Biology subjects

Qiu, S.

Publications and source records attributed to Qiu, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Overabundant endocannabinoids in neurons are detrimental to cognitive function

2-Arachidonoylglycerol (2-AG) is the most prevalent endocannabinoid involved in maintaining brain homeostasis. Previous studies have demonstrated that inactivating monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading 2-AG in the brain, alleviates neuropathology and prevents synaptic and cognitive decline in animal models of neurodegenerative diseases. However, we show that selectively inhibiting 2-AG metabolism in neurons impairs cognitive function in mice. This cognitive impairment appears to result from decreased expression of synaptic proteins and synapse numbers, impaired long-term synaptic plasticity and cortical circuit functional connectivity, and diminished neurogenesis. Interestingly, the synaptic and cognitive deficits induced by neuronal MAGL inactivation can be counterbalanced by inhibiting astrocytic 2-AG metabolism. Transcriptomic analyses reveal that inhibiting neuronal 2-AG degradation leads to widespread changes in expression of genes associated with synaptic function. These findings suggest that crosstalk in 2-AG signaling between astrocytes and neurons is crucial for maintaining synaptic and cognitive functions and that excessive 2-AG in neurons alone is detrimental to cognitive function.

neuroscience↗

bioRxiv2024

Inhibition on neutrophil extracellular traps by oligomeric procyanidins alleviate chemotherapy-induced chronic kidney injury via gut-kidney axis

Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic, but its use is limited by adverse effects in normal tissues. In particular, cisplatin administration often damages the kidneys. However, little is known about how to alleviate cisplatin-induced chronic kidney disease (CKD) specifically. Here, we found that repeated low-dose cisplatin (RLDC) recruited susceptible neutrophils to the proximal tubule, thereby promoting the progression of CKD in the mouse model. Mechanically, cisplatin destroyed the intestinal epithelium, which induced dysregulation of gut flora and intestinal leakage. Under the dual stimulation of intestinal bacteria and cisplatin, neutrophils become extremely susceptible to form Neutrophil extracellular traps (NETs), accumulating in the proximal tubule and promoted chronic inflammation, fibrosis, and chronic hypoxia, leading to poor regeneration that promoted CKD progression. NETs provided a scaffold for tissue factors (TF) adhesion and metalloid-matrix protease 9 (MMP-9) activation, which triggered local ischemia and hypoxia. In addition, NETs promoted inflammasome construction through NOD-like receptor thermal protein domain associated protein 3 (NLRP3) shear and secretion of mature interleukin-18 (IL18), which subsequently released interferon- {gamma} (IFN-{gamma}), contributing to renal interstitial fibrosis. We proposed that oligomeric procyanidins (OPCs) ameliorated RLDC-induced CKD through multi-targeting damage induced by NETs. OPCs ameliorated microcirculatory disorders and inhibited inflammation by protecting the intestinal mucosa barrier and subsequent bacterial endotoxin translocation. Furthermore, we found that OPCs altered the susceptibility of neutrophils to form NETs. In summary, OPC alleviates CKD by inhibiting NETs production via TF/MMP-9 and IL-18-NLRP3 pathways. OPCs protect the kidney through anti-inflammatory and antioxidant activities, and restore the balance of the intestinal flora.

immunology↗

bioRxiv2024

Erythropoietin-dependent Acquisition of CD71hiCD105hi Phenotype within CD235a- Early Erythroid Progenitors

