Biology subjects

Sullivan, A.

Publications and source records attributed to Sullivan, A..

7 recordsLinked to original sources

bioRxiv2022

Dynamic Transcriptomic Network Responses to Divergent Acute Exercise Challenges in Young Adults

Acute exercise elicits dynamic transcriptional changes that, when repeated, form the fundamental basis of adaptations in health, resilience, and performance. While moderate-intensity endurance training combined with conventional resistance training (traditional, TRAD) is often prescribed and recommended by public health guidance, high-intensity training combining maximal-effort intervals with intensive, limited-rest resistance training is a time-efficient alternative that may be used tactically (HITT) to seek whole body health benefits. Mechanisms of action of these distinct doses are incompletely characterized and have not been directly compared. We assessed transcriptome-wide responses in skeletal muscle and circulating extracellular vesicles (EVs) to a single exercise bout in young adults randomized to TRAD (n=21, 12M/9F, 22{+/-}3y) or HITT (n=19, 11M/8F, 22{+/-}2y). Next-generation sequencing captured small, long, and circular RNA in muscle and EVs. Analysis identified differentially expressed transcripts (|log2FC|>1, FDR[≤]0.05) immediately (h0, EVs only), h3, and h24 post-exercise within and between exercise doses. Additionally, all apparently responsive transcripts (FDR<0.2) underwent singular value decomposition to summarize data structures into latent variables (LVs) to deconvolve molecular expression circuits and inter-regulatory relationships. LVs were compared across time and exercise dose. TRAD generally elicited a stronger, more consistent transcriptional response than HITT, but considerable overlap and key differences existed. Findings reveal shared and unique molecular responses to divergent exercise stimuli and lay groundwork toward establishing relationships between protein-coding genes and lesser-understood transcripts that serve regulatory roles in response to exercise. Future work should advance the understanding of these circuits and whether they repeat in other populations or following other types of exercise/stress. NEW AND NOTEWORTHYWe examined small and long transcriptomics in skeletal muscle and serum-derived extracellular vesicles before and after a single exposure to traditional combined exercise (TRAD) and high-intensity tactical training (HITT). Across 40 young adults, we found more consistent protein-coding gene responses to TRAD, whereas HITT elicited differential expression of microRNA enriched in brain regions. Follow-up analysis revealed relationships and temporal dynamics across transcript networks, highlighting potential avenues for research into mechanisms of exercise response and adaptation.

bioinformatics↗

bioRxiv2022

Differential metabolism between biofilm and suspended Pseudomonas aeruginosa cultures in bovine synovial fluid by 2D NMR-based metabolomics

Total joint arthroplasty is a common surgical procedure resulting in improved quality of life; however, a leading cause of surgery failure is periprosthetic joint infection. Periprosthetic infection often involves biofilms, making treatment challenging. Periprosthetic joint infections are difficult to diagnose by traditional culturing methods and there are no clinical biomarkers for the presence of biofilms. Further, the metabolic state of pathogens in the joint space is difficult to diagnose, the mechanism of their tolerance to antibiotics and host defenses is not well understood, and their culturing in the laboratory is challenging. Thus, there is a critical need for improved pathogen- and phenotype-specific diagnosis as well as improved treatment strategies toward better patient outcomes. Here, we present a quantitative, untargeted NMR-based metabolomics strategy for Pseudomonas aeruginosa suspended culture and biofilm phenotypes grown in bovine synovial fluid. We identified 21 unique metabolites as potential markers of P. aeruginosa and one unique marker of the biofilm phenotype in synovial fluid. Significant differences in metabolic pathways were found between the suspended culture and biofilm phenotypes including creatine, glutathione, alanine, and choline metabolism and the tricarboxylic acid cycle. These unique metabolite and pathway differences have the potential to serve as targets for P. aeruginosa and specifically biofilm diagnosis and biofilm control in synovial fluid. Author SummaryJoint replacement surgery is a common procedure frequently required in later stages of life due to damage in the joint. Over one million joint replacement surgeries are performed annually with rates increasing every year. A devastating complication associated with joint replacement is the development of infection around the implant device in the joint space, known as a periprosthetic joint infection. Bacteria in the joint space can form a biofilm, which is a gel-like matrix encasing the cells that increases resistance to treatment and exacerbates chronic infections. A particular challenge for the diagnosis of biofilm-mediated periprosthetic joint infections is the slowly growing nature of biofilm-mediated phenotypes, resulting in frequent failure to detect these bacteria by clinical microbiological culturing methods. Small molecule metabolites are uniquely produced by strains of bacteria in the biofilm versus planktonic or suspended culture phenotype. Identification of metabolites as specific markers of infection and biofilm could allow a new culture-free diagnostic approach to diagnose infection by biofilm. Furthermore, knowledge of metabolic pathway populations in biofilm in joint fluid could point to specific targets to prevent biofilm formation in the joint space.

