Biology subjects

Meng, R.

Publications and source records attributed to Meng, R..

12 recordsLinked to original sources

bioRxiv2026

Visible Light Optical Coherence Tomography Reveals Aging at the RetinalPigment Epithelium-Bruch's Membrane Interface

Landmark histological studies have shown that as the retina ages, lipids and other debris accumulate within Bruchs membrane (BM) and in spaces introduced between BM and the retinal pigment epithelium (RPE). These deposits grow with age, increasing the risk of age-related macular degeneration (AMD), the leading cause of irreversible vision loss for older adults globally. Current in vivo imaging lacks specificity to study BM and the important spaces at the RPE/BM interface in living human eyes, while histological techniques suffer from processing artifacts that distort photoreceptors. Here we employ visible light Optical Coherence Tomography (OCT), with 1 micrometer depth resolution, to quantitatively analyze these tissues in living eyes. We identify age-related changes in a human cohort without retinal pathology: thickening and loss of contrast of the hyper-reflective BM band, and thickening of the RPE together with the sub-RPE basal laminar space (RPE+sBL). Both forms of thickening were locally coupled depending on eccentricity, suggesting related biosynthetic mechanisms. A thicker BM and RPE+sBL were locally associated with anomalies in the overlying photoreceptors. Thus, sub-clinical changes in aging eyes detected by visible light OCT resemble early versions of deposits found in AMD. Visible light OCT depicts the relationship between RPE+sBL, BM, and photoreceptors in aging, holding promise to precisely and non-invasively grade ocular phenotypes ranging from normal aging to early AMD. Significance StatementAs humans age, lipids and other debris deposit in Bruchs membrane (BM) of the human eye (1) and spaces introduced between the retinal pigment epithelium (RPE) and BM. These deposition processes are linked to the eventual development of age-related macular degeneration (AMD), the leading blinding disease amongst older adults. Here we investigate these deposits with visible light OCT imaging in living human subjects without overt retinal pathology. Whereas early RPE/BM deposits were previously assessed only in donor eyes postmortem via preparations that distort photoreceptors, our results shed light on these AMD precursors and overlying photoreceptor changes in living human eyes.

biophysics↗

bioRxiv2025

Machine Learning Models Based on Histological Images from Healthy Donors Identify ImageQTLs and Predict Chronological Age

Histological images offer a wealth of data. Mining these data holds significant potential for enhancing disease diagnosis and prognosis, though challenges remain, especially in non-cancer contexts. In this study, we developed a statistical framework that links raw histological images and their derived features to the genotype, transcriptome, and chronological age of the samples. We first demonstrated an association between image features and genotypes, identifying 906 image quantitative trait loci (imageQTLs) significantly associated with image features. Next, we identified differentially expressed (DE) genes by stratifying samples into image-similar groups based on image features and performing DE comparisons between groups. Additionally, we developed a deep-learning model that accurately predicts gene expression in specific tissues from raw images and their features, highlighting gene sets associated with observed morphological changes. Finally, we constructed another deep-learning model to predict chronological age directly from raw images and their features, revealing relationships between age and tissue morphology, especially aspects derived from nucleus features. Both models are supported by a computational approach that greatly compresses gigapixel whole-slide images and extracts interpretable nucleus features, integrating both large-scale tissue morphology and smaller local structures. We have made all interpretable nucleus features, imageQTLs, DE genes, and deep-learning models available as online resources for further research. Significance StatementThis study establishes a comprehensive framework that links histological image features to genotype, transcriptome, and chronological age in large-scale healthy tissue datasets, providing valuable insights into tissue morphology. By identifying 906 significant, interpretable imageQTLs and conducting differential expression analysis based on image features, we enhance understanding of genetic and morphological interactions. Additionally, we developed predictive models for both gene expression and chronological age from raw histological images, introducing a novel approach to studying age-related tissue-specific changes and presenting the first model to demonstrate the predictability of age from histological images.

bioinformatics↗

bioRxiv2025

WormAI: Artificial Intelligence of Networks for Nematode Phenotyping

The nematode Caenorhabditis elegans is a key model organism in biological research due to its genetic similarity to humans and its utility in studying complex processes. Traditional image analysis methods, such as those using ImageJ, are labour-intensive, which has led to the integration of AI. This study introduces an AI framework with three machine learning models: WormGAN, a Generative Adversarial Network for generating synthetic nematode images to enhance training data; WormDET, for precise movement tracking; and WormREG, for accurate anatomical measurements. Together, these tools significantly improve the efficiency and accuracy of phenotypic analysis. WormAI demonstrates substantial potential for high-throughput dataset analysis, advancing research in systems biology, drug discovery, and aging. This framework streamlines workflows, enabling faster and more precise discoveries in C. elegans studies.

