Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases

Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62x10(-)(9)-1.01x10(-)(1)(2)). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06-1.55, p = 8.9x10(-)(3)). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4x10(-)(8)(8)]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.

GWAS of butyrylcholinesterase activity identifies four novel loci, independent effects within BCHE and secondary associations with metabolic risk factors

Serum butyrylcholinesterase (BCHE) activity is associated with obesity, blood pressure and biomarkers of cardiovascular and diabetes risk. We have conducted a genome-wide association scan to discover genetic variants affecting BCHE activity, and to clarify whether the associations between BCHE activity and cardiometabolic risk factors are caused by variation in BCHE or whether BCHE variation is secondary to the metabolic abnormalities. We measured serum BCHE in adolescents and adults from three cohorts of Australian twin and family studies. The genotypes from approximately 2.4 million single-nucleotide polymorphisms (SNPs) were available in 8791 participants with BCHE measurements. We detected significant associations with BCHE activity at three independent groups of SNPs at the BCHE locus (P = 5.8 x 10(-262), 7.8 x 10(-47), 2.9 x 10(-12)) and at four other loci: RNPEP (P = 9.4 x 10(-16)), RAPH1-ABI2 (P = 4.1 x 10(-18)), UGT1A1 (P = 4.0 x 10(-8)) and an intergenic region on chromosome 8 (P = 1.4 x 10(-8)). These loci affecting BCHE activity were not associated with metabolic risk factors. On the other hand, SNPs in genes previously associated with metabolic risk had effects on BCHE activity more often than can be explained by chance. In particular, SNPs within FTO and GCKR were associated with BCHE activity, but their effects were partly mediated by body mass index and triglycerides, respectively. We conclude that variation in BCHE activity is due to multiple variants across the spectrum from uncommon/large effect to common/small effect, and partly results from (rather than causes) metabolic abnormalities.

Strong evidence for a novel schizophrenia risk locus on chromosome 1p31.1 in homogeneous pedigrees from Tamil Nadu, India

OBJECTIVE: The study of ethnically homogeneous populations may help to identify schizophrenia risk loci. The authors conducted a genomewide linkage scan for schizophrenia in an Indian population. METHOD: Participants were 441 individuals (262 affected probands and siblings) who were recruited primarily from one ethnically homogeneous group, the Tamil Brahmin caste, although individuals from other geographically proximal castes also participated. Genotyping of 124 affected sibling pair pedigrees was performed with 402 short tandem repeat polymorphisms. Linkage analyses were conducted using nonparametric exponential LOD (logarithm of the odds ratio for linkage) scores and parametric heterogeneity LOD scores. Parametric heterogeneity scores were calculated using simple dominant and recessive models, correcting for multiple statistics. The data were examined for evidence of consanguinity. Genomewide significance levels were determined using 10,000 gene dropping simulations. RESULTS: These findings revealed genomewide significant linkage to chromosome 1p31.1, through the use of both exponential and heterogeneity LOD scores, incorporating correction for multiple statistics and mild consanguinity. The estimated sibling recurrence risk associated with this putative locus was 1.95. Analysis for heterogeneity LOD scores also detected suggestive linkage to chromosomes 13q22.1 and 16q12.2. Using 117 tag single nucleotide polymorphisms (SNPs), family-based association analyses of phosphodiesterase 4B (PDE4B), the closest schizophrenia candidate gene, detected no convincing evidence of association, suggesting that the chromosome 1 peak represents a novel risk locus. CONCLUSIONS: This is the first study-to the authors' knowledge-to report significant linkage of schizophrenia to chromosome 1p31.1. Further investigation of this chromosome region in diverse populations is warranted to identify underlying sequence variants.

Research update: LANDMark study: Longitudinal assessment of neuropathy in diabetes using novel ophthalmic MARKers

The eye is a simple, non-invasive location for screening, diagnosing and follow up of diabetic peripheral neuropathy.

A novel approach to assessing road-curve crash severity

Curves are a common feature of road infrastructure; however crashes on road curves are associated with increased risk of injury and fatality to vehicle occupants. Countermeasures require the identification of contributing factors. However, current approaches to identifying contributors use traditional statistical methods and have not used self-reported narrative claim to identify factors related to the driver, vehicle and environment in a systemic way. Text mining of 3434 road-curve crash claim records filed between 1 January 2003 and 31 December 2005 at a major insurer in Queensland, Australia, was undertaken to identify risk levels and contributing factors. Rough set analysis was used on insurance claim narratives to identify significant contributing factors to crashes and their associated severity. New contributing factors unique to curve crashes were identified (e.g., tree, phone, over-steer) in addition to those previously identified via traditional statistical analysis of Police and licensing authority records. Text mining is a novel methodology to improve knowledge related to risk and contributing factors to road-curve crash severity. Future road-curve crash countermeasures should more fully consider the interrelationships between environment, the road, the driver and the vehicle, and education campaigns in particular could highlight the increased risk of crash on road-curves.

