Biology subjects

Bian, Y.

Publications and source records attributed to Bian, Y..

31 records · Page 2Linked to original sources

bioRxiv2023

Fusion dynamics and size-dependent droplet microstructure in ssDNA mediated protein phase separation

Biomolecular cocondensation involving proteins and nucleic acids has been recognized to play crucial roles in genome organization and transcriptional regulation. However, the biophysical mechanisms underlying the fusion dynamics and microstructure evolution of the droplets during the early stage of liquid-liquid phase separation (LLPS) remain elusive. In this work, we study the phase separation of linker histone H1, which is among the most abundant chromatin proteins, in the presence of single-stranded DNA (ssDNA) capable of forming G-quadruplex structures by using residue-resolved molecular dynamics simulations. Firstly, we uncovered a kinetic bottleneck step in the droplet fusion. Productive fusion events are triggered by the formation of ssDNA mediated electrostatic bridge within the contacting zone of two droplets. Secondly, the simulations revealed a size-dependence of the droplet microstructure and stoichiometry. With droplet growth, its microstructure evolves as driven by the maximization of the electrostatic contacts between ssDNA and the highly charged segment of H1. Finally, we showed that the folding of ssDNA to G-quadruplex promotes LLPS by increasing the multivalency and strength of protein-DNA interactions. These findings provided new mechanistic insights into the microstructure and growth dynamics of the biomolecular droplets formed during the early stage of the ssDNA-protein cocondensation.

biophysics↗

bioRxiv2023

Deconvolution Of Hematopoietic Stem/Progenitor Cell Signaling Predicts Inflammatory Niche Remodeling To Be A Determinant Of Tissue Failure And Outcome In Human AML

Cancer initiation is orchestrated by interplay between tumor-initiating cells and their stromal/immune environment. Here, by adapted scRNAsequencing, we decipher the predicted signaling between tissue-resident hematopoietic stem/progenitor cells (HSPCs) and their neoplastic counterparts with their native niches in the human bone marrow. LEPR+ stromal cells are identified as central regulators of hematopoiesis through predicted interactions with all cells in the marrow. Inflammatory niche remodeling and the resulting deprivation of critical HSPC regulatory factors is predicted to repress distinct high-output HSC subsets in NPM1-mutated AML, with relative resistance of clonal cells. Stromal gene signatures reflective of niche remodeling are associated with reduced relapse rates and favorable outcome after chemotherapy, across all genetic risk categories. Elucidation of the intercellular signaling defining human AML, thus, predicts that inflammatory remodeling of stem cell niches drives tissue repression and clonal selection, but may pose a vulnerability for relapse-initiating cells in the context of chemotherapeutic treatment. statement of significanceTumor-promoting inflammation is considered an enabling characteristic of tumorigenesis, but mechanisms remain incompletely understood. By deciphering the predicted signaling between tissue-resident stem cells and their neoplastic counterparts with their environment, we identify inflammatory remodeling of stromal niches as a determinant of normal tissue repression and clinical outcome in human AML. Key pointsO_LIA comprehensive taxonomy of the predicted interactions between LEPR+ stromal niches, HSPCs and adaptive/innate immune cells in the human NBM. C_LIO_LIInflammation-associated decline of stromal niches in AML represses residual normal hematopoiesis with relative resistance of leukemic cells. C_LIO_LIInflammatory decline of stromal niches is associated with reduced relapse risk and favorable outcome. C_LI

cancer biology↗

bioRxiv2022

Predicting individualized tissue gene expression profiles with multi-task learning

Predicting tissue expression profiles from peripheral surrogate samples, especially blood transcriptome, has become an effective alternative when invasive procedures are not ideal. However, existing approaches ignore tissue-shared intrinsic relevance, inevitably limiting predictive performance. Here, we propose a unified deep learning-based multi-task learning framework, Multi-tissue Transcriptome Mapping (MTM), enabling the prediction of individualized expression profiles from any available tissue of an individual. By jointly leveraging individualized cross-tissue information through multi-task learning, MTM achieves superior sample-level and gene-level performance. With the high prediction accuracy and the ability to preserve individualized biological variations, MTM could facilitate both fundamental and clinical biomedical research.

bioinformatics↗

bioRxiv2022

Knowledge Mapping of Alternative Splicing of Cancer From 2012 to 2021: A Bibliometric Analysis

