Biology subjects

Ye, J.

Publications and source records attributed to Ye, J..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

Amygdala GABA Neurons: Gatekeepers of Stress and Reproduction

Stress can disrupt menstrual cycles, cause infertility, and lead to other reproductive disorders. The posterodorsal medial amygdala (MePD) processes stress signals and regulates the gonadotropin-releasing hormone (GnRH) pulse generator through GABAergic inhibitory projections to the hypothalamus. However, how stress is processed in the MePD - especially involving its dense GABA and Urocortin-3 (UCN3) neurons - remains poorly understood. In this study, we combine in vivo GRadient-INdex (GRIN) lens mini-endoscopic calcium imaging (to track neuronal activity), optogenetics, clustering analysis, and computational modeling to investigate the MePD circuitry. Our findings reveal two anti-correlated GABA subpopulations in the MePD that dictate responses to both UCN3 neuron stimulation and restraint stress. Our computational modeling suggests that mutual inhibition between these GABA groups drives the anti-correlated activity and predicts how these interactions shape downstream responses to stimulation of GABA and UCN3 neurons. We test these predictions using optogenetics and confirm that GABA neurons are critical for the transmission of UCN3 signals to regulate luteinizing hormone (LH) pulse frequency. Our study is the first to show how GABA neurons in the amygdala mediate stress effects on reproductive health, uncovering key neural mechanisms linking emotional and reproductive functions.

physiology↗

bioRxiv2024

R-Spondin Mimetic, SZN-043, Induced Proliferation and Wnt Activity, Two Features Deficient in Human Alcohol-Associated Liver Disease

Liver regeneration is impaired in patients suffering from alcohol-associated liver (ALD) diseases. Wnt ligands and their FZD receptors are dysregulated in diseased livers. R-spondin and their receptors are known to regulate Wnt activity via the stabilization of FZD receptors. Here, we investigated the components of the Wnt and R-Spondin-signaling pathways and their activity in patients with ALD. We found that while hepatocytes retained high levels of differentiation markers such as ASGR1 and ASGR2, the expression of two R-spondin co-receptors, LGR4 and LGR5, and of Wnt target genes, CYP1A2 and others, were strongly reduced. SZN-043, a hepatocyte-targeted R-Spondin mimetic, is a new investigational drug that stimulates the physiological Wnt repair pathway and proliferation of hepatocytes. Here, we show that SZN-043 induced hepatocyte proliferation in all models tested, including humanized mouse livers, a chronic-binge alcohol-induced liver injury, and a CCl4-induced fibrosis mouse model. Altogether, SZN-043 could be beneficial for the treatment of ALD.

pathology↗

bioRxiv2024

Spatial Transcriptomic Profiling Of Advanced Ovarian Clear Cell Carcinoma Reveals Intra-Tumor Heterogeneity In Epithelial-Mesenchymal Gradient

Intratumoral heterogeneity is intrinsically comprised of molecular alterations of tumor cells and extrinsically from interconnections with microenvironments. This study explores the spatial heterogeneity of ovarian clear cell carcinoma (OCCC), a rare cancer with significance to East Asian women. We profile 21 primary-metastatic tumor pairs in a discovery cohort and 16 tumors in two validation cohorts using spatial transcriptomic (ST) platforms. Our integrative analysis revealed an inverse relationship between OXPHOS and inflammation along the EMT gradient. OCCC cells undergoing partial EMT have metabolic shifts and lose LCN2 expression, possibly via concomitant down-regulation of SOX9. Conversely, LCN2 expression correlated with OXPHOS-enriched tumor signature, low EMT, and better outcomes in OCCC. Single-cell ST profiling using CosMx further identifies nine spatially distinct cancer cell populations including the LCN2-high cancer subclone with a high epithelial score. SOX9 induction could partially restore epithelial-ness in LCN2-low cells suggesting that plasticity in OCCC is achieved via transcriptional reprogramming. Our findings provide further insights into epithelial-mesenchymal plasticity and the adaptive interactions between cancer cells and their microenvironments in OCCC.

