Mental fatigue is referred to as a psychophysiological or neurobiological state caused by prolonged periods of demanding cognitive activity. Sport and exercise science research studies have investigated the effects of experimentally induced mental fatigue on cognitive performance, with mixed results. It has been suggested that negative effects of mental fatigue on cognition performance in laboratory studies could translate to impaired sport performance. However, it remains unclear if impairments in sport performance are due to mental fatigue and how mental fatigue may differ from physical fatigue. Fatigue is well understood as a complex multifactorial construct involving interactions between physiological and neuropsychological responses across brain regions. It may be prudent for researchers to return to the origins of fatigue and cognition before attempting to connect mental fatigue and sport cognition. This article reviews the concept of mental fatigue, its mechanisms and neuroanatomical basis, models of cognition relevant to sports science, investigates how mental fatigue may influence cognition, and suggests future research directions. Mental fatigue as a construct separated from fatigue could be an oversight that has hindered the development of our understanding of mental fatigue. Future sports science research could work to enhance our knowledge of our definitions of fatigue.

Icing interventions on the injured skeletal muscle affect the macrophage-related regenerative events and muscle repair. However, despite its importance for the practice in sport medicine, the influence of different icing protocols on muscle regeneration remains unclear. Here, using a rodent model of mild muscle injury with necrosis in a small fraction of myofibers, the injured animals were allocated to four groups: non-icing control (Con) and a single treatment (Ice-1), three treatments (Ice-3), or nine treatments (Ice-9) with a 30-min icing each time within two days following injury. Muscle regeneration was compared between the groups on post-injury days 1, 3, 5, and 7. The results showed that compared with the Con group, muscle regeneration was faster in the Ice-9 group (but not in the Ice-1 and Ice-3 groups), as indicated by more rapid accumulation of satellite cells within the regenerating area and enlarged size of regenerating myofibers ( p<0.05, respectively). There was also less macrophage accumulation ( p<0.05) and a trend toward early removal of necrotic myofibers in the damaged/regenerating area in the Ice-9 group ( p=0.0535). These results demonstrate that in the case of mild muscle damage, more frequent icing treatment is more effective to stimulate muscle regeneration.

Background: Vascular oxidative stress and low-grade inflammation are important in the pathology of cardiovascular disorders, including hypertension. Cell culture and animal studies suggest that inorganic dietary nitrate may attenuate oxidative stress and inflammation through nitric oxide (NO), and there is a need to investigate whether this translates to humans. Aim: In this randomised, placebo-controlled crossover study, by measuring a combination of multiple blood biomarkers, we evaluated whether previously reported benefits of dietary nitrate translate to a reduced oxidative stress and an improved inflammation status in 15 men and women (age range: 56-71 years) with treated hypertension. Methods: We investigated the effects of a single similar to 400 mg-dose of nitrate at 3 h post-ingestion (3H POST) and the daily consumption of 2 x similar to 400 mg of nitrate over 4 weeks (4WK POST), through nitrate-rich versus nitrate-depleted (placebo) beetroot juice. Measurements included plasma nitrate and nitrite (NOx), oxidised low-density lipoprotein (oxLDL), F-2-isoprostanes, protein carbonyls, oxidised (GSSG) and reduced glutathione (GSH); and serum high-sensitive C-reactive protein (hsCRP), chemokines, cytokines, and adhesion molecules. Flow cytometry was used to assess the relative proportion of blood monocyte subsets. Results: At 4WK POST nitrate intervention, the oxLDL/NOx ratio decreased (mainly due to increases in plasma nitrate and nitrite) and the GSH/GSSG ratio (a sensitive biomarker for alterations in the redox status) increased, compared with placebo (for both ratios P < 0.01). The relative proportion of classical (CD14(+)CD16(-)) monocytes decreased at 4WK POST for placebo compared to nitrate intervention (P < 0.05). Other oxidative stress and inflammatory markers were not altered by increased nitrate intake relative to placebo. Conclusions: The data from this study point toward a subtle alteration in the redox balance toward a less pro-oxidative profile by a regular intake of inorganic nitrate from plant foods.

In this randomized placebo-controlled crossover study, we evaluated whether previously reported cardiovascular benefits of plant-derived inorganic nitrate via NO translate into improved vascular function and blood pressure-lowering in middle-aged and older men and women with treated hypertension.