BackgroundAs a processing method of RNA precursors, alternative splicing plays a critical role in normal cell physiological activities. Aberrant alternative splicing events are associated with cancer development and are promising targets for cancer treatment. However, no detailed and unbiased study describes the current state of alternative splicing of cancer research. This study aims to conduct a bibliometric analysis of alternative splicing of cancer research in the last decade to measure and recognize the current state and trends. MethodsWeb of Science Core Collection was used to acquire the articles. Utilizing three bibliometric tools (CiteSpace, VOSviewer, R-bibliometrix), we were able to measure and recognize the influence and collaboration data of individual articles, journals, and co-citations. Analysis of co-occurrence and bursts information helped us identify the trending research areas related to alternative splicing of cancer. ResultsFrom 2012 to 2021, the total number of papers on alternative splicing of cancer published in 766 academic journals was 3,507, authored by 20,406 researchers in 405 institutions from 80 countries/regions. Research involving alternative splicing of cancer genes was primarily conducted in the United States and China, with the United States retaining the prime status; simultaneously, the Chinese Academy of Sciences, Fudan University and National Cancer Institute were the institutions with strong research capabilities. Scorilas Andreas is the scholar with the most publications, while the most co-citations were generated by Wang, Eric T. Plos One published the most papers on alternative splicing of cancer, while J biol chem was the most co-cited academic journal in this field. Furthermore, these publications covered a wide range of areas, but were still primarily focused on the fields of molecular, biology, and immunology. The results of keyword co-occurrence analysis can be divided into three types: molecular (P53, CD44, Androgen receptor, SRSF3, ESRP1), pathological process (apoptosis, EMT, metastasis, angiogenesis, proliferation), and disease (breast cancer, colorectal cancer, prostate cancer, hepatocellular carcinoma, gastric cancer). ConclusionResearch on alternative splicing of cancer has been a hot topic over the past decade, increasing in intensity each year. Current alternative splicing of cancer studies focused on hallmarks of alternative splicing in cancer, and alternative splicing signatures including diagnostic and therapeutic targets. Among them, the current trends are splicing factors regulating epithelial-mesenchymal transition and other hallmarks, aberrant splicing events in tumors, and further mechanisms. These might give researchers interested in this field a forward-looking perspective and inform further research.

cancer biology↗

bioRxiv2022

Long-term passaging of replication competent pseudo-typed SARS-CoV-2 reveals the antiviral breadth of monoclonal and bispecific antibody cocktails

The continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses challenges to the effectiveness of neutralizing antibodies. Rational design of antibody cocktails is a realizable approach addressing viral immune evasion. However, evaluating the breadth of antibody cocktails is essential for understanding the development potential. Here, based on a replication competent vesicular stomatitis virus model that incorporates the spike of SARS-CoV-2 (VSV-SARS-CoV-2), we evaluated the breadth of a number of antibody cocktails consisting of monoclonal antibodies and bispecific antibodies by long-term passaging the virus in the presence of the cocktails. Results from over two-month passaging of the virus showed that 9E12+10D4+2G1 and 7B9-9D11+2G1 from these cocktails were highly resistant to random mutation, and there was no breakthrough after 30 rounds of passaging. As a control, antibody REGN10933 was broken through in the third passage. Next generation sequencing was performed and several critical mutations related to viral evasion were identified. These mutations caused a decrease in neutralization efficiency, but the reduced replication rate and ACE2 susceptibility of the mutant virus suggested that they might not have the potential to become epidemic strains. The 9E12+10D4+2G1 and 7B9-9D11+2G1 cocktails that picked from the VSV-SARS-CoV-2 system efficiently neutralized all current variants of concern and variants of interest including the most recent variants Delta and Omicron, as well as SARS-CoV-1. Our results highlight the feasibility of using the VSV-SARS-CoV-2 system to develop SARS-CoV-2 antibody cocktails and provide a reference for the clinical selection of therapeutic strategies to address the mutational escape of SARS-CoV-2.

cell biology↗

bioRxiv2022

Efficient Neutralization of SARS-CoV-2 Omicron and Other VOCs by a Broad Spectrum Antibody 8G3

