Our study demonstrates that UBR-ubiquitin ligases of the Arg/N-degron pathway are promising targets for the development of improved therapies for many cancer types. Mutations in dysferlin are responsible for a group of progressive, recessively inherited muscular dystrophies known as dysferlinopathies. Using recombinant proteins and affinity purification methods combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), we found that AMP-activated protein kinase (AMPK)γ1 was bound to a region of dysferlin located between the third and fourth C2 domains. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair of skeletal muscle fibers. Injury-induced AMPK complex accumulation was dependent on the presence of Ca2+, and the rate of accumulation was regulated by dysferlin. Furthermore, it was found that the phosphorylation of AMPKα was essential for plasma membrane repair, and treatment with an AMPK activator rescued the membrane-repair impairment observed in immortalized human myotubes with reduced expression of dysferlin and dysferlin-null mouse fibers. Finally, it was determined that treatment with the AMPK activator metformin improved the muscle phenotype in zebrafish and mouse models of dysferlin deficiency. These findings indicate that the AMPK complex is essential for plasma membrane repair and is a potential therapeutic target for dysferlinopathy. Ovary fragments from six sexually mature cats were vitrified in the presence or absence of betaine or ascorbic acid, loaded (7.4 or 74µM betaine; 20 or 200µM ascorbic acid) or not (1mM betaine or 0.3mM ascorbic acid) into CaCO3 microparticles, and assessed for follicular morphology, oxidative stress and mitochondrial activity Feline ovarian tissue was successfully preserved after vitrification in the presence of 74µM betaine loaded in CaCO3 microparticles, as confirmed by morphological analysis and the density of preantral follicles and stromal cells, as well as by the increased mitochondrial activity and decreased production of reactive oxygen species.Multiple neurodegenerative diseases are characterized by aggregation of tau molecules. GW 501516 Adult humans express six isoforms of tau that contain either 3 or 4 microtubule binding repeats (3R or 4R tau). Different diseases involve preferential aggregation of 3R (e.g Pick disease), 4R (e.g. progressive supranuclear palsy), or both 3R and 4R tau molecules [e.g. Alzheimer disease and chronic traumatic encephalopathy]. Three ultrasensitive cell-free seed amplification assays [called tau real-time quaking induced conversion (tau RT-QuIC) assays] have been developed that preferentially detect 3R, 4R, or 3R/4R tau aggregates in biospecimens. In these reactions, low-fg amounts of a given self-propagating protein aggregate (the seed) are incubated with a vast excess of recombinant tau monomers (the substrate) in multi-well plates. Over time, the seeds incorporate the substrate to grow into amyloids that can then be detected using thioflavin T fluorescence. Here we describe a tau RT-QuIC assay (K12 RT-QuIC) that, using a C-terminally extended recombinant 3R tau substrate (K12CFh), enables sensitive detection of Pick disease, Alzheimer disease, and chronic traumatic encephalopathy seeds in brain homogenates. The discrimination of Pick disease from Alzheimer disease and chronic traumatic encephalopathy cases is then achieved through the quantitative differences in K12 RT-QuIC assay thioflavin T responses, which correlate with structural properties of the reaction products. In particular, Fourier transform infrared spectroscopy analysis of the respective K12CFh amyloids showed distinct β-sheet conformations, suggesting at least partial propagation of the original seed conformations in vitro. Thus, K12 RT-QuIC provides a single assay for ultrasensitive detection and discrimination of tau aggregates comprised mainly of 3R, or both 3R and 4R, tau isoforms.BACKGROUND Systemic lupus erythematous (SLE) disproportionately impacts patients of color and socioeconomically disadvantaged patients. Similar disparities in HIV were reduced through a World Health Organization-endorsed Care Continuum strategy targeting “retention in care,” defined as having at least two annual visits or viral load lab tests. Using similar definitions, this study aimed to examine predictors of lupus retention in care, to develop an SLE Care Continuum and inform interventions to reduce disparities. We hypothesized that Black patients and those residing in disadvantaged neighborhoods would have lower retention in care. METHODS Abstractors manually validated 545 potential adult cases with SLE codes in 2013-2014 using 1997 American College of Rheumatology (ACR) or 2012 Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria. We identified 397 SLE patients who met ACR or SLICC criteria for definite lupus, had at least one baseline rheumatology visit, and were alive throuS Disadvantaged neighborhood residence was the strongest factor predicting poor SLE retention in care. Future interventions could geo-target disadvantaged neighborhoods and design retention programs with vulnerable populations to improve retention in care and reduce SLE outcome disparities.BACKGROUND Laparoscopy, by its minimally invasive nature, has revolutionized digestive and particularly colorectal surgery by decreasing post-operative pain, morbidity, and length of hospital stay. In this trial, we aim to assess whether low pressure in laparoscopic colonic surgery (7 mm Hg instead of 12 mm Hg) could further reduce pain, analgesic consumption, and morbidity, resulting in a shorter hospital stay. METHODS AND ANALYSIS The PAROS trial is a phase III, double-blind, randomized controlled trial. We aim to recruit 138 patients undergoing laparoscopic colectomy. Participants will be randomly assigned to either a low-pressure group (7 mm Hg) or a standard-pressure group (12 mm Hg). The primary outcome will be a comparison of length of hospital stay between the two groups. Secondary outcomes will compare post-operative pain, consumption of analgesics, morbidity within 30 days, technical and oncological quality of the surgical procedure, time to passage of flatus and stool, and ambulation. All adverse events will be recorded.