Biology subjects

Zhang, L.

Publications and source records attributed to Zhang, L..

At least 667 records · Page 37Linked to original sources

bioRxiv2024

Circular RNA circASH1L(4,5) protects microRNA-129-5p from target-directed microRNA degradation in human skin wound healing

Both circular RNAs (circRNA) and microRNAs (miRNA) have emerged to play important roles in health and disease. To understand their function in tissue repair, we profiled circRNA, linear RNA, and miRNA expression dynamics in human wound-edge keratinocytes across the wound healing process. Our investigation spotlighted circASH1L(4,5) and its engagement with miR-129-5p, both of which levels were increased with wound repair. Unlike conventional miRNA sponging, circASH1L enhanced miR-129 stability and silencing activity by protecting this miRNA from target-directed miRNA degradation (TDMD) triggered by NR6A1 mRNA. TGF-{beta} signaling, pivotal in wound healing, fostered circASH1L expression while suppressing NR6A1, thus enhancing the miR-129 abundance at the post-transcriptional level. Functionally, circASH1L and miR-129 enhanced keratinocyte migration and proliferation, crucial for re-epithelialization of human wounds. Collectively, our study uncovers circRNAs novel role as shields for miRNAs and sheds light on the physiological importance of regulated miRNA degradation in human skin wound healing.

molecular biology↗

bioRxiv2024

ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Transcriptome analysis in PDAC patient cohorts revealed downregulation of adrenoceptor alpha 2A (ADRA2A) in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/584316v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@edc5ceorg.highwire.dtl.DTLVardef@5579b6org.highwire.dtl.DTLVardef@1a9a000org.highwire.dtl.DTLVardef@147724a_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG HighlightsO_LIADRA2A is downregulated in the basal-like/squamous PDAC while its expression is maintained in the classical/progenitor PDAC subtype C_LIO_LIUpregulated ADRA2A expression correlates with improved PDAC survival and reduced invasion in PDAC cells C_LIO_LIUpregulated ADRA2A downregulates the MYC signaling pathway and promotes the classical/progenitor gene expression profile C_LIO_LIUpregulated ADRA2A induces a unique metabolic signature characterized by diminished amino acid and carnitine/acylcarnitine metabolism, resembling the classical/progenitor PDAC subtype C_LI

cancer biology↗

bioRxiv2024

Regulation of Interstitial Lung Diseases by Pulmonary Endothelial Cells via PLVAP

Withdrawal statementThe authors have withdrawn this manuscript because the preliminary results require further experimental validation and more comprehensive data collection to ensure scientific rigor. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

cell biology↗

bioRxiv2024

PVN-mPFC OT projections modulates pup-directed pup care or attacking in virgin mandarin voles

In many species, adult animals may exhibit caregiving or aggression towards conspecific offspring. The neural mechanisms underlying the infanticide and pup care remain poorly understood. Here, using monogamous virgin mandarin voles (Microtus mandarinus) that may exhibit pup care or infanticide, we found that more oxytocin (OT) neurons in the paraventricular nucleus (PVN) were activated during pup caring than infanticide. Optogenetic activation of OT neurons in the PVN facilitated pup-caring in male and female mandarin voles. In infanticide voles, optogenetic activation of PVN OT cells prolonged latency to approach and attack pups, whereas inhibition of these OT neurons facilitated approach and infanticide. In addition, OT release in the medial prefrontal cortex (mPFC) in pup-care voles increased upon approaching and retrieving pups, and decreased in infanticide voles upon attacking pups. Optogenetic activation of PVN OT neuron projections to the mPFC shortened the latency to approach and retrieve pups and facilitated the initiation of pup care, whereas inhibition of these projections had little effect. For pup-care females, neither activation nor inhibition of the fibers affected their behavior towards pups. In infanticide male and female voles, optogenetic activation of PVN-mPFC OT projection fibers prolonged the latency to approach and attack pups and suppressed the initiation of infanticide, whereas inhibition of these projections promoted approach and infanticide. Finally, we found that intraperitoneal injection of OT promoted pup care and inhibited infanticide behavior. It is suggested that the OT system, especially PVN OT neurons projecting to mPFC, modulates pup-directed behaviors and OT can be used to treat abnormal behavioral responses associated with some psychological diseases such as depression and psychosis.

