacts to the demonstrators distress influences the behavior of the demonstrator. Intriguingly, this was true to a similar extent across highly familiar and entirely unfamiliar rats. Injecting muscimol in the anterior cingulate of observers reduced freezing in the observers and in the demonstrators receiving the shocks. That rats share the distress of unfamiliar strains is at odds with evolutionary thinking that empathy should be biased towards close individuals. Using simulations, we support the complementary notion that distress transmission could be selected to more efficiently detect dangers in a group.

neuroscience↗

bioRxiv2018

Directed evolution of split APEX peroxidase

APEX is an engineered peroxidase that catalyzes the oxidation of a wide range of substrates, facilitating its use in a variety of applications, from subcellular staining for electron microscopy to proximity biotinylation for spatial proteomics and transcriptomics. To further advance the capabilities of APEX, we used directed evolution to engineer a split APEX tool (sAPEX). Twenty rounds of FACS-based selections from yeast-displayed fragment libraries, using three different yeast display configurations, produced a 200-amino acid N-terminal fragment (with 9 mutations relative to APEX2) called \"AP\" and a 50-amino acid C-terminal fragment called \"EX\". AP and EX fragments were each inactive on their own but reconstituted to give peroxidase activity when driven together by a molecular interaction. We demonstrate sAPEX reconstitution in the mammalian cytosol, on engineered RNA motifs within telomerase noncoding RNA, and at mitochondria-endoplasmic reticulum contact sites.

bioengineering↗

bioRxiv2018

Shared heritability and functional enrichment across six solid cancers

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg=0.57, p=4.6x10-8), breast and ovarian cancer (rg=0.24, p=7x10-5), breast and lung cancer (rg=0.18, p=1.5x10-6) and breast and colorectal cancer (rg=0.15, p=1.1x10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

genomics↗

bioRxiv2018

Emotional Mirrors in the Rat’s Anterior Cingulate Cortex

AbstractHow do the emotions of others affect us? The human anterior cingulate cortex (ACC) responds while experiencing pain in the self and witnessing pain in others, but underlying cellular mechanisms remain poorly understood. Here we show the ACC (area 24) contains neurons responding when a rat experiences pain and while witnessing another receive footshocks. Most of these do not respond to a fear conditioned tone (CS). Deactivating this region reduces freezing while witnessing footshocks to others but not while hearing the CS. A decoder trained on spike counts while witnessing footshocks can decode the animals own pain intensity when experiencing pain. Mirror-like neurons thus exist in ACC that encode the pain of others in a code shared with pain but not fear in the self.\n\nOne Sentence SummaryACC contains neurons responding selectively when a rat witnesses anothers pain and experiences pain in the self.

neuroscience↗

bioRxiv2018

Exogenous calcium ions enhance patulin adsorption capability of Saccharomyces cerevisiae

Patulin contamination is a severe issue that restricts the development of the global fruit processing industry. Yeast adsorbs patulin more effectively than other microbial adsorbents, and this adsorption process mainly depends on the function of the cell wall. Additionally, exogenous calcium ions aid in yeast cell wall formation according to reports. Therefore, in the present study, the effect of exogenous calcium concentrations on the cell wall structure and the patulin adsorption capability was studied. We showed that the ability of the yeast to adsorb patulin was strengthened with an increase in exogenous calcium concentrations between 1x10-4 - 1x10-2 mol/L. Moreover, yeast cell wall thickness, {beta}-1,3-glucan content and the activities of the key catalytic enzymes {beta}-1,3-glucanase and {beta}-1,3-glycosyl transferase were all increased within this range. The results indicated that exogenous calcium activates key enzymes and that these enzymes are crucial for cell wall network formation and patulin adsorption capability.\n\nImportanceThe present work illuminates that the exogenous calcium ions could determine the insoluble network structure by regulating key enzyme activities under certain concentrations, thus indirectly influencing the yeast cell patulin adsorption capability. It could enhance patulin adsorption capability of yeast walls and successfully apply to fruit juice industry.

microbiology↗

bioRxiv2018

The Genomic Basis of Arthropod Diversity

BackgroundArthropods comprise the largest and most diverse phylum on Earth and play vital roles in nearly every ecosystem. Their diversity stems in part from variations on a conserved body plan, resulting from and recorded in adaptive changes in the genome. Dissection of the genomic record of sequence change enables broad questions regarding genome evolution to be addressed, even across hyper-diverse taxa within arthropods.\n\nResultsUsing 76 whole genome sequences representing 21 orders spanning more than 500 million years of arthropod evolution, we document changes in gene and protein domain content and provide temporal and phylogenetic context for interpreting these innovations. We identify many novel gene families that arose early in the evolution of arthropods and during the diversification of insects into modern orders. We reveal unexpected variation in patterns of DNA methylation across arthropods and examples of gene family and protein domain evolution coincident with the appearance of notable phenotypic and physiological adaptations such as flight, metamorphosis, sociality and chemoperception.\n\nConclusionsThese analyses demonstrate how large-scale comparative genomics can provide broad new insights into the genotype to phenotype map and generate testable hypotheses about the evolution of animal diversity.

genomics↗

bioRxiv2018

Analysis of microbial community structure of pit mud for Chinese strong-flavor liquor fermentation using next generation DNA sequencing of full-length 16S rRNA

The pit is the necessary bioreactor for brewing process of Chinese strong-flavor liquor. Pit mud in pits contains a large number of microorganisms and is a complex ecosystem. The analysis of bacterial flora in pit mud is of great significance to understand liquor fermentation mechanisms. To overcome taxonomic limitations of short reads in 16S rRNA variable region sequencing, we used high-throughput DNA sequencing of near full-length 16S rRNA gene to analyze microbial compositions of different types of pit mud that produce different qualities of strong-flavor liquor. The results showed that the main species in pit mud were Pseudomonas extremaustralis 14-3, Pseudomonas veronii, Serratia marcescens WW4, and Clostridium leptum in Ruminiclostridium. The microbial diversity of pit mud with different quality was significantly different. From poor to good quality of pit mud (thus the quality of liquor), the relative abundances of Ruminiclostridium and Syntrophomonas in Firmicutes was increased, and the relative abundance of Olsenella in Actinobacteria also increased, but the relative abundances of Pseudomonas and Serratia in Proteobacteria were decreased. The surprising findings of this study include that the diversity of intermediate level quality of N pit mud was the lowest, and the diversity levels of high quality pit mud G and poor quality pit mud B were similar. Correlation analysis showed that there were high positive correlations (r > 0.8) among different microbial groups in the flora. Based on the analysis of the microbial structures of pit mud in different quality, the good quality pit mud has a higher microbial diversity, but how this higher diversity and differential microbial compositions contribute to better quality of liquor fermentation remains obscure.

molecular biology↗