The development of committed erythroid progenitors and their continued maturation into mature erythrocytes requires the cytokine erythropoietin (Epo). Here, we describe the immunophenotypic identification of a unique Epo-dependent colony-forming unit-erythroid (CFU-E) cell subtype that forms during early erythropoiesis (EE). This previously undescribed CFU-E subtype, termed late-CFU-E (lateC), lacks surface expression of the characteristic erythroid marker CD235a (glycophorin A) but has high levels of CD71 and CD105. LateCs could be prospectively detected in human bone marrow (BM) cells and, upon isolation and reculture, exhibited the potential to form CFU-E colonies in medium containing only Epo (no other cytokines) and continued differentiation along the erythroid trajectory. Analysis of ex vivo cultures of BM CD34+ cells showed that acquisition of the CD7hiCD105hi phenotype in lateCs is gradual and occurs through the formation of four EE cell subtypes. Of these, two are CD34+ burst-forming unit-erythroid (BFU-E) cells, distinguishable as CD7loCD105lo early BFU-E and CD7hiCD105lo late BFU-E, and two are CD34- CFU-Es, also distinguishable as CD71loCD105lo early CFU-E and CD7hiCD105lo mid-CFU-E. The transition of these EE populations is accompanied by a rise in CD36 expression, such that all lateCs are CD36+. Single cell RNA-sequencing analysis confirmed Epo-dependent formation of a CFU-E cluster that exhibits high coexpression of CD71, CD105, and CD36 transcripts. Gene set enrichment analysis revealed the involvement of genes specific to fatty acid and cholesterol metabolism in lateC formation. Overall, in addition to identifying a key Epo-dependent EE cell stage, this study provides a framework for investigation into mechanisms underlying other erythropoiesis-stimulating agents.

developmental biology↗

bioRxiv2024

Seq2Topt: a sequence-based deep learning predictor of enzyme optimal temperature

An accurate deep learning predictor is needed for enzyme optimal temperature (Topt), which quantitatively describes how temperature affects the enzyme catalytic activity. Seq2Topt, developed in this study, reached a superior accuracy on Topt prediction just using protein sequences (RMSE = 13.3 and R2=0.48) in comparison with existing models, and could capture key protein regions for enzyme Topt with multi-head attention on residues. Through case studies on thermophilic enzyme selection and predicting enzyme Topt shifts caused by point mutations, Seq2Topt was demonstrated as a promising computational tool for enzyme mining and in-silico enzyme design. Additionally, accurate deep learning predictors of enzyme optimal pH (Seq2pHopt, RMSE=0.92 and R2=0.37) and melting temperature (Seq2Tm, RMSE=7.57 and R2=0.64) were developed based on the model architecture of Seq2Topt, suggesting that the development of Seq2Topt could potentially give rise to a useful prediction platform of enzymes.

bioinformatics↗

bioRxiv2024

Fibrillarin modulates fetal hemoglobin silencing

Decoding the molecular mechanisms underlying human fetal ({gamma}) globin gene silencing impacts therapeutic strategies for {beta}-thalassemia and sickle cell disease. Here, we identified a nucleolar protein, fibrillarin (FBL), which mediates the methylation of glutamine104 in histone H2A and functions as a repressor of the {gamma}-globin gene in cultured erythroid cells, including those from {beta}-thalassemia patients. Conditional Fbl depletion in adult {beta}-YAC transgenic mice or in {beta}IVS-2-654-thalassemic mice reactivated the human {gamma}-globin gene or murine embryonic globin expression, respectively, which corrects hematologic and pathologic defects in {beta}-thalassemic mice. We showed that FBL plays a dual role in activating BCL11A expression and repressing {gamma}-globin gene expression, which is dependent on its histone methyltransferase activity. Our study may provide an alternative strategy for therapeutic targeted treatment of {beta}-hemoglobinopathies.

molecular biology↗

bioRxiv2024

Activity of prefrontal cortex serotonin 2A receptor expressing neurons is necessary for the head-twitch response of mice to psychedelic drug DOI in a sex-dependent manner

