HOST-PATHOGEN INTERACTIONS IN PNEUMOCYSTIS INFECTION

Pneumocystis remains the most common opportunistic infection in patients with HIV/AIDS and can cause a life-threatening fulminant pneumonia. Pneumocystis pneumonia is re-emerging in the HIV-negative population, as immunosuppressive medications have greater use clinically. As the at-risk population increases, understanding the underlying host responses that can lead to protection against Pneumocystis becomes imperative. To that end, we characterized the early CD4+ T-cell dependent eosinophilic response to Pneumocystis murina. Importantly, we demonstrated that eosinophils have potent anti-Pneumocystis activity both in vitro and in vivo. However, eosinophils in the lung can also lead to pathology as seen in allergic airway inflammation in asthma. We therefore compared Pneumocystis to the common airway allergen, house dust mite, and demonstrated that the immune response to both pathogens was highly similar. Pneumocystis antigen exposure resulted in increased airway hyperresponsiveness and mucus production in a Th2-dependent and eosinophil-independent manner. From a translational standpoint, a subset of patients with severe asthma had increased anti-Pneumocystis IgG and IgE antibodies. Patients with high anti-Pneumocystis IgG levels had worsened cough and lung function as measured by spirometry, suggesting that Pneumocystis exposure may be correlated with worsened disease. As Pneumocystis infection induces such a potent adaptive immune response, we next examined local immunity to Pneumocystis. Inducible bronchus associated lymphoid tissue (iBALT) has been characterized in several models of lung infection and contributes to protection. Pneumocystis infection and exposure in a co-housing model resulted in the formation of iBALT structures in a CXCL13-dependent manner. Importantly, CXCL13 regulation appeared to be dependent on both Th2 and Th17 CD4+ T-cells in vivo and in pulmonary fibroblasts in vitro. The host response to Pneumocystis is limited in patients with global immunosuppression and the identification of novel drug and vaccine targets is lacking. Towards that end, we annotated the Pneumocystis genome and as proof-of-principle, demonstrated that the kinome (specifically VPS34) was druggable in vitro. Additionally, we utilized various –omics techniques to identify Meu10 and GSC-1 as novel vaccine targets capable of providing partial protection against Pneumocystis. Together, these studies identified novel protective and pathologic immune responses to Pneumocystis and enabled a top-down approach of anti-Pneumocystis therapeutic development

The role of intra-session exercise sequence on the interference effect: a systematic review with meta-analysis

Background: There is a necessity for numerous sports to develop strength and aerobic capacity simultaneously, placing a significant demand upon the practice of effective concurrent training methods. Concurrent training requires the athlete to perform both resistance and endurance exercise within a training plan. This training paradigm has been associated with an ‘interference effect’, with attenuated strength adaptation in comparison to that following isolated resistance training. The effectiveness of the training programme rests on the intricacies of manipulating acute training variables, such as exercise sequence. The research, in the most part, does not provide clarity of message as to whether intra-session exercise sequence has the potential to exacerbate or mitigate the interference effect associated with concurrent training methods. Objective: The aim of the systematic review and meta-analysis was to assess whether intra-session concurrent exercise sequence modifies strength-based outcomes associated with the interference effect. Methods: Ten studies were identified from a systematic review of the literature, for the outcomes of lower-body dynamic and static strength, lower-body hypertrophy, maximal aerobic capacity, and body fat %. Each study examined the effect of intra-session exercise sequence on the specified outcomes, across a prolonged (≥5 wk) concurrent training programme in healthy adults. Results: Analysis of pooled data indicated that a resistance-endurance exercise sequence had a positive effect for lower-body dynamic strength, in comparison to the alternate sequence (weighted mean difference: 6.91% change; 95% CI: 1.96, 11.87% change; p=0.006), with no effect of exercise sequence for lower-body muscle hypertrophy (weighted mean difference: 1.15% change; 95% CI: -1.56, 3.87% change; p=0.40), lower-body static strength (weighted mean difference: -0.04% change; 95% CI: -3.19, 3.11% change; p=0.98), or the remaining outcomes of maximal aerobic capacity and body fat % (p>0.05). Conclusion: These results indicate that the practice of concurrent training with a resistance followed by endurance exercise order is beneficial for the outcome of lower-body dynamic strength, while alternating the order of stimuli offers no benefit for training outcomes associated with the interference effect

