Biology subjects

Lee, S. C.

Publications and source records attributed to Lee, S. C..

At least 19 recordsLinked to original sources

bioRxiv2026

Lactation Remodels the Maternal Lung to Promote Preemptive Innate Defense

Lactation is a hallmark of mammalian evolution, imposing extraordinary physiological demands on mothers to nourish their offspring. Yet how mothers maintain their own health while meeting these demands remains poorly understood. Here, we discover that lactation establishes a preemptive innate defense program in the maternal lung through enhanced epithelial production of surfactant proteins and mucin, vascular remodeling that supports granulocyte recruitment and accumulation of activated intravascular neutrophils. These tissue-wide adaptations safeguard lactating dams against diverse respiratory pathogens. We further identify prolactin and CGRP as neuroendocrine signals contributing to pulmonary remodeling and uncover parallel lactation-associated granulocyte adaptations in marsupial and non-human primate models. Together, our findings expand the framework of reproductive immunology, revealing that reproduction couples systemic fetal tolerance with tissue-specific immune adaptations that safeguard maternal health during lactation.

immunology↗

bioRxiv2026

Clonally expanded CD8 T cells in AML adopt an NK-like program distinct from canonical exhaustion

CD8 T cells are key mediators of anti-tumor immunity, yet their differentiation states and clonal architecture within the acute myeloid leukemia (AML) bone marrow microenvironment remain incompletely defined. We performed high dimensional immune profiling of bone marrow samples from 46 newly diagnosed AML patients using mass cytometry to probe the microenvironment and T cell states. We used single-cell RNA and T cell receptor (TCR) sequencing to define CD8 T cell phenotypes, transcriptional states, and clonal architecture. AML-associated CD8 T cells were skewed toward terminally differentiated effector memory cells re-expressing CD45RA (TEMRAs), while canonically exhausted T cell populations were rare. Functional studies revealed that TEMRA CD8 T cells robustly produced IFN{gamma} and TNF upon in vitro stimulation. Clonal expansion was concentrated within the TEMRA compartment. Comparison of TCR sequences with known viral epitopes identified a small subset of expanded viral-specific clonotypes, while the majority of highly expanded clonotypes had unknown specificity and may include AML-specific T cells. Differential gene expression analysis revealed shared cytotoxic effector programs during clonal expansion but diverging activation signatures: viral-specific clones upregulated canonical T cell receptor signaling genes, whereas expanded clones of unknown specificity exhibited enrichment of natural killer (NK) receptor-associated genes. These genes comprised the leukemia-associated NK-immune (LaNKi) score which was elevated in an independent AML dataset compared to pan cancer tumor infiltrating lymphocytes. These findings define the CD8 T cell differentiation landscape and clonal architecture in AML marrow at diagnosis and suggest that T cell dysfunction in AML diverges from classical activation and exhaustion paradigms.

cancer biology↗

bioRxiv2026

Cancer stem cell transcriptomic signatures reveal patient-to-patient heterogeneity emphasizing the need for patient-specific ovarian cancer targets

Background/Objectives: In high-grade serous ovarian cancer (HGSOC), the abilities of tumor cells to resist cytotoxic treatment and relapse are largely driven by ovarian cancer stem cells (CSCs). CSCs are a population of cells within a tumor that maintain stem-like qualities and have the capacity to produce metastasis and drive drug resistance. Based on the complexity of CSC signaling and emerging evidence of differential isoform usage in development, we hypothesize that CSCs possess a patient-specific, heterogeneous landscape which exploits isoform diversity to sustain stemness, metastasis and drug resistance. Methods: RNA-seq was generated from 3 patient-derived HGSOC (PD-HGSOC) to investigate stemness and differentiation status comparing standard culture and CSCs. The data was analyzed at both gene- and isoform-levels to identify patient-specific CSC features and define mechanisms of cancer-related stemness and plasticity. Results: CSCs exhibited higher stemness characteristics and identified differentially expressed gene sets across PD-HGSOCs. We noted that each patient had a distinct subset of genes regulating stemness phenotypes which suggested multiple mechanisms of CSC development and maintenance. Additionally, a large proportion of gene-level expression changes were driven by the differential expression of a single predominant isoform. Importantly, our isoform-level analysis enabled the identification of differential isoform usage that would not be detected with gene level expression analysis. Conclusions: CSC phenotypes such as chemoresistance, metastasis and self-renewal are conserved across patients, but arise from largely patient-specific gene and isoform programs. This CSC heterogeneity is reflective of the heterogeneity seen in patients and should be further evaluated in deriving precision-medicine approaches for HGSOC.

