Biology subjects

Baba, H.

Publications and source records attributed to Baba, H..

6 recordsLinked to original sources

bioRxiv2026

Diversity and stability of the gut microbiome of naked mole-rat (Heterocephalus glaber), the longest-lived rodent

The naked mole-rat is a subterranean rodent adapted to extreme hypoxia and low metabolic demands, with an exceptionally long lifespan relative to its small body size, while maintaining reproductive capacity. Using 16S rRNA gene sequencing of 24 samples and whole-metagenome sequencing of 11 samples from individuals up to 15 years of age, we characterized the gut microbiota and showed its complexity and distinctiveness compared with that of other rodents, including mice, squirrels, and rabbits. Although all animals were born and raised in a laboratory setting, the gut microbiota remained taxonomically stable across ages and retained key taxa previously reported in wild naked mole-rats (e.g., Treponema and Desulfovibrio). Metagenome-assembled genomes revealed the presence of archaeal methanogens and termite-gut-associated bacteria (e.g., Methanobacteria within Euryarchaeota and Avelusimicrobium within Elusimicrobiota), together with genes involved in hydrogen metabolism and archaeal methanogenesis. Compared with mice, the naked mole-rat gut microbiota was enriched in carbohydrate-active enzymes targeting plant cell-wall polysaccharides, resembling those found in ruminants. We also detected evidence of flagellates, ciliates, and fungi, which may further contribute to polysaccharide degradation and fermentation, potentially within the enlarged cecum. Together, this comprehensive analysis provides distinctive gut microbial features of the naked mole-rat that may be associated with the naked mole-rats low metabolic rate and exceptional longevity.

microbiology↗

bioRxiv2026

Developmental Hypoxia Increases Susceptibility to Cardiac Ventricular Arrhythmias in Adult Offspring

Ventricular arrhythmias are the leading cause of sudden cardiac death. It is well-established that environmental factors contribute to the origin and penetrance of ventricular arrhythmic disorders. However, to our knowledge, no studies have considered the role of the intrauterine environment. In this study, we investigated the long-term effects of fetal hypoxia on ventricular arrhythmia susceptibility. Pregnant Wistar rats were assigned to normoxia (21% O2) or hypoxia (13% O2 between gestational days 6-20), and offspring were raised to 6 months. Hearts were isolated and loaded with the fluorescent calcium- and voltage-sensitive indicators, Rhod-2 and RH237, respectively. Optical mapping was performed while the left ventricle was burst paced (10-20hz) to induce arrhythmias. Hearts isolated from adult offspring exposed to fetal hypoxia were more susceptible to arrythmia during burst pacing, compared to controls. This phenotype was associated with prolonged Ca2+ transients and action potentials, an increased frequency of Ca2+ waves and delayed after depolarisations, as well as lower gene and protein expression of the sarcoplasmic reticulum Ca2+ ATPase. Collectively, our data shows that fetal hypoxia can programme ventricular arrhythmia sensitivity in adulthood, driven by abnormalities in excitation-contraction coupling. This is the first evidence that some ventricular arrhythmias may have a developmental origin, highlighting pregnancy as a potential window for early preventive intervention.

developmental biology↗

bioRxiv2024

Integrated hepatic ferroptosis gene signature dictates pathogenic features of ferroptosis

