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Biology subjects

Zhang, L.

Publications and source records attributed to Zhang, L..

At least 1,225 records · Page 68Linked to original sources

Dopamine receptor DOP-1 engages a sleep pathway to modulate swimming in C. elegans

Animals require robust yet flexible programs to support locomotion. While it is clear that a variety of processes must be engaged to ensure rhythmic actions, the exact mechanisms remain largely unknown. Here we report a novel pathway that connects the D1-like dopamine receptor DOP-1 with a sleep mechanism to modulate swimming in C. elegans. We show that DOP-1 plays a negative role in sustaining swimming behavior. By contrast, a pathway through the D2-like dopamine receptor DOP-3 negatively regulates the initiation of swimming, but its impact fades quickly over a few minutes. We find that DOP-1 and the GPCR kinase GRK-2 function in the sleep interneuron RIS, where DOP-1 modulates the secretion of a sleep neuropeptide FLP-11. Our genetic studies further show that DOP-1 and FLP-11 act in the same pathway to modulate swimming. Together, these results delineate a functional connection between a dopamine receptor and a sleep program to regulate swimming in C. elegans. The temporal transition between DOP-3 and DOP-1 pathways highlights the dynamic nature of neuromodulation for rhythmic movements that persist over time. HIGHLIGHTSO_LIThe D1-like dopamine receptor DOP-1 regulates swimming at 10 minutes C_LIO_LIAn integrated function of DOP-1 and DOP-3 is required for the continuity of swimming C_LIO_LIDOP-1 and GRK-2 act in the sleep neuron RIS C_LIO_LIFLP-11, a neuropeptide that promotes sleep, negatively regulates swimming C_LI IN BRIEFXu et al. investigated genetic programs that modulate swimming behavior in the nematode C. elegans. They identified a functional link that couples a D1-like dopamine receptor to a sleep program that modulates the sustained phase rather than the initial phase of swimming.

genetics↗

Soluble guanylate cyclase stimulation mitigates skeletal and cardiac muscle dysfunction in a mdx model of Duchenne muscular dystrophy

The impairment of neuronal nitric oxide synthase (nNOS) signaling contributes to disease pathology in the muscle wasting disorder Duchenne muscular dystrophy (DMD). nNOS signal propagation occurs through nitric oxide sensitive soluble guanylate cyclase (sGC), a critical source of cyclic guanosine monophosphate (cGMP) in muscle. Although both nNOS and sGC activity are impaired in DMD patients, little is known about sGC as a therapeutic target. In this study, we tested the hypothesis that stimulating sGC activity with the allosteric agonist BAY41-8543 mitigates striated muscle pathology in the mdx4cv mouse model of DMD. In contrast to DMD patients, mdx mice exhibited greater basal sGC activity than wild type controls with preservation of cGMP levels due partly to upregulation of sGC in some muscles. Stimulating sGC activity in mdx mice with BAY41-8543 substantially reduced skeletal muscle damage, macrophage densities and inflammation and significantly increased resistance to contraction-induced fatigue. BAY41-8543 also enhanced in vivo diaphragm function while reducing breathing irregularities suggesting improved respiratory function. BAY41-8543 attenuated cardiac hypertrophic remodeling, fibrosis and diastolic dysfunction including left atrium enlargement in aged mdx mice. Overall, sGC stimulation significantly mitigated skeletal and cardio-respiratory dysfunction in mdx4cv mice. Importantly, this study provides compelling pre-clinical evidence supporting sGC as a novel target in DMD and the repurposing of FDA-approved sGC stimulators, such as riociguat and veraciguat, as a novel therapeutic approach for DMD.

physiology↗

EZH2 Engages TGFβ Signaling to Promote Breast Cancer Bone Metastasis via Integrin β1-FAK Activation

