Biology subjects

Liang, Y.

Publications and source records attributed to Liang, Y..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

Intratumoral cDC1-T Cell Clusters Serve as Sites of Local Costimulation to Enhance CTL-Mediated Tumor Rejection

T cells are essential for anti-tumor immunity, but their ability to eliminate tumors depends on coordinated interactions with type 1 conventional dendritic cells (cDC1s). While cDC1s are known for cross-presenting tumor-derived antigens in lymph nodes to prime CD8+ T cells, their role within the tumor itself remains less well understood. Here, we use the Skin Tumor Array by Micro-Poration (STAMP) model to investigate how cDC1-T cell interactions shape immune responses and influence tumor fate. Our data reveal that it is the spatial distribution of both cDC1s and T cells that determines whether a tumor can be rejected. We defined three primary immunotypes based on the spatial distribution of T cells and cDC1s: T cell-inflamed/dendritic cell-inflamed (TC-In/DC-In) tumors, where T cells and cDC1s co-infiltrate the tumor; T cell-inflamed/dendritic cell-excluded (TC-In/DC-Ex) tumors, where T cells infiltrate but cDC1s remain at the periphery; and T cell-excluded/dendritic cell-excluded (TC-Ex/DC-Ex) tumors, which lack both cDC1 and T cell infiltration. Notably, TC-In/DC-In tumors are more likely to undergo rejection, whereas TC-In/DC-Ex tumors persist despite T cell infiltration. Within TC-In/DC-In tumors, cDC1s engage in direct interactions with T cells, upregulate co-stimulatory molecules, and sustain effector T cell responses, while cDC1s in TC-In/DC-Ex tumors express higher migration-associated genes, suggesting a propensity to exit the tumor. We further show that chemokine modulation, particularly through CXCL9, CCL5, and XCL1, can reshape immune infiltration patterns to promote intra-tumoral cDC1-T cell clustering and improve tumor rejection. These findings underscore the unexpectedly important role of cDC1 positioning and function in sustaining effective anti-tumor immunity and highlight spatially organized cDC1-T cell clusters as critical hubs for local T cell activation.

immunology↗

bioRxiv2025

Sustained Glucose Turnover Flux Distinguishes Cancer Cachexia from Nutrient Limitation

Cancer cachexia is an involuntary weight loss condition characterized by systemic metabolic disorder. A comprehensive flux characterization of this condition however is lacking. Here, we systematically isotope traced eight major circulating nutrients in mice bearing cachectic C26 tumors (cxC26) and food intake-matched mice bearing non-cachectic C26 tumors (ncxC26). We found no difference in whole-body lipolysis and proteolysis, ketogenesis, or fatty acid and ketone oxidation by tissues between the two groups. In contrast, compared to ncxC26 mice ad libitum, glucose turnover flux decreased in food intake-controlled ncxC26 mice but not in cxC26 mice. Similarly, sustained glucose turnover flux was observed in two autochthonous cancer cachexia models despite reduced food intake. We identified glutamine and alanine as responsible for sustained glucose production and tissues with altered use of glucose and lactate in cxC26 mice. We provide a comprehensive view of metabolic alterations in cancer cachexia revealing those distinct from decreased nutrient intake. HighlightsO_LIQuantitative fluxomics of cancer cachexia under matched food intake and body weight C_LIO_LIIntact lipolysis, proteolysis, ketogenesis, and lipid oxidation in cachectic mice C_LIO_LISustained glucose consumption in cachectic mice despite reduced food intake C_LIO_LIIncreased glucose production from glutamine and alanine in cachectic mice C_LI

cancer biology↗

bioRxiv2025

Organic carbon oxidation state shapes fermentative methanogenic microbiomes and controls greenhouse gas fluxes

