The number of genome-wide association studies (GWAS) is growing rapidly leading to the discovery and replication of many new disease loci. Combining results from multiple GWAS datasets may ...potentially strengthen previous conclusions and suggest new disease loci, pathways or pleiotropic genes. However, no database or centralized resource currently exists that contains anywhere near the full scope of GWAS results.
We collected available results from 118 GWAS articles into a database of 56,411 significant SNP-phenotype associations and accompanying information, making this database freely available here. In doing so, we met and describe here a number of challenges to creating an open access database of GWAS results. Through preliminary analyses and characterization of available GWAS, we demonstrate the potential to gain new insights by querying a database across GWAS.
Using a genomic bin-based density analysis to search for highly associated regions of the genome, positive control loci (e.g., MHC loci) were detected with high sensitivity. Likewise, an analysis of highly repeated SNPs across GWAS identified replicated loci (e.g., APOE, LPL). At the same time we identified novel, highly suggestive loci for a variety of traits that did not meet genome-wide significant thresholds in prior analyses, in some cases with strong support from the primary medical genetics literature (SLC16A7, CSMD1, OAS1), suggesting these genes merit further study. Additional adjustment for linkage disequilibrium within most regions with a high density of GWAS associations did not materially alter our findings. Having a centralized database with standardized gene annotation also allowed us to examine the representation of functional gene categories (gene ontologies) containing one or more associations among top GWAS results. Genes relating to cell adhesion functions were highly over-represented among significant associations (p < 4.6 x 10(-14)), a finding which was not perturbed by a sensitivity analysis.
We provide access to a full gene-annotated GWAS database which could be used for further querying, analyses or integration with other genomic information. We make a number of general observations. Of reported associated SNPs, 40% lie within the boundaries of a RefSeq gene and 68% are within 60 kb of one, indicating a bias toward gene-centricity in the findings. We found considerable heterogeneity in information available from GWAS suggesting the wider community could benefit from standardization and centralization of results reporting.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Trials of GDNF in Parkinson's disease have yielded inconsistent results. In a randomised controlled trial, Whone et al. administer GDNF using a paradigm designed to optimize delivery to the putamen. ...18FDOPA PET reveals putamen-wide uptake, but GDNF does not differ from placebo in its effects on motor function.
Abstract
We investigated the effects of glial cell line-derived neurotrophic factor (GDNF) in Parkinson's disease, using intermittent intraputamenal convection-enhanced delivery via a skull-mounted transcutaneous port as a novel administration paradigm to potentially afford putamen-wide therapeutic delivery. This was a single-centre, randomized, double-blind, placebo-controlled trial. Patients were 35-75 years old, had motor symptoms for 5 or more years, and presented with moderate disease severity in the OFF state Hoehn and Yahr stage 2-3 and Unified Parkinson's Disease Rating Scale motor score (part III) (UPDRS-III) between 25 and 45 and motor fluctuations. Drug delivery devices were implanted and putamenal volume coverage was required to exceed a predefined threshold at a test infusion prior to randomization. Six pilot stage patients (randomization 2:1) and 35 primary stage patients (randomization 1:1) received bilateral intraputamenal infusions of GDNF (120 µg per putamen) or placebo every 4 weeks for 40 weeks. Efficacy analyses were based on the intention-to-treat principle and included all patients randomized. The primary outcome was the percentage change from baseline to Week 40 in the OFF state (UPDRS-III). The primary analysis was limited to primary stage patients, while further analyses included all patients from both study stages. The mean OFF state UPDRS motor score decreased by 17.3 ± 17.6% in the active group and 11.8 ± 15.8% in the placebo group (least squares mean difference: −4.9%, 95% CI: −16.9, 7.1, P = 0.41). Secondary endpoints did not show significant differences between the groups either. A post hoc analysis found nine (43%) patients in the active group but no placebo patients with a large clinically important motor improvement (≥10 points) in the OFF state (P = 0.0008). 18F-DOPA PET imaging demonstrated a significantly increased uptake throughout the putamen only in the active group, ranging from 25% (left anterior putamen; P = 0.0009) to 100% (both posterior putamina; P < 0.0001). GDNF appeared to be well tolerated and safe, and no drug-related serious adverse events were reported. The study did not meet its primary endpoint. 18F-DOPA imaging, however, suggested that intermittent convection-enhanced delivery of GDNF produced a putamen-wide tissue engagement effect, overcoming prior delivery limitations. Potential reasons for not proving clinical benefit at 40 weeks are discussed.
