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Rationale: Obesity is a major risk factor for asthma; the reasons for this are poorly understood, although it is thought that inflammatory changes in adipose tissue in obesity could contribute to airway inflammation and airway reactivity in individuals who are obese.Objectives: To determine if inflammation in adipose tissue in obesity is related to late-onset asthma, and associated with increased markers of airway inflammation and reactivity.Methods: We recruited a cohort of obese women with asthma and obese control women. We followed subjects with asthma for 12 months after bariatric surgery. We compared markers in adipose tissue and the airway from subjects with asthma and control subjects, and changes in subjects with asthma over time.Measurements and Main Results: Subjects with asthma had increased macrophage infiltration of visceral adipose tissue (P < 0.01), with increased expression of leptin (P < 0.01) and decreased adiponectin (p < 0.001) when controlled for body mass index. Similar trends were observed in subcutaneous adipose tissue. Airway epithelial cells expressed receptors for leptin and adiponectin, and airway reactivity was significantly related to visceral fat leptin expression (rho = -0.8; P < 0.01). Bronchoalveolar lavage cytokines and cytokine production from alveolar macrophages were similar in subjects with asthma and control subjects at baseline, and tended to increase 12 months after surgery.Conclusions: Obesity is associated with increased markers of inflammation in serum and adipose tissue, and yet decreased airway inflammation in obese people with asthma; these patterns reverse with bariatric surgery. Leptin and other adipokines may be important mediators of airway disease in obesity through direct effects on the airway rather than by enhancing airway inflammation. [ABSTRACT FROM AUTHOR]

Abstract The economic and environmental viability of dedicated terrestrial energy crops is in doubt. The production of large scale biomass (macroalgae) for biofuels in the marine environment was first tested in the late 1960’s. The culture attempts failed due to the engineering challenges of farming offshore. However the energy conversion via anaerobic digestion was successful as the biochemical composition of macroalgae makes it an ideal feedstock. The technology for the mass production of macroalgae has developed principally in China and Asia over the last 50 years to such a degree that it is now the single largest product of aquaculture. There has also been significant technology transfer and macroalgal cultivation is now well tried and tested in Europe and America. The inherent advantage of production of biofuel feedstock in the marine environment is that it does not compete with food production for land or fresh water. Here we revisit the idea of the large scale cultivation of macroalgae at sea for subsequent anaerobic digestion to produce biogas as a source of renewable energy, using a European case study as an example.

Abstract Background The blood-brain tumor barrier (BTB) impedes the delivery of therapeutic agents to brain tumors. While adequate delivery of drugs occurs in systemic tumors, the BTB limits delivery of anti-tumor agents into brain metastases. Results In this study, we examined the function and regulation of calcium-activated potassium (KCa) channels in a rat metastatic brain tumor model. We showed that intravenous infusion of NS1619, a KCa channel agonist, and bradykinin selectively enhanced BTB permeability in brain tumors, but not in normal brain. Iberiotoxin, a KCa channel antagonist, significantly attenuated NS1619-induced BTB permeability increase. We found KCa channels and bradykinin type 2 receptors (B2R) expressed in cultured human metastatic brain tumor cells (CRL-5904, non-small cell lung cancer, metastasized to brain), human brain microvessel endothelial cells (HBMEC) and human lung cancer brain metastasis tissues. Potentiometric assays demonstrated the activity of KCa channels in metastatic brain tumor cells and HBMEC. Furthermore, we detected higher expression of KCa channels in the metastatic brain tumor tissue and tumor capillary endothelia as compared to normal brain tissue. Co-culture of metastatic brain tumor cells and brain microvessel endothelial cells showed an upregulation of KCa channels, which may contribute to the overexpression of KCa channels in tumor microvessels and selectivity of BTB opening. Conclusion These findings suggest that KCa channels in metastatic brain tumors may serve as an effective target for biochemical modulation of BTB permeability to enhance selective delivery of chemotherapeutic drugs to metastatic brain tumors.

Abstract Background Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been identified. Some evidence has suggested that CD133 is a marker for a subset of leukemia and glioblastoma cancer stem cells. Especially, CD133 positive cells isolated from human glioblastoma may initiate tumors and represent novel targets for therapeutics. The gene expression and the drug resistance property of CD133 positive cancer stem cells, however, are still unknown. Results In this study, by FACS analysis we determined the percentage of CD133 positive cells in three primary cultured cell lines established from glioblastoma patients 10.2%, 69.7% and 27.5%, respectively. We also determined the average mRNA levels of markers associated with neural precursors. For example, CD90, CD44, CXCR4, Nestin, Msi1 and MELK mRNA on CD133 positive cells increased to 15.6, 5.7, 337.8, 21.4, 84 and 1351 times, respectively, compared to autologous CD133 negative cells derived from cell line No. 66. Additionally, CD133 positive cells express higher levels of BCRP1 and MGMT mRNA, as well as higher mRNA levels of genes that inhibit apoptosis. Furthermore, CD133 positive cells were significantly resistant to chemotherapeutic agents including temozolomide, carboplatin, paclitaxel (Taxol) and etoposide (VP16) compared to autologous CD133 negative cells. Finally, CD133 expression was significantly higher in recurrent GBM tissue obtained from five patients as compared to their respective newly diagnosed tumors. Conclusion Our study for the first time provided evidence that CD133 positive cancer stem cells display strong capability on tumor's resistance to chemotherapy. This resistance is probably contributed by the CD133 positive cell with higher expression of on BCRP1 and MGMT, as well as the anti-apoptosis protein and inhibitors of apoptosis protein families. Future treatment should target this small population of CD133 positive cancer stem cells in tumors to improve the survival of brain tumor patients.

Background: This study aimed to describe the nutrition knowledge, food security risk and eating disorder risk of development male rugby league players., Methods: Sixty athletes from one Australian professional rugby league club volunteered. A cross sectional online survey questionnaire consisted of three sections (Eating Disorders Inventory (EDI-3), Nutrition Knowledge and Food Security). All athletes completed the online survey without assistance using a personal electronic device., Results: The mean total knowledge score was 65.7±13.1%. There was a positive relationship between age and knowledge score, P=0.050, r 2 =0.06. The majority of players had breakfast everyday (N.=45, 73.8%), took pack lunches (N.=33, 55.0%), and had homemade evening meals (N.=55, 91.7%). The majority of players ate more than 1 hour before training (N.=45, 75%) and all players (n=60, 100%) ate within half an hour of training finishing. The majority of participants agreed that nutrition could influence physical and cognitive aspects of nutrition however, skill-based activities were perceived by fewer participants to be influenced by nutrition. The majority (N.=38, 63.3%) had high food security, six (10.0%) had marginal food security, whereas 10 (16.7%) and six (10.0%) had low and very low security respectively., Conclusions: These results show a concerning levels of eating disorder risk, food insecurity and poor nutrition knowledge amongst male development rugby league players. However, it does show that they believe nutrition can impact their health and performance, and they do mostly appear to adhere to the nutrition principals for optimising health and performance.

