Biology subjects

Tang, Y.

Publications and source records attributed to Tang, Y..

At least 181 records · Page 10Linked to original sources

bioRxiv2023

TCM-CMap: A Novel Computational Methodology to Link Gene Perturbation to Therapeutic Targets in Complex TCM Prescriptions

Herbal medicine, especially Traditional Chinese medicine (TCM), is a valuable resource of natural products for drug discovery with obvious therapeutic effects. However, the mechanisms of action (MOAs) of herbal medicine are often unknown due to limited target information and the complexity of multiple ingredients and targets. This study developed a Herb-CMap algorithm to prioritize active ingredients and targets within herbal medicine by integrating transcriptomics- based gene perturbation data with a random walk algorithm. This methodology bridges the gap between gene perturbation of herbal medicine and its therapeutic target. Using the Suhuang antitussive capsule (Suhuang) for treating cough variant asthma (CVA) as a case study, we identify and experimentally verify that quercetin and luteolin directly interact with Il17a, Pik3cb, Pik3cd, Akt1, and Tnf. These interactions inhibit the IL-17 signaling pathway and inactivate PI3K, Akt, and NF- {kappa}B, preventing lung inflammation and treating CVA. Our findings demonstrate the potential of the Herb-CMap methodology to provide insights into the molecular MOAs of herbal medicine, thereby advancing drug discovery from herbal medicine.

systems biology↗

bioRxiv2023

A wave of minor de novo DNA methylation initiates in mouse 8-cell embryos and co-regulates imprinted X- chromosome inactivation

DNA methylation is extensively reprogrammed during early stage of mammalian development and is essential for normal embryogenesis. It is well established that mouse embryos acquire genome-wide DNA methylation during implantation, referred to as de novo DNA methylation, from globally hypomethylated blastocysts. However, the fact that the main de novo DNA methyltransferase 3B (DNMT3B) is initially expressed as early as the 8-cell stage, contradicts the current knowledge about timing of initiation of de novo DNA methylation. Here, we reported that a previously overlooked minor wave of de novo DNA methylation initially occurs during the transition from the 8-cell to blastocyst stage, before the well-known large-scale de novo DNA methylation during implantation. Functional analyses indicated that minor de novo DNA methylation regulates proliferation, lineage differentiation and metabolic homeostasis of preimplantation embryos, and is critical for embryonic developmental potential and pregnancy outcomes. Furthermore, bioinformatic and functional analyses indicated that minor de novo DNA methylation preferentially occurs on the X chromosome and co-regulates imprinted X-chromosome inactivation via the interaction between DNMT3B and polycomb repressive complexes 2 core components during blastocyst formation. Thus, our study updates the current knowledge of embryonic de novo DNA methylation, thereby providing a novel insight of early embryonic epigenetic reprogramming. Summary statementA minor wave of de novo DNA methylation has been initiated prior to blastocyst formation, but not during the implantation period, and co-regulates imprinted X-chromosome inactivation.

developmental biology↗

bioRxiv2023

Asynchronous Detection of Erroneous Behaviors in Human-Robot Interaction with EEG: A Comparative Analysis of Machine Learning Models.

We present a comparative analysis of two distinct machine-learning models designed to detect asynchronous errors during Human-Robot Interaction (HRI). The models under scrutiny are a customized ResNet model and an ensemble model, both trained and validated using EEG data. The ResNet model is a unique adaptation of the Residual Network, comprising a one-dimensional convolutional layer followed by batch normalization and ReLU activation. It also features a custom Residual Block structure and an adaptive average pooling layer, concluding with a fully connected linear layer for binary classification. The ensemble model, on the other hand, incorporates various machine learning models such as MLP, logistic regression, SVM, random forest, and XGBoost, unified in a pipeline with feature extraction and transformation steps. A critical component of our research is the innovative probability map, which maintains a granularity of 0.1 seconds. This map forecasts the likelihood of forthcoming one-second intervals being classified as either Error or Non-error. Our comparative analysis reveals significant variations in the performance of the two models, both of which exhibit promising results in detecting erroneous behaviors during HRI. We provide detailed validation results, including the accuracy, F1 score, and confusion matrix for each model. This study offers valuable insights into the potential of machine learning in enhancing HRI efficiency and accuracy, indicating promising directions for future research.