Recombinant human neutrophil elastase (rHNE), a serine protease, was expressed in Pichia pastoris. Glycosylation sites were removed via bioengineering to prevent hyper-glycosylation (a common problem with this system) and the cDNA was codon optimized for translation in Pichia pastoris. The zymogen form of rHNE was secreted as a fusion protein with an N-terminal six histidine tag followed by the heme binding domain of Cytochrome B5 (CytB5) linked to the N-terminus of the rHNE sequence via an enteropeptidase cleavage site. The CytB5 fusion balanced the very basic rHNE (pI = 9.89) to give a colored fusion protein (pI = 6.87), purified via IMAC. Active rHNE was obtained via enteropeptidase cleavage, and purified via cation exchange chromatography, resulting in a single protein band on SDS PAGE (Mr = 25 KDa). Peptide mass fingerprinting analysis confirmed the rHNE amino acid sequence, the absence of glycosylation and the absence of an 8 amino acid C-terminal peptide as opposed to the 20 amino acids usually missing from the C-terminus of native enzyme. The yield of active rHNE was 0.41 mg/L of baffled shaker flask culture medium. Active site titration with alpha-1 antitrypsin, a potent irreversible elastase inhibitor, quantified the concentration of purified active enzyme. The Km of rHNE with methoxy-succinyl-AAPVpNA was identical with that of the native enzyme within the assay's limit of accuracy. This is the first report of full-length rHNE expression at high yields and low cost facilitating further studies on this major human neutrophil enzyme.

Background: Research in sport, military, and aerospace populations has shown that mental fatigue may impair cognitive performance. The effect of nutritional interventions that may mitigate such negative effects has been investigated. This systematic review and meta-analysis aimed to quantify the effects of nutritional interventions on cognitive domains often measured in mental fatigue research. Methods: A systematic search for articles was conducted using key terms relevant to mental fatigue in sport, military, and aerospace populations. Two reviewers screened 11,495 abstracts and 125 full texts. A meta-analysis was conducted whereby effect sizes were calculated using subgroups for nutritional intervention and cognitive domains. Results: Fourteen studies were included in the meta-analysis. The consumption of energy drinks was found to have a small positive effect on reaction time, whilst the use of beta-alanine, carbohydrate, and caffeine had no effect. Carbohydrate and caffeine use had no effect on accuracy. Conclusions: The results of this meta-analysis suggest that consuming energy drinks may improve reaction time. The lack of effect observed for other nutritional interventions is likely due to differences in the type, timing, dosage, and form of administration. More rigorous randomized controlled trials related to the effect of nutrition interventions before, during, and after induced mental fatigue are required.

Background: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome is a primary immunodeficiency characterized by retention of leukocytes in the bone marrow (myelokathexis), resulting in neutropenia, leukopenia, and in some cases hypogammaglobulinemia. WHIM syndrome is classically caused by gain-of-function mutations in CXCR4, with the resulting hyperactivation of the CXCR4-CXCL12 pathway. Patients diagnosed with WHIM syndrome have a heterogeneous phenotype yet typically experience recurrent sinopulmonary infections and unusual susceptibility to human papillomavirus (HPV), resulting in predisposition to warts and malignancy. There are no approved medications for WHIM syndrome. To date, all management strategies are symptomatic only, failing to address the underlying mechanism of WHIM syndrome, and are mostly ineffective for HPV infections. Mavorixafor is an investigational, oral CXCR4 antagonist that directly inhibits CXCR4-enhanced signaling in WHIM syndrome pathogenesis, and has been shown to increase white blood cell counts, decrease annualized infection rate, and reduce cutaneous warts in an open-label phase 2 clinical trial (NCT03005327) for patients with WHIM syndrome. Aims: Here, we describe the design, baseline characteristics, and status of a global phase 3, double-blind, placebo-controlled, randomized trial (4WHIM, NCT03995108) with open-label extension evaluating the safety and efficacy of mavorixafor in patients with WHIM syndrome. Methods: Eligibility for enrollment included age ≥12 years, diagnosis of WHIM syndrome, confirmed CXCR4 mutation, and absolute neutrophil count (ANC) ≤400 cells/µL without clinical evidence of active systemic infection. Patients were randomized in a 1:1 ratio to receive mavorixafor (adults, 400 mg; adolescents weighing ≤50 kg, 200mg; adolescents weighing >50 kg, 400mg) or placebo orally once daily. The primary endpoint is defined as number of hours above ANC threshold (500 cells/µL) over a 24-hour period, assessed every 3 months for 52 weeks. Secondary endpoints include the composite end point of infection and warts, infection rates and severity, change from baseline in cutaneous warts, and number of hours above absolute lymphocyte count (ALC) of ≥1000 cells/µL over a 24-hour period, and patient-reported quality-of-life assessment using age-appropriate questionnaires. Results: Enrollment for the trial has been completed, with a total of 31 patients enrolled globally. Demographics of the enrolled population include: 48% adolescents (age 12-18 years), 42% male, 71% with warts, 81% with nonsense CXCR4 mutations, and 19% with frameshift CXCR4 mutations. Mean and median ANC and ALC at screening visit were 220 cells/µL and 180 cells/µL, and 515 cells/µL and 440 cells/µL respectively. Summary/Conclusion: 4WHIM is the first double-blind, placebo-controlled, randomized trial in patients with WHIM syndrome; top-line clinical results are expected in Q4 2022. The study enrolled children (aged ≥ 12 years) and adults, all with genetically confirmed CXCR4 variants consisting of both nonsense and frameshift mutations. The patients all presented with severe neutropenia and lymphopenia and a high percentage of the patients had warts. This study represents an important next step in the development of the novel, orally bioavailable, targeted therapy mavorixafor for the treatment of patients with WHIM syndrome.