Bone metastasis is a frequent complication of breast cancer, occurring in about 50-70% of breast cancer patients with late-stage disease. The lack of effective therapy suggests that the precise molecular mechanisms underlying bone metastasis are still unclear. Enhancer of zeste homolog 2 (EZH2) is considered a breast cancer oncogene and its expression is correlated with metastasis of breast cancer, but its function in bone metastasis has not been well explored. Herein we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGF{beta}) signaling, a key pathway in bone metastasis. Knocking down EZH2 decreases bone metastasis incidence and outgrowth in vivo. EZH2 induces cancer cell proliferation and osteoclast maturation, when breast cancer cells are co-cultured with osteoblasts and osteoclasts together in vitro. Mechanistically, EZH2 increases transcription of ITGB1, which encodes for integrin {beta}1. Integrin {beta}1 activates focal adhesion kinase (FAK), which phosphorylates TGF{beta} receptor type I (TGF{beta}RI) at tyrosine 182, thus enhances the binding of TGF{beta}RI to TGF{beta} receptor type II (TGF{beta}RII), therefore activates Smad2 and increases parathyroid hormone-like hormone (PTHLH) expression. Clinically applicable FAK inhibitors but not EZH2 methyltransferase inhibitor effectively inhibits breast cancer bone metastasis in vivo. Overall, our data signify integrin {beta}1-FAK as a new downstream effector of EZH2 in breast cancer cells, and EZH2-integrin {beta}1-FAK axis cooperates with TGF{beta} signaling pathway to promote bone metastasis of breast cancer.

cancer biology↗

SARS-CoV-2 mutations acquired in mink reduce antibody-mediated neutralization

Transmission of SARS-CoV-2 from humans to farmed mink was observed in Europe and the US. In the infected animals viral variants arose that harbored mutations in the spike (S) protein, the target of neutralizing antibodies, and these variants were transmitted back to humans. This raised concerns that mink might become a constant source of human infection with SARS-CoV-2 variants associated with an increased threat to human health and resulted in mass culling of mink. Here, we report that mutations frequently found in the S proteins of SARS-CoV-2 from mink were mostly compatible with efficient entry into human cells and its inhibition by soluble ACE2. In contrast, mutation Y453F reduced neutralization by an antibody with emergency use authorization for COVID-19 therapy and by sera/plasma from COVID-19 patients. These results suggest that antibody responses induced upon infection or certain antibodies used for treatment might offer insufficient protection against SARS-CoV-2 variants from mink.

molecular biology↗

Bfimpute: A Bayesian factorization method to recover single-cell RNA sequencing data

Single-cell RNA-seq (scRNA-seq) offers opportunities to study gene expression of tens of thousands of single cells simultaneously, to investigate cell-to-cell variation, and to reconstruct cell-type-specific gene regulatory networks. Recovering dropout events in a sparse gene expression matrix for scRNA-seq data is a long-standing matrix completion problem. We introduce Bfimpute, a Bayesian factorization imputation algorithm that reconstructs two latent gene and cell matrices to impute final gene expression matrix within each cell group, with or without the aid of cell type labels or bulk data. Bfimpute achieves better accuracy than other six publicly notable scRNA-seq imputation methods on simulated and real scRNA-seq data, as measured by several different evaluation metrics. Bfimpute can also flexibly integrate any gene or cell related information that users provide to increase the performance. Availability: Bfimpute is implemented in R and is freely available at https://github.com/maiziezhoulab/Bfimpute.

bioinformatics↗

Single-cell transitional dynamics unravel stimulus- and cell type-dependent signaling outputs of distinct p53 regulatory feedback motifs

Despite myriad of systemic analysis, our quantitative understanding of signaling networks and their differential outputs is still limited, especially at the dynamic level. Here we employed a network motif approach to dissect key regulatory units of p53 pathway and determined how their collective activities generated context-specific dynamic responses. By combining single-cell imaging and mathematical modeling of dose-dependent p53 dynamics induced by three chemotherapeutics of distinct mechanism-of-action, including Etoposide, Nutlin-3a and 5-Fluouracil, and in five cancer cell types, we identified novel p53 dynamic modes and their mechanistic origins with new insight on previously unknown drug mediators and phenotypic heterogeneity of cancer cells. Our results established the functional roles of unique feedback motifs of p53 pathway in generating the stimulus- and cell type-specific signaling responses and demonstrated that transitional dynamics activated at intermediate stimulus levels can be exploited as novel quantitative readouts to uncover and elucidate the key building blocks of bio-networks.

