Biology subjects

Caldwell, R.

Publications and source records attributed to Caldwell, R..

7 recordsLinked to original sources

bioRxiv2026

Population genomics of skin Staphylococcus reveals disease-associated restructuring of species and strain diversity

Whole genome sequences of microbial isolates are essential to link microbial diversity to population and community ecology, because metagenomics alone cannot resolve strain-level variation, particularly in complex and mobile genetic elements that confer strain-specific traits such as virulence. We cultured and whole-genome sequenced 2,920 Staphylococcus isolates from healthy subjects and patients with Dariers disease and congenital ichthyosis. Our results show that disease imposes selection at the species level, while strain populations within those species diversify across individuals in a manner consistent with ecological drift, resulting in increased interpersonal heterogeneity of strain composition. Despite this variability, strain populations converged on shared functional traits, suggesting constraints imposed by the disease environment. We further examined key functional elements of clinical and ecological relevance, including the agr quorum sensing system, the mobile genetic element SCCmec that carries methicillin resistance, and CRISPR/Cas systems, contextualizing these features both within isolate population structure and the surrounding microbial community using metagenomic data. We found disease-dependent enrichment of virulence genes, striking species-specific phylogenetic sorting of agr variants, unexpected modularity of previously undocumented SCCmec elements in diseased skin, and links between phages in the microbiota and CRISPR spacers in the isolate genomes. Taken together, our integrated, large-scale analysis of isolate genomics and metagenomics reveals that skin disease restructures staphylococcal strain populations through combined effects of selection, drift, and functional constraint. One line summaryWhole-genome sequencing of 2,920 skin Staphylococcus isolates shows that disease selects at the species level while reshaping strain populations and their functional diversity within hosts.

microbiology↗

bioRxiv2024

BioMapAI: Artificial Intelligence Multi-Omics Framework Modeling of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic illness with a multifactorial etiology and heterogeneous symptomatology, posing major challenges for diagnosis and treatment. Here, we present BioMapAI, a supervised deep neural network trained on a four-year, longitudinal, multi-omics dataset from 249 participants, which integrates gut metagenomics, plasma metabolomics, immune cell profiling, blood laboratory data, and detailed clinical symptoms. By simultaneously modeling these diverse data types to predict clinical severity, BioMapAI identifies disease- and symptom-specific biomarkers and robustly classifies ME/CFS in both held-out and independent external cohorts. Using an explainable AI approach, we construct the first connectivity map spanning the microbiome, immune system, and plasma metabolome in health and ME/CFS, adjusted for age, gender, and additional clinical factors. This map uncovers disrupted associations between microbial metabolism (e.g., short-chain fatty acids, branched-chain amino acids, tryptophan, benzoate), plasma lipids and bile acids, and heightened inflammatory responses in mucosal and inflammatory T cell subsets (MAIT, {gamma}{delta}T) secreting IFN{gamma} and GzA. Overall, BioMapAI provides unprecedented systems-level insights into ME/CFS, refining existing hypotheses and hypothesizing new pathways associated to the diseases heterogeneous symptoms.

bioinformatics↗

bioRxiv2024

Genotype-environment-driven dysbiosis in the skin microbiome of ichthyosis

Monogenic skin disorders such as ichthyosis introduce multiple sources of disturbance to the skin, including the direct biochemical consequences of the genotype, the phenotypic changes in skin physiology, and an altered skin microbiome. The association between changes in the skin microbiome and the diseases genotypic and phenotypic effects are of both ecological and clinical interest but are historically obscured by 1) the limited resolution of metagenomic profiles, and 2) additional sources of variation such as age and topical/oral treatments. Here we characterize the skin microbiome from seven ichthyosis genotypes, at species, strain, and metabolic pathway levels. Critically, we assess the association between these microbiome features and the ichthyosis genotype and phenotype while adjusting for contextual host covariables. We show that the ichthyosis genotype, especially that caused by mutations in TGM1, and the ichthyosis phenotype, particularly transepidermal water loss (TEWL), and personal covariables, such as topical emollients and oral retinoids, collectively, and sometimes antagonistically, influence the species community, strain population, and metabolic potential of the skin microbiome. One Sentence SummarySpecies, strain, and the composition of metabolic pathways of the cutaneous microbiome in ichthyosis are influenced by the mutation genotype of ichthyosis, phenotypic features of ichthyosis such as transepidermal water loss, scaling, and skin hydration, and host age and treatment.

