Biology subjects

Zhang, W.

Publications and source records attributed to Zhang, W..

At least 577 records · Page 32Linked to original sources

bioRxiv2023

Pain hypersensitivity is dependent on autophagy protein Beclin 1 in males but not females

Chronic pain is a pervasive health, social, and economic problem affecting 1 in 5 individuals around the world. Increasingly, it is understood that alterations in fundamental cell biological processes are critical for chronic pain. A prominent cellular process is autophagy but whether it plays a role in pain is unknown. To investigate whether autophagy is involved in pain processing and is targetable for pain relief, we focused on Beclin 1, a component of the class III phosphatidylinositol 3-kinase (PI3K) complex necessary for initiating autophagy. Here, we found that inflammatory pain hypersensitivity in male mice lacking one allele of Becn1 is significantly greater than that in wild type mice. By contrast, in female mice, loss of Becn1 did not affect inflammation-induced pain hypersensitivity. Further, intrathecal delivery of an activator of Beclin 1, tat-beclin 1, reversed mechanical hypersensitivity induced by peripheral inflammation or peripheral nerve injury in males. Tat-beclin 1 also prevented mechanical hypersensitivity induced by exogenous brain-derived neurotrophic factor (BDNF), a core mediator of inflammatory and neuropathic pain in the spinal dorsal horn in males. Pain signaling pathways converge on enhancement of N-methyl-D-aspartate receptors (NMDARs) in spinal dorsal horn neurons. We found that loss of Beclin 1 increases expression of the pain-critical NMDAR subunit, GluN2B, in the dorsal horn and upregulates synaptic NMDAR-mediated currents in dorsal horn neurons from males but not females. From our converging lines of evidence, we conclude that inhibition of Beclin 1 in the dorsal horn is critical in mediating inflammatory and neuropathic pain signaling pathways in males. Our findings provide the basis for sex-specific therapeutic approaches targeting pain with a new class of analgesics - activators of Beclin 1.

neuroscience↗

bioRxiv2023

Integrative Multi-omic Profiling of Two Human Decedents Receiving Pig Heart Xenografts Reveals Strong Perturbations in Early Immune-Cell and Cellular Metabolism Responses.

BackgroundRecent advances in xenotransplantation in living and decedent humans using pig xenografts have laid promising groundwork towards future emergency use and first in human trials. Major obstacles remain though, including a lack of knowledge of the genetic incompatibilities between pig donors and human recipients which may led to harmful immune responses against the xenograft or dysregulation of normal physiology. In 2022 two pig heart xenografts were transplanted into two brain-dead human decedents with a minimized immunosuppression regime, primarily to evaluate onset of hyper-acute antibody mediated rejection and sustained xenograft function over 3 days. MethodsWe performed multi-omic profiling to assess the dynamic interactions between the pig and human genomes in the first two pig heart-xenografts transplants into human decedents. To assess global and specific biological changes that may correlate with immune-related outcomes and xenograft function, we generated transcriptomic, lipidomic, proteomic and metabolomics datasets, across blood and tissue samples collected every 6 hours over the 3-day procedures. ResultsSingle-cell datasets in the 3-day pig xenograft-decedent models show dynamic immune activation processes. We observe specific scRNA-seq, snRNA-seq and geospatial transcriptomic changes of early immune-activation leading to pronounced downstream T-cell activity and hallmarks of early antibody mediated rejection (AbMR) and/or ischemia reperfusion injury (IRI) in the first xenograft recipient. Using longitudinal multiomic integrative analyses from blood in addition to antigen presentation pathway enrichment, we also observe in the first xeno-heart recipient significant cellular metabolism and liver damage pathway changes that correlate with profound physiological dysfunction whereas, these signals are not present in the other xenograft recipient. ConclusionsSingle-cell and multiomics approaches reveal fundamental insights into early molecular immune responses indicative of IRI and/or early AbMR in the first human decedent, which was not evident in the conventional histological evaluations.

