Biology subjects

Lee, H. J.

Publications and source records attributed to Lee, H. J..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Force Propagation in Active Cytoskeletal Networks

Conventional materials science establishes clear structure-function relationships: grain boundaries modulate strength by blocking dislocations, and defect density limits conductivity through electron scattering. Active matter presents a fundamentally different challenge, components continuously consume energy to generate forces, creating a dual identity as both structural elements and force-generating machines. This material-machine duality raises a fundamental question: which structural parameters govern functional behavior in systems where constituents actively generate forces rather than merely responding to external inputs? Here we demonstrate that percolation is the critical mechanism that transforms active cytoskeletal networks from energy-dissipating materials into work-performing machines. Using light-controlled microtubule-kinesin networks, we show that increasing bundle length from 0.9 {micro}m to 5 {micro}m triggers a percolation transition that enables global force organization. Networks below the threshold remain incapable of performing coordinated work, while networks above it develop correlation lengths exceeding 240 {micro}m, generate 25-fold stronger forces, and extract 1000-fold more mechanical work, powering transport of live cells across 800 {micro}m distances. Network simulations reveal that introducing just 5-10% longer bundles creates a connected component containing 90% of microtubules, establishing the precise threshold that drives this material-to-machine transition. Our findings establish percolation as the fundamental mechanism governing whether active matter systems function as passive materials or as coordinated machines--providing design principles for both synthetic and biological systems. increasing bundle length from 0.9 {micro}m to 5 {micro}m increasing bundle length from 0.9 {micro}m to 5 {micro}m

biophysics↗

bioRxiv2025

Antigen reactivity defines tissue-resident memory and exhausted T cells in tumours

CD8+ T cells are a key weapon in the therapeutic armamentarium against cancer. While CD8+CD103+ T cells with a tissue-resident memory T (TRM) cell phenotype have been favourably correlated with patient prognoses1-6, the tumour microenvironment also contains dysfunctional exhausted T (TEX) cells that exhibit a myriad of TRM-like features, leading to conflation of these two populations. Here, we deconvolute TRM and TEX cells within the intratumoural CD8+CD103+ T cell pool across human cancers, ascribing markers and gene signatures that distinguish these CD8+ populations and enable their functional distinction. We found that while TRM cells exhibit superior functionality and are associated with long-term survival post-tumour resection, they are not associated with responsiveness to immune checkpoint blockade. Deconvolution of the two populations showed that tumour-associated TEX and TRM cells are clonally distinct, with the latter comprising both tumour-independent bystanders and tumour-specific cells segregated from their cognate antigen. Intratumoural TRM cells can be forced towards an exhausted fate when chronic antigen stimulation occurs, arguing that the presence or absence of continuous antigen exposure within the microenvironment is the key distinction between respective tumour-associated TEX and TRM populations. These results suggest unique roles for TRM and TEX cells in tumour control, underscoring the need for distinct strategies to harness these T cell populations in novel cancer therapies.

immunology↗

bioRxiv2025

Faster R-CNN Model for Predicting Endometrial Cancer Recurrence: A Five-Subclass Approach with Texture Analysis and Validation

PurposeThis study investigates the prediction of endometrial cancer (EC) recurrence using MRI-based texture analysis and deep learning. EC recurrence remains a major clinical challenge, and accurate prognostic tools are needed. The study aims to identify significant imaging biomarkers for recurrence risk and evaluate the performance of a Faster R-CNN deep learning model in classifying recurrence-free survival (RFS) and recurrence (REC) groups. Materials and MethodsA total of 112 patients with histopathologically confirmed EC who underwent pre-treatment MRI between 2009 and 2018 were included. MRI texture analysis was performed using histogram and gray-level co-occurrence matrix (GLCM) methods, analyzing perimeter, integrated density, entropy, and homogeneity. A Faster R-CNN deep learning model was trained and tested on five image subclasses, using 20,000 iterations to optimize performance. REC and RFS were classified based on clinical outcomes, and probability scores were calculated to define the REC score. Feature importance was assessed using a Random Forest model. ResultsSignificant clinical predictors of recurrence included high-grade tumors, FIGO stage III-IV, and cervical invasion. Texture analysis revealed notable differences in perimeter, integrated density, contrast, entropy, and homogeneity between REC and RFS groups. Faster R-CNN achieved an average precision of 0.86 and an AUC of 0.61. Feature importance analysis identified area as the most significant factor, while REC_score was independent of texture-based parameters. ConclusionMRI texture analysis combined with deep learning provides valuable predictive insights for EC recurrence. The study highlights the potential of integrating machine learning with imaging biomarkers for personalized risk assessment, offering a promising approach for improving EC patient management..

