Environmental boundary conditions for the origin of life converge to an organo-sulfur metabolism

Published in final edited form as: Nat Ecol Evol. 2019 December ; 3(12): 1715–1724. doi:10.1038/s41559-019-1018-8.It has been suggested that a deep memory of early life is hidden in the architecture of metabolic networks, whose reactions could have been catalyzed by small molecules or minerals before genetically encoded enzymes. A major challenge in unravelling these early steps is assessing the plausibility of a connected, thermodynamically consistent proto-metabolism under different geochemical conditions, which are still surrounded by high uncertainty. Here we combine network-based algorithms with physico-chemical constraints on chemical reaction networks to systematically show how different combinations of parameters (temperature, pH, redox potential and availability of molecular precursors) could have affected the evolution of a proto-metabolism. Our analysis of possible trajectories indicates that a subset of boundary conditions converges to an organo-sulfur-based proto-metabolic network fuelled by a thioester- and redox-driven variant of the reductive tricarboxylic acid cycle that is capable of producing lipids and keto acids. Surprisingly, environmental sources of fixed nitrogen and low-potential electron donors are not necessary for the earliest phases of biochemical evolution. We use one of these networks to build a steady-state dynamical metabolic model of a protocell, and find that different combinations of carbon sources and electron donors can support the continuous production of a minimal ancient 'biomass' composed of putative early biopolymers and fatty acids.80NSSC17K0295 - Intramural NASA; 80NSSC17K0296 - Intramural NASA; T32 GM100842 - NIGMS NIH HHSAccepted manuscrip

Changes in stress pathways as a possible mechanism of aerobic exercise training on brain health: a scoping review of existing studies

Physical activity (PA) in the form of aerobic exercise (AE) preserves and improves neurocognitive function across the lifespan. However, a mechanistic understanding of the pathways by which aerobic exercise impacts brain health is still lacking, particularly with respect to stress-related pathways. One mechanistic hypothesis is that AE improves neurocognitive health in part by modifying circulating levels of stress-related hormones and signaling factors associated with the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS), as commonly measured by the biomarkers cortisol (CORT) and salivary α-amylase (sAA). Thus, this hypothesis predicts that changes in stress biomarkers, such as CORT and sAA, are possible explanatory pathways mediating the positive effects of AE on neurocognitive health. In the present review article, we provide a summary of available studies examining the possibility that exercise-induced changes to stress biomarkers could partly account for exercise-related improvements in neurocognitive health. Our review indicates that despite the intuitive appeal of this hypothesis, there is insufficient evidence available to conclude that chronic and habitual AE affects neurocognitive health by altering stress biomarker pathways. The cross-sectional nature of the majority of reviewed studies highlights the need for well-controlled studies to adequately test this hypothesis

Effects of a laboratory-based aerobic exercise intervention on brain volume and cardiovascular health markers: protocol for a randomised clinical trial

INTRODUCTION: Physical activity (PA) has beneficial effects on brain health and cardiovascular disease (CVD) risk. Yet, we know little about whether PA-induced changes to physiological mediators of CVD risk influence brain health and whether benefits to brain health may also explain PA-induced improvements to CVD risk. This study combines neurobiological and peripheral physiological methods in the context of a randomised clinical trial to better understand the links between exercise, brain health and CVD risk. METHODS AND ANALYSIS: In this 12-month trial, 130 healthy individuals between the ages of 26 and 58 will be randomly assigned to either: (1) moderate-intensity aerobic PA for 150 min/week or (2) a health information control group. Cardiovascular, neuroimaging and PA measurements will occur for both groups before and after the intervention. Primary outcomes include changes in (1) brain structural areas (ie, hippocampal volume); (2) systolic blood pressure (SBP) responses to functional MRI cognitive stressor tasks and (3) heart rate variability. The main secondary outcomes include changes in (1) brain activity, resting state connectivity, cortical thickness and cortical volume; (2) daily life SBP stress reactivity; (3) negative and positive affect; (4) baroreflex sensitivity; (5) pulse wave velocity; (6) endothelial function and (7) daily life positive and negative affect. Our results are expected to have both mechanistic and public health implications regarding brain-body interactions in the context of cardiovascular health. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the University of Pittsburgh Institutional Review Board (IRB ID: 19020218). This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. TRIAL REGISTRATION NUMBER: NCT03841669