systems biology↗

bioRxiv2023

Transfer Learning Enhanced Graph Neural Network for Aldehyde Oxidase Metabolism Prediction and Its Experimental Application

Aldehyde oxidase (AOX) is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics. AOX-mediated metabolism can result in unexpected outcomes, such as the production of toxic metabolites and high metabolic clearance, which can lead to the clinical failure of novel therapeutic agents. Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability. In this study, we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism. AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction, while utilizing transfer learning from 13C nuclear magnetic resonance data to enhance its performance on both tasks. AOMP significantly outperformed the benchmark methods in both cross-validation and external testing. Using AOMP, we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability, which were validated through in vitro experiments. Furthermore, for the convenience of the community, we established the first online service for AOX metabolism prediction based on AOMP, which is freely available at https://aomp.alphama.com.cn.

bioinformatics↗

bioRxiv2023

Deep-learning Based Pathological Assessment of Frozen Procurement Kidney Biopsies Predicts Graft Loss and Guides Organ Utilization: A Large-scale Retrospective Study

BackgroundLesion scores on procurement donor biopsies are commonly used to guide organ utilization. However, frozen sections present challenges for histological scoring, leading to inter- and intra-observer variability and inappropriate discard. MethodsWe constructed deep-learning based models to recognize kidney tissue compartments in H&E stained sections from procurement biopsies performed at 583 hospitals nationwide in year 2011-2020. The models were trained and tested respectively on 11473 and 3986 images sliced from 100 slides. We then extracted whole-slide abnormality features from 2431 kidneys, and correlated with pathologists scores and transplant outcomes. Finally, a Kidney Donor Quality Score (KDQS) incorporating digital features and the Kidney Donor Profile Index (KDPI) was derived and used in combination with recipient demographic and peri-transplant characteristics to predict graft loss or assist organ utilization. ResultsOur model accurately identified 96% and 91% of normal/sclerotic glomeruli respectively; 94% of arteries/arterial intimal fibrosis regions; 90% of tubules. Three whole-slide features (Sclerotic Glomeruli%, Arterial Intimal Fibrosis%, and Interstitial Fibrosis%) demonstrated strong correlations with corresponding pathologists scores (n=2431), but had superior associations with post-transplant eGFR (n=2033) and graft loss (n=1560). The combination of KDQS and other factors predicted 1- and 4-year graft loss (discovery: n=520, validation: n=1040). Finally, by matching 398 discarded kidneys due to "biopsy findings" to transplanted population, the matched transplants from discarded KDQS<4 group (110/398, 27.6%) showed similar graft survival rate to unmatched transplanted kidneys (2-, 5-year survival rate: 97%, 86%). KDQS [≥] 7 (37/398, 9.3%) and 1-year survival model score [≥] 0.55 were determined to identify possible discards (PPV=0.92). ConclusionThis deep-learning based approach provides automatic and reliable pathological assessment of procurement kidney biopsies, which could facilitate graft loss risk stratification and organ utilization. Translational StatementThis deep-learning based approach provides rapid but more objective, sensitive and reliable assessment of deceased-donor kidneys before transplantation, and improves the prognostic value of procurement biopsies, thus could potentially reduce inappropriate discard and stratify patients needing monitoring or preventative measures after transplantation. The pipeline can be integrated into various types of scanners and conveniently generates report after slide scanning. Such report can be used in conjunction with pathologists report or independently for centers lacking renal pathologists.

bioinformatics↗

bioRxiv2023

A NanoDam toolkit for tissue-specific transcription factor profiling in C. elegans

During development of multicellular organisms, cells must execute precise molecular decisions to achieve cell fate specification and differentiation. These decisions are orchestrated by networks of transcription factors (TFs) which act to regulate gene expression of specific cohorts of genes to ultimately confer identity. Depending on the cellular context, TF expression can vary dramatically both spatially and temporally. These differences in expression patterns can result in tissue-specific differences in TF binding to downstream targets. To identify targets on a tissue-specific basis, Targeted DamID (TaDa) has been recently introduced to generate TF binding profiles in various models including C. elegans. However, TaDa suffers from portability such that a new promoter-TF fusion transgene must be constructed for every new experimental condition of interest. Here, we adapt NanoDam for usage in C. elegans, which relies on endogenous TF-GFP knock-ins, a plethora of which have already been generated by the community. We report that NanoDam single copy transgenes consisting of lowly expressed, tissue-specific GFP nanobody-Dam fusions, when combined with endogenous GFP-tagged alleles of TFs, results in robust, tissue-specific profiling. Using an endogenous GFP-tagged allele of EGL-43/EVI1, we performed NanoDam profiling of two disparate tissue types, the anchor cell (AC) and dopaminergic neurons, and identify targets unique to each and shared by both cell types. We also identify two GATA TFs, ELT-6 and EGL-18, as novel regulators of AC invasion. Together, we demonstrate that NanoDam is capable of profiling endogenous GFP-tagged TFs to identify novel downstream targets in specific cell types of C. elegans.

genetics↗

bioRxiv2023

Projectome-defined subtypes and modular intra-hypothalamic subnetworks of peptidergic neurons

The hypothalamus plays a vital role in coordinating essential neuroendocrine, autonomic, and somatomotor responses for survival and reproduction. While previous studies have explored population-level projections of hypothalamic neurons, the specific innervation patterns of individual hypothalamic axons remain unclear. To understand the organization of hypothalamic axon projections, we conducted a comprehensive reconstruction of single-cell projectomes from 7,180 mouse hypothalamic neurons expressing specific neuropeptides. Our analysis identified 31 distinct subtypes based on projectome-defined characteristics, with many exhibiting long-range axon collateral projections to multiple brain regions. Notably, these subtypes selectively targeted specific subdomains within downstream areas, either unilaterally or bilaterally. Furthermore, we observed that individual peptidergic neuronal types encompassed multiple projectome-defined subtypes, explaining their diverse functional roles. Additionally, by examining intra-hypothalamic axon projections, we uncovered six modular subnetworks characterized by enriched intramodular connections and distinct preferences for downstream targets. This modular organization of the intra-hypothalamic network likely contributes to the coordinated organization of hypothalamic outputs. In summary, our comprehensive projectome analysis reveals the organizational principles governing hypothalamic axon projections, providing a framework for understanding the neural circuit mechanisms underlying the diverse and coordinated functions of the hypothalamus.

neuroscience↗

bioRxiv2023

Deconstructing the contributions of heterogeneity to combination treatment of hormone sensitive breast cancer

Combination therapies are fundamental to cancer treatments, including in breast cancer the most common invasive malignancy in women. Breast cancer treatment is determined based on molecular subtypes, and since 2016, combination palbociclib and fulvestrant has been used to treat hormone receptor-positive breast cancer. However, the impact of heterogeneity of the tumour landscape and tumour composition dynamics on scheduling decisions remains poorly understood. To elucidate the contributions of variability at multiple scales to treatment outcomes in hormone receptor-positive breast cancer, we developed a simple mathematical model of two unique estrogen receptor positive (ER+) breast cancer cell types and their response to combination treatment with palbociclib and fulvestrant. We used this model to understand how the initial fraction of either cell type may impact the fraction remaining after treatment and examined how heterogeneity in pharmacokinetics and pharmacodynamics result in a large distribution of outcomes. Our results suggest that the pharmacokinetics and pharmacodynamics of fulvestrant were the major drivers of final tumour size and composition. We then leveraged our model to guide therapeutic scheduling of combination palbociclib and fulvestrant, demonstrating the use of mathematical modelling to improve our understanding of cancer biology and treatments.

cancer biology↗

bioRxiv2023

Large-scale genomic rearrangements boost SCRaMbLE in Saccharomyces cerevisiae

Genomic rearrangements contribute to gene copy number alterations, disruption of protein-coding sequences and/or perturbation of cis-regulatory networks. SCRaMbLE, a Cre/loxP-based system implanted in synthetic yeast chromosomes, can effectively introduce genomic rearrangements, and is thus a potential tool to study genomic rearrangements. However, the potential of SCRaMbLE to study genomic rearrangements is currently hindered, because a strain containing all 16 synthetic chromosomes is not yet available. Here, we constructed a yeast strain, SparLox83, containing 83 loxPsym sites distributed across all 16 chromosomes, with at least two sites per chromosome. Inducing Cre recombinase expression in SparLox83 produced versatile genome-wide genomic rearrangements, including inter-chromosomal events. Moreover, SCRaMbLE of the hetero-diploid strains derived from crossing SparLox83 with strains possessing synthetic chromosome III (synIII) from the Sc2.0 project led to increased diversity of genomic rearrangements and relatively faster evolution of traits compared to a strain with only synIII. Analysis of these evolved strains demonstrates that genomic rearrangements can perturb the transcriptome and 3D genome structure and can consequently impact phenotypes. In summary, a genome with sparsely distributed loxPsym sites can serve as a powerful tool to study the consequence of genomic rearrangements and help accelerate strain engineering in Saccharomyces cerevisiae.

synthetic biology↗

bioRxiv2023

Synergistic effects of dietary taurine and carbohydrates supplementation on skeleton muscle of juvenile turbot Scophthalmus maximus

The present study aims to investigate the effects of dietary taurine and carbohydrate levels on the skeleton muscle growth of turbot. Muscle samples of turbot were collected after 70 days of feeding trial by treatment groups of 0% (C), 0.4% (L1), 1.2% (L2) taurine with 15% dietary carbohydrate level, and 0.4% (H1), 1.2% (H2) taurine with 21% dietary carbohydrate level. Results showed that L2 and H2 treatment has given significantly higher hyperplasia with significantly high muscle fiber frequencies and muscle fiber density than that in the other groups. Hyperplastic muscle fiber generation was significantly stimulated by the high carbohydrate level (21%). Muscle density was not dependent on the level of carbohydrates. Aspartate, Threonine, Serine, Glutamine, Leucine, Phenylalanine, Isoleucine, Lysine, Histidine, and Arginine were significantly high in the H1 group than that in other all groups. H2 treatment was given a significantly higher amount of total collagen content than the other groups by increasing alkaline-soluble, alkaline-insoluble hydroxyproline, and total hydroxyproline levels. Hardness has significantly increased in all the treatment groups than that in the control group. And also, muscle hardness was significantly increased by the dietary carbohydrate levels. Intestine amylase, lipase, and trypsin enzyme activities were significantly increased in all the treatment groups than that in the control. Amylase and lipase activities were significantly highest in the H2 group. Taurine 1.2% with carbohydrates 21% treatment group (H2) was given significantly higher levels of cellular level muscle growth with more collagen in the skeletal muscle of Turbot.

cell biology↗

bioRxiv2023

Molecular signatures associated with successful implantation of the human blastocyst

Embryo implantation in humans is remarkably inefficient for reasons that remain largely unexplained, and high rates of implantation failure remain one of the greatest obstacles in treating infertility. The volume of gene expression data available from human embryos has rapidly accumulated in recent years. However, prioritization of these data to identify the subset of genes that determine successful implantation remains a challenge, in part, because comprehensive analyses cannot be performed on the same embryos that are transferred. Here, we leverage clinical morphologic grading--known for decades to correlate with implantation potential--and transcriptome analyses of matched embryonic and abembryonic samples to identify genes and cell-cell interactions enriched and depleted in human blastocysts of good and poor morphology, genome-wide. Unexpectedly, we discovered that the greatest molecular difference was in the state of the extraembryonic primitive endoderm (PrE), with relative deficiencies in PrE development in embryos of poor morphology at the time of embryo transfer. Together, our results support a model in which implantation success is most strongly reflected by factors and signals from the embryonic compartment and suggest that deficiencies in PrE development, in particular, are common among embryos with reduced implantation potential. Our study provides a valuable resource for those investigating the markers and mechanisms of human embryo implantation.

developmental biology↗

bioRxiv2023

Spatially-resolved single-cell atlas of ascidian endostyle provides insights into the origin of vertebrate pharyngeal organs

The pharynx is an endoderm innovation in deuterostome ancestors, the vertebrate descendent structure of which is a pharyngeal developmental organizer involving multi-germ layer and organ derivatives. However, the evolutionary origination of complicated pharynx organs in vertebrates is still largely unknown. Endostyle, a transitional pharyngeal organ exclusively in basal chordates provides an opportunity to reveal the origin of pharyngeal organs. Here, utilizing cutting-edged Stereo-seq and single-cell RNA-seq, we constructed the first spatially-resolved single-cell atlas in the endostyle of urochordate ascidian Styela clava, where the spatial location of Stereo-seq and high capture efficiency of single-cell RNA-seq complement each other and identified 23 highly differentiated cell types. We identified a previously overlooked hemolymphoid region (HLR), which harbors immune and blood cell clusters with enriched stemness capacities, illuminating a mixed rudiment and stem-cell niches for the blood and lymphoid system. More excitingly, we discovered a mechanical-sensitive hair cell candidate in zone 3 homologous to vertebrate acoustico-lateralis system, which was supported by the expression of in situ hybridization-verified inner ear-specific markers, including PTPRQ, USH2A, WHRN, and ADGRV1, ultracellular structure evidence and cross-species comparison. These results thoroughly renewed the comprehension of the basal-chordate pharynx and provides expressional evidence for multiplexed pharyngeal organ evolution.

evolutionary biology↗

bioRxiv2023

Syntheses of Pyrimidine-Modified Seleno-DNAs as Stable Antisense Molecules

Chemically modified antisense oligonucleotides (ASO) currently in pre-clinical and clinical experiments mainly focus on the 2-position derivatizations to enhance stability and targeting affinity. Considering the possible incompatibility of 2-modifications with RNase H stimulation and activity, we have hypothesized that the atom specific modifications on nucleobases can retain the complex structure and RNase H activity, while enhancing ASOs binding affinity, specificity, and stability against nucleases. Herein we report a novel strategy to explore our hypothesis by synthesizing the deoxynucleoside phosphoramidite building block with the seleno-modification at 5-position of thymidine, as well as its Se-oligonucleotides. Via X-ray crystal structural study, we found that the Se-modification was located in the major groove of nucleic acid duplex and didnt cause the thermal and structural perturbations. Surprisingly, our nucleobase-modified Se-DNAs were exceptionally resistant to nuclease digestion, while compatible with RNase H activity. This affords a novel avenue for potential antisense modification in the form of Se-antisense oli-gonucleotides (Se-ASO).

biochemistry↗

bioRxiv2023

MitoSort: robust demultiplexing of pooled single-cell genomics data using endogenous germline mitochondrial variants

Multiplexing across donors has emerged as a popular strategy to increase throughput, reduce costs, overcome technical batch effects, and improve doublet detection in single-cell genomic studies. Using endogenous genetic barcodes eliminates the need for additional experimental processing steps. Among the available choices for endogenous barcodes, the unique features of mtDNA variants render them a more computationally efficient and robust option compared to genome variants. Here we present MitoSort, a method that uses mtDNA germline variants to assign cells to their donor of origin and identify cross-genotype doublets. We evaluated the performance of MitoSort by in silico pooled mtscATAC-seq libraries and experimentally multiplexed data using cell hashing method. MitoSort achieve both high accuracy and efficiency on genotype clustering and doublet detection for mtscATAC-seq data, which fills a void left by the inadequacies of current computational techniques tailored for scRNA-seq data. Moreover, MitoSort exhibits versatility and can be applied to various single-cell sequencing approaches beyond mtscATAC-seq, as long as the mtDNA variants can be reliably detected. Furthermore, through a case study, we demonstrated that demultiplexing 8 individuals assayed at the same time with MitoSort, enables the comparison of cell composition without batch effects.

bioinformatics↗

bioRxiv2023

Induced pluripotent stem cell model revealed impaired neurovascular interaction in genetic small vessel disease CADASIL

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common genetic small vessel disease caused by variants in the NOTCH3 gene. Patients with CADASIL experience recurrent strokes, developing into cognitive defect and vascular dementia. CADASIL is a late-onset vascular condition, but migraine and brain MRI lesions appear in CADASIL patients as early as their teens and twenties, suggesting an abnormal neurovascular interaction at the neurovascular unit (NVU) where microvessels meet the brain parenchyma. To understand the molecular mechanisms of CADASIL, we established induced pluripotent stem cell (iPSC) models from CADASIL patients and differentiated the iPSCs into the major NVU cell types including brain microvascular endothelial-like cells (BMECs), vascular mural cells (MCs), astrocytes and cortical projection neurons. We then built an in vitro NVU model by co-culturing different neurovascular cell types in Transwells and evaluated the blood brain barrier (BBB) function by measuring transendothelial electrical resistance (TEER). Results showed that, while the wild-type MCs, astrocytes and neurons could all independently and significantly enhance TEER values of the iPSC-BMECs, such capability of MCs from iPSCs of CADASIL patients was significantly impeded. Additionally, the barrier function of the BMECs from CADASIL iPSCs was significantly impaired, accompanied with disorganised tight junctions in iPSC-BMECs, which could not be effectively rescued by the wild-type MCs, astrocytes and neurons. Our findings provide new insight into early disease pathologies on the neurovascular interaction and BBB function at the molecular and cellular levels for CADASIL, which helps inform future therapeutic development.

cell biology↗

bioRxiv2023

Decoding human in vitro terminal erythropoiesis originating from umbilical cord blood mononuclear cells and pluripotent stem cells

Ex vivo RBC production generates unsatisfactory expansion, {beta}-globin expression, and maturation of erythroid cells. The underlying mechanisms behind these limitations and ex vivo terminal erythropoiesis from different origins are largely unexplained. In this study, we mapped an atlas of ex vivo terminally differentiated cells from umbilical cord blood mononuclear cells (UCBMNs) and pluripotent stem cells (PSCs), and observed the differential regulatory dynamics of erythropoiesis from these two origins at a single-cell resolution. We detected the presence of hematopoietic stem progenitor cells (HSPCs), erythroid progenitor (e.g., CFU-E), and non-erythroid cells (e.g., macrophages) in the terminal populations. We observed that UCBMN-derived erythropoiesis is more active than PSC-derived erythropoiesis in terms of the cell cycle, stress erythropoiesis, and autophagy at single cell resolution, which may provide new insights into the limitations in cell expansion, globin expression, and maturation in ex vivo RBC production, respectively. We verified that a stress-erythropoiesis-related gene, TRIB3, increases the expression of globin genes in ex vivo erythropoiesis. As the major unexpected component detected in terminally differentiated cells, CFU-E were further characterized as having high- or low- expansion capacity based on CD99 expression, which generally decreased over erythropoiesis. By inhibiting CD99 gene expression using antagonists, we increased reticulocyte production in the population. Heterogeneous CFU-Es also exist in bone marrow. Moreover, decreased CD99 expression mediates the interactions between macrophages and CFU-E during ex vivo erythropoiesis. Overall, our results provide a reference for facilitating the development of strategies to improve ex vivo RBC regeneration. HighlightsO_LIWe performed scRNA-seq and cell typing of late stage UCBMN- and PSC-derived cells C_LIO_LIStress erythropoiesis, autophagy and cell cycle related gene expression different in two origins C_LIO_LICD99high progenitor cells are a proliferating colony forming unit erythroid subpopulation C_LI

cell biology↗

bioRxiv2023

DCBLD1 modulates angiogenesis by regulating of the VEGFR-2 endocytosis in endothelial cells

ObjectiveUnwanted angiogenesis is involved in the progression of various malignant tumors and cardiovascular diseases, and the factors that regulate angiogenesis are potential therapeutic targets. We tested the hypothesis that DCBLD1 (Discoidin, CUB, and LCCL domain-containing protein 1) is a co-receptor of VEGFR-2 and modulates angiogenesis in endothelial cells(ECs). Approach and ResultsA carotid artery ligation model and retinal angiogenesis assay were used to study angiogenesis using globe knockout or EC-specific conditional DCBLD1 knockout mice in vivo. Immunoblotting, immunofluorescence staining, plasma-membrane subfraction isolation, Co-immunoprecipitation and mass-spectrum assay were performed to clarify the molecular mechanisms.Loss of DCBLD1 impaired VEGF response and inhibited VEGF-induced EC proliferation and migration. DCBLD1 deletion interfered with adult and developmental angiogenesis. Mechanistically, DCBLD1 bound to VEGFR-2 and regulated the formation of VEGFR-2 complex with negative regulators: protein tyrosine phosphatases, E3 ubiquitin ligases(Nedd4 and c-Cbl), and also DCBLD1 knockdown promoted lysosome-mediated VEGFR-2 degradation in ECs. ConclusionsThese findings demonstrated the essential role of endothelial DCBLD1 in regulating VEGF signaling and provided evidence that DCBLD1 promotes VEGF-induced angiogenesis by limiting the dephosphorylation, ubiquitination, and lysosome degradation after VEGFR-2 endocytosis. We proposed that endothelial DCBLD1 is a potential therapeutic target for ischemic cardiovascular diseases by the modulation of angiogenesis through regulating of the VEGFR-2 endocytosis.

molecular biology↗

bioRxiv2023

Pharyngeal Mechanosensory Neurons Control Food Swallow in Drosophila melanogaster

As the early step of food ingestion, the swallow is under rigorous sensorimotor control. Nevertheless, the mechanisms underlying swallow control at a molecular and circuitry level remain largely unknown. Here, we find that mutation of the mechanotransduction channel genes nompC, Tmc, or piezo impairs the regular pumping rhythm of the cibarium during feeding of the fruit fly Drosophila melanogaster. A group of multi-dendritic mechanosensory neurons, which co-express the three channels, wrap the cibarium and are crucial for coordinating the filling and emptying of the cibarium. Inhibition of them causes difficulty in food emptying in the cibarium, while their activation leads to difficulty in cibarium filling. Synaptic and functional connections are detected between the pharyngeal mechanosensory neurons and the motor circuit that controls swallow. This study elucidates the role of mechanosensation in swallow, and provides insights for a better understanding of the neural basis of food swallow.

neuroscience↗

bioRxiv2023

A parabrachial-hypothalamic parallel circuit governs cold defense in mice

Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Remarkable advances have been made in understanding how neurocircuits centered in the hypothalamic preoptic area (POA), the brains thermoregulation center, control warm defense, whereas mechanisms by which the POA regulates cold defense remain unclear. Here, we confirmed that the pathway from the lateral parabrachial nucleus (LPB) to the POA, is critical for cold defense. Parallel to this pathway, we uncovered that a pathway from the LPB to the dorsomedial hypothalamus (DMH), namely the LPB[->]DMH pathway, is also essential for cold defense. Projection-specific blockings revealed that both pathways provide an equivalent and cumulative contribution to cold defense, forming a parallel circuit. Specifically, activation of the LPB[->]DMH pathway induced strong cold-defense responses, including increases in thermogenesis of brown adipose tissue (BAT), muscle shivering, heart rate, and physical activity. Further, we identified a subpopulation of somatostatin+ neurons in the LPB that target the DMH to promote BAT thermogenesis. Therefore, we reveal a parabrachial-hypothalamic parallel circuit in governing cold defense in mice. This not only enables resilience to hypothermia but also provides a scalable and robust network in heat production, reshaping our understanding of how neural circuits regulate essential homeostatic behaviors.

neuroscience↗