cancer biology↗

bioRxiv2025

Bazedoxifene rescues sexually dimorphic autistic-like abnormalities in mice carrying a biallelic MDGA1 mutation

In the accompanying study, we describe two pairs of MDGA1 missense mutations (Val116Met/Ala688Val and Tyr635Cys/Glu756Gln) from two patients with autism spectrum disorders (ASDs) and how these mutations exert distinct abnormalities in biological processes during central nervous system development. Here, we generated knockin (KI) mice harboring the murine version of Tyr635Cys/Glu756Gln MDGA1 (Mdga1Y636C/E751Q) and performed extensive behavioral analyses. Male KI mouse pups and adults exhibited impaired ultrasonic vocalizations and sensorimotor gating (ASD-relevant behavioral deficits), and thus exhibited phenotypes different from those of male Mdga1 conditional knockout (cKO) mice. In contrast, adult female KI mice did not exhibit a range of ASD-like behavioral abnormalities. Electrophysiological analyses performed using both juvenile and adult Mdga1Y636C/E751Q mice revealed sexually dimorphic and developmental stage-dependent compromises of GABAergic synaptic inhibition. In addition, proteomics analyses showed that the phospho-proteomic phenotypes differed between Mdga1Y636C/E751Q and Mdga1-cKO mice. Treatment of male Mdga1Y636C/E751Q KI mice with the FDA-approved estrogen receptor modulator, bazedoxifene, restores the KI-related molecular, GABAergic synapse, and behavioral changes. Collectively, our results suggest a novel treatment strategy for ASDs that present developmentally regulated and/or sexually dimorphic features.

neuroscience↗

bioRxiv2025

Garcinone C suppressed the proliferation of gastric cancer cells through regulating Hedgehog signaling

Garcinone C, a xanthone derived from Garcinia mangostana L, possesses antioxidant and anti-cancer effects. However, its role in gastric cancer remains unexplored. This study aimed to investigate the effects of garcinone C on gastric cancer cell proliferation and its underlying mechanism. We found that garcinone C suppressed gastric cancer cell growth by inducing G0/G1 arrest and apoptosis in a dose-dependent manner. Furthermore, garcinone C downregulated G0/G1 phase markers Cyclin D1 and p21, as well as apoptosis markers Bax, Bcl-2, cleaved-PARP, and c-caspase 3. Following the previous evidence demonstrated that aberrant Hedgehog (Hh) signaling is implicated in gastric cancer development, we confirmed that inhibiting Gli1/2 reduced the growth of AGS and MKN74 cells. Furthermore, garcinone C exerted similar effects to Gant61, inhibiting Hh signaling by reducing Gli1/2 levels and blocking their nuclear translocation. These findings suggest that garcinone C inhibits gastric cancer proliferation via the Hh signaling, indicating its potential as a therapeutic agent for treating gastric cancer.

