Biology subjects

Wang, C.

Publications and source records attributed to Wang, C..

At least 505 records · Page 28Linked to original sources

bioRxiv2024

Ultraviolet attenuates centromere-mediated meiotic genome stability and alters gametophytic ploidy consistency in flowering plants

Ultraviolet (UV) radiation influences development and genome stability in organisms; however, its impacts on meiosis, a special cell division essential for the delivery of genetic information over generations in eukaryotes, remain not yet elucidated. In this study, we demonstrate that UV attenuates the centromere-mediated meiotic chromosome stability and induces unreduced gametes in Arabidopsis thaliana. We show that UV reduces crossover (CO) rate but does not interfere with meiotic chromosome integrity. Functional centromere-specific histone 3 (CENH3) is required for the obligate CO formation, and plays a role in protection of homolog synapsis and sister-chromatid cohesion under UV stress. Moreover, UV specifically alters the orientation and organization of spindles and phragmoplasts at meiosis II, resulting in meiotic restitution and unreduced gametes. Further, we determine that UV-induced meiotic restitution does not rely on the UV Resistance Locus8-mediated UV perception and the Tapetal Development and Function1- and Aborted Microspores-dependent tapetum development, but occurs possibly via impacted JASON function and downregulated Parallel Spindle1. This study sheds light on the impacts of UV on meiotic genome stability and gametophytic ploidy consistency, which thus may influence genome evolution in flowering plants.

plant biology↗

bioRxiv2024

Proteus: pioneering protein structure generation for enhanced designability and efficiency

Diffusion-based generative models have been successfully employed to create proteins with novel structures and functions. However, the construction of such models typically depends on large, pre-trained structure prediction networks, like RFdiffusion. In contrast, alternative models that are trained from scratch, such as FrameDiff, still fall short in performance. In this context, we introduce Proteus, an innovative deep diffusion network that incorporates graph-based triangle methods and a multi-track interaction network, eliminating the dependency on structure prediction pre-training with superior efficiency. We have validated our models performance on de novo protein backbone generation through comprehensive in silico evaluations and experimental characterizations, which demonstrate a remarkable success rate. These promising results underscore Proteuss ability to generate highly designable protein backbones efficiently. This capability, achieved without reliance on pre-training techniques, has the potential to significantly advance the field of protein design. Codes are available at https://github.com/Wangchentong/Proteus.

bioinformatics↗

bioRxiv2024

Protein property prediction based on local environment by 3D equivariant convolutional neural networks

Predicting the properties of proteins is an important procedure in protein engineering. It determines the subspace of mutations for protein modifications, which is critical to the success of the project, but heavily relies on the knowledge and experience of scientists. In this study, we propose a novel deep 3D-CNN model, Eq3DCNN, specifically designed for local environment-related tasks in protein engineering. Eq3DCNN uses basic atom descriptors and their coordinates as inputs, utilizing customized data augmentations to enhance its training efficiency. To make the Eq3DCNN extracted features with more generalization capability, we incorporated a rotation equivariant module to get rotation invariant features. Using cross-validations with different data splitting strategies and under the scenarios of zero-shot predictions, we demonstrate that Eq3DCNN outperformed other 3D-CNN models in stability predictions, and also well-preformed on other prediction tasks, such as the binding pocket and the secondary structure predictions. Our results also identified the key factors that contribute to the models accuracy and the scope of its applications. These findings may help scientists in designing better mutation experiments and increasing the success rate in protein engineering.

bioinformatics↗

bioRxiv2024

Architecture of intact mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis

The multi-enzyme pyruvate dehydrogenase complex (PDC) links glycolysis to the citric acid cycle by converting pyruvate into acetyl-coenzyme A and is essential for cellular energy metabolism. Although individual components have been characterized, the structure of intact PDC remains unclear, hampering our understanding of its composition and multi-step catalytic reactions. Here, we report the in-situ architecture of intact PDC within mammalian mitochondria by cryo-electron tomography. The organization of peripheral E1 and E3 multimers varies substantially among PDCs. We discovered 1-46 E1 heterotetramers surrounding each PDC core, and up to 12 E3 dimers locating primarily along the pentagonal openings. Furthermore, we observed dynamic interactions of the substrate translocating lipoyl domains (LDs) with both E1 and E2, implicating the mechanism of substrate channeling. Our findings reveal the intrinsic dynamics of PDC peripheral compositions, suggesting an additional model in which the number of assembled E1 heterotetramer, E3 dimer, and functional LDs of PDC may be regulated to further control its catalytic activity.

