An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion.

Huntington's Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials.

Use of Intramolecular 1,5-Sulfur-Oxygen and 1,5-Sulfur-Halogen Interactions in the Design of -Methyl-5-aryl--(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine SMN2 Splicing Modulators.

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by low levels of functional survival motor neuron protein (SMN) resulting from a deletion or loss of function mutation of the survival motor neuron 1 () gene. Branaplam () elevates levels of full-length SMN protein in vivo by modulating the splicing of the related gene to enhance the exon-7 inclusion and increase levels of the SMN. The intramolecular hydrogen bond present in the 2-hydroxyphenyl pyridazine core of enforces a planar conformation of the biaryl system and is critical for the compound activity.

Erratum: Possible Role of Single Stranded DNA Binding Protein 3 on Skin Hydration by Regulating Epidermal Differentiation.

[This corrects the article on p. 432 in vol. 30, PMID: 30065583.

Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA).

Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein.

Possible Role of Single Stranded DNA Binding Protein 3 on Skin Hydration by Regulating Epidermal Differentiation.

Background: Skin hydration is a common problem both in elderly and young people as dry skin may cause irritation, dermatological disorders, and wrinkles. While both genetic and environmental factors seem to influence skin hydration, thorough genetic studies on skin hydration have not yet been conducted.

Objective: We used a genome-wide association study (GWAS) to explore the genetic elements underlying skin hydration by regulating epidermal differentiation and skin barrier function.

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals.

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues.

Identification of a possible susceptibility locus for UVB-induced skin tanning phenotype in Korean females using genomewide association study.

A two-stage genomewide association (GWA) analysis was conducted to investigate the genetic factors influencing ultraviolet (UV)-induced skin pigmentation in Korean females after UV exposure. Previously, a GWA study evaluating ~500 000 single nucleotide polymorphisms (SNPs) in 99 Korean females identified eight SNPs that were highly associated with tanning ability. To confirm these associations, we genotyped the SNPs in an independent replication study (112 Korean females).

Whole genome sequencing of an ethnic Pathan (Pakhtun) from the north-west of Pakistan.

Background: Pakistan covers a key geographic area in human history, being both part of the Indus River region that acted as one of the cradles of civilization and as a link between Western Eurasia and Eastern Asia. This region is inhabited by a number of distinct ethnic groups, the largest being the Punjabi, Pathan (Pakhtuns), Sindhi, and Baloch.

Results: We analyzed the first ethnic male Pathan genome by sequencing it to 29.

Variation block-based genomics method for crop plants.

Background: In contrast with wild species, cultivated crop genomes consist of reshuffled recombination blocks, which occurred by crossing and selection processes. Accordingly, recombination block-based genomics analysis can be an effective approach for the screening of target loci for agricultural traits.

Results: We propose the variation block method, which is a three-step process for recombination block detection and comparison.

Minke whale genome and aquatic adaptation in cetaceans.

The shift from terrestrial to aquatic life by whales was a substantial evolutionary event. Here we report the whole-genome sequencing and de novo assembly of the minke whale genome, as well as the whole-genome sequences of three minke whales, a fin whale, a bottlenose dolphin and a finless porpoise. Our comparative genomic analysis identified an expansion in the whale lineage of gene families associated with stress-responsive proteins and anaerobic metabolism, whereas gene families related to body hair and sensory receptors were contracted.

The tiger genome and comparative analysis with lion and snow leopard genomes.

Tigers and their close relatives (Panthera) are some of the world's most endangered species. Here we report the de novo assembly of an Amur tiger whole-genome sequence as well as the genomic sequences of a white Bengal tiger, African lion, white African lion and snow leopard. Through comparative genetic analyses of these genomes, we find genetic signatures that may reflect molecular adaptations consistent with the big cats' hypercarnivorous diet and muscle strength.

A genome-wide association study of a coronary artery disease risk variant.

Although over 30 common genetic susceptibility loci have been identified to be independently associated with coronary artery disease (CAD) risk through genome-wide association studies (GWAS), genetic risk variants reported to date explain only a small fraction of heritability. To identify novel susceptibility variants for CAD and confirm those previously identified in European population, GWAS and a replication study were performed in the Koreans and Japanese. In the discovery stage, we genotyped 2123 cases and 3591 controls with 521 786 SNPs using the Affymetrix SNP Array 6.

KAREBrowser: SNP database of Korea Association REsource Project.

The International HapMap Project and the Human Genome Diversity Project (HGDP) provide plentiful resources on human genome information to the public. However, this kind of information is limited because of the small sample size in both databases. A Genome-Wide Association Study has been conducted with 8,842 Korean subjects as a part of the Korea Association Resource (KARE) project.

BioSMACK: a linux live CD for genome-wide association analyses.

Recent advances in high-throughput genotyping technologies have enabled us to conduct a genome-wide association study (GWAS) on a large cohort. However, analyzing millions of single nucleotide polymorphisms (SNPs) is still a difficult task for researchers conducting a GWAS. Several difficulties such as compatibilities and dependencies are often encountered by researchers using analytical tools, during the installation of software.

Clinical validation of colorectal cancer biomarkers identified from bioinformatics analysis of public expression data.

Purpose: Identification of novel biomarkers of cancer is important for improved diagnosis, prognosis, and therapeutic intervention. This study aimed to identify marker genes of colorectal cancer (CRC) by combining bioinformatics analysis of gene expression data and validation experiments using patient samples and to examine the potential connection between validated markers and the established oncogenes such as c-Myc and K-ras.

Experimental Design: Publicly available data from GenBank and Oncomine were meta-analyzed leading to 34 candidate marker genes of CRC.

Genotyping of apolipoprotein E: comparative evaluation of different protocols.

Disease-associated gene polymorphisms provide both scientific insight into pathophysiological mechanisms and clinical information regarding risk and progression. Of special interest is the epsilon4 allele of the apolipoprotein E gene, which has emerged as a substantial risk factor for late-onset forms of Alzheimer disease and also influences the risk of cardiovascular disease. Genotyping of apolipoprotein E can be performed by several methods; presented here are a quality and cost-benefit analysis of four different protocols on a cohort of 42 clinical samples is included in the unit.

Clinical validity of the lung cancer biomarkers identified by bioinformatics analysis of public expression data.

Identification of molecular markers often leads to important clinical applications such as early diagnosis, prognosis, and drug targeting. Lung cancer, the leading cause of cancer-related deaths, still lacks reliable molecular markers. We have combined the bioinformatics analysis of the public gene expression data and clinical validation to identify biomarker genes for non-small-cell lung cancer.

Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors.

Sphingosine-1-phosphate (S1P) receptors are widely expressed in the central nervous system where they are thought to regulate glia cell function. The phosphorylated version of fingolimod/FTY720 (FTY720P) is active on a broad spectrum of S1P receptors and the parent compound is currently in phase III clinical trials for the treatment of multiple sclerosis. Here, we aimed to identify which cell type(s) and S1P receptor(s) of the central nervous system are targeted by FTY720P.

ECgene: an alternative splicing database update.

ECgene (http://genome.ewha.ac.