Biology subjects

Wang, J.

Publications and source records attributed to Wang, J..

At least 1,207 records · Page 67Linked to original sources

bioRxiv2024

Distal tuft dendrites shape and maintain new place fields

Hippocampal pyramidal neurons support episodic memory by integrating complementary information streams into new place fields. Distal tuft dendrites are widely thought to initiate place field formation by locally generating prolonged, globally-spreading Ca2+spikes known as plateau potentials. However, the hitherto experimental inaccessibility of distal tuft dendrites in the hippocampus has rendered their in vivo function entirely unknown. Here we gained direct optical access to this elusive dendritic compartment. We report that distal tuft dendrites do not serve as the point of origin for place field-forming plateau potentials. Instead, the timing and extent of peri-formation distal tuft recruitment is variable and closely predicts multiple properties of resultant place fields. Therefore, distal tuft dendrites play a more powerful role in hippocampal feature selectivity than simply initiating place field formation. Moreover, place field formation is not accompanied by global Ca2+influx as previously thought. In addition to shaping new somatic place fields, distal tuft dendrites possess their own local place fields. Tuft place fields are back-shifted relative to that of their soma and appear to maintain somatic place fields via post-formation plateau potentials. Through direct in vivo observation, we provide a revised dendritic basis for hippocampal feature selectivity during navigational learning.

neuroscience↗

bioRxiv2024

Cross-species alignment along the chronological axis reveals evolutionary effect on structural development of human brain

Disentangling evolution mysteries of human brain has always been an imperative endeavor in neuroscience. On the one hand, by spatially aligning the brains between human and nonhuman primates (NHPs), previous efforts in comparative studies revealed both correspondence and difference in brain anatomy, e.g., the morphological and the connectomic patterns. On the other hand, brain anatomical development along the temporal axis is evident for both human and NHPs in early life. However, it remains largely unknown whether we can conjugate the brain development phases between human and NHPs, and, especially, what the role played by the brain anatomy in the conjugation will be. Here, we proposed to embed the brain anatomy of human and macaque in the chronological axis for enabling the cross-species comparison on brain development. Specifically, we separately established the prediction models by using the brain anatomical features in gray matter and white matter tracts to predict the chronological age in the human and macaque samples with brain development. We observed that applying the trained models within-species could well predict the chronological age. Interestingly, by conducting the cross-species application of the trained models, e.g., applying the model trained in humans to the data of macaques, we found a significant cross-species imbalance regarding to the model performance, in which the model trained in macaque showed a higher accuracy in predicting the chronological age of human than the model trained in human in predicting the chronological age of macaque. The cross application of the trained model introduced the brain cross-species age gap (BCAP) as an individual index to quantify the cross-species discrepancy along the temporal axis of brain development for each participant. We further showed that BCAP was associated with the behavioral performance in both visual sensitivity test and picture vocabulary test in the human samples. Taken together, our study situated the cross-species brain development along the chronological axis, which highlighted the disproportionately anatomical development in the human brain to extend our understanding of the potential evolutionary effects.

neuroscience↗

bioRxiv2024

Hippocampal purinergic P2X7 receptor level is increased in Alzheimer's disease patients, and associated with amyloid and tau pathologies

INTRODUCTIONThe purinergic receptor P2X7R, which is expressed on microglia and astrocytes, plays an important role in Alzheimers disease (AD). We aimed to characterize the alterations in P2X7R expression in AD patients by APOE {varepsilon}4 allele, age and sex, as well as its association with amyloid and tau pathology. METHODSP2X7R staining and quantitative analysis of amyloid, tau, astrocytes and microglia were performed on postmortem hippocampal tissues from 35 AD patients; 31 nondemented controls; caudate/putamen tissue from corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) patients; and bran tissue from aged 3xTg mouse model of AD. RESULTSActivated microglia and reactive astrocytes were observed in the hippocampi of AD patients and exhibited altered morphology with denser cells and pronounced ramifications. Hippocampal P2X7R intensity was greater in the hippocampal subfields of AD patients than in those of nondemented controls and was correlated with amyloid level and Braak stage and was not affected by sex, APOE{varepsilon}4 allele, or age. P2X7R expression increased around A{beta} plaques, cerebral amyloid angiopathy, tau inclusions in the hippocampus from AD patients and tau inclusions in the caudate/putamen from CBD and PSP patients. DISCUSSIONWe found an increased hippocampal P2X7R level in AD compared to non-demented control, which correlated with amyloid and tau pathologies. P2X7R is a potential marker for neuroinflammation in AD.