Community-Centered Responses to Ebola in Urban Liberia: The View from Below

The West African Ebola epidemic has demonstrated that the existing range of medical and epidemiological responses to emerging disease outbreaks is insufficient, especially in post-conflict contexts with exceedingly poor healthcare infrastructures. This study provides baseline information on community-based epidemic control priorities and identifies innovative local strategies for containing EVD in Liberia.In this study the authors analyzed data from the 2014 Ebola outbreak in Monrovia and Montserrado County, Liberia. The data were collected for the purposes of program design and evaluation by the World Health Organization (WHO) and the Government of Liberia (GOL), in order to identify: (1) local knowledge about EVD, (2) local responses to the outbreak, and (3) community based innovations to contain the virus. At the time of data collection, the international Ebola response had little insight into how much local Liberian communities knew about Ebola, and how communities managed the epidemic when they could not get access to care due to widespread hospital and clinic closures. Methods included 15 focus group discussions with community leaders from areas with active Ebola cases. Participants were asked about best practices and what they were currently doing to manage EVD in their respective communities, with the goal of developing conceptual models of local responses informed by local narratives. Findings reveal that communities responded to the outbreak in numerous ways that both supported and discouraged formal efforts to contain the spread of the disease. This research will inform global health policy for both this, and future, epidemic and pandemic responses

Higher Expression of CCL2, CCL4, CCL5, CCL21, and CXCL8 Chemokines in the Skin Associated with Parasite Density in Canine Visceral Leishmaniasis

Several previous studies correlated immunopathological aspects of canine visceral leishmaniasis (CVL) with tissue parasite load and/or the clinical status of the disease. Recently, different aspects of the immune response in Leishmania-infected dogs have been studied, particularly the profile of cytokines in distinct compartments. However, the role of chemokines in disease progression or parasite burdens of the visceralising species represents an important approach for understanding immunopathology in CVL. We found an increase in inflammatory infiltrate, which was mainly composed of mononuclear cells, in the skin of animals presenting severe forms of CVL and high parasite density. Our data also demonstrated that enhanced parasite density is positively correlated with the expression of CCL2, CCL4, CCL5, CCL21, and CXCL8. In contrast, there was a negative correlation between parasite density and CCL24 expression. These findings represent an advance in the knowledge of the involvement of skin inflammatory infiltrates in CVL and the systemic consequences and may contribute to developing a rational strategy for the design of new and more efficient prophylactic tools and immunological therapies against CVL

A Review of Periprosthetic Femoral Fractures Associated With Total Hip Arthroplasty

Periprosthetic fractures of the femur in association with total hip arthroplasty are increasingly common and often difficult to treat. Patients with periprosthetic fractures are typically elderly and frail and have osteoporosis. No clear consensus exists regarding the optimal management strategy because there is limited high-quality research. The Vancouver classification facilitates treatment decisions. In the presence of a stable prosthesis (type-B1 and -C fractures), most authors recommend surgical stabilization of the fracture with plates, strut grafts, or a combination thereof. In up to 20% of apparent Vancouver type-B1 fractures, the femoral stem is loose, which may explain the high failure rates associated with open reduction and internal fixation. Some authors recommend routine opening and dislocation of the hip to perform an intraoperative stem stability test to rule out a loose component. Advances in plating techniques and technology are improving the outcomes for these fractures. For fractures around a loose femoral prosthesis (types B2 and 3), revision using an extensively porous-coated uncemented long stem, with or without additional fracture fixation, appears to offer the most reliable outcome. Cement-in-cement revision using a long-stem prosthesis is feasible in elderly patients with a well-fixed cement mantle. It is essential to treat the osteoporosis to help fracture healing and to prevent further fractures. We provide an overview of the causes, classification, and management of periprosthetic femoral fractures around a total hip arthroplasty based on the current best available evidence

MRI for high ankle sprains with an unstable syndesmosis: posterior malleolus bone oedema is common and time to scan matters

Purpose Early clinical examination combined with MRI allows accurate diagnosis of syndesmosis instability after a high ankle sprain. However, patients often present late. The aims of the current study were to describe MRI characteristics associated with syndesmosis instability and to test the hypothesis that MRI patterns would differ according to time from injury. Methods Over a 5-year period, 164 consecutive patients who had arthroscopically proven syndesmosis instability requiring fixation were retrospectively studied. Patients with distal fibula fractures were not included. Injuries were classified as acute in 108 patients ( 12 weeks). Results Posterior malleolus bone oedema was noted in 65 (60.2%), and posterior malleolus fracture in 17 (15.7%) of acute patients, respectively, which did not significantly differ over time. According to MRI, reported rates of posterior syndesmosis disruption significantly differed over time, observed in 101 (93.5%), 28 (87.5%) and 13 (54.2%) of acute, intermediate and chronic patients, respectively (p < 0.001). Apparent rates of PITFL injury significantly reduced with time (p < 0.001). Conclusions MRI detected a posterior syndesmosis injury in 93.5% of patients acutely but became less reliable with time. The clinical relevance of this study is that posterior malleolus bone oedema may be the only marker of a complete syndesmosis injury and can help clinically identify those injuries which require arthroscopic assessment for instability. If suspicious of a high ankle sprain, we advocate early MRI assessment to help determine stable versus unstable injuries as MRI becomes less reliable after 12 weeks