Organic compounds with a negative nominal oxidation state of carbon (NOSC) are thermodynamically recalcitrant in anaerobic ecosystems, but few studies have measured the influence of NOSC on carbon degradation rates, gaseous product yields, or microbiome composition. We amended anaerobic rice paddy sediment microcosms with monomeric organic carbon compounds varying in NOSC. Consistent with thermodynamic and stoichiometric predictions, negative NOSC compounds are catabolized more slowly but produce more methane per mole of carbon. Negative NOSC microbiomes have higher alpha diversity, more syntrophs and methanogens, and fewer fermentative bacteria. Strikingly, fermentative bacterial taxa display genomically encoded NOSC catabolic preferences both in the lab and field. Negative NOSC- preferring fermenters have longer predicted doubling times, consistent with the thermodynamic recalcitrance of their preferred substrates. We propose that microbial NOSC preference can be leveraged for predicting and engineering greenhouse gas fluxes and understanding bacterial population dynamics and trait evolution across redox gradients.

microbiology↗

bioRxiv2025

Sludge liquefaction and stratification enable ultra-high digestion rate and resource recovery for waste activated sludge treatment

Most of the energy, nitrogen/N and phosphorus/P entering wastewater treatment plants (WWTPs) accumulates in waste activated sludge (WAS). While these resources are theoretically recoverable through anaerobic digestion (AD), conventional sludge AD faces long-standing challenges of low organic loading rate and limited N/P recovery. Here, building on an innovative sludge liquefaction and stratification technique, we present a novel process entitled SPREAD that boasts 10 times higher organic loading rates and recovers 5 folds of N/P resources, relative to conventional sludge AD. We develop an anaerobic digestion database (ADDB) for multi-omics analyses of digestion microbiomes, and pinpoint the mechanism underlying the exceptionally high organic loading rate and remarkable N/P recovery in SPREAD. Importantly, we identify a negative correlation between the Gibbs free energy ({Delta}G) and the relative abundance of methanogens, enabling identification of bottleneck steps for stimulation and augmentation of methanogenic digestion. Our study provides a game-changing technology for the treatment and resource recovery from WAS and opens a new avenue for sustainable management and carbon/energy-neutrality of WWTPs.

bioengineering↗

bioRxiv2025

Systematic discovery of single-cell protein networks in cancer with Shusi

Context-specific protein-protein interaction (PPI) drive heterogeneity of primary tumor, forming a formidable challenge to effective cancer therapy. However, systematically mapping and modeling these interactions at single-cell resolution across diverse cancer types remains an unmet need. Here, we present Shusi, a large language model-enhanced variational graph auto-encoder model trained on over single cells across 23 cancer types, to predict context-specific PPIs. Shusi outperforms existing state-of-the-art methods, as validated through orthogonal experimental evidence. Cancer-specific mutations are significantly enriched in Shusi-predicted networks, offering complementary insights to conventional marker gene-based approaches. Through systematic evaluations, we demonstrate strong associations between Shusi-predicted network topologies, genetic vulnerabilities, and therapeutic sensitivity. Finally, in acute myeloid leukemia (AML), a blood cancer where cell-state heterogeneity drives clinical resistance, Shusi pinpointed potential targets as actionable vulnerabilities of resistant leukemia subpopulations, as validated experimentally in primary AML. Shusi offers a deep-learning tool for implementing precision medicine based on context-specific protein network architecture.

bioinformatics↗

bioRxiv2025

Separating anorexia-dependent and -independent effects in cancer cachexia

Cancer cachexia is characterized by unintentional weight loss and wasting away of fat and muscle tissues. Anorexia, or reduced food intake, is often implicated as a contributor to the negative energy balance in this condition. However, to what extent anorexia alone accounts for body weight loss and wasting of different tissues, and whether anorexia is responsible for other cachectic phenotypes such as physical performance impairment remains insufficiently characterized in preclinical models and patients. In this study, we demonstrate the critical need to address these questions in cancer cachexia research. Using the colon carcinoma 26 (C26) model of cancer cachexia as an example, we systematically determined how much each of the key phenotypes of cancer cachexia is driven by anorexia. Anorexia was the predominant driver for body weight loss, adipose tissue wasting, and muscle wasting, strikingly suggesting the lack of other mechanisms for causing these phenotypes in this model. In contrast, anorexia had no impact on physical performance, pointing to the existence of anorexia-independent mechanisms in causing fatigue. Thus, for a given preclinical model or patient group, anorexia can be the main cause for certain cachectic phenotypes and play no role in causing other cachectic phenotypes. Discriminating between anorexia-mediated and independent effects is essential for guiding research focus and ultimately unraveling the causal pathways of cancer cachexia.

