Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K
channel Kir2.1. The extracellular Cys (cysteine)
-to-Cys
disulfide ...bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys
-to-Cys
disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state.
We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1
variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments.
Kir2.1
mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1
cardiomyocytes showed significantly reduced inwardly rectifier K+ (I
) and inward Na+ (I
) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1
mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and Na
1.5 proteins.
The extracellular Cys
-to-Cys
disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the Na
1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.
The catalytic performance of two types of heterogeneous acid catalysts—sulfonic acid-functionalized materials and aluminum containing zeolites,—in the dehydration of sorbitol to isosorbide, in ...solventless and autogenous pressure conditions, has been studied. Catalysts screening evidenced strong differences between sulfonic acid-based materials and acid zeolites in terms of catalytic performance. Whereas sulfonic materials, such as Amberlyst-70 and SBA-15-Pr-SO
3
H, showed a very high catalytic activity, zeolites with beta structure evidenced good catalytic performance together with minimized promotion of side reactions (production of non-desired sorbitans, humins, etc.). Kinetic studies performed at different temperatures, adjusting to a Langmuir–Hinshelwood type model, allowed correlating the physicochemical properties of the acid materials with their catalytic performance in sorbitol dehydration. Thus, the analysis of initial selectivity through kinetic constants comparison indicated that commercial beta zeolite with a Si/Al ratio of 19 is the most selective catalyst for the production of isosorbide, though following a slower kinetics than the sulfonic materials. Furthermore, an equivalent hierarchical beta zeolite has been synthesised and evaluated, resulting in a slight improvement of the catalytic performance, in terms of both yield and selectivity to isosorbide. This improvement is attributed to the superior textural properties.
Thrombolysis is still used when primary angioplasty is delayed for a long time, but 25%-30% of patients require rescue angioplasty (RA). There are no established recommendations for antithrombotic ...management in RA. This registry analyzes regimens for antithrombotic management.
A retrospective, multicenter, observational registry of consecutive patients treated with RA at 8 hospitals. All variables were collected and follow-up took place at 6 months.
The study included 417 patients. Antithrombotic therapy in RA was: no additional drugs 22.3%, unfractionated heparin (UFH) 36.6%, abciximab 15.5%, abciximab plus UFH 10.5%, bivalirudin 5.7%, enoxaparin 4.3%, and others 4.7%. Outcomes at 6 months were: mortality 9.1%, infarction 3.3%, definite or probable stent thrombosis 4.3%, revascularization 1.9%, and stroke 0.5%. Mortality was related to cardiogenic shock, age > 75 years, and anterior location. The stent thrombosis rate was highest with bivalirudin (12.5% at 6 months). The incidence of bleeding at admission was high (14.8%), but most cases were not severe (82% BARC ≤2). Variables independently associated with bleeding were: femoral access (OR 3.30; 95% CI 1.3-8.3: p = 0.004) and post-RA abciximab infusion (OR 2.26; 95% CI 1.02-5: p = 0.04).
Antithrombotic treatment regimens in RA vary greatly, predominant strategies consisting of no additional drugs or UFH 70 U/kg. No regimen proved predictive of mortality, but bivalirudin was related to more stent thrombosis. There was a high incidence of bleeding, associated with post-RA abciximab infusion and femoral access.
The neural crest is a multipotent cell population that develops from the dorsal neural fold of vertebrate embryos in order to migrate extensively and differentiate into a variety of tissues. A number ...of gene regulatory networks coordinating neural crest cell specification and differentiation have been extensively studied to date. Although several publications suggest a common role for microRNA-145 (miR-145) in molecular reprogramming for cell cycle regulation and/or cellular differentiation, little is known about its role during in vivo cranial neural crest development. By modifying miR-145 levels in zebrafish embryos, abnormal craniofacial development and aberrant pigmentation phenotypes were detected. By whole-mount in situ hybridization, changes in expression patterns of
and Sry-related HMG box (Sox) transcription factors
and
were observed in overexpressed miR-145 embryos. In agreement, zebrafish
expression was downregulated by miR-145 overexpression. In silico and in vivo analysis of the
3'UTR revealed a conserved potential miR-145 binding site likely involved in its post-transcriptional regulation. Based on these findings, we speculate that miR-145 participates in the gene regulatory network governing zebrafish chondrocyte differentiation by controlling
expression.