Citation: Lindsay A and Peake JM (2021) Muscle Strength and Power: Primary Outcome Measures to Assess Cold Water Immersion Efficacy After Exercise With a Strong Strength or Power Component. Front. Sports Act. Living 3:655975. doi: 10.3389/fspor.2021.655975 Muscle Strength and Power: Primary Outcome Measures to Assess Cold Water Immersion Efficacy After Exercise With a Strong Strength or Power Component

Human neutrophil elastase (HNE) is a uniquely destructive serine protease with the ability to unleash a wave of proteolytic activity by destroying the inhibitors of other proteases. Although this phenomenon forms an important part of the innate immune response to invading pathogens, it is responsible for the collateral host tissue damage observed in chronic conditions such as chronic obstructive pulmonary disease (COPD), and in more acute disorders such as the lung injuries associated with COVID-19 infection. Previously, a combinatorially selected activity-based probe revealed an unexpected substrate preference for oxidised methionine, which suggests a link to oxidative pathogen clearance by neutrophils. Here we use oxidised model substrates and inhibitors to confirm this observation and to show that neutrophil elastase is specifically selective for the di-oxygenated methionine sulfone rather than the mono-oxygenated methionine sulfoxide. We also posit a critical role for ordered solvent in the mechanism of HNE discrimination between the two oxidised forms methionine residue. Preference for the sulfone form of oxidised methionine is especially significant. While both host and pathogens have the ability to reduce methionine sulfoxide back to methionine, a biological pathway to reduce methionine sulfone is not known. Taken together, these data suggest that the oxidative activity of neutrophils may create rapidly cleaved elastase "super substrates" that directly damage tissue, while initiating a cycle of neutrophil oxidation that increases elastase tissue damage and further neutrophil recruitment.

New Findings What is the central question of this study? The extent to which genetics determines adaptation to endurance versus resistance exercise is unclear. Previously, a divergent selective breeding rat model showed that genetic factors play a major role in the response to aerobic training. Here, we asked: do genetic factors that underpin poor adaptation to endurance training affect adaptation to functional overload? What is the main finding and its importance? Our data show that heritable factors in low responders to endurance training generated differential gene expression that was associated with impaired skeletal muscle hypertrophy. A maladaptive genotype to endurance exercise appears to dysregulate biological processes responsible for mediating exercise adaptation, irrespective of the mode of contraction stimulus. AbstractDivergent skeletal muscle phenotypes result from chronic resistance‐type versus endurance‐type contraction, reflecting the principle of training specificity. Our aim was to determine whether there is a common set of genetic factors that influence skeletal muscle adaptation to divergent contractile stimuli. Female rats were obtained from a genetically heterogeneous rat population and were selectively bred from high responders to endurance training (HRT) or low responders to endurance training (LRT; n = 6/group; generation 19). Both groups underwent 14 days of synergist ablation to induce functional overload of the plantaris muscle before comparison to non‐overloaded controls of the same phenotype. RNA sequencing was performed to identify Gene Ontology biological processes with differential (LRT vs. HRT) gene set enrichment. We found that running distance, determined in advance of synergist ablation, increased in response to aerobic training in HRT but not LRT (65 ± 26 vs. −6 ± 18%, mean ± SD, P < 0.0001). The hypertrophy response to functional overload was attenuated in LRT versus HRT (20.1 ± 5.6 vs. 41.6 ± 16.1%, P = 0.015). Between‐group differences were observed in the magnitude of response of 96 upregulated and 101 downregulated pathways. A further 27 pathways showed contrasting upregulation or downregulation in LRT versus HRT in response to functional overload. In conclusion, low responders to aerobic endurance training were also low responders for compensatory hypertrophy, and attenuated hypertrophy was associated with differential gene set regulation. Our findings suggest that genetic factors that underpin aerobic training maladaptation might also dysregulate the transcriptional regulation of biological processes that contribute to adaptation to mechanical overload.

