Biology subjects

Martin, C. G.

Publications and source records attributed to Martin, C. G..

5 recordsLinked to original sources

bioRxiv2025

Ecological relationships between human gut bacteria predicted from analysis of dense microbiome time series data from US travelers in Bangladesh

Gut microbiomes provide critical host homeostatic functions, resulting from a complex web of ecological interactions among community members. We studied these interactions using a time-lagged correlational strategy of dense longitudinal sequence data from Western individuals traveling abroad to Bangladesh who experienced diarrhea. We identified both negative (140) and positive (78) relationships between bacterial pairs. Positive relationships occurred in pairs that were significantly more phylogenetically distant, such as inter-order associations between Clostridiales and Bacteroidales, while negative relationships were more between more phylogenetically related pairs. Further analysis of computationally predicted genome content and metabolic pathways revealed that cooperative bacterial pairs overlapped less in function and offered each other metabolic support, while competitive pairs were more likely to compete for the same resources. Predicted levels of B vitamins (B5 and B3), enoyl acyl- carrier protein (acp) reductase II (FabK) and its metabolites, and nucleotide/nucleoside derivatives were able to differentiate negatively and positively associated microbe pairs. Ultimately, our findings show that combining time-series analysis with metabolic/genomic network analysis can identify relationships between bacteria with plausible causal mechanisms that are consistent with existing ecological and biochemical observations. IMPORTANCEUnderstanding how microbes in the gut interact with each other is important for devising strategies to target the human gut microbiome therapeutically. For instance, understanding competitive relationships, where a shared need of similar limited resources limits the degree to which two microbes can co-exist, can inform strategies for limiting colonization of undesirable microbes. Understanding cooperative relationships, where one microbe provides the other with substrates needed for growth, can inform strategies to promote desirable microbes. By evaluating dense time-series gut microbiome data from individuals who experienced diarrhea while traveling, we were able to predict both cooperative and competitive relationships among human gut microbes as those whose abundances were significantly related within an individual over time. Strikingly, in subsequent analyses performed using inferred genomic information, pairs with negative associations from the time series analysis were predicted to compete over more metabolic substrates, and pairs with positive associations had significantly more metabolic complementarity. These predictions regarding the underlying molecular bases of interactions could inform how nutritional environment will impact interactions between gut microbiome community members.

microbiology↗

bioRxiv2025

Network-based framework for studying etiology and phenotype diversity in primary ciliopathies

Recent advances in sequencing technologies have increasingly enabled the identification of genetic causes for human monogenic diseases. However, systematic understanding remains limited due to the rarity, genetic heterogeneity, and complex genotype-phenotype relationships of these diseases. Primary ciliopathies are a diverse group of rare disorders caused by variants in genes associated with the cilium, a cellular organelle involved in signaling during development and cell homeostasis. These genetic variants result in a wide spectrum of clinical phenotypes involving the brain, eye, kidney and skeleton. It remains unclear to what extent this phenotypic diversity can be attributed to the disease-causing genes and their specific roles in ciliary function. Here, we systematically compared human primary ciliopathies with each other and with mouse phenotypes by propagating known disease genes through a network of protein interactions. Network propagation improved the clustering of primary ciliopathies with shared clinical phenotypes and facilitated the identification of mouse phenotypes closely related to primary ciliopathies due to shared groups of proteins in the interaction network. By leveraging this phenotype-specific approach, we prioritized candidate genes for ciliopathies and identified likely pathogenic variants in CEP43, a novel candidate gene for human primary ciliopathies in three previously unsolved cases. This study demonstrates that network propagation enhances the genetic and phenotypic understanding of primary ciliopathies, aiding in the prioritization of candidate genes and identification of relevant mouse models for these rare disorders, and providing a framework for unraveling shared underlying mechanisms for other rare genetic diseases.

genetics↗

bioRxiv2024

Multimodal state-dependent connectivity analysis of arousal and autonomic centers in the brainstem and basal forebrain