neuroscience↗

bioRxiv2023

Transcriptome-wide RNA structure probing with temporal resolution

Reactive small-molecule probes are widely used for RNA structure probing, however current approaches largely measure average RNA transcript dynamics and do not resolve structural differences that occur during folding or transcript maturation. Here, we present SNIPER-seq, an RNA structure probing method relying upon metabolic labeling with 2-aminodeoxycytidine, structure-dependent 2-amino reaction with an aromatic isothiocyanate, and high-throughput RNA sequencing. Our method maps cellular RNA structure transcriptome-wide with temporal resolution enabling determination of transcript age-dependent RNA structural dynamics. We benchmark our approach against known RNA structures and investigate the dynamics of human 5S rRNA during ribosome biogenesis, revealing specific structural changes in 5S rRNA loops that occur over the course of several hours. Taken together, our work sheds light on the maturation and coordinated conformational changes that take place during ribosome biogenesis and provides a general strategy for surveying evolving RNA structural dynamics across the transcriptome.

biochemistry↗

bioRxiv2023

Efficient inhibition of fusion inhibitor HY3000 peptide to SARS-CoV-2 emerging EG.5, EG.5.1 and BA.2.86 variants

SARS-CoV-2 continues to evolve and spread. Recently, the Omicron EG.5 lineage, bearing an additional F456L mutation in spike (S) protein compared to its ancestor XBB.1.9.2, and its sub-variant EG.5.1, which carries a further Q52H mutation, have raised concerns due to their increased prevalence and extended immune escape properties. Additionally, an alarming variant, BA.2.86, has also garnered global concern because it contains over 30 amino acid mutations in its S protein compared to BA.2, including more than 10 changes in receptor-binding domain (RBD), reminiscent of the appearance of the Omicron variant in late 2021. Therefore, there is an urgent need to assess the effectiveness of current vaccines and therapeutics against EG.5, EG.5.1 and BA.2.86. In our previous work, we reported the design and broad-spectrum antiviral activity of a peptide fusion inhibitor HY3000 against SARS-CoV-2 and its variants including XBB.1.5. Here, we continued to evaluate the inhibitory potency of the HY3000 peptide against the prevailing EG.5 and EG.5.1, as well as XBB.1.16, FL.1.5.1, FY.3 and BA.2.86. Our data indicated that the peptide retained its potent inhibitory activities against these variants, indicating its potential as a good virus fusion inhibitor with broad-spectrum therapeutic effect against current and future SARS-CoV-2 variants. Currently, the HY3000 has been finished in Phase II clinical trial in China and has also been approved to conduct clinical investigation by U.S. Food and Drug Administration (FDA), suggesting a good application prospect against the ongoing COVID-19.

microbiology↗

bioRxiv2023

Multi-omics analysis reveals signatures of selection and loci associated with complex traits in pigs

Selection signatures that contribute to phenotypic diversity, especially morphogenesis in pigs, remain to be further elucidated. To reveal the regulatory role of genetic variations in phenotypic differences between Eastern and Western pig breeds, we performed a systematic analysis based on seven high-quality de novo assembled genomes, 1,081 resequencing data representing 78 domestic breeds, 162 methylomes, and 162 transcriptomes of skeletal muscle from Tongcheng (Eastern) and Landrace (Western) pigs at 27 developmental stages. Selective sweep uncovers different genetic architectures behind divergent selection directions for the Eastern and Western breeds. Notably, two loci showed functional alterations by almost fixed missense mutations. By integrating time-course transcriptome and methylome, we revealed differences in developmental timing during myogenesis between Eastern and Western breeds. Genetic variants under artificial selection have critical regulatory effects on progression patterns of heterochronic genes like GHSR and BDH1, by the interaction of local DNA methylation status, particularly during embryonic development. Altogether, our work not only provides valuable resources for understanding pig complex traits, but also contributes to human biomedical research.

