Biology subjects

Su, C.

Publications and source records attributed to Su, C..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

TestNet: A Testing Method for Inferring Microbial Networks with False Discovery Rate Control, for Clustered and Unclustered Samples

Most existing methods for inferring microbial networks generate only point estimates of Pearsons correlations without assessing their significance, and none can account for clustered samples. In this article, we introduce TestNet, a novel method that delivers well calibrated results by controlling the false discovery rate (FDR). We developed a permutation-based procedure to generate valid null replicates that account for compositional effects and extensive zeros in microbiome data, and clustering structures within the samples when present. Our results demonstrate that TestNet is the only method that effectively controls the FDR while maintaining high power across a wide range of scenarios.

bioinformatics↗

bioRxiv2025

Mosaic H3K9me3 at BREACHes predicts synaptic gene expression associated with fragile X syndrome cognitive severity

Diseases vary in clinical presentation across individuals despite the same molecular diagnosis. In fragile X syndrome (FXS), mutation-length expansion of a CGG short tandem repeat (STR) in FMR1 causes reduced gene expression and FMRP loss. Nevertheless, FMR1 and FMRP are limited predictors of adaptive functioning and cognition in FXS patients, suggesting that molecular correlates of clinical measures would add diagnostic value. We recently uncovered Megabase-scale domains of heterochromatin (BREACHes) in FXS patient-derived iPSCs. Here, we identify BREACHes in FXS brain tissue (N=4) and absent from sex/age-matched neurotypical controls (N=4). BREACHes span >250 genes and exhibit patient-specific H3K9me3 variation. Using N=4 FXS iPSC lines and N=7 single-cell isogenic FXS iPSC subclones, we observe a strong correlation between inter-sample H3K9me3 variation and heterogeneous BREACH gene repression. We demonstrate improved prediction of cognitive metrics in FXS patients with an additive model of blood FMRP and mRNA levels of H3K9me3-mosaic, but not H3K9me3-invariant, BREACH genes. Our results highlight the utility of H3K9me3 variation at BREACHes for identifying genes associated with FXS clinical metrics.

genomics↗

bioRxiv2025

Resilience and vulnerabilities of tumor cells under purine shortage stress

Purine metabolism is a promising therapeutic target in cancer; however how cancer cells respond to purine shortage,particularly their adaptation and vulnerabilities, remains unclear. Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated these responses in prostate, lung and glioma cancer models. We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multi-protein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. While this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the microtubule-stabilizing chemotherapeutic drug Docetaxel. Furthermore, we show that although cancer cells primarily rely on de novo purine biosynthesis, they also exploit Methylthioadenosine Phosphorylase (MTAP)-mediated purine salvage as a crucial alternative source of purine supply, especially under purine shortage stress. In support of this finding, combining DRP-104 with an MTAP inhibitor significantly enhances tumor suppression in prostate cancer (PCa) models in vivo. Finally, despite the resilience of the purine supply machinery, purine shortage-stressed tumor cells exhibit increased DNA damage and activation of the cGAS-STING pathway, which may contribute to impaired immunoevasion and provide a molecular basis of the previously observed DRP-104-induced anti-tumor immunity. Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.

cancer biology↗

bioRxiv2025

miR-379-3p counteracts cancer cachexia through regulation of pyrimidinergic receptor, mitochondrial stress and interferon response.

Cancer cachexia is a highly prevalent wasting syndrome in cancer patients. Inflammation is hallmarks of symptomatic cachexia, however early stages of cachexia are not well understood, including differences between biological sexes. In a mouse model of early cachexia, muscle from males showed strong mitochondrial defects, whereas females were characterized by inflammatory and stress response. We demonstrate a novel link between the increase in purinergic receptor P26Y, and dysregulated Ca2+ homeostasis, mitochondrial dysfunction and damage, and inflammation during early stages of cancer cachexia. Low levels of miR-379-3p were associated with poor survival of patients with lung cancer. Restoring miR-379-3p levels in mice prevented loss of muscle mass and function. miR-379-3p targeted P2r6y and restored mitochondrial content and function, inhibited type II interferon response, and regulated the expression of Ca2+-related and apoptotic markers. This supports miR-379-3p as a hub regulating multiple processes underlying cachexia and represent a therapeutic target for cancer patients.

cancer biology↗

bioRxiv2024

Environmental DNA vs. Community Science: Strengths and Limitations for Urban Odonata Surveys

