A critical histidine residue within LIMP-2 mediates pH sensitive binding to its ligand β-glucocerebrosidase

The lysosomal membrane protein type 2 is a novel identified lysosomal sorting receptor for β-glucocerebrosidase (GC). Mutations in both genes underlie human pathologies causing action myoclonus-renal failure syndrome (AMRF) and Gaucher disease (GD), respectively. We now demonstrate that the lumenal acidification mediated by the vacuolar (H(+) )-ATPase triggers the dissociation of LIMP-2 and GC in late endosomal/lysosomal compartments. Moreover, we identified a single histidine residue in LIMP-2 that is necessary for LIMP-2 and GC binding. This residue is in close proximity to a proposed coiled-coil domain, which determines the binding to GC and may function as a critical pH sensor.     

Design and synthesis of sulfonamidophenylethylamides as novel cardiac myosin activator

The sulfonamidophenylethylamide analogues were explored for finding novel and potent cardiac myosin activators. Among them, N-(4-(N,N-dimethylsulfamoyl)phenethyl-N-methyl-5-phenylpentanamide (13, CMA at 10 µM = 48.5%; FS = 26.21%; EF = 15.28%) and its isomer, 4-(4-(N,N-dimethylsulfamoyl)phenyl-N-methyl-N-(3-phenylpropyl)butanamide (27, CMA at 10 µM = 55.0%; FS = 24.69%; EF = 14.08%) proved to be efficient cardiac myosin activators both in in vitro and in vivo studies. Compounds 13 (88.2 + 3.1% at 5 µM) and 27 (46.5 + 2.8% at 5 µM) showed positive inotropic effect in isolated rat ventricular myocytes. The potent compounds 13 and 27 were highly selective for cardiac myosin over skeletal and smooth muscle myosin, and therefore these potent and selective amide derivatives could be considered a new class of cardiac myosin activators for the treatment of systolic heart failure.     

Rate and predictors of electrical failure in non-recalled defibrillator leads

BackgroundImplantable cardioverter defibrillator (ICD) leads are considered as the ‘weakest link’ in defibrillator systems due to FDA recalls and advisories involving popular lead models from major manufacturers. The rate of electrical failure of ICD leads not implicated in a recall is however not well determined.MethodsMedical records of patients implanted with ICDs at hospitals of the University of Pittsburgh Medical Center between 2002 and 2014 were analyzed. Leads were classified as having electrically failed if removed or replaced for reasons other than infection or heart transplantation. Patients were followed to endpoint of death or electrical lead failure.Results2410 consecutive ICD recipients (mean age 66 ± 13 years, women 22%, single/dual/biventricular-ICD 20%/44%/36%) were included. During a mean follow-up of 3.9 ± 3.3 years, 1272 patients (53%) died, 55 patients (2.3%) had ICD lead electrical failure, and 1052 (44%) patients were alive with functional leads at the time of last follow-up. Patients with failed leads had higher BMI (p = 0.07), better functional status (p = 0.04), higher serum creatinine (p = 0.004), wider QRS complex (p = 0.01), higher number of implanted leads (p = 0.06) and were more likely to have ischemic cardiomyopathy (p = 0.03). After adjusting for these variables in a binary logistic regression model, only a lower BMI, presence of non-ischemic cardiomyopathy, and a better functional status remained independently predictive of electrical failure.ConclusionsOnly 2.3% of non-recalled ICD leads experience electrical failure (annual failure rate of 0.6%). A higher patient functional status, lower BMI, and non-ischemic etiology of cardiomyopathy are independently associated with higher rates of ICD lead failure.     

Structural and functional regeneration after spinal cord injury in the weakly electric teleost fish, <Emphasis Type="Italic">Apteronotus</Emphasis><Emphasis Type="Italic">leptorhynchus</Emphasis>

In contrast to mammals, teleost fish exhibit an enormous potential to regenerate adult spinal cord tissue after injury. However, the mechanisms mediating this ability are largely unknown. Here, we analyzed the major processes underlying structural and functional regeneration after amputation of the caudal portion of the spinal cord in Apteronotus leptorhynchus, a weakly electric teleost. After a transient wave of apoptotic cell death, cell proliferation started to increase 5 days after the lesion and persisted at high levels for at least 50 days. New cells differentiated into neurons, glia, and ependymal cells. Retrograde tract tracing revealed axonal re-growth and innervation of the regenerate. Functional regeneration was demonstrated by recovery of the amplitude of the electric organ discharge, a behavior generated by spinal motoneurons. Computer simulations indicated that the observed rates of apoptotic cell death and cell proliferation can adequately explain the re-growth of the spinal cord. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Plantlet production from the male inflorescence tips of <Emphasis Type="Italic">Musa acuminata</Emphasis> cultivars from South India

Inflorescence apices are suitable explants for the rapid in vitro propagation of Musa spp. However, the diploid and triploid banana cultivars showed different in vitro responses with respect to the hormone combinations in Murashige and Skoog medium. The diploid cultivar (Sannachenkadali, AA) induced a maximum number of multiple shoots in 8.9 μM 6-benzyl adenine (BA) whereas the triploid cultivar (Red banana, AAA) exhibited maximum multiplication in 22.2 μM 6-benzyl adenine. MS medium supplemented with 11.4 μM indole acetic acid and 17.8 μM BA was also suitable for shoot proliferation in triploid cultivar but not in the diploid cultivar. The regenerated shoots were rooted in Murashige and Skoog basal medium within 10–15 days. The rooted plantlets were transferred to vermiculite and maintained at a temperature of 25 ± 2°C for 10 days and then at room temperature (30–32°C) for 2 weeks before transferring to potted soil compost mixture. The plantlets showed 100% survival.     