cell biology↗

bioRxiv2024

The kinematics and aerodynamics of hinged wing of honeybees during takeoff

In this study, we utilize a high-speed camera array to meticulously capture the intricate wing kinematics of honeybees during free voluntary takeoffs. This allows us to investigate the variation in kinematic parameters over time. According to the variation of Euler angles, the takeoff process can be categorized into three stages: initial, adjusting, and stable. Our analysis reveals that honeybees typically execute at least 15 wingbeats before taking off, with wing stroke amplitudes exceeding 100 degrees and wingbeat frequencies ranging from 180 to 260 Hz. Significantly, the hinged wing mechanism, connecting the forewing and hindwing via hamuli, undergoes considerable chordwise deformation during this process, with the angle between the fore- and hind-wings surpassing 50 degrees. Notably, the forewing and hindwing maintain a positive camber throughout the wingbeat cycle during takeoff, contributing to the enhanced thrust generation instead of lift, comparing to the flat wings. The positive camber can be passively formed at beginning and ending of each half stroke, but should be actively maintained around middle half-stroke.This study provides valuable insights for aeronautical engineers in the design of flapping wing micro air vehicles, specifically in the effective implementation of hinged wings inspired by the wing motion of honeybees.

biophysics↗

bioRxiv2024

Multiplexing of temporal and spatial information in the lateral entorhinal cortex

Episodic memory involves the processing of spatial and temporal aspects of personal experiences. The lateral entorhinal cortex (LEC) plays an essential role in subserving memory. However, the specific mechanism by which LEC integrates spatial and temporal information remains elusive. Here, we recorded LEC neurons while rats performed foraging and shuttling behaviors on one-dimensional, linear or circular tracks. Unlike open-field foraging tasks, many LEC cells displayed spatial firing fields in these tasks and demonstrated selectivity for traveling directions. Furthermore, some LEC neurons displayed changes in the firing rates of their spatial rate maps during a session, a phenomenon referred to as rate remapping. Importantly, this temporal modulation was consistent across sessions, even when the spatial environment was altered. Notably, the strength of temporal modulation was found to be greater in LEC compared to other brain regions, such as the medial entorhinal cortex (MEC), CA1, and CA3. Thus, the spatial rate mapping observed in LEC neurons may serve as a coding mechanism for temporal context, allowing for flexible multiplexing of spatial and temporal information.

neuroscience↗

bioRxiv2024

Modeling platinum resistance in a stem-like patient-derived ovarian cancer sample

BackgroundChemoresistance and tumor recurrence remain a significant challenge in ovarian cancer. Particularly in the context of platinum resistance, many mechanisms have been identified, including the activation of cellular processes like epithelial-mesenchymal transition (EMT), which generates cells with stemness characteristics. Current models of platinum resistance are limited or not adequate representations of the heterogeneity of the disease. Thus, to advance our understanding of chemoresistance in the context of cancer stem cells (CSC) in ovarian cancer, this study aims to develop an effective model for cisplatin resistance using a patient-derived cancer stem-like sample. MethodsPDX4, a patient-derived cancer cell line with stem-like properties, was exposed to increasing concentrations of cisplatin in vitro in parallel with vehicle treated cells. Once chemoresistance was established and confirmed, the resistance model was validated through comprehensive molecular profiling through RNA- and miRNA-sequencing, followed by the assessment of alterations in cell morphology, protein expression, and functional properties in the context of EMT and cancer stemness. Moreover, we explored potential signaling pathways involved in cisplatin resistance in these stem-like cancer cells. ResultsOur findings reveal the presence of distinct molecular signatures and phenotypic changes in cisplatin resistant PDX4 compared to their sensitive counterparts. Furthermore, we observed that chemoresistance was not inherently linked with increased stemness. In fact, although resistant cells expressed a combination of EMT and stemness markers, functional assays revealed that they were less proliferative, migratory, and clonogenic. JAK-STAT, hypoxia, and PI3K signaling pathways were enriched in these cells, indicating the activation of pathways that assist in DNA damage tolerance and cellular stress management. ConclusionThis novel, syngeneic model provides a valuable platform for investigating the underlying mechanisms of cisplatin resistance in a clinically relevant context, contributing to the development of targeted therapeutic strategies tailored to combat resistance in stem-like ovarian cancer.