microbiology↗

bioRxiv2022

Modeling COVID-19 disease biology to identify drug treatment candidates

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, there are a limited number of effective treatments. A variety of drugs that have been approved for other diseases are being tested for the treatment of COVID-19, and thus far only remdesevir, dexamethasone, baricitinib, tofacitinib, tocilizumab, and sarilumab have been recommended by the National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel for the therapeutic management of hospitalized adults with COVID-19. Using a disease biology modeling approach, we constructed a protein-protein interactome network based on COVID-19- associated genes/proteins described in research literature together with known protein-protein interactions in epithelial cells. Phenotype and disease enrichment analysis of the COVID-19 disease biology model demonstrated strong statistical enrichments consistent with patients clinical presentation. The model was used to interrogate host biological response induced by SARS-CoV-2 and identify COVID-19 drug treatment candidates that may inform on drugs currently being evaluated or provide insight into possible targets for potential new therapeutic agents. We focused on cancer drugs as they are often used to control inflammation, inhibit cell division, and modulate the host microenvironment to control the disease. From the top 30 COVID-19 drug candidates, twelve have a role as an antineoplastic agent, seven of which are approved for human use. Altogether, nearly 40% of the drugs identified by our model have been identified by others for COVID-19 clinical trials. Disease biology modeling incorporating disease-associated genes/proteins discussed in the research literature together with known molecular interactions in relevant cell types is a useful method to better understand disease biology and identify potentially effective therapeutic interventions.

systems biology↗

bioRxiv2022

Rapid aggregation of Staphylococcus aureus in synovial fluid is influenced by synovial fluid concentration, viscosity, and fluid dynamics-with evidence of polymer bridging

Early bacterial survival in the post-surgical joint is still a mystery. Recently, synovial fluid-induced aggregation was proposed as a potential mechanism of bacterial protection upon entry into the joint. As synovial fluid is secreted back into the joint cavity following surgery, rapid fluctuations in synovial fluid concentration, composition, and viscosity occur. These changes, along with fluid movement from post-operative joint motion, will modify the environment and potentially affect the kinetics of aggregate formation. Through this work, we sought to evaluate the influence of exposure time, synovial fluid concentration, viscosity, and fluid dynamics on aggregation. Furthermore, we aimed to elucidate the primary mechanism of aggregate formation by assessing the interaction of bacterial adhesins with synovial fluid polymer, fibrinogen. Following incubation in each simulated post-operative joint condition, the aggregates were imaged using confocal microscopy. Our analysis revealed the formation of two distinct aggregate phenotypes dependent on whether the incubation was conducted under static or dynamic conditions. Using a surface adhesin mutant, we have narrowed down the genetic determinants for synovial fluid aggregate formation and identified essential host polymers required. We report here that synovial fluid-induced aggregation is influenced by various changes specific to the post-surgical joint environment. While we now have evidence that select synovial fluid polymers facilitate bridging aggregation through essential bacterial adhesins, we suspect that their utility is limited by the increasing viscosity under static conditions. Furthermore, dynamic fluid movement recovers the ability of the bacteria with present surface proteins to aggregate under high viscosity conditions, yielding large, globular aggregates. ImportanceInfection is a major complication of knee and hip joint replacement surgery which is used to treat arthritis or joint damage. We have shown that Staphylococcus aureus, a common bacterial pathogen, aggregates upon contact with synovial fluid. Within seconds, the bacterial cells will interact with synovial fluid polymers in the joint fluid through their cell wall adhesins. The rapid formation of these aggregates likely aids in early bacterial survival in the joint-potentially contributing to the likelihood of developing an infection. By strengthening our basic understanding of the mechanics of synovial fluid aggregate formation under clinically relevant conditions, we hope to expand the knowledge of how to prevent or disrupt aggregation and reduce and more successfully treat these joint infections.