Serotonin 2A receptors (5-HT2ARs) mediate the effects of psychedelic drugs. 5-HT2AR agonists, such as (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), that produce a psychedelic experience in humans induce a head-twitch response (HTR) behavior in rodents. However, it is unknown whether the activity of 5-HT2AR expressing neurons is sufficient to produce the HTR in the absence of an agonist, or in which brain region 5-HT2ARs control the HTR. Here, we use an optogenetic approach to examine whether activation of 5-HT2AR expressing neurons in the mouse prefrontal cortex (PFC) is sufficient to induce HTRs alone, or may augment the HTR produced by DOI, and if inhibition of these neurons prevents DOI-induced HTRs in mice. We crossed Htr2a-Cre mice to Cre-dependent optogenetic lines Ai32 (channelrhodopsin) and Ai39 (halorhodopsin) to selectively activate and inhibit (respectively) 5-HT2AR-expressing neurons in the PFC of adult mice. We found that optogenetic stimulation of PFC 5-HT2AR expressing neurons in the absence of an agonist does not increase HTRs in mice. In both male and female Ai32 mice that received vehicle, there was no difference in HTRs in mice that expressed Htr2a-Cre compared with control mice, indicating that optogenetic activation of 5-HT2AR+ cells in the PFC was not sufficient to produce HTRs in the absence of an agonist. In female mice, activation of PFC 5-HT2AR expressing neurons augmented the HTR produced by DOI. However, this result was not seen in male mice. In contrast, inhibition of 5-HT2AR expressing neurons in the PFC prevented the increase in HTR produced by DOI in male, but not in female, mice. Together, these findings suggest that activation of 5-HT2ARs in the PFC is not sufficient to induce HTRs in the absence of a 5-HT2AR agonist but is necessary for induction of HTRs by a 5-HT2AR agonist in a sex-dependent manner.

neuroscience↗

bioRxiv2024

Opto-chemogenetic inhibition of L-type CaV1 channels in neurons through a membrane-assisted molecular linkage

Acute, specific, and robust inhibition of L-type Ca2+ (CaV1) channels has been sought after for both research and therapeutic applications. Compared to other available CaV1 antagonists, genetically-encoded modulators, such as CMI (C-terminus mediated inhibition) peptides encoded by CaV1 DCT (distal C-terminus), hold great potentials due to its affirmative mechanisms of action on both gating and signaling. Here, we find that membrane-anchoring with a Ras tag could essentially help form a type of intramolecular-equivalent linkage, by which the tag anchored-peptide appears to dimerize with another protein or peptide on the membrane, supported by the evidence from patch-clamp electrophysiology and FRET imaging. We then design and implement the constitutive and inducible CMI modules, with appropriate dynamic ranges targeting the short and long variants of CaV1.3, both naturally occurring in neurons. Upon optical (infrared-responsive nanoparticles) and/or chemical (rapamycin) induction of FRB/FKBP binding, DCT peptides with no CMI in the cytosol acutely translocate onto the membrane via FRB-Ras, where the physical linkage requirement could be fulfilled. The peptides robustly produce acute and potent inhibitions on both recombinant CaV1.3 channels and neuronal CaV1 activities, and thus the Ca2+ influx-neuritogenesis coupling. Validated through opto-chemogenetic induction, this prototype demonstrates channel modulation via membrane-assisted molecular linkage, promising broad applicability to diverse membrane proteins.

bioengineering↗

bioRxiv2024

Proteome trade-off between primary and secondary metabolism shapes acid stress induced bacterial exopolysaccharide production

The exopolysaccharide (EPS) produced by Lactiplantibacillus plantarum is a high-value bioproduct in food and health industries, and its biosynthesis has been found as a secondary metabolic pathway to mediate acid stress. To quantitatively investigate acid stress response in L. plantarum and model EPS production, this study measured metabolomics, proteomics and growth data for L. plantarum HMX2 cultured at 4 different pH values. The growth and metabolomics data showed that under acid stress, the EPS production flux was evidently enhanced while the glycolysis and cellular growth were inhibited. The following proteomic analysis found that EPS biosynthetic proteins were significantly up-regulated under acid stress and pinpointed Fur as the most probable transcriptional factor controlling EPS biosynthesis in L. plantarum. Furthermore, we identified a proteome trade-off between primary metabolism and EPS biosynthesis, which were then mechanistically depicted by a regulatory proteome constrained flux balance analysis (RPCFBA) model. As the first metabolic model that can simulate secondary metabolism, the RPCFBA model demonstrated good accuracy in predicting growth rates and EPS production fluxes of L. plantarum HMX2, validated by experimental data. The in-silico perturbation on carbon sources further showed the potential of applying the presented modeling framework to the design and control of microbial secondary metabolism.