cancer biology↗

bioRxiv2024

Reshaping the tumor microenvironment by degrading glycoimmune checkpoints Siglec-7 and -9

Cancer treatment has been rapidly transformed by the development of immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1. However, many patients fail to respond, especially those with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. Sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and -9 are newly designated glycoimmune checkpoints that are abundantly expressed by tumor-infiltrating myeloid cells. We discovered that T cells express only basal levels of Siglec transcripts; instead, they acquire Siglec-7 and -9 from interacting myeloid cells in the TME via trogocytosis, which impairs their activation and effector function. Mechanistically, Siglec-7 and -9 suppress T cell activity by dephosphorylating T cell receptor (TCR)-related signaling cascades. Using sulfur fluoride exchange (SuFEx) click chemistry, we developed a ligand that binds to Siglec-7 and -9 with high-affinity and exclusive specificity. Using this ligand, we constructed a Siglec-7/9 degrader that targets membrane Siglec-7 and -9 to the lysosome for degradation. Administration of this degrader induced efficient Siglec degradation in both T cells and myeloid cells in the TME. We found that Siglec-7/9 degradation has a negligible effect on macrophage phagocytosis, but significantly enhances T cell anti-tumor immunity. The degrader, particularly when combined with anti-CTLA-4, enhanced macrophage antigen presentation, reshaped the TME, and resulted in long-lasting T cell memory and excellent tumor control in multiple murine tumor models. These findings underscore the need to consider exogenous checkpoints acquired by T cells in the TME when selecting specific checkpoint blockade therapy to enhance T cell immunity.

immunology↗

bioRxiv2024

Bio-engineering a common probiotic to exploit colonic inflammation promotes reliable efficacy in translational models of colitis

The intricate balance between the gut microbiome and host health inspires innovations in drug development. Commensal bacteria provide a multi-targeted approach ideal for treating complex medical conditions, like inflammatory bowel disease (IBD). These bacteria are self-replicating factories with broad targets that promote balanced intestinal inflammation, mucosal barrier function, and eubiosis. Yet, the lack of superiority to gold-standard treatments and their clinical inconsistency makes most probiotics unreliable for disease treatments. Intestinal inflammation, a driving factor in many diseases, often overwhelms commensal bacteria, which lack the stress-resistance mechanisms necessary to withstand host immune defenses. To address this, we introduced a persistence platform BioPersist into E. coli Nissle 1917. We hypothesized that a bio-engineered probiotic, or genetically engineered microbial medicine (GEMM), designed to persist during inflammation would enhance probiotic bioavailability during colitis, leading to sustained therapeutic outcomes. We evaluated BioPersist in multiple translational colitis models such as in mice and pigs. BioPersist delayed the onset and reduced the severity of both chronic and acute colitis, proving more effective than 5-aminosalicylate. BioPersist thrived during inflammation promoting tolerogenic immune responses that limited infiltrating leukocyte activity and decreased TNF- from resident myeloid cells in the mesentery. The persistence feature of BioPersist allowed the probiotic to overcome the damaging inflammatory response, eliciting mucosal healing evident by the increase in microbially-derived butyric acid. Based on these preclinical results, BioPersist may be a novel therapeutic option for both human and veterinary applications that sustains efficacy during colitis. One Sentence SummaryAdding a persistence feature to a probiotic enhances its efficacy for colitis treatment, enhancing future human and veterinary therapeutic applications.

microbiology↗

bioRxiv2024

Enteropathogenic Escherichia coli induces Entamoeba histolytica Levy-like movement on fibronectin-rich substrate by reducing traction forces

