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To evaluate the perceptions of the general public and healthcare practitioners (HCP) in Canada about the relationship between running and knee joint health, and to explore HCP`s usual recommendations to runners with knee osteoarthritis (KOA). Non-runners and runners (with and without KOA) and HCP completed an online survey regarding the safety of running for knee joint health. HCP also provided information related to usual clinical recommendations. Proportions of agreement were compared between non-runners and runners. A total of 114 non-runners, 388 runners and 329 HCP completed the survey. Overall, running was perceived as detrimental for the knee joint by 13.1% of the general public, while 25.9% were uncertain. More uncertainty was reported regarding frequent (33.9%) and long-distance (43.6%) running. Statistical analyses revealed greater proportions of non-runners perceiving running negatively compared with runners. Overall, 48.4% believed that running in the presence of KOA would lead to disease progression, while 53.1% believed running would lead to premature arthroplasty. In HCP, 8.2%, 9.1% and 22.2% perceived that running in general, running frequently, or running long-distances are risk factors for KOA, respectively. 37.1% and 2.7% of HCP typically recommended patients with KOA to modify their running training or to quit running, respectively. High rates of uncertainty among the general public and HCP in Canada outline the need for further studies about running and knee joint health. Filling knowledge gaps will help inform knowledge translation strategies to better orientate the general public and HCP about the safety of running for knee joint health.

Knee braces were introduced to sports 30 years ago. However, knee brace use for non-contact anterior cruciate ligament injury prevention intervention remains contentious due to concerns about performance hindrances. Since knee brace use is a potential modifiable risk factor, we aimed to investigate the effect of discounting and continued functional knee brace (FKB) on lower extremity power-vertical jump (VJ), acceleration, speed, and agility performance. Prospective cohort crossover study. Twenty-seven healthy male athletes performed seven tests, over six days of 12 test sessions (S), during three test conditions (non-braced, braced, and removed brace or continued brace use). This study focuses on VJ, acceleration, speed, and agility performance during S12 when athletes were randomly selected to remove the FKB after 17.5 h or continue using the FKB for 21.0 h. After brace removal, nonsignificant performance levels improved in the VJ (2.7 %; 95 % CI 52.5–62.8; Cohen's effect size (ES) = trivial), acceleration (1.8 %; 95 % CI 0.500–0.562; ES = small), and agility (0.5 %; 95 % CI 9.25–10.13; ES = trivial), while a nonsignificant slower speed was recorded (0.5 %; 95 % CI 1.81–1.95; ES = trivial). Continued brace use led to a nonsignificant performance improvement in all tests; VJ (3.1 %; 95 % CI 53.5–60.2; ES = small), acceleration (1.5 %; 95 % CI 0.511–0.561; ES = trivial), speed (1.0 %; 95 % CI 1.83–1.95; ES = trivial), and agility (1.8 %; 95 % CI 9.26–10.04; ES = trivial). Removal of FKB led to improved performance in three performance tests, while continued brace use improved performance in all four tests.

Background Iliotibial band syndrome (ITBS) carries marked morbidity in runners. Its management is not standardized and lacks evidence base. We evaluated the effectiveness of three different exercises programs in reducing ITBS symptoms. Methods Patients were divided into three equal treatment groups: ITB stretching (group A), conventional exercise (group B), and experimental hip strengthening exercise (group C). Numeric pain rating scale (NPRS; every week), lower extremity functional scale (LEFS; every 2 weeks), dynamometer (DN; weeks 0, 2, 4, 6, 8), single-limb mini squat (SLMS; week 0, 8), and Y-balance test™ (YBT), between and within group’s differences were evaluated using ANOVA model. Results Twenty-four female runners (age 19–45 years) were included into one of three groups (A, B, and C). Statistical significance ( p < 0.05) within group C was observed for composite YBT and DN for injured and non-injured leg, the YBT (injured leg for the posterior medial), LEFS, NPRS, and the SLMS. Statistical significance ( p < 0.05) was found between group A and group C. The stretching group exhibited statistically significant ( p < 0.05) YBT anterior reach for the injured/non-injured leg and the LEFS. Conclusion There were no statistical differences between the three groups. The subjects who underwent experimental hip strengthening exercises consistently showed improvements in outcome measures, and never scored less than the other two groups. Trial registration ClinicalTrials.gov identifier (NCT number): NCT0229615

The active sites of 491 human protein kinase domains are highly conserved, which makes the design of selective inhibitors a formidable challenge. We used a structural bioinformatics approach to identify two selectivity filters, a threonine and a cysteine, at defined positions in the active site of p90 ribosomal protein S6 kinase (RSK). A fluoromethylketone inhibitor, designed to exploit both selectivity filters, potently and selectively inactivated RSK1 and RSK2 in mammalian cells. Kinases with only one selectivity filter were resistant to the inhibitor, yet they became sensitized after genetic introduction of the second selectivity filter. Thus, two amino acids that distinguish RSK from other protein kinases are sufficient to confer inhibitor sensitivity.