systems biology↗

bioRxiv2024

Katanin, kinesin-13 and ataxin-2 inhibit premature interaction between maternal and paternal genomes in C. elegans zygotes

Fertilization occurs before completion of oocyte meiosis in the majority of animal species and sperm contents move long distances within zygotes of mouse and C. elegans. If incorporated into the meiotic spindle, paternal chromosomes could be expelled into a polar body resulting in lethal monosomy. Through live imaging of fertilization in C. elegans, we found that the microtubule disassembling enzymes, katanin and kinesin-13 limit long range movement of sperm contents and that maternal ataxin-2 maintains paternal DNA and paternal mitochondria as a cohesive unit that moves together. Depletion of katanin or double depletion of kinesin-13 and ataxin-2 resulted in capture of the sperm contents by the meiotic spindle. Thus limiting movement of sperm contents and maintaining cohesion of sperm contents within the zygote both contribute to preventing premature interaction between maternal and paternal genomes.

cell biology↗

bioRxiv2024

Effect of Electroacupuncture Pretreatment on Cognitive Impairment and Mitophagy in Aging Model Rats and its mechanism

ObjectiveInvestigate the effects of "Shuanggu Yitong" EA pretreatment on cognitive impairment, mitochondrial function, and mitophagy in aging model rats, and to analyze the related mechanisms. MethodsForty 3-month-old male SD rats were randomly divided into a blank group, a model group, an EA group, and a sham EA group, with 10 rats in each group. And the Morris water maze test was performed after the intervention. HE staining, to observe the morphological changes of the hippocampus of the model rats. Nissl staining was used to observe the changes in the number of hippocampal neurons in rats, Western Blotting (WB) was used to observe the expression of endogenous PTEN-induced hypothetical kinase 1 (PINK1) and human Parkinsons protein 2 (Parkin) in the hippocampus, spectrophotometry was employed to detect the activity of respiratory chain complex I in the hippocampus of the model rats, and flow cytometry was utilized to detect hippocampal mitochondrial membrane potential (MMP) and hippocampal mitochondrial permeability transition pore (MPTP) opening. Results"Shuanggu Yitong" EA pretreatment relieved the cognitive impairment induced by D-galactose in subacute aging model rats. The mechanism of "Shuanggu Yitong" EA pretreatment in the improvement of cognitive impairment of subacute aging model rats may be related to the enhancement of Pink1/Parkin mediated mitophagy and the timely removal of accumulated abnormal mitochondria, thus improving mitochondrial function. Conclusion"Shuanggu Yitong" EA pretreatment can significantly improve the cognitive impairment induced by D-galactose in subacute aging model rats.

cell biology↗

bioRxiv2024

General Capillary Endothelial Cells Undergo Reprogramming into Arterial Endothelial Cells in Pulmonary Hypertension through HIF-2a/Notch4 Pathway

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling that result in right heart hypertrophy, failure, and premature death. The underlying mechanisms of loss of distal capillary endothelial cells (ECs) and obliterative vascular lesion formation remain unclear. Our recent single-cell RNA sequencing, spatial transcriptomics analysis, RNASCOPE, and immunostaining analysis showed that arterial ECs accumulation and loss of capillary ECs were evident in human PAH patients and pulmonary hypertension (PH) rodents. Pseudotime trajectory analysis of the single-cell RNA sequencing data suggest that lung capillary ECs transit to arterial ECs during the development of PH. Our study also identified CXCL12 as the marker for arterial ECs in PH. Capillary EC lineage tracing approach using capillary specific-Dre;Tdtomato reporter mice demonstrated that capillary ECs gave rise to arterial ECs during PH development. Genetic deletion of HIF-2a or pharmacological inhibition of Notch4 normalized the arterial programming in PH. In conclusion, our study demonstrates that capillary endothelium transits to arterial endothelium through the HIF-2a-Notch4 pathway during the development of PAH. Thus, targeting arterial EC transition might be a novel approach for treating PAH patients.

