Biology subjects

Chen, R.

Publications and source records attributed to Chen, R..

At least 181 records · Page 10Linked to original sources

bioRxiv2023

INHBA/Activin A promotes tumor growth and induces resistance to anti-PD-L1 therapy by suppressing IFN-γ signaling

Inhibin beta A (INHBA) and its homodimer activin A have pleiotropic effects on modulation of immune responses and tumor progression, respectively, but it remains uncertain whether tumors may release activin A to regulate anti-tumor immunity. As evidenced by our RNA-Seq and in vitro results, the interferon-{gamma} (IFN-{gamma}) signaling pathway was significantly down-regulated by tumor intrinsic activin A. Tumor INHBA deficiency led to lower expression of PD-L1 induced by IFN-{gamma}, resulting in poor responsiveness to anti-PD-L1 therapy. On the other hand, decreased secretion of IFN-{gamma}-stimulated chemokines, including C-X-C motif chemokine 9 (CXCL9) and 10 (CXCL10), impaired the infiltration of effector T cells into the tumor microenvironment. Furthermore, the activin A-specific antibody garetosmab improved anti-tumor immunity and its combination with the anti-PD-L1 antibody atezolizumab showed a superior therapeutic effect to monotherapy. Our findings reveal that INHBA/activin A is involved in anti-tumor immunity by inhibiting the IFN-{gamma} signaling pathway and considered to be a potential target to overcome anti-PD-L1 resistance in clinical cancer treatment.

immunology↗

bioRxiv2023

Large-Scale Information Retrieval and Correction of Noisy Pharmacogenomic Datasets through Residual Thresholded Deep Matrix Factorization

Pharmacogenomics studies are attracting an increasing amount of interest from researchers in precision medicine. The advances in high-throughput experiments and multiplexed approaches allow the large-scale quantification of drug sensitivities in molecularly characterized cancer cell lines (CCLs), resulting in a number of open drug sensitivity datasets for drug biomarker discovery. However, a significant inconsistency in drug sensitivity values among these datasets has been noted. Such inconsistency indicates the presence of substantial noise, subsequently hindering downstream analyses. To address the noise in drug sensitivity data, we introduce a robust and scalable deep learning framework, Residual Thresholded Deep Matrix Factorization (RT-DMF). This method takes a single drug sensitivity data matrix as its sole input and outputs a corrected and imputed matrix. Deep Matrix Factorization (DMF) excels at uncovering subtle patterns, due to its minimal reliance on data structure assumptions. This attribute significantly boosts DMFs ability to identify complex hidden patterns among nuisance effects in the data, thereby facilitating the detection of signals that are therapeutically relevant. Furthermore, RT-DMF incorporates an iterative residual thresholding (RT) procedure, which plays a crucial role in retaining signals more likely to hold therapeutic importance. Validation using simulated datasets and real pharmacogenomics datasets demonstrates the effectiveness of our approach in correcting noise and imputing missing data in drug sensitivity datasets (open source package available at https://github.com/tomwhoooo/rtdmf).

bioinformatics↗

bioRxiv2023

A niche-derived non-ribosomal peptide triggers planarian sexual development

Germ cells are regulated by local microenvironments (niches), which secrete instructive cues. Conserved developmental signaling molecules act as niche-derived regulatory factors, yet other types of niche signals remain to be identified. Single-cell RNA-sequencing of sexual planarians revealed niche cells expressing a non-ribosomal peptide synthetase (nrps). Inhibiting nrps led to loss of female reproductive organs and testis hyperplasia. Mass spectrometry detected the dipeptide {beta}-alanyl-tryptamine (BATT), which is associated with reproductive system development and requires nrps and a monoamine-transmitter-synthetic enzyme (AADC) for its production. Exogenous BATT rescued the reproductive defects after nrps or aadc inhibition, restoring fertility. Thus, a non-ribosomal, monoamine-derived peptide provided by niche cells acts as a critical signal to trigger planarian reproductive development. These findings reveal an unexpected function for monoamines in niche-germ cell signaling. Furthermore, given the recently reported role for BATT as a male-derived factor required for reproductive maturation of female schistosomes, these results have important implications for the evolution of parasitic flatworms and suggest a potential role for non-ribosomal peptides as signaling molecules in other organisms.