cancer biology↗

bioRxiv2026

Somatic DDX41 mutations confer neomorphic splicing activity in the pathogenesis of myelodysplastic neoplasms

Germline mutations in the RNA helicase DDX41 are the most common genetic predisposition to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), representing 5-7% of AML. Over 70% of patients acquire a somatic mutation at specific hotspots (R525H/G530D) in the helicase domain of DDX41 in trans, which is linked to disease progression. DDX41 has diverse cellular functions, including RNA splicing, ribosome biogenesis, R-loop resolution and inflammation. However, the mechanisms by which somatic DDX41 mutations drive MDS/AML pathogenesis are yet to be determined. Here, we systematically evaluated the function of pathogenic, missense germline and somatic DDX41 mutations. We report that DDX41 somatic mutations are gain of function alleles and fail to rescue AML cell growth, distinct from germline DDX41 mutations. DDX41 somatic mutations R525H and G530D drive widespread splicing changes in isogenic AML cell lines, consistent in genetically engineered murine bone marrow HSPCs and CD34+ cells from DDX41-mutant MDS/AML patients. Mechanistically, DDX41-R525H exhibits increased RNA binding affinity compared to wildtype, with aberrantly spliced RNA targets overlapping with enriched binding. Strikingly, aberrant splicing of SEPTIN7 is enriched exclusively in CD34+ HSPCs of patients harboring both germline and somatic DDX41 mutations but absent in samples with germline mutation alone or lacking DDX41 mutations altogether. SEPTIN7 mis-splicing introduces a premature stop codon resulting in its downregulation at the protein level. SEPTIN7 is a known regulator of cytokinesis, HSC polarity and repopulation capacity. Our results identify a novel mis-spliced candidate, SEPTIN7, whose deregulation implicates a mechanism by which the DDX41 somatic mutations promote dysplastic hematopoiesis.

cancer biology↗

bioRxiv2026

Characterization of tRNA ligase function in pathogenic fungi and trypanosomes reveals the ligase domain as a promising drug target

The majority of eukaryotes encode some intron-containing pre-tRNAs. Splicing of these pre-tRNAs requires a dedicated tRNA splicing machinery. The fungal and trypanosome tRNA ligase, Trl1, and the human RNA ligase, RTCB, catalyze an essential step in tRNA splicing. However, Trl1 and RTCB are nonhomologous and biochemically and structurally distinct from each other. Therefore, Trl1 could serve as a broad-spectrum antifungal and anti-trypanosomal target. While the functions and requirements of the three catalytic Trl1 domains have been extensively characterized in the model yeast Saccharomyces cerevisiae, the roles of Trl1 orthologs in pathogenic fungi remain unexplored. Here, we validate Trl1 as one of the few promising novel drug targets for the development of antifungal therapeutics. Functional analyses of the three Trl1 domains show that only the "sealing" domain is essential for growth and viability in Candida albicans and Aspergillus fumigatus. In contrast, the two "healing" domains are dispensable in these pathogenic fungi, suggesting the presence of redundant healing enzymes, unlike in S. cerevisiae. These findings indicate that only the sealing domain is a good drug target. Our analysis also shows that the Mucor enzyme, which only contains the sealing domain, is essential. Using a Caenorhabditis elegans infection model of C. albicans, we further demonstrated that inhibiting Trl1 expression protects worms during an established infection. In contrast to these fungal pathogens, we show that all three domains of Trl1 are essential in Trypanosoma brucei. Our findings show that the essentiality of the Trl1 sealing is conserved in important human pathogens and provides an impetus for future drug development. SIGNIFICANCEFungal infections are an important cause of human disease and death and difficult to treat and there is an urgent need to develop additional drugs. Based on studies in yeast, one promising target for antifungal drug development is the tRNA splicing pathway. Human tRNA ligase is fundamentally distinct from the fungal one. To investigate the possibility of developing tRNA ligase-targeting drugs, we investigated the function of the catalytic domains of fungal tRNA ligase in different fungal pathogens. Surprisingly, only the first domain is essential in these pathogens and yeast is not a good model fungus. In contrast, all three domains of Trypanosome tRNA ligase are essential. These findings provide an impetus for future drug development.