molecular biology↗

bioRxiv2025

SM3DD with Segmented PCA: A Comprehensive Method for Interpreting 3D Spatial Transcriptomics

We developed Standardised Minimum 3D Distance (SM3DD), an entirely cell segmentation/annotation-free approach to the analysis of spatial RNA datasets, using it to compare lung tissue from 16 clinically normal individuals to those of 18 SARS-CoV-2 patients who died from acute respiratory distress syndrome. RNA spatial coordinates were determined using the CosMx Spatial Molecular Imager (Bruker Spatial Biology, US). For each individual transcript location, we calculated the three-dimensional distances to the nearest transcript of each transcript type, standardising the distances to each transcript type. Mean SM3DDs were compared between normal and SARS-CoV-2 patients. Notably, hierarchical clustering of the directional log10(P) values organized genes by functionality, making it easier to interpret biological contexts and for FKBP11, where a decrease in distance to MZT2A was the most significant difference, suggesting a role in interferon signaling. Using a segmented principal components analysis of the entire SM3DD dataset, we identified multiple pathways, including SARS-CoV-2 infection, even though the assay did not include any SARS-CoV-2 transcripts.

bioinformatics↗

bioRxiv2025

Two telomere-to-telomere, gap-free genome assemblies and comparisons revealed the conserved key genes associated with sugar accumulation in Rubus genus

For the first time, we assembled two highly continuous, completely gap-free reference genomes of the Rubus subgenus: Rubus hirsutus Thunb. Penglei (XMM) and Rubus eustephanos Focke ex Diels Dahongpao (DHP), which are widely distributed in southern China with similar phenotypic traits (Figures 1A, 1B, and Figure S1), yet ripe fruits display distinct sugar accumulation levels (Table S1), making them ideal candidates for investigating the mechanisms underlying sugar accumulation in the Rubus genus. The XMM (213.53 Mb, 28,204 genes) and DHP (218.26 Mb, 28,569 genes) genomes exhibit close evolutionary relationships, diverging approximately 3.21 Mya. Comparative genomics identified extensive synteny, interspecific structural variations (translocations, inversions, segmental duplications), and presence/absence variation (PAV). Using Hi-C interaction heatmaps and Sanger sequencing, we validated interspecific structural inversions. Additionally, we identified a sugar transporter gene (MFS1), which is present in XMM but absent in DHP. Combined analysis of the gene family expansion/contraction and transcriptome identified two conserved key genes (RhSTP13 and RhSTP7) associated with sugar accumulation in Rubus genus and displayed distinct roles through transient expression assay. To facilitate functional genomics study, we also established a comprehensive Rubus database, RubusDB, a freely accessible repository consolidating all genomic, transcriptomic and phenotypic data of Rubus genus. These findings provide a foundational framework for elucidating the genetic basis of sugar accumulation, genome diversification, and trait improvement in Rubus species. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/646780v2_fig1.gif" ALT="Figure 1"> View larger version (72K): org.highwire.dtl.DTLVardef@1baca20org.highwire.dtl.DTLVardef@2c01eaorg.highwire.dtl.DTLVardef@131dc00org.highwire.dtl.DTLVardef@62a04f_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFIGURE 1.C_FLOATNO Phenotypic characterization, de novo genome assemblies, variation, and evolution of Rubus hirsutus Thunb. Penglei (XMM) and Rubus eustephanos Focke ex Diels Dahongpao (DHP). (A) Illustration of XMM whole plants, stem, flower bud and flower, respectively. (B) Illustration of DHP whole plants, stem, flower bud and flower, respectively. (C) The chromosome karyotype analysis of XMM. Bar = 10 {micro}m. (D) Circular diagram of XMM and DHP reference genomes. (a) Chromosomes are represented by centromeres (dark red) and telomeres (blue); (b) CEN18 density; (c) CEN17 density; (d) Gene density; (e) TE density; (f) PAV density; (g) SNP density; (h) Collinear lines at the center of diagram highlight homoeologous chromosomes relationships and non-homoeologous regions. (E) Genomic alignments between XMM and DHP. Inversions, duplications and translocations are marked with orange, blue and green ribbons, respectively. (F) Identification of large inversions in chromosome 7 between XMM and DHP. The three heatmaps show the chromatin interaction matrix, including mapping Hi-C data of DHP against DHP genome (left), mapping Hi-C data of DHP against XMM genome (middle) and mapping Hi-C data of XMM against XMM genome (right). The lower panel illustrates gene alignments between XMM and DHP. (G) Synteny, structural rearrangements, monomer, and identity distribution in the 16-20 Mbp region of chromosome 6 between XMM and DHP. (H) Local genome synteny of chromosome 5, with a structural variation that is present only in XMM. The PAV region includes a gene related to sugar transporter (MFS1, XMM05G025540). (I) Gene-level matchings of MFS genes in the PAVs region between XMM and DHP. (J) Phylogenetic relationships and divergence times between raspberries and other Rosaceae species. The black numbers close to the divergence nodes indicate the divergence times and the red bars represent the 95% confidence intervals. The red and black numbers indicate expanded and contracted ortholog groups at the corresponding node. Scale bar corresponds to 10 Mya. C_FIG

