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The study of the origin and implications of fatigue in exercise has been widely investigated, but not completely understood given the complex multifactorial mechanisms involved. Then, it is essential to understand the fatigue mechanism to help trainers and physicians to prescribe an adequate training load. The present narrative review aims to analyze the multifactorial factors of fatigue in physical exercise. To reach this aim, a consensus and critical review were performed using both primary sources, such as scientific articles, and secondary ones, such as bibliographic indexes, web pages, and databases. The main search engines were PubMed, SciELO, and Google Scholar. Central and peripheral fatigue are two unison constructs part of the Integrative Governor theory, in which both psychological and physiological drives and requirements are underpinned by homeostatic principles. The relative activity of each one is regulated by dynamic negative feedback activity, as the fundamental general operational controller. Fatigue is conditioned by factors such as gender, affecting men and women differently. Sleep deprivation or psychological disturbances caused, for example, by stress, can affect neural activation patterns, realigning them and slowing down simple mental operations in the context of fatigue. Then, fatigue can have different origins not only related with physiological factors. Therefore, all these prisms must be considered for future approaches from sport and clinical perspectives.

Britto discusses the study of Thurman et al regarding a single-cell atlas of large and small airways at birth in a porcine model of cystic fibrosis (CF). Thurman et al integrate groundbreaking developments on CF airways to chart the transcriptional topography of the porcine bronchial tree at birth, providing for the first time a detailed landscape of gene expression and epithelial cell-type distribution in newborn CFTR (CF transmembrane conductance regulator)-deficient (CFTR-/-) lungs. The findings of their study have impact within and beyond the CF field. The differential expression of host defense, mucins, and solute transport genes between large and small airways instructs us to consider these differences when modeling and interpreting pulmonary pathophysiology.

BackgroundUrban regeneration policies are area-based interventions addressing multidimensional problems. In this study, we analyse the impact of urban regeneration processes on the evolution of inequalities in mortality from certain causes. On the basis of Fundamental Cause Theory (FCT), our main hypothesis is that the impact of urban regeneration programmes will be more clearly observed on the causes of preventable deaths, as these programmes imply a direct or indirect improvement to a whole range of ‘flexible resources’ that residents in relevant areas have access to, and which ultimately may influence the inverse relationship between socioeconomic status and health.MethodsUsing a quasi-experimental design and data from Longitudinal Statistics on Survival and Longevity of Andalusia (Spain), we analyse differences in the evolution of standard mortality ratios for preventable and less-preventable causes of premature death. This encompasses 59 neighbourhoods in 37 municipalities where urban regeneration projects were implemented in the last decade within the framework of three different programmes and in 59 counterparts where these policies were not implemented.ResultsAs expected in line with FCT, there are no significant patterns in the evolution of internal differences in terms of less-preventable mortality. However, excessive preventable mortality strongly decreases in the neighbourhoods with intervention programmes, specifically in those where two or more projects were in force. This is even more apparent for women.ConclusionsThe urban regeneration policies studied seem to contribute to reducing health inequity when the interventions are more integral in nature.

Crohn’s disease (CD) results from a complex interplay between host genetic factors and endogenous microbial communities. In the current study, we used Ion Torrent sequencing to characterize the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in patients with CD and their nondiseased first-degree relatives (NCDR) in 9 familial clusters living in northern France-Belgium and in healthy individuals from 4 families living in the same area (non-CD unrelated [NCDU]). Principal component, diversity, and abundance analyses were conducted, and CD-associated inter- and intrakingdom microbial correlations were determined. Significant microbial interactions were identified and validated using single- and mixed-species biofilms. CD and NCDR groups clustered together in the mycobiome but not in the bacteriome. Microbiotas of familial (CD and NCDR) samples were distinct from those of nonfamilial (NCDU) samples. The abundance of Serratia marcescens and Escherichia coli was elevated in CD patients, while that of beneficial bacteria was decreased. The abundance of the fungus Candida tropicalis was significantly higher in CD than in NCDR ( P = 0.003) samples and positively correlated with levels of anti- Saccharomyces cerevisiae antibodies (ASCA). The abundance of C. tropicalis was positively correlated with S. marcescens and E. coli , suggesting that these organisms interact in the gut. The mass and thickness of triple-species ( C. tropicalis plus S. marcescens plus E. coli ) biofilm were significantly greater than those of single- and double-species biofilms. C. tropicalis biofilms comprised blastospores, while double- and triple-species biofilms were enriched in hyphae. S. marcescens used fimbriae to coaggregate or attach with C. tropicalis / E. coli , while E. coli was closely apposed with C. tropicalis . Specific interkingdom microbial interactions may be key determinants in CD. IMPORTANCE Here, we characterized the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in multiplex families with CD and healthy relatives and defined the microbial interactions leading to dysbiosis in CD. We identified fungal ( Candida tropicalis ) and bacterial ( Serratia marcescens and Escherichia coli ) species that are associated with CD dysbiosis. Additionally, we found that the level of anti- Saccharomyces cerevisiae antibodies (ASCA; a known CD biomarker) was associated with the abundance of C. tropicalis . We also identified positive interkingdom correlations between C. tropicalis , E. coli , and S. marcescens in CD patients and validated these correlations using in vitro biofilms. These results provide insight into the roles of bacteria and fungi in CD and may lead to the development of novel treatment approaches and diagnostic assays. Here, we characterized the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in multiplex families with CD and healthy relatives and defined the microbial interactions leading to dysbiosis in CD. We identified fungal ( Candida tropicalis ) and bacterial ( Serratia marcescens and Escherichia coli ) species that are associated with CD dysbiosis. Additionally, we found that the level of anti- Saccharomyces cerevisiae antibodies (ASCA; a known CD biomarker) was associated with the abundance of C. tropicalis . We also identified positive interkingdom correlations between C. tropicalis , E. coli , and S. marcescens in CD patients and validated these correlations using in vitro biofilms. These results provide insight into the roles of bacteria and fungi in CD and may lead to the development of novel treatment approaches and diagnostic assays.