systems biology↗

Bacterium-Enabled Transient Gene Activation by Artificial Transcription Factor for Resolving Gene Regulation in Maize

Cellular functions are diversified through intricate transcription regulations, and an understanding gene regulation networks is essential to elucidating many developmental processes and environmental responses. Here, we employed the Transcriptional-Activator Like effectors (TALes), which represent a family of transcription factors that are synthesized by members of the {gamma}-proteobacterium genus Xanthomonas and secreted to host cells for activation of targeted host genes. Through delivery by the maize pathogen, Xanthomonas vasicola pv. vasculorum, designer TALes (dTALes), which are synthetic TALes, were used to induce the expression of the maize gene glossy3 (gl3), a MYB transcription factor gene involved in the cuticular wax biosynthesis. RNA-Seq analysis of leaf samples identified 146 gl3 downstream genes. Eight of the nine known genes known to be involved in the cuticular wax biosynthesis were up-regulated by at least one dTALe. A top-down Gaussian graphical model predicted that 68 gl3 downstream genes were directly regulated by GL3. A chemically induced mutant of the gene Zm00001d017418 from the gl3 downstream gene, encoding aldehyde dehydrogenase, exhibited a typical glossy leaf phenotype and reduced epicuticular waxes. The bacterial protein delivery of artificial transcription factors, dTALes, proved to be a straightforward and powerful approach for the revelation of gene regulation in plants.

plant biology↗

Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation

The SARS-CoV-2 coronavirus responsible for the global pandemic contains a unique furin cleavage site in the spike protein (S) that increases viral infectivity and syncytia formation. Here, we show that O-glycosylation near the furin cleavage site is mediated by specific members of the GALNT enzyme family and is dependent on the novel proline at position 681 (P681). We further demonstrate that O-glycosylation of S decreases furin cleavage. Finally, we show that GALNT family members capable of glycosylating S are expressed in human respiratory cells that are targets for SARS-CoV-2 infection. Our results suggest that O-glycosylation may influence viral infectivity/tropism by modulating furin cleavage of S and provide mechanistic insight into the potential role of P681 mutations in the recently identified, highly transmissible B.1.1.7 variant.

biochemistry↗

High Affinity Chimeric Antigen Receptor with Cross-Reactive scFv to Clinically Relevant EGFR Oncogenic Isoforms

Tumor heterogeneity is a key reason for therapeutic failure and tumor recurrence in glioblastoma (GBM). Our chimeric antigen receptor (CAR) T cell (2173 CAR T cells) clinical trial (NCT02209376) against Epidermal growth factor receptor (EGFR) variant III (EGFRvIII) demonstrated successful trafficking of T cells across the blood brain barrier into GBM active tumor sites. However, CAR T cell infiltration was associated only with a selective loss of EGFRvIII+ tumor, demonstrating little to no effect on EGFRvIII- tumor cells. Post-CAR T treated tumor specimens showed continued presence of EGFR amplification and oncogenic EGFR extracellular domain (ECD) missense mutations, despite loss of EGFRvIII. To address tumor escape, we generated an EGFR-specific CAR by fusing monoclonal antibody (mAb) 806 to a 4-1BB co-stimulatory domain. The resulting construct was compared to 2173 CAR T cells in GBM, using in vitro and in vivo models. 806 CAR T cells specifically lysed tumor cells and secreted cytokines in response to amplified EGFR, EGFRvIII, and EGFR-ECD mutations in U87MG cells, GBM neurosphere-derived cell lines, and patient-derived GBM organoids. 806 CAR T cells did not lyse fetal brain astrocytes or primary keratinocytes to a significant degree. They also exhibited superior antitumor activity in vivo when compared to 2173 CAR T cells. The broad specificity of 806 CAR T cells to EGFR alterations gives us the potential to target multiple clones within a tumor and reduce opportunities for tumor escape via antigen loss.

cancer biology↗

DeepDRIM: a deep neural network to reconstruct cell-type-specific gene regulatory network using single-cell RNA-seq data