genomics↗

bioRxiv2023

Unsaturated intercellular vapor pressure is relevant for leaf water heavy isotope enrichment

Leaf intercellular vapor pressure (ei) can be unsaturated, but its effect on leaf water heavy isotope enrichment (LWE) has not yet been quantified. We evaluated the ecological relevance of unsaturated ei for LWE, i.e., for leaf water oxygen-18 and deuterium enrichment, using data from a boreal forest stand and a large-scale dataset. Unsaturated ei can firstly affect LWE by directly decreasing ei in the Craig Gordon model (Mechanism 1), which leads to an increased influence of atmospheric vapor isotopic enrichment above source water ({Delta}v), and a decreased influence of kinetic fractionation by diffusion through the stomata and boundary layer ({varepsilon}k). Unsaturated ei can secondly affect LWE by changing {varepsilon}k (Mechanism 2). To evaluate the effect of Mechanism 1 to LWE, we employed sensitivity tests on LWE model performance using varying measured intercellular relative humidity (RHcellular), or RHcellular fitted to observed LWE. To explore the effects of Mechanism 2 to LWE, we modified the calculation of {varepsilon}k and observed consequences to LWE predictions. Unsaturated ei is relevant to LWE by Mechanism 1, since a lowered RHcellular noticeably changed LWE predictions. It clearly improved deuterium predictions and conditionally improved oxygen-18 predictions. Isotope fractionation by Mechanism 2 is unlikely relevant to oxygen-18 and deuterium enrichment. Unsaturated ei must now be recognized as a variable that introduces error to heavy isotope enrichment models and reconstructions from organic material, via Mechanism 1. We suggest a correction for unsaturated ei for both oxygen-18 and deuterium enrichment using a variable RHcellular calculated from atmospheric relative humidity.

plant biology↗

bioRxiv2023

CDK6-mediated endothelial cell cycle acceleration drives arteriovenous malformations in hereditary hemorrhagic telangiectasia

Increased endothelial cell (EC) proliferation is a hallmark of arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT). The underlying mechanism and disease relevance of this abnormal cell proliferative state of the ECs remain unknown. Here, we report the identification of a CDK6-driven mechanism of cell cycle progression deregulation directly involved in EC proliferation and HHT vascular pathology. Specifically, HHT mouse liver ECs exhibited defects in their cell cycle control characterized by a G1/S checkpoint bypass and acceleration of cell cycle speed. Phosphorylated retinoblastoma (p-RB1)--a marker of G1/S transition through the restriction point--significantly accumulated in ECs of HHT mouse retinal AVMs and HHT patient skin telangiectasias. Mechanistically, ALK1 loss of function increased the expression of key restriction point mediators, and treatment with palbociclib or ribociclib, two CDK4/6 inhibitors, blocked p-RB1 increase and retinal AVMs in HHT mice. Palbociclib also improved vascular pathology in the brain and slowed down endothelial cell cycle speed and EC proliferation. Specific deletion of Cdk6 in ECs was sufficient to protect HHT mice from AVM pathology. Thus, CDK6-mediated endothelial cell cycle acceleration controls EC proliferation in AVMs and is a central determinant of HHT pathogenesis. We propose that clinically approved CDK4/6 inhibitors have repurposing potential in HHT.

cell biology↗

bioRxiv2023

Microsporidia Ser/Thr Protein Phosphatase PP1 Targets DCs MAPK Pathway and Impair Immune Functions