The study of insect decline remains a major frontier in insect biodiversity and conservation. Despite growing concern about accelerating rates of insect decline generally, relatively little data has been compiled about species of aquatic insects. Data is particularly lacking on the distribution of aquatic insects in urban ecosystems. Here, we compare environmental DNA (eDNA) metabarcoding and community science observation as means of monitoring Odonata within an urban system in Southwest Idaho. We show that the distribution of Odonata across this urban landscape is not uniform and that both monitoring methods have different strengths and weaknesses. We found that eDNA metabarcoding was very sensitive to the identification of genera from underrepresented families in the region, but was unable to distinguish between closely related genera, particularly from localities where eDNA could accumulate more damage. On the other hand, community science observations effectively identified the presence of genera from more speciose families but missed the presence of relatively rare species, and those that had a short flight season. These findings suggest that, in our study system, eDNA and community science are highly complementary of each other. In cases where only one method is employed for a monitoring or conservation project, care should be given to account for the biases of each approach.

ecology↗

bioRxiv2024

Data-driven inference of Boolean networks from transcriptomes to predict cellular differentiation and reprogramming

Boolean networks provide robust explainable and predictive models of cellular dynamics, especially for cellular differentiation and fate decision processes. Yet, the construction of such models is extremely challenging, as it requires integrating prior knowledge with experimental observation of transcriptome, potentially relating thousands of genes. We present a general methodology, implemented in the software tool BoNesis, for the qualitative modeling of gene regulation behind the observed state changes from transcriptome data and prior knowledge of the gene regulatory network. BoNesis allows computing ensembles of Boolean networks, where each of them is able to reproduce the modeled differentiation process. We illustrate the scalability and versatility of BoNesis with two applications: the modeling of hematopoiesis from single-cell RNA-Seq data, and modeling the differentiation of bone marrow stromal cells into adipocytes and osteoblasts from bulk RNA-seq time series data. For this later case, we took advantage of ensemble modeling to predict combinations of reprogramming factors for trans-differentiation that are robust to model uncertainties due to variations in experimental replicates and choice of binarization method. Moreover, we performed an in silico assessment of the fidelity and efficiency of the reprogramming, and conducted preliminary experimental validation.

systems biology↗

bioRxiv2024

Cell-type-specific mapping of enhancers and target genes from single-cell multimodal data

Mapping enhancers and target genes in disease-related cell types has provided critical insights into the functional mechanisms of genetic variants identified by genomewide association studies (GWAS). However, most existing analyses rely on bulk data or cultured cell lines, which may fail to identify cell-type-specific enhancers and target genes. Recently, single-cell multimodal data measuring both gene expression and chromatin accessibility within the same cells have enabled the inference of enhancer-gene pairs in a cell-type-specific and context-specific manner. However, this task is challenged by the datas high sparsity, sequencing depth variation, and the computational burden of analyzing a large number of enhancer-gene pairs. To address these challenges, we propose scMultiMap, a statistical method that infers enhancer-gene association from sparse multimodal counts using a joint latent-variable model. It adjusts for technical confounding, permits fast moment-based estimation and provides analytically derived p-values. In systematic analyses of blood and brain data, scMultiMap shows appropriate type I error control, high statistical power with greater reproducibility across independent datasets and stronger consistency with orthogonal data modalities. Meanwhile, its computational cost is less than 1% of existing methods. When applied to single-cell multimodal data from postmortem brain samples from Alzheimers disease (AD) patients and controls, scMultiMap gave the highest heritability enrichment in microglia and revealed new insights into the regulatory mechanisms of AD GWAS variants in microglia.

bioinformatics↗

bioRxiv2024

Identification and Diagnostic Potential of Pyroptosis-Related Genes in Endometriosis: A Novel Bioinformatics Analysis

ObjectiveThis study aimed to identify and analyze potential signatures of pyroptosis-related genes in EMs. MethodsTranscriptomic datasets related to endometriosis were retrieved from the GEO databases (GSE7305, GSE7307, and GSE11691). Differential gene expression analysis was performed to identify pyroptosis-related differentially expressed genes (PRDEGs) by intersecting DEGs with a curated list of PRGs. Various bioinformatics tools were employed to explore the biological functions and pathways associated with PRDEGs. ResultsWe identified 26 PRDEGs from combined datasets and constructed an EMs diagnostic model using LASSO regression based on pyroptosis scores. The model included 5 DEGs: KIF13B, BAG6, MYO5A, HEATR, and AK055981. Additionally, 21 Key Module Genes (KMGs) were identified, leading to the classification of 3 distinct EMs subtypes. These subtypes were analyzed for immune cell infiltration, revealing a complex immune landscape in EMs. ConclusionsThis study reveals pyroptosis crucial role in EMs and offers a novel diagnostic model based on pyroptosis-related genes. Modulating pyroptosis may provide a new therapeutic approach for managing EMs.

