Biology subjects

Wan, B.

Publications and source records attributed to Wan, B..

32 records · Page 2Linked to original sources

bioRxiv2024

DNA spontaneously wrapping around a histone core prefers negative supercoiling: A Brownian dynamics study

In eukaryotes, DNA achieves a highly compact structure primarily due to its winding around the histone cores. The nature wrapping of DNA around histone core form a 1.7 left-handed superhelical turns, contributing to negative supercoiling in chromatin. On the contrary, negative supercoils generated behind the polymerase during transcription may play a role in triggering nucleosome reassembly. To elucidate how supercoils influence the dynamics of wrapping of DNA around the histone cores, we developed a novel model to simulate the intricate interplay between DNA and histone. Our simulations revealed that both positively and negatively supercoiled DNAs are capable of wrapping around histone cores to adopt the nucleosome conformation. Most of all, our findings confirmed a preference for negative supercoiled DNA during nucleosome wrapping, and revealed that the both of the negative writhe and twist are comparatively beneficial to the formation of the DNA wrapping around histone. This advancement in the understanding of spontaneously nucleosome formation may provide insights into the intricate dynamics of chromatin assembly and its diverse functions. Our model thus can be further utilized to simulate the formations of multi-nucleosomes during re-assembling of the chromatin fiber, which will significantly enhance the understanding of the fundamental mechanisms governing the structure and function of chromatin. Author summaryThe compacted organization of DNA within chromatin is primarily attributed to its intricate winding around histone cores. This winding process involves 1.7 left-handed superhelical turns around the histone core, contributing to the negative supercoiling within chromatin fibers. To gain deeper insights into how DNA supercoiling impacts the dynamics of DNA wrapping around histone cores, we devised a novel computational model that simulates the intricate interplay between DNA and histone cores. Additionally, our simulations revealed that both of the positively and negatively supercoiled DNA can spontaneously adopt the nucleosome conformation upon wrapping around the histone core, and demonstrated a preferential tendency for negative supercoiling during nucleosome wrapping. Finally, we examined that both the negative writhe and twist components are comparatively advantageous for the formation of the nucleosome. The studies shed light on the intricate dynamics underlying chromatin assembly and its functional implications.

biophysics↗

bioRxiv2024

Contracted anterior-posterior systematic covariance of cortical thickness in early-onset schizophrenia

Background and HypothesisSchizophrenia is a neurodevelopmental condition with alterations in both sensory and association cortical areas. These alterations have been reported to follow structural connectivity patterning, and to occur in a system-level fashion. Here, we investigated whether pathological alterations of schizophrenia originated from an early disruption of cortical organization by using 7-17-years-old individuals with early-onset schizophrenia (EOS). Study DesignWe estimated cortical thickness using T1-weighted structural MRI data from 95 patients with antipsychotic-naive first-episode EOS and 99 typically developing (TD) controls. We then computed structural covariance of cortical thickness and estimated system-level organizational axes by performing nonlinear dimensionality reduction techniques on covariance matrices for the EOS and TD groups. Finally, we tested for group differences between EOS and TD individuals in terms of both structural covariance and covariance distances along the systematic axis. Study ResultsThe first covariance gradient differentiated motor regions from other cortical areas. Similar to the macrostructural axis in adults, the second gradient axis in young TD discriminated anterior from posterior regions and was compressed in EOS patients relative to TD controls. In addition, patients showed increased structural covariance between two ends of the systematic axis, with increased geodesic distance of covarying regions between two ends. ConclusionOur findings revealed a contracted organizational axis of cortical thickness in EOS patients, which was attributed to excessive distally coordinated changes between anterior and posterior regions of the cortex. Taken together, our study suggests a possible early disruption of system-level neurodevelopment in schizophrenia.

pathology↗

bioRxiv2024

Microstructural asymmetry in the human cortex

While macroscale brain asymmetry and its relevance for human cognitive function have been consistently shown, the underlying neurobiological signatures remain an open question. Here, we probe layer-specific microstructural asymmetry of the human cortex using intensity profiles from post-mortem cytoarchitecture. An anterior-posterior cortical pattern of left-right asymmetry was found, varying across cortical layers. A similar anterior-posterior pattern was observed using in vivo microstructural imaging, with in vivo asymmetry showing the strongest similarity with layer III. Microstructural asymmetry varied as a function of age and sex and was found to be heritable. Moreover, asymmetry in microstructure corresponded to asymmetry of intrinsic function, in particular in sensory areas. Last, probing the behavioral relevance, we found differential association of language and markers of mental health with asymmetry, illustrating a functional divergence between inferior-superior and anterior-posterior microstructural axes anchored in microstructural development. Our study highlights the layer-based patterning of microstructural asymmetry of the human cortex and its functional relevance.

