Pruittstensgaard1172

Oxysterols are cholesterol metabolites with multiple functions in controlling cellular homeostasis. In particular, 27-hydroxycholesterol (27-OH-Chol) has been shown to regulate a variety of physiological functions, but little is known about its uptake, intracellular trafficking, and efflux from cells. This is largely due to a lack of suitable analogs of 27-OH-Chol, which mimic this oxysterol closely. Here, we present the intrinsically fluorescent 27-hydroxy-cholestatrienol (27-OH-CTL), which differs from 27-OH-Chol only by having two additional double bonds in the steroid ring system. Based on molecular dynamics (MD) simulations, we show that 27-OH-CTL possesses almost identical membrane properties compared to 27-OH-Chol. By comparative imaging of 27-OH-CTL and of the cholesterol analogue cholestatrienol (CTL) in living cells, we assess the impact of a single hydroxy group on sterol trafficking. We find that human fibroblasts take up more CTL than 27-OH-CTL, but efflux the oxysterol analogue more efficiently. For both sterols, efflux includes shedding of vesicles from the plasma membrane. Intracellular, 27-OH-CTL accumulates primarily in lipid droplets (LDs), while CTL is mostly found in endosomes and lysosomes. Using fluorescence recovery after photobleaching (FRAP), we find for both sterols a rapidly exchanging pool, which moves orders of magnitude faster than sterol containing vesicles and LDs. In summary, by applying a new fluorescent derivative of 27-OH-Chol we demonstrate that human cells can distinguish sterols based on a single hydroxy group in the side chain, resulting in different transport itineraries, dynamics, and efflux kinetics. Both intrinsically fluorescent cholesterol and oxysterol analogues show rapid non-vesicular transport in human fibroblasts.Apolipoprotein D (ApoD) is a lipocalin superfamily member that plays important roles in the transport of small hydrophobic molecules, lipid metabolism, and stress resistance. Cuticular hydrocarbons are the principal components of the epicuticular lipid layer and play a critical role in water retention against environmental desiccation stress; however, the mechanism underlying the role of ApoD in insect desiccation tolerance has not yet been elucidated. Here, we report the molecular constitution, functional analysis, and phylogenetic relationship of the ApoD gene in Acyrthosiphon pisum (ApApoD). We found that ApApoD was transcribed throughout the life cycle of A. read more pisum, but was prominently expressed in the embryonic period and abdominal cuticle. In addition, we optimized the dose and silencing duration of RNAi, observing that RNAi against ApApoD significantly reduced the levels of both internal and cuticular hydrocarbons and adult fecundity. Moreover, cuticular hydrocarbon deficiency increased the sensitivity of aphids to desiccation stress and reduced their survival time, while desiccation stress significantly increased ApApoD expression. Together, it is confirmed that ApApoD participates in regulating cuticular hydrocarbon content of aphids under desiccation stress and is crucial for aphid reproduction. Therefore, the ApApoD gene of A. pisum may be a potential target for RNAi-based insect pest control due to its involvement in cuticular hydrocarbon accumulation and reproduction.

Echocardiographic assessment of diastolic function is complex but can aid in the diagnosis of heart failure, particularly in patients with preserved ejection fraction. In 2016, the American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI) published an updated algorithm for the evaluation of diastolic function. The objective of our study was to assess its impact on diastolic function assessment in a real-world cohort of echo studies.

We retrospectively identified 71,727 consecutive transthoracic echo studies performed at a tertiary care center between February 2010 and March 2016 in which diastolic function was reported based on the 2009 ASE Guidelines. We then programmed a software algorithm to assess diastolic function in these echo studies according to the 2016 ASE/EACVI Guidelines.

When diastolic function assessment based on the 2009 guidelines was compared to that using the 2016 guidelines, there were significant differences in proportion of studies classified as normal (23% vs. 32%) or indeterminate (43% vs. link2 36%) function, and mild (23% vs. 23%), moderate (10% vs. 8%), or severe (1% vs. link3 2%) diastolic dysfunction, with poor agreement between the two methods (Kappa 0.323, 95% CI 0.318-0.328). Furthermore, within the subgroup of studies with preserved ejection fraction and no evidence of myocardial disease, there was significant reclassification from mild diastolic dysfunction to normal diastolic function.

The updated guidelines result in significant differences in diastolic function interpretation in the real world. Our findings have important implications for the identification of patients with or at risk for heart failure.