cancer biology↗

bioRxiv2024

Single-cell transcriptomics reveals colonic immune perturbations during amyloid-β driven Alzheimer's disease in mice

The "gut-brain axis" is emerging as an important target in Alzheimers disease (AD). However, immunological mechanisms underlying this axis remain poorly understood. Using single-cell RNA sequencing of the colon immune compartment in the 5XFAD amyloid-{beta} (A{beta}) mouse model, we uncovered AD-associated changes in ribosomal activity, oxidative stress, and BCR/plasma cell activity. Strikingly, levels of colon CXCR4+ antibody secreting cells (ASCs) were significantly reduced. This corresponded with accumulating CXCR4+ B cells and gut-specific IgA+ cells in the brain and dura mater, respectively. Consistently, a chemokine ligand for CXCR4, CXCL12, was expressed at higher levels in 5XFAD glial cells and in in silico analyzed human brain studies, supporting altered neuroimmune trafficking. An inulin prebiotic fiber diet attenuated AD markers including A{beta} plaques and overall frailty. These changes corresponded to an expansion of gut IgA+ cells and rescued peripheral Tregs levels. Our study points to a key glia-gut axis and potential targets against AD. Study HighlightsO_LIAD is associated with altered immune parameters in the gut of 5XFAD mice. C_LIO_LI5XFAD colon has reduced ASCs, including CXCR4+ cells with a migratory gene signature. C_LIO_LI5XFAD brain gliosis includes increased CXCL12 expression. C_LIO_LICXCR4+ B cells and gut-specific IgA+ ASCs accumulate in the 5XFAD brain and/or dura mater. C_LIO_LIInulin diet attenuates AD disease parameters while boosting IgA+ cell and Treg levels. C_LI

immunology↗

bioRxiv2024

A Multiomics, Spatiotemporal, and Single Cell Atlas for Mapping Cell-Type-Specific Dysregulation at the Maternal-Fetal Interface

The placenta, the first organ to functionally mature, undergoes disordered development in many pregnancy complications. Molecular investigations have been hampered by the extreme cellular heterogeneity of the placenta, and this complexity is further exaggerated at the maternal-fetal interface where maternal and fetal cells co-mingle. We generated the paired single nucleus epigenomes and transcriptome for each of [~]200,000 cells at the human maternal-fetal interface from early pregnancy to term. These data identified cell-type-specific transcriptional regulatory programs and uncovered key transcription factors driving the lineage differentiation of placental cytotrophoblasts. Integrating spatial single cell proteomics profiling, we localized the observed cell types in situ, and characterized the dynamic stages and distinct features of endothelial cells of maternal spiral arteries remodeled by extravillous cytotrophoblasts. Integrative analyses of the single cell data across gestation enabled fine-mapping of the developmental trajectories of cytotrophoblasts and decidual stromal cells, and defining the signature molecular profiles of known and novel cell (sub)types. To demonstrate clinical value, we integrated the reference single cell data with large-scale population genomes from pregnancy complications and identified the most vulnerable maternal and fetal cell types in preeclampsia, preterm birth, and miscarriage. This study presents the most comprehensive placental and decidual single cell resource across gestation to date, reveals new insights into the drivers of normal human placentation, and uncovers the cellular basis of dysfunction associated with common pregnancy complications.

