Biology subjects

Yang, K.

Publications and source records attributed to Yang, K..

At least 127 records · Page 7Linked to original sources

bioRxiv2021

A multimodal study of a first episode psychosis cohort: potential markers of antipsychotic treatment resistance

Treatment resistant (TR) psychosis is considered to be a significant cause of disability and functional impairment. Numerous efforts have been made to identify the clinical predictors of TR. However, the exploration of molecular and biological markers is still at an early stage. To understand the TR condition and identify potential molecular and biological markers, we analyzed demographic information, clinical data, structural brain imaging data, and molecular brain imaging data in 7 Tesla magnetic resonance spectroscopy, from a first episode psychosis cohort that includes 138 patients. Age, gender, race, smoking status, duration of illness, and antipsychotic dosages were controlled in the analyses. We found that TR patients had a younger age at onset, more hospitalizations, more severe negative symptoms, a significant reduction in the volumes of the hippocampus (HP) and superior frontal gyrus (SFG), and a significant reduction in glutathione (GSH) levels in the anterior cingulate cortex (ACC), when compared to non-TR patients. The combination of multiple markers provided a better classification between TR and non-TR patients compared to any individual marker. Our study shows that ACC GSH, HP and SFG volumes, and age at onset could potentially be trait biomarkers for TR diagnosis, while hospitalization and negative symptoms could be used to evaluate the progression of the disease. Multimodal cohorts are essential in obtaining a comprehensive understanding of brain disorders.

neuroscience↗

bioRxiv2021

Sequential in vivo labeling of insulin secretory granule pools in INS-SNAP transgenic pigs

{beta}-cells produce, store and secrete insulin upon elevated blood glucose levels. Insulin secretion is a highly regulated process. The probability for insulin secretory granules to undergo fusion with the plasma membrane or being degraded is correlated with their age. However, the molecular features and stimuli connected to this behavior have not yet been fully understood. Furthermore, our understanding of {beta}-cell function is mostly derived from studies of ex vivo isolated islets and/or rodent models. To overcome this translational gap and study insulin secretory granule turnover in vivo, we have generated a transgenic pig model with the SNAP-tag fused to insulin. We demonstrate the correct targeting and processing of the tagged insulin and normal glycemic control of the pig model. Furthermore, we show specific single- and dual-color granular labeling of in vivo labeled pig pancreas. This model may provide unprecedented insights into the in vivo insulin secretory granule behavior in an animal close to humans.

cell biology↗

bioRxiv2021

Face processing of social cognition in patients with first episode psychosis: Its deficits and association with the right subcallosal anterior cingulate cortex

The clinical importance of social cognition is well acknowledged in patients with psychosis, in particular those with first episode psychosis (FEP). Nevertheless, its brain substrates and circuitries remain elusive, lacking precise analysis between multimodal brain characteristics and behavioral sub-dimensions within social cognition. In the present study, we examined face processing of social cognition in 79 FEP patients and 80 healthy controls (HCs). We looked for a possible correlation between face processing and multimodal MRI characteristics such as resting-state functional connectivity (rsFC) and brain volume. We observed worse recognition accuracy, longer recognition response time, and longer memory response time in FEP patients when compared with HCs. Of these, memory response time was selectively correlated with specific rsFCs, which included the right subcallosal sub-region of BA24 in the ACC (scACC), only in FEP patients. The volume of this region was also correlated with memory response time in FEP patients. The scACC is functionally and structurally important in FEP-associated abnormalities of face processing measures in social cognition.

neuroscience↗

bioRxiv2021

ER exit sites in Drosophila display abundant ER-Golgi vesicles and pearled tubes but no megacarriers