The commercial market for wearable health technology is growing but the value these technologies provide for consumers is debatable, as many technologies lack formal validation and are being abandoned at a high rate. The enabling of self-efficacy mechanisms in the design of health technologies, through the factors identified by self-determination theory and the Technology Acceptance Model, could increase the uptake and continued use of these devices. The aim of this research was to investigate how and why people use wearable health technology, and to evaluate their experiences from the perspective of perceptions of autonomy, safety, information security, information accuracy and willingness for continued use. Forty-eight sport enthusiasts or athletes, age range 18-65 and over, completed an online survey with 46 questions. A statistical analysis that included a Mann-Whitney U Test and a Person's Correlation analysis indicated that participants who were confident in their use of a health technology showed satisfaction with previous uses and a sense of autonomy leading to an overall positive experience. Issues around data and personal information security were identified, aligning with extant literature. Findings suggest that: (i) past experience play a role in people's perception of self-efficacy, (ii) the tracking of activities enables of autonomy and confidence, (iii) autonomy influences personal willingness to use health technologies, (iv) strong interest in personal health technologies motivates sustained engagement, and that (v) reliability and validity of data impacts on confidence in health technologies. A conceptual model is proposed for consideration when designing and evaluating health technologies, based on the factors supporting self-efficacy and trust in health technologies. Further research is required to develop this model with the aim of informing designers and developers about how to translate these factors into design features for the development of more effective personal health technology.

Our research objective is to examine the role of dysregulated immune responses in disease progression and changes in lung physiology in a rat model of COPD. Spontaneously hypertensive rats were exposed to tobacco smoke (TS) (90 mg/m3) or filtered air (FA) for up to 12 weeks. Necropsy timepoints of 4, 6, 8, 10 and 12 weeks were chosen to define the immunological and pathophysiological changes in the lung. Rats exposed to TS showed significant increases in macrophage, neutrophil and lymphocyte number in bronchoalveolar lavage compared to FA at all weeks examined. Proinflammatory cytokines IL-1β, IL-6 and IFN-γ in whole lung homogenates were significantly increased following exposure to TS compared to FA controls. Physiological airway obstruction due to TS exposure was noted by significant elevations in central airway resistance and tissue damping. Central airway resistance was significantly increased at 4 weeks, decreased at 6 weeks, but returned to significantly elevated levels at 10 and 12 weeks following TS exposure. Tissue damping showed a peak at 4 weeks, then a decreasing trend, although remaining significantly elevated through 12 weeks of TS exposure. Strong positive correlations were noted between proinflammatory cytokines IL-1β, IL-6, IFN-γ, TNF-α and the degree of tissue damping. These changes were associated with increases in central airway squamous epithelial metaplasia and distal airway mucous metaplasia. These findings suggest progressive airway obstruction with an abnormal inflammatory response to TS exposure in this rodent model of COPD. We conclude a dysregulated immunologic response, along with airway inflammation are strongly associated with the impairment of physiological lung function in TS-exposed rats.