Sport is becoming increasingly competitive and athletes are being exposed to greater physical demands, leaving them prone to injuries. Monitoring athletes with the use of wearable technology could provide a way to potentially manage training and competition loads and reduce injuries. One such technology is the VERT inertial measurement unit, a commercially available discrete wearable device containing a 3-axis accelerometer, 3-axis gyroscope and 3-axis magnetometer. Some of the main measurement outputs include jump count, jump height and landing impacts. While several studies have examined the accuracy of the VERT’s measures of jump height and jump count, landing impact force has not yet been investigated. The objective of this research study was to explore the validity of the VERT landing impact values. We hypothesized that the absolute peak VERT acceleration values during a jump-land cycle would fall within 10% of the peak acceleration values derived simultaneously from a research-grade accelerometer (Shimmer). Fourteen elite university-level volleyball players each performed 10 jumps while wearing both devices simultaneously. The results showed that VERT peak accelerations were variable (limits of agreement of -84.13% and 52.37%) and had a propensity to be lower (mean bias of -15.88%) when compared to the Shimmer. In conclusion, the validity of the VERT device’s landing impact values are generally poor, when compared to the Shimmer.

Impact-related mild traumatic brain injuries (mTBI) are a major public health concern, and remain as one of the most poorly understood injuries in the field of neuroscience. Currently, the diagnosis and management of such injuries are based largely on patient-reported symptoms. An improved understanding of the underlying pathophysiology of mTBI is urgently needed in order to develop better diagnostic and management protocols. Specifically, dynamic post-injury changes to the myelin sheath in the human brain have not been examined, despite 'compromised white matter integrity' often being described as a consequence of mTBI. In this preliminary cohort study, myelin water imaging was used to prospectively evaluate changes in myelin water fraction, derived from the T2 decay signal, in two varsity hockey teams (45 players) over one season of athletic competition. 11 players sustained a concussion during competition, and were scanned at 72 hours, 2 weeks, and 2 months post-injury. Results demonstrated a reduction in myelin water fraction at 2 weeks post-injury in several brain areas relative to preseason scans, including the splenium of the corpus callosum, right posterior thalamic radiation, left superior corona radiata, left superior longitudinal fasciculus, and left posterior limb of the internal capsule. Myelin water fraction recovered to pre-season values by 2 months post-injury. These results may indicate transient myelin disruption following a single mTBI, with subsequent remyelination of affected neurons. Myelin disruption was not apparent in the athletes who did not experience a concussion, despite exposure to repetitive subconcussive trauma over a season of collegiate hockey. These findings may help to explain many of the metabolic and neurological deficits observed clinically following mTBI.

IgE can trigger potent allergic responses, yet the mechanisms regulating IgE production are poorly understood. Here we reveal that IgE+ B cells are constrained by chronic activity of the IgE B cell receptor (BCR). In the absence of cognate antigen, the IgE BCR promoted terminal differentiation of B cells into plasma cells (PCs) under cell culture conditions mimicking T cell help. This antigen-independent PC differentiation involved multiple IgE domains and Syk, CD19, BLNK, Btk, and IRF4. Disruption of BCR signaling in mice led to consistently exaggerated IgE+ germinal center (GC) B cell but variably increased PC responses. We were unable to confirm reports that the IgE BCR directly promoted intrinsic apoptosis. Instead, IgE+ GC B cells exhibited poor antigen presentation and prolonged cell cycles, suggesting reduced competition for T cell help. We propose that chronic BCR activity and access to T cell help play critical roles in regulating IgE responses. Antibodies are proteins that recognize and bind to specific molecules, and so help the immune system to defend the body against foreign substances that are potentially harmful. In some cases, harmless substances – such as pollen, dust or food – can trigger this response and lead to an allergic reaction. A type of antibody called immunoglobulin E (IgE) is particularly likely to trigger an allergic response. In general, immune cells called plasma cells produce antibodies and release them into the body. However, in B cells – the cells from which plasma cells develop – the antibodies remain on the surface of the cells. Here, the antibody acts as a “receptor” that allows the B cell to tell when its antibody has bound to a specific substance. Generally, B cells only activate when their B cell receptors bind to a specific substance. This binding triggers signals inside the cell that determine its fate – such as whether it will develop into a plasma cell. Recent studies have shown that B cells that have IgE on their surface (IgE+ B cells) are predisposed to develop rapidly into plasma cells. To investigate why this is the case, Yang et al. have now studied B cells both in cell culture and in mice. The results show that the IgE B cell receptor autonomously signals to the cell even when it is not bound to a specific substance, in a manner that differs from other types of B cell receptors. This increases the likelihood that the IgE+ B cell will develop into a plasma cell and limits the competitive fitness of IgE+ B cells. These findings provide new insights into how IgE responses are regulated by the B cell receptor. The next step will be to determine, at a molecular level, the basis for the autonomous signaling produced by the IgE B cell receptor when it is not bound to a specific substance. It will then be possible to investigate how this mechanism compares with the way that signals are normally transmitted when a B cell receptor binds to a specific substance.