Background: There have been several published studies on the prevalence of low energy availability (LEA) risk amongst North American and European endurance athletes. Yet the prevalence and risk factors amongst rugby league players are less well understood. This study assessed the prevalence of low energy availability risk, eating disorder risk, and food security amongst players from a female National Rugby League squad in Australia., Methods: Players from one Australian professional rugby league club volunteered to participate in the study. An online questionnaire was conducted to determine the prevalence of low energy availability (Low Energy Availability in Females Questionnaire [LEAF-Q]), eating disorder risk (Eating Disorders Inventory [EDI-3]), and food security., Results: Differences between those "at risk" and "not at risk" based on their total LEAF-Q score were determined. Of the 28 players, 64% (N.=18) were at risk of LEA. Raw scores for the EDI-3 subscales, body dissatisfaction (P=0.043), bulimia (P=0.002), composite score (P=0.038), were significantly higher for those at risk and not at risk of LEA. Forty percent of players had some level of food insecurity., Conclusions: The results suggest LEA risk is similar to other populations and those at risk of LEA are more likely to have an elevated clinical risk of eating disorders. Food security is also an issue in this population and could contribute to LEA risk for some. Future research is needed amongst team sports athletes to understand interplay between eating disorder risk and food insecurity with LEA risk.

Pathological deposition and crosslinking of collagen type I by activated myofibroblasts drives progressive tissue fibrosis. Therapies that inhibit collagen synthesis have potential as antifibrotic agents. We identify the collagen chaperone cyclophilin B as a major cellular target of the natural product sanglifehrin A (SfA) using photoaffinity labeling and chemical proteomics. Mechanistically, SfA inhibits and induces the secretion of cyclophilin B from the endoplasmic reticulum (ER) and prevents TGF-β1-activated myofibroblasts from synthesizing and secreting collagen type I in vitro, without inducing ER stress or affecting collagen type I mRNA transcription, myofibroblast migration, contractility, or TGF-β1 signaling. In vivo, SfA induced cyclophilin B secretion in preclinical models of fibrosis, thereby inhibiting collagen synthesis from fibrotic fibroblasts and mitigating the development of lung and skin fibrosis in mice. Ex vivo, SfA induces cyclophilin B secretion and inhibits collagen type I secretion from fibrotic human lung fibroblasts and samples from patients with idiopathic pulmonary fibrosis (IPF). Taken together, we provide chemical, molecular, functional, and translational evidence for demonstrating direct antifibrotic activities of SfA in preclinical and human ex vivo fibrotic models. Our results identify the cellular target of SfA, the collagen chaperone cyclophilin B, as a mechanistic target for the treatment of organ fibrosis.

Growing evidence suggests that childhood ADHD is associated with larger impairments in working memory relative to inhibition. However, most studies have not considered the role of co-occurring anxiety on these estimates - a potentially significant confound given prior evidence that anxiety may increase working memory difficulties but decrease inhibition difficulties for these children. The current study extends prior work to examine the extent to which co-occurring anxiety may be systematically affecting recent estimates of the magnitude of working memory/inhibitory control deficits in ADHD. The carefully-phenotyped sample included 197 children with ADHD and 142 children without ADHD between the ages of 8 and 13 years (N = 339; M age  = 10.31, SD = 1.39; 144 female participants). Results demonstrated that ADHD diagnosis predicted small impairments in inhibitory control (d = 0.31) and large impairments in working memory (d = 0.99). However, child trait anxiety assessed dimensionally across multiple informants (child, parent, teacher) did not uniquely predict either executive function, nor did it moderate estimates of ADHD-related working memory/inhibition deficits. When evaluating anxiety categorically and controlling for ADHD, anxiety diagnosis predicted slightly better working memory (d = 0.19) but not inhibitory control for clinically evaluated children generally. Findings from the current study indicate that trait anxiety, measured dimensionally or categorically, does not differentially affect estimates of executive dysfunction in pediatric ADHD. Further, results suggest that trait anxiety is generally not associated with executive dysfunction above and beyond the impact of co-occurring ADHD. Future research is needed to further assess the role of anxiety in ADHD behavioral symptomatology, neurocognitive functioning, and mechanisms underlying these relations., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Nutrition knowledge influences adequate dietary intake in athletes. Inadequate dietary intakes can result in low energy availability (LEA) which can lead to relative energy deficiency in sport (RED-S). To date, there is little information on the relationship between nutrition knowledge and the risk of LEA in female team sport athletes. This study investigates if general and sports nutrition knowledge are associated with the risk of LEA in female team athletes., Methods: A cross-sectional design was used. Female athletes (>16 years) who participate in team sports in New Zealand were asked to complete an online questionnaire. The LEA in Females Questionnaire and the Abridged Sport Nutrition Knowledge Questionnaire were included. LEA risk and general/sports nutrition knowledge were assessed. The relationship between LEA risk and knowledge was analyzed using the Kruskal-Wallis Test of independent variables and χ 2 tests., Results: Among 100 female athletes, 53% were at-risk for LEA, and 70% (N.=67) had poor nutrition knowledge. Athletes who were "at-risk" for LEA and those who were "not at-risk" for LEA did not differ statistically in terms of age (P=0.350) or BMI (P=0.576). Of those "not at risk" 54% had an A-NSK score between 50 and 60% (i.e., average knowledge), whereas 54% of the athletes who were "at risk" for LEA had poor nutrition knowledge. There was no statistical difference between the groups (P=0.273)., Conclusions: The poor nutrition knowledge and the high rates of those "at risk" of LEA among team sports athletes indicates the need for more nutrition education in this population.

Two event-related potentials (ERPs) elicited following errors, the error-related negativity (ERN) and error positivity (Pe), have been proposed to reflect cognitive control, though the specific processes remain debated. Few studies have examined the ERN and Pe's relations with individual differences in cognitive control/executive functioning using well-validated tests administered separately from the inhibition tasks used to elicit the ERN/Pe. Additionally, neurocognitive tests of executive functions tend to strongly predict ADHD symptoms, but the extent to which task-based and EEG-based estimates of executive functioning/cognitive control account for the same variance in ADHD symptoms remains unclear. The current study addressed these limitations by examining relations between the ERN/Pe and three core executive functions (working memory, inhibitory control, set shifting) in a clinically-evaluated sample of 53 children ages 8-12 (M age  = 10.36, SD = 1.42; 77.4% White/Non-Hispanic; 16 girls) with and without ADHD. Results demonstrated that neither the ERN nor Pe were related to overall cognitive control/executive functioning, or to working memory or set shifting specifically (all 95%CIs include 0.0). In contrast, a larger Pe was associated with better-developed inhibitory control (β=-.35, 95%CI excludes 0.0), but did not capture aspects of inhibitory control that are important for predicting ADHD symptoms. Neither the ERN nor Pe predicted ADHD symptoms (95%CIs include 0.0). Results were generally robust to control for age, sex, SES, ADHD symptom cluster, and anxiety, and emphasize the need for caution when interpreting the ERN/Pe as indices of broad-based cognitive control/executive functioning, as well as using the ERN/Pe to examine cognitive processes contributing to ADHD symptomatology.

