Biology subjects

Wang, K.

Publications and source records attributed to Wang, K..

At least 253 records · Page 14Linked to original sources

bioRxiv2024

RBM7 deficiency promotes breast cancer metastasis by coordinating MFGE8 splicing switch and NF-kB pathway

Aberrant alternative splicing is well-known to be closely associated with tumorigenesis of various cancers. However, the intricate mechanisms underlying breast cancer metastasis driven by deregulated splicing events remain largely unexplored. Here, we unveiled that RBM7 is decreased in lymph node and distant organ metastases of breast cancer as compared to primary lesions and low expression of RBM7 is correlated with the reduced disease-free survival of breast cancer patients. Breast cancer cells with RBM7 depletion exhibited an increased potential for lung metastasis compared to scramble control cells. The absence of RBM7 stimulated breast cancer cell migration, invasion, and angiogenesis. Mechanistically, RBM7 controlled the splicing switch of MFGE8, favoring the production of the predominant isoform of MFGE8, MFGE8-L. This resulted in the attenuation of STAT1 phosphorylation and alterations in cell adhesion molecules. MFGE8-L exerted an inhibitory effect on the migratory and invasive capability of breast cancer cells, while the truncated isoform MFGE8-S, which lack the second F5/8 type C domain had the opposite effect. In addition, RBM7 negatively regulates the NF-{kappa}B cascade and an NF-{kappa}B inhibitor could obstruct the increase in HUVEC tube formation caused by RBM7 silencing. Clinically, we noticed a positive correlation between RBM7 expression and MFGE8 exon7 inclusion in breast cancer tissues, providing new mechanistic insights for molecular-targeted therapy in combating breast cancer.

cancer biology↗

bioRxiv2024

Hunting for peptide binders of specific targets with data-centric generative language models

Bioactive peptides have become strong candidates for a variety of clinical therapies due to their diverse advantages, which promotes the development of deep generative models for peptide design. Considering that existing methods cannot effectively deal with the conformational flexibility of peptides and are difficult to capture accurate residue-to-residue interaction dependencies, we propose a unified weakly order-dependent autoregressive language modeling architecture (PepGenWOA) for bioactive peptide generative design with tolerating out-of-order input as inductive bias. The superiority of PepGenWOA is demonstrated by generating three classes of therapeutic peptides, including antimicrobial peptides, anticancer peptides, and peptide binders. For antimicrobial and anticancer peptide generation, PepGenWOA not only comprehensively outperforms state-of-the-art baseline models, but also exhibits a significant propensity to incorporate specific types of residues that are beneficial for antimicrobial or anticancer bioactivity. For characteristic-guided peptide binder generation, the pretrained PepGenWOA is fine-tuned with Mixture-of-Experts-style plugins with lifelong learning paradigm, thereby achieving the best trade-off between memory stability for world knowledge and learning plasticity for new downstream tasks. The subsequent structure-based virtual screening anchors the 7 most promising candidates from the mega-scale synthetic sequence space, reducing the number of candidates for in vitro experimental validation by 5 orders of magnitude. A target binding rate of 28.6% with binding specificity further confirms the effectiveness of the fine-tuning strategy. Overall, PepGenWOA is a unified architecture for peptide generative design that can be flexibly customized for different task requirements, thereby harnessing generative language models to reach the "dark space" of biological language.

bioinformatics↗

bioRxiv2023

Structure of the hepatitis C virus E1/E2 envelope proteins in a homodimeric complex

Worldwide, 58 million individuals suffer from chronic hepatitis C virus (HCV) infection, a primary driver of liver cancer. The HCV envelope proteins, E1 and E2, form a heterodimer, which is the target for neutralizing antibodies. Despite high-resolution structural models of partial heterodimer elements, the structural landscape of higher-order E1/E2 oligomers remains unexplored. We determined a ~3.5 [A] cryo-electron microscopy structure of membrane-extracted HCV E1/E2 in a homodimeric arrangement. This structure includes detailed information on the homodimer interface, the E2-binding pocket for hypervariable region 1, antigenic site 412 conformation, and the organization of the E1/E2 transmembrane regions, including one internal to E1. This higher-order E1/E2 assembly could play a pivotal role in the design of novel vaccine antigens better mimicking E1/E2 complexes on the HCV particle.