Vigilance is a continuously altering state of cortical activation that influences cognition and behavior and is disrupted in multiple brain pathologies. Neuromodulatory nuclei in the brainstem and basal forebrain are implicated in arousal regulation and are key drivers of widespread neuronal activity and communication. However, it is unclear how their large-scale brain network architecture changes across dynamic variations in vigilance state (i.e., alertness and drowsiness). In this study, we leverage simultaneous EEG and 3T multi-echo functional magnetic resonance imaging (fMRI) to elucidate the vigilance-dependent connectivity of arousal regulation centers in the brainstem and basal forebrain. During states of low vigilance, most of the neuromodulatory nuclei investigated here exhibit a stronger global correlation pattern and greater connectivity to the thalamus, precuneus, and sensory and motor cortices. In a more alert state, the nuclei exhibit the strongest connectivity to the salience, default mode, and auditory networks. These vigilance-dependent correlation patterns persist even after applying multiple preprocessing strategies to reduce systemic vascular effects. To validate our findings, we analyze two large 3T and 7T fMRI datasets from the Human Connectome Project and demonstrate that the static and vigilance-dependent connectivity profiles of the arousal nuclei are reproducible across 3T multi-echo, 3T single-echo, and 7T single-echo fMRI modalities. Overall, this work provides novel insights into the role of neuromodulatory systems in vigilance-related brain activity.

neuroscience↗

bioRxiv2022

Epithelia delimits glial apical polarity against mechanical shear to maintain glia-neuron architecture

For an organ to maintain proper architecture and function, its different component cell-types must coordinate their cell-shapes with each other through life. While cell-intrinsic developmental mechanisms driving homotypic cell-cell coordination are known, how heterotypic cells collectively regulate cell-shape is less-clear. We report that, in a sense-organ, epithelial cells delimit and maintain polarity domains of contacting glia, and thereby, associated neuron shapes throughout life. Briefly, Hsp co-chaperone UNC-23/BAG2 keeps epithelial apical domains from deforming with animal movement. Epithelial apical domains stretch aberrantly and progressively in adult unc-23 mutant animals, which in an FGFR-dependent manner, dislocates glial apical cytoskeleton proteins SMA-1/{beta}H-Spectrin and actin. This alters glial apical polarity and cell shape, and concomitantly, associated neuron-ending shape. Notably, UNC-23 acts temporally at a developmental critical period to maintain glia-neuron shape in adults, and spatially within a defined anatomical zone. Lastly, intervention in either epithelia, glia or neuron ameliorate or phenocopy unc-23 neural defects. Epi/endothelia resist mechanical stress and contact glia-neuron units across central/peripheral nervous systems and species, and all components of the identified molecular pathway are conserved and disease-relevant. Thus, we posit that analogous epithelia-glia mechanobiological coupling may broadly regulate glia-neuron shapes through animal life.

neuroscience↗

bioRxiv2019

Dietary fat and fiber impacts intestinal microbiome resilience to antibiotics and Clostridoides difficile infection in mice

Clostridioides difficile infection (CDI), is the leading cause of hospital-acquired diarrhea and emerging evidence has linked dietary components with CDI pathogenesis, suggesting that dietary modulation may be an effective strategy for prevention. Here, we show that mice fed a high-fat/low-fiber "Western type" diet (WD) had dramatically increased mortality in a murine model of antibiotic-induced CDI compared to a low-fat/low-fiber (LF/LF) diet and standard mouse chow controls. We found that the WD had a pro- C. difficile bile acid composition that was driven in part by higher levels of primary bile acids that are produced to digest fat, and a lower level of secondary bile acids that are produced by the gut microbiome. This lack of secondary bile acids was associated with a greater disturbance to the gut microbiome with antibiotics in both the WD and LF/LF diet compared to mouse chow. Mice fed the WD also had the highest level of toxin TcdA just prior to the onset of mortality, but not of TcdB or increased inflammation. These findings indicate that dietary intervention to decrease fat may complement previously proposed dietary intervention strategies to prevent CDI in high-risk individuals. One Sentence SummaryA high-fat/low-fiber Western type diet promoted mortality in a mouse model of antibiotic-induced C. difficile infection compared to a low-fat/low-fiber diet and chow diet, suggesting that lower dietary fat may be an effective strategy for preventing C. difficile pathology.

microbiology↗