Biology subjects

Rai, A.

Publications and source records attributed to Rai, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Metabolic and transcriptional responses reveal co-option of symbiotic processes during early soybean-soybean cyst nematode interaction

The biochemical mechanisms by which virulent populations of soybean cyst nematode (Heterodera glycines, SCN) overcome host resistance are critical to understanding this economically important pathogen. Here, we deployed metabolic and transcriptome profiling of soybean roots during the SCN infection and establishment process to investigate the molecular and biochemical mechanisms of pathogen establishment. Across samples from a time series spanning nematode invasion to syncytium maturation, we demonstrate that compatible SCN infection does not bypass host immunity but systematically remodels it. In a compatible interaction between soybean carrying the high-copy Rhg1 resistance locus challenged with HG Type 2.5.7 SCN virulent on this host, we identify a 72-metabolite defense signature spanning isoflavonoids, triterpenoid saponins, and phenylpropanoids that persist across all infection stages. Despite activation of this metabolic defense signature by the pathogen on infection, defense transcription is near silence by 3 days post-infection, while defense metabolites persist, revealing a critical decoupling of transcriptional and metabolic defense programs at the precise window of syncytium initiation. Suppression of phenylpropanoid accumulation occurs downstream of PAL transcription, indicating a block at the metabolic level invisible to transcriptomics alone. By 5 days post-infection, cytokinin accumulation coincides with nodulin gene induction and phospholipid remodeling consistent with activation of the legume symbiosis program during syncytium maturation. Together, these findings establish that compatibility arises not from failed recognition but from progressive immune dismantling, including suppression of defense chemistry and co-option of the legume-rhizobium symbiosis machinery.

plant biology↗

bioRxiv2026

Depth-resolved analysis reveals target-dependent cryo-FIB damage profiles

Cryogenic focused ion beam (cryo-FIB) milling enables cellular cryo-electron tomography but can compromise high-resolution structural information near milled surfaces. Here we establish recombinant human apoferritin (apoF) as a reporter of depth-dependent structural preservation in cellular lamellae. ApoF yielded a 2.05 [A] in situ reconstruction. Apparent FIB damage was most pronounced within the first 15 nm for xenon, 30 nm for gallium, 45 nm for argon and remained detectable at least 75 nm from oxygen-milled surfaces under the workflows tested. Endogenous 70S ribosomes in the same xenon-milled tomograms showed a broader 30-45 nm profile, whereas {beta}-galactosidase showed a similar narrow xenon-associated profile in a different specimen. Xenon-milled lamellae 125-150 nm thick yielded the highest resolution among the thickness groups examined, with lower resolution in the thinner and thickest groups. These findings show structural preservation is constrained by both surface-associated damage and lamella thickness, with the apparent extent of damage varying by molecular reporter. Previous ribosome-based surface-exclusion estimates may therefore be overly conservative for some molecular targets.

molecular biology↗

bioRxiv2026

Unravelling the role of IRX4 variants in non-syndromic and Down syndrome associated congenital heart disease

IRX4 is a TALE- homeodomain transcription factor which is essential for cardiac development. In murine models, Irx4 deficiency leads to impaired ventricular function and results in cardiomyopathy. To elucidate the role of IRX4 in human congenital heart disease (CHD), Sanger sequencing of the IRX4 gene was performed in 205 individuals with non-syndromic CHD, 24 Down syndrome (DS) cases with CHD, 27 DS cases without CHD, and 150 healthy control individuals. Two novel (p.Ser24Asn and p.Thr217Iso) and one reported variant (rs2232376) were identified in non-syndromic CHD. Concurrently, rs2232376 was also detected in DS with CHD. The first novel (p.Ser24Asn) and reported (rs2232376) variants lie in the N-terminal region while the second novel (Thr217Iso) variant lies within the TALE homeodomain. In silico structural modelling suggested that both the novel variants (p.Ser24Asn and Thr217Iso) induce conformational changes in the IRX4 protein, potentially altering its DNA-binding affinity. A significant reduced expression of IRX4 muteins was noted in Western blotting by both variants (p.Ser24Asn and Thr217Iso). Furthermore, luciferase reporter assays demonstrated decline in the activity of Nanog promoter and HEY2 enhancer in response to both the variants which was further corroborated by decrease mRNA expression in qRT-PCR. Additional downstream targets, including Nfyc, Nppa, and Bmp10, also exhibited anomalous expression due to both the variants (p.Ser24Asn and Thr217Iso). Altogether, the aberrant expression of muteins as well as downstream target genes along with compromised activities of promoters substantiate the pathogenic potential of the identified IRX4 variants and underscore the critical role of IRX4 in regulating multiple stages of cardiogenesis.