The eukaryotic translation initiation factor 4B (eIF4B) plays a critical role in recruiting the 40S ribosomal subunit to the mRNA. In response to insulin, eIF4B is phosphorylated on Ser422 by S6K in a rapamycin‐sensitive manner. Here we demonstrate that the p90 ribosomal protein S6 kinase (RSK) phosphorylates eIF4B on the same residue. The relative contribution of the RSK and S6K modules to the phosphorylation of eIF4B is growth factor‐dependent, and the two phosphorylation events exhibit very different kinetics. The S6K and RSK proteins are members of the AGC protein kinase family, and require PDK1 phosphorylation for activation. Consistent with this requirement, phosphorylation of eIF4B Ser422 is abrogated in PDK1 null embryonic stem cells. Phosphorylation of eIF4B on Ser422 by RSK and S6K is physiologically significant, as it increases the interaction of eIF4B with the eukaryotic translation initiation factor 3.

Mycolactone is the exotoxin virulence factor of Mycobacterium ulcerans that causes the neglected tropical disease Buruli ulcer. We recently showed it to be a broad spectrum inhibitor of Sec61-dependent co-translational translocation of proteins into the endoplasmic reticulum (ER). An outstanding question is the molecular pathway linking this to its known cytotoxicity. We have now used translational profiling to better understand the reprogramming that occurs in cells exposed to mycolactone. Gene ontology identified enrichment in genes involved in cellular response to stress, and apoptosis signalling among those showing enhanced translation. Validation of these results supports a mechanism by which mycolactone activates an integrated stress response meditated by phosphorylation of eIF2α via multiple kinases (PERK, GCN, PKR) without activation of the ER stress sensors IRE1 or ATF6. The response therefore uncouples the integrated stress response from ER stress, and features translational and transcriptional modes of genes expression that feature the key regulatory transcription factor ATF4. Emphasising the importance of this uncoupled response in cytotoxicity, downstream activation of this pathway is abolished in cells expressing mycolactone-resistant Sec61α variants. Using multiple genetic and biochemical approaches, we demonstrate that eIF2α phosphorylation is responsible for mycolactone-dependent translation attenuation, which initially protects cells from cell death. However, chronic activation without stress remediation enhances autophagy and apoptosis of cells by a pathway facilitated by ATF4 and CHOP. Our findings demonstrate that priming events at the ER can result in the sensing of stress within different cellular compartments.

Disturbed blood flow (d-flow) causes endothelial cell (EC) dysfunction, leading to atherosclerotic plaque formation. We have previously shown that d-flow increases SUMOylation of p53 and ERK5 through downregulation of sentrin/SUMO-specific protease 2 (SENP2) function; however, it is not known how SENP2 itself is regulated by d-flow. Here, we determined that d-flow activated the serine/threonine kinase p90RSK, which subsequently phosphorylated threonine 368 (T368) of SENP2. T368 phosphorylation promoted nuclear export of SENP2, leading to downregulation of eNOS expression and upregulation of proinflammatory adhesion molecule expression and apoptosis. In an LDLR-deficient murine model of atherosclerosis, EC-specific overexpression of p90RSK increased EC dysfunction and lipid accumulation in the aorta compared with control animals; however, these pathologic changes were not observed in atherosclerotic mice overexpressing dominant negative p90RSK (DN-p90RSK). Moreover, depletion of SENP2 in these mice abolished the protective effect of DN-p90RSK overexpression. We propose that p90RSK-mediated SENP2-T368 phosphorylation is a master switch in d-flow-induced signaling, leading to EC dysfunction and atherosclerosis.