genomics↗

bioRxiv2025

Unique B Cell and Germinal Center Responses in Mice with Severe versus Mild Orientia tsutsugamushi Infection

The intracellular bacterium Orientia tsutsugamushi (Ot) is the causative agent of scrub typhus, an emerging and neglected tropical disease. Immunity against Ot infection in patients is known to be short-lived, as circulating antibodies can wane around one-year post-infection. However, its underlying mechanisms remain unclear; host immune signatures to clinically prevalent Ot strains are also undefined. In this study, we infected C57BL/6 mice with two clinically prevalent Ot strains with distinct virulence to examine splenic B cell and germinal center (GC) responses. While highly virulent Karp strain-infected mice had 50% mortality rates, intermediate virulent strain Gilliam-infected mice survived, gained body weight, and maintained relatively low bacterial burden levels during infection. Yet, Gilliam infection resulted in strong splenic B cell responses, as judged by absolute cell numbers of total splenic B cells, follicular B cells, and marginal zone (MZ) B cells alongside with significantly higher titers of total IgG and IgM antibodies at the late stage of infection. While altered splenic architecture with increased distance between white pulp regions was detectable in both strains, GC disorganization/collapse and MZ abrogation were only detected in Karp-infected spleens. To define the driving force of GC loss, we compared RNAseq profiles between spleens infected with the Karp or Gilliam strain, and found significantly upregulated inflammation biomarkers (Ccl2, Il33, Ifng) and severe scrub typhus-related inflammatory pathways (Il1, Il6, Tnf, and Ifng) in Karp infection at day 4 (D4, early stage of infection). IPA analysis further showed upregulated neutrophil degranulation and defense response pathways in Karp-infected spleens, while Gilliam-infected spleens showed upregulation of phagocytosis signaling pathways. Flow cytometry confirmed a marked influx of activated myeloid cell subsets (neutrophils, M1 macrophages, and inflammatory monocytes) in the spleen during Karp infection as compared to Gilliam infection, indicating excessive inflammatory infiltration in highly virulent Ot strain infection. Collectively, our findings establish several Ot strain-related immune signatures which help fill the knowledge gap of deficiencies in the host adaptive immune response during acute scrub typhus. Author SummaryThe intracellular bacterium O. tsutsugamushi (Ot) is the etiologic agent of the neglected tropical disease scrub typhus. It is well-known that immunity against Ot infection is short-lived, yet no in-depth studies have examined or compared adaptive immunity or deficiencies at cellular and molecular levels during acute Ot infection with clinically relevant Ot strains. In this study, we used two clinically prevalent Ot strains that cause differential diseases outcomes in the C57BL/6 murine model to examine B cell and germinal center (GC) responses. In sharp contrast to Karp infection, which caused 50% mortality rates by D12, Gilliam infection elicited self-limiting infection with low tissue splenic bacterial burdens. Yet, Gilliam-infected mice demonstrated robust humoral immune responses, as demonstrated by strong IgM and IgG antibody titers at D12 and absolute numbers of splenic B cell subsets at D8 and D12. While both Ot strains altered typical splenic white pulp architecture, only Karp infection abrogated GC and MZ structures. Comparison of RNAseq profiles of Karp-vs. Gilliam-infected spleens revealed several unique features, including Karp infection-associated upregulation of inflammation genes (Ccl2, Il33, Ifng) and inflammatory pathways (Il1, Il6, Tnf, Ifng) at D4, as well as upregulated leukocyte recruitment, neutrophil degranulation, and defense response pathways. In sharp contrast, Gilliam infection upregulated pathways involved in phagocytosis immunoregulatory interactions. Flow cytometry confirmed significant influx and activation of myeloid cell subsets (neutrophils, macrophages, M1 macrophages, monocytes) during Karp infection. Our study reveals unique patterns in the differential immune responses to two clinically prevalent Ot strains and helps understand potential mechanisms of immune alterations during severe scrub typhus.