Amebiasis, caused by Entamoeba histolytica, is a global health concern, affecting millions and causing significant mortality, particularly in areas with poor sanitation. Although recent studies have examined E. histolyticas interaction with human intestinal microbes, the impact of bacterial presence on the parasites motility, mechanical forces, and their potential role in altering invasiveness have not been fully elucidated. In this study, we utilized a micropillar-array system combined with live imaging to investigate the effects of enteropathogenic Escherichia coli on E. histolyticas motility characteristics, F-actin spatial localization, and traction force exerted on fibronectin-coated substrates. Our findings indicate that co-incubation with E. coli significantly enhances the motility of E. histolytica, as evidenced by the enhancement of Levy-like movement patterns, i.e., increased directionality and velocity. This increased motility is accompanied by a reduction in F-actin-dependent traction forces and podosome-like structures on fibronectin-coated substrates, but with increased F-actin localization in the upper part of the cytoplasm. These findings highlight the role of physical interactions and cellular behaviors in modulating the parasites virulence, providing new insights into the mechanistic basis of its pathogenicity. Author SummaryAmebiasis, caused by the protozoan parasite Entamoeba histolytica, is a major global health issue, affecting around 50 million people and resulting in 100,000 deaths annually. The disease is transmitted through contaminated food and water. Upon reaching the intestines, which are teeming with bacteria, E. histolytica begins its invasion by removing the protective mucus layer, followed by adhering to and detaching enterocytes, leading to the disruption and degradation of the epithelial barrier. Afterwards, E. histolytica invades along the fibronectin-rich basement membrane deep into the crypts of Lieberkuhn, eventually penetrating the fibronectin- rich lamina propria. This leads to further tissue destruction and potential dissemination to distant organs, causing severe complications. In our study, we explored how the presence of enteropathogenic bacteria affects the parasites motility and mechanical force generation, both of which are key to its pathogenicity. Using a micropillar-array system and live imaging, we found that exposure to enteropathogenic Escherichia coli significantly increases E. histolyticas motility while reducing its traction force on fibronectin-rich matrices. These changes in behavior highlight the role of bacterial interactions in enhancing the parasites virulence. Our findings provide important insights into the mechanistic basis of E. histolyticas pathogenicity, offering potential avenues for new treatments against amebiasis.

microbiology↗

bioRxiv2024

Single-cell Landscape of Immune Cells in Blood and Skin in Psoriasis

BackgroundPsoriasis is a systemic inflammatory disease for which there is currently no cure, in part due to an incomplete understanding of its pathophysiology. MethodsTo better understand the immune response in psoriasis, we performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) and on lesional and non-lesional skin samples from a cohort of 11 psoriasis patients and 8 healthy controls. Additionally, we conducted flow cytometry on PBMCs from a separate cohort of 13 psoriasis patients and 11 ankylosing spondylitis. FindingsOur study revealed altered immune signatures of specific myeloid and lymphocyte subsets in blood and skin, both in terms of cell numbers and gene expression. Specifically, we discovered elevated proportions of circulating CD14++ monocytes, increased expression of major histocompatibility complex (MHC) class II molecule by circulating CD16+ monocytes, as well as increased expression of genes related to skin homing and to pro-inflammatory responses in psoriasis by circulating plasmacytoid dendritic cells (pDCs). Circulating CD8+ T effector memory cells in psoriasis patients exhibited reduced abundance but increased skin-homing potential. In psoriatic lesions, we observed a hyperinflammatory myeloid-cell state and enrichment of IL17-producing cells with a tissue-resident memory T-cell signature. InterpretationThe changes in immune cell numbers and gene expression indicate a significant alteration in the immune landscape of psoriasis patients. This suggests that the immune system in psoriasis is reprogrammed, affecting both innate and adaptive branches. These findings provide new insights into the aberrant immune-cell signatures in the circulation and skin lesions in psoriasis, and thereby help to understand its pathophysiology. FundingThis study was financially supported by the National Natural Science Foundation of China (U23A6012), Science and Technology Planning Project of Guangzhou (2024A03J0055, 202206080005), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202204).