genetics↗

bioRxiv2026

The filopodial scaffold polyphosphate dictates cell adhesion-versus-invasion decisions

Inorganic polyphosphate (polyP) is an ancient polymer conserved across all life, serving cell type and location specific functions in every major compartment. Yet its role at the plasma membrane, where it accumulates to peak levels in many primary cells, is largely unknown. Here we identify polyP as a stabilizing component of filopodia, actin based membrane protrusions that govern cell adhesion, contact inhibition, and chemotaxis. Elevating cellular polyP increases filopodial stability and enhances cell adhesion, whereas reducing polyP accelerates filopodial disassembly and promotes cell migration. Mechanistically, we find that polyP acts as a structural filopodial scaffold, recruiting and organizing IRSp53, a membrane curvature inducing protein. We show that metastatic fibroblasts and breast cancer organoids carry markedly reduced and intracellularly reorganized polyP levels relative to their non transformed counterparts. Restoring endogenous polyP via lipid nanoparticle delivery suppresses their invasive phenotypes and reverses prometastatic gene expression signatures, implicating polyP as a primordial tumor suppressor.

cell biology↗

bioRxiv2026

CpG methylation and methionine metabolism account for phenotypic bifurcation of HIV transcription: a unique case of a pure epigenetic phenomenon

HIV transcription is characterized by its stochastic nature, which plays a pivotal role in determining the fate of a provirus--active replication or latent infection--and is therefore a critical determinant of the HIV latency establishment. Building upon our previous work, we identified a unique phenotype of stochastic HIV transcription in a Jurkat T cell clonal model harboring a single lentiviral-based vector, herein referred to as the HIV transcription-sensitized model. A defining feature of this cellular model is that the turnover of HIV transcription shows elevated frequency--a phenomenon designated phenotypic bifurcation--suggesting that, under certain conditions, the regulation of stochastic HIV transcription can be a pure epigenetic phenomenon. In continuation of and to further substantiate this premise, the present study characterizes the contributions of epigenetic regulation of CpG methylation, methionine metabolism that coordinates cell cycle events, and HIV antisense transcription to this phenomenon. This work adds direct causal evidence to the hypothesis that a potential lag prior to the entry of the G2 phase in the bifurcated state of low HIV transcription may serve as one of the underlying mechanisms that lead to the high CpG methylation level compared with that measured in the state of high HIV transcription, contributing to the cyclical turnover of phenotypic bifurcation of HIV transcription.

microbiology↗

bioRxiv2026

Microtubule Engagement by the WD40-Containing Tail of Kinesin-4 KIF21B

Kinesin tails are structurally diverse and mediate a range of functions, including autoinhibition, cargo binding, and microtubule regulation. Within the kinesin-4 family, KIF21A and KIF21B have emerged as key regulators of microtubule network organization and dynamics in neurons and immune cells, yet the molecular basis of this activity has remained unclear. Here, we combined single-particle cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) to examine how the KIF21B tail engages microtubules. We find that conserved residues in the WD40 {beta}-propeller and an adjacent N-terminal linker contact successive tubulin dimers along a single protofilament, forming an extended longitudinal binding mode that spans both the intradimer and interdimer interfaces. Cryo-EM 3D classification further revealed two distinct engagement states, a tilted state, in which the {beta}-propeller makes partial contacts with the microtubule while the linker remains anchored, and a flat state, in which the {beta}-propeller lies flush with the lattice surface. Cryo-ET of full-length KIF21B reveals multiple binding configurations on the microtubule lattice, including orientations consistent with crosslinking adjacent microtubules. Together, these findings provide a structural framework for tail-mediated microtubule attachment by a neuronal kinesin-4 and suggest how its distinctive WD40 domain may contribute to microtubule regulation and organization of microtubule arrays.