microbiology↗

bioRxiv2021

Escaping the Fate of Sisyphus: Assessing Resistome Hybridization Baits for Antimicrobial Resistance Gene Capture

Finding, characterizing, and monitoring reservoirs for antimicrobial resistance (AMR) is vital to protecting public health. Hybridization capture baits are an accurate, sensitive, and cost-effective technique used to enrich and characterize DNA sequences of interest, including antimicrobial resistance genes (ARGs), in complex environmental samples. We demonstrate the continued utility of a set of 19,933 hybridization capture baits designed from the Comprehensive Antibiotic Resistance Database (CARD)v1.1.2 and Pathogenicity Island Database (PAIDB)v2.0, targeting 3,565 unique nucleotide sequences that confer resistance. We demonstrate the efficiency of our bait set on a custom-made resistance mock community and complex environmental samples to increase the proportion of on-target reads as much as >200-fold. However, keeping pace with newly discovered ARGs poses a challenge when studying AMR, because novel ARGs are continually being identified and would not be included in bait sets designed prior to discovery. We provide imperative information on how our bait set performs against CARDv3.3.1, as well as a generalizable approach for deciding when and how to update hybridization capture bait sets. This research encapsulates the full life cycle of baits for hybridization capture of the resistome from design and validation (both in silico and in vitro) to utilization and forecasting updates and retirement. Originality-Significance StatementThis work is applicable to a wide range of research. It helps to define conditions under which hybridization capture is useful regarding not only antimicrobial resistance specifically, but also more generally how to assess the ongoing utility of existing bait sets - giving objective criteria for when and by what strategies baits should be updated. We also provide a method for quantifying and comparing antimicrobial resistance genes (ARGs) similar to what is used for RNAseq experiments. This approach improves comparison of ARGs across environments. Thus, the work provides an improved foundation for ARG future studies, while cutting across traditional areas of microbiology and extending beyond.

microbiology↗

bioRxiv2021

ePlant in 2021: New Species, Viewers, Data Sets, and Widgets

ePlant was introduced in 2017 for exploring large Arabidopsis thaliana data sets from the kilometre to nanometre scales. In the past four years we have used the ePlant framework to develop ePlants for 15 agronomically-important species: maize, poplar, tomato, Camelina sativa, soybean, potato, barley, Medicago truncatula, eucalyptus, rice, willow, sunflower, Cannabis sativa, wheat and sugarcane. We also updated the interface to improve performance and accessibility, and added two new views to the Arabidopsis ePlant - the Navigator and Pathways viewers. The former shows phylogenetic relationships between homologs in other species and their expression pattern similarities, with links to view data for those genes in the respective ePlants. The latter shows Plant Reactome metabolic reactions. We also describe new Arabidopsis data sets including single cell RNA-seq data from roots, and how to embed ePlant eFP expression pictographs into any web page.

bioinformatics↗

bioRxiv2021

Alpha-synuclein alters the faecal viromes of rats in a gut-initiated model of Parkinson's disease

Parkinsons disease (PD) is a chronic neurological disorder associated with the misfolding of alpha-synuclein (-syn) into Lewy body aggregates within nerve cells that contribute to their neurodegeneration. Recent evidence suggests -syn aggregation may begin in the gut and travel to the brain along the vagus nerve, with microbes a potential trigger initiating the misfolding of -syn. However, changes in the gut virome in response to -syn alterations have not been investigated. In this study, we show longitudinal changes in the faecal virome of rats administered either monomeric or preformed fibrils (PFF) of -syn directly into their enteric nervous system. Differential changes in rat viromes were observed when comparing monomeric and PFF -syn. The virome {beta}-diversity changes after -syn treatment were compounded by the addition of LPS as an adjunct. Changes in the diversity of rat faecal viromes were observed after one month and did not resolve within the studys five month observational period. Overall, these results suggest that microbiome alterations associated with PD may, partially, be reactive to host -syn associated changes.

microbiology↗