systems biology↗

bioRxiv2024

Few-shot Algorithms for Consistent Neural Decoding (FALCON) Benchmark

Intracortical brain-computer interfaces (iBCIs) can restore movement and communication abilities to individuals with paralysis by decoding their intended behavior from neural activity recorded with an implanted device. While this activity yields high-performance decoding over short timescales, neural data are often nonstationary, which can lead to decoder failure if not accounted for. To maintain performance, users must frequently recalibrate decoders, which requires the arduous collection of new neural and behavioral data. Aiming to reduce this burden, several approaches have been developed that either limit recalibration data requirements (few-shot approaches) or eliminate explicit recalibration entirely (zero-shot approaches). However, progress is limited by a lack of standardized datasets and comparison metrics, causing methods to be compared in an ad hoc manner. Here we introduce the FALCON benchmark suite (Few-shot Algorithms for COnsistent Neural decoding) to standardize evaluation of iBCI robustness. FALCON curates five datasets of neural and behavioral data that span movement and communication tasks to focus on behaviors of interest to modern-day iBCIs. Each dataset includes calibration data, optional few-shot recalibration data, and private evaluation data. We implement a flexible evaluation platform which only requires user-submitted code to return behavioral predictions on unseen data. We also seed the benchmark by applying baseline methods spanning several classes of possible approaches. FALCON aims to provide rigorous selection criteria for robust iBCI decoders, easing their translation to real-world devices. https://snel-repo.github.io/falcon/

neuroscience↗

bioRxiv2024

Variation in moment-to-moment brain state engagement changes across development and contributes to individual differences in executive function

Neural variability, or variation in brain signals, facilitates dynamic brain responses to ongoing demands. This flexibility is important during development from childhood to young adulthood, a period characterized by rapid changes in experience. However, little is known about how variability in the engagement of recurring brain states changes during development. Such investigations would require the continuous assessment of multiple brain states concurrently. Here, we leverage a new computational framework to study state engagement variability (SEV) during development. A consistent pattern of SEV changing with age was identified across cross-sectional and longitudinal datasets (N>3000). SEV developmental trajectories stabilize around mid-adolescence, with timing varying by sex and brain state. SEV successfully predicts executive function (EF) in youths from an independent dataset. Worse EF is further linked to alterations in SEV development. These converging findings suggest SEV changes over development, allowing individuals to flexibly recruit various brain states to meet evolving needs.

neuroscience↗

bioRxiv2024

The miR-290 and miR-302 clusters are essential for reprogramming of fibroblasts to induced pluripotent stem cells

The miR-290 and miR-302 clusters of microRNAs are highly expressed in naive and primed pluripotent stem cells, respectively. Ectopic expression of the embryonic stem cell-specific cell cycle regulating (ESCC) family of microRNAs arising from these two clusters dramatically enhances the reprogramming of both mouse and human somatic cells to induced pluripotency. Here, we used genetic knockouts to dissect the requirement for the miR-290 and miR-302 clusters during the reprogramming of mouse fibroblasts into induced pluripotent stem cells (iPSCs) with retrovirally introduced Oct4, Sox2, and Klf4. Knockout of either cluster alone did not negatively impact the efficiency of reprogramming. Resulting cells appeared identical to their embryonic stem cell microRNA cluster knockout counterparts. In contrast, the combined loss of both clusters blocked the formation of iPSCs. While rare double knockout clones could be isolated, they showed a dramatically reduced proliferation rate, a persistent inability to fully silence the exogenously introduced pluripotency factors, and a transcriptome distinct from individual miR-290 or miR-302 mutant ESC and iPSCs. Taken together, our data show that miR-290 and miR-302 are essential yet interchangeable in reprogramming to the induced pluripotent state. Impact StatementThe process by which somatic cell reprogramming yields induced pluripotent stem cells (iPSCs) is incompletely understood. MicroRNAs from the miR-290 and miR-302 clusters have been shown to greatly increase reprogramming efficiency, but their requirement in the process has not been studied. Here, we examine this requirement by genetically removing the miRNA clusters in somatic cells. We discover that somatic cells lacking either, but not both, of these miRNA clusters can form iPSC cells. This work thus provides new important insight into mechanisms underlying reprogramming to pluripotency.

developmental biology↗

bioRxiv2024

Prenatal glyphosate exposure disrupts the gut-brain axis across several generations in mice.