biochemistry↗

bioRxiv2026

BGC-QDR: A Quantum-Assisted Pipeline for Biosynthetic Gene Cluster Discovery and Ranking from Environmental DNA

Biosynthetic gene clusters (BGCs) encode enzymatic pathways for natural products with pharmaceutical potential, yet prioritizing candidates from fragmented environmental DNA (eDNA) assemblies remains computationally challenging. We present BGC-QDR (Biosynthetic Gene Cluster Quantum Discovery and Ranking), an open-source pipeline that integrates input quality control, Prodigal ORF prediction, Pfam HMM domain annotation, rule-based BGC classification, MiBIG 4.0 novelty assessment, and variational quantum classifier (VQC) ranking via PennyLane. BGC-QDR is designed as a quantum-assisted ranking framework for biologically informed BGC prioritization, not as a claim of quantum computational advantage over classical machine learning. We evaluate the pipeline on MiBIG 4.0 (2,636 annotated BGCs) using a 20-dimensional biosynthetic feature vector and stratified 10-fold cross-validation. The integrated VQC (6 qubits x 3 layers, 54 parameters) achieves accuracy of 0.789 {+/-} 0.076 and ROC-AUC of 0.835 {+/-} 0.057. Random Forest achieves the highest ROC-AUC (0.898 {+/-} 0.032), followed by Logistic Regression (0.874 {+/-} 0.020) and MLP (0.872 {+/-} 0.024). Wilcoxon signed-rank tests on per-fold AUC scores show that VQC ROC-AUC is significantly lower than Random Forest (p = 0.0098) and Logistic Regression (p = 0.037) at = 0.05, with no significant difference versus MLP (p = 0.064). Architecture ablation identifies 4 qubits x 3 layers as the best VQC configuration on hold-out validation (AUC = 0.737). Feature importance analysis highlights peptidyl carrier protein domains, cluster length, and module count as dominant predictors. BGC-QDR provides a reproducible, end-to-end workflow for eDNA-derived BGC discovery with integrated novelty scoring and quantum-assisted candidate ranking. The complete BGC-QDR source code, benchmark datasets, and reproduction instructions are publicly available at: Abhishekmishra2808/BGC-PIPELINE

bioinformatics↗

bioRxiv2026

K9HeartCircDB: A circRNA Atlas of Tachypacing-Induced Canine Dilated Cardiomyopathy

Cardiovascular disease (CVD) remains a leading cause of death worldwide. Dilated cardiomyopathy (DCM), a major cause of heart failure (HF), exhibits ventricular dilation, impaired systolic/diastolic function, arrythmias, and adverse cardiac remodeling. While genetic causes of DCM have been extensively studied, non-genetic and acquired forms of DCM-like HF are less well characterized, especially with respect to non-coding RNA regulation. Circular RNAs (circRNAs) are stable, covalently closed non-coding RNAs that regulate cellular function via sequestering miRNAs, RNA-binding proteins, or translation. Their role in canine HF that recapitulates features of non-genetic DCM remains largely unexplored. To address this, we developed K9HeartCircDB (https://www.k9heartcircdb.com/), a publicly accessible database that catalogs circRNAs expressed in canine left ventricular (LV) tissues under tachypacing-induced HF, a model of non-genetic DCM-like disease, and healthy control conditions. The online interface enables users to query and explore circRNAs based on exon composition, predicted miRNA binding sites, protein-coding potential, siRNA targets, and primer design for experimental validation. By providing an integrated and user-friendly platform for canine heart circRNA exploration, K9HeartCircDB offers a valuable resource to facilitate mechanistic and advance translational studies on non-genetic DCM-like disease.