neuroscience↗

bioRxiv2024

Cas1 mediates the interference stage in a phage-encoded CRISPR-Cas system

CRISPR-Cas systems are prokaryotic adaptive immune systems against invading phages and other mobile genetic elements, which function in three stages: adaptation, expression and interference. Interestingly, phages were also found to encode CRISPR-Cas systems to antagonize their hosts and establish infection. The Vibrio cholerae-infecting ICP1 phage was the first discovered phage with a functional CRISPR-Cas system against an antiphage region in the host genome. Nevertheless, this system lacks a domain essential for recruitment of helicase-nuclease Cas2/3 during target DNA cleavage, and how this system accomplishes the interference stage remains unknown. Here, surprisingly, we found that Cas1, a highly conserved component known to exclusively work in the adaptation stage, also mediates the interference stage through connecting Cas2/3 to the DNA bound-Cascade (Csy) complex of the ICP1 CRISPR-Cas system. A series of structures of Csy, Csy-dsDNA, Cas1-Cas2/3 and Csy-dsDNA-Cas1-Cas2/3 complexes collectively reveal the whole process of Cas1-mediated target DNA cleavage by the ICP1 CRISPR-Cas system. Together, these data support an unprecedented model in which Cas1 mediates the interference stage in a phage-encoded CRISPR-Cas system and also shed light on a unique model of primed adaptation.

microbiology↗

bioRxiv2024

Engulfment of viable neurons by reactive microglia in prion diseases

Microglia are recognized as the main cells in the central nervous system responsible for phagocytosis. During brain development, microglia eliminate excessive synapses and neurons, whereas in normal aging and neurodegenerative diseases, microglia are responsible for clearing protein aggregates and cell debris. The current study demonstrates that in prion disease, microglia effectively phagocytose prions or PrPSc during early preclinical stages. However, during the late preclinical stage, a critical shift occurs in microglial activity from PrPSc uptake to the engulfment of neurons. This change occurs before the manifestation of clinical symptoms and is followed by a rapid accumulation of total PrPSc, suggesting a potential link to neuronal dysfunction and behavioral deficits. Surprisingly, the engulfed neurons do not show apoptotic markers, indicating that microglia are targeting viable neurons. Despite up to 40% of neurons being partially engulfed at the clinical stage, there is no significant neuronal loss, suggesting that many engulfment events are incomplete, terminated or protracted. This phenomenon of partial engulfment by reactive microglia is independent of the CD11b pathway, previously associated with phagocytosis of newborn neurons during neurodevelopment. The study establishes partial engulfment as a consistent occurrence across multiple prion-affected brain regions, various mouse-adapted strains, and different subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) in humans. The current work describes a new phenomenon of partial engulfment of neurons by reactive microglia, shedding light on a novel aspect of neuronal-microglia interactions.