Novel fluorinated surfactants tentatively identified in firefighters using liquid chromatography quadrupole time-of flight tandem mass spectrometry and a case-control approach

Fluorinated surfactant-based aqueous film-forming foams (AFFFs) are made up of per- and polyfluorinated alkyl substances (PFAS) and are used to extinguish fires involving highly flammable liquids. The use of perfluorooctanesulfonic acid (PFOS) and other perfluoroalkyl acids (PFAAs) in some AFFF formulations has been linked to substantial environmental contamination. Recent studies have identified a large number of novel and infrequently reported fluorinated surfactants in different AFFF formulations. In this study, a strategy based on a case-control approach using quadrupole time-of-flight tandem mass spectrometry (QTOF-MS/MS) and advanced statistical methods has been used to extract and identify known and unknown PFAS in human serum associated with AFFF-exposed firefighters. Two target sulfonic acids [PFOS and perfluorohexanesulfonic acid (PFHxS)], three non-target acids [perfluoropentanesulfonic acid (PFPeS), perfluoroheptanesulfonic acid (PFHpS), and perfluorononanesulfonic acid (PFNS)], and four unknown sulfonic acids (Cl-PFOS, ketone-PFOS, ether-PFHxS, and Cl-PFHxS) were exclusively or significantly more frequently detected at higher levels in firefighters compared to controls. The application of this strategy has allowed for identification of previously unreported fluorinated chemicals in a timely and cost-efficient way.

Novel modulation strategy for a CLC resonant dual active bridge

This paper proposes a novel modulation strategy for a phase controlled Capacitor-Inductor-Capacitor (CLC) Resonant Dual Active Bridge (RDAB). The proposed modulation strategy improves the soft turn-on, Zero-Current-Switching (ZCS) and Zero-Voltage-Switching (ZVS) range of the converter while only minimally increasing the required reactive currents in the ac link. A mathematical analysis of the proposed modulation scheme is presented along with a theoretical loss comparison between several modulation strategies. The proposed modulation strategy was implemented and the experimental results are presented.

A novel concept for airport terminal design integrating flexibility

The current research proposed a conceptual design framework for airports to obtain flexible departure layouts based on passenger activity analysis obtained from Business Process Models (BPM). BPMs available for airport terminals were used as a design tool in the current research to uncover the relationships existing between spatial layout and corresponding passenger activities. An algorithm has been developed that demonstrates the applicability of the proposed design framework by obtaining relative spatial layouts based on passenger activity analysis. The generated relative spatial layout assists architects in achieving suitable alternative layouts to meet the changing needs of an airport terminal.

FreeS: A fast algorithm to discover frequent free subtrees using a novel canonical form

Web data can often be represented in free tree form; however, free tree mining methods seldom exist. In this paper, a computationally fast algorithm FreeS is presented to discover all frequently occurring free subtrees in a database of labelled free trees. FreeS is designed using an optimal canonical form, BOCF that can uniquely represent free trees even during the presence of isomorphism. To avoid enumeration of false positive candidates, it utilises the enumeration approach based on a tree-structure guided scheme. This paper presents lemmas that introduce conditions to conform the generation of free tree candidates during enumeration. Empirical study using both real and synthetic datasets shows that FreeS is scalable and significantly outperforms (i.e. few orders of magnitude faster than) the state-of-the-art frequent free tree mining algorithms, HybridTreeMiner and FreeTreeMiner.

Antimicrobial efficacy of a novel silver hydrogel dressing compared to two common silver burn wound dressings: Acticoat™ and PolyMem Silver

A novel burn wound hydrogel dressing has been previously developed which is composed of 2-acrylamido-2-methylpropane sulfonic acid sodium salt with silver nanoparticles. This study compared the antimicrobial efficacy of this novel dressing to two commercially available silver dressings; Acticoat™ and PolyMem Silver(®). Three different antimicrobial tests were used: disc diffusion, broth culture, and the Live/Dead(®) Baclight™ bacterial viability assay. Burn wound pathogens (P. aeruginosa, MSSA, A. baumannii and C. albicans) and antibiotic resistant strains (MRSA and VRE) were tested. All three antimicrobial tests indicated that Acticoat™ was the most effective antimicrobial agent, with inhibition zone lengths of 13.9-18.4mm. It reduced the microbial inocula below the limit of detection (10(2)CFU/ml) and reduced viability by 99% within 4h. PolyMem Silver(®) had no zone of inhibition for most tested micro-organisms, and it also showed poor antimicrobial activity in the broth culture and Live/Dead(®) Baclight™ assays. Alarmingly, it appeared to promote the growth of VRE. The silver hydrogel reduced most of the tested microbial inocula below the detection limit and decreased bacterial viability by 94-99% after 24h exposure. These results support the possibility of using this novel silver hydrogel as a burn wound dressing in the future

3D QSAR studies of N-4-arylacryloylpiperazin-1-yl-phenyl-oxazolidinones: A novel class of antibacterial agents

Three-dimensional QSAR studies for N-4-arylacryloylpiperazin-1-yl-phenyl-oxazolidinones were conducted using TSAR 3.3. The in vitro activities (MICs) of the compounds against Staphylococcus aureus ATCC 25923 exhibited a strong correlation with the prediction made by the model developed in the present study.