Systems Biology↗

bioRxiv2026

Pfcrt copy number amplification detected in a Plasmodium falciparum outbreak

Antimalarial resistance is one of the greatest threats to malaria elimination. Following an outbreak of Plasmodium falciparum infection in Sabah Malaysia in 2019, 98 samples were sequenced to search for adaptations driving the outbreak. The genomic data revealed evidence of clonal expansion of a strain carrying multiple copies of the chloroquine resistance transporter gene (pfcrt) in 86 cases. A TaqMan qPCR assay was developed to quantify pfcrt copy number, confirming the in silico evidence of duplication. Whilst point mutations in pfcrt have been associated with resistance to chloroquine and other drugs, copy number amplification has not been widely explored as a resistance mechanism. We investigated the genetic architecture of the duplication, revealing a wildtype haplotype (3D7 reference-type with 76K variant) and a novel mutant (with 76T mutation). Application of the TaqMan assay in 43 P. falciparum cases from neighbouring Palawan Island, the Philippines, identified a further two cases with pfcrt duplication. Assessment of the global genomic data in the MalariaGEN Pf8 repository identified a further 86 cases, including 73 (85%) from West Africa with evidence of pfcrt duplication. Amongst 47 monoclonal MalariaGEN cases, majority (95%) comprised wild type and mutant variants at codon 76. Our study reveals a potential previously unconsidered antimalarial resistance mechanism for P. falciparum and provides an assay for surveillance in other populations.

genomics↗

bioRxiv2026

A microRNA atlas of the human prefrontal cortex across the adult lifespan

Aging of the human brain is characterized by widespread changes in gene expression regulated in part by microRNAs (miRNAs). We present a lifespan miRNA atlas of the human dorsolateral prefrontal cortex generated from small RNA sequencing of 113 postmortem samples spanning 18 to 100 years of age. Differential expression analysis revealed progressive age-associated remodeling of miRNA expression, with the strongest differences observed between old and young individuals. Among the significantly altered miRNAs, miR-34a-5p emerged as one of the most robustly upregulated miRNAs in the aged cortex, alongside additional aging-associated miRNAs including miR-155-5p, miR-132-3p, miR-212-3p, miR-449a, and members of the miR-302 family. This atlas provides a resource for investigating miRNA dysregulation and small RNA regulatory networks during human cortical aging.

neuroscience↗

bioRxiv2026

Dual-Lipa: A sequential multi-omic subcellular landscape map of mouse heart

Spatial multi-omics can provide a unique understanding in molecular organisation and heterogeneity of organs including the heart. Heart function is dependent on the abundance and the spatial arrangement of proteins and lipids. Yet, an integrated multi-omics landscape of the heart at subcellular scale remains unknown. Here, we used a sequential lipid-proteomic analytical pipeline applied to the mouse heart to identify, map, and integrate lipid and protein features, revealing coordinated distinct molecular networks within defined subcellular niches. Here, we benchmark this dual extraction workflow for integrated global proteome-lipidome analyses to demonstrate its performance. We developed conserved subcellular proteome of mouse heart across 14 niches and applied the knowledge of subcellular proteome to spatially resolve the heart lipidome, identifying unique lipid features from different subcellular niches, including mitochondria (e.g., cardiolipin, LPC) and plasma membrane-enriched lipids (e.g., plasmalogens). We identified sex-dependent molecular differences in heart subcellular proteome between male and female, including RNA-protein complexes, mitochondrial calcium handling and immune regulatory pathways. We demonstrate that lipid-protein integrated multi-omics analysis of the heart by dual extraction workflow and mass spectrometry could enable previously unidentified discoveries in heart molecular composition and organisation and spatial cardiac biology. HighlightsO_LIResolved tissue-wide subcellular architecture of cardiac tissue through simultaneous high-resolution proteomics and lipidomics profiling. C_LIO_LISystematically evaluated MS-compatible dual extraction strategies for integrated proteome-lipidome recovery and performance. C_LIO_LIProteomics revealed major sex-dependent differences in mouse left ventricles, primarily involving cellular metabolism, immune regulation, detoxification pathways, and signalling responses. C_LIO_LILipidomics identified strong sex-specific lipid signatures, including differences in omega-3 vs omega-6 fatty-acid containing lipid species, triacylglycerides, and acylcarnitines. C_LIO_LIDeveloped supervised machine-learning models to classify 14 subcellular niches from tissue-wide fractionation proteomics and identified a conserved core subcellular proteome. C_LIO_LIApplied the tissue-wide subcellular proteome model to infer lipid subcellular localisation, revealing mitochondria-enriched lipids (e.g., cardiolipin, LPC) and plasma membrane-enriched lipids (e.g., plasmalogens) in the mouse left ventricle. C_LIO_LIMapped sex-specific subcellular distribution in the heart, highlighting pathways linked to RNA-protein complexes, mitochondrial calcium handling, and immune regulatory networks. C_LI

biochemistry↗

bioRxiv2026

Stable isotope-assisted computational mass spectrometry reveals root-specific alkaloids in Glycyrrhiza species