neuroscience↗

bioRxiv2024

Unraveling the Genetic Comorbidity Landscape of Alzheimer's Disease

Alzheimers disease (AD) has emerged as the most prevalent and complex neurodegenerative disorder among the elderly population. However, the genetic comorbidity etiology for AD remains poorly understood. In this study, we conducted pleiotropic analysis for 41 AD phenotypic comorbidities, identifying ten genetic comorbidities with 16 pleiotropy genes associated with AD. Through biological functional and network analysis, we elucidated the molecular and functional landscape of AD genetic comorbidities. Furthermore, leveraging the pleiotropic genes and reported biomarkers for AD genetic comorbidities, we identified 50 potential biomarkers for AD diagnosis. Our findings deepen the understanding of the occurrence of AD genetic comorbidities and provide new insights for the search for AD diagnostic markers. HighlightsThe present study has focused on the comorbidities associated with Alzheimers disease (AD) by constructing a landscape of these comorbidities at various levels, including diseases, genetics, and pathways. O_LIThe study findings reveal novel and significant pathways that contribute to the etiology of AD and its comorbidities. C_LIO_LIBy exploring pleiotropic genes and reported biomarkers of AD comorbidities, the study has identified several potential diagnostic biomarker candidates for AD. C_LI O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/583453v1_figG1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@2fc040org.highwire.dtl.DTLVardef@f6d801org.highwire.dtl.DTLVardef@1df65a4org.highwire.dtl.DTLVardef@18a307e_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic abstract.C_FLOATNO Study pipeline. C_FIG

neuroscience↗

bioRxiv2024

Molecular insights into the atypical activation mechanism of GPR156 in maintaining auditory function

The class C orphan GPCR GPR156, which lacks the typical extracellular region, plays a pivotal role in auditory function through Gi2/3. Here, we demonstrate that GPR156 with high constitutive activity is essential for maintaining auditory function, and we further present two cryo-EM structures of human GPR156. The GPR156 dimer in both the apo state and Gi3 protein-coupled state adopt a TM5/6-TM5/6 interface, indicating the high constitutive activity of GPR156 in the apo state. The C-terminus plays a dual role in promoting G protein binding within G-bound subunit while preventing the G-free subunit from binding to additional G protein. These observations explain how GPCR activity is maintained through dimerization and provide a mechanistic insight into the sustained role of GPR156 in maintaining auditory function.

molecular biology↗

bioRxiv2024

GDOP: A graph convolutional network-based drug "on-target" pathway prediction algorithm

Since most compounds do not induce changes in the transcriptomic levels of their target proteins in vivo, traditional gene set enrichment analysis methods can only retrieve downstream differentially expressed genes, which offer little hints to their targets. To address this problem, we proposed a graph convolutional network-based drug "on-target" pathway prediction algorithm, GDOP, which can predict small pathways that contain target gene through the power of deep learning algorithms. Our model receives as input structural information and biological characteristics (gene expression profiles) of molecules. After being trained on the publicly available LINCS data set, GDOP showed better generalization ability, reaching an AUC-ROC of 0.89 and an averaged Top10 accuracy of 0.63 on the test set. Besides, demonstrated that GDOP was able to use RNA-Seq data as input and achieved accuracy prediction results.

bioinformatics↗

bioRxiv2024

A 10-valent composite mRNA vaccine against both influenza and COVID-19

The COVID-19 pandemic caused by SARS-CoV-2 viruses has had a persistent and significant impact on global public health for four years. Recently, there has been a resurgence of seasonal influenza transmission worldwide. The co-circulation of SARS-CoV-2 and seasonal influenza viruses results in a dual burden on communities. Additionally, the pandemic potential of zoonotic influenza viruses, such as avian Influenza A/H5N1 and A/H7N9, remains a concern. Therefore, a combined vaccine against all these respiratory diseases is in urgent need. mRNA vaccines, with their superior efficacy, speed in development, flexibility, and cost-effectiveness, offer a promising solution for such infectious diseases and potential future pandemics. In this study, we present FLUCOV-10, a novel 10-valent mRNA vaccine created from our proven platform. This vaccine encodes hemagglutinin (HA) proteins from four seasonal influenza viruses and two avian influenza viruses with pandemic potential, as well as spike proteins from four SARS-CoV-2 variants. A two-dose immunization with the FLUCOV-10 elicited robust immune responses in mice, producing IgG antibodies, neutralizing antibodies, and antigen-specific cellular immune responses against all the vaccine-matched viruses of influenza and SARS-CoV-2. Remarkably, the FLUCOV-10 immunization provided complete protection in mouse models against both homologous and heterologous strains of influenza and SARS-CoV-2. These results highlight the potential of FLUCOV-10 as an effective vaccine candidate for the prevention of influenza and COVID-19. Author summaryAmidst the ongoing and emerging respiratory viral threats, particularly the concurrent and sequential spread of SARS-CoV-2 and influenza, our research introduces FLUCOV-10. This novel mRNA-based combination vaccine, designed to counteract both influenza and COVID-19, by incorporating genes for surface glycoproteins from various influenza viruses and SARS-CoV-2 variants. This combination vaccine showed highly effective in preclinical trials, generating strong immune responses, and ensuring protection against both matching and heterologous strains of influenza and SARS-CoV-2. FLUCOV-10 represents a significant step forward in our ability to address respiratory viral threats, showcasing potential as a singular, adaptable vaccine solution for global health challenges.