AO_SCPLOWBSTRACTC_SCPLOWSingle-cell RNA sequencing is used to capture cell-specific gene expression, thus allowing reconstruction of gene regulatory networks. The existing algorithms struggle to deal with dropouts and cellular heterogeneity, and commonly require pseudotime-ordered cells. Here, we describe DeepDRIM a supervised deep neural network that represents gene pair joint expression as images and considers the neighborhood context to eliminate the transitive interactions. Deep-DRIM yields significantly better performance than the other nine algorithms used on the eight cell lines tested, and can be used to successfully discriminate key functional modules between patients with mild and severe symptoms of coronavirus disease 2019 (COVID-19).

bioinformatics↗

Modeling of histone modifications reveals formation mechanism and function of bivalent chromatin

Bivalent chromatin is characterized by occupation of both activating histone modifications and repressive histone modifications. While bivalent chromatin is known to link with many biological processes, the mechanisms responsible for its multiple functions remain unclear. Here, we develop a mathematical model that involves antagonistic histone modifications H3K4me3 and H3K27me3 to capture the key features of bivalent chromatin. Three necessary conditions for the emergence of bivalent chromatin are identified, including advantageous methylating activity over demethylating activity, frequent noise conversions of modifications, and sufficient nonlinearity. The first condition is further confirmed by analyzing the experimental data from a recent study. Investigation of the composition of bivalent chromatin reveals that bivalent nucleosomes carrying both H3K4me3 and H3K27me3 account for no more than half of nucleosomes at the bivalent chromatin domain. We identify that bivalent chromatin not only allows transitions to multiple states but also serves as a stepping stone to facilitate a step-wise transition between repressive chromatin state and activating chromatin state, and thus elucidate crucial roles of bivalent chromatin in mediating phenotypical plasticity during cell fate determination.

systems biology↗

Comparative genomics of Chinese and international isolates of Escherichia albertii: population structure and evolution of virulence and antimicrobial resistance

Escherichia albertii is a newly recognized species in the genus Escherichia that causes diarrhea. The population structure, genetic diversity and genomic features has not been fully examined. Here, 169 E. albertii isolates from different sources and regions in China were sequenced and combined with 312 publicly available genomes for phylogenetic and genomic analyses. The E. albertii population was divided into 2 clades and 8 lineages, with lineage 3 (L3), L5 and L8 more common in China. Clinical isolates were observed in all clades/lineages. Virulence genes were found to be distributed differently among lineages: subtypes of the intimin encoding gene eae and the cytolethal distending toxin (Cdt) gene cdtB were lineage associated, the second type three secretion system (ETT2) island was truncated in L3 and L6. Seven new eae subtypes and 1 new cdtB subtype (cdtB-VI) were found. Alarmingly, 85.9% of the Chinese E. albertii isolates were predicted to be multidrug resistant (MDR) with 35.9% harboured genes capable of conferring resistance to 10 to 14 different drug classes. By in silico multi-locus sequence typing, majority of the MDR isolates belonged to 4 STs (ST4638, ST4479, ST4633 and ST4488). Thirty-four intact plasmids carrying MDR and virulence genes, and 130 intact prophages were identified from 17 complete E. albertii genomes. Ten plasmid replicon types were found to be significantly associated with MDR. The 130 intact prophages were clustered into 5 groups, with group 5 prophages harbouring more virulence genes. Our findings provided fundamental insights into the population structure, virulence variation and MDR of E. albertii. Impact statementE. albertii is newly recognized foodborne pathogen causing diarrhea. Elucidation of its genomic features is important for surveillance and control of E. albertii infections. In this work, 169 E. albertii genomes from difference sources and regions in China were collected and sequenced, which contributed to the currently limited genomic data pool of E. albertii. In combination with 312 publicly available genomes from 14 additional countries, the population structure of E. albertii was defined. The presence and subtypes of virulence genes in different lineages were significantly different, indicating potential pathogenicity variation. Additionally, the presence of multidrug resistance (MDR) genes was alarmingly high in the Chinese dominated lineages. MDR associated STs and plasmid subtypes were identified, which could be used as sentinels for MDR surveillance. Moreover, the subtypes of plasmids and prophages were distributed differently across lineages, and were found to contribute to the acquisition of virulence and MDR genes of E. albertii. Altogether, this work reveals the diversity of E. albertii and characterized its genomic features in unprecedented detail. Data SummaryAll newly sequenced data in this work were deposited in National Center for Biotechnology Information (NCBI) under the BioProject of PRJNA693666, including 6 complete genomes and raw reads of 164 E. albertii isolates.