Secretory cargos are collected at ER exit sites (ERES) before transport to the Golgi apparatus. Decades of research have provided many details of the molecular events underlying ER-Golgi exchanges. Essential questions, however, remain about the organization of the ER-Golgi interface in cells and the type of membrane structures mediating traffic from ERES. To investigate these, we used transgenic tagging in Drosophila flies, 3D-SIM and FIB-SEM to characterize ERES-Golgi units in collagen-producing fat body, imaginal discs and imaginal discs overexpressing ERES determinant Tango1. We found in front of ERES a pre-cis-Golgi region involved in both anterograde and retrograde transport. This pre-cis-Golgi is continuous with the rest of the Golgi, not a separate intermediate compartment or collection of large carriers, for which we found no evidence. We found, however, many vesicles, as well as pearled tubules connecting ERES and Golgi.

cell biology↗

bioRxiv2021

SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, in which core symptoms are defects of social interaction and evidently repetitive behaviors. Although around 50-70 % of ASD patients have comorbidity of intellectual disabilities (ID) or developmental delay (DD), there are some ASD patients who exhibit only core symptoms but without ID/DD, raising the question whether there are genetic components and neural circuits specific for core symptoms of ASD. Here, by focusing on ASD patients who do not show compound ID or DD, we identified a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene, coding the small ubiquitin-like modifiers (SUMO) deconjugating enzyme, as a potentially new candidate gene for ASD. We found that Senp1 haploinsufficient mice exhibited core symptoms of autism such as deficits in social interaction and repetitive behaviors, but normal learning and memory ability. Moreover, we found that the inhibitory and excitatory synaptic functions were severely affected in the retrosplenial agranular (RSA) cortex of Senp1 haploinsufficient mice. Lack of Senp1 led to over SUMOylation and degradation of fragile X mental retardation protein (FMRP) proteins, which is coded by the FMR1 gene, also implicated in syndromic ASD. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescued the defects of synaptic functions and core autistic-like symptoms of Senp1 haploinsufficient mice. Together, these results demonstrated that disruption of the SENP1-FMRP regulatory axis in the RSA may cause core autistic symptoms, which provide a candidate brain region of ASD for potential therapeutic intervene by neural modulation approaches.

neuroscience↗

bioRxiv2021

Anterior insula-associated social novelty recognition: orchestrated regulation by a local retinoic acid cascade and oxytocin signaling

BackgroundDeficits in social cognition consistently underlie functional disabilities in a wide range of psychiatric disorders. Neuroimaging studies have suggested that the anterior insula is a common core brain region that is impaired across neurological and psychiatric disorders, which include social cognition deficits. Nevertheless, neurobiological mechanisms of the anterior insula for social cognition remain elusive. MethodsTo determine the role of anterior insula in social cognition, we manipulated expression of Cyp26B1, an anterior insula-enriched molecule that is crucial for retinoic acid degradation and involved in the pathology of neuropsychiatric conditions. Social cognition was mainly assayed using the three-chamber social interaction test. We conducted multimodal analyses at the molecular, cellular, circuitry, and behavioral levels. ResultsAt the molecular/cellular level, anterior insula-mediated social novelty recognition is maintained by proper activity of the layer 5 pyramidal neurons, for which retinoic acid-mediated gene transcription can play a role. We also demonstrate that oxytocin influences the anterior insula-mediated social novelty recognition, not by direct projection of oxytocin neurons, nor by direct diffusion of oxytocin to the anterior insula, which contrasts the modes of oxytocin regulation onto the posterior insula. Instead, oxytocin affects oxytocin receptor-expressing neurons in the dorsal raphe nucleus where serotonergic neurons are projected to the anterior insula. Furthermore, we show that serotonin 5HT2C receptor expressed in the anterior insula influences social novelty recognition. ConclusionsAnterior insula plays a pivotal role in social novelty recognition that is partly regulated by a local retinoic acid cascade, but also remotely regulated by oxytocin via a non-classic mechanism.

animal behavior and cognition↗

bioRxiv2021

Ultrastructural distribution of presynaptic active zones and dense core vesicles in olfactory projection neurons of Drosophila

