Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects

The human sodium channel family includes seven neuronal channels that are essential for the initiation and propagation of action potentials in the CNS and PNS. In view of their critical role in neuronal firing and their strong sequence conservation during evolution, it is not surprising that mutations in the sodium channel genes are responsible for a growing spectrum of channelopathies. Nearly 700 mutations of the SCN1A gene have been identified in patients with Dravet's syndrome (severe myoclonic epilepsy of infancy), making this the most commonly mutated gene in human epilepsy. A small number of mutations have been found in SCN2A , SCN3A and SCN9A , and studies in the mouse suggest that SCN8A may also contribute to seizure disorders. Interactions between genetic variants of SCN2A and KCNQ2 in the mouse and variants of SCN1A and SCN9A in patients provide models of potential genetic modifier effects in the more common human polygenic epilepsies. New methods for generating induced pluripotent stem cells and neurons from patients will facilitate functional analysis of amino acid substitutions in channel proteins. Whole genome sequencing and exome sequencing in patients with epilepsy will soon make it possible to detect multiple variants and their interactions in the genomes of patients with seizure disorders.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79388/1/jphysiol.2010.188482.pd

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

Differential Regulation of Adiponectin Receptor Gene Expression by Adiponectin and Leptin in Myotubes Derived from Obese and Diabetic Individuals

Objective: This study aimed to investigate the regulation of adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2) gene expression in primary skeletal muscle myotubes, derived from human donors, after exposure to globular adiponectin (gAd) and leptin. Research Methods and Procedures: Four distinct primary cell culture groups were established [ Lean, Obese, Diabetic, Weight Loss (Wt Loss); n = 7 in each] from rectus abdominus muscle biopsies obtained from surgical patients. Differentiated myotube cultures were exposed to gAd (0.1 g/mL) or leptin (2.5 g/mL) for 6 hours. AdipoR1 and AdipoR2 gene expression was measured by real-time polymerase chain reaction analysis. Results: AdipoR1 mRNA expression in skeletal muscle myotubes derived from Lean subjects (p < 0.05) was stimulated 1.8-fold and 2.5-fold with gAd and leptin, respectively. No increase in AdipoR1 gene expression was measured in myotubes derived from Obese, Diabetic, or Wt Loss subjects. AdipoR2 mRNA expression was unaltered after gAd and leptin exposure in all myotube groups. Discussion: Adiponectin and leptin are rapid and potent stimulators of AdipoR1 in myotubes derived from lean healthy individuals. This effect was abolished in myotubes derived from obese, obese diabetic subjects, and obese-prone individuals who had lost significant weight after bariatric surgery. The incapacity of skeletal muscle of obese and diabetic individuals to respond to exogenous adiponectin and leptin may be further suppressed as a result of impaired regulation of the AdipoR1 gene

Seagrass Abundance Predicts Surficial Soil Organic Carbon Stocks Across the Range of Thalassia testudinum in the Western North Atlantic

The organic carbon (Corg) stored in seagrass meadows is globally significant and could be relevant in strategies to mitigate increasing CO2 concentration in the atmosphere. Most of that stored Corg is in the soils that underlie the seagrasses. We explored how seagrass and soil characteristics vary among seagrass meadows across the geographic range of turtlegrass (Thalassia testudinum) with a goal of illuminating the processes controlling soil organic carbon (Corg) storage spanning 23° of latitude. Seagrass abundance (percent cover, biomass, and canopy height) varied by over an order of magnitude across sites, and we found high variability in soil characteristics, with Corg ranging from 0.08 to 12.59% dry weight. Seagrass abundance was a good predictor of the Corg stocks in surficial soils, and the relative importance of seagrass-derived soil Corg increased as abundance increased. These relationships suggest that first-order estimates of surficial soil Corg stocks can be made by measuring seagrass abundance and applying a linear transfer function. The relative availability of the nutrients N and P to support plant growth was also correlated with soil Corg stocks. Stocks were lower at N-limited sites than at P-limited ones, but the importance of seagrass-derived organic matter to soil Corg stocks was not a function of nutrient limitation status. This finding seemed at odds with our observation that labile standard substrates decomposed more slowly at N-limited than at P-limited sites, since even though decomposition rates were 55% lower at N-limited sites, less Corg was accumulating in the soils. The dependence of Corg stocks and decomposition rates on nutrient availability suggests that eutrophication is likely to exert a strong influence on carbon storage in seagrass meadows