bioinformatics↗

bioRxiv2024

Role of CCK1 receptor in metabolic benefits of intestinal enteropeptidase inhibition in mice

Enteropeptidase (EP; enterokinase) is a serine protease that regulates intestinal protein digestion by converting trypsinogen into active trypsin, and thus initiates activation of the pancreatic zymogen cascade. Chronic inhibition of EP and trypsin (EP/T) with camostat (Foipan, FOY-305) or its active metabolite (FOY-251) causes weight loss in obese mice by reducing intestinal protein absorption and suppression of food intake, however, the mechanisms leading to appetite suppression are not well understood. We tested the hypothesis that cholecystokinin (CCK) signaling mediates the anorectic effects of EP/T inhibition using a CCK1R inhibitor (loxiglumide) or CCK1R knockout (KO) mice. Acute treatment with loxiglumide was able to partially reverse FOY-251-induced gallbladder contraction and delayed gastric emptying in mice. Chronic co-administration of loxiglumide reversed FOY-251 mediated effects on food intake and metabolism in diet-induced obese (DIO) mice. Chronic dosing of FOY-251 caused similar reductions in food intake but greater weight loss in CCK1R KO mice compared to wildtype (WT) mice, primarily due to fat mass loss. Pair fed (PF) groups revealed food intake-dependent and -independent mechanisms of weight loss by FOY-251. Notably, FOY-251 treatment induced sustained weight loss, whereas body weight loss rebounded in PF animals. In CCKR1 KO mice, FOY-251 caused greater weight loss, and increased protein calorie loss relative to that in WT mice, while having no effect on glycemic control or FGF21. Hence, CCK1R-dependent and - independent mechanisms modulate the metabolic effects of EP/T inhibition and may play a role in maintaining weight loss by this mechanism.

pharmacology and toxicology↗

bioRxiv2024

Single-cell genomics and regulatory networks for 388 human brains

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet, little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multi-omics datasets into a resource comprising >2.8M nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550K cell-type-specific regulatory elements and >1.4M single-cell expression-quantitative-trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized [~]250 disease-risk genes and drug targets with associated cell types. Summary Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/585576v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@70b24org.highwire.dtl.DTLVardef@6c9eddorg.highwire.dtl.DTLVardef@131fae2org.highwire.dtl.DTLVardef@4e0f1e_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2023

Integrating population-level and cell-based signatures for drug repositioning

Drug repositioning presents a streamlined and cost-efficient way to expand the range of therapeutic possibilities. Drugs with human genetic evidence are more likely to advance successfully through clinical trials towards FDA approval. Single gene-based drug repositioning methods have been implemented, but approaches leveraging a broad spectrum of molecular signatures remain underexplored. We propose a framework called "TReD" (Transcriptome-informed Reversal Distance) that integrates population-level disease signatures robust to reverse causality and cell-based, drug-induced transcriptome response profiles. TReD embeds the disease signature and drug response profiles in a high-dimensional normed space, quantifying the reversal potential of candidate drugs in a disease-related cell-based screening. Here, we implemented this framework to identify potential therapeutics relevant to COVID-19 and type 2 diabetes (T2D). For COVID-19, we identified 36 drugs showing potential reversal roles. Notably, nearly 70% (25/36) of the drugs have been linked to COVID-19 from other studies, with seven drugs supported by ongoing/completed clinical trials. For T2D, we observed reversal signals for 16 compounds on multiple disease signatures. Five drugs are supported by published literature, affirming potential therapeutic value. In summary, we propose a comprehensive genetics-anchored framework integrating population-level signatures and cell-based screening that has the potential to accelerate the search for new therapeutic strategies.

bioinformatics↗

bioRxiv2023

CD8 T-cell dysfunction is linked with CAR T-cell failure and can be mitigated by a non-alpha IL-2 agonist, pegenzileukin

