Angiotensin II type 1 receptor antagonists alleviate muscle pathology in the mouse model for laminin-alpha2-deficient congenital muscular dystrophy (MDC1A)

BACKGROUND: Laminin-alpha2-deficient congenital muscular dystrophy (MDC1A) is a severe muscle-wasting disease for which no curative treatment is available. Antagonists of the angiotensin II receptor type 1 (AT1), including the anti-hypertensive drug losartan, have been shown to block also the profibrotic action of transforming growth factor (TGF)-beta and thereby ameliorate disease progression in mouse models of Marfan syndrome. Because fibrosis and failure of muscle regeneration are the main reasons for the severe disease course of MDC1A, we tested whether L-158809, an analog derivative of losartan, could ameliorate the dystrophy in dyW/dyW mice, the best-characterized model of MDC1A. METHODS: L-158809 was given in food to dyW/dyW mice at the age of 3 weeks, and the mice were analyzed at the age of 6 to 7 weeks. We examined the effect of L-158809 on muscle histology and on muscle regeneration after injury as well as the locomotor activity and muscle strength of the mice. RESULTS: We found that TGF-beta signaling in the muscles of the dyW/dyW mice was strongly increased, and that L-158809 treatment suppressed this signaling. Consequently, L-158809 reduced fibrosis and inflammation in skeletal muscle of dyW/dyW mice, and largely restored muscle regeneration after toxin-induced injury. Mice showed improvement in their locomotor activity and grip strength, and their body weight was significantly increased. CONCLUSION: These data provide evidence that AT1 antagonists ameliorate several hallmarks of MDC1A in dyW/dyW mice, the best-characterized mouse model for this disease. Because AT1 antagonists are well tolerated in humans and widely used in clinical practice, these results suggest that losartan may offer a potential future treatment of patients with MDC1A

Multi-morbidities are Not a Driving Factor for an Increase of COPD-Related 30-Day Readmission Risk

Background and Objective: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States. COPD is expensive to treat, whereas the quality of care is difficult to evaluate due to the high prevalence of multi-morbidity among COPD patients. In the US, the Hospital Readmissions Reduction Program (HRRP) was initiated by the Centers for Medicare and Medicaid Services to penalize hospitals for excessive 30-day readmission rates for six diseases, including COPD. This study examines the difference in 30-day readmission risk between COPD patients with and without comorbidities.Methods: In this retrospective cohort study, we used Cox regression to estimate the hazard ratio of 30-day readmission rates for COPD patients who had no comorbidity and those who had one, two or three, or four or more comorbidities. We controlled for individual, hospital and geographic factors. Data came from three sources: Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases (SID), Area Health Resources Files (AHRF) and the American Hospital Association’s (AHA’s) annual survey database for the year of 2013.Results: COPD patients with comorbidities were less likely to be readmitted within 30 days relative to patients without comorbidities (aHR from 0.84 to 0.87, p \u3c 0.05). In a stratified analysis, female patients with one comorbidity had a lower risk of 30-day readmission compared to female patients without comorbidity (aHR = 0.80, p \u3c 0.05). Patients with public insurance who had comorbidities were less likely to be readmitted within 30 days in comparison with those who had no comorbidity (aHR from 0.79 to 0.84, p \u3c 0.05).Conclusion: COPD patients with comorbidities had a lower risk of 30-day readmission compared with patients without comorbidity. Future research could use a different study design to identify the effectiveness of the HRRP

Engineering spin-orbit torque in Co/Pt multilayers with perpendicular magnetic anisotropy

To address thermal stability issues for spintronic devices with a reduced size, we investigate spin-orbit torque in Co/Pt multilayers with strong perpendicular magnetic anisotropy. Note that the spin-orbit torque arises from the global imbalance of the spin currents from the top and bottom interfaces for each Co layer. By inserting Ta or Cu layers to strengthen the top-down asymmetry, the spin-orbit torque efficiency can be greatly modified without compromised perpendicular magnetic anisotropy. Above all, the efficiency builds up as the number of layers increases, realizing robust thermal stability and high spin-orbit-torque efficiency simultaneously in the multilayers structure

Programmable base editing of zebrafish genome using a modified CRISPR-Cas9 system.

Precise genetic modifications in model animals are essential for biomedical research. Here, we report a programmable "base editing" system to induce precise base conversion with high efficiency in zebrafish. Using cytidine deaminase fused to Cas9 nickase, up to 28% of site-specific single-base mutations are achieved in multiple gene loci. In addition, an engineered Cas9-VQR variant with 5'-NGA PAM specificities is used to induce base conversion in zebrafish. This shows that Cas9 variants can be used to expand the utility of this technology. Collectively, the targeted base editing system represents a strategy for precise and effective genome editing in zebrafish.The use of base editing enables precise genetic modifications in model animals. Here the authors show high efficient single-base editing in zebrafish using modified Cas9 and its VQR variant with an altered PAM specificity