J-wave syndromes: Brugada and early repolarization syndromes.

A prominent J wave is encountered in a number of life-threatening cardiac arrhythmia syndromes, including the Brugada syndrome and early repolarization syndromes. Brugada syndrome and early repolarization syndromes differ with respect to the magnitude and lead location of abnormal J waves and are thought to represent a continuous spectrum of phenotypic expression termed J-wave syndromes. Despite two decades of intensive research, risk stratification and the approach to therapy of these 2 inherited cardiac arrhythmia syndromes are still undergoing rapid evolution. Our objective in this review is to provide an integrated synopsis of the clinical characteristics, risk stratifiers, and molecular, ionic, cellular, and genetic mechanisms underlying these 2 fascinating syndromes that have captured the interest and attention of the cardiology community in recent years

Dronedarone.

Amiodarone is the most effective antiarrhythmic drug for maintaining sinus rhythm for patients with atrial fibrillation. Extra-cardiac side effects have been a limiting factor, especially during chronic use, and may offset its benefits. Dronedarone is a noniodinated benzofuran derivative of amiodarone that has been developed for the treatment of atrial fibrillation and atrial flutter. Similar to amiodarone, dronedarone is a potent blocker of multiple ion currents, including the rapidly activating delayed-rectifier potassium current, the slowly activating delayed-rectifier potassium current, the inward rectifier potassium current, the acetylcholine activated potassium current, peak sodium current, and L-type calcium current, and exhibits antiadrenergic effects. It has been studied for maintenance of sinus rhythm and control of ventricular response during episodes of atrial fibrillation. Dronedarone reduces mortality and morbidity in patients with high-risk atrial fibrillation, but may be unsafe in those with severe heart failure. This article will review evidence of safety and effectiveness of dronedarone in patients with atrial fibrillation

Resistance-gene-directed discovery of a natural-product herbicide with a new mode of action.

Bioactive natural products have evolved to inhibit specific cellular targets and have served as lead molecules for health and agricultural applications for the past century1-3. The post-genomics era has brought a renaissance in the discovery of natural products using synthetic-biology tools4-6. However, compared to traditional bioactivity-guided approaches, genome mining of natural products with specific and potent biological activities remains challenging4. Here we present the discovery and validation of a potent herbicide that targets a critical metabolic enzyme that is required for plant survival. Our approach is based on the co-clustering of a self-resistance gene in the natural-product biosynthesis gene cluster7-9, which provides insight into the potential biological activity of the encoded compound. We targeted dihydroxy-acid dehydratase in the branched-chain amino acid biosynthetic pathway in plants; the last step in this pathway is often targeted for herbicide development10. We show that the fungal sesquiterpenoid aspterric acid, which was discovered using the method described above, is a sub-micromolar inhibitor of dihydroxy-acid dehydratase that is effective as a herbicide in spray applications. The self-resistance gene astD was validated to be insensitive to aspterric acid and was deployed as a transgene in the establishment of plants that are resistant to aspterric acid. This herbicide-resistance gene combination complements the urgent ongoing efforts to overcome weed resistance11. Our discovery demonstrates the potential of using a resistance-gene-directed approach in the discovery of bioactive natural products

Notching early repolarization pattern in inferior leads increases risk of ventricular tachyarrhythmias in patients with acute myocardial infarction: a meta-analysis.

The aim of this of this meta-analysis was to examine the potential association between certain early repolarization (ER) characteristics and ventricular tachyarrhythmias (VTAs) in patients with acute myocardial infarction (AMI). We searched PubMed, Embase and Web of Science databases for records published until December 2014. Of the 658 initially identified records, 7 studies with a total of 1,565 patients (299 with ER and 1,266 without ER) were finally analyzed. Overall, patients with ER displayed a higher risk of VTAs following AMI compared to patients without ER [odds ratio (OR): 3.75, 95% CI: 2.62-5.37, p \u3c 0.00001]. Subgroup analyses showed that the diagnosis of ER prior to AMI onset is a better predictor of VTAs (OR: 5.70, p \u3c 0.00001) compared to those diagnosed after AMI onset (OR: 2.60, p = 0.00001). Remarkably, a notching morphology was a significant predictor of VTAs compared to slurring morphology (OR: 3.85, p = 0.002). Finally, an inferior ER location (OR: 8.85, p \u3c 0.00001) was significantly associated with increased risk of VTAs in AMI patients. In conclusion, our meta-analysis suggests that ER pattern is associated with greater risk of VTAs in patients with AMI. A notched ER pattern located in inferior leads confers the highest risk for VTAs in AMI

Meta-analysis of T peak –T end and T peak –T end /QT ratio for risk stratification in congenital long QT syndrome