Chimeric antigen receptor (CAR) T-cell therapy has been a breakthrough for relapsed or refractory large B-cell lymphoma (rrLBCL). However, suboptimal CAR T-cell activity can lead to therapeutic failure and dismal outcome. Using single cell RNA-sequencing of rrLBCL tumors, we identify a prominent population of clonally expanded dysfunctional CAR+ CD8 T-cells indicative of ongoing tumor cell engagement, proliferation, and dysfunction at the time of progression from CAR T-cell therapy. Furthermore, we show that rrLBCL patient-derived CAR T-cells are more prone to dysfunction and loss of cytotoxicity compared to healthy donor-derived CAR T-cells. Using both antigen-driven and CAR-driven models of T-cell dysfunction, we show that pegenzileukin, a non-alpha IL2 agonist, can prevent T-cell dysfunction. In both in vitro and in vivo CAR T-cell models, pegenzileukin improved T-cell expansion and tumor control. This provides pre-clinical rational for use of pegenzileukin in combatting T-cell dysfunction, a central mechanism of CAR T-cell failure. HIGHLIGHTSO_LITumor-infiltrating CD8 CAR T-cells show clonal expansion and dysfunction at the time of progression. C_LIO_LIrrLBCL patient-derived CAR T-cells are more prone to dysfunction compared to healthy-donor-derived CAR T-cells. C_LIO_LIPegenzileukin, a non-alpha IL2 agonist, rescues antigen- and CAR-driven CD8 T-cell dysfunction and improves CAR T-cell responses in vivo. C_LI

immunology↗

bioRxiv2023

FcyRIIB is a novel immune checkpoint in the tumor microenvironment limiting activity of Treg-targeting antibodies

Despite pre-clinical murine data supporting T regulatory (Treg) cell depletion as a major mechanism by which anti-CTLA-4 antibodies function in vivo, the two main antibodies tested in patients (ipilimumab and tremelimumab) have failed to demonstrate similar effects. We report analogous findings in an immunocompetent murine model humanized for CTLA-4 and Fcy receptors (hCTLA-4/hFcyR mice), where both ipilimumab and tremelimumab fail to show appreciable Treg depletion. Immune profiling of the tumor microenvironment (TME) in both mice and human samples revealed upregulation of the inhibitory Fcy receptor, FcyRIIB, which limits the ability of the antibody Fc fragment of human anti-CTLA-4 antibodies to induce effective antibody dependent cellular cytotoxicty/phagocytosis (ADCC/ADCP). Blocking FcyRIIB in humanized mice rescues Treg depleting capacity and anti-tumor activity of ipilimumab. For another target, CC motif chemokine receptor 8 (CCR8), which is selectively expressed on tumor infiltrating Tregs, we show that Fc engineering to enhance binding to activating Fc receptors, while limiting binding to the inhibitory Fc receptor, leads to consistent Treg depletion and single-agent activity across multiple tumor models, including B16, MC38 and MB49. These data reveal the importance of reducing engagement to the inhibitory Fc receptor to optimize Treg depletion by TME targeting antibodies. Our results define the inhibitory FcyRIIB receptor as a novel immune checkpoint limiting antibody-mediated Treg depletion in tumors, and demonstrate Fc variant engineering as a means to overcome this limitation and augment efficacy for a repertoire of antibodies currently in use or under clinical evaluation in oncology. Highlights- Fully human anti-CTLA-4 antibodies are limited in their capacity to deplete T regulatory cells and drive durable anti-tumor immunity in humanized FcyR/hCTLA-4 mice - The inhibitory Fcy receptor, FcyRIIB, is upregulated in the tumor microenvironment in patients and in humanized FcyR/hCTLA-4 mice - Blocking FcyRIIB leads to rescue of Treg depletion in humanized murine models - Fc engineering can improve the depleting capacity and in vivo anti-tumor activity of anti-CTLA and anti-CCR8 antibodies targeting tumor infiltrating Tregs

immunology↗

bioRxiv2021

ZFP541 is indispensable for pachytene progression by interacting with KCTD19 and activates meiotic gene expression in mouse spermatogenesis