Microsporidia are difficult to completely eliminate. Their persistence may disrupt host cell functions. Here in this study, we aimed to elucidate the impairing effects and consequences of microsporidia infection upon dendritic cells (DCs). We used the zoonotic microsporidia species, Enterocytozoon hellem, in our studies. In vivo experiments showed that E. hellem-infected mice were more susceptible to further pathogenic challenges. DCs were identified as the most affected group of cells. In vitro assays revealed that E. hellem infection impaired the immune functions of DCs as reflected by down-regulation of cytokine expression, lower extent of maturation and antigen presentation. E. hellem infection decreased the ability of DCs to prime and stimulate T cells, thereby hampering host immune cell functions. We further demonstrate that E. hellem Ser/Thr protein phosphatase PP1 directly interacts with host p38(MAPK14) to manipulate the p38 (MAPK14)/NFAT-5 axis of the MAPK pathway. Our study is the first to elucidate the molecular mechanisms of the impairing effects of microsporidia on host DCs immune functions. The emerging of microsporidiosis may be great threat to public health. HighlightsO_LIPersistence of Microsporidia within host impairs dendritic cell functions such as phagocytosis, maturation, antigen presentation and T cell priming, thereby disrupting both innate and adaptive immunities and making the host more vulnerable to secondary infections C_LIO_LIMicrosporidia impairs DCs function via Serine/Threonine Protein Phosphatase PP1 directly targeting DCs p38/MAPK pathway C_LIO_LILatent Microsporidia infection and persistence is a great threat to public health when assessing acute and emerging pathogen risk C_LI

microbiology↗

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

Bacterial Sphingolipids Exacerbate Colitis by Inhibiting ILC3-derived IL-22 Production.

Commensal bacteria of the Bacteroidetes phylum are the primary producers of sphingolipids in the gut lumen. These lipids serve dual roles as bacterial virulence factors and regulators of the host mucosal immune system, including regulatory T cells and invariant natural killer T cells (iNKT). Sphingolipid composition is significantly altered in fecal samples of patients with inflammatory bowel disease (IBD). However, the specific mechanisms by which bacterial sphingolipids modulate mucosal homeostasis and regulate intestinal inflammation remain unclear. In this study, we investigated the impact of bacterial sphingolipids on intestinal inflammation by mono-colonizing mice with Bacteroides fragilis strains that either express or lack sphingolipids during DSS-induced colitis. We discovered that B. fragilis sphingolipids exacerbate intestinal inflammation. Mice mono-colonized with B. fragilis lacking sphingolipids exhibited less severe DSS-induced colitis. This amelioration of colitis was associated with increased production of interleukin-22 (IL-22) by innate lymphoid cell type 3 (ILC3). Consistent with the inhibitory effect of sphingolipids on IL-22 production, mice colonized with B. fragilis lacking sphingolipids showed enhanced epithelial STAT3 activity, intestinal cell proliferation, and antimicrobial peptide production following DSS treatment compared to those colonized with B. fragilis producing sphingolipids. Additionally, colitis severity in mice colonized with B. fragilis lacking sphingolipids was exacerbated upon IL-22 blockade. Furthermore, our study reveals that bacterial sphingolipids restrict epithelial IL-18 production following DSS treatment and interfere with IL-22 production by a subset of ILC3 cells expressing both the interleukin-18 receptor (IL-18R) and major histocompatibility complex class II (MHC II). These findings indicate that B. fragilis-derived sphingolipids exacerbate mucosal inflammation by impeding epithelial IL-18 expression, resulting in compromised production of IL-22 by ILC3 cells. HighlightsO_LIB. fragilis-derived sphingolipids exacerbate DSS-induced colitis in mono-colonized C57BL/6 mice. C_LIO_LIB. fragilis-derived sphingolipids constrain ILC3-derived IL-22, leading to reduced colonic epithelial cell proliferation and compromised barrier function. C_LIO_LIB. fragilis-derived sphingolipids restrict epithelial NLRC4 inflammasome activation and IL-18 secretion. C_LIO_LIB. fragilis-derived sphingolipids modulate IL-22 production by IL18R+ MHC II+ ILC3s. C_LI

