Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Background The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. Methods In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. Results A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. Conclusions In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048 .)

Effect of carbohydrate-protein supplement timing on acute exercise-induced muscle damage

<p>Abstract</p> <p>Purpose</p> <p>To determine if timing of a supplement would have an effect on muscle damage, function and soreness.</p> <p>Methods</p> <p>Twenty-seven untrained men (21 ± 3 yrs) were given a supplement before or after exercise. Subjects were randomly assigned to a pre exercise (n = 9), received carbohydrate/protein drink before exercise and placebo after, a post exercise (n = 9), received placebo before exercise and carbohydrate/protein drink after, or a control group (n = 9), received placebo before and after exercise. Subjects performed 50 eccentric quadriceps contractions on an isokinetic dynamometer. Tests for creatine kinase (CK), maximal voluntary contraction (MVC) and muscle soreness were recorded before exercise and at six, 24, 48, 72, and 96 h post exercise. Repeated measures ANOVA were used to analyze data.</p> <p>Results</p> <p>There were no group by time interactions however, CK significantly increased for all groups when compared to pre exercise (101 ± 43 U/L) reaching a peak at 48 h (661 ± 1178 U/L). MVC was significantly reduced at 24 h by 31.4 ± 14.0%. Muscle soreness was also significantly increased from pre exercise peaking at 48 h.</p> <p>Conclusion</p> <p>Eccentric exercise caused significant muscle damage, loss of strength, and soreness; however timing of ingestion of carbohydrate/protein supplement had no effect.</p

Spatial and nonspatial implicit motor learning in Korsakoff’s amnesia: evidence for selective deficits

Patients with amnesia have deficits in declarative memory but intact memory for motor and perceptual skills, which suggests that explicit memory and implicit memory are distinct. However, the evidence that implicit motor learning is intact in amnesic patients is contradictory. This study investigated implicit sequence learning in amnesic patients with Korsakoff’s syndrome (N = 20) and matched controls (N = 14), using the classical Serial Reaction Time Task and a newly developed Pattern Learning Task in which the planning and execution of the responses are more spatially demanding. Results showed that implicit motor learning occurred in both groups of participants; however, on the Pattern Learning Task, the percentage of errors did not increase in the Korsakoff group in the random test phase, which is indicative of less implicit learning. Thus, our findings show that the performance of patients with Korsakoff’s syndrome is compromised on an implicit learning task with a strong spatial response component

Limitations of rupture forecasting exposed by instantaneously triggered earthquake doublet

Earthquake hazard assessments and rupture forecasts are based on the potential length of seismic rupture and whether or not slip is arrested at fault segment boundaries. Such forecasts do not generally consider that one earthquake can trigger a second large event, near-instantaneously, at distances greater than a few kilometers. Here we present a geodetic and seismological analysis of a magnitude 7.1 intra-continental earthquake that occurred in Pakistan in 1997. We find that the earthquake, rather than a single event as hitherto assumed, was in fact an earthquake doublet: initial rupture on a shallow, blind 2 reverse fault was followed just 19 seconds later by a second rupture on a separate reverse fault 50 km away. Slip on the second fault increased the total seismic moment by half, and doubled both the combined event duration and the area of maximum ground shaking. We infer that static Coulomb stresses at the initiation location of the second earthquake were probably reduced as a result of the first. Instead, we suggest that a dynamic triggering mechanism is likely, although the responsible seismic wave phase is unclear. Our results expose a flaw in earthquake rupture forecasts that disregard cascading, multiple-fault ruptures of this type

Tumour necrosis factor and PI3-kinase control oestrogen receptor alpha protein level and its transrepression function

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2410160

Combined artificial bee colony algorithm and machine learning techniques for prediction of online consumer repurchase intention