Licorice (Glycyrrhiza) is a medicinal plant widely used in approximately 70% of traditional Japanese Kampo formulations and is known to produce a wide array of specialized metabolites with diverse pharmacological properties. Although hundreds of metabolites have been reported, the overall chemical diversity of Glycyrrhiza remains poorly characterized. Here, using mass spectrometry data obtained from fully 13C-labeled leaves and roots of Glycyrrhiza uralensis and Glycyrrhiza glabra, we determined the carbon number, followed by molecular formula and substructure prediction in combination with MS/MS similarity-based molecular networking. After excluding redundant ions, including isotopic peaks, adducts, and in-source fragments, we extracted 3,060 unique metabolite features with assigned carbon numbers. Among these, substructure information was assigned to 1,015 features (33%) across the four plant tissues, revealing the tissue-specific metabolome profiles. Furthermore, we discovered five previously unreported alkaloids, homopipecolic acid-conjugated flavonoids, in the roots of G. uralensis and G. glabra, and Glycine max, another member of the Fabaceae family. Two of these structures were validated using nuclear magnetic resonance spectroscopy. We further proposed a biosynthetic route involving a spontaneous reaction between 1-piperideine and malonyl glycoside substrates and confirmed the formation of the conjugated product using authentic standards.

biochemistry↗

bioRxiv2026

Splenic tropism of Plasmodium vivax in acute infection and spleen-attenuated systemic inflammation

BackgroundIn chronic asymptomatic Plasmodium vivax infections, the spleen accounts for more than 98% of total-body parasite biomass. Whether this splenic tropism also exists in acute infection and how the spleen influences pathogenesis have not been systematically explored. Materials and MethodsIn Papua, Indonesia, we compared plasma levels of P. vivax lactate dehydrogenase [PvLDH]) and circulating parasitemia in 24 spleen-intact and 25 previously splenectomized patients with acute uncomplicated vivax malaria. Clinical and hematology data were collected and plasma markers of intravascular hemolysis (cell-free hemoglobin [CFHb]), endothelial activation (angiopoietin-2), inflammation (interleukin [IL]-1 beta, IL-6, IL-18, IL-10, tumor necrosis factor-alpha) and neutrophil activation (elastase) were measured by ELISA. Giemsa-based histology in one spleen from an untreated patient splenectomized for trauma during an episode of acute vivax malaria enabled direct assessment of splenic and circulating parasitemia and biomass microscopically. ResultsCirculating parasitemia was 4-times higher in splenectomized compared to spleen-intact patients (median 21,100 vs 4,820 parasites/{micro}L, p=0.0002) but total-body P. vivax biomass (PvLDH) was 3-times lower in patients without a spleen (median 721 vs 2,140 ng/mL, p=0.026). Parasite staging and greater organ-specific symptoms suggest redistribution of parasites in the absence of a spleen. Linear regression modeling, adjusting for circulating parasitemia, patient age, sex and duration of fever, demonstrated an 8.1-fold higher PvLDH concentration in spleen-intact patients (95% confidence interval [CI]: 3.4-19.5-fold, p<0.0001), indicating a splenic biomass accounting for 89% (95%CI: 77.3-95.1%) of total-body parasites. Histopathology revealed a spleen-to-blood biomass ratio of 10.7, in-line with the PvLDH-based estimate. In spleen-intact patients, splenic P. vivax biomass correlated strongly with markers of disease intensity, endothelial activation and systemic inflammation, whereas circulating parasitemia correlated weakly or not at all. Compared to spleen-intact patients, CFHb, endothelial activation and systemic inflammation were higher in splenectomized patients while inflammasome-dependent responses were lower. ConclusionsP. vivax is predominantly an infection of the spleen, even in acute clinical vivax malaria. We conservatively estimate that 89% of total-body parasite biomass in acute infection is splenic. While the size of this hidden population correlates with disease intensity, the spleen likely regulates inflammatory pathways and heme-associated pathology.

