Biology subjects

Cox, L.

Publications and source records attributed to Cox, L..

5 recordsLinked to original sources

bioRxiv2026

MicroRNA regulatory targets of VO2peak in older adult participants of the Study of Muscle Mobility and Aging (SOMMA)

Skeletal muscle aging (sarcopenia) is associated with reduced peak oxygen consumption (VO peak) during exercise, a key determinant of physical function and overall health. However, the molecular mechanisms linking muscle aging to low VO peak remain poorly understood. We aimed to identify miRNA signatures and miRNA-gene regulatory networks associated with VO peak in older adults. Using small RNA and mRNA sequencing, we analyzed skeletal muscle from 72 SOMMA participants (70-79 years old) with low or high VO peak (n = 18/group) and from 36 participants spanning the full VO peak spectrum. Differential expression was assessed using LIMMA, with pathway and network analyses performed using Ingenuity Pathway Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA). We detected 1,408 miRNAs and 16,210 genes; among these, 14 miRNAs and 2,018 genes were differentially expressed (FDR < 0.05). The 14 miRNAs regulated 142 genes, and expression of 10 miRNAs inversely correlated with 50 genes enriched in mitochondrial, sirtuin-1, and nitric oxide signaling pathways. Regression analyses identified 21 miRNAs and 1,744 genes significantly correlated with VO peak after adjusting for age and sex. WGCNA revealed 10 co-expression modules associated with VO peak, with the cyan module showing the strongest correlation and enrichment for nitric oxide signaling genes. These findings highlight novel miRNA-mediated molecular pathways potentially contributing to low VO peak and skeletal muscle aging in older adults. Future studies will further investigate these miRNA-gene interactions to uncover therapeutic targets for preserving muscle function with age.

molecular biology↗

bioRxiv2024

Mycelium as a scaffold for biomineralized engineered living materials

Engineered living materials (ELMs) are garnering considerable attention as a promising alternative to traditional building materials because of their potentially lower carbon footprint and additional functionalities conferred by living cells. However, biomineralized ELMs designed for load-bearing purposes are limited in their current design and usage for several reasons, including (1) low microbial viability and (2) limited control of specimen internal microarchitecture. We created third generation biomineralized ELMs from fungal mycelium scaffolds that were mineralized either by the fungus itself or by ureolytic bacteria. Both self-mineralized (i.e. fungally-mineralized) and bacterially-mineralized scaffolds retained high microbial viability for at least four weeks in room temperature or accelerated dehydration storage conditions, without the addition of protectants against desiccation. The microscale modulus of calcium carbonate varied with the different biomineralized scaffold conditions, and moduli were largest and stiffest for bacterial biomineralization of fungal mycelium. As an example of how mycelium scaffolds can enable the design of complex internal geometries of biomineralized materials, osteonal-bone mimetic architectures were patterned from mycelium and mineralized using ureolytic bacteria. These results demonstrate the potential for mycelium scaffolds to enable new frontiers in the design of biomineralized ELMs with improved viability and structural complexity. Progress and PotentialBiomineralized engineered living materials (ELMs) offer new approaches for increasing the sustainability of building materials and processes. However, the design and usage of biomineralized ELMs is constrained by several important limitations, including low microbial viability and limited ability to control internal microarchitecture. Fungal mycelium scaffolds, biomineralized by either fungi or bacteria, achieve much higher viability of ureolytic microorganisms than what has been reported for biomineralized ELMs. Further, mycelium scaffolds permit the manufacturing of complex architectures, such as inspired by the structure of osteonal bone. Mycelium scaffolds have the potential to enable new frontiers in the design and use of biomineralized ELMs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=71 SRC="FIGDIR/small/592484v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@338d98org.highwire.dtl.DTLVardef@94f956org.highwire.dtl.DTLVardef@7d8ed6org.highwire.dtl.DTLVardef@12cb61e_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2021

Human gut derived Anaerotruncus colihominis ameliorates experimental autoimmune encephalomyelitis