molecular biology↗

bioRxiv2025

MDS-associated SF3B1 mutations promote aberrant fate choice of hematopoietic stem cell via mis-splicing of mediator kinase module component CDK8

Mutations in RNA splicing factor SF3B1 are among the most common in MDS and are strongly associated with MDS with ring sideroblasts (MDS-RS). While aberrant splicing of terminal erythroid regulators has been implicated in MDS pathogenesis, the impact of SF3B1 mutations on early hematopoietic progenitor function remains unclear. Here, we identify CDK8, a key kinase of the mediator complex involved in transcriptional regulation, as a recurrent mis-spliced target in SF3B1-mutant MDS. Mutant SF3B1 induces cryptic 3' splice site selection in CDK8, leading to loss of CDK8 mRNA and protein. Using primary human HSPCs, our study identifies CDK8 as an important regulator of HSPC homeostasis and cell fate determination. CDK8 depletion results in expansion of HSPCs and shifts differentiation toward the erythroid and myeloid lineages, mirroring phenotypes observed in SF3B1-mutant MDS. Lastly, functional restoration of CDK8 rescues early erythroid phenotypes in SF3B1-mutant cells. These findings implicate CDK8 mis-splicing as a mechanistic driver of altered progenitor fate and dysplasia in SF3B1-mutant MDS, linking aberrant splicing to transcriptional dysregulation and hematopoietic lineage commitment.

cancer biology↗

bioRxiv2025

Comparing phenotypic manifolds with Kompot: Detecting differential abundance and gene expression at single-cell resolution

Single-cell studies are frequently designed to compare across conditions such as health and disease. However, existing computational approaches typically rely on grouping cells into discrete populations before making comparisons, which can limit resolution for detecting state-dependent changes. Here, we introduce Kompot, a statistical framework for comparative analysis of multi-condition single-cell data. Kompot quantifies both differential abundance, capturing how cells redistribute across the phenotypic space, and differential expression, identifying condition-specific transcriptional changes that may be localized, heterogeneous, or oppositely regulated across states. By modeling cell density and gene expression as continuous functions over a shared cell-state representation, Kompot enables single-cell resolution inference with principled uncertainty estimates, without requiring predefined clusters or cell types. Applying Kompot to aging murine bone marrow, we identified a continuum of shifts in hematopoietic stem cell and mature cell states, transcriptional remodeling of monocytes independent of compositional changes, and divergent regulation of oxidative stress response genes across cell types. We demonstrate the utility of Kompot in disease settings by identifying cell-state and gene expression changes associated with improved efficacy of combinatorial immunotherapy in melanoma. Additionally, Kompot enables multi-sample comparative analysis by accounting for sample-to-sample heterogeneity. By capturing both global and cell-state-specific effects of perturbation, the Kompot framework is broadly applicable to dissecting condition-specific effects in complex single-cell landscapes.

bioinformatics↗

bioRxiv2024

IdentifiHR: predicting homologous recombination deficiency in high-grade serous ovarian carcinoma using gene expression