bioinformatics↗

bioRxiv2024

Evaluating Physiological Indicators in Detecting Deception using the Comparison Question Test (CQT)

Despite significant advancements in deception detection, traditional methods often fall short in real-world applications. This study addresses these limitations by evaluating the effectiveness of various physiological measures -- pupil response, electrodermal activity (EDA), heart rate (HR), and facial temperature changes -- in predicting deception using the Comparison Question Test (CQT). It also fills a critical research gap by validating these methods within an Asian context. Employing a between-subjects design, data was collected from a diverse sample of 118 participants from Singapore, including Chinese, Indian, and Malay individuals. The research aims to identify which physiological indicators, in combination, offer the most robust predictions of deceptive behavior. Key innovations include the adaptation of the CQT with a modified directed lie paradigm and an expanded sample size to assess the relative importance of each physiological measure. The studys findings reveal that pupil response is the most significant predictor of deception, with EDA enhancing the models explanatory power. HR, while relevant, adds limited value when combined with pupil response and EDA, and facial temperature changes were statistically non-significant. The study highlights the need for further research into the interactions among physiological measures and their application in varied contexts. This research contributes valuable insights into improving deception detection methodologies and sets the stage for future investigations that could incorporate additional physiological indicators and explore real-world applications.

bioengineering↗

bioRxiv2024

Variant-to-function mapping of late-onset Alzheimer's disease GWAS signals in human microglial cell models implicates RTFDC1 at the CASS4 locus

Late-onset Alzheimers disease (LOAD) research has principally focused on neurons over the years due to their known role in the production of amyloid beta plaques and neurofibrillary tangles. In contrast, recent genomic studies of LOAD have implicated microglia as culprits of the prolonged inflammation exacerbating the neurodegeneration observed in patient brains. Indeed, recent LOAD genome-wide association studies (GWAS) have reported multiple loci near genes related to microglial function, including TREM2, ABI3, and CR1. However, GWAS alone cannot pinpoint underlying causal variants or effector genes at such loci, as most signals reside in non-coding regions of the genome and could presumably confer their influence frequently via long-range regulatory interactions. We elected to carry out a combination of ATAC-seq and high-resolution promoter-focused Capture-C in two human microglial cell models (iPSC-derived microglia and HMC3) in order to physically map interactions between LOAD GWAS-implicated candidate causal variants and their corresponding putative effector genes. Notably, we observed consistent evidence that rs6024870 at the GWAS CASS4 locus contacted the promoter of nearby gene, RTFDC1. We subsequently observed a directionallly consistent decrease in RTFDC1 expression with the the protective minor A allele of rs6024870 via both luciferase assays in HMC3 cells and expression studies in primary human microglia. Through CRISPR-Cas9-mediated deletion of the putative regulatory region harboring rs6024870 in HMC3 cells, we observed increased pro-inflammatory cytokine secretion and decreased DNA double strand break repair related, at least in part, to RTFDC1 expression levels. Our variant-to-function approach therefore reveals that the rs6024870-harboring regulatory element at the LOAD CASS4 GWAS locus influences both microglial inflammatory capacity and DNA damage resolution, along with cumulative evidence implicating RTFDC1 as a novel candidate effector gene.