neuroscience↗

bioRxiv2024

Environmental factors and host sex influence the skin microbiome structure of Hong Kong newt (Paramesotriton hongkongensis) in a coldspot of chytridiomycosis in subtropical East Asia

Chytridiomycosis, an infectious skin disease caused by the chytrid fungi, Batrachochytrium dendrobatidis and B. salamandrivorans, has been threatening global amphibian biodiversity. On the skin of chytrid-resistant amphibians, some antifungal bacteria likely defend them against chytridiomycosis, reducing the mortality of resistant amphibians. The Hong Kong newt (Paramesotriton hongkongensis) inhabits East Asia which is a suspected origin of chytrids. Asymptomatic infection in the newts suggests their long-term coexistence with chytrids. Thus, the skin microbiomes of this resistant species warrant investigation, along with other factors that can affect the microbiome. Among the 149 newts sampled in their natural habitats in Hong Kong, putative antifungal bacteria were found on all newts. There were 314 amplicon sequence variants distributed over 25 genera of putative antifungal bacteria, abundant ones included Acinetobacter, Flavobacterium, and Novosphingobium spp. The skin microbiome compositions were strongly influenced by the inter-site geographical distances. Despite inter-site differences, we identified some core skin microbes across sites, which could be vital to P. hongkongensis. The dominant cores included family Comamonadaceae, family Chitinophagaceae, and class Betaproteobacteria. Moreover, habitat elevation and host sex also exhibited significant effects on skin microbiome compositions. The antifungal bacteria found on these newts offer an important resource for conservation against chytridiomycosis, such as probiotic treatments for susceptible species.

ecology↗

bioRxiv2024

A Multimodal Characterization of Low-Dimensional Thalamocortical Structural Connectivity Patterns

The human thalamus is a bilateral and heterogeneous grey matter structure that plays a crucial role in coordinating whole-brain activity. Investigations of its complex structural and functional internal organization revealed to a certain degree overlapping parcellations, however, a consensus on thalamic subnuclei boundaries remains absent. Recent work suggests that thalamic organization might additionally reflect continuous axes transcending nuclear boundaries. In this study, we used a multimodal approach to uncover how low-dimensional axes that describe thalamic connectivity patterns to the cortex are related to internal thalamic microstructural features, functional connectivity, and structural covariance. We computed a thalamocortical structural connectome via probabilistic tractography on diffusion MRI and derived two main axes of thalamic organization. The principal thalamic gradient, extending from medial to lateral and differentiating between transmodal and unimodal nuclei, was related to intrathalamic myelin profiles, and patterns of functional connectivity, while the secondary axis showed correspondence to core-matrix cell type distributions. Lastly, exploring multimodal thalamocortical associations on a global scale, we observed that the medial-to- lateral gradient consistently differentiated limbic, frontoparietal, and default mode network nodes from dorsal and ventral attention networks across modalities. However, the link with sensory modalities varied. In sum, we show the coherence between lower dimensional patterns of thalamocortical structural connectivity and various modalities, shedding light on multiscale thalamic organization.

neuroscience↗

bioRxiv2024

De novo multi-mechanism antimicrobial peptide design via multimodal deep learning

Artificial intelligence (AI)-driven discovery of antimicrobial peptides (AMPs) is yet to fully utilise their three-dimensional (3D) structural characteristics, microbial specie-specific antimicrobial activities and mechanisms. Here, we constructed a QLAPD database comprising the sequence, structures and antimicrobial properties of 12,914 AMPs. QLAPD underlies a multimodal, multitask, multilabel, and conditionally controlled AMP discovery (M3-CAD) pipeline, which is proposed for the de novo design of multi-mechanism AMPs to combat multidrug-resistant organisms (MDROs). This pipeline integrates the generation, regression, and classification modules, using a innovative 3D voxel coloring method to capture the nuanced physicochemical context of amino acids, significantly enhancing structural characterizations. QL-AMP-1, discovered by M3-CAD, which possesses four antimicrobial mechanisms, exhibited low toxicity and significant activity against MDROs. The skin wound infection model demonstrates its considerable antimicrobial effects and negligible toxicity. Altogether, integrating 3D features, specie-specific antimicrobial activities and mechanisms enhanced AI-driven AMP discovery, making the M3-CAD pipeline a viable tool for de novo AMP design.