immunology↗

bioRxiv2025

SIRT6 activator fucoidan extends healthspan and lifespan in aged wild-type mice

SIRT6 is a protein deacylase, deacetylase, and mono-ADP-ribosylase (mADPr) regulating biological pathways important for longevity including DNA repair and silencing of LINE1 retrotransposons. SIRT6 knockout mice die by 30 days of age, whereas SIRT6 overexpression increases lifespan in male mice. Finding safe pharmacological activators of SIRT6 would have clinical benefits. Fucoidan, a polysaccharide purified from brown seaweed, has been identified as an activator of SIRT6 deacetylation activity. Here, we show that fucoidan also activates SIRT6 mADPr activity, which was shown to be elevated in certain human centenarians. Administering fucoidan to aged mice led to a significant increase in median lifespan in male mice. Both male and female mice demonstrated a marked reduction in frailty and epigenetic age. Fucoidan-treated mice showed repression of LINE1 elements suggesting that the beneficial effects of fucoidan are mediated, at least in part, by SIRT6. As brown seaweed rich in fucoidan is a popular food item in South Korea and Japan, countries with the highest life expectancy, we propose that fucoidan supplementation should be explored as a safe strategy for activating SIRT6 and improving human healthspan and lifespan.

molecular biology↗

bioRxiv2025

Spatial transcriptomics elucidates the central role of cerebral vasculatures in the progression of Japanese encephalitis

The cellular and molecular mechanisms underlying the neuropathology of Japanese encephalitis virus (JEV) remain obscure. Herein, we designed Stereo-seq chips to simultaneously capture the in situ transcriptomes of both the host and JEV, constructing a comprehensive spatiotemporal pathological landscape for Japanese encephalitis (JE). This study reveals the central role of the vascular system in JE pathogenesis, particularly the meninges, which displayed the strongest signal of inflammation and cell death in the JEV-infected brain. The activation of the Ackr1+ endothelial cells, disruption of the blood-brain barrier, the migration of JEV-infected monocytes, secretion of immune factors by the infected cells, and the occurrence of pyroptosis and necroptosis form a positive feedback loop, resulting in an increasing influx of immune cells and tissue damage. JEV infection leads to neurological impairments, which may be attributed to the interaction between viral proteins and host cellular factors such as Stat1, Stat3, Nfkb1, and Sp1. As the vascular system serves as a central receiver and amplifier of inflammatory signals, regulating inflammation within the vascular system is essential in mitigating JE progression.

immunology↗

bioRxiv2025

Trained Immunity Affecting Dendritic Cell Differentiation and Function in Rheumatoid Arthritis

Rheumatoid arthritis affects [~]0.5-1% of the adult population and results in joint inflammation, chronic pain, and many systemic comorbidities. Immune and inflammatory tissue damage is the main pathogenic mechanism in rheumatoid arthritis, and involves the hyperactivation of both innate and adaptive immune systems. Trained immunity has become well established as an important feature of the innate immune system that allows the host to mount functionally altered immune responses based on their previous history of immune exposures, independently of the classical adaptive immunological memory. However, the role of trained immunity in systemic autoimmune and inflammatory disorders remains poorly understood. In the current work, we demonstrate that emergency myelopoiesis is induced in chronic rheumatoid arthritis in murine models and acts not only to enhance innate immune cell numbers but also to produce functionally altered innate immune cells. Such effects are cell-intrinsic to hematopoietic stem and progenitor cells (HSPCs) and persist independently of the inflammatory disease milieu. Importantly, these trained immunity mechanisms impact not only macrophages but also dendritic cells, which are the major antigen presenting cells that bridge the innate and adaptive immune responses. Trained dendritic cells show changes in global gene expression profiles, and significantly altered responses to recall immune stimulation and capacity for T cell activation. This study therefore represents the first demonstration of dendritic cell trained immunity in rheumatoid arthritis.