physiology↗

bioRxiv2024

Endothelial fatty acid-binding proteins contribute to the pathogenesis of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Single-cell RNA sequencing (scRNAseq) analysis found that both FABP4 and FABP5 were highly induced in endothelial cells (ECs) of Egln1Tie2Cre (CKO) mice, which was also observed in pulmonary arterial ECs (PAECs) from idiopathic PAH (IPAH) patients, and in whole lungs of pulmonary hypertension (PH) rats. Plasma levels of FABP4/5 were upregulated in IPAH patients and directly correlated with severity of hemodynamics and biochemical parameters using plasma proteome analysis. Genetic deletion of both Fabp4 and 5 in CKO mice (Egln1Tie2Cre/Fabp4-5-/-, TKO) caused a reduction of right ventricular systolic pressure (RVSP) and RV hypertrophy, attenuated pulmonary vascular remodeling and prevented the right heart failure assessed by echocardiography, hemodynamic and histological analysis. Employing bulk RNA-seq and scRNA-seq, and spatial transcriptomic analysis, we showed that Fabp4/5 deletion also inhibited EC glycolysis and distal arterial programming, reduced ROS and HIF-2 expression in PH lungs. Thus, PH causes aberrant expression of FABP4/5 in pulmonary ECs which leads to enhanced ECs glycolysis and distal arterial programming, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.

molecular biology↗

bioRxiv2024

Identification and classification of the genomes of novel Microviruses in a poultry slaughterhouse

Microviridae is a family of phages with circular ssDNA genomes and they are widely found in various environments and organisms. In this study, Virome techniques were employed to explore potential members of Microviridae in poultry slaughterhouse, leading to the identification of 98 novel and complete microvirus genomes. Using a similarity clustering network classification approach, these viruses were found to belong to at least 6 new subfamilies within Microviridae and 3 higher-level taxonomic units. Analysis of their genomes found that the genome size, GC content and genome structure of these new taxa showed evident regularities, validating the rationality of our classification method. Compared with the 19 families classified by previous researchers for microviruses dataset, our method can divide microviruses into about 45 more detailed clusters, which may serve as a new standard for classifying Microviridae members. Furthermore, addressing the scarcity of host information for microviruses, this study significantly broadened their host range and discovered over 20 possible new hosts, including important pathogenic bacteria such as Helicobacter pylori and Vibrio cholerae, as well as different taxa demonstrated differential host specificity. The findings of this study effectively expand the diversity of the Microviridae, providing new insights for their classification and identification. Additionally, it offers a novel perspective for monitoring and controlling pathogenic microorganisms in poultry slaughterhouse environments.

microbiology↗

bioRxiv2023

Systematic elucidation of independently modulated genes in Lactobacillus plantarum reveals a trade-off between secondary and primary metabolism

Lactobacillus plantarum is a probiotic bacteria widely used in food and health industries, but its gene regulatory information is limited in existing databases, which impedes the research of its physiology and its applications. To obtain a better understanding of the transcriptional regulatory network of L. plantarum, independent component analysis (ICA) of its transcriptomes was used to derive 45 sets of independently modulated genes (iModulons). Those iModulons were annotated for associated transcription factors (TFs) and functional pathways, and active iModulons in response to different growth conditions were identified and characterized in detail. Eventually, the analysis of iModulon activities reveals a trade-off between regulatory activities of secondary and primary metabolism in L. plantarum.

systems biology↗

bioRxiv2023

A telomere-to-telomere genome assembly of Zhonghuang 13, a widely-grown soybean variety from the original center of Glycine max