In Drosophila melanogaster, olfactory projection neurons (PNs) convey odor information from the peripheral olfactory center to higher brain regions. The anatomical and physiological properties of PNs have been well characterized at the cellular and circuit level. The ultrastructural features of PNs remain unknown however, particularly with respect to presynaptic active zones (PAZs) and dense core vesicles (DCVs). In the current study, membrane-labeled electron microscopy was used to volume-reconstruct 89 PN axonal boutons and identify the internal PAZs and DCVs. Based on ultrastructural parameters, these PN boutons could be classified into three morphological distinct subtypes. Interestingly, the distributions of PAZs and DCVs were distinct within these three subtypes. DCVs were enriched in membrane labeled GH146-positive boutons, suggesting that GH146-positive PNs release both neurotransmitters and neuromodulators. The study identified the detailed distributions of PAZs and DCVs in PN boutons and indicates that neuromodulators mediated by DCVs may play an important role in PNs for olfactory processing.

neuroscience↗

bioRxiv2020

Predicting compound activity from phenotypic profiles and chemical structures

Recent advances in deep learning enable using chemical structures and phenotypic profiles to accurately predict assay results for compounds virtually, reducing the time and cost of screens in the drug-discovery process. We evaluate the relative strength of three high-throughput data sources--chemical structures, images (Cell Painting), and gene-expression profiles (L1000)--to predict compound activity using a sparse historical collection of 16,170 compounds tested in 270 assays for a total of 585,439 readouts. All three data modalities can predict compound activity with high accuracy in 6-10% of assays tested; replacing million-compound physical screens with computationally prioritized smaller screens throughout the pharmaceutical industry could yield major savings. Furthermore, the three profiling modalities are complementary, and in combination they can predict 21% of assays with high accuracy, and 64% if lower accuracy is acceptable. Our study shows that, for many assays, predicting compound activity from phenotypic profiles and chemical structures might accelerate the early stages of the drug-discovery process.

bioinformatics↗

bioRxiv2020

Chromosome-scale assembly of the genome of Salix dunnii reveals a male-heterogametic sex determination system on chromosome 7

Sex determination systems in plants can involve either female or male heterogamety (ZW or XY, respectively). Here we used Illumina short reads, Oxford Nanopore Technologies (ONT) long reads, and Hi-C reads to assemble the first chromosome-scale genome of a female willow tree (Salix dunnii), and to predict genes using transcriptome sequences and available databases. The final genome sequence of 328 Mb in total was assembled in 29 contigs, and includes 31,501 genes. We inferred a male heterogametic sex determining factor on chromosome 7, suggesting that, unlike the female heterogamety of most species in the genus Salix, male heterogamety evolved in the subgenus Salix. The S. dunnii X-linked region occupies about 3.21 Mb of chromosome 7, and is probably in a pericentromeric region. Our data suggest that this region is enriched for transposable element insertions, and about one third of its 124 protein-coding genes were gained via duplications from other genome regions. We detect purifying selection on the genes that were ancestrally present in the region, though some have been lost. Transcriptome data from female and male individuals show more male- than female-biased genes in catkin and leaf tissues, and indicate enrichment for male-biased genes in the pseudo-autosomal regions. Our study provides valuable genomic resources for studying sex chromosome evolution in Salicaceae family.

genomics↗

bioRxiv2020

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

The parasitic worm product, ES-62 protects against collagen-induced arthritis, a mouse model of rheumatoid arthritis (RA) by suppressing the synovial fibroblast (SF) responses perpetuating inflammation and driving joint destruction. Such SF responses are shaped during disease progression by the inflammatory microenvironment of the joint that promotes remodelling of their epigenetic landscape, inducing an "aggressive" pathogenic SF phenotype. Critically, exposure to ES-62 in vivo induces a stably imprinted "safe" phenotype that exhibits responses more typical of healthy SFs. Surprisingly however, DNA methylome analysis reveals that rather than simply preventing the pathogenic rewiring of SFs, ES-62 induces further epigenetic remodelling, including targeting genes associated with ciliogenesis and differentiation, to program a distinct "protective" phenotype. Such unique behaviour signposts potential DNA methylation signatures predictive of pathogenesis and its resolution and hence, candidate mechanisms by which novel therapeutic interventions could prevent SFs from perpetuating joint inflammation and destruction in RA.