microbiology↗

bioRxiv2024

Secondary microglia formation center in the human fetal brain

Yolk sac-derived microglia migrate and populate the brain during development, constituting 10-15% of the total brain cells. The human brain is the largest and most complex brain with the highest cognitive capacity among all species. Therefore, the limitations of rodent brain studies in interpreting the human brain are evident. By co-immunostaining microglia in 50 {micro}m fetal brain sections from 7.5 to 16 gestational weeks (gw) and combining high-resolution scanning, we identified a highly proliferative microglia aggregate (0.108-2.129 mm2) that expanded in Downs Syndrome fetal brain (4.168 mm2) and was located near the ganglion eminence, in which Ki67+ microglia accounted for 23.4% of total microglia compared to 6.3% in other brain regions. The microglia in the aggregates lack phagocytic bulbs, membrane ruffles, and long/branching processes compared to microglia in other brain regions. Introducing human microglia into cortical organoids, but not macrophages, replicated proliferative microglial aggregates on the brain organoid surface and sufficiently penetrated deeper regions of the cortical organoids. Penetrating microglia display phagocytic capacity, enhance immunity, and accelerate the maturation of brain organoids. The large proliferative microglial aggregate may be a unique secondary microglial formation center in the human fetal brain to compensate for the enormous microglial demands during brain expansion.

neuroscience↗

bioRxiv2024

Single-cell multiomics reveals a gene regulatory circuit promoting leukemia cell differentiation

Cancer differentiation therapy aims to induce maturation of neoplastic cells, yet how cell fate is determined in oncogenic cellular contexts is poorly understood. Here we integrate chromatin accessibility and transcriptome analysis at single-cell levels to investigate the mechanism driving the differentiation trajectory of the PML/RAR+ acute promyeloid leukemia (APL) cell line model, NB4, under the induction of all-trans-retinoid acid (ATRA). We show that differentiating NB4 cells navigate through an intermediate cell fate decision point that leads to either terminal granulopoiesis or a transient immature-lymphocyte-like state. Functional perturbation studies indicate that ATRA signaling activates discrete PML/RAR-target enhancers to induce a positive feedforward gene regulatory circuit involving two myeloid-lineage transcription factors, SPI1 and CEBPE, which is both necessary and sufficient to activate a myelocytic gene expression program in NB4. Further, ectopic expression of SPI1 and CEBPE also promotes myelocytic differentiation in non-APL leukemia cell lines HL60 and K562. Together, these results shed light on the differentiation trajectory of therapy-induced cell decisions of APL and suggest a gene regulatory circuit that may be broadly exploited to promote terminal differentiation of leukemia.

cancer biology↗

bioRxiv2024

Armored Bicistronic CAR T Cells with Dominant-negative TGF-β Receptor II to Overcome Resistance in Glioblastoma.