Soybean (Glycine max) stands as a globally significant agricultural crop, and the comprehensive assembly of its genome is of paramount importance for unraveling its biological characteristics and evolutionary history. Nevertheless, previous soybean genome assemblies have harbored gaps and incompleteness, which have constrained in-depth investigations into soybean. Here, we present the first Telomere-to-Telomere (T2T) assembly of the Chinese soybean cultivar "Zhonghuang 13" (ZH13) genome, termed ZH13-T2T, utilizing PacBio Hifi and ONT ultralong reads. We employed a multi-assembler approach, integrating Hifiasm, NextDenovo, and Canu, to minimize biases and enhance assembly accuracy. The assembly spans 1,015,024,879 bp, effectively resolving all 393 gaps that previously plagued the reference genome. Our annotation efforts identified 50,564 high-confidence protein-coding genes, 707 of which are novel. ZH13-T2T revealed longer chromosomes, 421 not-aligned regions (NARs), 112 structure variations (SVs), and a substantial expansion of repetitive element compared to earlier assemblies. Specifically, we identified 25.67 Mb of tandem repeats, an enrichment of 5S and 48S rDNAs, and characterized their genotypic diversity. In summary, we deliver the first complete Chinese soybean cultivar T2T genome. The comprehensive annotation, along with precise centromere and telomere characterization, as well as insights into structural variations, further enhance our understanding of soybean genetics and evolution.

plant biology↗

bioRxiv2023

Functional connectome through the human life span

The lifespan growth of the functional connectome remains unknown. Here, we assemble task-free functional and structural magnetic resonance imaging data from 33,250 individuals aged 32 postmenstrual weeks to 80 years from 132 global sites. We report critical inflection points in the nonlinear growth curves of the global mean and variance of the connectome, peaking in the late fourth and late third decades of life, respectively. After constructing a fine-grained, lifespan-wide suite of system-level brain atlases, we show distinct maturation timelines for functional segregation within different systems. Lifespan growth of regional connectivity is organized along a primary-to-association cortical axis. These connectome-based normative models reveal substantial individual heterogeneities in functional brain networks in patients with autism spectrum disorder, major depressive disorder, and Alzheimers disease. These findings elucidate the lifespan evolution of the functional connectome and can serve as a normative reference for quantifying individual variation in development, aging, and neuropsychiatric disorders.

neuroscience↗

bioRxiv2023

Expansion Mass Spectrometry Imaging: Achieving One-Micron Level Resolution for Lipid Analysis in Tissues

A novel method for enhanced resolution, termed expansion mass spectrometry imaging (Ex-MSI), has been developed for lipid mass spectrometry imaging, utilizing existing commercially available mass spectrometers without necessitating modifications. This approach involves embedding tissue sections in a swellable polyelectrolyte gel, with the target biomolecules indirectly anchored to the gel network. By employing matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), the method has realized an enhancement in spatial resolution that surpasses the conventional resolution limits of commercial instruments by approximately 4.5 folds. This enhancement permits the detailed visualization of intricate structures within the mouse brain at a subcellular level, with a lateral resolution nearing 1 m. As a physical technique for achieving resolution beyond standard capabilities, this approach is readily adaptable and presents a powerful tool for high-definition imaging in biological research.

biochemistry↗

bioRxiv2023

DLTKcat: deep learning based prediction of temperature dependent enzyme turnover rates

The enzyme turnover rate, kcat, quantifies enzyme kinetics by indicating the maximum efficiency of enzyme catalysis. Despite its importance, kcat values remain scarce in databases for most organisms, primarily due to the cost of experimental measurements. To predict kcat and account for its strong temperature dependence, DLTKcat was developed in this study and demonstrated superior performance (log10-scale RMSE = 0.88, R2 = 0.66) than previously published models. Through two case studies, DLTKcat showed its ability to predict the effect of protein sequence mutations and temperature changes on kcat values. Although its quantitative accuracy is not high enough yet to model the responses of cellular metabolism to temperature changes, DLTKcat has the potential to eventually become a computational tool to describe the temperature dependence of biological systems.

systems biology↗