The aim of this study was to analyze the cardiac autonomic function at rest, at maximum exercise, and in recovery after exercise and to determine sex-specific and age-specific values for resting ...heart rate (RHR), hear rate (HR)-peak, HR recovery (HRR), and HR variability at rest in master runners. Fifty endurance runners (21 women) participated in this study (43.28 ± 5.25 years). The subjects came from different athletic clubs in Andalusia (Spain), and the testing protocol was performed in-season. A 3-km running test was performed and the cardiovascular response was monitored. Regarding sex, no significant differences were found regarding cardiovascular autonomic function at rest, during exercise, and following maximal exercise, only at rest, the standard deviation of all R-R intervals and low frequency values displayed significantly (p < 0.05) lower scores in women. 46% of athletes showed an RHR < 60 bpm. Additionally, HR-peak showed a significant correlation with age (r = −0.369; p = 0.009) and HRR5min (r = 0.476, p = 0.001). Also, endurance performance was inversely associated with obesity traits and cardiometabolic risk factors. In summary, age, sex, fitness, or anthropometrics characteristics did not show a relevant influence on cardiovascular autonomic modulation in master runners. However, the 3-km performance displayed a significant negative association with several factors of cardiometabolic risk.
Background. Background matching, as a camouflage strategy, is one of the most outstanding examples of adaptation, where little error or mismatch means high vulnerability to predation. It is assumed ...that the interplay of natural selection and adaptation are the main evolutionary forces shaping the great diversity of phenotypes observed in mimicry; however, there may be other significant processes that intervene in the development of mimicry such as phenotypic plasticity. Based on observations of background mismatching during reproduction events of egg-cowries, sea snails of the family Ovulidae that mimic the octocoral where they inhabit, we wondered if they match the host species diversity. Using observations in the field and molecular systematics, we set out to establish whether the different egg-cowrie color/shape polymorphisms correspond to distinct lineages restricted to specific octocoral species. Methods. Collection and observations of egg-cowries and their octocoral hosts were done using SCUBA diving between 2009 and 2012 at two localities in the Tropical Eastern Pacific (TEP), Malpelo Island and Cabo Corrientes (Colombia). Detailed host preference observations were done bi-annually at Malpelo Island. We analyzed the DNA sequence of the mitochondrial genes COIand 16S rDNA, extensively used in phylogenetic and DNA barcoding studies, to assess the evolutionary relationship among different egg-cowrie colorations and morphologies. Results. No genetic divergence among egg-cowries associated to different species of the same octocoral genus was observed based on the two mitochondrial genes analyzed. For instance, all egg-cowrie individuals from the two sampled localities observed on 8 different Pacifigorgia-Eugorgia species showed negligible mitochondrial divergence yet large morphologic divergence, which suggests that morphologies belonging to at least two sea snail species, Simnia avena(=S. aequalis) and Simnialena rufa, can cross-fertilize. Discussion. Our study system comprised background-matching mimicry, of the masquerade type, between egg-cowries (Simnia/Simnialena) and octocorals (Pacifigorgia/Eugorgia/Leptogorgia). We observed mimicry mismatches related to fitness trade-offs, such as reproductive aggregations vs. vulnerability against predators. Despite the general assumption that coevolution of mimicry involves speciation, egg-cowries with different hosts and colorations comprise the same lineages. Consequently, we infer that there would be significant tradeoffs between mimicry and the pursuit of reproductive aggregations in egg-cowries. The findings of this study not only contribute to the understanding of the evolution of mimicry in egg-cowries, a poorly studied group of marine gastropods, but also to the development of a new biologically meaningful board game that could be implemented as a learning tool.
