Biology subjects

Mak, S.

Publications and source records attributed to Mak, S..

7 recordsLinked to original sources

bioRxiv2026

DNA damage drives a unique, Alzheimer's disease-relevant senescent state in neurons

Alzheimers disease (AD) shares molecular hallmarks with the canonical drivers of cellular senescence. Senescent cells have also been shown to accumulate in the brain with age, yet the mechanisms linking AD pathology to the accumulation of senescent cells in the brain remain unclear. Here, we demonstrate that DNA damage in patient-derived directly induced neurons (iNs) drives a senescent-like cell state with relevance to AD. DNA damage-induced senescent iNs show significant transcriptional concordance with human AD neurons and a weighted gene co-expression network analysis (WGCNA) uncovers candidate regulators associated with the senescent-like state in neurons. Direct comparison of iNs to the original patient fibroblasts reveals striking cell-type specific senescence signatures following DNA damage. iNs adopt a p21-associated senescent-like state characterized by a senescence-associated secretory phenotype (SASP) and predicted activation of NF-{kappa}1. In contrast, fibroblasts develop a p16-associated senescent state lacking a SASP phenotype and show a predicted repression of NF-{kappa}1. Early responses to DNA damage further reveal divergent DNA damage response (DDR), with neurons exhibiting higher accumulation of damage lesions relative to fibroblasts. Together, these findings demonstrate that DNA damage drives a unique senescent-like neuronal state that models molecular features of AD, while also revealing fundamental cell-type specific differences in senescent-like phenotypes and DDR.

cell biology↗

bioRxiv2026

Identification of miR-187 as a modulator of early oogenesis and female fecundity in medaka

MicroRNAs (miRNAs) are known regulators of ovarian function in vertebrates, yet their physiological roles in fish reproduction remain poorly understood. Here, we identified miR-187 as one of the most ovarian-enriched miRNAs in medaka (Oryzias latipes) and we uncovered its function in vivo using CRISPR/Cas9-mediated gene inactivation. miR-187-3p is expressed in oocytes and granulosa cells in the ovary, and in discrete brain areas. Its loss-of-function leads to a significant reduction in female fecundity. High-resolution 3D imaging of whole ovaries revealed that mir-187 mutants accumulate early stage I follicles and show reduced progression to later stages, indicating a defect in early follicle recruitment and growth. Transcriptomic profiling of mutant ovaries revealed extensive gene-expression remodeling, including downregulation of key regulators of steroidogenesis, Wnt/{beta}-catenin signaling, and TGF-{beta} pathways, and upregulation of genes associated with early follicle activation and immature somatic cell states. Using an expression-based target-prediction pipeline, we identified several putative miR-187-3p targets, including nr6a1a (gcnf) and dpagt1, two genes previously implicated in oocyte differentiation and female fertility in mammals. Together, our results demonstrate that miR-187 acts as a previously unrecognized regulator of early folliculogenesis and female reproductive capacity in medaka, expanding the repertoire of miRNAs with essential in vivo roles in teleost oogenesis and female fecundity. AUTHOR SUMMARYSuccessful fish reproduction depends on the continuous production of oocytes within the ovary. This process depends on the coordinated development of germ cells and the supporting somatic cells. Although microRNAs (miRNAs) are known to post-transcriptionally regulate gene expression, their physiological roles in the fish ovary and female reproduction remain poorly understood. In this study, we used the medaka to investigate the function of miR-187, a miRNA strongly enriched in the ovary. By generating a CRISPR/Cas9 knockout line, we showed that females lacking miR-187 produce fewer eggs and display defects in early follicle development. Using whole-ovary 3D imaging, we found that mutant females accumulate early follicles that fail to progress through normal growth stages. Transcriptomic analyses revealed broad gene-expression changes affecting pathways involved in follicle activation, somatic cell maturation, and ovarian signaling. Our results demonstrate that miR-187 is a previously unrecognized regulator of early folliculogenesis and female fecundity in medaka. This work expands the landscape of miRNA-mediated regulation in the ovary and highlights the importance of post-transcriptional mechanisms in controlling reproductive success in teleosts. Grant supportThe DYNAMO project (French National Research Agency, ANR-18-CE20-0004). The OVOPAUSE project (French National Research Agency, ANR-22-CE45-00017-02). The IMMO project (INRAE Metaprogramme DIGIT-BIO).

developmental biology↗

bioRxiv2025

Possible origins of kombucha in spontaneous fermentation

Although the microbial composition and functional attributes of kombucha have been extensively studied, the origins and mechanisms of the formation of their biofilm (Symbiotic Culture of Bacteria and Yeasts, or SCOBY) remain speculative. Based on historical reports and the concept of community coalescence, this study establishes a proof-of-concept, demonstrating how a kombucha-like biofilm can form spontaneously from microbes associated with plants, insects, and humans in a sweetened tea medium. Metagenomic analyses revealed microbial dynamics during fermentation, uncovering shifts in community composition driven by acetic acid bacteria, lactic acid bacteria, and yeasts. Comparative analyses with existing fermented beverages demonstrated microbial similarities to kombucha metagenomes. Pangenomic analyses focused on Fructobacillus evanidus, a species present in both the bee microbiome and our spontaneous fermentation. The MAGs of F. evanidus from the fermented beverage showed evidence of genetic streamlining, characterized by the loss of genes essential for survival in shifting and highly competitive environments, such as the bee gut, and adaptation to the more stable conditions of fermentation. This study offers insights into the origins of kombucha, integrating historical, microbiological, ecological and evolutionary perspectives to answer the question Is this a kombucha?, and gesturing toward further physical, chemical and sensory dimensions that could be explored.

