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Chalmers et al. provide evidence in multiple cohorts of patients with systemic lupus erythematous that CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), interact within the kidney to contribute to lupus nephritis. Image credit: Phoi Tiet.
Neuronal ceroid lipofuscinosis type 7 (CLN7) disease is a lysosomal storage disease caused by mutations in the facilitator superfamily domain containing 8 (MFSD8) gene, which encodes a membrane-bound lysosomal protein MFSD8. To test the effectiveness and safety of adeno-associated viral (AAV) gene therapy, an in vitro study demonstrated that AAV2/MFSD8 dose-dependently rescued lysosomal function in fibroblasts from a CLN7 patient. An in vivo efficacy study using intrathecal administration of AAV9/MFSD8 to Mfsd8-/- mice at postnatal day (p)7-10 or p120 with high or low dose led to clear age- and dose-dependent effects. A high dose of AAV9/MFSD8 at p7-10 resulted in widespread MFSD8 mRNA expression, tendency of amelioration of subunit c of mitochondrial ATP synthase accumulation and glial fibrillary acidic protein immunoreactivity, normalization of impaired behaviors, doubled median lifespan, and extended normal body weight gain. In vivo safety studies in rodents concluded that intrathecal administration of AAV9/MFSD8 was safe and well-tolerated. In summary, these results demonstrated that the AAV9/MFSD8 vector is both effective and safe in preclinical models. Investigational New Drug application #19766 to initiate a Phase I intrathecal gene transfer trial for AAV9/MFSD8 was approved by the US FDA and the trial is enrolling CLN7 patients at Children’s Health in Dallas, TX in collaboration with UTSW Medical Center (clinicaltrials.gov NCT04737460).
Xin Chen, Thomas Dong, Yuhui Hu, Frances C. Shaffo, Nandkishore R. Belur, Joseph R. Mazzulli, Steven J. Gray
Despite being the first homolog of the bacterial RecQ helicase to be identified in humans the function of RECQL1 remains poorly characterised. Furthermore, unlike other members of the human RECQ family of helicases, mutations in RECQL1 have not been associated with a genetic disease. Here we identify two families with a novel genome instability disorder, named RECON (RECql ONe) Syndrome caused by biallelic mutations in the RECQL gene. The affected individuals exhibit short stature, progeroid facial features, a hypoplastic nose, xeroderma and skin photosensitivity. Affected individuals were homozygous for the same missense mutation in RECQL1 (p.Ala459Ser) located within its zinc binding domain. Biochemical analysis of the mutant RECQL1 protein revealed that the p.A459S missense mutation compromised its ATPase, helicase and fork restoration activity, whilst its capacity to promote single-strand DNA annealing was largely unaffected. At the cellular level, this mutation in RECQL1 gave rise to a defect in the ability to repair DNA damage induced by exposure to topoisomerase poisons and a failure of DNA replication to progress efficiently in the presence of abortive topoisomerase lesions. Taken together, RECQL1 is the fourth member of the RecQ family of helicases to be associated with a human genome instability disorder.
Bassam Abu-Libdeh, Satpal S. Jhujh, Srijita Dhar, Joshua A. Sommers, Arindam Datta, Gabriel M.C. Longo, Laura J. Grange, John J. Reynolds, Sophie L. Cooke, Gavin S. McNee, Robert Hollingworth, Beth L. Woodward, Anil N. Ganesh, Stephen J. Smerdon, Claudia M. Nicolae, Karina Durlacher-Betzer, Vered Molho-Pessach, Abdulsalam Abu-Libdeh, Vardiella Meiner, George-Lucian Moldovan, Vassilis Roukos, Tamar Harel, Robert M. Brosh Jr., Grant S. Stewart
Piezo1 forms mechanically-activated non-selective cation channels that contribute to endothelial response to fluid flow. Here we reveal an important role in the control of capillary density. Conditional endothelial-specific deletion of Piezo1 in adult mice depressed physical performance. Muscle microvascular endothelial cell apoptosis and capillary rarefaction were evident and sufficient to account for the effect on performance. There was selective upregulation of thrombospondin-2 (TSP2), an inducer of endothelial apoptosis, with no effect on thrombospondin-1 (TSP1), a related important player in muscle physiology. TSP2 was poorly expressed in muscle endothelial cells but robustly expressed in muscle pericytes, in which nitric oxide (NO) repressed the Tsp2 gene without effect on Tsp1. In the endothelial cells, Piezo1 was required for normal expression of endothelial nitric oxide synthase (eNOS). The data suggest an endothelial-pericyte partnership of muscle in which endothelial Piezo1 senses blood flow to sustain capillary density and thereby maintain physical capability.