microbiology↗

bioRxiv2023

Species- and strain-effects in interferon, innate immunity, and barrier transcriptional response of microbiome interactions of 3D respiratory epithelial cultures

The microbiome modulates the respiratory epitheliums immunomodulatory functions. To explore how the microbiomes biodiversity affects microbe-epithelial interactions, we screened 58 phylogenetically diverse microbes for their transcriptomic effect on tracheobronchial air-liquid interface cell (ALI) cultures. We found distinct species- and strain-level differences in host innate immunity, and epithelial barrier response. Strikingly, we found that host interferon, an antiviral immune response, was one of the most variable host processes, and this variability was not driven by microbial phylogenetic diversity, bioburden, nor by the microbes ability to stimulate other innate immunity pathways. Our study provides a foundation for understanding how the respiratory microbiomes biodiversity affects epithelial, and particularly, antiviral innate immunity.

microbiology↗

bioRxiv2023

RNA binding proteins and glycoRNAs form domains on the cell surface for cell penetrating peptide entry

The composition and organization of the cell surface determine how cells interact with their environment. Traditionally, glycosylated transmembrane proteins were thought to be the major constituents of the external surface of the plasma membrane. Here, we provide evidence that a group of RNA binding proteins (RBPs) are present on the surface of living cells. These cell surface RBPs (csRBPs) precisely organize into well-defined nanoclusters that are enriched for multiple RBPs, glycoRNAs, and their clustering can be disrupted by extracellular RNase addition. These glycoRNA-csRBP clusters further serve as sites of cell surface interaction for the cell penetrating peptide TAT. Removal of RNA from the cell surface, or loss of RNA binding activity by TAT, causes defects in TAT cell internalization. Together, we provide evidence of an expanded view of the cell surface by positioning glycoRNA-csRBP clusters as a regulator of communication between cells and the extracellular environment.

cell biology↗

bioRxiv2022

Individually unique, fixed body patterns of Octopus chierchiae allow for photo-identification in long-term studies

The Lesser Pacific Striped Octopus, Octopus chierchiae, is a small iteroparous octopus known to inhabit intertidal regions of the Pacific coast of Central America. Many details about its life history and ecology remain unknown. For apparently rare and delicate animals such as O. chierchiae, non-extractive sampling methods are necessary to study individuals and populations over time. After photographically documenting the physical development of 25 octopuses from hatching, we have concluded that O. chierchiae has individually unique stripe configurations that remain constant throughout their post-hatchling lifetimes. Furthermore, using photographs taken of animals in captivity on different dates over many months, we show that untrained volunteers can accurately identify whether or not a pair of images depicts the same individual octopus. These results demonstrate that laboratory-reared individuals could be identified via photographs taken at different points in their lifetimes, which suggests wild individuals can also be recognized and observed for longitudinal field studies. In addition, our results imply potential for photoidentification and community science to be used as non-extractive, non-intrusive sampling methods for future studies of wild O. chierchiae.

zoology↗

bioRxiv2019

Analytical characterization of Parylene-C degradation mechanisms on Utah arrays: evaluation of in vitro Reactive Accelerated Aging model compared to multiyear in vivo implantation

Implantable neural microelectrodes are integral components of neuroprosthetic technologies and can transform treatments for many neural-mediated disorders. However, dielectric material degradation during long-term (> 1 year) indwelling periods restricts device functional lifetimes to a few years. This comprehensive work carefully investigates in vivo material degradation and also explores the ability of in vitro Reactive Accelerated Aging (RAA) to evaluate implant stability. Parylene C-coated Utah electrode arrays (UEAs) implanted in feline peripheral nerve for 3.25 years were explanted and compared to RAA-processed devices, aged in phosphate buffered saline (PBS) + 20 mM H2O2 at either 67 or 87 {degrees}C (28 or 7 days, respectively). Electron microscopy revealed similar physical damage characteristics between explants and RAA (87{degrees} C) devices. Parylene C degradation was overwhelmingly apparent for UEAs from both RAA cohorts. Controls aged in PBS alone displayed almost no damage. Spectroscopic characterization (EDX, XPS, FTIR) found clear indications of oxidation and chlorine abstraction for parylene C aged in vivo. While in vitro aging was also accompanied by signs of oxidation, changes in the chemistry in vivo and in vitro were statistically different. Analysis of RAA- aged devices identified UEA fabrication approaches that may greatly improve device resistance to degradation. This work underscores the need for an improved understanding of in vivo damage mechanisms, to facilitate the critical need for representative in vitro accelerated testing paradigms for long-term implants.

bioengineering↗