Background & AimsFerroptosis, a distinctive form of cell death induced by iron-dependent lipid peroxidation, is implicated in various biological processes, including liver diseases. Establishing an iron overload-induced ferroptosis model and identifying hepatic gene signatures associated with ferroptosis are crucial for understanding its role in liver pathogenesis. MethodsF-box and leucine-rich repeat protein 5 (FBXL5) is a substrate-recognition component of the SCF E3 ligase complex that restricts intracellular iron levels. In this study, we used liver-specific Fbxl5-null mice to establish an iron overload-induced ferroptosis model. Transcriptome analysis identified genes involved in hepatic ferroptosis. Integrating these gene signatures with another ferroptosis model enabled the assessment of ferroptosis-related pathology in murine liver injury models and in 174 patients undergoing liver resection surgery. ResultsIron overload induced severe liver damage in liver-specific Fbxl5-null mice, characterized by elevated liver enzymes, histopathological changes, and lipid peroxidation. Transcriptome analysis revealed a distinct set of genes associated with hepatic ferroptosis response. Generating a gene signature for evaluating ferroptosis enhanced the understanding of ferroptosis-related pathologies in liver diseases. Iron overload exacerbated liver damage in murine ischemia-reperfusion injury models via ferroptosis induction. In human patients, elevated serum iron levels correlated with sustained post-operative liver damage, indicating heightened susceptibility to ferroptosis. ConclusionHere, a murine model of iron overload-induced hepatic ferroptosis was established, and a gene signature indicative of hepatic ferroptosis response in both mice and humans was identified. These findings underscore the role of ferroptosis in liver injury progression and suggest potential therapeutic targets for liver disease intervention. HIGHLIGHTSO_LILiver-specific Fbxl5 knockout mice provide an iron-induced ferroptotic injury model C_LIO_LIIntegrated gene signature of iron- and acetaminophen-induced liver injury dictates ferroptosis C_LIO_LIIron overload aggravates hepatic ischemia-reperfusion injury in mice C_LIO_LIPatients with high iron levels show delayed post-operative liver damage recovery C_LI IMPACT AND IMPLICATIONSOur study elucidated the critical role of iron in liver disease pathogenesis and ischemia-reperfusion injury (IRI). By establishing a murine model of iron overload-induced ferroptosis, we confirmed that iron overload exacerbated hepatic IRI, underscoring the importance of ferroptosis in liver damage. Additionally, the development of an integrated gene signature for hepatic ferroptosis response provides a valuable tool for evaluating ferroptosis in liver diseases. Via analysis of patient data, we also highlighted the clinical relevance of ferroptosis in post-operative liver damage, offering insights into potential therapeutic strategies targeting iron and ferroptosis to improve outcomes in patients with liver diseases.

molecular biology↗

bioRxiv2024

Shift in cellular crosstalk reveals the immunosuppressive environment in cholangiocarcinoma patients.

Background and aimsCholangiocarcinoma (CCA) is a deadly disease, and this cancer entity is characterized by an abundant stroma. The tumor microenvironment (TME) plays an important role in aggressive behavior and poor response to therapeutics; however, underlying pathways are unknown. MethodsTo fill this gap, we used multiplexed immunohistochemistry, high-dimensional phenotyping, and transcriptomics to analyze human CCA samples and identify cell cluster crosstalk in patients with a poor prognosis. ResultsOur findings confirmed the presence of Tregs and the lack of effector memory cells in the tumor. New findings are the spatiality of the effector memory cells being more present in the peripheral tissue, for some reason these immune cells fail to reach the tumor niche. We revealed cancer crosstalk with macrophages and stromal cells and identified responsible genes in the poor prognosis group. Amongst the responsible ligand pairs are GAS6-AXL belonging to the TAM family. We then identified VCAN-TLR2 to be present and influencing the ECM in a way to supports immune exhaustion. Last, EGFR-TGF-{beta} is expressed in macrophages and this finding is important in Tregs induction and blocking cytotoxic T cell function. ConclusionsThe multiple mechanisms leading to the exclusion of relevant immune cells needed for an anti-cancer response and mechanisms leading to active immune suppression are part of complex cell-cell crosstalk. This study provides a deeper insight into the immune exhausted phenotype in CCA.

cancer biology↗

bioRxiv2021

Hematopoietic stem and progenitor cells integrate Bacteroides-derived innate immune signals to promote gut tissue repair

Bone marrow (BM)-resident hematopoietic stem and progenitor cells (HSPCs) are often activated by bacterial insults to replenish the host hemato-immune system, but how they integrate the associated tissue damage signals to initiate distal tissue repair is largely unknown. Here, we showed that acute gut inflammation expands HSPCs in the BM through GM-CSFR activation, and directs them to inflamed mesenteric lymph nodes for further differentiation into myeloid cells specialized in gut tissue repair. We also identified that this process is exclusively mediated by Bacteroides, a commensal gram-negative bacteria, that activates innate immune signaling. In contrast, chronic gut inflammation reduces HSC potential for hematopoietic reconstitution and immune response against infection. Similarly, microbial signals contribute to aging-associated HSPC expansion. These findings establish a cross-organ communication that promotes tissue regeneration, but if sustained, impairs tissue homeostasis that may be relevant to aging and chronic disorders. SummaryThe infiltrating microbiota Bacteroides upon acute colitis directed MPP migration from the BM to the MLN for their subsequent expansion and differentiation into tissue-repairing Ly6C+/G+ cells, whereas chronic colitis impairs HSC functionality similarly as aging.

pathology↗

bioRxiv2021

Origins of cancer genome complexity revealed by haplotype-resolved genomic analysis of evolution of Barretts esophagus to esophageal adenocarcinoma

The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we performed haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barretts esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identified distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data.

genomics↗