neuroscience↗

bioRxiv2024

Drug inhibition and substrate alternating flipping mechanisms of human VMAT2

Vesicular monoamine transporters (VMAT1/2) are responsible for loading and packaging monoamine neurotransmitters into synaptic vesicles, including serotonin (5-HT), dopamine (DA), norepinephrine, and histamine. Dysregulation of VMAT2 within the central nervous system can lead to schizophrenia, mood disorders, and Parkinsons disease, due to the imbalances of these monoamine neurotransmitters. Medications such as tetrabenazine (TBZ) and valbenazine (VBZ) targetting VMAT2 are approved for treating chorea associated with Huntingtons disease and Tardive Dyskinesia. Our cryo-EM studies and molecular dynamics (MD) simulations on VMAT2 bound to drug inhibitors (TBZ and VBZ) and substrates (5-HT and DA), unveil the inhibition mechanism of VMAT2, alternating flipping mechanism of substrates during loading, translocation, and release, as well as the interplay between protonation of crucial acidic residues and substrate release. These findings enhance the understanding of VMAT-mediated monoamine neurotransmitter transport, fostering drug development for neurological and neuropsychiatric disorders, with a specific emphasis on VMATs.

neuroscience↗

bioRxiv2024

Exploring the conformational space of protein-protein complex with transformer-based generative model

Protein-protein interactions are the basis of many protein functions, and understanding the contact and conformational changes of protein-protein interactions is crucial for linking protein structure to biological function. Although difficult to detect experimentally, molecular dynamics (MD) simulations are widely used to study the conformational ensembles and dynamics of protein-protein complexes, but there are significant limitations in sampling efficiency and computational costs. In this study, a generative neural network was trained on protein-protein complex conformations obtained from molecular simulations to directly generate novel conformations with physical realism. We demonstrated the use of a deep learning model based on the transformer architecture to explore the conformational ensembles of protein-protein complexes through MD simulations. The results showed that the learned latent space can be used to generate unsampled conformations of protein-protein complexes for obtaining new conformations complementing pre-existing ones, which can be used as an exploratory tool for the analysis and enhancement of molecular simulations of protein-protein complexes.

bioinformatics↗

bioRxiv2024

Revolutionizing GPCR-Ligand Predictions: DeepGPCR with experimental Validation for High-Precision Drug Discovery

G-protein coupled receptors (GPCRs), crucial in various diseases, are targeted of over 40% of approved drugs. However, the reliable acquisition of experimental GPCRs structures is hindered by their lipid-embedded conformations. Traditional protein-ligand interaction models falter in GPCR-drug interactions, caused by limited and low-quality structures. Generalized models, trained on soluble protein-ligand pairs, are also inadequate. To address these issues, we developed two models, DeepGPCR_BC for binary classification and DeepGPCR_RG for affinity prediction. These models use non-structural GPCR-ligand interaction data, leveraging graph convolutional networks (GCN) and mol2vec techniques to represent binding pockets and ligands as graphs. This approach significantly speeds up predictions while preserving critical physical-chemical and spatial information. In independent tests, DeepGPCR_BC surpassed Autodock Vina and Schrodinger Dock with an AUC of 0.72, accuracy of 0.68, and TPR of 0.73, whereas DeepGPCR_RG demonstrated a Pearson correlation of 0.39 and RMSE of 1.34. We applied these models to screen drug candidates for GPR35 (Q9HC97), yielding promising results with 3 (F545-1970, K297-0698, S948-0241) out of 8 candidates. Furthermore, we also successfully obtained 6 active inhibitors for GLP-1R. Our GPCR-specific models pave the way for efficient and accurate large-scale virtual screening, potentially revolutionizing drug discovery in the GPCR field.

