AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Evaluation of stroke risk associated with the use of typical or atypical antipsychotics among patients with cardiovascular diseases

Background: Concerns regarding stroke safety associated with the use of atypical antipsychotics among dementia patients have been raised. Although observational studies have found conflicting associations of stroke risk with the use of typical or atypical antipsychotics among the elderly with or without dementia, patients with cardiovascular diseases (CVDs), a high-risk for the stroke population, have not been examined. Little evidence has been provided regarding comparison of the stroke risk between the two antipsychotic classes. This study aimed to evaluate the comparative stroke risk with atypical versus typical antipsychotic use among CVD patients. Materials and Methods: We conducted a population-based nested case-control study analyzing the Taiwan National Health Insurance Research Database from January 1, 1996 to December 31, 2007. A total of 7,460 CVD patients was followed-up, among which 580 hospitalized cases with stroke were identified and matched to 5,398 randomly selected controls. Conditional logistic regressions were employed to quantify the difference in stroke risk associated with atypical versus typical antipsychotics. Results: Any use and current use of atypical antipsychotics were associated with a 1.67-fold (95% confidence interval [CI], 1.21-2.30) and a 2.30-fold (95% CI, 1.56-3.40) increased risk of stroke relative to any typical antipsychotic use, respectively. The stroke risk associated with current use of atypical antipsychotics persisted even compared with current use of typical antipsychotics (adjusted odds ratio, 1.53; 95% CI, 1.02-2.33). Conclusions: Use of atypical antipsychotics is associated with an increased risk of stroke requiring hospitalization compared to typical antipsychotic use among CVD patients. Healthcare professionals should take this risk into account when choosing between typical and atypical antipsychotic treatments among CVD patients

KMUP-1 Attenuates Endothelin-1-Induced Cardiomyocyte Hypertrophy through Activation of Heme Oxygenase-1 and Suppression of the Akt/GSK-3β, Calcineurin/NFATc4 and RhoA/ROCK Pathways

The signaling cascades of the mitogen activated protein kinase (MAPK) family, calcineurin/NFATc4, and PI3K/Akt/GSK3, are believed to participate in endothelin-1 (ET-1)-induced cardiac hypertrophy. The aim of this study was to investigate whether KMUP-1, a synthetic xanthine-based derivative, prevents cardiomyocyte hypertrophy induced by ET-1 and to elucidate the underlying mechanisms. We found that in H9c2 cardiomyocytes, stimulation with ET-1 (100 nM) for 4 days induced cell hypertrophy and enhanced expressions of hypertrophic markers, including atrial natriuretic peptide and brain natriuretic peptide, which were all inhibited by KMUP-1 in a dose-dependent manner. In addition, KMUP-1 prevented ET-1-induced intracellular reactive oxygen species generation determined by the DCFH-DA assay in cardiomyocytes. KMUP-1 also attenuated phosphorylation of ERK1/2 and Akt/GSK-3β, and activation of calcineurin/NFATc4 and RhoA/ROCK pathways induced by ET-1. Furthermore, we found that the expression of heme oxygenase-1 (HO-1), a stress-response enzyme implicated in cardio-protection, was up-regulated by KMUP-1. Finally, KMUP-1 attenuated ET-1-stimulated activator protein-1 DNA binding activity. In conclusion, KMUP-1 attenuates cardiomyocyte hypertrophy induced by ET-1 through inhibiting ERK1/2, calcineurin/NFATc4 and RhoA/ROCK pathways, with associated cardioprotective effects via HO-1 activation. Therefore, KMUP-1 may have a role in pharmacological therapy of cardiac hypertrophy

An unusual case of diffuse ST elevation mimicking acute myocardial infarction: A challenge of emergent percutaneous coronary intervention?

Coronary artery disease combined sepsis associated myocardial ischemia resulting in diffuse ST elevation on electrocardiogram has rarely been reported. We reported a rare case of diffuse ST elevation precipitated by septic shock and preexisting severe atherosclerosis heart disease. In clinical scenario, it is imperative for physicians to be aware of non-ischemic ST elevation etiologies and avoid inappropriate activation of the percutaneous coronary intervention (PCI) protocol, while not missing ST elevation myocardial infarction

Differences in Physiological Signals Due to Age and Exercise Habits of Subjects during Cycling Exercise

Numerous studies indicated the physical benefits of regular exercise, but the neurophysiological mechanisms of regular exercise in elders were less investigated. We aimed to compare changes in brain activity during exercise in elderly people and in young adults with and without regular exercise habits. A total of 36 healthy young adults (M/F:18/18) and 35 healthy elderly adults (M/F:20/15) participated in this study. According to exercise habits, each age group were classified into regular and occasional exerciser groups. ECG, EEG, and EMG signals were recorded using V-AMP with a 1-kHz sampling rate. The participants were instructed to perform three 5-min bicycle rides with different exercise loads. The EEG spectral power of elders who exercised regularly revealed the strongest positive correlation with their exercise intensity by using Pearson correlation analysis. The results demonstrate that exercise-induced significant cortical activation in the elderly participants who exercised regularly, and most of the p-values are less than 0.001. No significant correlation was observed between spectral power and exercise intensity in the elders who exercised occasionally. The young participants who exercised regularly had greater cardiac and neurobiological efficiency. Our results may provide a new exercise therapy reference for adult groups with different exercise habits, especially for the elders