Kinetics of the conformational cycle of Hsp70 reveals the importance of the dynamic and heterogeneous nature of Hsp70 for its function.

Hsp70 is a conserved molecular chaperone that plays an indispensable role in regulating protein folding, translocation, and degradation. The conformational dynamics of Hsp70 and its regulation by cochaperones are vital to its function. Using bulk and single-molecule fluorescence resonance energy transfer (smFRET) techniques, we studied the interdomain conformational distribution of human stress-inducible Hsp70A1 and the kinetics of conformational changes induced by nucleotide and the Hsp40 cochaperone Hdj1. We found that the conformations between and within the nucleotide- and substrate-binding domains show heterogeneity. The conformational distribution in the ATP-bound state can be induced by Hdj1 to form an "ADP-like" undocked conformation, which is an ATPase-stimulated state. Kinetic measurements indicate that Hdj1 binds to monomeric Hsp70 as the first step, then induces undocking of the two domains and closing of the substrate-binding cleft. Dimeric Hdj1 then facilitates dimerization of Hsp70 and formation of a heterotetrameric Hsp70-Hsp40 complex. Our results provide a kinetic view of the conformational cycle of Hsp70 and reveal the importance of the dynamic nature of Hsp70 for its function.

Prevention of aortic dissection and aneurysm via an ALDH2-mediated switch in vascular smooth muscle cell phenotype.

AIMS: Aortic aneurysm/dissection (AAD) is a life-threatening disorder lacking effective pharmacotherapeutic remedies. Aldehyde dehydrogenase 2 (ALDH2) polymorphism is tied with various risk factors for AAD including hypertension, atherosclerosis, and hypercholesterolaemia although direct correlation between the two remains elusive. METHODS AND RESULTS: Two independent case-control studies were conducted involving 307 AAD patients and 399 healthy controls in two geographically distinct areas in China. Our data revealed that subjects carrying mutant ALDH2 gene possessed a ∼50% reduced risk of AAD compared with wild-type (WT) alleles. Using 3-aminopropionitrile fumarate (BAPN)- and angiotensin II (Ang II)-induced AAD animal models, inhibition of ALDH2 was found to retard development of AAD. Mechanistically, ALDH2 inhibition ablated pathological vascular smooth muscle cell (VSMC) phenotypical switch through interaction with myocardin, a determinant of VSMC contractile phenotype. Using microarray and bioinformatics analyses, ALDH2 deficiency was found to down-regulate miR-31-5p, which further altered myocardin mRNA level. Gain-of-function and loss-of-function studies verified that miR-31-5p significantly repressed myocardin level and aggravated pathological VSMC phenotypical switch and AAD, an effect that was blunted by ALDH2 inhibition. We next noted that ALDH2 deficiency increased Max expression and decreased miR-31-5p level. Moreover, ALDH2 mutation or inhibition down-regulated levels of miR-31-5p while promoting myocardin downstream contractile genes in the face of Ang II in primary human VSMCs. CONCLUSIONS: ALDH2 deficiency is associated with a lower risk of AAD in patients and mice, possibly via suppressing VSMC phenotypical switch in a miR-31-5p-myocardin-dependent manner. These findings favour a role for ALDH2 and miR-31-5p as novel targets for AAD therapy.

Ambient high temperature and mortality in Jinan, China: A study of heat thresholds and vulnerable populations.

BACKGROUND: Understanding the health consequences of continuously rising temperatures-as is projected for China-is important in terms of developing heat-health adaptation and intervention programs. This study aimed to examine the association between mortality and daily maximum (Tmax), mean (Tmean), and minimum (Tmin) temperatures in warmer months; to explore threshold temperatures; and to identify optimal heat indicators and vulnerable populations. METHODS: Daily data on temperature and mortality were obtained for the period 2007-2013. Heat thresholds for condition-specific mortality were estimated using an observed/expected analysis. We used a generalised additive model with a quasi-Poisson distribution to examine the association between mortality and Tmax/Tmin/Tmean values higher than the threshold values, after adjustment for covariates. RESULTS: Tmax/Tmean/Tmin thresholds were 32/28/24°C for non-accidental deaths; 32/28/24°C for cardiovascular deaths; 35/31/26°C for respiratory deaths; and 34/31/28°C for diabetes-related deaths. For each 1°C increase in Tmax/Tmean/Tmin above the threshold, the mortality risk of non-accidental-, cardiovascular-, respiratory, and diabetes-related death increased by 2.8/5.3/4.8%, 4.1/7.2/6.6%, 6.6/25.3/14.7%, and 13.3/30.5/47.6%, respectively. Thresholds for mortality differed according to health condition when stratified by sex, age, and education level. For non-accidental deaths, effects were significant in individuals aged ≥65 years (relative risk=1.038, 95% confidence interval: 1.026-1.050), but not for those ≤64 years. For most outcomes, women and people ≥65 years were more vulnerable. CONCLUSION: High temperature significantly increases the risk of mortality in the population of Jinan, China. Climate change with rising temperatures may bring about the situation worse. Public health programs should be improved and implemented to prevent and reduce health risks during hot days, especially for the identified vulnerable groups.

Acute Coronary Artery Air Embolism Complicating a CT-guided percutaneous lung biopsy: A case report.

Systemic air embolism is a fatal complication of computed tomography-guided percutaneous lung biopsy. Here, we report a case of acute coronary artery air embolism following computed tomography (CT) guided percutaneous lung biopsy. The patient exhibited cardiac symptoms, and CT showed air density in left ventricle and aorta, indicating air embolism. Trendelenburg positioning and coronary angiography were performed during the treatment, and the patient was discharged without obvious complications.

Perioperative nursing care of a patient with urogenital sinus malformation who underwent vaginal calculus removal and correction: a case report.

Cases of urogenital sinus malformation with a huge calculus are complex and rare. Improper nursing care of these cases can lead to a series of problems. We report here a 23-year-old married woman who was admitted to hospital because of primary amenorrhea and failed sexual intercourse for 5 years. Through combined diagnosis and treatment of radiology, ultrasound, urology, gynecology, and other disciplines, the patient was diagnosed with urogenital sinus malformation, a vaginal calculus, and primary amenorrhea. After full preparation, the patient underwent an operation for extraction of the vaginal calculus, urethroplasty, vaginoplasty, and hysteroscopy. The calculus of the patient was removed and the vagina was returned to its normal anatomy. Patients with urogenital sinus malformation and a huge calculus have complex care requirements and experience a particular state of vulnerability during the diagnostic phase. By establishing good communication with patients and providing proper perioperative nursing, physiological and psychological rehabilitation of these patients can be achieved.