Meiosis is essential for fertility in sexually reproducing species, extensive studies tried to delineate this sophisticated process. Notwithstanding, the molecules involved in meiosis have not been fully characterized. In this study, we investigate the role of zinc finger protein 541 (ZFP541) and its interacting protein potassium channel tetramerization domain containing 19 (KCTD19) in mice. We demonstrate that they are indispensable for male fertility by regulating proper pachytene progression. ZFP541 is expressed starting from leptotene to round spermatids, and KCTD19 is initially expressed in pachytene. Depletion of Zfp541 or Kctd19 leads to infertility in male mice, and exhibits retarded progression from early to mid/late pachynema. In addition, Zfp541-/- spermatocytes show abnormal programmed DNA double-strand breaks (DSBs) repair, impaired crossover formation/resolution, and asynapsis of the XY chromosomes. Immunoprecipitation-mass spectrometry (IP-MS) and in vitro Co-IP reveal that ZFP541 interacts with KCTD19, histone deacetylase 1/2 (HDAC1), HDAC2 and deoxynucleotidyltransferase terminal-interacting protein 1 (DNTTIP1). Furthermore, RNA-seq and CUT&Tag analyses demonstrate that ZFP541 binds to the promoter regions of genes involved in meiosis and post-meiosis including Kctd19, and activates their transcription. Taken together, our studies reveal a ZFP541-Kctd19 transcription regulatory axis and the crucial role of ZFP541 and KCTD19 for pachytene progression and fertility in male mice.

developmental biology↗

bioRxiv2021

MBNL1 and RBFOX1 co-regulate alternative splicing events transcriptome-wide through a conserved buffering mechanism

Alternative splicing (AS) is controlled by cis-regulatory elements recognized by networks of trans-acting factors. Here we investigate modes and mechanisms of AS co-regulation by MBNL1 and RBFOX1, two RNA binding proteins (RBPs) critical for developmental AS transitions. We generated two cell models that express each RBP under separate inducible promoters. Transcriptome-wide categorization of the impacts of RBFOX1 expression on MBNL1 splicing revealed a common co-regulatory mode through which RBFOX1 buffers MBNL1 dose-dependent splicing regulation by reducing the total range of exon inclusion or exclusion. Minigene mutational analysis and in vitro binding experiments suggest that this buffering mechanism occurs through a shared cis-regulatory element previously unidentified as critical for MBNL1-dependent activity. Overall, our studies define a conserved co-regulatory mechanism through which RBFOX1 and MBNL1 can fine-tune and provide redundancy for AS outcomes. These studies indicate overlapping use of RNA motifs with potential implications for when activity of RBPs is disrupted.

biochemistry↗

bioRxiv2020

Autonomous sensing the insulin peptide by an olfactory G protein coupled receptor modulates glucose metabolism

Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by {beta} cells(1-3). By screening the expression and functional characterization of olfactory receptors in pancreatic islets, we identified Olfr109 as the receptor to detect insulin peptides. Engagement of one insulin peptide, insB:9-23, with Olfr109 diminished insulin secretion through Gi-cAMP signalling and promoted macrophage proliferation. Remarkably, Olfr109 deficiency alleviated intra-islet inflammatory responses and improved glucose homeostasis in Akita- and HFD-fed mice. We further determined the binding mode between the insB:9-23 and Olfr109. A pepducin-based Olfr109 antagonist improved glucose homeostasis in diabetic and obese mouse models. Collectively, we found that pancreatic {beta} cells use Olfr109 to autonomously detect self-secreted insulin peptides and this detection arrests insulin secretion and crosstalk with macrophages to increase intra-islet inflammation.

physiology↗

bioRxiv2019

Asian Zika virus isolate significantly changes the transcriptional profile and alternative RNA splicing events in a neuroblastoma cell line

Alternative splicing of pre-mRNAs expands a single genetic blueprint to encode multiple functionally diverse protein isoforms. Viruses have previously been shown to interact with, depend on, and alter host splicing machinery. The consequences however incited by viral infection on the global alternative slicing (AS) landscape are under appreciated. Here we investigated the transcriptional and alternative splicing profile of neuronal cells infected with a contemporary Puerto Rican Zika virus (ZIKVPR) isolate, the prototypical Ugandan ZIKV (ZIKVMR) isolate and dengue virus 2 (DENV2). Our analyses revealed that ZIKVPR induced significantly more differential changes in expressed genes compared to ZIKVMR or DENV2, despite all three viruses showing equivalent infectivity and viral RNA levels. Consistent with the transcriptional profile, ZIKVPR induced a higher number of alternative splicing events compared to ZIKVMR or DENV2, and gene ontology analyses highlighted alternative splicing changes in genes associated with mRNA splicing. All three viruses modulated alternative splicing with ZIKVPR having the largest impact on splicing. ZIKV alteration of the transcriptomic landscape during infection caused changes in cellular RNA homeostasis, which might dysregulate neurodevelopment and function leading to neuropathologies such as microcephaly and Guillain-Barre syndrome associated with the ZIKV infection.

microbiology↗