Glyphosate, a widely used herbicide in North America, has become prevalent in the food supply, raising concerns about potential health impacts. In this exploratory study, male and female F0 mice were exposed to glyphosate through drinking water during mating and gestation. We investigated whether prenatal exposure at dietary-relevant levels (0.01 mg/kg/day, Average American Diet, [AAD]) or the U.S. EPAs acceptable daily intake (1.75 mg/kg/day, [EPA upper limit]) altered gut, metabolic, and behavioral outcomes across two generations in mice with or without genetic susceptibility to colitis (Muc2+/- and Muc2-/-, respectively). Healthy (Muc2+/-) offspring of glyphosate-exposed mice exhibited colonic goblet cell depletion, reduced mucin-2 expression, and pro-inflammatory cytokine profiles in both F1 and F2 generations. These healthy (Muc2+/-) offspring also developed metabolic dysfunction, including impaired glucose tolerance, insulin resistance, and reduced GLP-1 in serum. Behavioral deficits were also observed in healthy (Muc+/-) mice including reduced locomotion and working memory, and these changes were associated with altered microbiome composition and gut-brain mediators. These findings suggest that prenatal glyphosate exposure, even below regulatory thresholds, may disrupt multiple physiological systems across generations, highlighting the need for further research and regulatory consideration.

pharmacology and toxicology↗

bioRxiv2024

Dual-Targeted Microbubbles Promote Apoptosis of M1 Macrophages by Inhibiting Telomerase Activity for Atherosclerosis Therapy

It is known that M1 macrophages are the dominant phenotype in progressive atherosclerosis (AS). Studies have shown that telomerase in macrophages can be activated during the atherosclerosis formation, but how to regulate the telomerase activity of M1 macrophages is the focus of treatment of AS. Herein, we report a dual-targeted microbubbles delivery system encapsulating the telomerase inhibitor BIBR1532 (Ab-MMB1532), designed for precise targeted therapy of AS. The Ab-MMB1532 exhibits excellent biocompatibility and remarkable targeting capability towards M1 macrophages with its targeting advantage notably accentuated under high shear forces. Furthermore, it significantly downregulates telomerase activity. Metabolomics analysis indicates that the decrease in telomerase activity upregulates the expression of aspartic acid, a key protein in the Caspase pathway of apotosis. In vivo, Ab-MMB1532 efficiently targeted and accumulated within AS lesions, leading to significantly delay of the AS progression by inhibiting telomerase activity and promoting apoptosis of M1 macrophages after 4-week treatment. In summary, Ab-MMB1532 provides a new approach for potentially safer and more effective treatment of AS in the future.

bioengineering↗

bioRxiv2024

Transocular detection of premotor Parkinson's disease via retinal neurovascular coupling through functional OCT angiography

Early detection of Parkinsons disease (PD) is essential for timely initiating neuroprotective interventions before significant loss of dopaminergic (DAergic) neurons, but faces challenges in accurately and noninvasively detecting subtle neuronal changes in the midbrain. Here, we propose a transocular functional imaging method termed fOCTA-rNVC, which detects premotor PD by measuring alterations in retinal neurovascular coupling (rNVC) at the capillary level using specialized functional OCT angiography (fOCTA). Our findings demonstrate that capillary rNVC is significantly attenuated and delayed due to concurrent retinal dopaminergic degeneration in premotor PD mice. Notably, this PD-related rNVC attenuation can be temporarily reversed in acute levodopa challenge. Utilizing the functional characteristics of capillary rNVC in PD, we achieved an impressive accuracy of [~]100% in detecting premotor PD mice even with only [~]14.1% loss of midbrain DAergic neurons, at which stage prompt treatment offered superior outcomes. In contrast, no significant changes were observed in retinal thickness or vasculature in the premotor PD mice. These findings suggest that fOCTA-rNVC is a promising noninvasive solution for accurately detecting premotor PD and guiding early interventions.

