Biology subjects

Nathan, V.

Publications and source records attributed to Nathan, V..

9 recordsLinked to original sources

bioRxiv2026

Impaired Fermentation in the Absence of Gut Microbiota Promotes Inulin-Induced Intestinal Inflammation

Background and aims: Inflammatory bowel diseases (IBD) are characterized by altered gut microbiota composition and impaired dietary fiber fermentation, which can complicate symptom management. Although inulin is a well-established prebiotic fiber, it can exacerbate gut inflammation under certain conditions. We hypothesized that impaired microbial fermentation leaves intact inulin in the gut to activate epithelial immune receptors and promote inflammation, whereas effective fermentation reduces this pro-inflammatory signaling. Methods: We used germ-free (GF) and conventional (CONV) interleukin-10 knockout (Il10-/-) and wild-type (WT) C57BL/6J mice to assess the role of microbial fermentation and host genetic susceptibility in IBD. GF Il10-/- mice were colonized with fecal microbiota from ulcerative colitis (UC) patients or healthy individuals with fiber intolerance (FI). Mice were fed inulin or structurally distinct, physicochemically matched fiber analogs. Colonic inflammatory and barrier-related gene expression and protein levels were assessed by qPCR and ELISA. Results: In GF Il10-/- mice, inulin, but not cellulose, induced weight loss, diarrhea, and rectal prolapse. Increased colonic toll-like receptor expression (TLR2, TLR4) as well as elevated serum amyloid A (SAA) and lipocalin-2 levels indicated immune activation by unfermented inulin in GF mice. Colonization with dysbiotic microbiota attenuated these effects. {beta}-fructan fibers including fructooligosaccharides and chicory-derived inulin elicited marked inflammatory responses, whereas agave-derived inulin did not, highlighting the influence of fiber composition in inflammation associated with IBD. Conclusions: Effective microbial fermentation is essential for host tolerance to fermentable fibers. These findings underscore the need of personalized nutrition when recommending fiber supplementation in immune-compromised individuals or those with gut dysbiosis.

immunology↗

bioRxiv2026

LAP-TLR2 Axis Drives Inflammatory Pathology during Listeria monocytogenes Gastroenteritis

Listeria monocytogenes (Lm) causes acute gastroenteritis that precedes systemic invasive listeriosis, yet the molecular mechanisms coordinating bacterial virulence with host inflammatory responses during the enteric phase remain poorly understood. We show that Lm-associated gastroenteritis is dose-dependent, and a high infectious dose (~1x10^10 CFU/mouse), reflecting epidemic cases, recapitulates hallmark features of gastroenteritis in a mouse model, including early onset, epithelial erosion, and profound inflammatory cell infiltration. We identify Listeria adhesion protein (LAP), rather than classical virulence factors such as internalin A and listeriolysin O, as the primary mediator of enteric pathology, driving epithelial cell death and neutrophil recruitment. Transcriptomic (mRNA-seq) profiling implicates LAP-driven engagement of the TLR2-MyD88 pathway. Using the HEK-Dual hTLR2 (NF-kB) reporter cell line and TLR2 knockout mice, we show that LAP engages TLR2 to activate TNFalpha; NF-kB signaling and compromises the gut epithelial barrier. Disease severity correlates with myeloid hyperactivation and intestinal ion channel dysregulation, as CD11b-; mice exhibit attenuated diarrhea despite elevated bacterial tissue loads. Finally, studies in MLCK knock-out mice confirm that this myeloid-driven pathology requires MLCK-dependent tight junction opening for paracellular neutrophil migration, which works in concert with LAP-TLR2 signaling during Lm-induced gastroenteritis.

microbiology↗

bioRxiv2026

Microbial Growth in an Enceladus Ocean Analog Medium Informed by Mineral Stability Modeling

Evidence from the Cassini mission confirmed that Saturns moon Enceladus hosts a subsurface alkaline ocean where rock-water reactions may generate redox disequilibria capable of supporting microbial metabolisms. To investigate potential microbial survival under simulated Enceladus ocean conditions, we used thermodynamic modeling to develop a salt formulation consistent with one possible Enceladus ocean composition and supplemented it with putative microbial energy sources to create a growth medium. The medium was inoculated with samples from diverse ocean world analog environments on Earth to determine which microorganisms could persist under Enceladus-like conditions. The microorganisms persisting in this geochemically bounded medium were heterotrophic, metabolically versatile bacteria with low carbon requirements. Genomic and physiological analyses further showed the presence of multiple stress-response pathways, sodium-based bioenergetic systems, osmoregulation strategies, and other adaptations consistent with survival in alkaline, low-nutrient settings. These results suggest that some stress-tolerant heterotrophic bacteria may serve as useful model organisms for life in Enceladus subsurface ocean. These findings demonstrate the value of geochemically modeled media as a framework for constraining habitability, identifying relevant biosignatures, and probing potential microbial survival strategies beyond Earth.