cancer biology↗

bioRxiv2025

The Environment-Dependent Regulatory Landscape of the E. coli Genome

1All cells respond to changes in both their internal milieu and the environment around them through the regulation of their genes. Despite decades of effort, there remain huge gaps in our knowledge of both the function of many genes (the so-called y-ome) and how they adapt to changing environments via regulation. Here we describe a joint experimental and theoretical dissection of the regulation of a broad array of more than 100 biologically interesting genes in E. coli across 39 diverse environments, enabling us to identify the binding sites and transcription factors that mediate regulatory control. Using a combination of mutagenesis, massively parallel reporter assays, mass spectrometry, and tools from information theory and statistical physics, we go from complete ignorance of a promoters environment-dependent regulatory architecture to a quantitative description of its binding sites, candidate transcription factors that bind them where identifiable, and the conditions under which they act. As proof of principle of the biological insights to be gained from such a study, we chose a combination of genes from the y-ome, toxin-antitoxin pairs, and genes hypothesized to be part of regulatory modules; we discovered a host of new insights into their underlying regulatory landscape and resulting biological function. We highlight discoveries for y-ome genes, including transcription start sites and transcription factor binding sites at base-pair resolution, and their dependence on growth conditions.

molecular biology↗

bioRxiv2025

Longitudinal deep phenotyping in a mouse model of West syndrome reveals temporal dynamics of synapse remodeling, gliosis, and proteomic and lipidomic changes during seizure evolution

Neurodevelopmental disorders can have long-lasting effects, causing not only early pediatric symptoms but also a range of neurological issues throughout adulthood. West syndrome is a severe neurodevelopmental disorder marked by infantile spasms, an early symptom that typically subsides with age. However, many patients progress to other seizure forms, known as seizure evolution, which is closely linked to poor long-term outcomes. Despite its clinical significance, the neurobiological mechanisms behind seizure evolution in West syndrome remain poorly understood. Recent genetic studies have consistently identified the CYFIP2 p.Arg87Cys variant in West syndrome patients, and the Cyfip2+/R87C mouse model carrying this mutation has been shown to recapitulate key symptoms of the disorder, including infantile spasms. In this study, we aimed to gain deeper insight into seizure evolution by conducting longitudinal deep phenotyping of the Cyfip2+/R87C mouse model from the neonatal stage to seven months of age. We tracked seizure activity through behavioral and EEG recordings and employed multi-omic analyses, including tissue and single-cell level transcriptomics, ultrastructural analysis, proteomics, and lipidomics, to capture a comprehensive view of molecular and cellular changes. Our results showed that after an initial period of neonatal spasms, Cyfip2+/R87C mice entered a seizure-free phase, followed by spontaneous recurrent seizures in adulthood, ultimately leading to premature death. This progression was associated with synaptic remodeling, sequential activation of different glial cell types, lipid droplet accumulation in astrocytes, and significant proteomic and lipidomic changes in the brain. These findings suggest that seizure evolution in West syndrome involves complex, time-dependent interactions between neurons and glial cells, along with alterations in lipid metabolism. Our study highlights the potential of longitudinal multi-omic approaches to uncover underlying mechanisms of seizure evolution and suggests that targeting these changes could offer novel therapeutic strategies. Additionally, the dataset generated here may provide valuable insights for other epilepsy and neurodevelopmental disorder models.

neuroscience↗

bioRxiv2025

Tissue-specific improvements in CD4+ T cell responses after treatment for visceral leishmaniasis.

Visceral leishmaniasis (VL) is a life-threatening parasitic disease that requires robust CD4+ T cell-mediated immunity for parasite control. However, the heterogeneity and transcriptional dynamics of CD4+ T cell responses in VL remain poorly defined. In this study, we use a model of experimental VL with tissue-specific immunity and single-cell RNA sequencing to provide a high-resolution assessment of CD4+ T cell responses. Our analysis reveals the complexity of CD4+ T cell differentiation in VL, identifying distinct Th1 subsets with transcriptional heterogeneity that may reflect functional specialisation. Despite minimal transcriptional differences between splenic and hepatic CD4+ T cells, we identified shifts in subset composition, including the emergence of a stem-like CD4+ T cell population in the spleen, which was suppressed by the transcription factor Bhlhe40. Bhlhe40 deficiency skewed CD4+ T cell differentiation, impairing Th1 responses while promoting Tr1 cells, resulting in defective parasite control in the liver. Additionally, AmBisome treatment induced a profound transcriptional shift in CD4+ T cells, leading to the maintenance of stem-like CD4+ T cells in the spleen and the expansion of tissue resident memory-like cells in the liver. These findings uncover key regulatory mechanisms that shape CD4+ T cell differentiation in VL and provide insights into how immune-modulatory strategies could enhance long-term immunity.