bioengineering↗

bioRxiv2024

High-throughput drug screening for inhibition of influenza A virus infection based on human SIRT1 promoter and Genipin suppressing influenza A virus by activation of AMPK-SIRT1-PGC-1α signaling pathway

The energy metabolism crisis is considered an important risk factor for severe influenza A virus (IAV) infection. During virus replication, the host cells "metabolic reprogramming" is beneficial for increasing the energy demand of the virus. SIRT1 plays a major role in altering metabolic reprogramming, and upregulation of SIRT1 expression can defend against viral infection. This study established a high-throughput drug screening method for human SIRT1 promoter. Nine natural medicines were selected from 134 traditional Chinese medicines. Among them, the activity of Gardenia jasminoides Ellis was relatively high. Further research has found that the plant extract and its active compound Genipin and its derivatives can significantly inhibit IAV replication, improve the survival rate of infected mice, and inhibit pneumonia. In addition, Genipin significantly increased the levels of energy metabolism core regulatory factors SIRT1, PPAR {gamma}, PGC-1 , and p-AMPK, inhibited IAV induced activation of MAPKs and NF-{kappa}B, and alleviated inflammatory response. The pharmacological antagonists of SIRT1 and PGC-1 , as well as siRNA, significantly counteracted the effects of Genipin on IAV replication and inflammation. In summary, we found that Genipin and its derivatives could significantly inhibit IAV replication and inflammation, possibly by activating the AMPK-SIRT1-PGC-1 signaling pathway and altering metabolic reprogramming.

pharmacology and toxicology↗

bioRxiv2024

Spatial Transcriptomics Reveals a Myeloma Cell Architecture with Dysfunctional T-Cell Distribution, Neutrophil Traps, and Inflammatory Signaling

The bone marrow (BM) is a complex tissue where spatial relationships influence cell behavior, signaling, and function. Consequently, understanding the whole dynamics of cellular interactions requires complementary spatial techniques that preserve and map the architecture of cell populations in situ. We successfully conducted spatial transcriptional profiling using Visium Spatial Gene Expression in formalin-fixed paraffin-embedded (FFPE) BM samples obtained from healthy and Multiple Myeloma (MM) mouse models and patients, addressing the technical challenges of applying spatial technology to long bone samples. A custom data-analysis framework that combines spatial with single-cell transcriptomic profiles identified both the BM cellular composition and the existing cell relations. This allowed us to visualize the spatial distribution of transcriptionally heterogeneous MM plasma cells (MM-PC). We spatially delineated transcriptional programs associated with MM, including NETosis and IL-17-driven inflammatory signaling, which were inversely correlated to malignant PC-enriched regions. Furthermore, a gradient of MM-PC density spatially correlated with a shift from effector-to-exhausted T cell phenotypes. The translational relevance of our findings was confirmed using FFPE BM biopsies from MM patients with varying levels of malignant PC infiltration. In summary, we provide the first spatial transcriptomics analysis applied to a mouse and human mineralized bone tissue and illustrate the BM cellular architecture of MM, revealing deregulated mechanisms underlying MM intercellular communication.

cancer biology↗

bioRxiv2024

Deficiency in a special dynein DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and mice