developmental biology↗

bioRxiv2023

Origin and evolution of the bread wheat D genome

Bread wheat (Triticum aestivum) is a globally dominant crop and major source of calories and proteins for the human diet. Compared to its wild ancestors, modern bread wheat shows lower genetic diversity caused by polyploidisation, domestication, and breeding bottlenecks1,2. Wild wheat relatives represent genetic reservoirs, harbouring diversity and beneficial alleles that have not been incorporated into bread wheat. Here, we establish and analyse pangenome resources for Tauschs goatgrass, Aegilops tauschii, the donor of the bread wheat D genome. This new pangenome facilitated the cloning of a disease resistance gene and haplotype analysis across a complex disease resistance locus, allowing us to discern alleles from paralogous gene copies. We also reveal the complex genetic composition and history of the bread wheat D genome, involving previously unreported contributions from genetically and geographically discrete Ae. tauschii subpopulations. Together, our results reveal the complex history of the bread wheat D genome and demonstrate the potential of wild relatives in crop improvement.

genomics↗

bioRxiv2023

Group-common and individual-specific effects of structure-function coupling in human brain networks with graph neural networks

The human cerebral cortex is organized into functionally segregated but synchronized regions bridged by the structural connectivity of white matter pathways. While structure-function coupling has been implicated in cognitive development and neuropsychiatric disorders, it remains unclear to what extent the structure-function coupling reflects a group-common characteristic or varies across individuals, at both the global and regional brain levels. By leveraging two independent, high-quality datasets, we found that the graph neural network accurately predicted unseen individuals functional connectivity from structural connectivity, reflecting a strong structure-function coupling. This coupling was primarily driven by network topology and was substantially stronger than that of the correlation approaches. Moreover, we observed that structure-function coupling was dominated by group-common effects, with subtle yet significant individual-specific effects. The regional group and individual effects of coupling were hierarchically organized across the cortex along a sensorimotor-association axis, with lower group and higher individual effects in association cortices. These findings emphasize the importance of considering both group and individual effects in understanding cortical structure-function coupling, suggesting insights into interpreting individual differences of the coupling and informing connectivity-guided therapeutics.

neuroscience↗

bioRxiv2023

Dynamic Responses of Striatal Cholinergic Interneurons Control the Extinction and Updating of Goal-Directed Learning

Striatal cholinergic interneurons (CINs) regulate behavioral flexibility, but their exact contribution to this process remains elusive. In this study, we report that extinction learning enhances acetylcholine (ACh) release. Mimicking this enhancement by optogenetically inducing CIN burst firing promotes extinction learning. CINs receive excitatory thalamic inputs, and we observed that extinction training augmented thalamic activity. Optogenetically stimulating these thalamic inputs caused CIN burst firing and enhanced ACh release, strengthening extinction learning. Notably, CIN burst firing is usually followed by a pause in firing. We found that disrupting this pause through continuous optogenetic stimulation reversibly impaired the updating of goal-directed behaviors. Furthermore, excessive alcohol consumption reduced thalamus-induced burst-pause firing in CINs and impaired the reversal of goal-directed learning. In summary, thalamic-driven CIN burst firing promotes extinction learning, while the pause is pivotal for reversing goal-directed behavior, a process impacted by excessive alcohol. These findings shed light on how CINs dynamic responses affect behavioral flexibility. HighlightsH1. Burst firing of CINs promotes extinction learning H2. Thalamic-CIN excitation enhances extinction learning H3. Pause of CIN is critical for the reversal of goal-directed learning H4. Chronic alcohol consumption reduces the burst-pause of CINs and impairs the reversal of goal-directed learning.

neuroscience↗

bioRxiv2023

Feeding disruptions lead to a significant increase in disease modules in adult mice

Feeding disruption is intimately associated with numerous diseases, yet its molecular mechanisms remain to be elucidated in circadian biology. We discovered that in the liver of adult mice, feeding disruption can lead to a substantial increase in disease modules in the transcriptome. This increase in disease modules occurs far earlier than the individuals aging and disease onset. In contrast, calorie restriction significantly reduces the formation of disease modules. This offers a critical missing link between feeding disruption and the molecular systems mechanisms of disease.

neuroscience↗

bioRxiv2023

Integrated multi-omics single cell atlas of the human retina

Single-cell sequencing has revolutionized the scale and resolution of molecular profiling of tissues and organs. Here, we present an integrated multimodal reference atlas of the most accessible portion of the mammalian central nervous system, the retina. We compiled around 2.4 million cells from 55 donors, including 1.4 million unpublished data points, to create a comprehensive human retina cell atlas (HRCA) of transcriptome and chromatin accessibility, unveiling over 110 types. Engaging the retina community, we annotated each cluster, refined the Cell Ontology for the retina, identified distinct marker genes, and characterized cis-regulatory elements and gene regulatory networks (GRNs) for these cell types. Our analysis uncovered intriguing differences in transcriptome, chromatin, and GRNs across cell types. In addition, we modeled changes in gene expression and chromatin openness across gender and age. This integrated atlas also enabled the fine-mapping of GWAS and eQTL variants. Accessible through interactive browsers, this multimodal cross-donor and cross-lab HRCA, can facilitate a better understanding of retinal function and pathology.