bioengineering↗

bioRxiv2023

Diverging asymmetry of intrinsic functional organization in autism

Autism is a neurodevelopmental condition involving atypical sensory-perceptual functions together with language and socio-cognitive deficits. Previous work has reported subtle alterations in the asymmetry of brain structure and reduced laterality of functional activation in individuals with autism relative to non-autistic individuals (NAI). However, whether functional asymmetries show altered intrinsic systematic organization in autism remains unclear. Here, we computed inter- and intra-hemispheric asymmetry of intrinsic functional gradients capturing connectome organization along three axes, stretching between sensory-default, somatomotor-visual, and default-multiple demand networks, to study system-level hemispheric imbalances in autism. We observed decreased leftward functional asymmetry of language network organization in individuals with autism, relative to NAI. Whereas language network asymmetry varied across age groups in NAI, this was not the case in autism, suggesting atypical functional laterality in autism may result from altered developmental trajectories. Finally, we observed that intra-but not inter-hemispheric features were predictive of the severity of autistic traits. In sum, our findings illustrate how regional and patterned functional lateralization is altered in autism at the system level. Such differences may be rooted in altered developmental trajectories of functional organization asymmetry in autism.

neuroscience↗

bioRxiv2022

Non-specific vs specific DNA binding free energetics of a transcription factor domain protein for target search and recognition

Transcription factor (TF) proteins regulate gene expression by binding to specific sites on the genome. In the facilitated diffusion model, an optimized search process is achieved by the TF protein alternating between 3D diffusion in the bulk and 1D diffusion along DNA. While undergoing 1D diffusion, the protein can switch from a search mode for fast diffusion along non-specific DNA to a recognition mode for stable binding to specific DNA. It was recently noticed that for a small TF domain protein, re-orientations on DNA other than conformational changes happen between the non-specific and specific DNA binding. We here conducted all-atom molecular dynamics simulations with steering forces to reveal the protein-DNA binding free energetics, with a difference between the non-specific and specific binding about 10 kBT, confirming that the search and recognition modes are distinguished only by protein orientations on the DNA. As the binding free energy difference differs from that being estimated from experimental measurements about 4-5 kBT on 15-bp DNA constructs, we hypothesize that the discrepancy comes from DNA sequences flanking the 6-bp central binding sites impacting on the dissociation kinetics measurements. The hypothesis is supported by a simplified spherical protein-DNA model along with stochastic simulations and kinetic modeling.

biophysics↗

bioRxiv2021

Asymmetry of cortical functional hierarchy in humans and macaques suggests phylogenetic conservation and adaptation

The human cerebral cortex is symmetrically organized along large-scale axes but also presents inter-hemispheric differences in structure and function. The quantified contralateral homologous difference, i.e., asymmetry, is a key feature of the human brain left-right axis supporting functional processes, such as language. Here, we assessed whether the asymmetry of cortical functional organization is heritable and phylogenetically conserved between humans and macaques. Our findings indicate asymmetric organization along an axis describing a hierarchical functional trajectory from perceptual/action to abstract cognition. Whereas language network showed leftward asymmetric organization, frontoparietal network showed rightward asymmetric organization. These asymmetries were heritable and comparable between humans and macaques, suggesting (phylo)genetic conservation. However, both language and frontoparietal networks showed a qualitatively larger asymmetry in humans relative to macaques and variable heritability in humans. This may reflect an evolutionary adaptation allowing for experience-dependent specialization, linked to higher-order cognitive functions uniquely developed in humans.

neuroscience↗

bioRxiv2021

rdrugtrajectory: An R Package for the Analysis of Drug Prescriptions in Electronic Health Care Records

Primary care electronic health care records are rich with patient and clinical information. Studying electronic health care records has resulted in marked improvements to national health care processes and patient-care decision making, and is a powerful supplementary source of data for drug discovery effort. We present the R package rdrugtrajectory, designed to yield demographic and patient-level characteristics of drug prescriptions in the UK Clinical Practice Research Datalink dataset. The package operates over Clinical Practice Research Datalink Gold clinical, referral and therapy datasets and includes features such as first drug prescriptions analysis, cohort-wide prescription information, cumulative drug prescription events, the longitudinal trajectory of drug prescriptions, and a survival analysis timeline builder to identify risks related to drug prescription switching. The rdrugtrajectory package has been made freely available via the GitHub repository.