Introduction: Severe respiratory illness is the most prominent manifestation of patients infected with SARS-CoV-2, and yet the molecular mechanisms underlying severe lung disease in COVID-19 affected patients still require elucidation. Human leukocyte antigen class I (HLA-I) expression is crucial for antigen presentation and the host's response to SARS-CoV-2., Methods: To gain insights into the immune response and molecular pathways involved in severe lung disease, we performed immunopeptidomic and proteomic analyses of lung tissues recovered at four COVID-19 autopsy and six non-COVID-19 transplants., Results: We found signals of tissue injury and regeneration in lung fibroblast and alveolar type I/II cells, resulting in the production of highly immunogenic self-antigens within the lungs of COVID-19 patients. We also identified immune activation of the M2c macrophage as the primary source of HLA-I presentation and immunogenicity in this context. Additionally, we identified 28 lung signatures that can serve as early plasma markers for predicting infection and severe COVID-19 disease. These protein signatures were predominantly expressed in macrophages and epithelial cells and were associated with complement and coagulation cascades., Discussion: Our findings emphasize the significant role of macrophage-mediated immunity in the development of severe lung disease in COVID-19 patients., Competing Interests: DK is a scientific advisor for Immunitrack and Breakbio. DK owns equity in Affimed N.V., Agenus, Armata Pharmaceuticals, Breakbio, BioMarin Pharmaceutical, Celldex Therapeutics, Editas Medicine, Gilead Sciences, Immunitybio, ImmunoGen, IMV, Lexicon Pharmaceuticals, Neoleukin Therapeutics. BeiGene, a Chinese biotech company, supported unrelated SARS COV-2 research at TIGL. EK has an unrelated financial interest in Novartis AG. EK receives unrelated research funding from Bayer AG and 10x Genomics, Inc. CW receives funding support from Pharmacyclics and holds equity in BioNTech, Inc. SY holds equity in Yihui Bio, Inc. RK receives grant support from Boehringer Ingelheim and Bayer, LH receives grants from Boehringer Ingelheim and has received personal consulting fees from Boehringer Ingelheim, Pliant Therapeutics, Bioclinica, Abbvie and Biogen Idec. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Yin, Klaeger, Chea, Carulli, Rachimi, Black, Filbin, Hariri, Knipe, Padera, Stevens, Lane, Carr, Wu, Kim and Keskin.)

Females are often underrepresented in the scientific literature, but awareness of the need for female-specific research is increasing. Review articles have been published on the effects of the menstrual cycle on aspects of exercise performance and physiology, yet to date no research has reviewed the effect of menstrual cycle phase on dietary energy intake. Fluctuations in endogenous sex hormones across the menstrual cycle influence a range of physiological processes, including those involved in nutritional status. Observational research typically quantifies female athletes' nutritional intakes at a single time point; however, this may provide inaccurate information if dietary intake fluctuates across the menstrual cycle. Similarly, this may have implications for interventional research, where dietary intake is often poorly controlled or monitored. This review aimed to synthesize the published literature on dietary energy intakes of naturally menstruating females in various phases of the menstrual cycle. The review critiques the relevant literature in light of recent publications on good practice for female research, explores the impact of the menstrual cycle on energy intake, identifies gaps within the evidence base, and informs future research. Overall, energy intake appears to be lower in the follicular phase compared with the luteal phase, with a particular decrease in the days leading up to and including ovulation. The magnitude of these fluctuations is not yet clearly quantifiable and most likely varies, both between individuals, and from cycle to cycle. This review notes the lack of high-quality research investigating the energy intakes of females across the menstrual cycle, and the very limited data available for female athletes and others who undertake large amounts of physical activity. It also highlights the need for researchers to take into consideration anovulatory cycles and the potential effects of premenstrual disorders on dietary intake., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Life Sciences Institute.)

Histological and lineage immunofluorescence examination revealed that healthy conducting airways of humans and animals harbor sporadic poorly differentiated epithelial patches mostly in the dorsal noncartilage regions that remarkably manifest squamous differentiation. In vitro analysis demonstrated that this squamous phenotype is not due to intrinsic functional change in underlying airway basal cells. Rather, it is a reversible physiological response to persistent Wnt signaling stimulation during de novo differentiation. Squamous epithelial cells have elevated gene signatures of glucose uptake and cellular glycolysis. Inhibition of glycolysis or a decrease in glucose availability suppresses Wnt-induced squamous epithelial differentiation. Compared with pseudostratified airway epithelial cells, a cascade of mucosal protective functions is impaired in squamous epithelial cells, featuring increased epithelial permeability, spontaneous epithelial unjamming, and enhanced inflammatory responses. Our study raises the possibility that the squamous differentiation naturally occurring in healthy airways identified herein may represent "vulnerable spots" within the airway mucosa that are sensitive to damage and inflammation when confronted by infection or injury. Squamous metaplasia and hyperplasia are hallmarks of many airway diseases, thereby expanding these areas of vulnerability with potential pathological consequences. Thus, investigation of physiological and reversible squamous differentiation from healthy airway basal cells may provide critical knowledge to understand pathogenic squamous remodeling, which is often nonreversible, progressive, and hyperinflammatory.