immunology↗

bioRxiv2025

Acute testicular hyperthermia leads to a rapid loss of global piRNA levels and a consequent increase in transcript abundance, including LINE1 activity within heat-sensitive male germ cells.

ObjectiveTo understand the immediate impact that testicular heat stress has on isolated populations of precursor male germ cells including Spermatocytes and Spermatids. DesignMice were given testicular heat stress and pre-cursor male germ cells were immediately isolated. RNA sequencing was performed and validated using qPCR. SubjectsThis work was carried out in adult male CD1 mice. ResultsUsing next-generation RNA sequencing 134 differentially expressed transcripts were found to be differentially expressed upon exposure to testicular hyperthermia, 93% of which were upregulated. In addition, testicular hyperthermia induced 395 differential splicing events and altered the usage of 61 polyadenylation sites. To explain these observations and understand why transcript abundance appears to favour upregulation following testicular hyperthermia, we assessed global piRNA levels and found an overall, rapid reduction. Concomitantly, we observed an increase in transposable element RNA (LINE1) and protein (ORF1p) abundance. Furthermore, increased LINE1 expression appeared to be correlated with DNA damage in the male germline. At 24 hours post heat stress, piRNA levels recovered close to control levels, coincident with a significant reduction in LINE1 transcript expression within spermatocytes. ConclusionTesticular hyperthermia needs to be considered in the context of all reproductive outcomes. Affected spermatozoa are likely to be genetically compromised, leading to adverse outcomes such as infertility or loss of embryo following fertilization.

molecular biology↗

bioRxiv2025

Selective manipulation of excitatory and inhibitory neurons in top-down and bottom-up visual pathways using ultrasound stimulation

IntroductionTechniques for precise manipulation of neurons in specific neural pathways are crucial for excitatory/inhibitory (E/I) balance and investigation of complex brain circuits. Low-intensity focused ultrasound stimulation (LIFUS) has emerged as a promising tool for noninvasive deep-brain targeting at high spatial resolution. However, there is a lack of studies that extensively investigate the modulation of top-down and bottom-up corticothalamic circuits via selective manipulation of excitatory and inhibitory neurons. Here, a comprehensive methodology using electrophysiological recording and c-Fos staining is employed to demonstrate pulse repetition frequency (PRF)-dependent E/I selectivity of ultrasound stimulation in the top-down and bottom-up corticothalamic pathways of the visual circuit in rodents. Materials and methodsUltrasound stimulation at various PRFs is applied to either the lateral posterior nucleus of the thalamus (LP) or the primary visual cortex (V1), and multi-channel single-unit activity is recorded from the V1 using a silicon probe. Results and conclusionOur results demonstrate that high frequency PRFs, particularly at 3 kHz and 1 kHz, are effective at activating the bidirectional corticothalamic visual pathway. In addition, brain region-specific PRFs modulate E/I cortical signals, corticothalamic projections, and synaptic neurotransmission, which is imperative for circuit-specific applications and behavioral studies.

neuroscience↗

bioRxiv2025

WormID-Benchmark: Extracting Whole-Brain Neural Dynamics of C. elegans At the Neuron Resolution