Pseudomonas Aeruginosa Sabotages the Generation of Host Proresolving Lipid Mediators

Recurrent Pseudomonas aeruginosa infections coupled with robust, damaging neutrophilic inflammation characterize the chronic lung disease cystic fibrosis (CF). The proresolving lipid mediator, 15-epi lipoxin A4 (15-epi LXA4), plays a critical role in limiting neutrophil activation and tissue inflammation, thus promoting the return to tissue homeostasis. Here, we show that a secreted P. aeruginosa epoxide hydrolase, cystic fibrosis transmembrane conductance regulator inhibitory factor (Cif), can disrupt 15-epi LXA4 transcellular biosynthesis and function. In the airway, 15-epi LXA4 production is stimulated by the epithelial-derived eicosanoid 14,15-epoxyeicosatrienoic acid (14,15-EET). Cif sabotages the production of 15-epi LXA4 by rapidly hydrolyzing 14,15-EET into its cognate diol, eliminating a proresolving signal that potently suppresses IL-8-driven neutrophil transepithelial migration in vitro. Retrospective analyses of samples from patients with CF supported the translational relevance of these preclinical findings. Elevated levels of Cif in bronchoalveolar lavage fluid were correlated with lower levels of 15-epi LXA4, increased IL-8 concentrations, and impaired lung function. Together, these findings provide structural, biochemical, and immunological evidence that the bacterial epoxide hydrolase Cif disrupts resolution pathways during bacterial lung infections. The data also suggest that Cif contributes to sustained pulmonary inflammation and associated loss of lung function in patients with CF

An Interactive, Mobile-Based Tool for Personal Social Network Data Collection and Visualization Among a Geographically Isolated and Socioeconomically Disadvantaged Population: Early-Stage Feasibility Study with Qualitative User Feedback

Background: Personal social networks have a profound impact on our health, yet collecting personal network data for use in health communication, behavior change, or translation and dissemination interventions has proved challenging. Recent advances in social network data collection software have reduced the burden of network studies on researchers and respondents alike, yet little testing has occurred to discover whether these methods are: (1) acceptable to a variety of target populations, including those who may have limited experience with technology or limited literacy; and (2) practical in the field, specifically in areas that are geographically and technologically disconnected, such as rural Appalachian Kentucky. Objective: We explored the early-stage feasibility (Acceptability, Demand, Implementation, and Practicality) of using innovative, interactive, tablet-based network data collection and visualization software (OpenEddi) in field collection of personal network data in Appalachian Kentucky. Methods: A total of 168 rural Appalachian women who had previously participated in a study on the use of a self-collected vaginal swab (SCVS) for human papillomavirus testing were recruited by community-based nurse interviewers between September 2013 and August 2014. Participants completed egocentric network surveys via OpenEddi, which captured social and communication network influences on participation in, and recruitment to, the SCVS study. After study completion, we conducted a qualitative group interview with four nurse interviewers and two participants in the network study. Using this qualitative data, and quantitative data from the network study, we applied guidelines from Bowen et al to assess feasibility in four areas of early-stage development of OpenEddi: Acceptability, Demand, Implementation, and Practicality. Basic descriptive network statistics (size, edges, density) were analyzed using RStudio. Results: OpenEddi was perceived as fun, novel, and superior to other data collection methods or tools. Respondents enjoyed the social network survey component, and visualizing social networks produced thoughtful responses from participants about leveraging or changing network content and structure for specific health-promoting purposes. Areas for improved literacy and functionality of the tool were identified. However, technical issues led to substantial (50%) data loss, limiting the success of its implementation from a researcher\u27s perspective, and hindering practicality in the field. Conclusions: OpenEddi is a promising data collection tool for use in geographically isolated and socioeconomically disadvantaged populations. Future development will mitigate technical problems, improve usability and literacy, and test new methods of data collection. These changes will support goals for use of this tool in the delivery of network-based health communication and social support interventions to socioeconomically disadvantaged populations