Children with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often experience social impairments. These children also frequently struggle with emotion regulation, and extant literature suggests that emotion dysregulation predicts social impairment in both clinical and neurotypical populations. However, the evidence base linking ADHD/ASD with social impairment comes primarily from samples meeting full diagnostic criteria for ADHD and/or ASD despite evidence that both syndromes reflect extreme ends of natural continuums that are normally distributed across the general population. To our knowledge, the present study is the first to concurrently examine unique and overlapping relations among ADHD/ASD symptoms, emotion regulation, and social difficulties using multi-informant measures (parent, teacher) with a clinically-evaluated sample of 108 children ages 8-13 (40 girls; 66% White/Non-Hispanic) with and without clinically-elevated ASD and ADHD symptoms and other common clinical disorders. Bias-corrected, bootstrapped conditional effects modeling revealed that ADHD-inattentive (β=-0.23) and ASD-social communication (β=-0.20) symptoms predicted social impairment directly, whereas ADHD-hyperactive/impulsive (β=-0.06) and ASD-restricted/repetitive behavior/interests (β=-0.06) symptoms predicted social impairment only via their shared associations with emotion dysregulation. Sensitivity analyses revealed that most relations were robust to control for item overlap across measures. In contrast, only the ADHD-inattention/social impairment link was robust to control for mono-informant bias, highlighting the importance of multi-informant methods and the potential for different determinants of social functioning across settings. Overall, this study implicates emotion regulation skills and all four ADHD/ASD symptom clusters as potential influences on children's social functioning, albeit with a more nuanced and potentially setting-specific pattern than suggested by prior work., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background & Aims: Early reports suggest significant difficulty with enteral feeding in critically ill COVID-19 patients. This study aimed to characterize the prevalence, clinical manifestations, and outcomes of feeding intolerance in critically ill patients with COVID-19., Methods: We examined 323 adult patients with COVID-19 admitted to the intensive care units (ICUs) of Massachusetts General Hospital between March 11 and June 28, 2020 who received enteral nutrition. Systematic chart review determined prevalence, clinical characteristics, and hospital outcomes (ICU complications, length of stay, and mortality) of feeding intolerance., Results: Feeding intolerance developed in 56% of the patients and most commonly manifested as large gastric residual volumes (83.9%), abdominal distension (67.2%), and vomiting (63.9%). Length of intubation (OR 1.05, 95% CI 1.03-1.08), ≥1 GI symptom on presentation (OR 0.76, 95% CI 0.59-0.97), and severe obesity (OR 0.29, 95% CI 0.13-0.66) were independently associated with development of feeding intolerance. Compared to feed-tolerant patients, patients with incident feeding intolerance were significantly more likely to suffer cardiac, renal, hepatic, and hematologic complications during their hospitalization. Feeding intolerance was similarly associated with poor outcomes including longer ICU stay (median [IQR] 21.5 [14-30] vs. 15 [9-22] days, P < 0.001), overall hospitalization time (median [IQR] 30.5 [19-42] vs. 24 [15-35], P < 0.001) and in-hospital mortality (33.9% vs. 16.1%, P < 0.001). Feeding intolerance was independently associated with an increased risk of death (HR 3.32; 95% CI 1.97-5.6)., Conclusions: Feeding intolerance is a frequently encountered complication in critically ill COVID-19 patients in a large tertiary care experience and is associated with poor outcomes., Competing Interests: Conflict of interest KS has received research support from AstraZeneca, Takeda, and Gelesis, has served as a speaker for Shire, and has served as a consultant to Gelesis, Synergy, and Shire., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objectives: The aim of this study was to develop and validate a questionnaire assessing knowledge of signs and symptoms of relative energy deficiency in sport among healthcareprofessionals and physically active individuals., Design: Cross-sectional study., Methods: The questionnaire was created in two phases: 1)Item development was established through a literature review, expert review (n = 4), and pre-testing among healthcare professionals, dietetic students, and the general population (n = 35). 2) Validity (item analysis, construct validity) and internal reliability were assessed by administrating the questionnaire to healthcare professionals (n = 97) and physically active individuals who engaged in moderate to intense physical activity (n=77). The questionnaire was re-administered in a subset of the same groups (n = 88) for test-retest reliability., Results: The expert responses showed >80% acceptability and pretesting through interviews indicated good content and face validity. Item response analysis resulted in removal of 6 items due to low discrimination ability. Significantly higher knowledge scores in health professionals compared with non-health professionals (mean difference (95% CI) = 2.8 (1.9, 3.7)) confirmed construct validity. Internal consistency, assessed using Cronbach's alpha (α = 0.79), and test-retest reliability using intra-class correlation coefficients (intra-class correlation coefficients = 0.80; Spearman's correlation = 0.84, p < 0.001) were good. The final questionnaire had 18 items assessing knowledge of signs and symptoms of Relative Energy Deficiency in Sport., Conclusions: The questionnaire provides a valid and reliable tool to assess knowledge of signs and symptoms of Relative Energy Deficiency in Sport among health professionals and physically active individuals, which could guide future education requirements by assessing current knowledge., (Copyright © 2022 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Idiopathic pulmonary fibrosis is a progressive lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. We previously identified HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) as YAP inhibitors based on a high-throughput small-molecule screen in primary human lung fibroblasts. Here we report that several Aurora kinase inhibitors were also identified from the top hits of this screen. MK-5108, a highly selective inhibitor for AURKA (Aurora kinase A), induced YAP phosphorylation and cytoplasmic retention and significantly reduced profibrotic gene expression in human lung fibroblasts. The inhibitory effect on YAP nuclear translocation and profibrotic gene expression is specific to inhibition of AURKA, but not Aurora kinase B or C, and is independent of the Hippo pathway kinases LATS1 and LATS2 (Large Tumor Suppressor 1 and 2). Further characterization of the effects of MK-5108 demonstrate that it inhibits YAP nuclear localization indirectly via effects on actin polymerization and TGFβ (Transforming Growth Factor β) signaling. In addition, MK-5108 treatment reduced lung collagen deposition in the bleomycin mouse model of pulmonary fibrosis. Our results reveal a novel role for AURKA in YAP-mediated profibrotic activity in fibroblasts and highlight the potential of small-molecule screens for YAP inhibitors for identification of novel agents with antifibrotic activity.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease which leads to significant morbidity and mortality from respiratory failure. The two drugs currently approved for clinical use slow the rate of decline in lung function but have not been shown to halt disease progression or reverse established fibrosis. Thus, new therapeutic targets are needed. Endothelial injury and the resultant vascular permeability are critical components in the response to tissue injury and are present in patients with IPF. However, it remains unclear how vascular permeability affects lung repair and fibrosis following injury. Lipid mediators such as sphingosine-1-phosphate (S1P) are known to regulate multiple homeostatic processes in the lung including vascular permeability. We demonstrate that endothelial cell-(EC) specific deletion of the S1P receptor 1 (S1PR1) in mice (EC- S1pr1 -/- ) results in increased lung vascular permeability at baseline. Following a low-dose intratracheal bleomycin challenge, EC- S1pr1 -/- mice had increased and persistent vascular permeability compared with wild-type mice, which was strongly correlated with the amount and localization of resulting pulmonary fibrosis. EC- S1pr1 -/- mice also had increased immune cell infiltration and activation of the coagulation cascade within the lung. However, increased circulating S1P ligand in ApoM-overexpressing mice was insufficient to protect against bleomycin-induced pulmonary fibrosis. Overall, these data demonstrate that endothelial cell S1PR1 controls vascular permeability in the lung, is associated with changes in immune cell infiltration and extravascular coagulation, and modulates the fibrotic response to lung injury.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited heart disease which can cause life-threatening ventricular arrhythmias and cardiac dysfunction. The autosomal dominant form of ARVD/C is caused by mutations in the cardiac desmosome, such as those in the plakoglobin plakophilin-2 (PKP2) gene. Here, we generated three human induced pluripotent stem cell (iPSC) lines from the peripheral blood mononuclear cells (PBMCs) of three ARVD/C patients carrying pathogenic variants in their PKP2 genes (c.2065&#95;2070delinsG; c.235C>T; c.1725&#95;1728dup). All lines show the typical morphology of pluripotent stem cells, demonstrate high expression of pluripotent markers, display normal karyotype, and differentiate into all three germ layers in vitro. These lines are valuable resources for studying the pathological mechanisms of ARVD/C caused by PKP2 mutation., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Idiopathic pulmonary fibrosis (IPF) primarily affects the aged population and is characterised by failure of alveolar regeneration, leading to loss of alveolar type 1 (AT1) cells. Aged mouse models of lung repair have demonstrated that regeneration fails with increased age. Mouse and rat lung repair models have shown retinoic acid (RA) treatment can restore alveolar regeneration. Herein, we seek to determine the signalling mechanisms that become activated on RA treatment prior to injury, which support alveolar differentiation., Design: Partial pneumonectomy lung injury model and next-generation sequencing of sorted cell populations were used to uncover molecular targets regulating alveolar repair. In vitro organoids generated from epithelial cells of mouse or patient with IPF co-cultured with young, aged or RA-pretreated murine fibroblasts were used to test potential targets., Main Outcome Measurements: Known alveolar epithelial cell differentiation markers, including HOPX and AGER for AT1 cells, were used to assess outcome of treatments., Results: Gene expression analysis of sorted fibroblasts and epithelial cells isolated from lungs of young, aged and RA-pretreated aged mice predicted increased platelet-derived growth factor subunit A (PDGFA) signalling that coincided with regeneration and alveolar epithelial differentiation. Addition of PDGFA induced AT1 and AT2 differentiation in both mouse and human IPF lung organoids generated with aged fibroblasts, and PDGFA monoclonal antibody blocked AT1 cell differentiation in organoids generated with young murine fibroblasts., Conclusions: Our data support the concept that RA indirectly induces reciprocal PDGFA signalling, which activates regenerative fibroblasts that support alveolar epithelial cell differentiation and repair, providing a potential therapeutic strategy to influence the pathogenesis of IPF., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Human pluripotent stem cells (PSCs), which are composed of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), provide an opportunity to advance cardiac cell therapy-based clinical trials. However, an important hurdle that must be overcome is the risk of teratoma formation after cell transplantation due to the proliferative capacity of residual undifferentiated PSCs in differentiation batches. To tackle this problem, we propose the use of a minimal noncardiotoxic doxorubicin dose as a purifying agent to selectively target rapidly proliferating stem cells for cell death, which will provide a purer population of terminally differentiated cardiomyocytes before cell transplantation. In this study, we determined an appropriate in vitro doxorubicin dose that (a) eliminates residual undifferentiated stem cells before cell injection to prevent teratoma formation after cell transplantation and (b) does not cause cardiotoxicity in ESC-derived cardiomyocytes (CMs) as demonstrated through contractility analysis, electrophysiology, topoisomerase activity assay, and quantification of reactive oxygen species generation. This study establishes a potentially novel method for tumorigenic-free cell therapy studies aimed at clinical applications of cardiac cell transplantation.