immunology↗

bioRxiv2023

weIMPUTE: A User-Friendly Web-Based Genotype Imputation Platform

Genotype imputation is a critical preprocessing step in genome-wide association studies (GWAS), enhancing statistical power for detecting associated single nucleotide polymorphisms (SNPs) by increasing marker size. In response to the needs of researchers seeking user-friendly graphical tools for imputation without requiring informatics or computer expertise, we have developed weIMPUTE, a web-based imputation graphical user interface (GUI). Unlike existing genotype imputation software, weIMPUTE supports multiple imputation software, including SHAPEIT, Eagle, Minimac4, Beagle, and IMPUTE2, while encompassing the entire workflow, from quality control to data format conversion. This comprehensive platform enables both novices and experienced users to readily perform imputation tasks. For reference genotype data owners, weIMPUTE can be installed on a server or workstation, facilitating web-based imputation services without data sharing. weIMPUTE represents a versatile imputation solution for researchers across various fields, offering the flexibility to create personalized imputation servers on different operating systems.

bioinformatics↗

bioRxiv2023

Rapid and visual detection of Schistosoma japonicum circulating nucleic acids by CRISPR-Cas12a

BackgroundSchistosomiasis is the second most destructive parasitic disease globally. It poses a serious threat to human health if not diagnosed and treated promptly. However, the current detection methods have limitations due to their dependence on specialized equipments and personnel, and the long detection time, resulting in less-than-ideal detection outcomes. Therefore, more accurate and sensitive assays are required to aid in the control of schistosomiasis. This study aims to develop a rapid and practical method for detecting Schistosoma japonicum circulating nucleic acid by combining the Cas12a protein in the CRISPR (Clustered regularly interspaced short palindromic repeats) system with recombinase-mediated isothermal nucleic acid amplification technology. Methodology/Principal FindingsWe created a CRISPR-Cas12a detection method for Schistosomiasis. SjR2 and SjCHGCS19 genes with repetitive copies in the Schistosoma japonicum genome were targeted for detection. The CRISPR-Cas12a detection method can achieve a detection sensitivity of 1 cp/{micro}L, with no cross-reaction with the other three human-infecting trematode parasites. To vividly simulate clinical patients at different infection stages, we collected rabbits serums at 1 d, 3 d, 1 w, 3 w, 5 w, and 7 w post-infection. Circulating Schistosoma japonicum DNA in the serum can be detected as early as 3 days post-infection. The sample and positive rates of each stage were analyzed and the CRISPR-Cas12a detection method prevailed to Nested-PCR. Additionally, our assay offers flexible results readout options, including lateral test strips. Conclusions/SignificanceThis CRISPR-Cas12a detection method enables sensitive and specific detection of Schistosomiasis by detecting highly repetitive SjR2 and SjCHGCS19 genes. The method was fully validated with rabbits serums collected at different infection stages, which can be applied to monitoring the early infection of schistosomiasis in resource-limited regions. Author SummaryWith the development of schistosomiasis prevention and control efforts in recent years, the prevalence rate and infection intensity of schistosomiasis have decreased, making early and accurate diagnoses more challenging. Combining CRISPR-Cas12a protein with isothermal amplification technology, a detection method for the multi-copy sequences SjR2 and SjCHGCS19 in the genome of Schistosoma japonicum was developed in this study. The results demonstrated that the detection sensitivity of this method could reach 1 cp/{micro}L, with no cross reactivity with three other fluke-like human parasites. In this study, serum samples from 15 rabbits infected with Schistosoma japonicum were used to validate the method. The results demonstrated that rabbits could be identified as early as the third day after infection. CRISPR-Cas12a detection method has a higher positive rate than traditional Nested-PCR. In addition, lateral test strips enable direct observation of our assay results. The aforementioned research findings indicate that the CRISPR-Cas12a-based detection method can be utilized for the early diagnosis of schistosomiasis. In conjunction with the result reading method of the lateral test strips, it also provides a new method for the on-site diagnosis of schistosomiasis in environments with limited access to resources.