Proteomics offers the opportunity to identify and quantify many proteins and to explore how they correlate and interact with each other in biological networks. This study aimed to characterize changes in the muscle proteome during the destruction, repair, and early-remodeling phases after impact trauma in male Wistar rats. Muscle tissue was collected from uninjured control rats and rats that were euthanized between 6 h and 14 days after impact injury. Muscle tissue was analyzed using unbiased, data-independent acquisition LC-MS/MS. We identified 770 reviewed proteins in the muscle tissue, 296 of which were differentially abundant between the control and injury groups (P ≤ 0.05). Around 50 proteins showed large differences (≥10-fold) or a distinct pattern of abundance after injury. These included proteins that have not been identified previously in injured muscle, such as ferritin light chain 1, fibrinogen γ-chain, fibrinogen β-chain, osteolectin, murinoglobulin-1, T-kininogen 2, calcium-regulated heat-stable protein 1, macrophage-capping protein, retinoid-inducible serine carboxypeptidase, ADP-ribosylation factor 4, Thy-1 membrane glycoprotein, and ADP-ribosylation factor-like protein 1. Some proteins increased between 6 h and 14 days, whereas other proteins increased in a more delayed pattern at 7 days after injury. Bioinformatic analysis revealed that various biological processes, including regulation of blood coagulation, fibrinolysis, regulation of wound healing, tissue regeneration, acute inflammatory response, and negative regulation of the immune effector process, were enriched in injured muscle tissue. This study advances the understanding of early muscle healing after muscle injury and lays a foundation for future mechanistic studies on interventions to treat muscle injury.

Regular postexercise cooling attenuates muscle hypertrophy, yet its effects on the key molecular factors that regulate muscle growth and remodeling are not well characterized. In the present study, nine men completed two sessions of single-leg resistance exercise on separate days. On 1 day, they sat in cold water (10°C) up to their waist for 10 min after exercise. On the other day, they exercised at a low intensity for 10 min after exercise. Muscle biopsies were collected from the exercised leg before, 2, 24, and 48 h after exercise in both trials. These muscle samples were analyzed to evaluate changes in genes and proteins involved in muscle growth and remodeling. Muscle-specific RING finger 1 mRNA increased at 2 h after both trials (P < 0.05), while insulin-like growth factor (IGF)-1 Ec, IGF-1 receptor, growth arrest and DNA damage-inducible protein 45, collagen type I alpha chain A, collagen type III alpha chain 1, laminin and tissue inhibitor of metallopeptidase 1 mRNA increased 24−48 h after both trials (P < 0.05). By contrast, atrogin-1 mRNA decreased at all time points after both trials (P < 0.05). Protein expression of tenascin C increased 2 h after the active recovery trial (P < 0.05), whereas FoxO3a protein expression decreased after both trials (P < 0.05). Myostatin mRNA and ubiquitin protein expression did not change after either trial. These responses were not significantly different between the trials. The present findings suggest that regular cold water immersion attenuates muscle hypertrophy independently of changes in factors that regulate myogenesis, proteolysis and extracellular matrix remodeling in muscle after exercise.

An increasing body of evidence suggests that age-related immune changes and chronic inflammation contribute to cancer development. Recognizing that exercise has protective effects against cancer, promotes immune function, and beneficially modulates inflammation with ageing, this review outlines the current evidence indicating an emerging role for exercise immunology in preventing and treating cancer in older adults. A specific focus is on data suggesting that muscle- derived cytokines (myokines) mediate anti-cancer effects through promoting immunosurveillance against tumourigenesis or inhibiting cancer cell viability. Previous studies suggested that the exercise-induced release of myokines and other endocrine factors into the blood increases the capacity of blood serum to inhibit cancer cell growth in vitro. However, little is known about whether this effect is influenced by ageing. Prostate cancer is the second most common cancer in men. We therefore examined the effects of serum collected before and after exercise from healthy young and older men on the metabolic activity of androgen-responsive LNCaP and androgen-unresponsive PC3 prostate cancer cells. Exercise-conditioned serum collected from the young group did not alter cell metabolic activity, whereas post-exercise serum (compared with pre-exercise serum) from the older men inhibited the metabolic activity of LNCaP cancer cells. Serum levels of candidate cancer-inhibitory myokines oncostatin M and osteonectin increased in both age groups following exercise. Serum testosterone increased only in the younger men postexercise, potentially attenuating inhibitory effects of myokines on the LNCaP cell viability. The data from our study and the evidence in this review suggest that mobilizing serum factors and immune cells may be a key mechanism of how exercise counteracts cancer in the older population.