Chimeric antigen receptor (CAR) T cells have shown significant efficacy in hematological diseases. However, CAR T therapy has demonstrated limited efficacy in solid tumors, including glioblastoma (GBM). One of the most important reasons is the immunosuppressive tumor microenvironment (TME), which promotes tumor growth and suppresses immune cells to eliminate tumor cells. The human transforming growth factor-beta (TGF-{beta}) plays a crucial role in forming the suppressive GBM TME and driving the suppression of the anti-GBM response. In order to mitigate TGF-{beta} mediated suppressive activity, we combined a dominant-negative TGF-{beta} receptor II (dnTGF{beta}RII) with our previous bicistronic CART-EGFR-IL13R2 construct, currently being evaluated in a clinical trial, to generate CART-EGFR-IL13R2-dnTGF{beta}RII, a tri-modular construct we are developing for clinical application. We hypothesized that this approach would more effectively subvert resistance mechanisms observed with GBM. Our data suggests that CART-EGFR-IL13R2-dnTGF{beta}RII significantly augmented T cell proliferation and enhanced functional responses, particularly in a TGF{beta}-rich tumor environment. Additionally, in vivo studies validated the safety and efficacy of the dnTGF{beta}RII cooperating with CARs in targeting and eradicating GBM in a NSG mouse model.

cancer biology↗

bioRxiv2024

Genome-Wide Association Study Reveals Influence of Cell-specific Gene Networks on Soybean Root System Architecture

Root system architecture (RSA) describes the shape and arrangement of a plants roots in the soil including the angle, rate of growth, and type of individual roots, which facilitates the uptake of nutrients and water. In crop improvement efforts, RSA has been less well studied due to the technical challenges associated with phenotyping roots as well as a focus on above-ground traits such as yield. We developed a gel-based root phenotyping system called RADICYL (Root Architecture 3D Cylinder), which is a non-invasive, high-throughput approach that enabled us to measure 15 RSA traits. We leveraged RADICYL to perform a comprehensive genome-wide association study (GWAS) with a panel of 371 diverse soybean elite lines, cultivars, landraces, and closely related species to identify gene networks underlying RSA. We identified 54 significant single nucleotide polymorphisms (SNPs) in our GWAS, some of which were shared across multiple RSA traits while others were specific to a given trait. We generated a single cell atlas of the soybean root using single nuclei RNA sequencing (snRNAseq) to explore the associated genes in the context of root tissues. Using gene co-expression network (GCN) analyses applied to RNA-seq of soybean root tissues, we identified network-level associations of genes predominantly expressed in endodermis with root width, and of those expressed in metaphloem with lateral root length. Our results suggest that pathways active in the endodermis and metaphloem cell-types influence soybean root system architecture.

plant biology↗

bioRxiv2024

Virological traits of the SARS-CoV-2 BA.2.87.1 lineage

The highly mutated SARS-CoV-2 BA.2.87.1 lineage was recently detected in South Africa, but its transmissibility is unknown. Here, we report that BA.2.87.1 efficiently enters human cells but is more sensitive to antibody-mediated neutralization than the currently dominating JN.1 variant. Acquisition of adaptive mutations might thus be needed for high transmissibility.

molecular biology↗

bioRxiv2024

CNVeil enables accurate and robust tumor subclone identification and copy number estimation from single-cell DNA sequencing data

Single-cell DNA sequencing (scDNA-seq) has significantly advanced cancer research by enabling precise detection of chromosomal aberrations, such as copy number variations (CNVs), at a single-cell level. These variations are crucial for understanding tumor progression and heterogeneity among tumor subclones. However, accurate CNV inference in scDNA-seq has been constrained by several factors, including low coverage, sequencing errors, and data variability. To address these challenges, we introduce CNVeil, a robust quantitative algorithm designed to accurately reveal CNV profiles while overcoming the inherent noise and bias in scDNA-seq data. CNVeil incorporates a unique bias correction method using normal cell profiles identified by a PCA-based Gini coefficient, effectively mitigating sequencing bias. Subsequently, a multi-level hierarchical clustering, based on selected highly variable bins, is employed to initially identify coarse subclones for robust ploidy estimation and further identify fine subclones for segmentation. To infer the CNV segmentation landscape, a novel change rate-based across-cell breakpoint identification approach is specifically designed to diminish the effects of low coverage and data variability on a per-cell basis. Finally, a consensus segmentation is utilized to further standardize read depth for the inference of the final CNV profile. In comprehensive benchmarking experiments, where we compared CNVeil with seven state-of-the-art CNV detection tools, CNVeil exhibited exceptional performance across a diverse set of simulated and real scDNA-seq data in cancer genomics. CNVeil excelled in subclone identification, segmentation, and CNV profiling. In light of these results, we anticipate that CNVeil will significantly contribute to single-cell CNV analysis, offering enhanced insights into chromosomal aberrations and genomic complexity.