Staphylococcus aureus is a prominent human pathogen that readily adapts to host immune defenses. Here, we show that, in contrast to Gram-negative pathogens, S. aureus induces a distinct airway immunometabolic response dominated by the release of the electrophilic metabolite, itaconate. The itaconate synthetic enzyme, IRG1, is activated by host mitochondrial stress, which is induced by staphylococcal glycolysis. Itaconate inhibits S. aureus glycolysis and selects for strains that re-direct carbon flux to fuel extracellular polysaccharide (EPS) synthesis and biofilm formation. Itaconate-adapted strains, as illustrated by S. aureus isolates from chronic airway infection, exhibit decreased glycolytic activity, high EPS production, and proficient biofilm formation even before itaconate stimulation. S. aureus thus adapts to the itaconate-dominated immunometabolic response by producing biofilms, which are associated with chronic infection of the human airway. The authors show that the pathogen Staphylococcus aureus induces a distinct airway immunometabolic response, dominated by release of itaconate. This metabolite, in turn, potentiates extracellular polysaccharide synthesis and biofilm formation in S. aureus , which may facilitate chronic infection.

How extinct, non-avian theropod dinosaurs moved is a subject of considerable interest and controversy. A better understanding of non-avian theropod locomotion can be achieved by better understanding terrestrial locomotor biomechanics in their modern descendants, birds. Despite much research on the subject, avian terrestrial locomotion remains little explored in regards to how kinematic and kinetic factors vary together with speed and body size. Here, terrestrial locomotion was investigated in twelve species of ground-dwelling bird, spanning a 1,780-fold range in body mass, across almost their entire speed range. Particular attention was devoted to the ground reaction force (GRF), the force that the feet exert upon the ground. Comparable data for the only other extant obligate, striding biped, humans, were also collected and studied. In birds, all kinematic and kinetic parameters examined changed continuously with increasing speed, while in humans all but one of those same parameters changed abruptly at the walk-run transition. This result supports previous studies that show birds to have a highly continuous locomotor repertoire compared to humans, where discrete 'walking' and 'running' gaits are not easily distinguished based on kinematic patterns alone. The influences of speed and body size on kinematic and kinetic factors in birds are developed into a set of predictive relationships that may be applied to extinct, non-avian theropods. The resulting predictive model is able to explain 79-93% of the observed variation in kinematics and 69-83% of the observed variation in GRFs, and also performs well in extrapolation tests. However, this study also found that the location of the whole-body centre of mass may exert an important influence on the nature of the GRF, and hence some caution is warranted, in lieu of further investigation.

Animal performance fundamentally influences behaviour, ecology, and evolution. It typically varies monotonously with size. A notable exception is maximum running speed; the fastest animals are of intermediate size. Here we show that this peculiar allometry results from the competition between two musculoskeletal constraints: the kinetic energy capacity, which dominates in small animals, and the work capacity, which reigns supreme in large animals. The ratio of both capacities defines the physiological similarity index Γ, a dimensionless number akin to the Reynolds number in fluid mechanics. The scaling of Γ indicates a transition from a dominance of muscle forces to a dominance of inertial forces as animals grow in size; its magnitude defines conditions of “dynamic similarity“ that enable comparison and estimates of locomotor performance across extant and extinct animals; and the physical parameters that define it highlight opportunities for adaptations in musculoskeletal “design” that depart from the eternal null hypothesis of geometric similarity. The physiological similarity index challenges the Froude number as prevailing dynamic similarity condition, reveals that the differential growth of muscle and weight forces central to classic scaling theory is of secondary importance for the majority of terrestrial animals, and suggests avenues for comparative analyses of locomotor systems. How fast can animals run? Here, the authors show that maximum running speed is limited by different musculoskeletal constraints across animal size: kinetic energy capacity in small animals, and work capacity in large animals.

Integrated urban development strategies are shaping a new policy frame to cope with the complexity of urban problems. This implies multi-level policy mixes involving multiple goals, the collaboration between different actors, and policy theories based on complementarity between different policy tools (and their causal processes). As in other policies, the third aspect has been less analysed. This article studied the theory behind policy mixes developed in the European Union URBAN I Initiative framework and the effects on its employment inclusion goal. The policy theory suggests complementary effects between policy actions oriented toward economic activities and those oriented at increasing employment skills to, in turn, increase residents’ inclusion in the labour market. The quasi-experimental approach applied at the neighbourhood level in Spain showed a moderate influence on employment among the youngest age cohorts and a more evident impact on business density. Nevertheless, evidence concerning the complementarity between actions oriented at improving labour market demand and labour market supply in targeted neighbourhoods suggested in the program theory is less convincing. This exercise showed the methodological challenges in assessing the effectiveness of integral urban initiatives and offered some suggestions regarding the policy theory behind them through a European Union case.

Rationale Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine. Objective The major aims were to investigate the pharmacokinetics and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model. Methods Mephedrone was administered to male Sprague–Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180–240 min. Results Mephedrone plasma concentrations after i.v. administration fit a two-compartment model ( α  = 10.23 h −1 , β  = 1.86 h −1 ). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59 ± 3.67 %. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85 ± 0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic–pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect. Conclusions We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude, and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.