BackgroundApproximately half of all high-grade serous ovarian carcinomas (HGSCs) have a therapeutically targetable defect in the homologous recombination (HR) DNA repair mechanism. While there are genomic and transcriptomic methods, developed for other cancer types, to identify HR deficient (HRD) samples, there are no gene expression-based tools to predict HR repair status in HGSC specifically. We have built the first HGSC-specific model to predict HR repair status using gene expression. MethodsWe separated The Cancer Genome Atlas (TCGA) cohort of HGSCs (n = 361) into training (n = 288) and testing (n = 73) sets and labelled each case as HRD or HR proficient (HRP) based on the clinical standard for classification, being a score of HRD genomic damage. Using the training set, we performed differential gene expression analysis between HRD and HRP cases. The 2604 significantly differentially expressed genes were then used to tune and train a penalised logistic regression model. ResultsIdentifiHR is an elastic net penalised logistic regression model that uses the expression of 209 genes to predict HR status in HGSC. These genes capture known regions of HR-specific copy number alteration, which impact gene expression levels, and preserve the genomic damage signal. IdentifiHR has an accuracy of 85% in the TCGA test set and of 91% in an independent cohort of 99 samples, collected from primary tumours before (n = 74/99) and after autopsy (n = 6/99), in addition to ascites (n = 12/99) and normal fallopian tube samples (n = 7/99). Further, IdentifiHR is 84% accurate in pseudobulked single-cell HGSC sequencing from 37 patients and outperforms existing gene expression-based methods to predict HR status, being BRCAness, MutliscaleHRD and expHRD. ConclusionsIdentifiHR is an accurate model to predict HR status in HGSC using gene expression alone, that is available as an R package from https://github.com/DavidsonGroup/IdentifiHR.

cancer biology↗

bioRxiv2024

hoodscanR: profiling single-cell neighborhoods in spatial transcriptomics data

Understanding complex cellular niches and neighborhoods have provided new insights into tissue biology. Thus, accurate neighborhood identification is crucial, yet existing methodologies often struggle to detect informative neighborhoods and generate cell-specific neighborhood profiles. To address these limitations, we developed hoodscanR, a Bioconductor package designed for neighborhood identification and downstream analyses using spatial data. Applying hoodscanR to breast and lung cancer datasets, we showcase its efficacy in conducting detailed neighborhood analyses and identify subtle transcriptional changes in tumor cells from different neighborhoods. Such analyses can help researchers gain valuable insights into disease mechanisms and potential therapeutic targets.

bioinformatics↗

bioRxiv2024

The amino acid permease Byc1 is involved in calcineurin-dependent thermos-tolerance in Cryptococcus neoformans

Cryptococcosis is one of the most serious infectious fungal diseases. It is known to infect the human respiratory tract and central nervous system and cause meningitis and encephalitis, especially in patients with AIDS. In the sub-Saharan area, cryptococcosis causes more mortality than tuberculosis. Cryptococcus neoformans is the etiological agent. There has been a growing number of reports of antifungal resistance in C. neoformans, and this fungus is also primarily resistant to the newest antifungal drug class, the echinocandins. Despite advances in modern medicine, the morbidity and mortality of C. neoformans infections remain unacceptably high. In C. neoformans, calcineurin, a serine/threonine phosphatase, is required for growth at the human host temperature, and calcineurin mutants are not virulent in murine models of cryptococcal meningitis. Therefore, calcineurin has long been considered an antifungal target. However, calcineurin is highly conserved in fungi and humans, and thus direct pharmacological inhibition of calcineurin can risk lowering host immunity as the human calcineurin is required for T-cell responses. A previous study demonstrated that there is a link between calcineurin, an amino acid permease, and protein kinase As in Mucorales. In this study, we further reveal the existence of a novel link between calcineurin and an amino acid permease, Byc1, for a thermo-tolerance phenotype in this fungus. We found that calcineurin negatively regulates the expression of the BYC1 gene and that byc1{Delta} mutants are partially resistant to FK506. Moreover, we revealed that overexpression of the BYC1 gene recapitulates the calcineurin mutants thermos-sensitive phenotypes, including FK506 sensitivity and lowered virulence in a murine infection model. We also found that protein kinase A (Pka1) mutants are also partially resistant to FK506. These results support the link between calcineurin, Byc1, and Pka1 in C. neoformans and will serve as a platform for developing novel antifungal drugs against the calcineurin pathway without directly targeting the phosphatase.

microbiology↗

bioRxiv2023

Clinicopathologic Dissociation: Robust Lafora Body Accumulation in Malin KO Mice Without Observable Changes in Home-cage Behavior