Fibrosis is a macrophage-driven process of uncontrolled extracellular matrix accumulation. Neuronal guidance proteins such as netrin-1 promote inflammatory scarring. We found that macrophage-derived netrin-1 stimulates fibrosis through its neuronal guidance functions. In mice, fibrosis due to inhaled bleomycin engendered netrin-1-expressing macrophages and fibroblasts, remodeled adrenergic nerves, and augmented noradrenaline. Cell-specific knockout mice showed that collagen accumulation, fibrotic histology, and nerve-associated endpoints required netrin-1 of macrophage but not fibroblast origin. Adrenergic denervation; haploinsufficiency of netrin-1's receptor, deleted in colorectal carcinoma; and therapeutic α1 adrenoreceptor antagonism improved collagen content and histology. An idiopathic pulmonary fibrosis (IPF) lung microarray data set showed increased netrin-1 expression. IPF lung tissues were enriched for netrin-1+ macrophages and noradrenaline. A longitudinal IPF cohort showed improved survival in patients prescribed α1 adrenoreceptor blockade. This work showed that macrophages stimulate lung fibrosis via netrin-1-driven adrenergic processes and introduced α1 blockers as a potentially new fibrotic therapy.

Arterial stiffness is an important marker of vascular damage and a strong predictor of cardiovascular diseases (CVD). Given that pathophysiological processes leading to an increased arterial stiffness begin during childhood, the aim of this clustered observational study was to determine the relationship between modifiable factors including dietary patterns and indices of aortic arterial stiffness and wave reflection in 9-11-year-old children. Data collection was conducted between April and December 2015 in 17 primary schools in Dunedin, New Zealand. Dietary data were collected using a previously validated food frequency questionnaire and identified using principal component analysis method. Arterial stiffness (carotid-femoral pulse wave velocity, PWV) and central arterial wave reflection (augmentation index, AIx) were measured using the SphygmoCor XCEL system (Atcor Medical, Sydney, Australia). Complete data for PWV and AIx analyses were available for 389 and 337 children, respectively. The mean age of children was 9.7 ± 0.7 years, 49.0% were girls and 76.0% were classified as "normal weight". The two identified dietary patterns were "Snacks" and "Fruit and Vegetables". Mean PWV and AIx were 5.8 ± 0.8 m/s and -2.1 ± 14.1%, respectively. There were no clinically meaningful relationships between the identified dietary pattern scores and either PWV or AIx in 9-11-year-old children.

Idiopathic pulmonary fibrosis is a lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. In this study, we developed a high-throughput small-molecule screen for YAP inhibitors in primary human lung fibroblasts. Multiple HMG-CoA (hydroxymethylglutaryl-coenzyme A) reductase inhibitors (statins) were found to inhibit YAP nuclear localization via induction of YAP phosphorylation, cytoplasmic retention, and degradation. We further show that the mevalonate pathway regulates YAP activation, and that simvastatin treatment reduces fibrosis markers in activated human lung fibroblasts and in the bleomycin mouse model of pulmonary fibrosis. Finally, we show that simvastatin modulates YAP in vivo in mouse lung fibroblasts. Our results highlight the potential of small-molecule screens for YAP inhibitors and provide a mechanism for the antifibrotic activity of statins in idiopathic pulmonary fibrosis.

