Calpains, Cleaved Mini-Dysferlin(C72), and L-Type Channels Underpin Calcium-Dependent Muscle Membrane Repair

Dysferlin is proposed as a key mediator of calcium-dependent muscle membrane repair, although its precise role has remained elusive. Dysferlin interacts with a new membrane repair protein, mitsugumin 53 (MG53), an E3 ubiquitin ligase that shows rapid recruitment to injury sites. Using a novel ballistics assay in primary human myotubes, we show it is not full-length dysferlin recruited to sites of membrane injury but an injury-specific calpain-cleavage product, mini-dysferlin(C72). Mini-dysferlin(C72)-rich vesicles are rapidly recruited to injury sites and fuse with plasma membrane compartments decorated by MG53 in a process coordinated by L-type calcium channels. Collective interplay between activated calpains, dysferlin, and L-type channels explains how muscle cells sense a membrane injury and mount a specialized response in the unique local environment of a membrane injury. Mini-dysferlin(C72) and MG53 form an intricate lattice that intensely labels exposed phospholipids of injury sites, then infiltrates and stabilizes the membrane lesion during repair. Our results extend functional parallels between ferlins and synaptotagmins. Whereas otoferlin exists as long and short splice isoforms, dysferlin is subject to enzymatic cleavage releasing a synaptotagmin-like fragment with a specialized protein-or phospholipid-binding role for muscle membrane repair

Non-statistical intermolecular energy transfer from vibrationally excited benzene in a mixed nitrogen-benzene bath.

A chemical dynamics simulation was performed to model experiments [N. A. West et al., J. Chem. Phys. 145, 014308 (2016)] in which benzene molecules are vibrationally excited to 148.1 kcal/mol within a N2-benzene bath. A significant fraction of the benzene molecules are excited, resulting in heating of the bath, which is accurately represented by the simulation. The interesting finding from the simulations is the non-statistical collisional energy transfer from the vibrationally excited benzene C6H6 * molecules to the bath. The simulations find that at ∼10-7 s and 1 atm pressure there are four different final temperatures for C6H6 * and the bath. N2 vibration is not excited and remains at the original bath temperature of 300 K. Rotation and translation degrees of freedom of both N2 and C6H6 in the bath are excited to a final temperature of ∼340 K. Energy transfer from the excited C6H6 * molecules is more efficient to vibration of the C6H6 bath than its rotation and translation degrees of freedom, and the final vibrational temperature of the C6H6 bath is ∼453 K, if the average energy of each C6H6 vibration mode is assumed to be RT. There is no vibrational equilibration between C6H6 * and the C6H6 bath molecules. When the simulations are terminated, the vibrational temperatures of the C6H6 * and C6H6 bath molecules are ∼537 K and ∼453 K, respectively. An important question is the time scale for complete energy equilibration of the C6H6 * and N2 and C6H6 bath system. At 1 atm and 300 K, the experimental V-T (vibration-translation) relaxation time for N2 is ∼10-4 s. The simulation time was too short for equilibrium to be attained, and the time for complete equilibration of C6H6 * vibration with translation, rotation, and vibration of the bath was not determined

Membrane TNF confers protection to acute mycobacterial infection

BACKGROUND: Tumour necrosis factor (TNF) is crucial for the control of mycobacterial infection as TNF deficient (KO) die rapidly of uncontrolled infection with necrotic pneumonia. Here we investigated the role of membrane TNF for host resistance in knock-in mice with a non-cleavable and regulated allele (mem-TNF). METHODS: C57BL/6, TNF KO and mem-TNF mice were infected with M. tuberculosis H37Rv (Mtb at 100 CFU by intranasal administration) and the survival, bacterial load, lung pathology and immunological parameters were investigated. Bone marrow and lymphocytes transfers were used to test the role of membrane TNF to confer resistance to TNF KO mice. RESULTS: While TNF-KO mice succumbed to infection within 4–5 weeks, mem-TNF mice recruited normally T cells and macrophages, developed mature granuloma in the lung and controlled acute Mtb infection. However, during the chronic phase of infection mem-TNF mice succumbed to disseminated infection with necrotic pneumonia at about 150 days. Reconstitution of irradiated TNF-KO mice with mem-TNF derived bone marrow cells, but not with lymphocytes, conferred host resistance to Mtb infection in TNF-KO mice. CONCLUSION: Membrane expressed TNF is sufficient to allow cell-cell signalling and control of acute Mtb infection. Bone marrow cells, but not lymphocytes from mem-TNF mice confer resistance to infection in TNF-KO mice. Long-term infection control with chronic inflammation likely disrupting TNF mediated cell-cell signalling, additionally requires soluble TNF