microbiology↗

bioRxiv2025

Convergent Evolution of Sociality Causes Reduction of Mutation Rates in Spiders

Germline mutation rates influence the pace of molecular evolution, yet the roles of selection and life history in shaping their evolution remain to be determined. Comparative systems with replicated evolutionary transitions provide a unique opportunity to determine how changes in life history influence germline mutation rates. In the spider genus Stegodyphus, permanent sociality evolved independently three times within the past million years and is associated with obligate inbreeding, female-biased sex ratios, reduced fecundity, and sharply reduced effective population sizes. We sequenced 202 parent-offspring trios from 34 full-sibling families across three social and four closely related subsocial species and analysed quality-filtered trios in a phylogenetic comparative framework. Each independent transition to sociality was associated with an approximately 2-fold reduction in the de novo mutation rate in the germline. Phylogenetic analyses of synonymous branch lengths suggest that the mutation rates declined in parallel with the transitions to sociality. These rapid reductions in mutation rates in social lineages with small effective population sizes run counter to the drift-barrier hypothesis, which predicts that reduced selection efficacy would lead to higher mutation rates. We find no evidence that reduced mutation rates in the social species was favoured by selection for improving DNA repair efficiency, since there is no upregulation of DNA repair pathway genes in the ovaries of the social species. On the contrary, the mutation rate is reduced across mutational classes and in somatic tissue in social species compared with their subsocial counterparts. These patterns suggest that the reduction in mutation rate in social spiders is a consequence of convergent life history changes, including reduced body size and production of fewer, larger eggs. Our results highlight that the evolution of sociality, which entails major life history changes, can rapidly reshape fundamental evolutionary parameters, such as the germline mutation rate.

evolutionary biology↗

bioRxiv2024

Food Fermentation in Space Is Possible, Distinctive, and Beneficial

Space exploration is expanding, which demands new technologies and enables new scientific questions. Food, as a bridge between disciplines, can bring these fundamental and applied goals together. Here we investigate whether food fermentation in space is possible, and if so, how it compares with fermentation on Earth. We fermented a miso, a traditional Japanese condiment, on the International Space Station over 30 days, and compared it with two earthbound controls. Using a specially-built environmental sensing box, we gathered metadata for temperature, relative humidity, pressure, and radiation. We analyzed the three misos with shotgun metagenomics to investigate the microbial communities composition and safety; whole genome sequencing to investigate the mutation rate of Aspergillus oryzae; untargeted metabolomics to quantify aromatic compounds, amino acids and organic acids; colorimetry to quantify color; and sensory analysis to describe the misos flavours and quantify liking and sensory difference. Across these datasets, we found that overall, the space miso is recognizable as a miso, suggesting fermentation in space is possible. We also found certain differences in the space miso: specifically the presence of Bacillus velezensis, a higher mutation rate of A. oryzae, higher attributions of roasted and nutty flavours, and the most different sensory impression. Taken together, these observations suggest unique features of the space environment--what we might call space terroir--which could be harnessed to create more flavorful, nourishing foods for long-term space missions and to address fundamental questions about the biology of novel environments. Significance StatementOur study presents, to our knowledge, the first time a food product has been fermented in space. We demonstrate that fermentation in space is possible with safe and successful results, a proof of concept that offers fermentation as a new tool for space research and future long-term space exploration missions. We also document how the space environment shapes the fermentation process in unique ways, suggesting a space terroir. These findings on the feasibility and novelty of fermentation in space open up directions for further multidisciplinary research across science, health, systems design, and society and culture.

microbiology↗

bioRxiv2022

A contractile injection system mediates developmentally regulated intra-strain cell death in Streptomyces coelicolor

Extracellular contractile injection systems (eCIS) are encoded in diverse clades of bacterial species. Although closely related to contractile phage tails, these entities can inject toxic proteins into eukaryotic cells. The roles of eCIS in mediating cytotoxic activities has led to a view of them as defense mechanisms that are not central to normal bacterial lifecycles. Here, we provide evidence that eCIS play an entirely distinct role in Streptomyces coelicolor (Sco), where they appear to participate in the complex developmental process of this species. In particular, we have shown that Sco produces eCIS particles as a part of its normal growth cycle and that strains lacking functional eCIS particles exhibit pronounced alterations in their developmental program. Most intriguingly, eCIS-deficient mutants display significantly reduced levels of cell death and altered morphology during liquid growth. These data suggest that Sco eCIS function by inducing intra-strain lethality rather than by attacking foreign species.

microbiology↗

bioRxiv2019

T-loops Refold after Telomerase Extension and Unfold Again at Late S/G2 for C-strand Fill-in

Telomeres are the structures that protect the ends of each chromosome and prevent them from being recognized as broken DNA in need of repair. During human fetal development telomere length is ~15 kb and is maintained by the ribonucleoprotein telomerase. In neonates telomerase becomes spliced into inactive forms in most tissues. Afterwards, lagging strand synthesis fails to copy the very end and telomeres become progressively shorter as cells divide. Part of the mechanism for avoiding the DNA damage machinery is by forming a t-loop structure that has no free end. The telomeric 3 overhang is inserted into the duplex DNA where it displaces the G-rich strand, forming a D-loop. It is unknown whether this D-loop is the size of the overhang, or whether branch migration results in a larger D-loop. Telomere t-loops must unfold for replication and telomerase extension during S phase. It is also unknown whether t-loops remain unfolded after replication until C-strand fill-in at late S/G2, or if they refold after replication and then unfold again for fill-in at late S/G2. We have developed a biochemical t-loop assay to address these issues, and demonstrate that most t-loops persist throughout S phase both before and after their replication. HighlightsO_LIT-loops unfold twice during each S-phase C_LIO_LIVirtually all telomeres are packaged into t-loops C_LIO_LILarge amounts of t-loops can easily be purified without specialized materials C_LI

molecular biology↗