The updated guidelines result in significant differences in diastolic function interpretation in the real world. Our findings have important implications for the identification of patients with or at risk for heart failure.Longstanding theories in the field of neurophysiology have held that walking in rats is an unconscious, rhythmic locomotion that does not require cortical involvement. However, recent studies have suggested that the extent of cortical involvement during walking actually varies depending on the environmental conditions. To determine the impact of environmental conditions on cortical engagement in freely walking rats, we recorded limb kinematics and signals from implanted electroencephalography arrays in rats performing a series of natural behaviors. We found that rat gaits were significantly different across various locomotion terrains (e.g. walking on an upslope vs. downslope). Further, rat forelimbs and hindlimbs showed similar patterns of motion. The results also suggested that rat cortical engagement during walking varied across environmental conditions. Specifically, α band power significantly increased during 30° downslope walking in the posterior parietal, left secondary motor, and left somatosensory clusters. Additionally, during 30° upslope walking, the β band power was greater in the left primary motor and left and right secondary motor sources. Further, rats walking on up- or downslopes of varying steepness were found to have different cortical activities. Compared with 10° downslope walking, α band power was greater during 30° downslope locomotion in the left primary motor and somatosensory sources. These findings support the hypothesis that cortical contribution during walking in rats is influenced by environmental conditions, underlining the importance of goal-directed behaviors for motor function rehabilitation and neuro-prosthetic control in brain-machine interfaces.Variability in P-glycoprotein (P-gp) efflux transporting activity was supposed to be involved in altered intestinal absorption and bioavailability of clopidogrel in patients; however, reliable evidence is still lacking. In this study, we sought to determine whether P-gp could play an important role in the metabolic activation of and platelet response to clopidogrel in mice. Abcb1a/1b knock-out (KO) and wild-type (WT) mice were used to evaluate differences in the intracellular accumulation of clopidogrel in the intestine, liver, and brain tissues and in systemic exposure of clopidogrel and its main metabolites as well as the mechanisms involved. Results indicated that, compared with WT mice, KO mice exhibited an 84% increase in systemic exposure of clopidogrel active thiol metabolite H4 and a 14.5% rise of suppression of ADP-induced platelet integrin αIIbβ3 activation, paralleled by a 41% decrease in systemic exposure of clopidogrel due to enhanced systemic clearance. Furthermore, KO mice displayed a 45% increase in Cyp3a11 but a 23% decrease in Ces1 at their protein levels compared with WT mice. Concurrently, intracellular clopidogrel concentrations in the tissues examined did not differ significantly between KO and WT mice. We conclude that although P-gp does not transport clopidogrel and its major metabolites in mice, P-gp-deficient mice exhibit elevated formation of the active metabolite H4 and enhanced antiplatelet effect of clopidogrel through up-regulation of Cyp3a11 and down-regulation of Ces1, suggesting that P-gp activity may correlate inversely with the formation of H4 and antiplatelet efficacy of clopidogrel in clinical settings due to P-gp and CYP3A4 interplay.Bone-derived cytokines refer to various proteins and peptides that are released from the skeleton and can distribute in organisms to regulate homeostasis by targeting many organs, such as the pancreas, brain, testicles, and kidneys. In addition to providing support and movement, many studies have disclosed the novel endocrine function of bone, and bone can modulate glucose and energy metabolism as well as phosphate metabolism by versatile bone-derived cytokines. However, this specific exoskeletonfunction of bone-derived cytokines in the regulation of homeostasis and the pathological response caused by skeletal dysfunction are still not very clear, and elucidation of the above mechanisms is of great significance for understanding the pathological processes of metabolic disorders and in the search for novel therapeutic measures for maintaining organ stability and physical fitness.

The Wound-QoL is a validated and feasible questionnaire for measuring disease-specific health-related quality of life in chronic wounds, originally developed for use in German. The objective of this study was to translate the Wound-QoL for use in clinical care and in clinical trials in Spain and to validate this version.

Two independent fourth- and back translations of the Wound-QoL from the original German version were conducted, followed by an expert consensus of the resulting versions. After refinement, the final tool was piloted in N=10 patients and then used in the validation study.

A total of 115 patients were recruited. Mean age was 69.5 (SD 14.5) years, 60.0% were female. The Spanish version of Wound-QoL showed high internal consistency (Cronbach's alpha>0.8 in all scales). Factor analysis resulted in the same scales as the original version. There were satisfactory distribution characteristics of the global score and the subscales. Construct validity and convergent validity with other outcomes (generic QoL, healing rate) were satisfactory. The vast majority of patients considered the Wound-QoL a simple and feasible tool. Mean time needed for completing the questionnaire was 5minutes. Overall, 99.1% of the participants found it easy to understand the questions and 94.7% stated that the questionnaire suits the personal situation.

The Spanish version of the Wound-QoL shows good validity in clinical practice. It can be recommended for use in clinical routine and trials.

The Spanish version of the Wound-QoL shows good validity in clinical practice. It can be recommended for use in clinical routine and trials.Colchicine has shown potential therapeutic benefits in cardiovascular conditions owing to its broad anti-inflammatory properties. Here, we performed a meta-analysis to determine the efficacy and safety of colchicine in patients with coronary artery disease (CAD). A systematical search in electronic databases of PubMed, The Cochrane Library, and Scopus were carried out to identify eligible studies. Only randomized controlled trials evaluating the cardiovascular effects of colchicine in CAD patients were included. Study-level data of cardiovascular outcomes or adverse events were pooled using random-effect models. We finally included 5 randomized controlled trials with follow-up duration ≥6 months, comprising a total of 11,790 patients with CAD. Compared with placebo or no treatment, colchicine administration was associated with a significantly lower incidence of major adverse cardiovascular events (relative risk [RR] 0.65, 95% confidence interval [CI] 0.52 to 0.82). Such a benefit was not modified by the clinical phenotype of CAD (p for interaction = 0.