pathology↗

bioRxiv2020

New evidence concerning the genome designations of the AC(DC) tetraploid Avena species

The tetraploid Avena species in the section Pachycarpa Baum, including A. insularis, A. maroccana, and A. murphyi, are thought to be involved in the evolution of hexaploid oats; however, their genome designations are still being debated. Repetitive DNA sequences play an important role in genome structuring and evolution, so understanding the chromosomal organization and distribution of these sequences in Avena species could provide valuable information concerning genome evolution in this genus. In this study, the chromosomal organizations and distributions of six repetitive DNA sequences (including three SSR motifs (TTC, AAC, CAG), one 5S rRNA gene fragment, and two oat A and C genome specific repeats) were investigated using non-denaturing fluorescence in situ hybridization (ND-FISH) in the three tetraploid species mentioned above and in two hexaploid oat species. Preferential distribution of the SSRs in centromeric regions was seen in the A and D genomes, whereas few signals were detected in the C genomes. Some intergenomic translocations were observed in the tetraploids; such translocations were also detected between the C and D genomes in the hexaploids. These results provide robust evidence for the presence of the D genome in all three tetraploids, strongly suggesting that the genomic constitution of these species is DC and not AC, as had been thought previously.

genetics↗

bioRxiv2020

Heat Stress Interferes with Formation of Double-Strand Breaks and Homology Synapsis in Arabidopsis thaliana

Meiotic recombination (MR) drives novel combination of alleles and contributes to genomic diversity in eukaryotes. In this study, we showed that heat stress (36-38{degrees}C) over fertile threshold fully abolished crossover (CO) formation in Arabidopsis. Cytological and genetic studies in wild-type plants, and the syn1 and rad51 mutants suggested that heat stress reduces generation of SPO11-dependent double-strand breaks (DSBs). In support, the abundance of recombinase DMC1, which is required for MR-specific DSB repair, was significantly reduced under heat stress. In addition, we showed that high temperatures induced disassembly and/or instability of ASY4-but not SYN1-mediated chromosome axis. At the same time, ASY1-associated lateral element of synaptonemal complex (SC) was partially affected, while the ZYP1-dependent central element of SC was disrupted, indicating that heat stress impairs SC formation. Moreover, quantitative RT-PCR revealed that genes involved in DSB formation; e.g. SPO11-1, PRD1, 2 and 3, were not impacted; however, recombinase RAD51 and chromosome axis factors ASY3 and ASY4 were significantly downregulated under heat stress. Taken together, these findings revealed that heat stress inhibits MR via compromised DSB formation and homolog synapsis, which are possible downstream effects of the impacted chromosome axis. Our study thus provides evidence shedding light on how increase of environmental temperature influences MR in Arabidopsis.

plant biology↗

bioRxiv2020

Longitudinal changes in brain metabolites in healthy subjects and patients with first episode psychosis (FEP): a 7-Tesla MRS study