Chimeric somatostatin/dopamine compounds such as BIM-23A760, an sst2/sst5/D
receptors-agonist, have emerged as promising new approaches to treat pituitary adenomas. However, information on direct in ...vitro effects of BIM-23A760 in normal and tumoral pituitaries remains incomplete. The objective of this study was to analyze BIM-23A760 effects on functional parameters (Ca
signaling, hormone expression/secretion, cell viability and apoptosis) in pituitary adenomas (n = 74), and to compare with the responses of normal primate and human pituitaries (n = 3-5). Primate and human normal pituitaries exhibited similar sst2/sst5/D2 expression patterns, wherein BIM-23A760 inhibited the expression/secretion of several pituitary hormones (specially GH/PRL), which was accompanied by increased sst2/sst5/D2 expression in primates and decreased Ca
concentration in human cells. In tumoral pituitaries, BIM-23A760 also inhibited Ca
concentration, hormone secretion/expression and proliferation. However, BIM-23A760 elicited stimulatory effects in a subset of GHomas, ACTHomas and NFPAs in terms of Ca
signaling and/or hormone secretion, which was associated with the relative somatostatin/dopamine-receptors levels, especially sst5 and sst5TMD4. The chimeric sst2/sst5/D
compound BIM-23A760 affects multiple, clinically relevant parameters on pituitary adenomas and may represent a valuable therapeutic tool. The relative ssts/D
expression profile, particularly sst5 and/or sst5TMD4 levels, might represent useful molecular markers to predict the ultimate response of pituitary adenomas to BIM-23A760.
It is estimated that approximately one in three women develop chronic venous disease (CVD) during pregnancy, a broad spectrum of morphofunctional disorders affecting the venous system in different ...regions of the body, including the lower limbs. A growing body of evidence supports the diverse maternofetal consequences derived from this condition, with the placenta being an organ particularly affected. Among other consequences, having CVD during pregnancy has been associated with systemic inflammation and altered cytokines and chemokine profiles in the maternal and fetal serum related to this condition. In the present work, we aimed to analyze if these inflammatory changes also occurred in the placental tissue of women with CVD, exploring by immunohistochemistry and real-time PCR (RT-qPCR) gene and protein expression of critical inflammatory markers like allograft inflammatory factor 1 (AIF-1), interleukin 10 (IL-10), IL-12A, and IL-18. Our results demonstrate an enhanced tissue expression of AIF-1, IL-12A, and IL-18, accompanied by a decrease in IL-10 in the placentas of women who had undergone CVD during pregnancy. Overall, our results suggest a possible pathophysiological role of inflammation in the placental tissue of women with CVD during pregnancy, although the precise consequences of this feature remain to be deeply analyzed.
•Chronic immobilization protects from the effects of an acute immobilization.•Chronic unpredictable stress partially protects from an acute immobilization.•There is evidence of cross-adaptation ...between different stressors.
Exposure to chronic unpredictable stress (CUS) is gaining acceptance as a putative animal model of depression. However, there is evidence that chronic exposure to stress can offer non-specific stress protection from some effects of acute superimposed stressors. We then compared in adult male rats the protection afforded by prior exposure to CUS with the one offered by repeated immobilization on boards (IMO) regarding some of the negative consequences of an acute exposure to IMO. Repeated exposure to IMO protected from the negative consequences of an acute IMO on activity in an open-field, saccharin intake and body weight gain. Active coping during IMO (struggling) was markedly reduced by repeated exposure to the same stressor, but it was not affected by a prior history of CUS, suggesting that our CUS protocol does not appear to impair active coping responses. CUS exposure itself caused a strong reduction of activity in the open-field but appeared to protect from the hypo-activity induced by acute IMO. Moreover, prior CUS offered partial protection from acute IMO-induced reduction of saccharin intake and body weight gain. It can be concluded that a prior history of CUS protects from some of the negative consequences of exposure to a novel severe stressor, suggesting the development of partial cross-adaptation whose precise mechanisms remain to be studied.
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