bioinformatics↗

bioRxiv2024

The Co-Evolution of Jawed Vertebrates and Interferon Regulatory Factor 5 Generates Unique Inflammation and Innate Immunity

The emergence of jaws in early vertebrates introduced a novel feeding apparatus and potent oral defenses but also increased the risk of physical injury and pathogen exposure. Innate immunity and inflammation constitute the bodys first line of defense against invading microbes and tissue damage, aiming to eliminate threats and restore internal homeostasis. Interferon regulatory factor 5 (IRF5) plays a critical role in orchestrating innate immunity and inflammation by regulating the transcription of genes that encode type I interferons (IFNs) and pro-inflammatory cytokines. Despite this, the evolution of IRF5 has remained poorly understood. We have identified the IRF5 and IRF6 genes in cartilaginous fish, including sharks. As cartilaginous fish represent one of the oldest surviving jawed vertebrate lineages, the presence of these genes suggests the genes have ancient origins potentially dating back hundreds of millions of years to early jawed vertebrates. Furthermore, our analysis shows that IRF5 has conserved nuclear export sequences and phosphorylation sites for activation throughout evolution from cartilaginous fish to humans, indicating these regulatory elements evolved early and have been maintained across jawed vertebrates. Additionally, the shift in subcellular localization of IRF5 from nucleus to cytosol, and of other interferon related IRFs, aligns with functional enhancements of IRFs in innate immunity and the emergence of IFNs across jawed vertebrates. This analysis implies that the evolution of jaws may have driven the emergence of new IRF members, the expansion of their functions, and the development of a unique inflammation and innate immune system.

immunology↗

bioRxiv2024

Retrotransposon-mediated variation of a chitin synthase gene confers insect resistance to Bacillus thuringiensis Vip3Aa toxin

Bacillus thuringiensis (Bt) crops expressing Vip3Aa are highly efficacious in controlling major lepidopteran pests and delaying evolution of pest resistance. Although practical resistance to Vip3Aa in the field has not been reported, to proactively manage the pest resistance, there is an urgent need to better understand the genetic basis of resistance to Vip3Aa. This is particularly important for the fall armyworm (Spodoptera frugiperda), one of the most destructive pests around the world, which has evolved practical resistance to Bt crystal (Cry) toxins. Here, a highly Vip3Aa-resistant (resistance ratio: 5,562-fold) strain of S. frugiperda was selected in the laboratory. Results from bulked segregant analysis, fine-scale mapping, and genetic linkage analysis indicate that a mutation in the midgut-specific chitin synthase gene, SfCHS2, is strongly associated with high-level resistance to Vip3Aa. The resistance is ascribed to the transcriptional variation caused by retrotransposon insertion. The same variation of SfCHS2 was also detected in a field population. Importantly, knockout of SfCHS2 via CRISPR/Cas9 in susceptible S. frugiperda confers its complete resistance (>10,000-fold) to Vip3Aa. Also, we demonstrate that knockout of CHS2 can result in complete resistance to Vip3Aa in additional lepidopteran species, suggesting a general role of this gene in Vip3Aa resistance among lepidopteran pests. These results reported here would contribute to monitor and management of pest resistance to Vip3Aa.

genetics↗