molecular biology↗

bioRxiv2023

An Endogenous Aryl Hydrocarbon Receptor Ligand Induces Preeclampsia-like Phenotypes: Transcriptome, Phosphoproteome, and Cell Functions

BackgroundPreeclampsia (PE) is one hypertensive disorder and a leading cause of maternal and fetal mortality and morbidity during human pregnancy. Aryl hydrocarbon receptor (AhR) is a transcription factor, which regulates vascular functions. Exogenous and endogenous AhR ligands can induce hypertension in animals. However, if dysregulation of endogenous AhR ligands contributes to the pathophysiology of PE remains elusive. MethodsWe measured AhR activities in human maternal and umbilical vein sera. We also applied physiological, cellular, and molecular approaches to dissect the role of endogenous AhR ligands in vascular functions during pregnancy using pregnant rats and primary human umbilical vein endothelial cells (HUVECs) as models. ResultsPE elevated AhR activities in human umbilical vein sera. Exposure of pregnant rats to an endogenous AhR ligand, 2-(1H-indole-3-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) increased blood pressure and proteinuria, while decreased uteroplacental blood flow and reduced fetal and placental weights, all of which are hallmarks of PE. ITE dampened vascular growth and fetal sex-specifically altered immune cell infiltration in rat placentas. ITE also decreased cell proliferation and cell monolayer integrity in HUVECs in vitro. RNA sequencing analysis revealed that ITE dysregulated transcriptome in rat placentas and HUVECs in a fetal sex-specific manner. Bottom-up phosphoproteomics showed that ITE disrupted phosphoproteome in HUVECs. These ITE-dysregulated genes and phosphoproteins were enriched in biological functions and pathways which are highly relevant to diseases of heart, liver, and kidney, vascular functions, inflammation responses, cell death, and kinase inhibition. ConclusionsDysregulation of endogenous AhR ligands during pregnancy may lead to the development of PE with underlying impaired vascular functions, fetal sex-specific immune cell infiltration and transcriptome, and phosphoproteome. Thus, this study has provided a novel mechanism for the development of PE and potentially other forms of hypertensive pregnancies. These AhR ligand-activated genes and phosphoproteins might represent promising therapeutic and fetal sex-specific targets for PE-impaired vascular functions.

pathology↗

bioRxiv2023

DNA sensor ABCF1 phase separates with cccDNA to inhibit HBV replication

Objectives: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) contributes to viral persistence and recurrence. However, it is still less known how the host immune system responds to cccDNA and suppresses HBV replication. Therefore, it is essential to explore host proteins that interact with cccDNA and efficiently suppress HBV replication. Design: The interaction of cccDNA and ABCF1 was assessed by ChIP and pull-down assay. HBV replication was assessed in different cell models, including cccDNA surrogate-transfected and HBV-infected hepatocytes models. Phase separation of recombinant ABCF1 fusion proteins with cccDNA was observed by fluorescence microscopy. Results: Our data found that ABCF1 interacts with cccDNA to form phase-separated condensates via the poly-glutamine (PolyQ) of N-terminal intrinsically disordered low-complexity domain (LCD). Subsequently, ABCF1-cccDNA phase separation not only activates the type I/III interferon (IFN-I/III) pathway but also prevents Pol II accumulation on cccDNA to inhibit HBV transcription. Conclusions: Taken together, our study showed that ABCF1 acts as an antiviral restriction factor of HBV cccDNA by phase-separation-driven innate immune signaling and transcription inhibition. These findings shed new light on the understanding of host defense against cccDNA and provide a novel promising therapeutic strategy for HBV infection.

microbiology↗

bioRxiv2023

The somato-cognitive action network links diverse neuromodulatory targets for Parkinson's disease