molecular biology↗

bioRxiv2023

WTAP is Transcriptionally Regulated by p65 and Promotes Inflammation through m6A Modification and Phase Separation

Emerging evidence has linked dysregulation of N6-methyladenosine (m6A) to inflammation and inflammatory diseases, but the underlying mechanism still needs investigation. Here, we found that high m6A modification in a variety of hyperinflammatory states is p65-dependent, because Wilms tumor 1 associated protein (WTAP), a key component of the writer complex, is transcriptionally regulated by p65 and its overexpression can lead to higher m6A modification. Mechanistically, upregulated WTAP is more prone to phase separation to facilitate the aggregation of "writer" complex to nuclear speckles and the deposition of m6A marks onto transcriptionally active inflammatory transcripts, thereby accelerating proinflammatory response. Furthermore, myeloid deficiency of WTAP attenuates the severity of LPS-induced sepsis and DSS-induced IBD. Thus, the proinflammatory effect of WTAP is a general risk-increasing mechanism, and interrupting the assembly of m6A writer complex by targeting the phase separation of WTAP to reduce the global m6A level may be a potential and promising therapeutic strategy for alleviating hyperinflammation.

immunology↗

bioRxiv2023

Ultrahigh Resolution Lipid Mass Spectrometry Imaging of High-Grade Serous Ovarian Cancer Mouse Models

No effective screening tools for ovarian cancer (OC) exist, making it one of the deadliest cancers among women. Considering little is known about the detailed progression and metastasis mechanism of OC at a molecular level, it is crucial to gain more insights on how metabolic and signaling alterations accompany its development. Herein, we present a comprehensive study using ultra-high-resolution Fourier transform ion cyclotron resonance matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to investigate the spatial distribution and alterations of lipids in ovarian tissues collected from double knockout (n = 4) and a triple mutant mouse models (n = 4) of high-grade serous ovarian cancer (HGSC). Lipids belonging to a total of 15 different classes were annotated and their abundance changes compared to those in healthy mouse reproductive tissue (n = 4), mapping onto major lipid pathways involved in OC progression. From intermediate-stage OC to advanced HGSC, we provide a direct visualization of lipid distributions and their biological links to inflammatory response, cellular stress, cell proliferation, and other processes. We also show the ability to distinguish tumors at different stages from healthy tissues via a number of highly specific lipid biomarkers, providing targets for future panels that could be useful in diagnosis.

cancer biology↗

bioRxiv2023

Di- and tri-methylation of histone H3K36 play distinct roles in DNA double-strand break repair

Histone H3 Lys36 (H3K36) methylation and its associated modifiers are crucial for DNA double-strand break (DSB) repair, but the mechanism governing whether and how different H3K36 methylation forms impact repair pathways is unclear. Here, we unveil the distinct roles of H3K36 dimethylation (H3K36me2) and H3K36 trimethylation (H3K36me3) in DSB repair via non-homologous end joining (NHEJ) or homologous recombination (HR). Yeast cells lacking H3K36me2 or H3K36me3 exhibit reduced NHEJ or HR efficiency. yKu70 and Rfa1 bind H3K36me2- or H3K36me3-modified peptides and chromatin, respectively. Disrupting these interactions impairs yKu70 and Rfa1 recruitment to damaged H3K36me2- or H3K36me3-rich loci, increasing DNA damage sensitivity and decreasing repair efficiency. Conversely, H3K36me2-enriched intergenic regions and H3K36me3-enriched gene bodies independently recruit yKu70 or Rfa1 under DSB stress. Importantly, human KU70 and RPA1, the homologs of yKu70 and Rfa1, exclusively associate with H3K36me2 and H3K36me3 in a conserved manner. These findings provide valuable insights into how H3K36me2 and H3K36me3 regulate distinct DSB repair pathways, highlighting H3K36 methylation as a critical element in the choice of DSB repair pathway.