Numerous mutations in the spike protein of SARS-CoV-2 B.1.1.529 Omicron variant pose a crisis for antibody-based immunotherapies. The efficacy of emergency use authorized (EUA) antibodies that developed in early SARS-CoV-2 pandemic seems to be in flounder. We tested the Omicron neutralization efficacy of an early B cell antibody repertoire as well as several EUA antibodies in pseudovirus and authentic virus systems. More than half of the antibodies in the repertoire that showed good activity against WA1/2020 previously had completely lost neutralizing activity against Omicron, while antibody 8G3 displayed non-regressive activity. EUA antibodies Etesevimab, Casirivimab, Imdevimab and Bamlanivimab were entirely desensitized by Omicron. Only Sotrovimab targeting the non-ACE2 overlap epitope showed a dramatic decrease activity. Antibody 8G3 efficiently neutralized Omicron in pseudovirus and authentic virus systems. The in vivo results showed that Omicron virus was less virulent than the WA1/2020 strain, but still caused deterioration of health and even death in mice. Treatment with 8G3 quickly cleared virus load of mice. Antibody 8G3 also showed excellent activity against other variants of concern (VOCs), especially more efficient against authentic Delta plus virus. Collectively, our results suggest that neutralizing antibodies with breadth remains broad neutralizing activity in tackling SARS-CoV-2 infection despite the universal evasion from EUA antibodies by Omicron variant.

cell biology↗

bioRxiv2022

Orphan nuclear receptors Err2 and 3 promote a feature-specific terminal differentiationprogram underlying gamma motor neuron function and proprioceptive movement control

Motor neurons are commonly thought of as mere relays between the central nervous system and the movement apparatus, yet, in mammals about one-third of them function exclusively as regulators of muscle proprioception. How these gamma motor neurons acquire properties to function differently from the muscle force-producing alpha motor neurons remains unclear. Here, we found that upon selective loss of the orphan nuclear receptors Err2 and Err3 (Err2/3) in mice, gamma motor neurons acquire characteristic structural (e.g. synaptic wiring), but not functional (e.g. physiological firing rates) properties necessary for regulating muscle proprioception, thus disrupting gait and precision movements in vivo. Moreover, Err2/3 operate via transcriptional activation of neural activity modulators, one of which (Kcna10) promoted gamma motor neuron functional properties. Our work identifies a long-sought mechanism specifying gamma motor neuron properties necessary for proprioceptive movement control, which implies a feature-specific terminal differentiation program implementing neuron subtype-specific functional but not structural properties. SummaryThe transcription factors Err2 and 3 promote functional properties in a subset of motor neurons necessary for executing precise movements.

neuroscience↗

bioRxiv2022

Comprehensive Evaluation of ACE2-Fc Combination with Neutralization Antibody on Broad Protection against SARS-CoV-2 and Its Variants

Emerging SARS-CoV-2 variants are threatening the efficacy of antibody therapies. Combination treatments including ACE2-Fc have been developed to overcome the evasion of neutralizing antibodies (NAbs) in individual cases. Here we conducted a comprehensive evaluation of this strategy by combining ACE2-Fc with NAbs of diverse epitopes on the RBD. NAb+ACE2-Fc combinations efficiently neutralized HIV-based pseudovirus carrying the spike protein of the Delta or Omicron variants, achieving a balance between efficacy and breadth. In an antibody escape assay using replication-competent VSV-SARS-CoV-2-S, all the combinations had no escape after fifteen passages. By comparison, all the NAbs without combo with ACE2-Fc had escaped within six passages. Further, the VSV-S variants escaped from NAbs were neutralized by ACE2-Fc, revealing the mechanism of NAb+ACE2-Fc combinations survived after fifteen passages. We finally examined ACE2-Fc neutralization against pseudovirus variants that were resistant to the therapeutic antibodies currently in clinic. Our results suggest ACE2-Fc is a universal combination partner to combat SARS-CoV-2 variants including Delta and Omicron.

cell biology↗

bioRxiv2021

Broad ultra-potent neutralization of SARS-CoV-2 variants by monoclonal antibodies specific to the tip of RBD

