Rapamycin induces transactivation of the EGFR and increases cell survival.

The mammalian target of rapamycin (mTOR) signaling network regulates cell growth, proliferation and cell survival. Deregulated activation of this pathway is a common event in diverse human diseases such as cancers, cardiac hypertrophy, vascular restenosis and nephrotic hypertrophy. Although mTOR inhibitor, rapamycin, has been widely used to inhibit the aberrant signaling due to mTOR activation that plays a major role in hyperproliferative diseases, in some cases rapamycin does not attenuate the cell proliferation and survival. Thus, we studied the mechanism(s) by which cells may confer resistance to rapamycin. Our data show that in a variety of cell types the mTOR inhibitor rapamycin activates extracellularly regulated kinases (Erk1/2) signaling. Rapamycin-mediated activation of the Erk1/2 signaling requires (a) the epidermal growth factor receptor (EGFR), (b) its tyrosine kinase activity and (c) intact autophosphorylation sites on the receptor. Rapamycin treatment increases tyrosine phosphorylation of EGFR without the addition of growth factor and this transactivation of receptor involves activation of c-Src. We also show that rapamycin treatment triggers activation of cell survival signaling pathway by activating the prosurvival kinases Erk1/2 and p90RSK. These studies provide a novel paradigm by which cells escape the apoptotic actions of rapamycin and its derivatives that inhibit the mTOR pathway

Regulation of B cell fate by chronic activity of the IgE B cell receptor.

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

3-D kinematic comparison of treadmill and overground running.

Studies investigating the mechanics of human movement are often conducted using the treadmill. The treadmill is an attractive device for the analysis of human locomotion. Studies comparing overground and treadmill running have analyzed discrete variables, however differences in excursion from footstrike to peak angle and range of motion during stance have yet to be examined. This study aimed to examine the 3-D kinematics of the lower extremities during overground and treadmill locomotion to determine the extent to which the two modalities differ. Twelve participants ran at 4.0m/s in both treadmill and overground conditions. 3-D angular kinematic parameters during the stance phase were collected using an eight camera motion analysis system. Hip, knee and ankle joint kinematics were quantified in the sagittal, coronal and transverse planes, then compared using paired t-tests. Of the parameters analyzed hip flexion at footstrike 12° hip range of motion 17°, peak hip flexion 12.7°, hip transverse plane range of motion 8° peak knee flexion 5° and peak ankle excursion range 6.6°, coronal plane ankle angle at toe-off 6.5° and peak ankle eversion 6.3° were found to be significantly different. These results lead to the conclusion that the mechanics of treadmill locomotion cannot be generalized to overground

Effects of footwear variations on three-dimensional kinematics and tibial accelerations of specific movements in American football

American football is associated with a high rate of non-contact chronic injuries. Players are able to select from both high and low cut footwear. The aim of the current investigation was to examine the influence of high and low cut American football specific footwear on tibial accelerations and three-dimensional (3D) kinematics during three sport specific movements. Twelve male American football players performed three movements, run, cut and vertical jump whilst wearing both low and high cut footwear. 3D kinematics of the lower extremities were measured using an eight-camera motion analysis system alongside tibial acceleration parameters which were obtained using a shank mounted accelerometer. Tibial acceleration and 3D kinematic differences between the different footwear were examined using either repeated measures or Friedman’s ANOVA. Tibial accelerations were significantly greater in the low cut footwear in comparison to the high cut footwear for the run and cut movements. In addition, peak ankle eversion and tibial internal rotation parameters were shown to be significantly greater in the low cut footwear in the running and cutting movement conditions. The current study indicates that the utilization of low cut American football footwear for training/performance may place American footballers at increased risk from chronic injuries

Inhibition of Sec61-dependent translocation by mycolactone uncouples the integrated stress response from ER stress, driving cytotoxicity via translational activation of ATF4

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 compartmentsWellcome Trus

Sex differences in knee loading in recreational runners

Patellofemoral pain is the most common chronic pathology in recreational runners. Female runners are at greater risk of developing patellofemoral pain, although the exact mechanism behind this is not fully understood. This study aimed to determine whether female recreational runners exhibit distinct knee loading compared to males. Fifteen males and 15 females recreational runners underwent 3D running analysis at 4.0 m s−1±5%. Sagittal/coronal joint moments, patellofemoral contact forces (PTF) and pressures (PCP) were compared between sexes. The results show that females exhibited significantly greater knee extension (p<0.008, pη2=0.27: males=3.04; females=3.47 N m kg−1) and abduction (p<0.008, pη2=0.28: males=0.54; females=0.82 N m kg−1) moments as well as PTF (p<0.008, pη2=0.29: males=3.25; females=3.84 B.W.) and PCP (p<0.008, pη2=0.26: males=7.96; females=9.27 MPa) compared to males. Given the proposed relationship between knee joint loading and patellofemoral pathology, the current investigation provides insight into the incidence of patellofemoral pain in females

The Effects of Different Passive Static Stretching Intensities on Recovery from Unaccustomed Eccentric Exercise - A Randomized Controlled Trial

Effects of passive static stretching intensity on recovery from unaccustomed eccentric exercise of right knee extensors was investigated in 30 recreationally active males randomly allocated into three groups: high-intensity (70-80% maximum perceived stretch), low-intensity (30-40% maximum perceived stretch), and control. Both stretching groups performed 3 sets of passive static stretching exercises of 60s each for hamstrings, hip flexors, and quadriceps, over 3 consecutive days, post-unaccustomed eccentric exercise. Muscle function (eccentric and isometric peak torque) and blood biomarkers (CK and CRP) were measured before (baseline) and after (24, 48, and 72h) unaccustomed eccentric exercise. Perceived muscle soreness scores were collected immediately (time 0), and after 24, 48, and 72h post-exercise. Statistical time x condition interactions observed only for eccentric peak torque (p=.008). Magnitude-based inference analyses revealed low-intensity stretching had most likely, very likely, or likely beneficial effects on perceived muscle soreness (48-72h and 0-72h) and eccentric peak torque (baseline-24h and baseline-72h), compared with high-intensity stretching. Compared with control, low-intensity stretching had very likely or likely beneficial effects on perceived muscle soreness (0-24h and 0-72h), eccentric peak torque (baseline-48h and baseline-72h), and isometric peak torque (baseline-72h). High-intensity stretching had likely beneficial effects on eccentric peak torque (baseline-48h), but likely harmful effects eccentric peak torque (baseline-24h) and CK (baseline-48h and baseline-72h), compared with control. Therefore, low-intensity stretching is likely to result in small-to-moderate beneficial effects on perceived muscle soreness and recovery of muscle function post-unaccustomed eccentric exercise, but not markers of muscle damage and inflammation, compared with high-intensity or no stretching.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author