Lafora Disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD, as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, [~]6-7 months and [~]12 months of age, malin deficient mice ("KO") and wild type (WT) littermates underwent a standardized home-cage behavioral assessment designed to non-obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion and voluntary wheel-running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across timepoints, we identified age-related nocturnal hypoactivity, diminished sucrose preference and reduced wheel-running. Neuropathological examinations in subsets of the same mice revealed expected age dependent LB accumulation, gliosis and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. Using an in vitro assay of neocortical function, paroxysmal increases in network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but were similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced post-ictal suppression of movement, feeding and drinking behavior. Together, these results highlight a stark clinicopathologic dissociation in a mouse model of LD, where LBs accrue substantially without clinically meaningful changes in overall wellbeing. Our findings allude to a delay between LB accumulation and neurobehavioral decline: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse.

neuroscience↗

bioRxiv2023

Expanding the Cell-Free Reporter Protein Toolbox by Employing a Split mNeonGreen System to Reduce Protein Synthesis Workload

The cell-free system offers potential advantages in biosensor applications, but their limited substrate supply poses a challenge in balancing enough sensing resources to detect low limits of analyte while providing a robust output signal. In this study, we harnessed split versions of fluorescent proteins, particularly split super-folder green fluorescent protein and mNeonGreen, to improve energy efficiency and enhance detection limit in the cell-free system. A comparative analysis of the expression of 1-10 and eleventh segments of beta strands in both whole-cell and cell-free platforms revealed distinct fluorescence patterns. Moreover, integrating SynZip peptide linkers substantially improved complementation, achieving a fluorescence intensity reaching 73.6% of the full-length protein and a 4.8-fold increase in expression compared to the split system without the SynZip peptide linkers. The split protein reporter system can enable energy-efficient sensing of low analyte levels in the cell-free system, broadening the toolbox of cell-free biosensor repertoire.

synthetic biology↗

bioRxiv2023

Chromatin remodeling of histone H3 variants underlies epigenetic inheritance of DNA methylation

Epigenetic inheritance refers to the faithful replication of DNA methylation and histone modification independent of DNA sequence. Nucleosomes block access to DNA methyltransferases, unless they are remodeled by DECREASE IN DNA METHYLATION1 (DDM1Lsh/HELLS), a Snf2-like master regulator of epigenetic inheritance. We show that DDM1 activity results in replacement of the transcriptional histone variant H3.3 for the replicative variant H3.1 during the cell cycle. In ddm1 mutants, DNA methylation can be restored by loss of the H3.3 chaperone HIRA, while the H3.1 chaperone CAF-1 becomes essential. The single-particle cryo-EM structure at 3.2 [A] of DDM1 with a variant nucleosome reveals direct engagement at SHL2 with histone H3.3 at or near variant residues required for assembly, as well as with the deacetylated H4 tail. An N-terminal autoinhibitory domain binds H2A variants to allow remodeling, while a disulfide bond in the helicase domain is essential for activity in vivo and in vitro. We show that differential remodeling of H3 and H2A variants in vitro reflects preferential deposition in vivo. DDM1 co-localizes with H3.1 and H3.3 during the cell cycle, and with the DNA methyltransferase MET1Dnmt1. DDM1 localization to the chromosome is blocked by H4K16 acetylation, which accumulates at DDM1 targets in ddm1 mutants, as does the sperm cell specific H3.3 variant MGH3 in pollen, which acts as a placeholder nucleosome in the germline and contributes to epigenetic inheritance.

molecular biology↗

bioRxiv2023

Darapladib, an inhibitor of Lp-PLA2, sensitizes cancer cells to ferroptosis by remodeling lipid metabolism

Arachidonic and adrenic acids in the membrane play key roles in ferroptosis, but how these fatty acids are manipulated in cells is largely unknown. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen identified that darapladib (SB-480848), an inhibitor of Lp-PLA2, synergistically induced ferroptosis with GPX4 inhibitors. Notably, darapladib was able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, Lp-PLA2 was located in the membrane and cytoplasm and suppressed ferroptosis, suggesting the critical role of intracellular Lp-PLA2. Lipidomic analysis showed that phosphatidylethanolamine (PE) species were generally enriched, while lysophosphatidylethanolamine (lysoPE) and free fatty acid levels were reduced, upon darapladib treatment. Finally, combination treatment with darapladib and PACMA31, a GPX4 inhibitor, efficiently inhibited tumor growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment.

cancer biology↗

bioRxiv2023

Genetic and Environmental interactions contribute to immune variation in rewilded mice

The relative and synergistic contributions of genetics and environment to inter-individual immune response variation remain unclear, despite its implications for understanding both evolutionary biology and medicine. Here, we quantify interactive effects of genotype and environment on immune traits by investigating three inbred mouse strains rewilded in an outdoor enclosure and infected with the parasite, Trichuris muris. Whereas cytokine response heterogeneity was primarily driven by genotype, cellular composition heterogeneity was shaped by interactions between genotype and environment. Notably, genetic differences under laboratory conditions can be decreased following rewilding, and variation in T cell markers are more driven by genetics, whereas B cell markers are driven more by environment. Importantly, variation in worm burden is associated with measures of immune variation, as well as genetics and environment. These results indicate that nonheritable influences interact with genetic factors to shape immune variation, with synergistic impacts on the deployment and evolution of defense mechanisms.

immunology↗

bioRxiv2022

Exploring the Neoantigen burden in Breast Carcinoma Patients

In this study we performed a multi-omics analysis comprising whole-exome sequencing (WES) and RNA sequencing (RNA-Seq) on seven breast cancer patients, consisting of three Estrogen receptor (ER) positive and four Triple negative breast cancer (TNBC) subtypes to understand the neoantigen burden in breast cancer tumor samples. We predicted both class-I and class-II human leukocyte antigen (HLA) bound neoantigens by analyzing matched tumor-normal pair of exomes. Across all the patients, we predicted 434 unique neoantigens (NeoFil) in total, affecting 237 different genes and 87% of them (n = 378) are expressed at RNA level (Neoexp). The missense mutations (87%) are the major contributor in neoantigen (Neoexp) generation, followed by frameshift (11%) and indels (2%). The neoantigens (NeoFil) were found to be positively correlated with the somatic mutations (R2 = 0.89). We also noted that the vast majority (99.98%) of the predicted neoantigens are patient specific. Overall, the current study offers significant insight into the neoantigen profile in tumor types with intermediate/low mutation burdens like breast cancer.

cancer biology↗

bioRxiv2022

On the Mental Status of Stargazer Mice

In many childhood-onset genetic epilepsies, seizures are accompanied by neurobehavioral impairments and motor disability. In the Stargazer mutant mouse, genetic disruptions of Cacng2 result in absence-like spike-wave seizures, cerebellar gait ataxia and vestibular dysfunction. Here, we combine videotracking and instrumented home-cage monitoring to resolve the neurobehavioral facets of the murine Stargazer syndrome. We find that despite their gait ataxia, stargazer mutants display horizontal hyperactivity and variable rates of repetitive circling behavior. While feeding rhythms, circadian or ultradian oscillations in activity are unchanged, mutants exhibit fragmented sleep bouts, atypical licking dynamics and lowered sucrose preference. Mutants also display an attenuated response to visual and auditory home-cage perturbations, together with profound reductions in voluntary wheel-running. Our results reveal that the seizures and ataxia of Stargazer mutants occur in the context of a more pervasive behavioral syndrome with elements of encephalopathy, repetitive behavior and anhedonia. These findings expand our understanding of the function of Cacng2/CACNG2, variants in which have been identified in patients with bipolar disorder and schizophrenia.

neuroscience↗

bioRxiv2022

Clostridia isolated from helminth-colonized humans promote hatching of Trichuris muris

Soil transmitted intestinal worms known as helminths colonize over 1.5 billion people worldwide. Although helminth colonization has been associated with altered composition of the gut microbiota, such as increases in Clostridia, individual species have not been isolated and characterized. Here, we isolated and sequenced the genome of 13 Clostridia from the Orang Asli, an indigenous population in Malaysia with high prevalence of helminth infections. Metagenomic analysis of 650 fecal samples from urban and rural Malaysians revealed higher prevalence and abundance of these isolates compared to individuals in the United States, with Peptostreptococcaceae family members displaying a specific association with helminth colonization. Remarkably, Peptostreptococcaceae isolated from the Orang Asli displayed superior capacity to induce hatching of eggs from the murine helminth Trichuris muris. These findings support a model in which helminths select for gut colonization of microbes that in turn support their life cycle by promoting egg hatching.

microbiology↗