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

Functional and regional selectivity of the cardiac preganglionic sympathetic neurones

Upregulation of sympathetic activity is known to be a significant factor in the development of life threatening arrhythmias that can lead to sudden cardiac death. Sympathetic pathways therefore pose as a target for treatment, however a better understanding of the anatomy and physiology of cardiac sympathetic nerves is necessary. Right and left spinal sympathetic neurones differentially innervate specific regions of the heart but whether they exhibit functional selectivity and distinct effects on cardiac electrophysiology has yet to be demonstrated. A novel refinement of the original isolated innervated rabbit heart preparation, that allows controlled segmental stimulation, was used to study the effects of left and right-sided sympathetic chain stimulation on effective refractory period, action potential duration restitution and ventricular fibrillation threshold. A right-left difference in the functional effects was observed, with the left sympathetics displaying a preferential effect on ventricular electrophysiology with shorter effective refractory periods, steeper restitution slopes and smaller ventricular fibrillation thresholds than the right. The results also reveal previously unidentified characteristics of the lower thoracic spinal outflow on the left side having a dominant effect on cardiac electrophysiology and high potential to cause ventricular arrhythmias. Optical mapping was used to investigate the heterogeneous regional selectivity of the left and right sympathetics. The base of the ventricle elicited the shortest action potential durations and steepest restitution curves with sympathetic stimulation, which was reversed by removal of the left sympathetics. This knowledge improves our understanding of sympathetic nerve control and highlights the potential for more focused clinical treatments for a variety of chronic cardiac arrhythmias, by selectively removing caudal sympathetic outflows on the left side. Our findings also suggest that the left sympathetics primarily innervate at the base of the ventricle and for the first time reveal the mechanisms that give rise to the antiarrhythmic results of left cardiac sympathetic denervation

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms

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New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele