Biology subjects

Zhou, Q.

Publications and source records attributed to Zhou, Q..

At least 109 records · Page 6Linked to original sources

bioRxiv2024

Molecular basis of enhanced GLP-1 signaling mediated by GLP-1(9-36) in conjunction with LSN3318839

Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) is essential for glucose metabolism and energy balance. It is primarily activated by the endogenous hormone GLP-1(7-36) and its weaker metabolite GLP-1(9-36). Although GLP-1(9-36) was previously considered biologically inactive, emerging evidence indicate that it exerts cardioprotective and insulinotropic actions. Here, we present cryo-electron microscopy structures showing that GLP-1(9-36) binds to an atypical site composed of the upper halves of transmembrane helices 1 (TM1) and 2 (TM2), extracellular loop 1, and the extracellular domain, distinct from the binding site of GLP-1(7-36). Meanwhile, LSN3318839, an orally effective positive allosteric modulator selective for GLP-1(9-36), anchors in the TM1-TM2 cleft and repositions GLP-1(9-36) to adopt a binding pose like GLP-1(7-36), thereby enhancing GLP-1R-mediated signal transduction. Mutagenesis and molecular dynamics simulations confirmed the crucial interactions and structural adjustments involved in this modulation. Our study uncovers a novel binding mode of GLP-1 metabolite and allosteric modulation that augments GLP-1R signaling, both are potentially insightful to unveil the physiological role of GLP-1(9-36) and design better small molecule therapeutics targeting GLP-1R.

molecular biology↗

bioRxiv2024

Engineering Microglial Cells to Promote Spinal Cord Injury Recovery

Spinal cord injury (SCI) can result in irreversible damage, leading to lifelong paralysis for affected individuals. Microglias dual impact on neuronal regeneration after SCI, driven by their distinct roles at different stages, merits further study. We conducted a bioinformatic analysis of single-cell transcriptomes (scRNA), spatial transcriptomic (ST) data, and bulk RNA-seq data from Gene Expression Omnibus (GEO) datasets. The data were processed using R packages such as "Seurat", "DESeq2","limma" and "GSVA." Additionally, we utilized Gene Set Enrichment Analysis (GSEA) and the Enrichr web servers. Analysis of single-cell data and spatial transcriptomics has revealed notable changes in the microglial cell landscape in SCI. These changes encompass the inhibition of innate microglial cells, while reactive microglial cells exhibit pronounced reactive hyperplasia. Moreover, the TGF{beta} signaling pathway plays a crucial role in regulating the migration of innate microglial cells to enhance SCI recovery. However, reactive microglial cells exhibiting high Trem2 expression contribute to the neuroinflammatory response and can effectively modulate neural cell death in SCI. In particular, inhibiting Trem2 in reactive microglial cells not only reduces inflammation but also mitigates spinal cord injury, and enhancing the TGF{beta} signaling pathway. Whats more, the use of iPSC-derived microglial cells, which have demonstrated their capacity to augment the potential for replacing the functions of naive microglial cells, iPSC-derived microglia have the potential to replace the functions of naive microglial cells, holds significant promise in addressing SCI. Therefore, we posit that the engineering of microglial cells to promote the SCI recovery. The approach of inhibiting Trem2-mediated neuroinflammatory responses and transplanting iPSC-derived microglia with long-term TGF{beta} stimulation may offer potential improvements in SCI recovery.

neuroscience↗

bioRxiv2024

Targeting NOTCH2-JAG1 juxtacrine signaling reverses macrophage-mediated tumor resistance to taxol

Taxanes are widely used in chemotherapy, but primary and acquired resistance limit the clinical efficacy. Studies have shown tumor interaction with macrophages in the tumor microenvironment (TME) plays a significant role in taxane resistance, yet therapeutic strategies that directly deplete or repolarize macrophages are challenging and with considerable risk of side effects. Here we uncovered that tumor-macrophage interaction can be selectively targeted by inhibiting post-mitotic NOTCH2-JAG1 juxtacrine signaling in the TME, which strongly sensitizes paclitaxel response. Using translatome profiling, we found significant NOTCH2 upregulation during paclitaxel-induced prolonged mitosis. NOTCH2 was subsequently activated in the post-mitotic G1 phase by JAG1 expressed on the neighboring macrophages and tumor cells, which promoted tumor cell survival and upregulated cytokines that recruited JAG1-expressing macrophages, thus generating a positive feedback loop that further enhanced the pro-tumor NOTCH2 activity. By targeting this NOTCH2-JAG1 axis using NOTCH2 shRNA or a pan-NOTCH inhibitor, macrophage recruitment and paclitaxel resistance were significantly attenuated in multiple mouse tumor models of ovarian cancer. Clinical samples from paired primary and recurrent ovarian cancer patients also showed significant correlation of higher NOTCH2 expression with worse prognosis. Our results thus point to combining NOTCH2 inhibitor with taxane as an effective therapeutic strategy to selectively disrupt tumor-macrophage interaction in the TME and overcome macrophage-mediated taxane resistance in NOTCH2-positive tumors.

cancer biology↗

bioRxiv2024

Decoding the anti-aging effect of retinol in reshaping the human skin microbiome niches

Retinol has been widely added to skincare products due to its ability to promote the proliferation of skin keratinocytes and regulate skin cell collagen expression. While it is known the skin harbors a myriad of commensal bacteria, the impact of retinol on the skin microbiome, as well as the role of the skin microbiome in mediating the anti-aging properties of retinol, remains poorly understood. In this study, we incorporated phenomics, metagenomics and metabolomics to explore the human skin alterations during the anti-aging process mediated by retinol, and potential interactions between retinol, skin microbiome and metabolites. Topical retinol significantly improved skin conditions, including enhancing skin hydration, acidifying the epidermis, strengthening the skin barrier, and reducing the number and volume of wrinkles. Furthermore, retinol also reshaped the skin microecology by altering the structure and function of the skin microbiome as well as the host and microbial metabolites. Through GEM construction, we identified 2 skin microorganism, Sericytochromatia sp. and Corynebacterium kefirresidentii capable of oxidizing retinol to retinal. Over 10 skin microbes can utilize UDP-glucose as a carbon source, potentially accelerating RAG hydrolysis and increasing glucuronic acid consumption. The retinoic acid and retinol generated by RAG hydrolysis are reused by skin cells and microbes, enhancing retinol metabolism and its effective duration. This combined effect between the skin microbiome and retinol improves skin condition and anti-aging efficacy.

microbiology↗

bioRxiv2024

Multi-talker speech comprehension at different temporal scales in listeners with normal and impaired hearing

Comprehending speech requires deciphering a range of linguistic representations, from phonemes to narratives. Prior research suggests that in single-talker scenarios, the neural encoding of linguistic units follows a hierarchy of increasing temporal receptive windows. Shorter temporal units like phonemes and syllables are encoded by lower-level sensory brain regions, whereas longer units such as sentences and paragraphs are processed by higher-level perceptual and cognitive areas. However, the brains representation of these linguistic units under challenging listening conditions, such as a cocktail party situation, remains unclear. In this study, we recorded electroencephalogram (EEG) responses from both normal-hearing and hearing-impaired participants as they listened to individual and dual speakers narrating different parts of a story. The inclusion of hearing-impaired listeners allowed us to examine how hierarchically organized linguistic units in competing speech streams affect comprehension abilities. We leveraged a hierarchical language model to extract linguistic information at multiple levels--phoneme, syllable, word, phrase, and sentence--and aligned these model activations with the EEG data. Our findings showed distinct neural responses to dual-speaker speech between the two groups. Specifically, compared to normal-hearing listeners, hearing-impaired listeners exhibited poorer model fits at the acoustic, phoneme, and syllable levels as well as the sentence levels, but not at the word and phrase levels. These results suggest that hearing-impaired listeners experience disruptions at both shorter and longer temporal scales, while their processing at medium temporal scales remains unaffected.

neuroscience↗

bioRxiv2024

Multiomics mapping and characterization of cellular senescence in aging human muscle uncovers novel senotherapeutics for sarcopenia

Cellular senescence is recognized as a hallmark of organismal aging but how it drives aging particularly in human tissues is not fully understood, partly due to the complex heterogeneous nature of senescence. Here in this study, we leverage single-nucleus multiomics to profile senescence in mononucleated cells of human skeletal muscle and provide the first senescence atlas. We demonstrate the intra-and inter-populational transcriptomic and epigenomic heterogeneity and dynamics of senescence in the cells. We also identify commonalities and variations in senescence-associated secretory phenotypes (SASPs) among the cells and elucidate the function of SASPs in mediating cellular interactions and niche deregulation. Furthermore, we identify targetable SASP factors and demonstrate the possibility of using Maraviroc as a pharmacological senotherapeutic for treating age-associated sarcopenia in muscle. Lastly, we define transcription factors that govern senescence state and SASP induction in aging muscle and elucidate the key function and the underlying mechanism of JUNB in regulating SASP activation in senescent cells. Altogether, our findings demonstrate the prevalence and function of cellular senescence in skeletal muscle and identify a novel pharmacological intervention for sarcopenia.

cell biology↗

bioRxiv2024

Filament structures unveil the dynamic organization of human acetyl-CoA 1 carboxylase

Human acetyl-CoA carboxylases (ACCs) catalyze the carboxylation of acetyl-CoA, which is the rate-limiting step in fatty acid synthesis. The molecular mechanism underlying the dynamic organization of ACCs is largely unknown. Here, we determined the cryo-EM structure of human ACC1 in its inactive state, which forms a unique filament structure and is in complex with acetyl-CoA. We also determined the cryo-EM structure of human ACC1 activated by dephosphorylation and citrate treatment, at a resolution of 2.55 [A]. Notably, the covalently linked biotin binds to a site that is distant from the acetyl-CoA binding site when acetyl-CoA is absent, suggesting a potential coordination between biotin binding and acetyl-CoA binding. These findings provide insights into the structural dynamics and regulatory mechanisms of human ACCs. TeaserCryo-EM structures reveal how human acetyl-CoA carboxylase 1 changes shape to control its activity.

biochemistry↗

bioRxiv2024

Maternal total sleep deprivation causes oxidative stress and mitochondrial dysfunction in oocytes associated with fertility decline in mice

Previous studies have shown sleep deprivation has an impact on several aspects of health and disease. Sleep deprivation suppresses melatonin production and excessive HPA activation in women, which may reduce the chances of fertility. However, little is known about how and by what relevant mechanisms it affects female fertility. In this study, female mice underwent 72 hours of total sleep deprivation (TSD) caused by rotating wheel or 2 different controls: a stationary wheel, or forced movement at night. Even though, there was no evident anomaly of natural ovulation, the TSD female mice showed impaired early embryo development . Overall levels of estrogen and FSH were lower throughout the estrus cycle (especially in proestrus). RNA Sequencing (RNA-Seq) was used to discover differentially expressed genes (DEGs) that might be involved in oocyte quality after TSD. A total of 42 genes showed significant differential expression in GV oocytes after TSD. These included genes such as Usmg5, Atp5k, Ccnd2 and Tpm3, which were enriched in gene ontology terms of mitochondrial protein complex, oxidoreductase activity, cell division, cell cycle G1/S phase transition, as well as others. The increased concentrations of reactive oxygen species (ROS) in germinal vesicle (GV) and metaphase II (MII) oocytes from TSD mice were observed, which might be induced by impaired mitochondrial function caused by TSD. The GV oocytes displayed increased mitochondrial DNA (mtDNA) copy number and a significant transient increase in inner mitochondrial membrane potential ({bigtriangleup}{psi}m) from the TSD mice probably due to compensatory effect. In contrast, MII oocytes in the TSD group showed a decrease in the mtDNA copy number and a lower {bigtriangleup} {psi}m compared with the controls. Furthermore, abnormal distribution of mitochondria in the GV and MII oocytes was also observed in TSD mice, suggesting mitochondrial dysfunction. In addition, abnormal spindle and abnormal arrangement of chromosomes in MII oocytes were markedly increased in the TSD mice compared with the control mice. In conclusion, our results suggest that TSD significantly alters the oocyte transcriptome, contributing to oxidative stress and disrupted mitochondrial function, which then resulted in oocyte defects and impaired early embryo development in female mice.

developmental biology↗

bioRxiv2024

The antimicrobial peptides pipeline: a bacteria-centric AMP predictor

Antimicrobial peptides (AMPs), unlike antibiotics, are encoded in genomes. AMPs are exported from the cell after expression and translation. In the case of bacteria, the exported peptides target other microbes to give the producing bacterium a competitive edge. While AMPs are sought after for their similar antimicrobial activity to traditional antibiotics, it is difficult to predict which combinations of amino acids will confer antimicrobial activity. Many computer algorithms have been designed to predict whether a sequence of amino acids will exhibit antimicrobial activity, but the vast majority of validated AMPs in databases are still of eukaryotic origin. This defies common sense since the vast majority of life on earth is prokaryotic. The antimicrobial peptides pipeline, presented here, is a bacteria-centric AMP predictor that predicts AMPs by taking design inspiration from the sequence properties of bacterial genomes with the intention to improve detection of naturally occurring bacterial AMPs. The pipeline integrates multiple concepts of comparative biology to search for candidate AMPs at the primary, secondary and tertiary peptide structure level. Results showed that the antimicrobial peptides pipeline identifies known AMPs that are missed by state-of-the-art AMP predictors, and that the pipeline yields more AMP candidates from real bacterial genomes than from fake genomes, with the rate of AMP detection being significantly higher in the genomes of seven nosocomial pathogens than in the fake genomes.

bioinformatics↗

bioRxiv2024

IL-4 Licenses B Cell Activation Through Cholesterol Synthesis

Lymphocyte activation involves a transition from quiescence and associated catabolic metabolism to a metabolic state with noted similarities to cancer cells such as heavy reliance on aerobic glycolysis for energy demands and increased nutrient requirements for biomass accumulation and cell division1-3. Following antigen receptor ligation, lymphocytes require spatiotemporally distinct "second signals". These include costimulatory receptor or cytokine signaling, which engage discrete programs that often involve remodeling of organelles and increased nutrient uptake or synthesis to meet changing biochemical demands4-6. One such signaling molecule, IL-4, is a highly pleiotropic cytokine that was first identified as a B cell co-mitogen over 30 years ago7. However, how IL-4 signaling mechanistically supports B cell proliferation is incompletely understood. Here, using single cell RNA sequencing we find that the cholesterol biosynthetic program is transcriptionally upregulated following IL-4 signaling during the early B cell response to influenza virus infection, and is required for B cell activation in vivo. By limiting lipid availability in vitro, we determine cholesterol to be essential for B cells to expand their endoplasmic reticulum, progress through cell cycle, and proliferate. In sum, we demonstrate that the well-known ability of IL-4 to act as a B cell growth factor is through a previously unknown rewiring of specific lipid anabolic programs, relieving sensitivity of cells to environmental nutrient availability.

immunology↗

bioRxiv2024

Structural insights into human propionyl-CoA carboxylase (PCC) and 3-methylcrotonyl-CoA carboxylase (MCC)

Propionyl-CoA carboxylase (PCC) and 3-methylcrotonyl-CoA carboxylase (MCC) are biotin-dependent carboxylases (BDCs) that catalyze the metabolism of odd-chain fatty acids, cholesterol, and specific amino acids. For human PCC and MCC, only a low-resolution (15 [A]) three-dimensional structure of human PCC has been reported. Here, we report high-resolution (2.29-3.38 [A]) cryo-EM structures of human PCC and MCC holoenzymes in their apo and acetyl-CoA and propionyl-CoA-bound states. Propionyl-CoA and acetyl-CoA bind to PCC with almost identical binding modes, indicating that the acyl-CoA specificity of PCC is largely attributed to minor differences in interactions mediated by the acyl groups. In MCC, biotin is relocated from an exo-site to an endo-site upon acetyl-CoA binding, suggesting coordination between biotin binding and acyl-CoA binding. Our work provides insights into the substrate specificity and catalytic process of BDCs.

biochemistry↗

bioRxiv2024

Social anxiety links of amygdala switch cross puberty

Socioemotional functions have been linked to the amygdala through molecular mechanisms observed in animals. However, these links remain largely unestablished in the development of the human amygdala during puberty. By precisely tracing the amygdala with longitudinal data spanning childhood and adolescence, our aim is to capture the dynamic relationship between social anxiety and amygdala geometry. Around the onset of puberty (10-11.5 years), we detected shifting associations between amygdala volume and social anxiety. Higher social anxiety is associated with a larger amygdala in mid-childhood but a smaller amygdala in early adolescence. Further geometry analysis revealed regional deformations that underpinned the shift. Our findings reconcile inconsistent results from previous studies and respect the intrinsic dimension of development in resolving amygdala-anxiety links during puberty.

neuroscience↗

bioRxiv2024

Validation of ferroptosis in canine cancer cells to enable comparative oncology and translational medicine

Ferroptosis is a cell death mechanism that has attracted significant attention as a potential basis for the development of new cancer therapies. Validation of ferroptosis biology in species commonly used in translation and pre-clinical development is a necessary foundation for enabling the advancement of such ferroptosis modulating drugs. Here, we demonstrate that canine cancer cells exhibit sensitivity to a wide range of ferroptosis-inducing perturbations in a manner indistinguishable from human cancer cells, and recapitulate characteristic patterns of ferroptotic response across tumor types seen in the human setting. The foundation provided herein establishes the dog as a relevant efficacy and toxicology model for ferroptosis and creates new opportunities to leverage the canine comparative oncology paradigm to accelerate the development of ferroptosis-inducing drugs for human cancer patients.

cancer biology↗

bioRxiv2024

Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developing Drosophila brain

Glia derived secretory factors play diverse roles in supporting the development, physiology, and stress responses of the central nervous system (CNS). Through transcriptomics and imaging analyses, we have identified Obp44a as one of the most abundantly produced secretory proteins from Drosophila CNS glia. Protein structure homology modeling and Nuclear Magnetic Resonance (NMR) experiments reveal Obp44a as a fatty acid binding protein (FABP) with a high affinity towards long-chain fatty acids in both native and oxidized forms. Further analyses demonstrate that Obp44a effectively infiltrates the neuropil, traffics between neuron and glia, and is secreted into hemolymph, acting as a lipid chaperone and scavenger to regulate lipid and redox homeostasis in the developing brain. In agreement with this essential role, deficiency of Obp44a leads to anatomical and behavioral deficits in adult animals and elevated oxidized lipid levels. Collectively, our findings unveil the crucial involvement of a noncanonical lipid chaperone to shuttle fatty acids within and outside the brain, as needed to maintain a healthy brain lipid environment. These findings could inspire the design of novel approaches to restore lipid homeostasis that is dysregulated in CNS diseases.

developmental biology↗

bioRxiv2024

Soft-lithographically defined template for arbitrarily patterned acoustic bioassembly

Acoustic bioassembly is recently regarded as a highly efficient biofabrication tool to generate functional tissue mimics. Despite their capacity of directly patterning live cells with close intercellular proximity, most acoustic bioassembly techniques are currently limited to generate some specific simple types of periodic and symmetric patterns, which represents an urgent challenge to emulate geometrically complex cytoarchitecture in human tissue. To address this challenge, we herein demonstrate a soft-lithographically defined acoustic bioassembly (SLAB) technique that enables to assemble live cells into geometrically defined arbitrary multicellular structures. Particularly, we employed a widely accessible soft lithography technique to fabricate a PDMS construct that works as an amplitude modulation template to define the pressure distribution of near-field acoustic waves. We found that zero pressure areas of the near-field acoustic waves at the PDMS surface distribute above the air-filling regions of the PDMS construct when both the PDMS top layer and air layer are approximately one-tenth of the acoustic wavelength. Using this technique, bioparticles can be assembled into symmetrical or asymmetrical patterns. Specifically, we have demonstrated the SLAB of endothelial spheroids and hepatic cells into liver tissue mimics (LTMs). The functional analysis further indicates that the formed LTMs displayed liver-specific functions, including albumin secretion, urea synthesis, glucose metabolism, and lipid storage. We expect this SLAB technique will be broadly used to construct complex functional tissues for tissue engineering and regenerative medicine.

bioengineering↗

bioRxiv2024

The Transcription Factor OsNAC5 Mediates Cadmium Stress Response and Accumulation in Rice

Cadmium (Cd) is a toxic heavy metal that endangers human health through contaminated rice consumption. Reducing Cd uptake in rice is essential for minimizing grain Cd accumulation. However, the transcriptional regulation of Cd uptake in rice remains largely elusive. This study reveals that the transcription factor OsNAC5 in Oryza sativa positively regulates the Cd transporter gene OsNRAMP1, influencing Cd uptake. OsNAC5 is primarily expressed in roots, localized to the nucleus, and upregulated by Cd-induced H2O2. Knocking out OsNAC5 reduces Cd levels in both shoots and roots and increases Cd sensitivity. OsNRAMP1 expression, enhanced by Cd stress, depends on OsNAC5, which binds to "CATGTG" motifs in the OsNRAMP1 promoter activating its expression. Loss of OsNAC5 function decreases Cd accumulation in rice grains. Our findings elucidate the transcriptional regulation of Cd stress response in rice and suggest biotechnological approaches to reduce Cd uptake in crops. Declaration of Competing InterestThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

plant biology↗

bioRxiv2024

Extracellular electron transfer drives efficient H2-independent methylotrophic methanogenesis by Methanomassiliicoccus, a seventh order methanogen

Methylotrophic methanogenesis is achieved via methyl group dismutation or H2 reduction. This study reports extracellular electron droving efficient methylotrophic methanogenesis. The 7th order methanogen Methanomassiliicoccus luminyensis exclusively implements H2-dependent methylotrophic methanogenesis, but strain CZDD1 isolated from paddy soil possessed a higher methane-producing rate in coculture with Clostridium malenominatum CZB5 or the electrogenic Geobacter metallireducens. Chronoamperometry detected current production from CZB5, and current consumption accompanied CH4 production in a methanol-containing electrochemical culture of CZDD1. This demonstrated that M. luminyensis was capable of both direct species electron transfer (DIET) and extracellular electron transfer (EET) in methylotrophic methanogenesis. EET and DIET also enabled CZDD1 to produce methane from dimethyl arsenate. Differential transcriptomic analysis on H2-versus EET- and DIET-cocultures suggested that a membrane-bound Fpo-like complex and archaella of M. luminyensis CZDD1 could accept extracellular electrons. Given the ubiquitous environmental distribution of Methanomassiliicoccus strains, EET driven methylotrophic methanogenesis may contribute significantly to methane emission.

microbiology↗

bioRxiv2024

Geny: A Genotyping Tool for Allelic Decomposition of Killer Cell Immunoglobulin-Like Receptor Genes

Accurate genotyping of Killer cell Immunoglobulin-like Receptor (KIR) genes plays a pivotal role in enhancing our understanding of innate immune responses, disease correlations, and the advancement of personalized medicine. However, due to the high variability of the KIR region and high level of sequence similarity among different KIR genes, the currently available genotyping methods are unable to accurately infer copy numbers, genotypes and haplotypes of individual KIR genes from next-generation sequencing data. Here we introduce Geny, a new computational tool for precise genotyping of KIR genes. Geny utilizes available KIR haplotype databases and proposes a novel combination of expectation-maximization filtering schemes and integer linear programming-based combinatorial optimization models to resolve ambiguous reads, provide accurate copy number estimation and estimate the haplotype of each copy for the genes within the KIR region. We evaluated Geny on a large set of simulated short-read datasets covering the known validated KIR region assemblies and a set of Illumina short-read samples sequenced from 25 validated samples from the Human Pangenome Reference Consortium collection and showed that it outperforms the existing genotyping tools in terms of accuracy, precision and recall. We envision Geny becoming a valuable resource for understanding immune system response and consequently advancing the field of patient-centric medicine.

bioinformatics↗