Assessing Research Collaboration through Co-authorship Network Analysis

This is the final version. Available from Society of Research Administrators International via the link in this recordMaterial used with permission from Society of Research Administrators InternationalInterdisciplinary research collaboration is needed to perform transformative science and accelerate innovation. The Science of Team Science strives to investigate, evaluate, and foster team science, including institutional policies that may promote or hinder collaborative interdisciplinary research and the resources and infrastructure needed to promote team science within and across institutions. Social network analysis (SNA) has emerged as a useful method to measure interdisciplinary science through the evaluation of several types of collaboration networks, including co-authorship networks. Likewise, research administrators are responsible for conducting rigorous evaluation of policies and initiatives. Within this paper, we present a case study using SNA to evaluate interprogrammatic collaboration (evidenced by co-authoring scientific papers) from 2007-2014 among scientists who are members of four formal research programs at an NCI-designated Cancer Center, the Markey Cancer Center (MCC) at the University of Kentucky. We evaluate change in network descriptives over time and implement separable temporal exponential-family random graph models (STERGMs) to estimate the effect of author and network variables on the tendency to form a co-authorship tie. We measure the diversity of the articles published over time (Blau's Index) to understand whether the changes in the co-authorship network are reflected in the diversity of articles published by research members. Over the 8-year period, we found increased inter-programmatic collaboration among research members as evidenced by co-authorship of published scientific papers. Over time, MCC Members collaborated more with others outside of their research program and outside their initial dense co-authorship groups, however tie formation continues to be driven by co-authoring with individuals of the same research program and academic department. Papers increased in diversity over time on all measures with the exception of author gender. This inter-programmatic research was fostered by policy changes in cancer center administration encouraging interdisciplinary research through both informal (e.g., annual retreats, seminar series) and formal (e.g., requiring investigators from more than two research programs on applications for pilot funding) means. Within this cancer center, interdisciplinary co-authorship increased over time as policies encouraging this collaboration were implemented. Yet, there is room for improvement in creating more interdisciplinary and diverse ties between research program members.This research was supported by the Research Communications Office as well as the Biostatistics and Bioinformatics and the Cancer Research Informatics Shared Resources of the University of Kentucky Markey Cancer Center, funded by the National Cancer Institute Cancer Center Support Grant (P30CA177558). Dr. Eddens’ contribution was supported in part by a Building Interdisciplinary Research Careers in Women’s Health grant (#K12 DA035150) from the Office of Women’s Health Research, administered by the Department of Obstetrics and Gynecology of the College of Medicine, University of Kentucky. Dr. Vanderford is supported by the University of Kentucky’s Cancer Center Support Grant (NCI P30CA177558) and the Center for Cancer and Metabolism (NIGMS P20GM121327)

The efficacy of protein supplementation during recovery from muscle-damaging concurrent exercise

This study investigated the effect of protein supplementation on recovery following muscle-damaging exercise, which was induced with a concurrent exercise design. Twenty-four well-trained male cyclists were randomised to three independent groups receiving 20 g protein hydrolysate, iso-caloric carbohydrate or low-calorific placebo supplementation, per serve. Supplement serves were provided twice daily, from the onset of the muscle-damaging exercise, for a total of four days and in addition to a controlled diet (6 g·kg-1·d-1 carbohydrate, 1.2 g·kg-1·d-1 protein, remainder from fat). Following the concurrent exercise session at time-point 0 h; a simulated high-intensity road cycling trial and 100 drop-jumps, recovery of outcome measures was assessed at 24, 48 and 72 h. The concurrent exercise protocol was deemed to have caused exercise-induced muscle damage (EIMD), owing to time effects (p0.05) were observed for any of the outcome measures. The present results indicate that protein supplementation does not attenuate any of the indirect indices of EIMD imposed by concurrent exercise, when employing great rigour around the provision of a quality habitual diet and the provision of appropriate supplemental controls