microbiology↗

bioRxiv2026

Jag2 patterns early differentiation in the epidermal stem cell layer

Adult stem cell function depends on continuous input from the surrounding microenvironment. However, the cues that pattern this function in high turnover tissue that undergo continuous cellular remodeling remain poorly understood. Here we demonstrate that inputs from epithelial neighbors at distinct stages of differentiation cooperatively influence cell fate in the skin epidermis. Stem cells initiate differentiation of their neighbors via the Notch ligand Jag2, linking fate decisions to the composition of the local stem cell environment. When this signal is lost, misoriented divisions and engagement with distinct ligands in the suprabasal layers can partially restore upward flux differentiating cells. Although these mechanisms help to sustain barrier function, they ultimately disrupt tissue architecture, underscoring the need for balanced fates in the stem cell compartment. Together, our findings demonstrate that distinct cellular environments reinforce early epidermal differentiation, with stem cells themselves acting as key mediators of cell fate and tissue organization.

cell biology↗

bioRxiv2026

Experimental Quality Control Induces Changes in Allen Mouse Brain Connectomes

The Allen Mouse Brain Connectivity Atlas (AMBCA) is widely used to represent structural connectivity in the mouse brain. The AMBCA consists of tracer injection experiments where neuronal projections axonally connected to the initial injection site are labelled. The resulting whole-brain structural connectomes, derived from a subset of these experiments in C57BL/6 mice, have been used in several studies of connectomic architectures. However, through close inspection of n=437 distinct experiments used in a publicly-available connectome (Knox et al., 2018), we observed experiments with off-target injections, diffuse projections, unrealistically small injections and projections, and anatomical misalignments, affecting the accuracy and applicability of these connectivity experiments. We applied a combined automated and manual quality control (QC) and identified n=56 ([~]13% of the original n=437) experiments representing a wide variety of injection and projection failures across the brain. Automated QC was used to detect extreme injection and projection sizes and misalignments, while manual QC was used to detect subtle off-target tracer spreading. Using the remaining n=381 experiments, we rebuilt two different connectomes using previously-published methods; specifically: the regionalized voxel model from Knox et al. (2018), and the homogeneous model from Oh et al. (2014). Our rebuilt connectomes show strong losses in connectivity between regions with limited evidence of structural connectivity by other methods (e.g. hippocampus-medulla, cerebellum-isocortex) and gains in connectivity between regions with strong connectivity evidence (hypothalamus-cerebellum, hypothalamus-isocortex). Finally, we analyzed the rich club and community organization to demonstrate the potential downstream impacts on the representation of the overall structural connectome architectures of our QCd connectomes and observed subtle whole-brain organizational changes. We present our rebuilt connectomes, and particularly highlight the regionalized voxel model, as more accurate representations of structural connectivity derived from the AMBCA.

neuroscience↗

bioRxiv2025

Lower Bound Estimates for Electrophysiological Power Dissipation in Human Gray Matter

The human brain is popularly described as remarkably energy efficient, with its metabolic power consumption estimated at approximately 20 watts (W). Biophysical models have partitioned this power budget across distinct cellular processes, but these theoretical estimates have yet to be empirically constrained using whole-brain electrophysiological data. Here, we used magnetoencephalography (MEG) source imaging of resting-state human brain activity to derive empirical lower-bound estimates of electrical power dissipation in cortical gray matter. We found that the total power dissipated by currents, primarily associated with post-synaptic potentials, ranges between 10-9 and 10-10 W, several orders of magnitude lower than prevailing metabolic estimates. Using finite element modeling (FEM), we observed that electrophysiological power dissipation is predominantly confined to gray matter. Additionally, spatial variations in MEG-derived power dissipation partially correlated with regional oxygen metabolism measured by PET, yet notable discrepancies emerged across large-scale functional brain networks. These results underscore a critical divergence between electrophysiological and metabolic indices of brain energy use, and highlight the need for more integrated biophysical models to bridge this gap and better characterize the physiological underpinnings of regional brain energetics.