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) continue to wreak havoc across the globe. Higher transmissibility and immunologic resistance of VOCs bring unprecedented challenges to epidemic extinguishment. Here we describe a monoclonal antibody, 2G1, that neutralizes all current VOCs and has surprising tolerance to mutations adjacent to or within its interaction epitope. Cryo-electron microscopy structure showed that 2G1 bound to the tip of receptor binding domain (RBD) of spike protein with small contact interface but strong hydrophobic effect, which resulted in nanomolar to sub-nanomolar affinities to spike proteins. The epitope of 2G1 on RBD partially overlaps with ACE2 interface, which gives 2G1 ability to block interaction between RBD and ACE2. The narrow binding epitope but high affinity bestow outstanding therapeutic efficacy upon 2G1 that neutralized VOCs with sub-nanomolar IC50 in vitro. In SARS-CoV-2 and Beta- and Delta-variant-challenged transgenic mice and rhesus macaque models, 2G1 protected animals from clinical illness and eliminated viral burden, without serious impact to animal safety. Mutagenesis experiments suggest that 2G1 could be potentially capable of dealing with emerging SARS-CoV-2 variants in future. This report characterized the therapeutic antibodies specific to the tip of spike against SARS-CoV-2 variants and highlights the potential clinical applications as well as for developing vaccine and cocktail therapy.

cell biology↗

bioRxiv2021

SE(3)-Equivariant Energy-based Models for End-to-End Protein Folding

Accurate prediction of protein structures is critical for understanding the biological function of proteins. Nevertheless, most structure optimization methods are built upon pre-defined statistical energy functions, which may be sub-optimal in formulating the conformation space. In this paper, we propose an end-to-end approach for protein structure optimization, powered by SE(3)-equivariant energy-based models. The conformation space is characterized by a SE(3)-equivariant graph neural network, with substantial modifications to embed the protein-specific domain knowledge. Furthermore, we introduce continuously-annealed Langevin dynamics as a novel sampling algorithm, and demonstrate that such process converges to native protein structures with theoretical guarantees. Extensive experiments indicate that SE(3)-Fold achieves comparable structure optimization accuracy, compared against state-of-the-art baselines, with over 1-2 orders of magnitude speed-up.

bioinformatics↗

bioRxiv2020

Kcns3 Deficiency Disrupts Parvalbumin Neuron Physiology in Mouse Prefrontal Cortex: Implications for the pathophysiology of schizophrenia

The unique fast spiking (FS) phenotype of cortical parvalbumin-positive (PV) neurons depends on multiple subtypes of voltage-gated potassium channels (Kv). PV neurons selectively express Kcns3, the gene encoding Kv9.3 subunits, suggesting that Kcns3 expression is critical for the FS phenotype. KCNS3 expression is lower in PV neurons in schizophrenia, but the effects of this alteration are unclear, because Kv9.3 subunit function is poorly understood. We therefore assessed the role of Kv9.3 subunits in PV neuron function by combining gene expression analyses, computational modeling, and electrophysiology in acute slices from the cortex of Kcns3-deficient mice Kcns3 mRNA levels were ~50% lower in cortical PV neurons from Kcns3-deficient relative to wildtype mice. While silent per se, Kv9.3 subunits are believed to amplify the Kv2.1 current in Kv2.1-Kv9.3 channel complexes. Hence, to assess the consequences of reducing Kv9.3 levels, we simulated the effects of decreasing the Kv2.1-mediated current in a computational model. The FS cell model with reduced Kv2.1 produced spike trains with irregular inter-spike intervals, or stuttering, and greater Na+ channel inactivation, possibly due to a smaller afterhyperpolarization. As in the computational model, PV basket cells (PVBCs) from Kcns3-deficient mice displayed spike trains with strong stuttering, which depressed PVBC firing, and smaller afterhyperpolarization. Moreover, Kcns3 deficiency impaired the recruitment of PVBCs by stimuli mimicking synaptic input during cortical UP states, which elicited bursts of spikes at gamma frequency. Our data suggest that Kv9.3 subunits are critical for PVBC physiology, and that KCNS3 deficiency in schizophrenia may impair the substrate of gamma oscillations. Significance statementIn the neocortex, Kcns3, the gene encoding voltage-dependent potassium (Kv) channel subunits Kv9.3, is selectively expressed by parvalbumin-positive (PV) neurons. Moreover, KCNS3 expression is decreased in PV neurons in schizophrenia. Kv 9.3 subunits are believed to amplify the current mediated by Kv2.1 subunits, however Kv9.3 function has not been investigated in PV cells. Here, simulations in a computational model and electrophysiological experiments with Kcns3-deficient mice revealed that Kcns3 deficiency disrupts repetitive firing in cortical PV neurons, possibly enhancing Na+ channel inactivation, and particularly with stimuli eliciting firing at gamma frequency band (30-80Hz). Our results suggest that Kv9.3 subunits are essential for PV neuron electrophysiology and that KCNS3 deficiency likely contributes to PV neuron dysfunction and gamma oscillation impairments in schizophrenia.