The newly-recognized somato-cognitive action network (SCAN) is posited to be important in movement coordination. Functional disruptions in Parkinsons disease (PD) correspond with complex, non-effector-specific motor symptoms, indicating that SCAN dysfunction may underlie these symptoms. Along the same lines, the SCAN may link multiple neuromodulatory targets used for PD treatment. To investigate the role of the SCAN in PD, we leveraged resting-state precision functional mapping, analyzing data from 673 individuals across 6 independent datasets and 5 types of neuromodulation. Our findings revealed functional abnormalities within the SCAN in PD patients and the selective involvement of the SCAN in diverse neuromodulatory targets. Moreover, our data suggests causal links between SCAN connectivity changes and motor symptom alleviation following both invasive and non-invasive neuromodulation. Collectively, these findings underscore the critical role of the SCAN in the pathophysiology of PD and its brain stimulation treatments, and suggest the SCAN as a promising candidate target for neuromodulation.

neuroscience↗

bioRxiv2023

Spatially resolved molecular and cellular atlas of the mouse brain

A comprehensive atlas of genes, cell types, and their spatial distribution across a whole mammalian brain is fundamental for understanding function of the brain. Here, using snRNA-seq and Stereo-seq techniques, we generated a mouse brain atlas with spatial information for 308 cell clusters with single-cell resolution involving over 6 million cells as well as for 29,655 genes. We have identified new astrocyte clusters, and demonstrated that distinct cell clusters exhibit preference for cortical subregions. In addition, we identified 155 genes exhibiting regional specificity in the brainstem, and 513 long non-coding RNA exhibited regional specificity in the adult brain. Parcellation of brain regions based on spatial transcriptomic information showed large overlap with that by traditional method. Furthermore, we have uncovered 411 transcription factor regulons with spatiotemporal specificity during development. Thus, our study has discovered genes and regulon with spatiotemporal specificity, and provided a high-resolution spatial transcriptomic atlas of the mouse brain.

neuroscience↗

bioRxiv2023

Xanthomonas euvesicatoria effector XeAvrRxo1 triggers a Rxo1-mediated defense response in Nicotiana benthamiana and its chaperone Xe4429 functions as an antitoxin, an expression repressor, and an enhancer of XeAvrRxo1 secretion

Xanthomonas euvesicatoria (X. euvesicatoria) is the causal agent of bacterial spot disease that threatens pepper and tomato production around the globe. X. euvesicatoria gene Xe4428 encodes a type III effector (T3E) that shares 89.67% amino acid identity with Xanthomonas oryzae pv. oryzicola (Xoc) T3E AvrRxo1. Deletion of Xe4428 in the genome of X. euvesicatoria (strain Xcv85-10) compromised its virulence to infect pepper and Nicotiana benthamiana plants. Transient co-expression of Xe4428 and Rxo1 on pepper and N. benthamiana plant leaves results in a robust hypersensitive reaction. Thus, Xe4428, renamed as XeAvrRxo1, is a bona fide orthologue of XocAvrRxo1 that possesses both virulence and avirulence functions. Expression of XeAvrRxo1 in E. coli and X. euvesicatoria is toxic to both bacterial cells. Another X. euvesicatoria gene Xe4429, encodes a putative chaperone of XeAvrRxo1, which can interact with XeAvrRxo1 to suppress its toxicity in X. euvesicatoria and E. coli bacterial cells. Xe4429 also binds to the promoter region of XeavrRxo1 and represses its transcription/translation in X. euvesicatoria bacterial cells. In addition, expression of Xe4429 can enhance the secretion and translocation of XeAvrRxo1 into plant cells. Therefore, Xe4429 functions as an antitoxin, a transcription repressor, and a type III chaperone that is capable of enhancing the secretion and translocation of XeAvrRxo1 during pathogenesis.

pathology↗

bioRxiv2023

GABA(A) receptor activation drives GABARAP-Nix mediated autophagy to radiation-sensitize primary and brain-metastatic lung adenocarcinoma tumors