Effects of Cycling Intensity on Acute Signaling Adaptations to 8-weeks Concurrent Training in Trained Cyclists

© 2022 Jones, Eddens, Kupusarevic, Simoes, Furber, Van Someren and Howatson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). https://creativecommons.org/licenses/by/4.0/This study examined whether the intensity of endurance stimuli modifies the adaptation in strength and endurance following concurrent training and whether the acute molecular response to concurrent exercise is affected by training status. Using a parallel group design, trained cyclists were randomized to either resistance exercise followed by moderate intensity continuous training (RES + MICT, n = 6), or resistance exercise followed by work matched high intensity interval training (RES + HIIT, n = 7), across an 8 weeks training programme. A single RES + MICT or RES + HIIT exercise stimulus was completed 1 week before and within 5 days of completing the training programme, to assess phosphorylation of protein kinases of the mTOR and AMPK signaling pathways. There were no main effects of time or group on the phosphorylation of protein kinases in response to concurrent exercise stimulus pre- and post-training intervention (p > 0.05). Main effects of time were observed for all maximal strength exercises; back-squat, split-squat, and calf-raise (p 0.05). Whilst preliminary data due to limited sample size the intensity of endurance activity had no effect on performance outcomes, following concurrent training. Further, the acute molecular response to a concurrent exercise stimulus was comparable before and after the training intervention, suggesting that training status had no effect on the molecular responses assessed.Peer reviewedFinal Published versio

Colorectal Cancer Prevention: Perspectives of Key Players from Social Networks in a Low-Income Rural US Region

Social networks influence health behavior and health status. Within social networks, “key players” often influence those around them, particularly in traditionally underserved areas like the Appalachian region in the USA. From a total sample of 787 Appalachian residents, we identified and interviewed 10 key players in complex networks, asking them what comprises a key player, their role in their network and community, and ideas to overcome and increase colorectal cancer (CRC) screening. Key players emphasized their communication skills, resourcefulness, and special occupational and educational status in the community. Barriers to CRC screening included negative perceptions of the colonoscopy screening procedure, discomfort with the medical system, and misinformed perspectives on screening. Ideas to improve screening focused on increasing awareness of women\u27s susceptibility to CRC, providing information on different screening tests, improving access, and the key role of health-care providers and key players themselves. We provide recommendations to leverage these vital community resources

Aerobic exercise intensity does not affect the anabolic signaling following resistance exercise in endurance athletes

Abstract: This study examined whether intensity of endurance stimulus within a concurrent training paradigm influenced the phosphorylation of signaling proteins associated with the mTOR and AMPK networks. Eight male cyclists completed (1) resistance exercise (RES), 6 × 8 squats at 80% 1-RM; (2) resistance exercise and moderate intensity cycling of 40 min at 65% V̇O2peak, (RES + MIC); (3) resistance exercise and high intensity interval cycling of 40 min with 6 alternating 3 min intervals of 85 and 45% V̇O2peak (RES + HIIC), in a cross-over design. Muscle biopsies were collected at rest and 3 h post-RES. There was a main effect of condition for mTORS2448 (p = 0.043), with a greater response in the RES + MIC relative to RES condition (p = 0.033). There was a main effect of condition for AMPKα2T172 (p = 0.041), with a greater response in RES + MIC, relative to both RES + HIIC (p = 0.026) and RES (p = 0.046). There were no other condition effects for the remaining protein kinases assessed (p > 0.05). These data do not support a molecular interference effect in cyclists under controlled conditions. There was no intensity-dependent regulation of AMPK, nor differential activation of anabolism with the manipulation of endurance exercise intensity.Peer reviewe