bioinformatics↗

bioRxiv2024

Phylogenomics resolves a 100-year-old debate regarding the evolutionary history of caddisflies (Insecta: Trichoptera)

Trichoptera (caddisfly) phylogeny provides an interesting example of aquatic insect evolution, with rich ecological diversification, especially for underwater architecture. Trichoptera provide numerous critical ecosystem services and are also one of the most important groups of aquatic insects for assessing water quality. The phylogenetic relationships of Trichoptera have been debated for nearly a century. In particular, the phylogenetic position of the "cocoon-makers" within Trichoptera has long been contested. Here, we designed a universal single-copy orthologue and sets of ultraconserved element markers specific for Trichoptera for the first time. Simultaneously, we reconstructed the phylogenetic relationship of Trichoptera based on genome data from 111 species, representing 29 families and 71 genera. Our phylogenetic inference clarifies the probable phylogenetic relationships of "cocoon-makers" within Integripalpia. Hydroptilidae is considered as the basal lineage within Integripalpia, and the families Glossosomatidae, Hydrobiosidae, and Rhyacophilidae formed a monophyletic clade, sister to the integripalpian subterorder Phryganides. The resulting divergence time and ancestral state reconstruction suggest that the most recent common ancestor of Trichoptera appeared in the early Permian and that diversification was strongly correlated with habitat change.

zoology↗

bioRxiv2024

EmbB and EmbC Regulate the Sensitivity of Mycobacterium abscessus to Echinomycin

Treatment of Mycobacterium abscessus (Mab) infection is a major challenge due to its intrinsic resistance to most available drugs. It is thus imperative to find new anti-Mab drugs. In this study, we investigated the activity and intrinsic resistance mechanism of echinomycin (ECH) against Mab. ECH is active against Mab (MIC: 2 {micro}g/mL). The embC gene knockout strain (Mab{Delta}embC) showed hyper-sensitive to ECH (MIC: 0.0078-0.0156 {micro}g/mL). The MICs of ECH-resistant strains screened based on the Mab{Delta}embC strain were 0.25-1 {micro}g/mL. Mutations were found in the EmbB, including Asp306Ala, Asp306Asn, Arg350Gly, Val555Ile, and Gly581Ser, which led to increased resistance to ECH when overexpressed in Mab{Delta}embC individually (0.25-0.5 {micro}g/mL). The EmbB mutants edited by the CRISPR/Cpf1 system became more resistant to ECH (MIC: 0.25-0.5 {micro}g/mL). The permeability of gene-edited and overexpressed Mab strains was reduced, as shown by the ethidium bromide accumulation assay, but it was still significantly higher than that of the parent Mab. To summarize, our study demonstrates that ECH has a strong anti-Mab activity and confirms that EmbB and EmbC are related to the sensitivity of Mab to ECH. EmbB mutation may partially compensate for the function of EmbC. Impact StatementMycobacterium abscessus (Mab) is a rapidly growing, intrinsic multidrug-resistant Mycobacterium. This study demonstrated that echinomycin (ECH) has potent antibacterial activity against Mab, and the mechanism of ECH resistance to Mab is related to EmbB and EmbC. EmbB and EmbC can alter the sensitivity of Mab to ECH by altering the permeability of its cell wall. In addition, there is a functional complementary evolution between EmbB and EmbC to regulate sensitivity to ECH. Overall, our study provides a novel anti-Mab drug candidate ECH and a scientific foundation for developing effective strategies to prevent and control Mab.

microbiology↗

bioRxiv2024

Exploring the repository of de novo designed bifunctional antimicrobial peptides through deep learning

Antimicrobial peptides (AMPs) are attractive candidates to combat antibiotic resistance for their capability to target bio-membranes and restrict a wide range of pathogens. It is a daunting challenge to discover novel AMPs due to their sparse distributions in a vast peptide universe, especially for peptides that demonstrate potencies for both bacterial membranes and viral envelopes. Here we establish a de novo AMP design framework by bridging a deep generative module and a graph-encoding activity regressor. The generative module learns hidden grammars of AMP features and produces candidates sequentially pass antimicrobial predictor and antiviral classifiers. We discover 16 bifunctional AMPs and experimentally validated their abilities to inhibit a spectrum of pathogens in vitro and in animal models. Notably, P076 is a highly potent bactericide with the minimal inhibitory concentration of 0.21 M against multidrug-resistant A. baumannii, while P002 broadly inhibits five enveloped viruses. Our study provides feasible means to uncover sequences that simultaneously encode antimicrobial and antiviral activities, thus bolstering the function spectra of AMPs to combat a wide range of drug-resistant infections.