Mucociliary clearance, the physiological process by which mammalian conducting airways expel pathogens and unwanted surface materials from the respiratory tract, depends on the coordinated function of multiple specialized cell types, including basal stem cells, mucus-secreting goblet cells, motile ciliated cells, cystic fibrosis transmembrane conductance regulator (CFTR)-rich ionocytes, and immune cells 1,2 . Bronchiectasis, a syndrome of pathological airway dilation associated with impaired mucociliary clearance, may occur sporadically or as a consequence of Mendelian inheritance, for example in cystic fibrosis, primary ciliary dyskinesia (PCD), and select immunodeficiencies 3 . Previous studies have identified mutations that affect ciliary structure and nucleation in PCD 4 , but the regulation of mucociliary transport remains incompletely understood, and therapeutic targets for its modulation are lacking. Here we identify a bronchiectasis syndrome caused by mutations that inactivate NIMA-related kinase 10 (NEK10), a protein kinase with previously unknown in vivo functions in mammals. Genetically modified primary human airway cultures establish NEK10 as a ciliated-cell-specific kinase whose activity regulates the motile ciliary proteome to promote ciliary length and mucociliary transport but which is dispensable for normal ciliary number, radial structure, and beat frequency. Together, these data identify a novel and likely targetable signaling axis that controls motile ciliary function in humans and has potential implications for other respiratory disorders that are characterized by impaired mucociliary clearance.

Background: Iron deficiency is a common deficiency disease worldwide with athletes at increased risk., Methods: A proposed new mechanism of exercise-induced iron deficiency in athletes involves the iron-regulatory hormone hepcidin, however, there is limited information on this amongst elite athletes. This study describes iron status in elite female rugby Sevens players., Results: Blood samples were collected at the start and mid-season and analyzed for serum iron, serum ferritin (SF), soluble transferring receptor (sTfR), high sensitivity C-reactive Protein (hsCRP) and hepcidin. Of the 17 players 18% were iron deficient (SF<30 µg/L) with 29-35% of players with sub-optimal iron stores at some point during the study (SF<45 µg/L). Serum hepcidin was strongly correlated with SF (r=0.61, P=0.0001)., Conclusions: Some elite female rugby Sevens players have sub-optimal iron stores over the course of a season.

Hepcidin, a peptide hormone with an acknowledged evolutionary function in iron homeostasis, was discovered at the turn of the 21st century. Since then, the implications of increased hepcidin activity have been investigated as a potential advocate for the increased risk of iron deficiency in various health settings. Such implications are particularly relevant in the sporting community where peaks in hepcidin postexercise (∼3-6 hr) are suggested to reduce iron absorption and recycling, and contribute to the development of exercise-induced iron deficiency in athletes. Over the last decade, hepcidin research in sport has focused on acute and chronic hepcidin activity following single and repeated training blocks. This research has led to investigations examining possible methods to attenuate postexercise hepcidin expression through dietary interventions. The majority of macronutrient dietary interventions have focused on manipulating the carbohydrate content of the diet in an attempt to determine the health of athletes adopting the low-carbohydrate or ketogenic diets, a practice that is a growing trend among endurance athletes. During the process of these macronutrient dietary intervention studies, an observable coincidence of increased cumulative hepcidin activity to low energy availability has emerged. Therefore, this review aims to summarize the existing literature on nutritional interventions on hepcidin activity, thus, highlighting the link of hepcidin to energy availability, while also making a case for the use of hepcidin as an individualized biomarker for low energy availability in males and females.

Preseason in rugby union is a period of intensive training where players undergo conditioning to prepare for the competitive season. In some cases, this includes modifying body composition through weight gain or fat loss. This study aimed to describe the macronutrient intakes of professional rugby union players during pre-season training. It was hypothesized that players required to gain weight would have a higher energy, carbohydrate and protein intake compared to those needing to lose weight. Twenty-three professional rugby players completed 3 days of dietary assessment and their sum of eight skinfolds were assessed. Players were divided into three groups by the team coaches and medical staff: weight gain, weight maintain and weight loss. Mean energy intakes were 3,875 ± 907 kcal·d -1 (15,965 ± 3,737 kJ·d -1 ) (weight gain 4,532 ± 804 kcal·d -1 ; weight maintain 3,825 ± 803 kcal·d -1 ; weight loss 3,066 ± 407 kcal·d -1 ) and carbohydrate intakes were 3.7 ± 1.2 g·kg -1 ·d -1 (weight gain 4.8 ± 0.9 g.kg -1 ·d -1 ; weight maintain 2.8 ± 0.7 g·kg -1 ·d -1 ; weight loss 2. 6 ± 0.7 g·kg -1 ·d -1 ). The energy and carbohydrate intakes are similar to published intakes among rugby union players. There were significant differences in energy intake and the percent of energy from protein between the weight gain and the weight loss group.

Evidence suggests that omega-3 fatty acid supplementation could reduce muscle soreness and maintain muscle function following eccentric exercise-induced muscle damage. The aim of this applied field study was to investigate the effectiveness of consuming a protein-based supplement containing 1546 mg of omega-3 polyunsaturated fatty acid (PUFA) (551 mg eicosapentaenoic acid (EPA) and 551 mg docosahexaenoic acid (DHA)) twice daily (FO) compared to a protein-based placebo (P) on muscle soreness, countermovement jump (CMJ) performance and psychological well-being in 20 professional Rugby Union players during 5 weeks of pre-season training. Players completed a 5-point-Likert soreness scale with 5 indicating "no soreness" and a questionnaire assessing fatigue, sleep, stress and mood each morning of training, plus they performed CMJ tests once or twice per week. Data were analysed using magnitude-based inferential statistics and are presented as percent beneficial/trivial/harmful. On day 35, there was a likely (% beneficial/trivial/harmful: 94/5/1) moderate (0.75, standardized mean difference (SMD)) beneficial effect of FO vs. P on the change in lower body muscle soreness compared with day 0 (FO: -3.8 ± 21.7%; P: -19.4 ± 11.2%). There was a likely (92/7/0) moderate (SMD: 0.60) beneficial effect of FO vs. P on CMJ performance (change from baseline to day 35, FO: +4.6 ± 5.9%; P: -3.4 ± 8.6%). From day 20, a moderate beneficial effect of FO on fatigue was observed. In terms of practical relevance, the moderate beneficial effect of adding fish oil to a protein-based supplement on muscle soreness translated into the better maintenance of explosive power in elite Rugby Union players during pre-season training.