In non-small cell lung cancer (NSCLC) treatment, targeted therapies benefit only a subset of NSCLC, while radiotherapy responses are not durable and toxicity limits therapy. We find that a GABA(A) receptor activator, AM-101, impairs viability and clonogenicity of NSCLC primary and brain metastatic cells. Employing an ex vivo chip, AM-101 is as efficacious as the chemotherapeutic docetaxel, which is used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a survival benefit to mice bearing NSCLC intracranial tumors. GABA(A) receptor activation stimulates a selective-autophagic response via multimerization of GABA(A) Receptor-Associated Protein (GABARAP), stabilization of mitochondrial receptor Nix, and utilization of ubiquitin-binding protein p62. A targeted-peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP-Nix multimerization axis triggering autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity. HighlightsO_LIActivating GABA(A) receptors intrinsic to lung primary and metastatic brain cancer cells triggers a cytotoxic response. C_LIO_LIGABA(A) receptor activation works as well as chemotherapeutic docetaxel in impairing lung cancer viability ex vivo. C_LIO_LIGABA(A) receptor activation increases survival of mice bearing lung metastatic brain tumors. C_LIO_LIA selective-autophagic response is stimulated by GABA(A) receptor activation that includes multimerization of GABARAP and Nix. C_LIO_LIEmploying a new nanomolar affinity peptide that abrogates autophagosome formation inhibits cytotoxicity elicited by GABA(A) receptor activation. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/569295v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1df2f4eorg.highwire.dtl.DTLVardef@19ac26forg.highwire.dtl.DTLVardef@1533986org.highwire.dtl.DTLVardef@e59653_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Escaping herbivory through chemical novelty? Field performance and herbivore attack of the cardenolide-producing crucifer plant Erysimum cheiranthoides

Plants in the Brassicaceae produce glucosinolates as potent defenses against generalist herbivores, but many specialists can tolerate or deactivate these compounds. As a potential counter-adaptation, plants in the genus Erysimum evolved novel cardenolide defenses alongside ancestral glucosinolates. Here we grew the dually defended E. cheiranthoides and the phenologically similar Rhamnospermum nigrum in agricultural fields surrounded by Brassicaceae crops and monitored herbivore communities, leaf damage, and plant performance of focal plants over two seasons. In the second year, we additionally manipulated herbivore density and plant competition to identify direct and indirect effects on plant fitness. Both plant species were attacked by a diverse community of specialist herbivores, but most herbivores strongly preferred R. nigrum, reaching higher densities and causing intense damage that suppressed growth of these plants. A similar herbivore community attacked dually-defended E. cheiranthoides, but herbivores occurred at lower densities, caused less damage, and had no negative effect on growth. Consequently, herbivore suppression through pesticide application increased R. nigrum growth but provided no benefit to E. cheiranthoides. In fact, for E. cheiranthoides growing under heterospecific competition, pesticide application reduced growth due to increased competition by R. nigrum. Our results agree with a successful escape of E. cheiranthoides from herbivory, as even though plants are still attacked when herbivores are abundant, these herbivores caused little damage and caused no reduction in fitness. However, the escape from herbivory has likely come at loss of competitive ability when herbivore pressure is low, which would explain why despite its key innovation, E. cheiranthoides has been unable to gain dominance in any plant community.

ecology↗

bioRxiv2023

Single-cell imaging of protein dynamics of paralogs reveals mechanisms of gene retention

Gene duplication is common across the tree of life, including yeast and humans, and contributes to genomic robustness. In this study, we examined changes in the subcellular localization and abundance of proteins in response to the deletion of their paralogs originating from the whole-genome duplication event, which is a largely unexplored mechanism of functional divergence. We performed a systematic single-cell imaging analysis of protein dynamics and screened subcellular redistribution of proteins, capturing their localization and abundance changes, providing insight into forces determining paralog retention. Paralogs showed dependency, whereby proteins required their paralog to maintain their native abundance or localization, more often than compensation. Network feature analysis suggested the importance of functional redundancy and rewiring of protein and genetic interactions underlying redistribution response of paralogs. Translation of non-canonical protein isoform emerged as a novel compensatory mechanism. This study provides new insights into paralog retention and evolutionary forces that shape genomes.