immunology↗

bioRxiv2025

Promoter-centric gene regulation in drug-resistant cancer

In eukaryotic cells, gene-distal regulatory elements (REs) facilitate long-range gene regulation, ensuring cell type-specific transcriptional programs. This mechanism is frequently disrupted in cancer, often driven by transcription factors (TFs) that serve as targets for cancer therapy. However, targeting these TFs can lead to acquired resistance mechanisms that are not fully understood. We demonstrate that mesothelioma cancer cells, dependent on the oncogenic driver TF family TEAD, develop resistance to a pan-TEAD inhibitor and revert to an evolutionarily ancient, promoter-centric gene regulatory mechanism to recover gene expression following TEAD inhibition. Base-pair-resolution 3D chromatin conformation mapping reveals that RE-promoter interactions are disrupted in resistant cells, despite epigenetic and transcriptomic recovery. Mechanistically, in resistant cells, TF complexes, including resistance-specific FOSL1 and KLF4, preferentially bind and enhance promoter activity to recover gene expression, rendering distal REs dispensable. Our findings highlight promoter elements and promoter-specific TFs as potential therapeutic targets using a model of drug-resistant cancer.

cancer biology↗

bioRxiv2025

Peroxisomal Dysfunction Drives Loss of Dynamic Nutrient Responses to Initiate Metabolic Inflexibility During Aging

Aging results in a loss of metabolic flexibility during fasting, characterized by the inability to acutely switch between metabolic substrates and reduced lipid mobilization. However, the drivers of these effects intracellularly remain unclear. Here, in Caenorhabditis elegans, we show that loss of coordinated inter-organelle dynamics causally initiates metabolic inflexibility with age. In young animals, peroxisomes emerge as the priming orchestrators of the fasting response, simultaneously governing lipid droplets (LDs) utilization and mitochondrial bioenergetics. With age, peroxisomal priming is lost, leading to mitochondrial fragmentation and impaired dynamic nutrient responses during fasting. Notably, dietary restriction (DR) exerts a rejuvenating effect on peroxisomal function, thereby preserving mitochondrial integrity and promoting longevity. Our study uncovers the expansive network of organelles enabling lipid mobilization during youth, providing critical context to the poorly understood role of peroxisomes in actively maintaining organelle homeodynamics and metabolic flexibility throughout the aging process.

cell biology↗

bioRxiv2025

Amyloid-β precursor protein promotes tumor growth by establishing an immune-exclusive tumor microenvironment

During initiation and progression, cancerous tissue hijacks a series of elaborate tissue homeostatic mechanisms to avoid immune surveillance, including neuro-immune interactions. Here, we show that amyloid-{beta} precursor protein (APP) and its {beta}-cleavage product amyloid-{beta}1-42 (A{beta}1-42), well-known in the pathogenesis of Alzheimers disease (AD), are expressed in multiple cancer tissues. However, the oncogenic activity of APP is due to its E1 domain, instead of A{beta}1-42. Mechanistically, APP restricts immune cells influx into tumor microenvironment (TME) and impairs CD8+ T cell and NK cell-based immunity, by dampening type I interferon (IFN) response in TME. We also provide proof-of-concept that vaccination targeting APP is effective for cancer prevention. Our current study reveals a previously unrecognized role of APP in cancer immune surveillance, and provides a new strategy for cancer prevention and treatment by targeting APP.

cancer biology↗

bioRxiv2025

Nonlinear Relationship Between the C-Reactive Protein to Albumin Ratio and Chronic Kidney Disease: A Cross-Sectional Analysis Using the NHANES Database