Background and objectives: Congenital long QT syndrome (LQTS) predisposes affected individuals to ventricular tachycardia/fibrillation (VF/VF), potentially resulting in sudden cardiac death. The Tpeak–Tend interval and the Tpeak–Tend/QT ratio, electrocardiographic markers of dispersion of ventricular repolarization, were proposed for risk stratification but their predictive values in LQTS have been controversial. A systematic review and meta-analysis was conducted to examine the value of Tpeak–Tend intervals and Tpeak–Tend/QT ratios in predicting arrhythmic and mortality outcomes in congenital LQTS. Method: PubMed and Embase databases were searched until 9th May 2017, identifying 199 studies. Results: Five studies on long QT syndrome were included in the final meta-analysis. Tpeak–Tend intervals were longer (mean difference [MD]: 13 ms, standard error [SE]: 4 ms, P = 0.002; I2 = 34%) in congenital LQTS patients with adverse events [syncope, ventricular arrhythmias or sudden cardiac death] compared to LQTS patients without such events. By contrast, Tpeak–Tend/QT ratios were not significantly different between the two groups (MD: 0.02, SE: 0.02, P = 0.26; I2 = 0%). Conclusion: This meta-analysis showed that Tpeak–Tend interval is significant higher in individuals who are at elevated risk of adverse events in congenital LQTS, offering incremental value for risk stratification

The Tpeak – Tend interval as an electrocardiographic risk marker of arrhythmic and mortality outcomes: a systematic review and meta-analysis

Background: The Tpeak – Tend interval, an electrocardiographic marker reflecting transmural dispersion of repolarization, has been used to predict ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death (SCD) in different clinical settings. Objective: This systematic review and meta-analysis evaluated the significance of Tpeak – Tend interval in predicting arrhythmic and/or mortality endpoints. Methods: PubMed, Embase, Cochrane Library and CINAHL Plus databases were searched through 30th November 2016.Results: Of the 854 studies identified initially, 33 observational studies involving 155856 patients were included in our meta-analysis. Tpeak – Tend interval prolongation (mean cut-off: 103.3 ± 17.4 ms) was a significant predictor of the arrhythmic or mortality outcomes (odds ratio (OR): 1.14, 95% CI: 1.11 to 1.17, p < 0.001). When different end-points were analyzed, the ORs are as follows: VT/VF (1.10, 95% CI: 1.06 to 1.13, p < 0.0001), SCD (1.27, 95% CI 1.17 to 1.39, p < 0.0001), cardiovascular death (1.40, 95% CI 1.19 to 1.64, p < 0.0001), and all-cause mortality (4.56, 95% CI 0.62 to 33.68, p < 0.0001). Subgroup analysis for each disease revealed that the risk of VT/VF or death was highest for Brugada syndrome (OR: 5.68, 95% CI: 1.57 to 20.53, p < 0.01), followed by hypertension (OR: 1.52, 95% CI: 1.26 to 1.85, p < .0001), heart failure (OR: 1.07, 95% CI: 1.04 to 1.11, p < .0001) and ischemic heart disease (OR: 1.06, 95% CI: 1.02 to 1.10, p = 0.001). In the general population, a prolonged Tpeak – Tend interval also predicted arrhythmic or mortality outcomes (OR: 1.59, 95% CI: 1.21 to 2.09, p < 0.001).Conclusion: The Tpeak – Tend interval is useful risk stratification tool in different diseases and in the general population

3D-VLA: A 3D Vision-Language-Action Generative World Model

Recent vision-language-action (VLA) models rely on 2D inputs, lacking integration with the broader realm of the 3D physical world. Furthermore, they perform action prediction by learning a direct mapping from perception to action, neglecting the vast dynamics of the world and the relations between actions and dynamics. In contrast, human beings are endowed with world models that depict imagination about future scenarios to plan actions accordingly. To this end, we propose 3D-VLA by introducing a new family of embodied foundation models that seamlessly link 3D perception, reasoning, and action through a generative world model. Specifically, 3D-VLA is built on top of a 3D-based large language model (LLM), and a set of interaction tokens is introduced to engage with the embodied environment. Furthermore, to inject generation abilities into the model, we train a series of embodied diffusion models and align them into the LLM for predicting the goal images and point clouds. To train our 3D-VLA, we curate a large-scale 3D embodied instruction dataset by extracting vast 3D-related information from existing robotics datasets. Our experiments on held-in datasets demonstrate that 3D-VLA significantly improves the reasoning, multimodal generation, and planning capabilities in embodied environments, showcasing its potential in real-world applications.Comment: Project page: https://vis-www.cs.umass.edu/3dvla

Interleukin-17 Inhibits Adult Hippocampal Neurogenesis

Interleukin 17(A) (IL-17) is a potent pro-inflammatory cytokine that acts as a central regulator of inflammatory response within the brain, but its physiological roles under non-inflammatory conditions remain elusive. Here we report that endogenous IL-17 ablates neurogenesis in the adult dentate gyrus (DG) of hippocampus. Genetic deletion of IL-17 increased the number of adult-born neurons in the DG. Further, we found that IL-17 deletion altered cytokine network, facilitated basal excitatory synaptic transmission, enhanced intrinsic neuronal excitability, and increased expression of proneuronal genes in neuronal progenitor cells (NPCs). Our findings suggest a profound role of IL-17 in the negative regulation of adult hippocampal neurogenesis under physiology conditions