systems biology↗

bioRxiv2023

TranSiGen: Deep representation learning of chemical-induced transcriptional profile

With the advancement of high-throughput RNA sequencing technologies, the use of chemical-induced transcriptional profiling has greatly increased in biomedical research. However, the usefulness of transcriptomics data is limited by inherent random noise and technical artefacts that may cause systematical biases. These limitations make it challenging to identify the true signal of perturbation and extract knowledge from the data. In this study, we propose a deep generative model called Transcriptional Signatures Generator (TranSiGen), which aims to denoise and reconstruct transcriptional profiles through self-supervised representation learning.TranSiGen uses cell basal gene expression and compound molecular structure representation to infer the chemical-induced transcriptional profile. Results demonstrate the effectiveness of TranSiGen in learning and predicting differential expression genes. The representation derived from TranSiGen can also serve as an alternative phenotype information, with applications in ligand-based virtual screening, drug response prediction, and phenotype-based drug repurposing. We envisage that integrating TranSiGen into the drug discovery and mechanism research pipeline will promote the development of biomedicine.

bioinformatics↗

bioRxiv2023

High-quality genome assembly of a white eared pheasant individual and related functional and genetics data resources

White eared pheasant (WT), (Crossoptilon crossoptilon), inhibiting at high altitudes (3000[~]4,300 m), is a Galliformes bird native to the Qinghai, Sichuan, Yunnan and Tibet Province of China. Due to the difficulty of sequencing the precious species, there is no high-quality genome assembly for the species, hampering the understanding of their genetic mechanisms. To fill the gap, we sequenced and assembled a WT individual using Illumina short reads, PacBio long reads and Hi-C reads. With a contig N50 of 19.63 Mb, scaffold N50 of 29.59 Mb, total length of 1.02 Gb and BUSCO completeness of 97.2%, the assembly is highly complete. Evaluation shows that the assembly is at chromosome-level with only six gaps. Thus, our assembly provides a valuable genetic resource for the crossoptilon species. To further provide resources for gene annotation and population genetics analysis, we also sequenced transcriptomes of 20 tissues of the WT individual and re-sequenced another 10 individuals of WT. Our assembled WT genome and the sequencing data can be valuable resources to study the crossoptilon species.

bioinformatics↗

bioRxiv2023

Do chemical language models provide a better compound representation?

In recent years, several chemical language models have been developed, inspired by the success of protein language models and advancements in natural language processing. In this study, we explore whether pre-training a chemical language model on billion-scale compound datasets, such as Enamine and ZINC20, can lead to improved compound representation in the drug space. We compare the learned representations of these models with the de facto standard compound representation, and evaluate their potential application in drug discovery and development by benchmarking them on biophysics, physiology, and physical chemistry datasets. Our findings suggest that the conventional masked language modeling approach on these extensive pre-training datasets is insufficient in enhancing compound representations. This highlights the need for additional physicochemical inductive bias in the modeling beyond scaling the dataset size.

bioinformatics↗

bioRxiv2023

Bni5 tethers myosin-II to septins to enhance retrograde actin flow and the robustness of cytokinesis