bioinformatics↗

bioRxiv2021

Integrative analysis reveals unique features of the Smc5/6 complex

Structural maintenance of chromosomes (SMC) complexes are critical chromatin modulators. In eukaryotes, the cohesin and condensin SMC complexes organize chromatin, while the Smc5/6 complex directly regulates DNA replication and repair. The molecular basis for Smc5/6s distinct functions is currently poorly understood. Here, we report an integrative structural study of the budding yeast Smc5/6 complex using electron microscopy, cross-linking mass spectrometry, and computational modeling. We show that while the complex shares a similar overall organization with other SMC complexes, it possesses several unique features. In contrast to the reported folded-arm structures of cohesin and condensin, our data suggest that Smc5 and Smc6 arm regions do not fold back on themselves. Instead, these long filamentous regions interact with subunits uniquely acquired by the Smc5/6 complex, namely the Nse2 SUMO ligase and the Nse5-Nse6 subcomplex. Further, we show that Nse5-Nse6 subcomplex adopts a novel structure with an extensive dimerization interface and multiple domains contacting other subunits of the Smc5/6 complex. We also provide evidence that the Nse5-Nse6 module uses its SUMO-binding motifs to contribute to Nse2-mediated sumoylation. Collectively, our integrative multi-scale study identifies distinct structural features of the Smc5/6 complex and functional cooperation amongst its co-evolved unique subunits.

molecular biology↗

bioRxiv2020

VirusDIP: Virus Data Integration Platform

MotivationThe Coronavirus Disease 2019 (COVID-19) pandemic poses a huge threat to human public health. Viral sequence data plays an important role in the scientific prevention and control of epidemics. A comprehensive virus database will be vital useful for virus data retrieval and deep analysis. To promote sharing of virus data, several virus databases and related analyzing tools have been created. ResultsTo facilitate virus research and promote the global sharing of virus data, we present here VirusDIP, a one-stop service platform for archive, integration, access, analysis of virus data. It accepts the submission of viral sequence data from all over the world and currently integrates data resources from the National GeneBank Database (CNGBdb), Global initiative on sharing all influenza data (GISAID), and National Center for Biotechnology Information (NCBI). Moreover, based on the comprehensive data resources, BLAST sequence alignment tool and multi-party security computing tools are deployed for multi-sequence alignment, phylogenetic tree building and global trusted sharing. VirusDIP is gradually establishing cooperation with more databases, and paving the way for the analysis of virus origin and evolution. All public data in VirusDIP are freely available for all researchers worldwide. Availabilityhttps://db.cngb.org/virus/ Contactweixiaofeng@cngb.org

bioinformatics↗

bioRxiv2020

CD147 (BSG) but not ACE2 expression is detectable in vascular endothelial cells within single cell RNA sequencing datasets derived from multiple tissues in healthy individuals

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is associated with a wide range of systemic manifestations. Several observations support a role for vascular endothelial dysfunction in the pathogenesis including an increased incidence of thrombotic events and coagulopathy and the presence of vascular risk factors as an independent predictor of poor prognosis. It has recently been reported that endothelitis is associated with viral inclusion bodies suggesting a direct role for SARS-CoV-2 in the pathogenesis. The ACE2 receptor has been shown to mediate SARS-CoV-2 uptake and it has been proposed that CD147 (BSG) can function as an alternative cell surface receptor. To define the endothelial cell populations that are susceptible to infection with SARS-CoV-2, we investigated the expression of ACE2 as well as other genes implicated in the cellular entry of SARS-Cov-2 in the vascular endothelium through the analysis of single cell sequencing data derived from multiple human tissues (skin, liver, kidney, lung and intestine). We found that CD147 (BSG) but not ACE2 is detectable in vascular endothelial cells within single cell sequencing datasets derived from multiple tissues in healthy individuals. This implies that either ACE2 is not expressed in healthy tissue but is instead induced in response to SARS-Cov2 or that SARS-Cov2 enters endothelial cells via an alternative receptor such as CD147.

genomics↗

bioRxiv2020

CNSA: a data repository for archiving omics data

With the application and development of high-throughput sequencing technology in life and health sciences, massive multi-dimensional biological data brings the problem of efficient management and utilization. Database development and biocuration are the prerequisites for the reuse of these big data. Here, relying on China National GeneBank (CNGB), we present CNGB Sequence Archive (CNSA) for archiving omics data, including raw sequencing data and its analytical data and related metadata which are organized into six objects, namely Project, Sample, Experiment, Run, Assembly, and Variation at present. Moreover, CNSA has created the correlation model of living samples, sample information, and analytical data on some projects, so that all data can be traced throughout the life cycle from the living sample to the sample information to the analytical data. Complying with the data standards commonly used in the life sciences, CNSA is committed to building a comprehensive and curated data repository for the storage, management and sharing of omics data, improving the data standards, and providing free access to open data resources for worldwide scientific communities to support academic research and the bio-industry. Database URL: https://db.cngb.org/cnsa/

genomics↗