Vosslindahl5882

an, Iran, and Institut Pasteur in Paris, France. The authors declare no competing interests.

N/A.

N/A.Biallelic Parkin (PRKN) mutations cause autosomal recessive Parkinson's disease (PD); however, the role of monoallelic PRKN mutations as a risk factor for PD remains unclear. We investigated the role of single heterozygous PRKN mutations in three large independent case-control cohorts totalling 10 858 PD cases and 8328 controls. Overall, after exclusion of biallelic carriers, single PRKN mutations were more common in PD than controls conferring a >1.5-fold increase in the risk of PD [P-value (P) = 0.035], with meta-analysis (19 574 PD cases and 468 488 controls) confirming increased risk [Odds ratio (OR) = 1.65, P = 3.69E-07]. Carriers were shown to have significantly younger ages at the onset compared with non-carriers (NeuroX 56.4 vs. 61.4 years; exome 38.5 vs. 43.1 years). Stratifying by mutation type, we provide preliminary evidence for a more pathogenic risk profile for single PRKN copy number variant (CNV) carriers compared with single nucleotide variant carriers. Studies that did not assess biallelic PRKN mutations or consist of predominantly early-onset cases may be biasing these estimates, and removal of these resulted in a loss of association (OR = 1.23, P = 0.614; n = 4). Importantly, when we looked for additional CNVs in 30% of PD cases with apparent monoallellic PRKN mutations, we found that 44% had biallelic mutations, suggesting that previous estimates may be influenced by cryptic biallelic mutation status. While this study supports the association of single PRKN mutations with PD, it highlights confounding effects; therefore, caution is needed when interpreting current risk estimates. Together, we demonstrate that comprehensive assessment of biallelic mutation status is essential when elucidating PD risk associated with monoallelic PRKN mutations.

In patients with atherosclerotic disease, minimally invasive cardiac surgery using retrograde perfusion for cardiopulmonary bypass via femoral cannulation (FC) carries a higher risk of brain embolization compared with antegrade perfusion. However, guidelines for selecting antegrade versus retrograde perfusion do not exist. We developed a computed tomography (CT)-based perfusion strategy and assessed outcomes.

We studied 270 minimally invasive cardiac surgery patients, aged 68 ± 13, 124 female, body surface area 1.6 ± 0.2 m2. Antegrade perfusion using axillary cannulation (AC) was selected if any of the following preoperative enhanced CT scan criteria were satisfied anywhere in the aorta or iliac arteries thrombosis thickness >3 mm, thrombosis >one-third of the total circumference and calcification present in the total circumference. FC was selected otherwise. Asymptomatic brain injury was assessed by diffusion-weighted magnetic resonance imaging.

AC and FC were selected in 95 (35%) and 175 patients, respectively. AC patients were 10 years older (P < 0.001) and had higher EuroSCORE II (2.7 ± 3.4 vs 1.7 ± 1.9, P = 0.002). selleck inhibitor The median cardiopulmonary time and cross-clamp times were not significantly different. No patients died in hospital. There was no immediate stroke in either group during 48 h after surgery. Asymptomatic brain injury was detected in 25 (26%) and 27 (15%) AC and FC patients, respectively, P = 0.03.

We believe our CT-based perfusion strategy using AC or FC minimized brain embolic rates. AC can be a good alternative to prevent brain embolization for minimally invasive cardiac surgery patients with advanced atherosclerotic disease.

We believe our CT-based perfusion strategy using AC or FC minimized brain embolic rates. AC can be a good alternative to prevent brain embolization for minimally invasive cardiac surgery patients with advanced atherosclerotic disease.Caspase (or cysteinyl-aspartate specific proteases) enzymes play important roles in apoptosis and inflammation, and the non-identical but overlapping specificity profiles (that is, cleavage recognition sequence) direct cells to different fates. Although all caspases prefer aspartate at the P1 position of the substrate, the caspase-6 subfamily shows preference for valine at the P4 position, while caspase-3 shows preference for aspartate. In comparison with human caspases, caspase-3a from zebrafish has relaxed specificity and demonstrates equal selection for either valine or aspartate at the P4 position. In the context of the caspase-3 conformational landscape, we show that changes in hydrogen bonding near the S3 subsite affect selection of the P4 amino acid. Swapping specificity with caspase-6 requires accessing new conformational space, where each landscape results in optimal binding of DxxD (caspase-3) or VxxD (caspase-6) substrate and simultaneously disfavors binding of the other substrate. Within the context of the caspase-3 conformational landscape, substitutions near the active site result in nearly equal activity against DxxD and VxxD by disrupting a hydrogen bonding network in the substrate binding pocket. The converse substitutions in zebrafish caspase-3a result in increased selection for P4 aspartate over valine. Overall, the data show that the shift in specificity that results in a dual function protease, as in zebrafish caspase-3a, requires fewer amino acid substitutions compared with those required to access new conformational space for swapping substrate specificity, such as between caspases-3 and -6.Overeating is a complex behavioral phenotype in terms of both physiology and psychology. The mere transference of the diagnostic criteria for substance use disorders to define food addiction is too simplistic, for the following reasons 1) a range of somatic and mental disorders require exclusion; 2) food addiction requires distinction from the physiological need to ingest sufficient calories to maintain a high body weight; 3) intentional weight loss can induce an eating behavior mimicking food addiction; 4) the concept lacks validation, especially in light of the high prevalence of "food addiction" in patients with anorexia nervosa; and 5) this construct has not led to novel and successful treatments for overeating and obesity. The concept of food addiction has the potential to distract from the need for focus on environmental influencers to combat the obesity pandemic.