genomics↗

bioRxiv2024

miRNA family miR-29 inhibits PINK1-PRKN dependent mitophagy via ATG9A

Loss-of-function mutations in the genes encoding PINK1 and PRKN result in early-onset Parkinson disease (EOPD). Together the encoded enzymes direct a neuroprotective pathway that ensures the elimination of damaged mitochondria via autophagy. We performed a genome-wide high content imaging miRNA screen for inhibitors of the PINK1-PRKN pathway and identified all three members of the miRNA family 29 (miR-29). Using RNAseq we identified target genes and found that siRNA against ATG9A phenocopied the effects of miR-29 and inhibited the initiation of PINK1-PRKN mitophagy. Furthermore, we discovered two rare, potentially deleterious, missense variants (p.R631W and p.S828L) in our EOPD cohort and tested them experimentally in cells. While expression of wild-type ATG9A was able to rescue the effects of miR-29a, the EOPD-associated variants behaved like loss-of-function mutations. Together, our study validates miR-29 and its target gene ATG9A as novel regulators of mitophagy initiation. It further serves as proof-of-concept of finding novel, potentially disease-causing EOPD-linked variants specifically in mitophagy regulating genes. The nomination of genetic variants and biological pathways is important for the stratification and treatment of patients that suffer from devastating diseases, such as EOPD.

neuroscience↗

bioRxiv2024

Molecular and cellular dynamics of the developing human neocortex at single-cell resolution

The development of the human neocortex is a highly dynamic process and involves complex cellular trajectories controlled by cell-type-specific gene regulation1. Here, we collected paired single-nucleus chromatin accessibility and transcriptome data from 38 human neocortical samples encompassing both the prefrontal cortex and primary visual cortex. These samples span five main developmental stages, ranging from the first trimester to adolescence. In parallel, we performed spatial transcriptomic analysis on a subset of the samples to illustrate spatial organization and intercellular communication. This atlas enables us to catalog cell type-, age-, and area-specific gene regulatory networks underlying neural differentiation. Moreover, combining single-cell profiling, progenitor purification, and lineage-tracing experiments, we have untangled the complex lineage relationships among progenitor subtypes during the transition from neurogenesis to gliogenesis in the human neocortex. We identified a tripotential intermediate progenitor subtype, termed Tri-IPC, responsible for the local production of GABAergic neurons, oligodendrocyte precursor cells, and astrocytes. Remarkably, most glioblastoma cells resemble Tri-IPCs at the transcriptomic level, suggesting that cancer cells hijack developmental processes to enhance growth and heterogeneity. Furthermore, by integrating our atlas data with large-scale GWAS data, we created a disease-risk map highlighting enriched ASD risk in second-trimester intratelencephalic projection neurons. Our study sheds light on the gene regulatory landscape and cellular dynamics of the developing human neocortex.

neuroscience↗

bioRxiv2024

Chromosome-level de novo genome unveils the evolution of Gleditsia sinensis and thorns development

Gleditsia Linn is widely distributed in the world and Gleditsia sinensis as an important Leguminosae specie, especially its thorns, has been used in the Chinese medicine as a chief ingredient for centuries. While the lack of genome database limits its in-depth research, especially genetic regulation and molecular developmental mechanism. In this investigation, a chromosome-level de novo genome of G. sinensis was assembled through PacBio HiFi, Illumina sequencing as well as those from Hi-C, genetic mapping and K-mer analysis. The G. sinensis harbors 786.13 Mb sized genome (contig N50=1.58 Mb, scaffold N50=51.53 Mb, 2n=28) with 36, 408 protein-coding genes. The full-length transcriptome sequencing of diverse tissues was performed to assist genome functional annotation. The comparative and evolutionary analysis unveiled that G. sinensis diverged from the Cretaceous period approximately 76.31 million years ago (Mya) and the close relationship between G. sinensis and other 8 Leguminosae species. The whole-genome duplication (WGD) analysis indicated G. sinensis underwent three WGD events and might go through another WGD event after differentiating from other Leguminosae plants. The Weighted Gene Coexpression Network Analysis based on phenotype and differentially expressed genes further demonstrated that GsinMYB should be involved in the development of thorns via regulating late thorn differentiation. This investigation provides a high level genome of Gleditsia for Leguminosae species evolution comparison and functional elucidation and also key insights for further study on the molecular regulation mechanisms of the thorns development as a special abnormal stem organ in plants and the molecular breeding of G. sinensis.