BackgroundThe gut microbiome plays an important role in autoimmunity including multiple sclerosis and its mouse model called experimental autoimmune encephalomyelitis (EAE). Prior studies have demonstrated that the multiple sclerosis gut microbiota can contribute to disease hence making it a potential therapeutic target. In addition, antibiotic treatment has been shown to ameliorate disease in the EAE mouse model of multiple sclerosis. Yet, to this date, the mechanisms mediating these antibiotics effects are not understood. Furthermore, there is no consensus on the gut derived bacterial strains that drive neuroinflammation in multiple sclerosis. ResultsHere we characterized the gut microbiome of untreated and vancomycin treated EAE mice over time to identify bacteria with neuroimmunomodulatory potential. We observed alterations in the gut microbiota composition following EAE induction. We found that vancomycin treatment ameliorates EAE and that this protective effect is mediated via the microbiota. Notably, we observed increased abundance of bacteria known to be strong inducers of regulatory T cells, including members of Clostridium clusters XIVa and XVIII in vancomycin-treated mice during the presymptomatic phase of EAE, as well as at disease peak. We identified 50 bacterial taxa that correlate with EAE severity. Interestingly, several of these taxa exist in the human gut and some of them have been implicated in multiple sclerosis including Anaerotruncus colihominis, a butyrate producer, which had a positive correlation with disease severity. We found that Anaerotruncus colihominis ameliorates EAE and this is associated with induction of ROR{gamma}t+ regulatory T cells in the mesenteric lymph nodes. ConclusionsWe identified vancomycin as a potent modulator of the gut-brain axis by promoting the proliferation of bacterial species that induce regulatory T cells. In addition, our findings reveal 50 gut commensals as regulator of the gut-brain axis that can be used to further characterize pathogenic and beneficial host-microbiota interactions in multiple sclerosis patients. Our findings suggest that elevated Anaerotruncus colihominis in multiple sclerosis patients may represent a protective mechanism associated with recovery from the disease.

microbiology↗

bioRxiv2021

Contemporary clinical isolates of Staphylococcus aureus from pediatric osteomyelitis patients display unique characteristics in a mouse model of hematogenous osteomyelitis

Osteomyelitis can result from the direct inoculation of pathogens into bone during injury or surgery, or from spread via the bloodstream, a condition called hematogenous osteomyelitis (HOM). HOM disproportionally affects children, and more than half of cases are caused by Staphylococcus (S.) aureus. Laboratory models of osteomyelitis mostly utilize direct injection of bacteria into the bone or the implantation of foreign material, and therefore do not directly interrogate the pathogenesis of pediatric hematogenous osteomyelitis. In this study, we inoculated mice intravenously and characterized resultant musculoskeletal infections using two strains isolated from adults (USA300-LAC and NRS384) and five new methicillin-resistant S. aureus isolates from pediatric osteomyelitis patients. All strains were capable of creating stable infections over five weeks, although the incidence varied. Micro-computed tomography (microCT) analysis demonstrated decreases in trabecular bone volume fraction but little effect on bone cortices. Histologic assessment revealed differences in the precise focus of musculoskeletal infection, with varying mixtures of bone-centered osteomyelitis and joint-centered septic arthritis. Whole genome sequencing of three new isolates demonstrated distinct strains, two within the USA300 lineage and one USA100 isolate. Interestingly, the USA100 strain showed a distinct predilection for septic arthritis, compared to the USA300 strains, including NRS384 and LAC, which more frequently led to osteomyelitis or mixed bone and joint infections. Collectively, these data outline the feasibility of using pediatric osteomyelitis clinical isolates to study the pathogenesis of HOM in murine models and lay the groundwork for future studies investigating strain-dependent differences in musculoskeletal infection. ImportanceThe inflammation of bone tissue is called osteomyelitis, and more than half of cases are caused by an infection with the bacterium Staphylococcus aureus. In children, the most common route of infection is hematogenous, wherein bacteria seed the bone from the bloodstream without another known site of infection. Although these infections pose a significant health problem, they are understudied in the laboratory because of a dearth of robust animal models. In this study, we utilized several previously uncharacterized clinical isolates of S. aureus derived from children with bone infections to generate reproducible and stable musculoskeletal infection in mice with many features seen in human osteomyelitis, making them a valuable resource for future mechanistic and therapeutic studies.

pathology↗

bioRxiv2020

COVID Moonshot: Open Science Discovery of SARS-CoV-2 Main Protease Inhibitors by Combining Crowdsourcing, High-Throughput Experiments, Computational Simulations, and Machine Learning

We report the results of the COVID Moonshot, a fully open-science, crowd sourced, structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. We discovered a non-covalent, non-peptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>840 ligand-bound X-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this campaign were shared rapidly and openly, creating a rich open and IP-free knowledgebase for future anti-coronavirus drug discovery.

biochemistry↗