Fiona Bartoli, Marjolaine Debant, Eulashini Chuntharpursat-Bon, Elizabeth L. Evans, Katie E. Musialowski, Gregory Parsonage, Lara C. Morley, T. Simon Futers, Piruthivi Sukumar, T. Scott Bowen, Mark T. Kearney, Laeticia Lichtenstein, Lee D. Roberts, David J. Beech
Women have higher prevalence of asthma compared to men. In asthma, allergic airway inflammation is initiated by IL-33 signaling through ST2, leading to increased IL-4, IL-5, and IL-13 production and eosinophil infiltration. Foxp3+ Tregs suppress and ST2+ Tregs promote allergic airway inflammation. Clinical studies showed the androgen, dehydroepiandrosterone (DHEA), reduced asthma symptoms in patients, and mouse studies showed androgen receptor (AR) signaling decreased allergic airway inflammation. Yet, the role of AR signaling on lung Tregs remains unclear. Using AR deficient and Foxp3 fate-mapping mice, we determined that AR signaling increased Treg suppression during Alternaria extract (Alt Ext, allergen) challenge by stabilizing Foxp3+ Tregs and limiting the number of ST2+ ex-Tregs and IL-13+ Th2 and ex-Tregs. AR signaling also decreased Alt Ext-induced ST2+ Tregs in mice by limiting Gata2 expression, a transcription factor for ST2, and by decreasing Alt Ext-induced IL-33 production from murine airway epithelial cells. We confirmed our findings in human cells where 5α-dihydrotestosterone (DHT), an androgen, decreased IL-33-induced ST2 expression in lung Tregs and decreased Alt Ext induced IL-33 secretion in human bronchial epithelial cells. Our findings showed that AR signaling stabilized Treg suppressive function, providing a mechanism for the sex difference in asthma.
Vivek D. Gandhi, Jacqueline-Yvonne Cephus, Allison E. Norlander, Nowrin U. Chowdhury, Jian Zhang, Zachary J. Ceneviva, Elie Tannous, Vasiliy V. Polosukhin, Nathan D. Putz, Nancy Wickersham, Amrit Singh, Lorraine B. Ware, Julie A Bastarache, Ciara M. Shaver, Hong Wei Chu, Ray S. Peebles Jr, Dawn C. Newcomb
Inherited germline mutations in the BRCA1 (BReast CAncer gene 1) or BRCA2 (BReast CAncer gene 2) genes (herein BRCA1/2) greatly increase the risk of breast and ovarian cancer, presumably by elevating somatic mutational errors as a consequence of deficient DNA repair. However, this has never been directly demonstrated by a comprehensive analysis of the somatic mutational landscape of primary, non-cancer, mammary epithelial cells of women diagnosed with pathogenic BRCA1 or BRCA2 germline mutations. Here we used an accurate, single-cell whole genome sequencing approach to first show that telomerized primary mammary epithelial cells heterozygous for a highly penetrant BRCA1 variant displayed a robustly elevated mutation frequency as compared to their isogenic control cells. We then demonstrated a small but statistically significant increase in mutation frequency in mammary epithelial cells isolated from the breast of BRCA1/2 mutation carriers as compared to those obtained from age-matched controls with no genetically increased risk for breast cancer.
Shixiang Sun, Kristina Brazhnik, Moonsook Lee, Alexander Y. Maslov, Yi Zhang, Zhenqiu Huang, Susan Klugman, Ben H. Park, Jan Vijg, Cristina Montagna
JCI This Month is a digest of the research, reviews, and other features published each month.
Animals, plants, and bacteria all display behavioral patterns that coincide with Earth’s light and dark cycles. These oscillating behaviors are the manifestation of the molecular circadian clock, a highly conserved network that maintains a near 24-hour rhythm even in the absence of light. In mammals, light signals are transmitted via the superchiasmatic nucleus (SCN) in the hypothalamus to synchronize peripheral clocks and coordinate physiological functions with the organism’s active period. This collection of reviews, curated by Amita Sehgal, considers the critical role of the circadian system in human health. Technology, work, and social obligations can disrupt optimal sleep and wake schedules, leaving humans vulnerable to diseases affecting the heart, brain, metabolism, and more. Sleep disorders as well as normal variations in human chronotype may exacerbate circadian disruptions, with profound consequences. These reviews emphasize that ongoing efforts to understand the complexities of human circadian rhythm will be essential for developing chronotherapies and other circadian-based interventions.