Job Strain, Health and Sickness Absence: Results from the Hordaland Health Study

MW and SBH are funded by NSW Health. M. Henderson and M. Hotopf were supported by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King’s College London. AM and SO were funded by the Norwegian Research Council

The cytoprotective drug amifostine modifies both expression and activity of the pro-angiogenic factor VEGF-A

Peer reviewedPublisher PD

Testing the role of predicted gene knockouts in human anthropometric trait variation

National Heart, Lung, and Blood Institute (NHLBI) S.L. is funded by a Canadian Institutes of Health Research Banting doctoral scholarship. G.L. is funded by Genome Canada and Génome Québec; the Canada Research Chairs program; and the Montreal Heart Institute Foundation. C.M.L. is supported by Wellcome Trust (grant numbers 086596/Z/08/Z, 086596/Z/08/A); and the Li Ka Shing Foundation. N.S. is funded by National Institutes of Health (grant numbers HL088456, HL111089, HL116747). The Mount Sinai BioMe Biobank Program is supported by the Andrea and Charles Bronfman Philanthropies. GO ESP is supported by NHLBI (RC2 HL-103010 to HeartGO, RC2 HL-102923 to LungGO, RC2 HL-102924 to WHISP). The ESP exome sequencing was performed through NHLBI (RC2 HL-102925 to BroadGO, RC2 HL- 102926 to SeattleGO). EGCUT work was supported through the Estonian Genome Center of University of Tartu by the Targeted Financing from the Estonian Ministry of Science and Education (grant number SF0180142s08); the Development Fund of the University of Tartu (grant number SP1GVARENG); the European Regional Development Fund to the Centre of Excellence in Genomics (EXCEGEN) [grant number 3.2.0304.11-0312]; and through FP7 (grant number 313010). EGCUT were further supported by the US National Institute of Health (grant number R01DK075787). A.K.M. was supported by an American Diabetes Association Mentor-Based Postdoctoral Fellowship (#7-12-MN- 02). The BioVU dataset used in the analyses described were obtained from Vanderbilt University Medical Centers BioVU which is supported by institutional funding and by the Vanderbilt CTSA grant ULTR000445 from NCATS/NIH. Genome-wide genotyping was funded by NIH grants RC2GM092618 from NIGMS/OD and U01HG004603 from NHGRI/NIGMS. Funding to pay the Open Access publication charges for this article was provided by a block grant from Research Councils UK to the University of Cambridge

No evidence of a common DNA variant profile specific to world class endurance athletes

There are strong genetic components to cardiorespiratory fitness and its response to exercise training. It would be useful to understand the differences in the genomic profile of highly trained endurance athletes of world class caliber and sedentary controls. An international consortium (GAMES) was established in order to compare elite endurance athletes and ethnicity-matched controls in a case-control study design. Genome-wide association studies were undertaken on two cohorts of elite endurance athletes and controls (GENATHLETE and Japanese endurance runners), from which a panel of 45 promising markers was identified. These markers were tested for replication in seven additional cohorts of endurance athletes and controls: from Australia, Ethiopia, Japan, Kenya, Poland, Russia and Spain. The study is based on a total of 1520 endurance athletes (835 who took part in endurance events in World Championships and/or Olympic Games) and 2760 controls. We hypothesized that world-class athletes are likely to be characterized by an even higher concentration of endurance performance alleles and we performed separate analyses on this subsample. The meta-analysis of all available studies revealed one statistically significant marker (rs558129 at GALNTL6 locus, p = 0.0002), even after correcting for multiple testing. As shown by the low heterogeneity index (I2 = 0), all eight cohorts showed the same direction of association with rs558129, even though p-values varied across the individual studies. In summary, this study did not identify a panel of genomic variants common to these elite endurance athlete groups. Since GAMES was underpowered to identify alleles with small effect sizes, some of the suggestive leads identified should be explored in expanded comparisons of world-class endurance athletes and sedentary controls and in tightly controlled exercise training studies. Such studies have the potential to illuminate the biology not only of world class endurance performance but also of compromised cardiac functions and cardiometabolic diseases