biochemistry↗

bioRxiv2023

Repressor sequestration activates translation of germ granule localized mRNA

Biomolecular condensates organize and compartmentalize biochemical processes within cells1. Among these, ribonucleoprotein (RNP) granules are characterized as storage depots for translationally repressed mRNA2-8. Whether RNP granules can also activate translation and how such translation is achieved remains unclear9. This question is particularly relevant for embryonic germ granules, whose activity has been linked to germ cell fate10-13. Here, we use single-molecule imaging to show that embryonic germ cell RNP granules in Drosophila are the sites of active translation for nanos mRNA. Translating nanos mRNA is oriented with the 5end preferentially at the germ granule surface while the 3UTR is buried within the granule. Untranslated nanos mRNAs remain internal within the granule. Quantitative analysis of translational kinetics demonstrates that germ granules activate translation by antagonizing translational repression rather than changing the rate or efficiency of translation. We generated separation-of-function mutations in the disordered linker region of the scaffold protein Oskar that specifically impede nanos translation without affecting germ granule morphology or RNA localization. These mutations reveal that nanos translation is dependent on the sequestration of translational repressors within germ granules. Together, our findings show that RNP granules regulate localized protein synthesis through compartmentalized relief of translational repression raising the possibility that similar repressor-activator switches control translation in other condensates.

cell biology↗

bioRxiv2023

The DeMixSC deconvolution framework uses single-cell sequencing plus a small benchmark dataset for improved analysis of cell-type ratios in complex tissue samples

Bulk deconvolution with single-cell/nucleus RNA-seq data is critical for understanding heterogeneity in complex biological samples, yet the technological discrepancy across sequencing platforms limits deconvolution accuracy. To address this, we introduce an experimental design to match inter-platform biological signals, hence revealing the technological discrepancy, and then develop a deconvolution framework called DeMixSC using the better-matched, i.e., benchmark, data. Built upon a novel weighted nonnegative least-squares framework, DeMixSC identifies and adjusts genes with high technological discrepancy and aligns the benchmark data with large patient cohorts of matched-tissue-type for large-scale deconvolution. Our results using a benchmark dataset of healthy retinas suggest much-improved deconvolution accuracy. Further analysis of a cohort of 453 patients with age-related macular degeneration supports the broad applicability of DeMixSC. Our findings reveal the impact of technological discrepancy on deconvolution performance and underscore the importance of a well-matched dataset to resolve this challenge. The developed DeMixSC framework is generally applicable for deconvolving large cohorts of disease tissues, and potentially cancer.

bioinformatics↗

bioRxiv2023

Characterization of Ralstonia pseudosolanacearum diversity and screening host resistance to manage bacterial wilt in South Asia

In South Asia, bacterial wilt pathogens in the Ralstonia solanacearum species complex (RSSC) impose major constraints on eggplant, tomato, and pepper production. To improve the efficacy of bacterial wilt management, the goals of this study were to (1) conduct a survey of RSSC pathogens in Bangladesh and Nepal, (2) characterize the genetic diversity of these isolates, and (3) screen 37 tomato, eggplant, and pepper accessions for resistance to six representative isolates from South Asia. We isolated 99 isolates from Bangladesh and 20 isolates from Nepal and determined that all are phylotype I isolates of the Ralstonia pseudosolanacearum species. We sequenced and assembled draft genomes for 25 isolates. Phylogenomic analyses suggest that there is a wide diversity of endemic phylotype I isolates in South Asia, and possible introductions of two clonal phylotype I lineages into Bangladesh and Nepal. We contextualize our newly described isolates based on prior reports of RSSC diversity in South Asia and global reports of RSSC pathogens on eggplant and pepper. Greenhouse trials revealed multiple tomato, eggplant, and pepper accessions that exhibit promising levels of resistance to six phylotype I isolates from South Asia.

microbiology↗

bioRxiv2023

starTracer: An Accelerated Approach for Precise Marker Gene Identification in Single-Cell RNA-Seq Analysis

We introduce starTracer, a novel R package designed to enhance the specificity and efficiency of marker gene identification in single-cell RNA-seq data analysis. The package consists of two primary functional modules: "searchMarker" and "filterMarker". The "searchMarker" module, operating as an independent pipeline, exhibits superior flexibility by accepting a variety of input file types. Its primary output is a marker gene matrix, where genes are sorted by their potential to function as cluster-specific markers, with those exhibiting the greatest potential positioned at the top of the matrix for each respective cluster. In contrast, the "filterMarker" module is designed as a complementary pipeline to the Seurat "FindAllMarkers" function, providing a more accurate marker gene list for each cluster in conjunction with Seurat results. Benchmark analyses demonstrate that starTracer not only achieves excellent specificity in identifying marker genes compared to Seurat but also significantly surpasses it in processing speed. Impressively, the speed improvement ranges by 1~2 orders of magnitude compared to Seurat, as observed across three independent datasets. It is worth noting that starTracer exhibits increasing speed improvement with larger data volumes. It also excels in identifying markers in smaller clusters. Furthermore, the "filterMarker" reordering process considerably enhances Seurats marker matrix specificity. These advantages solidify starTracer as an invaluable tool for researchers working with single-cell RNA-seq data, merging robust accuracy with exceptional speed.