genomics↗

bioRxiv2024

Emotional prosody modulates visual mental imagery

Perceptual stimulis emotional properties are vital for human evolution and adaptation. While visual imagery is predominantly regarded as a weak form of perception, the influence of cross-modal emotional features on imagery is still unknown. The present study aims to investigate how emotional prosody modulates imagery quality (i.e., accuracy and clarity) and neural mechanisms using a combination of behavioral tasks and functional magnetic resonance imaging (fMRI). At the behavioral level, our results showed that frustrated conditions induced significant prosody effects on visual mental imagery quality measures, and the effects were particularly pronounced in individuals with lower imagery use tendency. At the neural level, compared with the neutral condition, the emotional prosody conditions (both happy and frustrated) showed stronger activation in various regions including the middle occipital gyrus, supporting the critical role of primary visual system in imagery. Moreover, compared to the frustrated prosody condition, the happy prosody showed stronger activation in the precuneus and anterior cingulate cortex, which are core components of the default mode network. A machine learning prediction analysis with a random forest model identified a significant brain-behavioral correlation between prosody-linked neural activity and individual imagery use tendency. A subsequent Shapley Additive exPlanations (SHAP) analysis further highlighted the primary visual and default mode regions as top contributors to this prediction. Taken together, these results provide new insights for the understanding of how emotional prosody modulates visual mental imagery, considering individual differences, and provide compelling evidence for incorporating emotion as important shaping factor in more general model for imagery.

neuroscience↗

bioRxiv2024

A conserved Pol II elongator SPT6L mediates Pol V transcription elongation to regulate RNA-directed DNA methylation in Arabidopsis

In plants, the plant-specific RNA polymerase V (Pol V) transcripts non-coding RNAs and provides a docking platform for the association of accessory proteins in the RNA-directed DNA methylation (RdDM) pathway. Various components have been uncovered that are involved in the process of DNA methylation, but it is still not clear how the transcription of Pol V is regulated. Here, we found that the conserved Pol II elongator, SPT6L, bound to thousands of intergenic regions in an RNA polymerase II (Pol II) independent manner. The intergenic enrichment of SPT6L, interestingly, co-occupied with the largest subunit of Pol V (NRPE1) and mutation of SPT6L led to the reduction of DNA methylation but not Pol V enrichment. Furthermore, the association of SPT6L at Pol V loci was dependent on the Pol V associated factor, SPT5L, rather than the presence of Pol V, and the interaction between SPT6L and NRPE1 was compromised in spt5l. Finally, Pol V RIP-seq revealed that SPT6L is required to maintain the amount and length of Pol V transcripts. Our findings thus uncovered the critical role of a Pol II conserved elongator in Pol V mediated DNA methylation and transcription, and shed light on the mutual regulation between Pol V and II in plants.

plant biology↗

bioRxiv2024

Suppression of epileptic seizures by transcranial activation of K+-selective channelrhodopsin

Optogenetics is a valuable tool for studying the mechanisms of neurological diseases and is now being developed for therapeutic applications. In rodents and macaques, improved channelrhodopsins have been applied to achieve transcranial optogenetic stimulation. While transcranial photoexcitation of neurons has been achieved, noninvasive optogenetic inhibition for treating hyperexcitability-induced neurological disorders has remained elusive. There is a critical need for effective inhibitory optogenetic tools that are highly light-sensitive and capable of suppressing neuronal activity in deep brain tissue. In this study, we developed a highly sensitive K+-conductive channelrhodopsin (hsKCR) by molecular engineering of the recently discovered Hyphochytrium catenoides kalium (potassium) channelrhodopsin 1. Transcranial activation of hsKCR significantly prolongs the time to the first seizure, increases survival, and decreases seizure activity in several mouse epileptic models. Our approach for transcranial optogenetic inhibition of neural hyperactivity may be adapted for cell type-specific neuromodulation in both basic and preclinical settings.