A novel paradigm in the service sector i.e. services through the web is a progressive mechanism for rendering offerings over diverse environments. Internet provides huge opportunities for companies to provide personalized online services to their customers. But prompt novel web services introduction may unfavorably affect the quality and user gratification. Subsequently, prediction of the consumer intention is of supreme importance in selecting the web services for an application. The aim of study is to predict online consumer repurchase intention and to achieve this objective a hybrid approach which a combination of machine learning techniques and Artificial Bee Colony (ABC) algorithm has been used. The study is divided into three phases. Initially, shopping mall and consumer characteristic’s for repurchase intention has been identified through extensive literature review. Secondly, ABC has been used to determine the feature selection of consumers’ characteristics and shopping malls’ attributes (with > 0.1 threshold value) for the prediction model. Finally, validation using K-fold cross has been employed to measure the best classification model robustness. The classification models viz., Decision Trees (C5.0), AdaBoost, Random Forest (RF), Support Vector Machine (SVM) and Neural Network (NN), are utilized for prediction of consumer purchase intention. Performance evaluation of identified models on training-testing partitions (70-30%) of the data set, shows that AdaBoost method outperforms other classification models with sensitivity and accuracy of 0.95 and 97.58% respectively, on testing data set. This study is a revolutionary attempt that considers both, shopping mall and consumer characteristics in examine the consumer purchase intention.N/

Mechanics of the IL2RA Gene Activation Revealed by Modeling and Atomic Force Microscopy

Transcription implies recruitment of RNA polymerase II and transcription factors (TFs) by DNA melting near transcription start site (TSS). Combining atomic force microscopy and computer modeling, we investigate the structural and dynamical properties of the IL2RA promoter and identify an intrinsically negative supercoil in the PRRII region (containing Elf-1 and HMGA1 binding sites), located upstream of a curved DNA region encompassing TSS. Conformational changes, evidenced by time-lapse studies, result in the progressive positioning of curvature apex towards the TSS, likely facilitating local DNA melting. In vitro assays confirm specific binding of the General Transcription Factors (GTFs) TBP and TFIIB over TATA-TSS position, where an inhibitory nucleosome prevented preinitiation complex (PIC) formation and uncontrolled DNA melting. These findings represent a substantial advance showing, first, that the structural properties of the IL2RA promoter are encoded in the DNA sequence and second, that during the initiation process DNA conformation is dynamic and not static

Temporal context and conditional associative learning

<p>Abstract</p> <p>Background</p> <p>We investigated how temporal context affects the learning of arbitrary visuo-motor associations. Human observers viewed highly distinguishable, fractal objects and learned to choose for each object the one motor response (of four) that was rewarded. Some objects were consistently preceded by specific other objects, while other objects lacked this task-irrelevant but predictive context.</p> <p>Results</p> <p>The results of five experiments showed that predictive context consistently and significantly accelerated associative learning. A simple model of reinforcement learning, in which three successive objects informed response selection, reproduced our behavioral results.</p> <p>Conclusions</p> <p>Our results imply that not just the representation of a current event, but also the representations of past events, are reinforced during conditional associative learning. In addition, these findings are broadly consistent with the prediction of attractor network models of associative learning and their prophecy of a persistent representation of past objects.</p

Dynamic Regulation of H3K27 Trimethylation during Arabidopsis Differentiation

During growth of multicellular organisms, identities of stem cells and differentiated cells need to be maintained. Cell fate is epigenetically controlled by the conserved Polycomb-group (Pc-G) proteins that repress their target genes by catalyzing histone H3 lysine 27 trimethylation (H3K27me3). Although H3K27me3 is associated with mitotically stable gene repression, a large fraction of H3K27me3 target genes are tissue-specifically activated during differentiation processes. However, in plants it is currently unclear whether H3K27me3 is already present in undifferentiated cells and dynamically regulated to permit tissue-specific gene repression or activation. We used whole-genome tiling arrays to identify the H3K27me3 target genes in undifferentiated cells of the shoot apical meristem and in differentiated leaf cells. Hundreds of genes gain or lose H3K27me3 upon differentiation, demonstrating dynamic regulation of an epigenetic modification in plants. H3K27me3 is correlated with gene repression, and its release preferentially results in tissue-specific gene activation, both during differentiation and in Pc-G mutants. We further reveal meristem- and leaf-specific targeting of individual gene families including known but also likely novel regulators of differentiation and stem cell regulation. Interestingly, H3K27me3 directly represses only specific transcription factor families, but indirectly activates others through H3K27me3-mediated silencing of microRNA genes. Furthermore, H3K27me3 targeting of genes involved in biosynthesis, transport, perception, and signal transduction of the phytohormone auxin demonstrates control of an entire signaling pathway. Based on these and previous analyses, we propose that H3K27me3 is one of the major determinants of tissue-specific expression patterns in plants, which restricts expression of its direct targets and promotes gene expression indirectly by repressing miRNA genes