neuroscience↗

bioRxiv2025

Slow wave stimulation using a smartwatch improves sleep quality

BackgroundSlow-wave sleep is critical for sleep quality, cognitive function, and mood. Slow-wave entrainment (SWE) via rhythmic sensory stimulation can enhance slow-wave activity. However, existing implementations rely on EEG systems, thereby limiting accessibility and scalability. Consumer smartwatches offer an opportunity to deliver SWE in home settings without EEG hardware. ObjectiveThis study evaluated whether smartwatch-delivered sensory stimulation applied during smartwatch-estimated deep sleep elicits acute changes in frontal slow-wave EEG activity during home sleep, and whether individual differences in neural responsiveness to stimulation are associated with next-day behavioral and sleep measures. MethodsIn a randomized crossover design, participants recruited offline from the Boston area slept at home for two nights while wearing a consumer smartwatch for stimulation delivery and a portable EEG headband for neural recording. On a single night, participants received block-wise auditory, vibrotactile, or combined stimulation, guided by an automated on-watch sleep-staging model based on heart rate and motion. On the other night, no stimulation was delivered. Event-related changes in frontal delta (1-4 Hz) power were quantified relative to pre-stimulation baselines. Sleep disruption, subjective sleep quality, mood, and cognitive performance were assessed using questionnaires and a computerized Trail Making Test emailed to participants and completed online. ResultsInitiation of sensory stimulation was associated with significant increases in frontal delta power relative to pre-stimulation baseline and matched non-stimulation blocks.Stimulation blocks exhibited lower disruption rates than non-stimulation blocks, suggesting improved sleep stability during stimulation periods. No significant group-level differences were observed between stimulation and non-stimulation nights on measures of sleep quality, mood, or cognition. However, across participants, larger stimulation-evoked increases in delta power were associated with more favorable next-day subjective sleep and mood ratings and fewer clicks to complete the Trail Making Test. 68/93 participants were stimulated overnight. ConclusionsSmartwatch-based slow-wave entrainment delivered during home sleep can elicit reproducible delta EEG responses without sleep disruption. Individual differences in neural responsiveness to stimulation were associated with next-day behavioral measures, suggesting that wearable-based SWE may represent a scalable and accessible approach for improving sleep health. Trial RegistrationThe experiment was retrospectively registered at ISRCTN (registration number pending)

neuroscience↗

bioRxiv2024

A novel quinone biosynthetic pathway illuminates the evolution of aerobic metabolism

The dominant organisms in modern oxic ecosystems rely on respiratory quinones with high redox potential (HPQs) for electron transport in aerobic respiration and photosynthesis. The diversification of quinones, from low redox potential in anaerobes to HPQs in aerobes, is assumed to have followed Earths surface oxygenation [~]2.3 billion years ago. However, the evolutionary origins of HPQs remain unresolved. Here, we characterize the structure and biosynthetic pathway of a novel ancestral HPQ, methyl-plastoquinone, that is unique to bacteria of the phylum Nitrospirota. Methyl-plastoquinone is structurally related to the two previously known HPQs, plastoquinone from Cyanobacteriota/chloroplasts and ubiquinone from Pseudomonadota/mitochondria, respectively. We demonstrate a common origin of the three HPQ biosynthetic pathways that predates the emergence of Nitrospirota, Cyanobacteriota, and Pseudomonadota. An ancestral HPQ biosynthetic pathway evolved [≥] 3.4 billion years ago in an extinct lineage and was laterally transferred to these three phyla [~]2.5-3.2 billion years ago. We show that Cyanobacteriota and Pseudomonadota were ancestrally aerobic and thus propose that aerobic metabolism using HPQs significantly predates Earths surface oxygenation. Two of the three HPQ pathways were later obtained by eukaryotes through endosymbiosis forming chloroplasts and mitochondria, enabling their rise to dominance in modern oxic ecosystems. Significance statementOxygenic photosynthesis and aerobic respiration by bacteria and eukaryotes rely on respiratory quinones with high redox potential that facilitate membrane-bound electron transport. These quinones are integral to aerobic metabolism and therefore the evolution of aerobic metabolism and quinone biosynthesis must be intertwined. Only two types of high redox potential quinones have been described in bacteria and eukaryotes. Here, we describe the structure and biosynthetic pathway of a third type, methyl-plastoquinone, that is exclusive to bacteria of the phylum Nitrospirota. We then use phylogenetic analysis to show that the three high redox potential quinones have a single evolutionary origin and are much older than previously considered, predating the Great Oxygenation Event, when significant amounts of O2 first accumulated in the atmosphere.

microbiology↗

bioRxiv2023

Topological stratification of continuous genetic variation in large biobanks

Biobanks now contain genetic data from millions of individuals. Dimensionality reduction, visualization and clustering are standard when exploring data at these scales; while efficient and tractable methods exist for the first two, clustering remains challenging because of uncertainty about sources of population structure. In practice, clustering is commonly performed by drawing shapes around dimensionally reduced data or assuming populations have a "type" genome. We propose a method of clustering data with topological analysis that is fast, easy to implement, and integrates with existing pipelines. The approach is robust to the presence of sub-populations of varying sizes and wide ranges of population structure patterns. We use UMAP and HDBSCAN, respectively methods of dimensionality reduction and density clustering, on data from three biobanks. We illustrate how topological genetic strata can help us understand structure within biobanks, evaluate distributions of genotypic and phenotypic data, examine polygenic score transferability, identify potential influential alleles, and perform quality control.

genomics↗