ObjectiveThe C-reactive protein to albumin ratio (CAR) has gained attention as an inflammatory biomarker with potential relevance in various diseases. However, its relationship with chronic kidney disease (CKD) remains inadequately understood. This study aims to investigate the association between CAR and CKD prevalence in a diverse, multi-ethnic U.S. cohort. MethodsThis cross-sectional analysis utilized data from the 1999-2010 National Health and Nutrition Examination Survey (NHANES). Multivariable regression and subgroup analyses were conducted to control for confounding factors and examine the link between CAR and CKD. A restrictive cubic spline model was employed to explore potential nonlinear associations. ResultsAmong 30,049 participants aged 18 years or older, 5,423 (18.05%) had CKD. Compared to the lowest quartile (Q1) of log-transformed CAR, CKD risk was higher in the second (Q2), third (Q3), and fourth (Q4) quartiles, with odds ratios of 1.28, 1.29, and 1.63, respectively. A dose-response relationship was observed, indicating that higher CAR levels were significantly associated with increased CKD risk. ConclusionElevated CAR is independently associated with a higher prevalence of CKD, suggesting its potential utility as a biomarker for CKD risk assessment in diverse populations. Further studies are needed to confirm these findings and explore underlying mechanisms.

bioinformatics↗

bioRxiv2025

Tracking mobilization uncovers an evolutionarily conserved mechanism in suppressing transpositions during somatic development

Transposon mobilizations could cause gene mutations and even genomic instability, whose aberrant activation is tightly linked with cancer, neurodegenerative disorder and other pathologies. However, the precise suppression mechanisms of transposon mobilizations during somatic development throughout evolution remain largely obscure. Here, by spatiotemporally monitoring transpositions with single-cell resolution, we determined a highly conserved mechanism in suppressing transposon mobilizations. We identified that Cramp1 safeguards the genomic integrity in both Drosophila hindgut regeneration and mouse embryonic erythropoiesis through silencing transposon mobility. Cramp1 is characterized as a major hallmark that specifically binds to the DNA sequences of histone gene cluster to initiate transcription of linker histone H1, which subsequently promotes H3K36me2-established heterochromatin for transposon silencing. Our finding highlights that with the endless arms race between hosts and transposons during evolution, the core mechanisms will also evolve to suppress transposon mobilizations during somatic development. One-sentence abstractCramp1 plays an evolutionarily conserved role in specifically initiating linker histone H1 transcription and triggering H1-H3K36me2-established heterochromatin to suppress transposon mobilizations and maintain genome integrity during somatic development.

genetics↗

bioRxiv2025

A-TWAS: An aggregated transcriptome-wide association study model incorporating multiple Bayesian priors

MotivationTranscriptome-wide association study (TWAS) is a significant methodology utilized for identifying associations between genes and diseases by integrating transcriptome and genome-wide association studies (GWAS) data. The approach has been successful in pinpointing risk genes for various diseases, including Alzheimers disease, schizophrenia, and different types of cancers. TWAS typically involves two key steps: imputation and association analysis. In the imputation step, the original PrediXcan employs the elastic-net model, while subsequent research endeavors have delved into more intricate models such as FUSION and TIGAR. Despite these advancements, the existing individual methods may not capture the intricate genotype-expression relationships in a comprehensive way. Given the complexity of genetic contributions of genotypes to gene expression, sophisticated modeling techniques are imperative. In response to this, we have introduced Aggregated-TWAS (A-TWAS), a comprehensive tool that amalgamates multiple imputation models to accommodate diverse genetic architectures. A-TWAS utilizes several continuous shrinkage priors, including Laplace, Horseshoe, and Horseshoe+, to ensure precise imputation results while incorporating the benefits of Bayesian variable selection methods. In the association phase of TWAS, we employ the aggregated Cauchy association test (ACAT) to obtain an omnibus p-value. ResultWe demonstrate the effectiveness of A-TWAS through comprehensive simulations and real data analyses. Simulation studies highlight that A-TWAS produces substantial improvements in predictive R2 and statistical power, while maintaining the type error I at a low level. Furthermore, TWASs are conducted on schizophrenia and obsessive-compulsive symptoms datasets. In comparison to standard methods, the Bayesian imputation model demonstrates superior accuracy, and A-TWAS, by integrating multiple Bayesian priors, identifies a notably greater number of disease-relevant genes. Availability and ImplementationThe source code of A-TWAS is available at https://github.com/Yilan-Liang/A-TWAS.

bioinformatics↗