microbiology↗

bioRxiv2024

Integrating short-read and long-read single-cell RNA sequencing for comprehensive transcriptome profiling in mouse retina

The vast majority of protein-coding genes in the human genome produce multiple mRNA isoforms through alternative splicing, significantly enhancing the complexity of the transcriptome and proteome. To establish an efficient method for characterizing transcript isoforms within tissue samples, we conducted a systematic comparison between single-cell long-read and conventional short-read RNA sequencing techniques. The transcriptome of approximately 30,000 mouse retina cells was profiled using 1.54 billion Illumina short reads and 1.40 billion Oxford Nanopore long reads. Consequently, we identified 44,325 transcript isoforms, with a notable 38% previously uncharacterized and 17% expressed exclusively in distinct cellular subclasses. We observed that long-read sequencing not only matched the gene expression and cell-type annotation performance of short-read sequencing but also excelled in the precise identification of transcript isoforms. While transcript isoforms are often shared across various cell types, their relative abundance shows considerable cell-type-specific variation. The data generated from our study significantly enhance the existing repertoire of transcript isoforms, thereby establishing a foundational resource for future research into the mechanisms and implications of alternative splicing within retinal biology and its links to related diseases.

bioinformatics↗

bioRxiv2024

CAMKV Kinase Signaling Is a Novel Therapeutic Avenue with Prognostic Relevance in Neuroblastoma

Neuroblastoma (NB) can be a highly aggressive malignancy in children. However, the precise mechanisms driving NB tumorigenesis remain elusive. This study revealed the critical role of CREB phosphorylation in NB cell proliferation. By employing a CRISPR-Cas9 knockout screen targeting calcium/calmodulin-dependent protein kinase (CaMK) family members, we identified the CaM kinase-like vesicle-associated (CAMKV) protein as a kinase that mediates direct phosphorylation of CREB to promote NB cell proliferation. CAMKV was found to be a transcriptional target of MYCN/MYC in NB cells. CAMKV knockout and knockdown effectively suppressed NB cell proliferation and tumor growth both in vitro and in vivo. Bioinformatic analysis revealed that high CAMKV expression is significantly correlated with poor patient survival. High-risk NB frequently had high CAMKV protein levels by Immunohistochemical staining. Integrated transcriptomic and proteomic analyses of CAMKV knockdown cells unveiled downstream targets involved in CAMKV-regulated phosphorylation and signaling pathways, many of which are linked to neural development and cancer progression. We identified small molecule inhibitors targeting CAMKV and further demonstrated the efficacy of one inhibitor in suppressing NB tumor growth and prolonging the survival of mice bearing xenografted tumors. These findings reveal a critical role for CAMKV kinase signaling in NB growth and identified CAMKV kinase as a potential therapeutic target and prognostic marker for patients with NB.

cancer biology↗

bioRxiv2024

Host 5-HT affects Plasmodium transmission in mosquitoes via modulating mosquito mitochondrial homeostasis

Malaria parasites hijack the metabolism of their mammalian host during the blood-stage cycle. Anopheles mosquitoes depend on mammalian blood to survive and to transmit malaria parasites. However, it remains understudied whether changes in host metabolism affect parasite transmission in mosquitoes. In this study, we discovered that Plasmodium infection significantly decreased the levels of the tryptophan metabolite, 5-hydroxytryptamine (5-HT), in both humans and mice. The reduction led to the decrease of 5-HT in mosquitoes. Oral supplementation of 5-HT to Anopheles stephensi enhanced its resistance to Plasmodium berghei infection by promoting the generation of mitochondrial reactive oxygen species. This effect was due to the accumulation of dysfunctional mitochondria caused by 5-HT-mediated inhibition of mitophagy. Elevating 5-HT levels in mouse serum significantly suppressed parasite infection in mosquitoes. In summary, our data highlight the critical role of metabolites in animal blood in determining the capacity of mosquitoes to control parasite infection.