bioengineering↗

bioRxiv2023

Immunities Specific to Both of the M Protein Ectodomain and RBD Synergize to Confer Cross-protection against SARS-CoV-2 Infections

The effectiveness of the prototypic SARS-CoV-2 vaccine largely decreased overtime against the emerging virus strains, necessitating the universal vaccine development. The most abundant structural membrane (M) protein is highly conserved in amino acid sequence, which arouses our research interests in developing a universal immunogen based on it. Serological analysis showed that IgG responses specific to its N-terminal peptides can be strongly detected in many serum samples from both convalescent patients and vaccinees receiving inactivated vaccines, indicating the potential existence of human B-cell epitopes in reactive peptides. Microneutralization assays showed that the N-terminal peptide S2M2-30-specific hyperimmune serum was capable of cross-neutralizing the authentic viruses including wild-type HKU-001a, B.1.617.2/Delta, and Omicron subvariant BQ.1.1, and synergized with RBD-specific serum in reinforcing antiviral activities. Strong S2M2-30-specific immunities elicited in hACE2-transgenic mice could effectively inhibit B.1.1.7/Alpha (UK) infections. Our results suggest the potentiality of conserved M peptides as vaccine targets for conferring cross-protections against sarbecoviruses.

immunology↗

bioRxiv2023

Improving the Circularization Efficiency, Stability and Translatability of Circular RNA by circDesign

Synthetic circular RNA (circRNA) has emerged as a promising platform for vaccine and therapeutic development, featuring its uniqueness in a closed-loop structure, cap-independent translation mechanism, and prolonged expression. However, the rational design of a circRNA sequence to jointly improve its stability and protein coding potential remains challenging. In this study, we present circDesign, an efficient algorithm to achieve the optimal design of circRNA by ensuring optimized folding of each segment, which leads to enhanced circularization efficiency, stability, and translatability. Using rabies virus glycoprotein (RABV-G) as the model antigen, we demonstrated that circDesign-generated circRNAs exhibited higher stability and protein translation efficiency in vitro and in vivo compared to other codon adaptation index (CAI)-optimized sequences, thus leading to enhanced in vivo immunogenicity. Ribosome and polysome profiling further revealed that an intact internal ribosome entry site (IRES) structure is critical for efficient translation. By intentionally disrupting the IRES motifs, we observed that the resulting circRNA sequences had lower translatability compared to circDesign-generated sequences. Taken together, our circular RNA design algorithm provides a general strategy to leverage the capability of circRNA as next-generation vaccines or therapeutics.

bioengineering↗

bioRxiv2023

Data-driven discovery of innate immunomodulators via machine learning-guided high throughput screening

The innate immune response is vital for the success of prophylactic vaccines and immunotherapies. Control of signaling in innate immune pathways can improve prophylactic vaccines by inhibiting unfavorable systemic inflammation and immunotherapies by enhancing immune stimulation. In this work, we developed a machine learning-enabled active learning pipeline to guide in vitro experimental screening and discovery of small molecule immunomodulators that improve immune responses by altering the signaling activity of innate immune responses stimulated by traditional pattern recognition receptor agonists. Molecules were tested by in vitro high throughput screening (HTS) where we measured modulation of the nuclear factor{kappa} -light-chain-enhancer of activated B-cells (NF-{kappa}B) and the interferon regulatory factors (IRF) pathways. These data were used to train data-driven predictive models linking molecular structure to modulation of the NF-{kappa}B and IRF responses using deep representational learning, Gaussian process regression, and Bayesian optimization. By interleaving successive rounds of model training and in vitro HTS, we performed an active learning-guided traversal of a 139,998 molecule library. After sampling only[~] 2% of the library, we discovered viable molecules with unprecedented immunomodulatory capacity, including those capable of suppressing NF-{kappa}B activity by up to 15-fold, elevating NF-{kappa}B activity by up to 5-fold, and elevating IRF activity by up to 6-fold. We extracted chemical design rules identifying particular chemical fragments as principal drivers of specific immunomodulation behaviors. We validated the immunomodulatory effect of a subset of our top candidates by measuring cytokine release profiles. Of these, one molecule induced a 3-fold enhancement in IFN-{beta} production when delivered with a cyclic di-nucleotide stimulator of interferon genes (STING) agonist. In sum, our machine learning-enabled screening approach presents an efficient immunomodulator discovery pipeline that has furnished a library of novel small molecules with a strong capacity to enhance or suppress innate immune signaling pathways to shape and improve prophylactic vaccination and immunotherapies.