neuroscience↗

bioRxiv2024

G-quadruplexes as pivotal components of cis-regulatory elements in the human genome

Cis-regulatory elements have the ability to precisely regulate gene expression in cells, and G-quadruplexes (G4s), as non-canonical secondary structures, may potentially play a role in this regulation. However, a lack of systematic studies exists to uncover the connection between these two elements. Here, we comprehensively characterized the associations between G4s and human candidate cis-regulatory elements (cCREs) inferred from the Encyclopedia of DNA Elements (ENCODE) data. Our findings demonstrate that G4s are prominently enriched in most types of cCREs, particularly in elements with promoter-like signatures (PLS). Furthermore, we observed that the co-occurrence of CTCF signals with H3K4me3 or H3K27ac signals significantly strengthens the association between cCREs and G4s. This association becomes more pronounced when examining cell type-specific cCREs and G4s. Interestingly, compared to cCREs, genetic variants occurring in G4s, especially within their G-runs, often exhibit higher regulatory potential and deleterious effects. Runs of several consecutive guanines (G-runs) in the vicinity of transcriptional start sites tend to be more constrained in mammalian evolution than cCREss G-runs. Besides, the presence of G4s, is often linked to a more favorable local chromatin environment for the activation and execution of regulatory functions of cCREs, potentially attributable to the formation of G4 secondary structures. Finally, we discovered that G4-associated cCREs exhibit widespread activation in a variety of cancers. Altogether, our study suggests that G4s are integral components of human cis-regulatory elements, and the G4 primary sequences are associated with the localization of the cCREs, while the G4 structures are linked to the activation of the cCREs. Therefore, we propose to define G4s as pivotal regulatory elements in the human genome.

genomics↗

bioRxiv2024

Spindle Oscillation Emerges at the Critical State of the Electrically Coupled Network in Thalamic Reticular Nucleus

Spindle oscillation is a waxing-and-waning neural oscillation observed in the brain, initiated at the thalamic reticular nucleus (TRN) and typically occurring at 7-15 Hz. Experiments have shown that in the adult brain, electrical synapses, rather than chemical synapses, dominate between TRN neurons, suggesting that the traditional view of spindle generation via chemical synapses may need reconsideration. Based on known experimental data, we develop a computational model of the TRN network, where heterogeneous neurons are connected by electrical synapses. The model shows that the interplay between synchronizing electrical synapses and desynchro-nizing heterogeneity leads to multiple synchronized clusters with slightly different oscillation frequencies, whose summed activity produces spindle oscillation as seen in local field potentials. Our results suggest that during spindle oscillation, the network operates at the critical state, which is known for facilitating efficient information processing. This study provides insights into the underlying mechanism of spindle oscillation and its functional significance.

neuroscience↗

bioRxiv2023

Integrated-omics profiling unveils the disparities of host defense to ECM scaffolds during wound healing in aged individuals.

Extracellular matrix (ECM) scaffold membranes have exhibited promising potential to better the outcomes of wound healing by creating a regenerative microenvironment around. However, when compared to the application in younger individuals, the performance of the same scaffold membrane in promoting re-epithelialization and collagen deposition was observed dissatisfying in aged mice. To comprehensively elucidate the mechanisms underlying this age-related disparity, we conducted an integrated analysis, combing single-cell RNA sequencing (scRNA-Seq) with spatial transcriptomics, to explore the complex cellular niches surrounding the ECM scaffolds. Through intergroup comparative analysis and cell-cell communication, we identified and characterized the senescent SPP1+ macrophages may impede the activation of the type L immune response, thus inhibiting the repair ability of epidermal cells and fibroblasts around the ECM scaffolds. These findings contribute to a deeper understanding of biomaterial applications in varied physiological contexts, thereby paving the way for the development of precision-based biomaterials tailored specifically for aged individuals in future therapeutic strategies.

immunology↗