树麻雀代谢率和器官重量在光周期驯化中的变化

为探讨光周期对树麻雀代谢产热和代谢器官变化的影响,对成年树麻雀 Passer montanus 进行温度为25℃、两种光周期16 L:8 D(LD组)和8 L:16 D(SD组)4周的气候箱驯化后,测定其体重、基础代谢率(BMR)、体脂和水分含量,以及各器官、组织的鲜重和干重.结果 显示,SD组麻雀BMR显著大于LD组,作为代谢活性器官的消化道显著增生是其BMR显著增加的主要原因之一;麻雀通过增加体重和能量储备物脂肪来实现对较长黑暗环境的适应是其成功的生存策略.SD组麻雀体重的显著增加和水分含量显著降低,说明短光照的刺激引起麻雀能量储备的增加和代谢活性器官消化道增生.光周期驯化的结果验证了"中心限制假说",即麻雀体内存在着与BMR相关的"代谢机器",中心器官(消化道)是改变麻雀BMR的基础之一.     

Tracing the invasion characteristics of the yellow-legged hornet,Vespa velutina nigrithorax (Hymenoptera: Vespidae), in Korea using newly detected variable mitochondrial DNA sequences

The yellow-legged hornet, Vespa velutina nigrithorax (Hymenoptera: Vespidae), invaded South Korea in 2003 through Busan metropolitan city, which is located in the southeast region of the country. Previous studies aiming to trace the origin of V. velutina in Korea used a portion of mitochondrial (mt) COI and detected a single haplotype common to the site of origin. However, no subsequent study on invasive dynamics such as additional entry and/or another site of entry has been performed. In this study, segments of mt COI, CytB, and lrRNA were sequenced from 238 individuals collected in 11 Korean and two Japanese localities, but no variation in each gene was observed. Thus, we developed two intergenic spacer (IGS) sequences from the publicly available mt genome of V. velutina, which provided substantially increased variability (i.e., 19 haplotypes with 1.74% maximum sequence divergence in 1,129–1,146-bp-long concatenated sequences). Population genetic analyses using the concatenated sequences unexpectedly provided higher genetic diversity estimates in the northwest and southwest regions, both of which also harbor international cargo ports, than in the southeast region, in which Busan is located. Furthermore, this genetic result was roughly concordant with our questionnaire survey demonstrating that V. velutina was observed in apiaries located in the northwest and southwest regions up to 2012, when there was no reported prevalent distribution of the hornet beyond the southeast region. These results collectively suggest that the northwest and southwest regions of Korea are additional sites of V. velutina entry to the country, independent from the southeast region origin.     

Free radicals,cytokines and nitric oxide in cardiac failure and myocardial infarction

Myocardial infarction is the most common cause of congestive cardiac failure. Free radicals, cytokines, nitric oxide (NO) and antioxidants play a major role both in atherosclerosis and myocardial damage and preservation. In the early stages of atherosclerosis, neutrophils and monocytes infiltrate the intima and generate free radicals which damage the endothelial cells. As a result, production of NO and prostacyclin by the endothelial cells declines, which have cardioprotective actions. This also has relevance to the beneficial action of aspirin since, it can modulate both prostanoid and l-arginine-NO systems and NF-kB translocation. In both acute myocardial infarction and chronic congestive cardiac failure, the plasma levels of various inflammatory mediators such as interleukins and tumour necrosis factor- (TNF) are elevated. TNF, produced by the inflammatory cells and the myocardium, can suppress myocardial contractility and induce the production of free radicals, which in turn can further damage the myocardium. Transforming growth factor (TGF), polyunsaturated fatty acids and the glucose-insulin-potassium regimen can antagonize the harmful actions of TNF and protect the myocardium. This explains why efforts made to reduce the levels of pro-inflammatory cytokines have beneficial action and preserve the myocardium.     

Regression analysis of doubly censored failure time data using the additive hazards model

Doubly censored failure time data arise when the survival time of interest is the elapsed time between two related events and observations on occurrences of both events could be censored. Regression analysis of doubly censored data has recently attracted considerable attention and for this a few methods have been proposed (Kim et al., 1993, Biometrics 49, 13-22; Sun et al., 1999, Biometrics 55, 909-914; Pan, 2001, Biometrics 57, 1245-1250). However, all of the methods are based on the proportional hazards model and it is well known that the proportional hazards model may not fit failure time data well sometimes. This article investigates regression analysis of such data using the additive hazards model and an estimating equation approach is proposed for inference about regression parameters of interest. The proposed method can be easily implemented and the properties of the proposed estimates of regression parameters are established. The method is applied to a set of doubly censored data from an AIDS cohort study.