immunology↗

bioRxiv2023

FM3VCF: A Software Library for Accelerating the Loading of Large VCF Files in Genotype Data Analyses

BackgroundThe increasing size of genotype data has led to the loading of VCF files becoming a computational bottleneck in various analyses, including imputation and genome-wide association studies (GWAS). To address this issue, we developed a software library, FM3VCF (fast M3VCF), that utilizes multiple CPU threads to accelerate this process. FindingsFM3VCF can convert VCF files into the exclusive data format of MINIMAC4[1], M3VCF[1], and efficiently read and parse data from VCF files. In comparison to m3vcftools[1], FM3VCF is approximately 20 times faster for compressing VCF files to M3VCF format. Furthermore, FM3VCF is approximately 3 times faster than HTSlib[2], including decompressing and parsing, for reading compressed VCF files. FM3VCF is written in C and is open-source, available for download from https://github.com/Oliver-111/m3vcf under the MIT/BSD license. ConclusionFM3VCF is a powerful tool for accelerating the loading of large VCF files in genotype data analyses. By fully utilizing multiple CPU threads, FM3VCF can significantly reduce the computational burden in various genomic analyses.

bioinformatics↗

bioRxiv2023

Astrocytes gate long-term potentiation in hippocampal interneurons

Long-term potentiation is involved in physiological processes such as learning and memory, motor learning and sensory processing, and pathological conditions such as addiction. In contrast to the extensive studies on the mechanism of long-term potentiation on excitatory glutamatergic synapses onto excitatory neurons (LTPE[->]E), the mechanism of LTP on excitatory glutamatergic synapses onto inhibitory neurons (LTPE[->]I) remains largely unknown. In the central nervous system, astrocytes play an important role in regulating synaptic activity and participate in the process of LTPE[->]E, but their functions in LTPE[->]I remain incompletely defined., We studied the role of astrocytes in regulating LTPE[->]I in the hippocampal CA1 region and their impact on cognitive function using electrophysiological, pharmacological, confocal calcium imaging, chemogenetics and behavior tests. We showed that LTPE[->]I in the stratum oriens of hippocampal CA1 is astrocyte independent. However, in the stratum radiatum, synaptically released endocannabinoids increase astrocyte Ca2+ via type-1 cannabinoid receptors, stimulate D-serine release, and potentiate excitatory synaptic transmission on inhibitory neurons through the activation of (N-methyl-D-aspartate) NMDA receptors. We also revealed that chemogenetic activation of astrocytes is sufficient for inducing NMDA-dependent de novo LTPE[->]I in the stratum radiatum of the hippocampus. Furthermore, we found that disrupting LTPE[->]I by knocking down {gamma}CaMKII in interneurons of the stratum radiatum resulted in dramatic memory impairment. Our findings suggest that astrocytes release D-serine, which activates NMDA receptors to regulate LTPE[->]I, and that cognitive function is intricately linked with the proper functioning of this LTPE[->]I pathway.

neuroscience↗