The collaboration between septins and myosin-II in driving processes outside of cytokinesis remains largely uncharted. Here, we demonstrate that Bni5 in the budding yeast S. cerevisiae interacts with myosin-II, septin filaments, and the septin-associated kinase Elm1 via distinct domains at its N- and C-termini, thereby tethering the mobile myosin-II to the stable septin hourglass at the division site from bud emergence to the onset of cytokinesis. The septin and Elm1-binding domains, together with a central disordered region, of Bni5 control timely remodeling of the septin hourglass into a double ring, enabling the actomyosin ring constriction. The Bni5-tethered myosin-II enhances retrograde actin cable flow, which contributes to the asymmetric inheritance of mitochondria-associated protein aggregates during cell division, and also strengthens cytokinesis against various perturbations. Thus, we have established a biochemical pathway involving septin-Bni5-myosin-II interactions at the division site, which can inform mechanistic understanding of the role of myosin-II in other retrograde flow systems. SummaryOkada et al. have determined the molecular mechanism underlying the Bni5 interactions with septins and myosin-II at the cell division site and uncovered its roles in promoting retrograde actin flow and the robustness of cytokinesis in budding yeast.

cell biology↗

bioRxiv2023

Attenuating amyloid-beta pathology in mice with in situ programmed astrocytes

Astrocytes are abundant cells in the central nervous system that provide trophic support for neurons and clear detrimental factors, such as A{beta} oligomers (A{beta}Os). However, in the brains of Alzheimers disease (AD) patients, astrocytes lose these physiological functions. Here, we genetically engineered astrocytes with an anti-A{beta}O chimeric antigen receptor (CAR), constructed by replacing the antigen-binding domain of MerTK with an A{beta}O-specific single-chain variable fragment, to direct their phagocytic activity against A{beta}Os. CAR-engineered astrocytes (CAR-As) showed significantly enhanced phagocytosis of A{beta}Os due to effective activation of Rac1, Cdc42 and RhoA and markedly decreased release of pro-inflammatory cytokines due to inhibition of the NF-{kappa}B and cytokine receptor signalling pathways. Consistently, in situ CAR-As markedly ameliorated the cognitive deficits of APP/PS1 transgenic mice possibly by clearing A{beta}Os and creating a non-inflammatory microenvironment for neuronal survival and the restoration of microglia to a healthy phenotype. Our present study is the first to introduce a CAR-A-based therapy, validate its feasibility and effectiveness, and highlight its potential application for the treatment of AD and other brain disorders.

neuroscience↗

bioRxiv2023

Charting the transcriptomic landscape of primary and metastatic cancers in relation to their origin and target normal tissues

Metastasis is a leading cause of cancer-related deaths, yet understanding how metastatic tumors adapt from their origin to target tissues is challenging. To address this, we assessed whether primary and metastatic tumors resemble their tissue of origin or target tissue in terms of gene expression. We analyzed gene expression profiles from various cancer types, including single-cell and bulk RNA-seq data, in both paired and unpaired primary and metastatic patient cohorts. We quantified the transcriptomic distances between tumor samples and their normal tissues, revealing that primary tumors are more similar to their tissue of origin, while metastases shift towards the target tissue. Pathway-level analysis highlighted critical transcriptomic changes during metastasis. Notably, primary cancers exhibited higher activity in cancer hallmarks, including Activating Invasion and Metastasis, compared to metastatic cancers. This comprehensive landscape analysis provides insight into how cancer tumors adapt to their metastatic environments, providing a transcriptome-wide view of the processes involved.

cancer biology↗

bioRxiv2023

Super-Resolution Imaging of Fast Morphological Dynamics of Neurons in Behaving Animals

Neurons are best studied in their native working states in which their functional and morphological dynamics support animals natural behaviors. Super-resolution microscopy can potentially reveal these dynamics in much higher details but has been challenging in behaving animals due to severe motion artifacts. Here, we report multiplexed line-scanning structured illumination microscopy, which could tolerate motions of up to 50 m/s while achieving 150 and 100 nm lateral resolutions in its linear and nonlinear forms respectively over large fields-of-view. We continuously imaged the dynamics of spinules in dendritic spines and axonal boutons volumetrically over thousands of frames and tens of minutes in mouse brains during sleep-wake cycles. Super-resolution imaging of axonal boutons revealed their prevalent spinule dynamics on a scale of seconds. Simultaneous two-color imaging further enabled analyses of the correlation between the spatial distributions of diverse PSD-95 clusters and the structural dynamics of dendrites in the brains of awake mice.

neuroscience↗