The nematode C. elegans is a premier model organism for studying neural circuit function due to its fully mapped connectome and genetically identifiable neurons. Recent advances in 3D light microscopy and fluorescent protein tagging have enabled whole-brain imaging at single-neuron resolution. However, extracting meaningful neural dynamics from these high-resolution recordings requires addressing three fundamental challenges: (i) accurate detection of individual neurons in fluorescence images, (ii) precise identification of neuron classes based on anatomical and colorimetric cues, and (iii) robust tracking of neurons over time in calcium imaging videos. To systematically evaluate these challenges, we introduce WormID-Bench, a large-scale, multi-laboratory dataset comprising 118 worms from five distinct research groups, along with standardized evaluation metrics for detection, identification, and tracking. Our benchmark reveals that existing computational approaches show substantial room for improvement in sensitivity, specificity, and generalization across diverse experimental conditions. By providing an open and reproducible benchmarking framework1, WormID-Bench aims to accelerate the development of high-throughput and scalable computational tools for whole-brain neural dynamics extraction in C. elegans, setting the stage for broader advancements in functional connectomics.

neuroscience↗

bioRxiv2024

Temporally overlapping mechanisms diversify clonal B cell responses in vivo.

Naive B cells amplify and diversify their responses when activated by cognate antigen, via Myc-dependent clonal expansion, immunoglobulin class switch recombination (CSR), phenotypic variation, and somatic hypermutation (SHM). Whether these mechanisms act combinatorially in vivo to diversify clonal responses to a single pathogen remains unclear. Since diversity in the antigenic targets, functional classes, and production kinetics of parasite-specific antibodies influences immunity to malaria, we test here whether individual B cell clones diversify over time during Plasmodium infection and treatment. During the first week of infection, amid widespread Type I Interferon (IFN)-mediated bystander activation, CSR initiates soon after Myc up-regulation, and overlaps partially with clonal expansion, resulting in isotype variegation amongst clones. During the second week of infection, expanded clones that seed germinal centres (GC) bifurcate into extra-follicular plasmablasts, exhibit isotype variegation, and initiate SHM, revealing substantial intra-clonal diversification. Over the following month, GC clones exhibit SHM at approximately four mutations per week, with IgG mutational diversity and IgM+ cells also preserved in GCs over time. Anti-malarial intervention does not impede SHM, but instead exerts quantitative limits on GC size, plasma cell emergence, circulating IgG levels, and protection against re-infection. Finally, contemporaneous B cell development relocates from bone marrow to spleen during infection and treatment. Thus, multiple temporally overlapping mechanisms combine in vivo to amplify, diversify, and safeguard humoral immune responses. We present this data as a temporal, multi-parameter atlas of B cell differentiation in vivo: https://bcell-dynamics.science.unimelb.edu.au Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/628863v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@c57890org.highwire.dtl.DTLVardef@6e5936org.highwire.dtl.DTLVardef@a2e872org.highwire.dtl.DTLVardef@14abbac_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPartial temporal overlap of CSR with clonal expansion leads to isotype variegation in clones. C_LIO_LIClones seeding GCs bifurcate into plasmablasts and exhibit isotype variegation. C_LIO_LIGC B cells accrue [~]4 mutations/week, a rate unaffected by anti-malarials. C_LIO_LIPlasmodium infection triggers antigen-independent Type I IFN-mediated bystander activation. C_LIO_LIB cell development is preserved in malaria by shifting from bone marrow to spleen. C_LI

immunology↗

bioRxiv2024

Deconvoluting TCR-dependent & -independent activation is vital for reliable Ag-specific CD4+ T cell characterization by AIM assay

AIM assays are thought to detect antigen (Ag)-specific T cell responses in an HLA- and cytokine-independent manner. Recent studies using AIM assays identified prominent Th17-like (CCR6+) CD4+ T cells and circulating follicular T helper cells (cTfh) in anti-viral contexts, but were not observed with peptide/HLA tetramer staining. We demonstrate that CD39+ Treg-like and CD26hi Th22-like cells can be activated by cytokines in a TCR-independent manner during in vitro Ag stimulation, leading to non-specific upregulation of prototypical AIM readouts. Transcriptional analysis of memory CD4+ T cells that underwent TCR-dependent or -independent activation enabled discrimination of bona fide Ag-specific T cells from cytokine-activated Treg and Th22 cells. CXCR4 downregulation emerged as a hallmark of clonotypic expansion and TCR-dependent activation in memory CD4+ T cells and cTfh. Tracking tetramer-binding cells during re-stimulation showed that CXCR4-CD137+ cells provide a more accurate measure of the Ag-specific population than standard AIM readouts. This modified assay excludes the predominately CCR6+ cytokine-activated T cells that contribute to an average 12-fold overestimation of the Ag-specific population. As AIM assays enable the rapid study of T cell responses against emerging pathogens, our findings provide a highly accurate approach to characterize genuine Ag-specific T cell responses that contribute to protective immunity.