pathology↗

bioRxiv2024

Arginine Di-methylation of RIPK3 Safeguards Necroptosis for Intestinal Homeostasis

The necroptosis mediated by RIPK3 is stringently regulated for intestinal homeostasis. Here we found that mice lacking Prmt5 (Protein arginase methyltransferase 5) in intestinal epithelial cells (IECs) caused premature death with IECs necroptosis, villus atrophy and loss of Paneth cells. This pathology can be partially rescued by antibiotic treatment, germ-free breeding condition and pharmaceutical inhibition of RIPK1 and RIPK3, but aggravated for embryonic lethality by Caspase-8 deficiency, which demonstrating the importance of commensal bacteria and necroptosis for the Prmt5-IEC deficiency. Intriguingly, tumor-necrosis factor (TNF) receptor 1(Tnfr1) deficiency could not completely rescue the pathology, and mice deficit in Z- DNA binding protein 1(ZBP1) exhibited shorter lifespan compared with Prmt5 null mice, suggesting Prmt5 loss might trigger TNFR-RIPK1-depenfent and ZBP1- dependent necroptosis. Mechanically, we identified the 479-arginine residue of RIPK3 di-methylated by PRMT5 was an endogenous checkpoint for necroptosis. Furthermore, RIPK3-R479K mutation had higher affinity with both RIPK1 and ZBP1 by immunoprecipitation and STORM (Stochastic Optical Reconstruction Microscopy) analysis, which might explain the endogenous necroptosis triggered by mutated RIPK3 even without upstream stimuli. Moreover, the peptide of RIPK3-SDMA (Symmetric dimethylarginine of 479) could rescue lethality of Prmt5 lacking mice through necrosome formation inhibition, which demonstrating the great potential for necroptosis-related disease treatment through RIPK3 dimethylation targeting.

cell biology↗

bioRxiv2024

From Sight to Insight: A Multi-task Approach with the Visual Language Decoding Model

Visual neural decoding aims to unlock the mysteries of how the human brain interprets the visual world. While early studies made some progress in decoding visual activity for singular type of information, they failed to concurrently reveal the multi-level interweaving linguistic information in the brain. Here, we developed a novel Visual Language Decoding Model (VLDM) capable of decoding categories, semantic labels, and textual descriptions from visual perceptual activities simultaneously. We selected the large-scale NSD dataset to ensure the efficiency of the decoding model in joint training and evaluation across multiple tasks. For category decoding, we achieved the effective classification of 12 categories with an accuracy of nearly 70%, significantly surpassing the chance level. For label decoding, we attained the precise prediction of 80 specific semantic labels with a 16-fold improvement over the chance level. For text decoding, the scores of the decoded text surpassed the corresponding baseline levels by remarkable margins on six evaluation metrics. This study contributes significantly to extensive applications in multi-layered brain-computer interfaces, potentially leading to more natural and efficient human-computer interaction experiences.

neuroscience↗

bioRxiv2024

Brainwide mesoscale functional networks revealed by focal infrared neural stimulation of the amygdala

The primate amygdala serves to evaluate emotional content of sensory inputs and modulate emotional and social behaviors; it modulates cognitive, multisensory and autonomic circuits predominantly via the basal (BA), lateral (LA), and central (CeA) nuclei, respectively. Based on recent electrophysiological evidence suggesting mesoscale (millimeters-scale) nature of intra-amygdala functional organization, we have investigated the connectivity of these nuclei using Infrared Neural Stimulation of single mesoscale sites coupled with mapping in ultrahigh field 7T functional Magnetic Resonance Imaging (INS-fMRI). Stimulation of multiple sites within amygdala of single individuals evoked mesoscale functional connectivity maps, allowing comparison of BA, LA and CeA connected brainwide networks. This revealed a mesoscale nature of connected sites, complementary spatial patterns of functional connectivity, and topographic relationships of nucleus-specific connections. Our data reveal a functional architecture of systematically organized brainwide networks mediating sensory, cognitive, and autonomic influences from the amygdala.