Asthenoteratozoospermia, a prevalent cause of male infertility, lacks a well-defined etiology. DNAH12 is a special dynein featured by the absence of a microtubule-binding domain, however, its functions in spermatogenesis remain largely unknown. Through comprehensive genetic analyses involving whole-exome sequencing and subsequent Sanger sequencing on infertile patients and fertile controls from six distinct families, we unveiled six biallelic mutations in DNAH12 that co-segregate recessively with male infertility in the studied families. Transmission electron microscopy (TEM) revealed pronounced axonemal abnormalities, including inner dynein arms (IDAs) impairment and central pair (CP) loss in sperm flagella of the patients. Mouse models (Dnah12-/- and Dnah12mut/mut) were generated and recapitulated the reproductive defects in the patients. Noteworthy, DNAH12 deficiency did not show effects on cilium organization and function. Mechanistically, DNAH12 was confirmed to interact with two other IDA components DNALI1 and DNAH1, while disruption of DNAH12 leads to failed recruitment of DNALI1 and DNAH1 to IDAs and compromised sperm development. Furthermore, DNAH12 also interacts with radial spoke head proteins RSPH1, RSPH9, and DNAJB13 to regulate CP stability. Moreover, the infertility of Dnah12-/- mice could be overcome by intracytoplasmic sperm injection (ICSI) treatment. Collectively, DNAH12 plays a crucial role in the proper organization of axoneme in sperm flagella, but not cilia, by recruiting DNAH1 and DNALI1 in both humans and mice. These findings expand our comprehension of dynein component assembly in flagella and cilia and provide a valuable marker for genetic counseling and diagnosis of asthenoteratozoospermia in clinical practice.

genetics↗

bioRxiv2024

LucaOne: Generalized Biological Foundation Model with Unified Nucleic Acid and Protein Language

AbstractThe language of biology, encoded in DNA, RNA, and proteins, forms the foundation of life but remains challenging to decode due to its complexity. Traditional computational methods often struggle to integrate information across these molecules, limiting a comprehensive understanding of biological systems. Advances in Natural Language Processing (NLP) with pre-trained models offer new possibilities for interpreting biological language. Here, we introduce LucaOne, a pre-trained foundation model trained on nucleic acid and protein sequences from 169,861 species. Through large-scale data integration and semisupervised learning, LucaOne demonstrates an understanding of key biological principles, such as DNA-Protein translation. Using few-shot learning, it effectively comprehends the central dogma of molecular biology and performs competitively on tasks involving DNA, RNA, or protein inputs. Our results highlight the potential of unified foundation models to address complex biological questions, providing an adaptable framework for bioinformatics research and enhancing the interpretation of lifes complexity.

bioinformatics↗

bioRxiv2024

Genetic variants associated with cell-type-specific intra-individual gene expression variability reveal new mechanisms of genome regulation

Gene expression levels can vary substantially across cells, even in a seemingly homogeneous cell population. Identifying the relationships between genetic variation and gene expression is critical for understanding the mechanisms of genome regulation. However, the genetic control of gene expression variability among the cells within individuals has yet to be extensively examined. This is primarily due to the statistical challenges, such as the need for sufficiently powered cohorts and adjusting mean-variance dependence. Here, we introduce MEOTIVE (Mapping genetic Effects On inTra-Individual Variability of gene Expression), a novel statistical framework to identify genetic effects on the gene expression variability (sc-veQTL) accounting for the mean-variance dependence. Using single-cell RNA-seq data of 1.2 million peripheral blood mononuclear cells from 980 human donors, we identified 14 - 3,488 genes with significant sc-veQTLs (study-wide q-value < 0.05) across different blood cell types, 2,103 of which were shared across more than one cell type. We further detected 55 SNP-gene pairs (in 34 unique genes) by directly linking genetic variations with gene expression dispersion (sc-deQTL) regardless of mean-variance dependence, and these genes were enriched in biological processes relevant to immune response and viral infection. An example is rs1131017 (p<9.08x10-52), a sc-veQTL in the 5UTR of RPS26, which shows a ubiquitous dispersion effect across cell types, with higher dispersion levels associated with lower auto-immune disease risk, including rheumatoid arthritis and type 1 diabetes. Another example is LYZ, which is associated with antibacterial activity against bacterial species and was only detected with a monocyte-specific deQTL (rs1384) located at the 3 UTR region (p=1.48x10-11) and replicated in an independent cohort. Our results demonstrate an efficient and robust statistical method to identify genetic effects on gene expression variability and how these associations and their involved pathways confer auto-immune disease risk. This analytical framework provides a new approach to unravelling the genetic regulation of gene expression at the single-cell resolution, advancing our understanding of complex biological processes.

genomics↗