The pharmacophore concept is of central importance in computer-aided drug design (CADD) mainly because of its successful application in medicinal chemistry and, in particular, high-throughput virtual screening (HTVS). The simplicity of the pharmacophore definition enables the complexity of molecular interactions between ligand and receptor to be reduced to a handful set of features. With many p...

An important message taken from human genome sequencing projects is that the human population exhibits approximately 99.9% genetic similarity. Variations in the remaining parts of the genome determine our identity, trace our history and reveal our heritage. The precise delineation of phenotypically causal variants plays a key role in providing accurate personalized diagnosis, prognosis, and tre...

OBJECTIVES This study was designed to establish a patient-controlled, ambulatory norepinephrine treatment of refractory orthostatic hypotension due to primary autonomic failure. BACKGROUND Autonomic dysfunction leads to disabling postural hypotension. Particularly in primary autonomic dysfunction, repeated syncope and immobilization can be the result. Medical treatment of orthostatic hypotens...

Genome-wide association studies (GWAS) link common variants to a trait of interest. Decreasing sequencing costs enable large-scale efforts such as the UK Biobank genotype and phenotype ∼500,000 individuals for over 7,000 traits. However, due multiple testing corrections approximately 200 billion tests, many clinically statistically significant associations are unappreciated. By re-analyzing dat...

Despite decades of study, the atomic-scale mechanisms of fatigue crack growth remain elusive. Here we use the coupled atomistic–discrete dislocation method, a multiscale simulation method, to examine the influence of dislocation glide resistance on near-threshold fatigue crack growth in an aluminum alloy. The simulations indicate that the threshold increases with an increase in dislocation glid...

We describe a novel computational method for estimating the probability that a point mutation at each position in a genome will influence fitness. These fitness consequence (fitCons) scores serve as evolution-based measures of potential genomic function. Our approach is to cluster genomic positions into groups exhibiting distinct “fingerprints” based on high-throughput functional genomic data, ...

Abstract Funding Acknowledgements Type of funding sources: None. Background Previous studies have shown genetic testing in sudden unexpected death the young (SUDY) cases identify a pathogenic variant 13-27% cases. This diagnostic yield increased up to 39% when was combined with family evaluation. The 100,000 Genomes Project launched investigate role whole genome sequencing (WGS) as tool for can...

The importance of computational chemistry in modern scientific research is well established. Continuous improvement in software and algorithms for the modeling of chemical interactions has transformed molecular modeling into a powerful tool for many current day research projects. From a medical perspective, one of the ultimate goals in computer-aided drug design (CADD) is the accurate predictio...

introduction: with prevalence figures close to 0.2% at birth, hearing loss (hl) is the most frequent sensory impairment in childhood. in developed countries, genetic causes account for more than 60% of congenital hl, most often resulting in non-syndromic deafness, which is usually autosomal recessive. hereditary nonsyndromic hearing loss (nshl) in iran is highly heterogeneous, rendering molecul...

OBJECTIVE Levodopa is the gold standard in the pharmacological treatment of Parkinson's disease (PD) and its oral administration is associated with the development of disabling motor and non-motor complications in advanced disease. Levodopa is rapidly metabolized and has a short plasma half-life thus requiring frequent, repeated dosing. Impaired gastric emptying is common in PD, and likely cont...