Rugby is a worldwide intermittent team sport. Players tend to be heavier than the majority of similar team sport athletes on whom the dietary guidelines have been developed. Therefore, the aim of the current review was to describe the intakes of rugby union players. Article databases were searched up to February 2017 and were included if they were published in English and reported dietary intakes of male rugby union players. Of the research articles identified, energy intakes were lower than two of three studies that reported intakes and expenditure, which would suggest the players were losing weight that is somewhat supported by the decreases in skinfolds seen during preseason. However, it should also be noted that there are errors in both the measurement of energy intakes and expenditure. Carbohydrate intakes ranged from 2.6 to 6.5 g·kg -1 ·day -1 , which is lower than the current relative to body mass recommendations; however, this would not be classed as a low-carbohydrate diet. The consistently low intakes of carbohydrate suggest that these intake levels maybe sufficient for performance, given the players greater body mass or there are errors in the measurements. However, there is currently no evidence for the carbohydrate needs of rugby union players in terms of performance. The lower intakes than expenditure would suggest the players were losing weight. Previous research shows that rugby union players lose body fat during preseason training.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease causing fibrotic remodeling of the peripheral lung, leading to respiratory failure. Peripheral pulmonary epithelial cells lose normal alveolar epithelial gene expression patterns and variably express genes associated with diverse conducting airway epithelial cells, including basal cells. Single-cell RNA sequencing of pulmonary epithelial cells isolated from IPF lung tissue demonstrated altered expression of LncRNAs, including increased MEG3. MEG3 RNA was highly expressed in subsets of the atypical IPF epithelial cells and correlated with conducting airway epithelial gene expression patterns. Expression of MEG3 in human pulmonary epithelial cell lines increased basal cell-associated RNAs, including TP63, KRT14, STAT3, and YAP1, and enhanced cell migration, consistent with a role for MEG3 in regulating basal cell identity. MEG3 reduced expression of TP73, SOX2, and Notch-associated RNAs HES1 and HEY1, in primary human bronchial epithelial cells, demonstrating a role for MEG3 in the inhibition of genes influencing basal cell differentiation into club, ciliated, or goblet cells. MEG3 induced basal cell genes and suppressed genes associated with terminal differentiation of airway cells, supporting a role for MEG3 in regulation of basal progenitor cell functions, which may contribute to tissue remodeling in IPF.

There is limited research studying fluid and electrolyte balance in rugby union players, and a paucity of information regarding the test-retest reliability. This study describes the fluid balance of elite rugby union players across multiple squads and the reliability of fluid balance measures between two equivalent training sessions. Sixty-one elite rugby players completed a single fluid balance testing session during a game simulation training session. A subsample of 21 players completed a second fluid balance testing session during an equivalent training session. Players were weighed in minimal clothing before and after each training session. Each player was provided with their own drinks which were weighed before and after each training session. More players gained body weight (9 (14.8%)) during training than lost greater than 2% of their initial body mass (1 (1.6%)). Pre-training body mass and rate of fluid loss were significantly associated (r = 0.318, p = .013). There was a significant correlation between rate of fluid loss in sessions 1 (1.74 ± 0.32 L h -1 ) and 2 (1.10 ± 0.31 L. h -1 ), (r = 0.470, p = .032). This could be useful for nutritionists working with rugby squads to identify players with high sweat losses.

It is well documented that short sleep duration is associated with excess body weight and poor food intake in children. It has been suggested that sleep timing behaviour may also be an important predictor of weight and other related behaviours, independent of sleep duration; however, there is a lack of research investigating these relationships. The present study investigated sleep timing in association with diet and physical activity levels in 439 children aged 9-11 years old from New Zealand. Sleep and physical activity data were collected using accelerometry, and food choice using a short food-frequency questionnaire. Participants were classified into one of four sleep timing behaviour categories using the median split for sleep-onset and -offset times. Differences between sleep timing groups for weekly consumption frequency of selected food groups, dietary pattern scores and minutes of moderate-to-vigorous physical activity were examined. Children in the late sleep/late wake category had a lower 'Fruit & Vegetables' pattern score [mean difference (95% CI): -0.3 (-0.5, -0.1)], a lower consumption frequency of fruit and vegetables [mean weekly difference (95% CI): -2.9 (-4.9, -0.9)] and a higher consumption frequency of sweetened beverages [mean weekly difference (95% CI): 1.8 (0.2, 3.3)] compared with those in the early sleep/early wake category. Additionally, children in the late sleep/late wake category accumulated fewer minutes of moderate-to-vigorous physical activity per day compared with those in the early sleep/early wake category [mean difference (95% CI): -9.4 (-15.3, -3.5)]. These findings indicate that sleep timing, even after controlling for sleep duration, was associated with both food consumption and physical activity., (© 2017 European Sleep Research Society.)

Background: Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in patients with allergic asthma., Objectives: We sought to determine whether glycolysis is altered in patients with allergic asthma and to address its importance in the pathogenesis of allergic asthma., Methods: We examined alterations in glycolysis in sputum samples from asthmatic patients and primary human nasal cells and used murine models of allergic asthma, as well as primary mouse tracheal epithelial cells, to evaluate the relevance of glycolysis., Results: In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1-dependent manner. Furthermore, administration of IL-1β into the airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A occurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1β or IL-1α resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1β- or IL-1α-mediated proinflammatory responses and the stimulatory effects of IL-1β on house dust mite (HDM)-induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of κB kinase ε was downstream of HDM or IL-1β and required for HDM-induced glycolysis and pathogenesis of allergic airways disease. Small interfering RNA ablation of lactate dehydrogenase A attenuated HDM-induced increases in lactate levels and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatic patients intrinsically produced more lactate compared with cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatic patients, notably those with greater than 61% neutrophils. A positive correlation was observed between sputum lactate and IL-1β levels, and lactate content correlated negatively with lung function., Conclusions: Collectively, these findings demonstrate that IL-1β/inhibitory κB kinase ε signaling plays an important role in HDM-induced glycolysis and pathogenesis of allergic airways disease., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Research shows that cardiorespiratory (CRF) and muscular fitness in childhood are associated with a healthier cardiovascular profile in adulthood. Identifying factors associated with measures of fitness in childhood could allow for strategies to optimize cardiovascular health throughout the lifecourse. The aim of this study was to examine the association between dietary patterns and both CRF and muscular fitness in 9⁻11-year-olds. In this study of 398 children, CRF and muscular fitness were assessed using a 20-m shuttle run test and digital hand dynamometer, respectively. Dietary patterns were derived using principal component analysis. Mixed effects linear regression models were used to assess associations between dietary patterns and CRF and muscular fitness. Most children had healthy CRF (99%, FITNESSGRAM) and mean ± SD muscular fitness was 15.2 ± 3.3 kg. Two dietary patterns were identified; &ldquo;Snacks&rdquo; and &ldquo;Fruit and Vegetables&rdquo;. There were no significant associations between either of the dietary patterns and CRF. Statistically significant but not clinically meaningful associations were seen between dietary patterns and muscular fitness. In an almost exclusively fit cohort, food choice is not meaningfully related to measures of fitness. Further research to investigate diet-fitness relationships in children with lower fitness levels can identify key populations for potential investments in health-promoting behaviors.