Objective7 Tesla (T) longitudinal magnetic resonance spectroscopy (MRS) offers a precise measurment of metabolic levels in human brain via a non-invasive approach. Studying longitudinal changes in neurometabolites could help identify trait and state markers for diseases and understand inconsistent findings from different researchers due to differences in the age of study participants and duration of illness. This study is the first to report novel longitudinal patterns in young adulthood from both physiological and pathological viewpoints using 7T MRS. MethodsUtilizing a four-year longitudinal cohort with 38 first episode psychosis (FEP) patients (onset within 2 years) and 48 healthy controls (HC), the authors examined the annual percentage changes of 9 neurometabolites in 5 brain regions. ResultsBoth FEP patients and HC subjects were found to have significant longitudinal reductions in glutamate (Glu) in the anterior cingulate cortex (ACC). Only FEP patients were found to have a significant decrease over time in {gamma}-aminobutyric acid (GABA), N-acetyl aspartate (NAA), myo-inositol (mI), and total choline (tCho: phosphocholine plus glycerophosphocholine) in the ACC. Uniquely, glutathione (GSH) was found to have a near zero annual percentage change in both FEP patients and HC subjects in all 5 brain regions over a four-year timespan in young adulthood. ConclusionsGSH could be a trait marker for diagnostic applications at least in young adulthood. Glu, GABA, NAA, mI, and tCho in the ACC are associated with the patients status and could be state markers for mechanistic studies of psychotic disorders, including those for progressive pathological changes and medication effects in young adulthood.

neuroscience↗

bioRxiv2020

Multi-modal single cell analysis reveals brain immune landscape plasticity during aging and gut microbiota dysbiosis

The brain contains a diverse array of immune cell types. The phenotypic and functional plasticity of brain immune cells collectively contribute to brain tissue homeostasis and disease progression. Immune cell plasticity is profoundly influenced by local tissue microenvironment cues and systemic factors. Yet, the transcriptional mechanism by which systemic stimuli, such as aging and gut microbiota dysbiosis, reshape brain immune cell plasticity and homeostasis has not been fully delineated. Using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), we analyzed compositional and transcriptional changes of the brain immune landscape in response to aging and gut dysbiosis. We first examined the discordance between canonical surface marker-defined immune cell types (Cell-ID) and their transcriptome signatures, which suggested transcriptional plasticity among immune cells despite sharing the same cell surface markers. Specifically, inflammatory and patrolling Ly6C+ monocytes were shifted predominantly to a pro-inflammatory transcriptional program in the aged brain, while brain ILCs shifted toward an ILC2 transcriptional profile. Finally, aging led to an increase of ILC-like cells expressing a T memory stemness (Tscm) signature in the brain. Antibiotics (ABX)-induced gut dysbiosis reduced the frequency of ILCs exhibiting Tscm-like properties in the aged mice, but not in the young mice. Enabled by high-resolution single-cell molecular phenotyping, our study revealed that systemic changes due to aging and gut dysbiosis prime the brain environment for an increased propensity for neuroinflammation, which provided insights into gut dysbiosis in age-related neurological diseases. Manuscript SummaryGolomb et al. performed Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) on immune cells from the brains of young and aged mice with and without antibiotics-induced gut dysbiosis. High resolution, single cell immunophenotyping enabled the dissection of extensive transcriptional plasticity of canonically identified monocytes and innate lymphoid cells (ILCs) in the aged brain. Through differential gene expression and trajectory inference analyses, the authors revealed tissue microenvironment-dependent cellular responses influenced by aging and gut dysbiosis that may potentiate neuroinflammatory diseases. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

immunology↗

bioRxiv2020

A gustatory receptor tuned to the steroid plant hormone brassinolide in Plutella xylostella (Lepidoptera: Plutellidae)

Feeding and oviposition deterrents help phytophagous insects to identify host plants. The taste organs of phytophagous insects contain bitter gustatory receptors (GRs). To explore their function, we focused on PxylGr34, a bitter GR in Plutella xylostella (L.). We detected abundant PxylGr34 transcripts in the larval head and specific expression of PxylGr34 in the antennae of females. Analyses using the Xenopus oocyte expression system and two-electrode voltage-clamp recording showed that PxylGr34 is specifically tuned to the plant hormone brassinolide (BL) and its analog 24-epibrassinolide. Electrophysiological analyses revealed that the medial sensilla styloconica on the maxillary galea of the 4th instar larvae are responsive to BL. Dual-choice bioassays demonstrated that BL inhibits larval feeding and female ovipositing. Knock-down of PxylGr34 by RNAi abolished BL-induced feeding inhibition. These results shed light on gustatory coding mechanisms and deterrence of insect feeding and ovipositing, and may be useful for designing plant hormone-based pest management strategies.