immunology↗

bioRxiv2024

SUMO Inhibition Plus CD40 Agonism Increases Anti-Tumor Immunogenicity Through Interferon Mediated Macrophage Activation

Resistance to immunotherapy is a cardinal feature of pancreatic ductal adenocarcinoma (PDAC). Inhibition of Small Ubiquitin-like MOdifier (SUMO), a post-translational modification with important immune regulatory functions, augments responsiveness to immunotherapy in non-PDAC models via pro-immunogenic effects on myeloid cells, cancer cells, and T-cells. Recently, it has been reported that SUMO inhibition has direct immunogenic effects on PDAC. Here, we report that the novel combination of SUMO inhibition with a small molecule, TAK-981, plus antibody-mediated CD40 agonism improves survival in an aggressive orthotopic mouse model of PDAC by enhancing anti-tumoral immunogenicity. This combination amplifies CD8+ T-cell tumor infiltration and induces significant changes among macrophages. TAK-981 also leads to enhanced cancer specific MHC-I expression both in vitro and in vivo by augmenting interferon signaling. We show that the improvement in survival is mediated by macrophages. Our findings show that SUMO inhibition complements CD40 agonism to enhance immune activity in PDAC via interferon signaling, improving survival in an aggressive pre-clinical model of PDAC and translating previous findings to a characteristically immunosuppressive and highly aggressive solid malignancy.

cancer biology↗

bioRxiv2024

Analysis of the progression of cervical cancer in Guatemala- from pre-malignancy to invasive disease

To better understand cervical cancer progression, we analyzed RNA from 262 biopsies from women referred for colposcopy We determined HPV type and analyzed the expression of 51 genes. HPV31 was significantly more prevalent in precancer than stage 1 cancer and invasive cancer (p < 0.0001) and HPV16 increased in invasive disease (p < 0.0001). CCNE1, MELTF, and ULBP2 were significantly increased in HPV16-positive compared to HPV31 precancers while NECTIN2 and HLA-E expression decreased. Markers of the innate immune system, DNA repair genes, and cell cycle genes are significantly increased during cancer progression (p = 0.0001). In contrast, the TP53 and RB1 tumor suppressor gene expression is significantly decreased in cancer cells. TheT cell markers CD28 and FLT3LG expression decreased in cancer while FOXP3, IDO1, and ULBP2 expression increased. There is a significantly higher survival rate in individuals with increased expression of CD28 (p = 0.0005), FOXP3 (p = 0.0002), IDO1 (p = 0.038), FLT3LG (p = 0.026), APOBEC3B (p = 0.0011), and RUNX3 (p = 0.019), and a significantly lower survival rate in individuals with increased expression of ULBP2 (p = 0.035). These results will help us understand the molecular factors influencing the progression of cervical precancer to cancer.

cancer biology↗

bioRxiv2024

Motor-driven microtubule diffusion in a photobleached dynamical coordinate system