neuroscience↗

bioRxiv2020

MicroRNA variants and HLA-miRNA interactions are novel rheumatoid arthritis susceptibility factors

ObjectiveAlthogh Genome-wide association studies have identified >100 variants for rheumatoid arthritis (RA),the reported genetic variants only explain <40% of RA heritability. We conducted a systemic association study between common East-Asian miRNA SNPs with RA in a large Han Chinese cohort to explain missing heritability and identify miRNA epistatic interactions. Methods4 HLA SNPs (HLA-DRB1, HLA-DRB9, HLA-DQB1 and TNFAIP3) and 225 common SNPs located in miRNA which might influence the miRNA target binding or pre-miRNA stability were genotyped in 1,607 rheumatoid arthritis and 1,580 matched normal individuals. A meta-analysis with previous GWAS studies (4,873 RA cases and 17,642 controls) was performed to discovery another novel miRNA RA-associated SNPs. Results2 novel SNPs including rs1414273 (miR-548ac, OR=0.84, P=8.26x10-4) and rs2620381 (miR-627, OR=0.77, P=2.55x10-3) conferred significant association with RA. Individuals carried 8 risk alleles showed 15.38 (95%CI: 4.69-50.49, P<1.0x10-6) times more risk to be affected by RA. In addition, rs5997893 (miR-3928) showed significant epistasis effect with rs4947332 (HLA-DRB1, OR=4.23, P=0.04) and rs2967897 (miR-5695) with rs7752903 (TNFAIP3, OR=4.43, P=0.03). Finally, we demonstrated targets of the significant miRNAs showed enrichment in immune related genes (P=2.0x10-5) and FDA approved drug target genes (P=0.014). Conclusions6 novel miRNA SNPs including rs1414273 (miR-548ac, P=8.26x10-4), rs2620381 (miR-627, P=2.55x10-3), rs4285314 (miR-3135b, P=1.10x10-13), rs28477407 (miR-4308, P=3.44x10-5), rs5997893 (miR-3928, P=5.9x10-3) and rs45596840 (miR-4482, P=6.6x10-3) were confirmed to be significantly associated with RA in a Chinese population. Our study suggests that miRNAs might be interesting targets to accelerate the understanding of the pathogenesis and drug development for rheumatoid arthritis.

genetics↗

bioRxiv2018

Osteoblastic PLEKHO1 contributes to joint inflammation in rheumatoid arthritis

Osteoblasts participating in the inflammation regulation gradually obtain concerns. However, its role in joint inflammation of rheumatoid arthritis (RA) is largely unknown. Pleckstrin homology domain-containing family O member 1 (PLEKHO1) was previously identified as a negative regulator of osteogenic lineage activity. Here we demonstrated that PLEKHO1 was highly expressed in osteoblasts of articular specimens from RA patients and inflammatory arthritis mice. Genetic deletion of osteoblastic Plekho1 ameliorated joint inflammation in mice with collagen-induced arthritis (CIA) and K/BxN serum-transfer arthritis (STA), whereas overexpressing Plekho1 only within osteoblasts in CIA and STA mice demonstrated exacerbated local inflammation. Further in vitro studies indicated that PLEKHO1 was required for TRAF2-mediated RIP1 ubiquitination to activate NF-kB for inducing inflammatory cytokines production in osteoblasts. Moreover, osteoblastic PLEKHO1 inhibition improved joint inflammation and attenuated bone formation reduction in CIA mice and non-human primate arthritis model. These data strongly suggest that highly expressed PLEKHO1 in osteoblast mediates joint inflammation in RA. Targeting osteoblastic PLEKHO1 may exert dual therapeutic action of alleviating joint inflammation and promoting bone formation in RA.

cell biology↗