genetics↗

bioRxiv2024

MASTR-seq: Multiplexed Analysis of Short Tandem Repeats with sequencing

More than 60 human disorders have been linked to unstable expansion of short tandem repeat (STR) tracts. STR length and the extent of DNA methylation is linked to disease pathology and can be mosaic in a cell type-specific manner in several repeat expansion disorders. Mosaic phenomenon have been difficult to study to date due to technical bias intrinsic to repeat sequences and the need for multi-modal measurements at single-allele resolution. Nanopore long-read sequencing accurately measures STR length and DNA methylation in the same single molecule but is cost prohibitive for studies assessing a target locus across multiple experimental conditions or patient samples. Here, we describe MASTR-seq, Multiplexed Analysis of Short Tandem Repeats, for cost-effective, high-throughput, accurate, multi-modal measurements of DNA methylation and STR genotype at single-allele resolution. MASTR-seq couples long-read sequencing, Cas9-mediated target enrichment, and PCR-free multiplexed barcoding to achieve a >ten-fold increase in on-target read mapping for 8-12 pooled samples in a single MinION flow cell. We provide a detailed experimental protocol and computational tools and present evidence that MASTR-seq quantifies tract length and DNA methylation status for CGG and CAG STR loci in normal-length and mutation-length human cell lines. The MASTR-seq protocol takes approximately eight days for experiments and one additional day for data processing and analyses. Key pointsO_LIWe provide a protocol for MASTR-seq: Multiplexed Analysis of Short Tandem Repeats using Cas9-mediated target enrichment and PCR-free, multiplexed nanopore sequencing. C_LIO_LIMASTR-seq achieves a >10-fold increase in on-target read proportion for highly repetitive, technically inaccessible regions of the genome relevant for human health and disease. C_LIO_LIMASTR-seq allows for high-throughput, efficient, accurate, and cost-effective measurement of STR length and DNA methylation in the same single allele for up to 8-12 samples in parallel in one Nanopore MinION flow cell. C_LI

genomics↗

bioRxiv2024

Seeing halos: Spatial and consumer-resource constraints to landscape of fear patterns

Coral halos are algae-free space surrounding coral patches linked to the landscape of fear hypothesis, where risk-averse herbivores avoid grazing too far from coral shelter. Halo patterns thus provide insight into the state of overfished predator populations on reefs. However, halos are absent in some protected reefs and their sizes are uncorrelated with predator abundance. Here, we show that these observations are consistent with the landscape of fear hypothesis. When coral are dispersed, herbivores have more even shelter from predators across the seascape, allowing herbivores to overgraze and halos to oscillate. When coral are clustered, shelter is limited and halos can stabilize, but reducing herbivore limitation drives critical transitions to cycles that are difficult to recover from. Discordance between theory and observations may, therefore, arise from differences in underlying coral spatial distributions, with broad implications for how the landscape of fear influences pattern formation and ecological resilience in patchy ecosystems.

ecology↗

bioRxiv2024

Enhancing radiotherapy response via intratumoral injection of the TLR9 agonist CpG to stimulate CD8 T cells in an autochthonous mouse model of sarcoma

Radiation therapy is frequently used to treat cancers including soft tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to radiation therapy (RT) in transplanted tumors, but the mechanism(s) remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft tissue sarcomas with high tumor mutation burden. Treatment with a single fraction of 20 Gy RT and two doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to RT + CpG, we performed bulk RNA-seq, single-cell RNA-seq, and mass cytometry. Sarcomas treated with 20 Gy and CpG demonstrated increased CD8 T cells expressing markers associated with activation and proliferation, such as Granzyme B, Ki-67, and interferon-{gamma}. CpG + RT also upregulated antigen presentation pathways on myeloid cells. Furthermore, in sarcomas treated with CpG + RT, TCR clonality analysis suggests an increase in clonal T-cell dominance. Collectively, these findings demonstrate that RT + CpG significantly delays tumor growth in a CD8 T cell-dependent manner. These results provide a strong rationale for clinical trials evaluating CpG or other TLR9 agonists with RT in patients with soft tissue sarcoma.

cancer biology↗

bioRxiv2023

CD5L associates with IgM via the J chain

CD5 antigen-like (CD5L), also known as Sp or AIM (Apoptosis inhibitor of macrophage), emerges as an integral component of serum immunoglobulin M (IgM). However, the molecular mechanism underlying the interaction between IgM and CD5L has remained elusive. In this study, we present a cryo-electron microscopy structure of the IgM pentamer core in complex with CD5L. Our findings reveal that CD5L binds to the joining chain (J chain) in a Ca2+-dependent manner and further links to IgM via a disulfide bond. We further show that CD5L reduces IgM binding to the mucosal transport receptor pIgR, but does not impact the binding of the IgM-specific receptor FcR. Additionally, CD5L does not affect IgM-mediated complement activation. These results offer new insights into our understanding of IgM and shed light on the functions of the IgM-CD5L complex in the immune system.

biochemistry↗

bioRxiv2023

J chain dictates the recognition of IgA by FcRL4

Fc-receptor-like 4 (FcRL4) selectively recognizes systemic IgA. The cryo-electron microscopy structure of the FcRL4-Fc (IgA-Fc)-Joining (J) chain complex reveals that FcRL4 interacts with Fc-J in a 1:1 stoichiometry, with FcRL4 primarily interacting with the J chain. The binding of Fc-J to FcRL4 would hinder the binding of pIgR, but not FcRI. These findings provide new insights into IgA and emphasize significant differences between various IgA receptors.