Design and synthesis of novel 3-hydroxy-cyclobut-3-ene-1,2-dione derivatives as thyroid hormone receptor β (TR-β) selective ligands

Design and synthesis of a novel 3-hydroxy-cyclobut-3-ene-1,2-dione derivatives are reported and their in vitro thyroid hormone receptor selectivity has been evaluated in the thyroid luciferase receptor assay. The 3-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)-phenylamino]-4-hydroxy-cyclobut-3-ene-1,2-dione 21 has shown selectivity towards thyroid hormone receptor β.

Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies

MicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNAs' Target Sites (poly-miRTS)-centric multistage meta-analysis for lumbar spine (LS)-, total hip (HIP)-, and femoral neck (FN)-bone mineral density (BMD). In stage I, 41,102 poly-miRTSs were meta-analyzed in 7 cohorts with a genome-wide significance (GWS) α=0.05/41,102=1.22×10-6. By applying α=5×10-5 (suggestive significance), 11 poly-miRTSs were selected, with FGFRL1 rs4647940 and PRR5 rs3213550 as top signals for FN-BMD (P-value=7.67×10-6 and 1.58×10-5) in gender-combined sample. In stage II in silico replication (two cohorts), FGFRL1 rs4647940 was the only signal marginally replicated for FN-BMD (P-value=5.08×10-3) at α=0.10/11=9.09×10-3. PRR5 rs3213550 was also selected based on biological significance. In stage III de novo genotyping replication (two cohorts), FGFRL1 rs4647940 was the only signal significantly replicated for FN-BMD (P-value=7.55×10-6) at α=0.05/2=0.025 in gender-combined sample. Aggregating three stages, FGFRL1 rs4647940 was the single stage I-discovered and stages II- and III-replicated signal attaining GWS for FN-BMD (P-value=8.87×10-12). Dual-luciferase reporter assays demonstrated that FGFRL1 3' untranslated region harboring rs4647940 appears to be hsa-miR-140-5p's target site. In a zebrafish microinjection experiment, dre-miR-140-5p is shown to exert a dramatic impact on craniofacial skeleton formation. Taken together, we provided functional evidence for a novel FGFRL1 poly-miRTS rs4647940 in a previously known 4p16.3 locus, and experimental and clinical genetics studies have shown both FGFRL1 and hsa-miR-140-5p are important for bone formation. © The Author 2015. Published by Oxford University Press. All rights reserved.

Novel TBK1 truncating mutation in a familial amyotrophic lateral sclerosis patient of Chinese origin

Missense and frameshift mutations in TRAF family member-associated NF-kappa-B activator (TANK)-binding kinase 1 (TBK1) have been reported in European sporadic and familial amyotrophic lateral sclerosis (ALS) cohorts. To assess the role of TBK1 in ALS patient cohorts of wider ancestry, we have analyzed whole-exome sequence data from an Australian cohort of familial ALS (FALS) patients and controls. We identified a novel TBK1 deletion (c.1197delC) in a FALS patient of Chinese origin. This frameshift mutation (p.L399fs) likely results in a truncated protein that lacks functional domains required for adapter protein binding, as well as protein activation and structural integrity. No novel or reported TBK1 mutations were identified in FALS patients of European ancestry. This is the first report of a TBK1 mutation in an ALS patient of Asian origin and indicates that sequence variations in TBK1 are a rare cause of FALS in Australia. © 2015 Elsevier Inc.

Whole-exome re-sequencing in a family quartet identifies POP1 mutations as the cause of a novel skeletal dysplasia

Recent advances in DNA sequencing have enabled mapping of genes for monogenic traits in families with small pedigrees and even in unrelated cases. We report the identification of disease-causing mutations in a rare, severe, skeletal dysplasia, studying a family of two healthy unrelated parents and two affected children using whole-exome sequencing. The two affected daughters have clinical and radiographic features suggestive of anauxetic dysplasia (OMIM 607095), a rare form of dwarfism caused by mutations of RMRP. However, mutations of RMRP were excluded in this family by direct sequencing. Our studies identified two novel compound heterozygous loss-of-function mutations in POP1, which encodes a core component of the RNase mitochondrial RNA processing (RNase MRP) complex that directly interacts with the RMRP RNA domains that are affected in anauxetic dysplasia. We demonstrate that these mutations impair the integrity and activity of this complex and that they impair cell proliferation, providing likely molecular and cellular mechanisms by which POP1 mutations cause this severe skeletal dysplasia. © 2011 Glazov et al.