ecology↗

bioRxiv2020

Curcumin combined with Glu-GNPs enhancing radiosensitivity of transplanted tumor of MDA-MB-231-luc cells in nude mice

Breast cancer is the first cause of cancer death in women all over the world. And the morbidity of breast cancer has been increasing in recent years. Nowadays, the treatment of breast cancer is still a problem. Radiotherapy resistance is one of the important factors leading to poor prognosis of clinical treatment. Curcumin, a plant polyphenol from Curcuma longa, has antitumor activity and inhibition of tumor recurrence and metastasis. However, the influence of curcumin on radiosensitivity of breast carcinoma xenografts, the synergistic effect and possible mechanism of curcumin and Glucose-Gold nanoparticles (Glu-GNPs) in nude mice in vivo need to be further explored. The model of transplanted tumor in nude mice was established and sensitized by intravenous injection of curcumin and Glu-GNPs. The results showed that curcumin can significantly inhibit the growth of tumor, and has no obvious effect on the body weight of nude mice, and Curcumin, Glu-GNPs and X-ray irradiation treatment alone or in combination could reduce the expression of VEGF and HSP90 mRNA and protein compared with model group in tumor tissue. The inhibition of irradiation resistance may be related to inhibiting the synthesis of VEGF and HSP90. This study suggested that curcumin and Glu-GNPs have the radiosensitization effect in vivo, which provides an experimental basis for the clinical development of green radiosensitizers.View Full Text

cancer biology↗

bioRxiv2020

High fat diet disrupts diurnal interactions between REG3g and small intestinal gut microbes resulting in metabolic dysfunction

Gut microbial diurnal oscillations are important diet-dependent drivers of host circadian rhythms and metabolism that ensure optimal energy balance. Yet, the interplay between diet, microbes, and host factors that sustain intestinal oscillations is complex and poorly understood. Here, we report the host C-type lectin antimicrobial peptide Reg3{gamma} works with key ileal microbes to orchestrate these interactions in a bi-directional manner, independent from the intestinal core circadian clock. High fat diet diminishes physiologically relevant microbial oscillators essential for host metabolic homeostasis, resulting in arrhythmic host Reg3{gamma} expression and increased abundance and oscillation of Reg3{gamma}-independent gut microbes. This illustrates a transkingdom co-evolved biological rhythm involving reciprocating, sensor-effector signals between key host and microbial components that ultimately drive metabolism, but are also heavily influenced by diet. Restoring the gut microbiotas capacity to sense and transduce dietary signals mediated by specific host factors such as Reg3{gamma} could be harnessed to improve metabolic dysfunction.

microbiology↗

bioRxiv2020

Targeting the SARS-CoV-2 Main Protease to Repurpose Drugs for COVID-19

Guided by a computational docking analysis, about 30 FDA/EMA-approved small molecule medicines were characterized on their inhibition of the SARS-CoV-2 main protease (MPro). Of these tested small molecule medicines, six displayed an IC50 value in inhibiting MPro below 100 M. Three medicines pimozide, ebastine, and bepridil are basic small molecules. Their uses in COVID-19 patients potentiate dual functions by both raising endosomal pH to slow SARS-CoV-2 entry into the human cell host and inhibiting MPro in infected cells. A live virus-based microneutralization assay showed that bepridil inhibited cytopathogenic effect induced by SARS-CoV-2 in Vero E6 cells completely at and dose-dependently below 5 M and in A549 cells completely at and dose-dependently below 6.25 M. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.

pharmacology and toxicology↗