genomics↗

Molecular mechanism behind the involvement of apple flavonoid glycosyltransferase gene MdGT1 in the color of apple leaves

Nowadays, the plant family 1 UDP-glycosyltransferases (UGTs) are more and more investigated owing to their contribution to the plant secondary metabolism and diverse biological roles. Apple (Malus domestica) is one of the most widely cultivated fruit trees with great economical importance. However, poor knowledge is known about the apple UGTs. In this study, we identified 229 members of family 1 through a genome-wide analysis of the apple UGTs, which were clustered into 18 groups, from A to R. We also performed detailed analysis to 34 apple UGTs with quantitavive RT-PCR, and discovered a number of stress-regulated UGTs. Among them, we characterized the role of MD09G1064900, also named as MdUGT83L3, which is significantly induced by salt and cold. In vivo analysis showed that it has high activity towards cyanidin, and moderate activity towards quercetin and keampferol. The transgenic callus and regenerated apple plants overexpressing MdUGT83L3 showed enhanced tolerance to salt and cold treatments. Overexpression of MdUGT83L3 also increased anthocyanin accumulation in the callus tissues and enhanced ROS clearing upon exposed to salt and cold stresses. Futhermore, via yeast-two-hybrid assay, EMSA and CHIP analysis, we also found that MdUGT83L3 could be directly regualted by MdMYB88. Our study indicated that MdUGT83L3, under the regulation of MdMYB88, plays important roles in salt and cold stress adaptation via modulating flavonoid metabolism in apple.

molecular biology↗

ESD1 Affects Seed Setting Rate in Rice by Controlling Embryo Sac Development

Seed setting rate is one of the critical factors that determine rice yield. Grain formation is a complex biological process, whose molecular mechanism is yet to be improved. Here we investigated the function of an OVATE family protein, Embryo Sac Development 1 (ESD1), in the regulation of seed setting rate in rice (Oryza sativa) by examining its loss-of-function mutants generated via CRISPR/Cas9 technology. ESD1 was predominantly expressed at stage 6 of panicle development, especially in the ovules. esd1 mutants displayed reduced seed setting rates with normal stamen development and pollen tube growth but abnormal pistil group. Investigation of embryo sacs revealed that during the mitosis of functional megaspores, some egg cells degraded during differentiation in esd1 mutants, thereby hindering subsequent fertilization process and reducing seed setting rate. In addition, the transcriptional level of OsAPC6, a reported embryo sac developing gene, was found to be significantly reduced in esd1 mutants. These results support that ESD1 is an important modulator of embryo sac development and seed setting rate in rice. Together, this finding demonstrates that ESD1 positively regulates the seed setting rate by controlling embryo sac development in rice, and has implications for the improvement of rice yield.

plant biology↗

SiCEP3, a C-terminally encoded peptides from Setaria italica, promotes ABA import and signaling pathway

C-terminally encoded peptides (CEPs) are small peptides, typically post-translationally modified, and highly conserved in many species. CEPs are known to play roles in inhibition of plant growth and regulation of development, but the mechanisms are not well understood. In this study, we searched for CEP peptides in foxtail millet (Setaria italica). The 14 peptides we identified are divided into two subfamilies. The transcripts of most SiCEPs were more abundant in roots than in other tissues. SiCEP3, SiCEP4, and SiCEP5 were also expressed at high levels in panicles. Moreover, expression of all SiCEPs was induced by biotic stress and phytohormones. SiCEP3 overexpression and application of biosynthetic SiCEP3 both inhibited the growth of seedlings. In the presence of ABA, growth inhibition and ABA content of seedlings increased with the concentration of SiCEP3. Transcripts encoding two ABA transporters and one ABA receptor were induced by SiCEP3, ABA, and the two in combination. Further analysis revealed that SiCEP3 promoted ABA transport via NRT1.2 and ABCG40. In addition, SiCEP3, ABA, or the combination inhibited the kinase activities of CEP receptors CEPR1/2. Taken together, our results indicated that the CEP-CEPR module mediates ABA signaling by regulating ABCG40, NRT1.2, and PYL4 in planta. HighlightSiCEP3, a C-terminally encoded peptide, can promote ABA import and signaling pathway by inhibiting the kinase activity of its receptors under abiotic stress in Setaria italica.