biochemistry↗

bioRxiv2023

Circadian photoreceptor CRYPTOCHROME promotes wakefulness under short winter-like days via a GABAergic circuitry

A cardinal symptom of seasonal affective disorder (SAD, also known as winter depression) is hypersomnolence, while the cause of this "winter sleepiness" is not known. Here we found that lack of the circadian photoreceptor cryptochrome (cry) leads to increased sleep under short winter-like days in fruit flies, reminiscent of the hypersomnolence in SAD. CRY functions in neurons that synthesize the major inhibitory neurotransmitter GABA, including the small ventral lateral neurons which are known to be circadian pacemakers, and down-regulates the GABAergic tone. This in turn leads to increased neural activity of the wake-promoting large ventral lateral neurons, a subset of circadian neurons that are inhibited by GABA-A receptor. CRY protein is known to be degraded by light, thus rendering CRY to be functional within this GABAergic circuitry to enhance wakefulness only under short day length. Taken together, we demonstrate a mechanism that specifically regulates wakefulness under short winter-like days, which may provide insights regarding the winter sleepiness in SAD.

neuroscience↗

bioRxiv2023

High plasticity of ribosomal DNA organization in budding yeast

In eukaryotic genomes, ribosomal DNA (rDNA) generally resides as a highly repetitive and dynamic structure, making it difficult to study. Here, a synthetic rDNA array on chromosome III in budding yeast was constructed to serve as the sole source of rRNA. Utilizing the loxPsym site within each rDNA repeat and the Cre recombinase, we were able to reduce the copy number to as few as eight copies. Additionally, we constructed strains with two or three rDNA arrays, and found that the presence of multiple arrays did not affect the formation of a single nucleolus. Although alteration on the position and number of rDNA arrays did impact three-dimensional genome structure, the additional rDNA arrays had no deleterious influence on cell growth or transcriptomes. Together, this study sheds light on the high plasticity of rDNA organization and opens up opportunities for future rDNA engineering. HighlightsO_LIA method was established for efficient construction of synthetic rDNA arrays in budding yeast C_LIO_LIThe rDNA repeats in a haploid yeast can be reduced to as few as eight copies to support cell viability C_LIO_LIYeast cells with two or three DNA arrays on distinct chromosomes form a single nucleolus. C_LIO_LIDispersed rDNA arrays result in no deleterious influence on cell growth or transcriptomes. C_LI

synthetic biology↗

bioRxiv2023

A Quadrivalent mRNA immunization elicits potent immune responses against vaccinia and monkeypox viral antigens - a step closer to a broad orthopoxvirus vaccine

The global outbreak of the 2022 monkeypox virus infection of human raised the public health concerns of the threat of human-to-human transmission of zoonotic diseases. Given the evidence that other orthopoxviruses including cowpox and camelpox were also reported infectious to human, and that the reemerging risk of smallpox as a bioterrorist or accidental laboratory escape exists, there is an urgent need to develop a poxvirus vaccine with a broad protection of orthopoxviruses to stockpile for future emergency. Extensive studies of vaccinia virus (VACV) suggested that multiple VACV antigens, such as A27, L1, A33 and B5, showed high level similarity in terms of immunogenicity to their respective homologous antigens of other orthopoxviruses. These findings paved the ground for VACV antigens to be used as potential vaccine targets for development of a universal poxvirus vaccine. In this study, we construct a novel poxvirus vaccine candidate, mRNA-ALAB-LNP, encoding four vaccinia viral antigens A27, L1, A33 and B5. Strong anti-L1-specific antibody and moderate anti-A33-, anti-A27- and anti-B5-specific antibody responses were induced in mice after a single immunization. The antibody responses to all four antigens were significantly boosted after the second shot with all IgG titers >5 logs and highest being anti-A33 IgG. The high level of binding antibodies showed potent neutralizing capability against vaccinia virus. Specific IFN-{gamma} responses were detected to all four antigens with the highest cellular response being that induced by the same antigen, A33. When evaluating the cross reactivity, equivalent or better serum IgG responses were seen in responses to corresponding monkeypox antigens A35, M1, A29 and B6, in comparison to vaccinia antigens. Apparently, the mRNA vaccine encoding four vaccinia antigens induced immunity not only to vaccinia virus but also to monkeypox, suggesting that the mRNA-ALAB may be a candidate for potential vaccine development against infection of monkeypox, smallpox and possibly other orthopoxviruses.

immunology↗