Motor-driven cytoskeletal remodeling in cellular systems can often be accompanied by a diffusive-like effect at local scales, but distinguishing the contributions of the ordering process, such as active contraction of a network, from this active diffusion is difficult to achieve. Using light-dimerizable kinesin motors to spatially control the formation and contraction of a microtubule network, we deliberately photobleach a grid pattern onto the filament network serving as a transient and dynamic coordinate system to observe the deformation and translation of the remaining fluorescent squares of microtubules. We find that the network contracts at a rate set by motor speed but is accompanied by a diffusive-like spread throughout the bulk of the contracting network with effective diffusion constant two orders of magnitude lower than that for a freely-diffusing microtubule. We further find that on micron scales, the diffusive timescale is only a factor of {approx} 3 slower than that of advection regardless of conditions, showing that the global contraction and long-time relaxation from this diffusive behavior are both motor-driven but exhibit local competition within the network bulk. O_TEXTBOXSignificance StatementCytoskeletal reorganization can come at the cost of local diffusive-like disordering effects from the same active elements, but distinguishing these processes can be challenging. By photobleaching an actively contracting microtubule network, we show that the bulk redistribution of filaments exhibit a diffusion-like reorganization that can be tuned by the effective motor speed. By tuning these parameters, we show a conserved relationship between active contraction rates and effective diffusion constants, suggesting that while advection of the cytoskeletal network dominates over scales of tens to hundreds of microns, motors additionally induce a diffusive-like effect that begins to compete with advection at micron scales. C_TEXTBOX

biophysics↗

bioRxiv2024

Gut metagenomes of Asian octogenarians reveal metabolic potential expansion and distinct microbial species associated with aging phenotypes

While rapid demographic changes in Asia are driving the incidence of chronic diseases related to aging, the limited availability of high-quality in vivo data hampers our ability to understand complex multi-factorial contributions, including gut microbial, to healthy aging. Leveraging the availability of a well-phenotyped cohort of community-living octogenarians in Singapore, we used deep shotgun metagenomic sequencing to do high-resolution taxonomic and functional characterization of their gut microbiomes (n=234). Joint species-level analysis with other Asian cohorts identified a distinct age-associated shift in Asian gut metagenomes, characterized by a reduction in microbial richness, and enrichment of specific Alistipes and Bacteroides species (e.g. Alistipes shahii and Bacteroides xylanisolvens). Functional pathway analysis confirmed that these changes correspond to a metabolic potential expansion in aging towards alternate pathways that synthesize and utilize amino-acid precursors, relative to the dominant microbial guilds that typically produce butyrate in the gut from pyruvate (e.g. Faecalibacterium prausnitzii, Roseburia inulinivorans). Extending these observations to key clinical markers helped identify >10 robust gut microbial associations to inflammation, cardiometabolic and liver health, including potential probiotic species such as Parabacteroides goldsteinii and pathobionts such as Klebsiella pneumoniae, highlighting the role of the microbiome as biomarkers and potential intervention targets for promoting healthy aging.

genomics↗

bioRxiv2024

Bisphenol TMC disturbs mitochondrial activity and biogenesis, reducing lifespan and healthspan in the nematode Caenorhabditis elegans

Rising concerns about Bisphenol A (BPA) toxicity have prompted the search for safer alternatives. However, concerns persist regarding the safety of replacements like bisphenol TMC (BPTMC), a rapidly emerging BPA substitute. Utilizing the in vivo model organism Caenorhabditis elegans (C. elegans), whose shared genes mirror human biology, we aim to unveil the potential toxicity of BPTMC on a live animal. C. elegans exposed to 1 mM BPTMC exhibited developmental delays, reduced reproduction, and diminished longevity. Furthermore, an investigation into mortality at various animal stages, oxidative stress, and thermal stress revealed additional compromised toxicity. Notably, exposure to BPTMC resulted in mitochondrial abnormalities, including reduced oxygen consumption, lowered mitochondrial membrane potential, and decreased ATP levels. Additionally, BPTMC increased ROS levels but decreased mitochondrial population. Transcriptome analysis revealed that BPTMC induces alterations in the expression of genes associated with mitochondrial biogenesis. Our findings raise crucial concerns about BPTMC as a safe BPA alternative. The observed widespread toxicity across key life stages suggests a need for further investigation into the potential toxicity of BPTMC on human health and environmental consequences.

pharmacology and toxicology↗