Background: A major goal of asthma therapy is to achieve disease control, with maintenance of lung function, reduced need for rescue medication, and prevention of exacerbation. Despite current standard of care, up to 70% of patients with asthma remain poorly controlled. Analysis of serum and sputum biomarkers could offer insights into parameters associated with poor asthma control., Objective: To identify signatures as determinants of asthma disease control, we performed proteomics using Olink proximity extension analysis., Methods: Up to 3 longitudinal serum samples were collected from 23 controlled and 25 poorly controlled asthmatics. Nine of the controlled and 8 of the poorly controlled subjects also provided 2 longitudinal sputum samples. The study included an additional cohort of 9 subjects whose serum was collected within 48 hours of asthma exacerbation. Two separate pre-defined Proseek Multiplex panels (INF and CVDIII) were run to quantify 181 separate protein analytes in serum and sputum., Results: Panels consisting of 9 markers in serum (CCL19, CCL25, CDCP1, CCL11, FGF21, FGF23, Flt3L, IL-10Rβ, IL-6) and 16 markers in sputum (tPA, KLK6, RETN, ADA, MMP9, Chit1, GRN, PGLYRP1, MPO, HGF, PRTN3, DNER, PI3, Chi3L1, AZU1, and OPG) distinguished controlled and poorly controlled asthmatics. The sputum analytes were consistent with a pattern of neutrophil activation associated with poor asthma control. The serum analyte profile of the exacerbation cohort resembled that of the controlled group rather than that of the poorly controlled asthmatics, possibly reflecting a therapeutic response to systemic corticosteroids., Conclusions and Clinical Relevance: Proteomic profiles in serum and sputum distinguished controlled and poorly controlled asthmatics, and were maintained over time. Findings support a link between sputum neutrophil markers and loss of asthma control., (© 2018 John Wiley & Sons Ltd.)

Pulmonary fibrosis is thought to result from dysregulated wound repair after repetitive lung injury. Many cellular responses to injury involve rearrangements of the actin cytoskeleton mediated by the two isoforms of the Rho-associated coiled-coil-forming protein kinase (ROCK), ROCK1 and ROCK2. In addition, profibrotic mediators such as transforming growth factor-β, thrombin, and lysophosphatidic acid act through receptors that activate ROCK. Inhibition of ROCK activation may be a potent therapeutic strategy for human pulmonary fibrosis. Pharmacological inhibition of ROCK using nonselective ROCK inhibitors has been shown to prevent fibrosis in animal models; however, the specific roles of each ROCK isoform are poorly understood. Furthermore, the pleiotropic effects of this kinase have raised concerns about on-target adverse effects of ROCK inhibition such as hypotension. Selective inhibition of one isoform might be a better-tolerated strategy. In the present study, we used a genetic approach to determine the roles of ROCK1 and ROCK2 in a mouse model of bleomycin-induced pulmonary fibrosis. Using ROCK1- or ROCK2-haploinsufficient mice, we found that reduced expression of either ROCK1 or ROCK2 was sufficient to protect them from bleomycin-induced pulmonary fibrosis. In addition, we found that both isoforms contribute to the profibrotic responses of epithelial cells, endothelial cells, and fibroblasts. Interestingly, ROCK1- and ROCK2-haploinsufficient mice exhibited similar protection from bleomycin-induced vascular leak, myofibroblast differentiation, and fibrosis; however, ROCK1-haploinsufficient mice demonstrated greater attenuation of epithelial cell apoptosis. These findings suggest that selective inhibition of either ROCK isoform has the potential to be an effective therapeutic strategy for pulmonary fibrosis.

Background: To determine athletes perceived and measured indices of fluid balance during training and the influence of hydration strategy use on these parameters., Methods: Thirty-three professional rugby union players completed a 120 minute training session in hot conditions (35°C, 40% relative humidity). Pre-training hydration status, sweat loss, fluid intake and changes in body mass (BM) were obtained. The use of hydration assessment techniques and players perceptions of fluid intake and sweat loss were obtained via a questionnaire., Results: The majority of players (78%) used urine colour to determine pre-training hydration status but the use of hydration assessment techniques did not influence pre-training hydration status (1.025 ± 0.005 vs. 1.023 ± 0.013 g . ml -1 , P = .811). Players underestimated sweat loss (73 ± 17%) to a greater extent than fluid intake (37 ± 28%) which resulted in players perceiving they were in positive fluid balance (0.5 ± 0.8% BM) rather than the measured negative fluid balance (-1.0 ± 0.7% BM). Forty-eight percent of players used hydration monitoring strategies during exercise but no player used changes in BM to help guide fluid replacement., Conclusion: Players have difficulty perceiving fluid intake and sweat loss during training. However, the use of hydration monitoring techniques did not affect fluid balance before or during training.

McIntosh, ND, Love, TD, Haszard, J, Osborne, H, and Black, KE. β-hydroxy β-methylbutyrate (HMB) supplementation effects on body mass and performance in elite male rugby union players. J Strength Cond Res 32(1): 19-26, 2018-Preseason is characterized by high training volumes with short recovery periods β-hydroxy β-methylbutyrate (HMB) has been postulated to assist with recovery. β-hydroxy β-methylbutyrate has been shown to improve strength and body composition among untrained groups; the benefits of HMB among trained populations are unclear because of the methodologies employed. This randomized control trail determined the effects of 11 weeks HMB supplementation on body mass and performance measures in 27 elite rugby players. β-hydroxy β-methylbutyrate group (n = 13), mean ± SD age 20.3 ± 1.2 years, body mass 99.6 ± 9.1 kg; placebo group (n = 14), age 21.9 ± 2.8 years body mass 99.4 ± 13.9 kg for placebo. During the supplementation period, body mass increased with HMB 0.57 ± 2.60 kg but decreased with placebo 1.39 ± 2.02 kg (p = 0.029). There were no significant differences in any of the 4 strength variables (p > 0.05). However, on the yo-yo intermittent recovery test (YoYo IR-1), the placebo group improved 4.0 ± 2.8 levels but HMB decreased 2.0 ± 3.0 levels (p = 0.003). The results of this study suggest that HMB could be beneficial for gaining or maintaining body mass during periods of increased training load. However, it appears that HMB may be detrimental to intermittent running ability in this group although further research is required before firm conclusions can be made. Only 6 participants on HMB managed to complete both YoYo IR-1 tests because of injury, a larger sample size is required to fully investigate this potentially negative effect. Further, the mechanisms behind this decrement in performance cannot be fully explained and requires further biochemical and psychological investigation.

This corrects the article DOI: 10.1038/nm.4419.