In studies of expression quantitative trait loci (eQTLs), it is of increasing interest to identify eGenes, the genes whose expression levels are associated with variation at a particular genetic ...variant. Detecting eGenes is important for follow-up analyses and prioritization because genes are the main entities in biological processes. To detect eGenes, one typically focuses on the genetic variant with the minimum p value among all variants in cis with a gene and corrects for multiple testing to obtain a gene-level p value. For performing multiple-testing correction, a permutation test is widely used. Because of growing sample sizes of eQTL studies, however, the permutation test has become a computational bottleneck in eQTL studies. In this paper, we propose an efficient approach for correcting for multiple testing and assess eGene p values by utilizing a multivariate normal distribution. Our approach properly takes into account the linkage-disequilibrium structure among variants, and its time complexity is independent of sample size. By applying our small-sample correction techniques, our method achieves high accuracy in both small and large studies. We have shown that our method consistently produces extremely accurate p values (accuracy > 98%) for three human eQTL datasets with different sample sizes and SNP densities: the Genotype-Tissue Expression pilot dataset, the multi-region brain dataset, and the HapMap 3 dataset.
To describe in detail the retinal structure and function of a group of patients with cobalamin C (cblC) disease.
Patients (n = 11, age 4 months to 15 years) with cblC disease (9/11, early onset) ...diagnosed by newborn screening underwent complete ophthalmic examinations, fundus photography, near-infrared reflectance imaging, and spectral-domain optical coherence tomography (SD-OCT). Electroretinograms (ERGs) were performed in a subset of patients.
Patients carried homozygous or compound heterozygote mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Late-onset patients had a normal exam. All early-onset patients showed a maculopathy; older subjects had a retina-wide degeneration (n = 4; >7 years of age). In general, retinal changes were first observed before 1 year of age and progressed within months to a well-established maculopathy. Pseudocolobomas were documented in three patients. Measurable visual acuities ranged from 20/200 to 20/540. Nystagmus was present in 8/11 patients; 5/6 patients had normal ERGs; 1/6 had reduced rod-mediated responses. Spectral-domain OCT showed macular thinning, with severe ganglion cell layer (GCL) and outer nuclear layer (ONL) loss. Inner retinal thickening was observed in areas of total GCL/ONL loss. A normal lamination pattern in the peripapillary nasal retina was often seen despite severe central and/or retina-wide disease.
Patients with early-onset cblC and MMACHC mutations showed an early-onset, unusually fast-progressing maculopathy with severe central ONL and GCL loss. An abnormally thickened inner retina supports a remodeling response to both photoreceptor and ganglion cell degeneration and/or an interference with normal development in early-onset cblC.
α
-Helical transmembrane proteins are the most important drug targets in rational drug development. However, solving the experimental structures of these proteins remains difficult, therefore ...computational methods to accurately and efficiently predict the structures are in great demand. We present an improved structure prediction method TMDIM based on Park et al. (Proteins 57:577–585, 2004) for predicting bitopic transmembrane protein dimers. Three major algorithmic improvements are introduction of the packing type classification, the multiple-condition decoy filtering, and the cluster-based candidate selection. In a test of predicting nine known bitopic dimers, approximately 78% of our predictions achieved a successful fit (RMSD <2.0 Å) and 78% of the cases are better predicted than the two other methods compared. Our method provides an alternative for modeling TM bitopic dimers of unknown structures for further computational studies. TMDIM is freely available on the web at
https://cbbio.cis.umac.mo/TMDIM
. Website is implemented in PHP, MySQL and Apache, with all major browsers supported.
While the Cluster spacecraft were located near the high‐latitude magnetopause, between 1010 and 1040 UT on 16 January 2004, three typical flux transfer event (FTE) signatures were observed. During ...this interval, simultaneous and conjugated all‐sky camera measurements, recorded at Yellow River Station, Svalbard, are available at 630.0 and 557.7 nm that show poleward‐moving auroral forms (PMAFs), consistent with magnetic reconnection at the dayside magnetopause. Simultaneous FTEs seen at the magnetopause mainly move northward, but having duskward (eastward) and tailward velocity components, roughly consistent with the observed direction of motion of the PMAFs in all‐sky images. Between the PMAFs meridional keograms, extracted from the all‐sky images, show intervals of lower intensity aurora which migrate equatorward just before the PMAFs intensify. This is strong evidence for an equatorward eroding and poleward moving open‐closed boundary associated with a variable magnetopause reconnection rate under variable IMF conditions. From the durations of the PMAFs, we infer that the evolution time of FTEs is 5–11 minutes from its origin on the magnetopause to its addition to the polar cap.
The aim of the present study was to assess the efficacy and safety of teneligliptin in combination with metformin in Korean patients with type 2 diabetes mellitus who were inadequately controlled ...with metformin monotherapy. Patients glycated haemoglobin (HbA1c) 7.0–10.0%, on stable metformin ≥1000 mg/day were randomized 2 : 1 to receive 20 mg teneligliptin plus metformin (n = 136) or placebo plus metformin (n = 68). The primary endpoint was the change in HbA1c levels from baseline to week 16. The mean baseline HbA1c was 7.9% in the teneligliptin group and 7.8% in the placebo group. The differences between the teneligliptin and placebo groups regarding changes in HbA1c and fasting plasma glucose levels were −0.78 % and −1.24 mmol/l (22.42 mg/dl), respectively, at week 16. The incidence of adverse events was similar between the groups. The addition of teneligliptin once daily to metformin was effective and generally well tolerated in Korean patients with type 2 diabetes.