pathology↗

bioRxiv2026

A Genetic Mechanism Linking Hippo Signaling to Dorsoventral Patterning for Control of Head and Eye Development

The integration of growth and patterning in developing tissues is a complex process involving both intrinsic and extrinsic cues. The Hippo pathway, a conserved regulator of organ size, controls growth and patterning in Drosophila, including the development of the eye-antennal imaginal disc into adult structures. Defective Proventriculus (Dve), a SATB1/2 ortholog and K-50 type transcription factor regulates dorsal-ventral (DV) patterning during Drosophila eye development. Dve works with Wingless (Wg) to suppress eye development and promote head cuticle fate, thereby influencing the positioning of eyes and interocular distance. Our study investigates the role of the Hippo effector Yorkie (Yki), and dve in coordinating growth and patterning during eye development, specifically focusing on the regulation of the head cuticle domain. Here we show that Hippo signaling, mediated by Yki, regulates the size of the head cuticle domain and morphogenetic furrow (MF) progression, and that Dve suppresses Yki activity in the dorsal head region. Furthermore, Yki regulates several DV patterning genes like pnr, wg and mirr, to coordinate eye and head development. Mutations in mammalian orthologs of yki, dve, pnr and wg are associated with facial dysmorphia and several developmental disorders. Our studies thus reveal new genetic mechanisms by which growth and patterning are coordinated for head and eye development across species.

developmental biology↗

bioRxiv2026

Decoding Ethiopia's unique and structurally divergent Plasmodium falciparum populations using genomics

Previous genome-wide studies suggest that Ethiopian Plasmodium falciparum parasites are unique and structurally divergent from sub-Saharan African populations but were limited by small sample sizes. The emergence of molecular markers associated with reduced artemisinin susceptibility in northern Ethiopia, and the drug pressures created by sympatric P. falciparum and P. vivax, may have fostered a distinct and permissive genetic background for the emergence and spread of multidrug resistant parasites. To characterise parasite population structure and evolutionary dynamics in this setting, we generated whole-genome sequencing data for 163 P. falciparum isolates from southern Ethiopia (2017-2021) and integrated these with 854 isolates from across sub-Saharan Africa. Ethiopian parasites exhibited markedly reduced diversity, highly conserved genomes, and distinct admixture ancestry. Near-fixation of chloroquine and antifolate associated resistance markers, potentially driven by P. vivax co-circulation, suggests persistent drug-related selection pressures. We identified a previously undescribed deletion in the pfmdr1 5' UTR that is common in Ethiopia and potentially widespread across African populations. Although clinically relevant pfk13 variants have emerged in northern Ethiopia, these were not detected in southern Ethiopia. However, strong genetic connectivity between regions indicates the potential for rapid spread of resistance and is therefore important for public health policy and practice.

genomics↗

bioRxiv2026

Aging-related Transcriptomic Changes with Spatial Resolution in the Human Prefrontal Cortex

The human prefrontal cortex (PFC), whose laminar organization is essential for cognitive function, is among the first regions to show age-related functional decline1,2. Single-cell sequencing studies revealed cell type-dependent aging effects but lacked spatial specificity3-6. Spatial transcriptomics (ST) advanced our molecular understanding of the human PFC7, yet whether aging-driven changes differ across PFC layers remains unclear. Here, we performed whole-transcriptome ST on postmortem PFC from 37 individuals across the adult lifespan. We mapped cortical layers and revealed aging mechanisms across layers. This represents one of the largest and most comprehensive lifespan ST analysis of the human PFC brain, offering crucial insight into how the brain ages and identifying potential molecular targets to mitigate cognitive aging and extend healthspan.

neuroscience↗

bioRxiv2025

Disruption of the Wnt-antagonist Apc in the pituitary stem cells drives the development of adamantinomatous craniopharyngioma.