neuroscience↗

bioRxiv2024

Ultrastructure expansion microscopy (U-ExM) of mouse and human kidneys for analysis of subcellular structures

Ultrastructure expansion microscopy (U-ExM) involves the physical magnification of specimens embedded in hydrogels, which allows for super-resolution imaging of subcellular structures using a conventional diffraction-limited microscope. Methods for expansion microscopy exist for several organisms, organs, and cell types, and used to analyze cellular organelles and substructures in nanoscale resolution. Here, we describe a simple step-by-step U-ExM protocol for the expansion, immunostaining, imaging, and analysis of cytoskeletal and organellar structures in kidney tissue. We detail the critical modified steps to optimize isotropic kidney tissue expansion, and preservation of the renal cell structures of interest. We demonstrate the utility of the approach using several markers of renal cell types, centrioles, cilia, the extracellular matrix, and other cytoskeletal elements. Finally, we show that the approach works well on mouse and human kidney samples that were preserved using different fixation and storage conditions. Overall, this protocol provides a simple and cost-effective approach to analyze both pre-clinical and clinical renal samples in high detail, using conventional lab supplies and standard widefield or confocal microscopy.

cell biology↗

bioRxiv2024

Asymmetric representation of symmetric semantic information in the human brain

Specific pairs of semantic entities have symmetric relationships, such as word pairs with opposite meanings (e.g., "intelligent" and "stupid"; "human" and "mechanical"). Such semantic symmetry is a key feature of semantic information. However, the representation of symmetric semantic information in the brain is not yet understood. Additionally, it is unclear whether symmetric pairs of semantic information do have symmetric representations in the brain? We addressed this question in a data-driven manner by using the voxelwise modeling of movie-evoked cortical response measured by functional magnetic resonance imaging. In this modeling, response in each voxel was predicted from semantic labels designated for each movie scene. The semantic labels consisted of 30 different items, including 15 pairs of semantically symmetric items. Each item was manually evaluated using a 5-point scale. By localizing the semantic representation associated with each item based on the voxelwise accuracy of brain-response predictions, we found that semantic representations of symmetric item pairs are broadly distributed but with little overlap in the cortex. Additionally, the weight of voxelwise models revealed highly complex, various patterns of cortical representations for each item pair. These results suggest that symmetric semantic information is rather asymmetric and heterogeneous representations in the human brain. Significance statementThis study aimed to investigate if symmetric pairs of semantic information have symmetric representations in the human brain using statistical modeling of functional magnetic resonance imaging signals evoked by naturalistic movies. We built a model based on movie labeling of symmetric semantic items to quantify the cortical representations of symmetric semantic entities. These findings showed that symmetric pairs of semantic entities are represented in widespread cortical regions; however, still exhibit little overlap in localization and heterogeneous representations. These results offer significant insights into the cortical representations of semantic symmetry and advance the understanding of representational structure of semantic information in the human brain.

neuroscience↗

bioRxiv2024

Causal mediation analysis for time-varying heritable risk factors with Mendelian Randomization

Understanding the causal mechanisms of diseases is crucial in clinical research. When randomized experiments are unavailable, Mendelian Randomization (MR) leverages genetic mutations to mitigate confounding. However, most MR analyses assume static risk factors, oversimplifying dynamic risk factor effects. The framework of life-course MR addresses this but struggles with limited GWAS cohort sizes and correlations across time points. We propose FLOW-MR, a computational approach estimating causal structural equations for temporally ordered traits using only GWAS summary statistics. FLOW-MR enables inference on direct, indirect, and path-wise causal effects, demonstrating superior efficiency and reliability, especially with noisy data. By incorporating a spike-and-slab prior, it mitigates challenges from extreme polygenicity and weak instruments. Applying FLOW-MR, we uncovered a childhood-specific protective effect of BMI on breast cancer and analyzed the evolving impacts of BMI, systolic blood pressure, and cholesterol on stroke risk, revealing their causal relationships.

genetics↗