Three different ZnO nanomaterials (nanobelts, nanorods, and nanowires) were synthesized at three different substrate temperatures from the thermal evaporation of ball-milled ZnO powders at 1380°C. ...Transmission electron microscopy revealed that the ZnO nanobelts are single crystalline with the growth direction perpendicular to the
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lattice planes, and that the ZnO nanorods and nanowires are single crystalline with the growth directions perpendicular to the (0
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1) and
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lattice planes, respectively. In cathodoluminescence, the peak energy of near band-edge emission was determined for the nanobelts, nanorods, and nanowires.
The dynamic response of seismic isolated continuous girder bridges subjected to either near-fault or far-field ground motions is compared to the non-isolated ones. Near-fault earthquake ground motion ...data are collected from the 1999 Taiwan Chi-Chi earthquake. The earthquake data recorded at the same sites from other events serve as far-field ground motions. Typical three-span continuous concrete box girder bridges designed under Taiwan seismic design specifications of highway bridges are adopted for this study. These bridges are assumed straight, founded on rigid rock and only the longitudinal response is considered. Parametric studies for the dynamic responses of isolated bridges by input near-fault ground motions are developed. The PGV/PGA value of near-fault earthquake records is identified as the key parameter governing the bridge response.
To describe in detail the phenotype of a patient with Bietti crystalline dystrophy (BCD) complicated by choroidal neovascularization (CNV) and the response to intravitreal Bevacizumab (Avastin
; ...Genentech/Roche).
A 34-year-old woman with BCD and mutations in CYP4V2 (c.802-8_806del13/p.H331P:c992A>C) underwent a complete ophthalmic examination, full-field flash electroretinography (ERG), kinetic and two-color dark-adapted perimetry, and dark-adaptometry. Imaging was performed with spectral domain optical coherence tomography (SD-OCT), near infrared (NIR) and short wavelength (SW) fundus autofluorescence (FAF), and fluorescein angiography (FA).
Best-corrected visual acuity (BCVA) was 20/20 and 20/60 for the right and left eye, respectively. There were corneal paralimbal crystal-like deposits. Kinetic fields were normal in the peripheral extent. Retinal crystals were most obvious on NIR-reflectance and corresponded with hyperreflectivities within the RPE on SD-OCT. There was parafoveal/perifoveal hypofluorescence on SW-FAF and NIR-FAF. Rod > cone sensitivity loss surrounded fixation and extended to ~10° of eccentricity corresponding to regions of photoreceptor outer segment-retinal pigmented epithelium (RPE) interdigitation abnormalities. The outer nuclear layer was normal in thickness. Recovery of sensitivity following a ~76% rhodopsin bleach was normal. ERGs were normal. A subretinal hemorrhage in the left eye co-localized with elevation of the RPE on SD-OCT and leakage on FA, suggestive of CNV. Three monthly intravitreal injections of Bevacizumab led to restoration of BCVA to baseline (20/25).
crystals in BCD were predominantly located within the RPE. Photoreceptor outer segment and apical RPE abnormalities underlie the relatively extensive retinal dysfunction observed in relatively early-stage BCD. Intravitreal Bevacizumab was effective in treating CNV in this setting.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Recently, investigators have proposed state-of-the-art Identity-by-descent (IBD) mapping methods to detect IBD segments between purportedly unrelated individuals. The IBD information can then be used ...for association testing in genetic association studies. One approach for this IBD association testing strategy is to test for excessive IBD between pairs of cases ('pairwise method'). However, this approach is inefficient because it requires a large number of permutations. Moreover, a limited number of permutations define a lower bound for P-values, which makes fine-mapping of associated regions difficult because, in practice, a much larger genomic region is implicated than the region that is actually associated.
In this article, we introduce a new pairwise method 'Fast-Pairwise'. Fast-Pairwise uses importance sampling to improve efficiency and enable approximation of extremely small P-values. Fast-Pairwise method takes only days to complete a genome-wide scan. In the application to the WTCCC type 1 diabetes data, Fast-Pairwise successfully fine-maps a known human leukocyte antigen gene that is known to cause the disease.
Fast-Pairwise is publicly available at: http://genetics.cs.ucla.edu/graphibd.
Genetic association studies of multiple populations investigate a wider range of risk alleles than studies of a single ethnic group. In this study, we developed a multiethnic tagging strategy, ...exploiting differences in linkage disequilibrium (LD) structure between populations, to comprehensively capture common genetic variation across 60 genes spanning multiple DNA repair pathways, in five racial/ethnic populations. Over 2600 SNPs were genotyped in each population and single- and multi-marker predictors of common alleles were selected to capture the LD patterns specific to each group. Coding variants (n = 211) were genotyped to test whether combinations of putative functional variants in DNA repair pathway genes could have cumulative effects on risk. Tests of association were conducted in a multiethnic breast cancer study (2093 cases and 2303 controls), with validation of the top allelic associations (P ≤ 0.01) performed in additional studies of 6483 cases and 7309 controls. A variant in the FANCA gene (rs1061646, 0.15–0.68 frequency across populations) was associated with risk in the initial study (P = 0.0052), and in the replication studies (P = 0.032). In a combined analysis (8556 cases and 9605 controls), this SNP yielded an 8% increase in risk per allele. Combinations of coding variants in these genes were not associated with breast cancer and together, these data suggest that common variation in these DNA repair pathway genes are not strongly associated with breast cancer risk. The methods utilized in this study, applied to multiple populations, provide a framework for testing in association studies in diverse populations.
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