Adamantinomatous craniopharyngiomas (aCPs) are complex intracranial neoplasms that generally arise in the sellar and suprasellar region of the brain which affect the endocrine and nervous systems causing severe sequelae. Activating mutations resulting in degradation-resistant forms of {beta}-catenin (CTNNB1) have been shown to be the main driver for many of these neoplasms. However, the underlying genetic driver for a proportion of these tumours is still unknown. Using murine transgenic models, we show that genetic disruption of the Wnt-antagonist and tumour suppressor, adenomatous polyposis coli (Apc), within the pituitary progenitors/stem cells, leads to pituitary tumours that closely resemble human aCPs. These tumours present classic histopathological hallmarks of aCPs, such as large deposits of wet keratin, stellar-reticular-like cells, large cystic components and clusters of accumulating nucleo-cytoplasmic {beta}-catenin that are slow-dividing and exhibit a secretory phenotype. We show that a hypomorphic allele of Apc is sufficient for tumour development, indicating that disruption of Apc function can lead to aCP formation. Moreover, we identify that bi-allelic loss of Apc in the Sox2+ve pituitary stem cells is sufficient to initiate tumour formation, indicating that Sox2+ve stem cells are the cell origin of these Apc-driven aCPs. Transcriptomic analyses of early tumour-initiating cells revealed that Apc-driven clusters of accumulating {beta}-catenin undergo senescence-associated secretory phenotype (SASP), which is p21-mediated and results in secretion of inflammasome, angiosome and developmental growth factors. Our data unequivocally show a causal role for the disruption of the tumour suppressor Apc as a primary driver of aCPs independent of mutations in {beta}-catenin. We provide murine models representing a novel genetic subtype of human aCPs offering insights into aCP pathogenesis. Our work reinforces the importance of genetic testing for mutations in APC in patients with aCPs and identifies a potential need to screen patients with familial adenomatous polyposis (FAP) or spectrum of APC-pathogenic syndromes for aCPs in early life.

cancer biology↗

bioRxiv2025

Exploring the Microbial Geobiological Pattern Across the Serpentinization Sites through Metagenomic and Elemental Composition Analyses

It is well-known that ultramafic rocks can continuously generate hydrogen through the serpentinization process associated with dynamic geochemical and geobiological interactions. This study aims to gain an improved understanding of these dynamic processes through the understanding of diverse microbial populations in order to maximize the geologic hydrogen production potential. The water samples were collected from a near surface serpentinite site in Northern California, USA. Elemental analyses of these water samples revealed the presence of essential dissolved minerals such as magnesium, calcium, and potassium, along with trace elements including iron, cobalt, and nickel. These elements act as cofactors for enzymes involved in microbial metabolic processes and Non-metric Multidimensional Scaling analysis supports this corelation. Furthermore, the analysis of total organic carbon (TOC) showed significant levels of organic carbon, suggesting a link with biological carbon cycling processes. Metagenomic analysis uncovered a diverse microbial community of hydrogen-fueled microbial consortia at the sampling sites, encompassing hydrogenogenic and hydrogenotrophic microorganisms. We examine hydrogen-metabolizing communities, including sulfate-reducing bacteria, acetogens, and methanogens, supported by diversity in hydrogenase enzymes across various sampling sites. These observations are corroborated by genomic accession data and abundance profiling of genes associated with acetogenesis, methanogenesis, and carbon monoxide metabolism. These investigations provide new insights into hydrogen-metabolizing microorganisms in northern California and propose frameworks for optimizing hydrogen production through the inhibition of hydrogen metabolism. O_FIG O_LINKSMALLFIG WIDTH=155 HEIGHT=200 SRC="FIGDIR/small/678891v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@11e5041org.highwire.dtl.DTLVardef@126ea56org.highwire.dtl.DTLVardef@1e2cd4forg.highwire.dtl.DTLVardef@11537f2_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe association of the serpentinization process with dynamic geochemical and geobiological interactions. C_LIO_LIMetagenomic study found an assorted microbial community of hydrogen-fueled consortia at the different sampling sites in Northern California C_LIO_LIHydrogen-metabolizing communities counted, including sulfate-reducing bacteria, acetogens, and methanogens. C_LI

microbiology↗