cell biology↗

Pancreatic cancer prognosis is predicted by a novel ATAC-array technology for assessing chromatin accessibility

We investigated tumor-cell-intrinsic chromatin accessibility patterns of pancreatic ductal adenocarcinoma (PDAC) by ATAC-seq on EpCAM+ PDAC malignant epithelial cells, sorted from 54 freshly resected human tumors, and discovered a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identified two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further developed a novel chromatin accessibility microarray methodology termed "ATAC-Array", an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this novel methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validated ATAC-array technology in both the original ATAC-Seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a novel, lowcost, clinically feasible technology for assessing chromatin accessibility profiles.

cancer biology↗

Topological analysis of single-cell data reveals shared glial landscape of macular degeneration and neurodegenerative diseases

1One Sentence SummaryA novel topological machine learning approach applied to single-nucleus RNA sequencing from human retinas with age-related macular degeneration identifies interacting disease phase-specific glial activation states shared with Alzheimers disease and multiple sclerosis. 2 AbstractNeurodegeneration occurs in a wide range of diseases, including age-related macular degeneration (AMD), Alzheimers disease (AD), and multiple sclerosis (MS), each with distinct inciting events. To determine whether glial transcriptional states are shared across phases of degeneration, we sequenced 50,498 nuclei from the retinas of seven AMD patients and six healthy controls, generating the first single-cell transcriptomic atlas of AMD. We identified groupings of cells implicated in disease pathogenesis by applying a novel topologically-inspired machine learning approach called diffusion condensation. By calculating diffusion homology features and performing persistence analysis, diffusion condensation identified activated glial states enriched in the early phases of AMD, AD, and MS as well as an AMD-specific proangiogenic astrocyte state promoting pathogenic neovascularization in advanced AMD. Finally, by mapping the expression of disease-associated genes to glial states, we identified key signaling interactions creating hypotheses for therapeutic intervention. Our topological analysis identified an integrated disease-phase specific glial landscape that is shared across neurodegenerative conditions affecting the central nervous system.

neuroscience↗

Identifying long non-coding RNAs and characterizing their functional roles in swine mammary gland from colostrogenesis to lactogenesis

Long non-coding RNAs (lncRNAs) play important regulatory roles in milk biological processes. While, little is known about the identification and function of swine lncRNAs in response to mammary gland development. Here, we identified 286 differentially expressed (DE) lncRNAs in mammary gland at different stages from 14 days prior to (-) parturition to day 1 after (+) parturition using the published RNA-seq data. The expression pattern of these DE lncRNAs was examined, and most of lncRNAs expressions were strongly changed from Day -2 to Day +1. Functional annotation revealed that the DE lncRNAs were mainly involved in the mammary gland developing, lactation developing, milk composition metabolism and colostrum function. By performing the weighted gene co-expression network analysis (WGCNA), we identified 7 out of 12 lncRNA-mRNA modules, including 35 lncRNAs and 319 mRNAs, which were highly associated with the mammary gland at Day -14, Day -2 and Day +1. Integrated analysis of the DE lncRNAs expression pattern examination, targets prediction, function annotation and WGCNA suggested that 18 lncRNAs (such as, XLOC_020627, ENSSSCG00000051193, XLOC_025150, ENSSSCG00000042618, XLOC_963181, ENSSSCG00000051701, XLOC_018030, and XLOC_025146) and their 20 target genes (such as, ACTN4, ADCY1, CSN3, SMO, CSN2, PRKAG2, FIBCD1, and GALNT7), were considered as the promising candidates for swine parturition and colostrum occurrence processes. Our research provided the insights into lncRNA profiles and their regulating mechanisms from colostrogenesis to lactogenesis in swine.

genetics↗