bioinformatics↗

bioRxiv2023

Commensal microbiome dysbiosis elicits IL-8 signaling to drive fibrotic skin disease

Commensal bacteria are core players in wound healing whose function in the opposite pathophysiological process-scarring is presently unclear. Here, we document the association between bacteria and a specific skin fibrotic disease-keloid, which might offer a promising avenue for translational practice. ABSTRACTWound healing is an intensely studied topic involved in many relevant pathophysiological processes, including fibrosis. Despite the large interest in fibrosis, the network that related to commensal microbiota and skin fibrosis remain mysterious. Here, we pay attention to keloid, a classical yet intractable skin fibrotic disease to establish the association between commensal microbiota to scaring tissue. Our histological data reveal the presence of microbiota in the keloids. 16S rRNA sequencing characterize microbial composition and divergence between the pathological and normal skin tissue. Moreover, the data show elevation of interleukin-8 both in the circulation and keloid tissue, which elicited the collagen accumulation and migratory program of dermal fibroblasts via CXCR1/2 receptor. Our research provides insights into the pathology of human fibrotic diseases, advocating commensal bacteria and IL-8 signaling as useful targets in future interventions of recurrent keloid disease.

microbiology↗

bioRxiv2023

Androgen blockade primes NLRP3 in macrophages to induce tumor phagocytosis

Immune-based therapies induce durable remissions in subsets of patients across multiple malignancies. However, there is limited efficacy of immunotherapy in metastatic castrate-resistant prostate cancer (mCRPC), manifested by an enrichment of immunosuppressive (M2) tumor- associated macrophages (TAM) in the tumor immune microenvironment (TME). Therefore, therapeutic strategies to overcome TAM-mediated immunosuppression are critically needed in mCRPC. Here we discovered that NLR family pyrin domain containing 3 (NLRP3), an innate immune sensing protein, is highly expressed in TAM from metastatic PC patients treated with standard-of-care androgen deprivation therapy (ADT). Importantly, ex vivo studies revealed that androgen receptor (AR) blockade in TAM upregulates NLRP3 expression, but not inflammasome activity, and concurrent AR blockade/NLRP3 agonist (NLRP3a) treatment promotes cancer cell phagocytosis by immunosuppressive M2 TAM. In contrast, NLRP3a monotherapy was sufficient to enhance phagocytosis of cancer cells in anti-tumor (M1) TAM, which exhibit high de novo NLRP3 expression. Critically, combinatorial treatment with ADT/NLRP3a in a murine model of advanced PC resulted in significant tumor control, with tumor clearance in 55% of mice via TAM phagocytosis. Collectively, our results demonstrate NLRP3 as an AR-regulated "macrophage phagocytic checkpoint", inducibly expressed in TAM by ADT and activated by NLRP3a treatment, the combination resulting in TAM-mediated phagocytosis and tumor control.

cancer biology↗

bioRxiv2023

SACNet: A Multiscale Diffeomorphic Convolutional Registration Network with Prior Neuroanatomical Constraints for Flexible Susceptibility Artifact Correction in Echo Planar Imaging

Susceptibility artifacts (SAs), inevitable in brain diffusion MR (dMRI) scans acquired using single-shot echo planar imaging (EPI), severely compromise the accurate detection of human brain structure. Existing SA correction (SAC) methods offer inadequate correction quality and limited applicability across diverse datasets with varied acquisition protocols. To address these challenges, we proposed SACNet, a SAC framework based on unsupervised registration convolutional networks, featuring: i) a novel diffeomorphism regularization function to avoid unnatural SAC warps, modified from a potential well function; ii) an integration with prior neuroanatomical constraints and coarse-to-fine processing strategy to enables multi-scale geometric and intensity recoveries in severe distorted areas; iii) a unified registration framework that incorporates multiple phase-encoding (PE) EPI images and structural images, ensuring compatibility with both single- and inverse-PE protocols, with or without field maps. Utilizing simulated dMRI images and over 2000 brain scans from neonatal, child, adult and traveling participants, our method consistently demonstrates state-of-the-art correction performance. Notably, SACNet effectively reduces SAs-related multicenter effects compared to existing methods. We have developed user-friendly tools using containerization techniques, hope to facilitate SAC correction quality across extensive neuroimaging studies.

neuroscience↗