Nuclear spins are highly coherent quantum objects. In large ensembles, their control and detection via magnetic resonance is widely exploited, for example, in chemistry, medicine, materials science ...and mining. Nuclear spins also featured in early proposals for solid-state quantum computers
and demonstrations of quantum search
and factoring
algorithms. Scaling up such concepts requires controlling individual nuclei, which can be detected when coupled to an electron
. However, the need to address the nuclei via oscillating magnetic fields complicates their integration in multi-spin nanoscale devices, because the field cannot be localized or screened. Control via electric fields would resolve this problem, but previous methods
relied on transducing electric signals into magnetic fields via the electron-nuclear hyperfine interaction, which severely affects nuclear coherence. Here we demonstrate the coherent quantum control of a single
Sb (spin-7/2) nucleus using localized electric fields produced within a silicon nanoelectronic device. The method exploits an idea proposed in 1961
but not previously realized experimentally with a single nucleus. Our results are quantitatively supported by a microscopic theoretical model that reveals how the purely electrical modulation of the nuclear electric quadrupole interaction results in coherent nuclear spin transitions that are uniquely addressable owing to lattice strain. The spin dephasing time, 0.1 seconds, is orders of magnitude longer than those obtained by methods that require a coupled electron spin to achieve electrical driving. These results show that high-spin quadrupolar nuclei could be deployed as chaotic models, strain sensors and hybrid spin-mechanical quantum systems using all-electrical controls. Integrating electrically controllable nuclei with quantum dots
could pave the way to scalable, nuclear- and electron-spin-based quantum computers in silicon that operate without the need for oscillating magnetic fields.
Platelets are anucleated cells produced by megakaryocytes, from which they inherit all the components necessary to carry their functions. They circulate in blood vessels where they play essential ...roles in coagulation, wound repair or inflammation, and have been implicated in various pathological conditions such as thrombosis, viral infection or cancer progression. The importance of these cells has been established over a century ago, and effective anti-platelet medications with different mechanisms of action have since been developed. However, these therapies are not always effective and can incur adverse events, thus a better understanding of platelets molecular processes is needed to address these issues and improve our understanding of platelet functions. In recent years, an increasing number of studies have leveraged OMICs technologies to analyze their content and identify molecular signatures and mechanisms associated with platelet functions and platelet related disorders. In particular, the increased accessibility of microarrays and RNA sequencing opened the way for studies of the platelet transcriptome under a wide array of conditions. These studies revealed distinct expression profiles in diverse pathologies, which could lead to the discovery of novel biomarkers and therapeutic targets, and suggests a dynamic transcriptome that could influence platelet mechanisms. In this review, we highlight the different sources of transcript level variability in platelets while summarizing recent advances and discoveries from this emerging field.
•The platelet transcriptome is dynamic and translated.•An increasing number of platelet transcriptome studies report differentially expressed genes in diverse conditions.•This review focus on the different sources of transcript level variability in platelets.
We present a detailed description and verification of a discontinuous Galerkin finite element method (DG) for the multi-component chemically reacting compressible Navier-Stokes equations that retains ...the desirable properties of DG, namely discrete conservation and high-order accuracy in smooth regions of the flow. Pressure equilibrium between adjacent elements is maintained through the consistent evaluation of the thermodynamics model and the resulting weak form, as well as the proper choice of nodal basis. As such, the discretization does not generate unphysical pressure oscillations in smooth regions of the flow or at material interfaces where the temperature is continuous. Additionally, we present an hp-adaptive DG method for solving systems of ordinary differential equations, DGODE, which is used to resolve the temporal evolution of the species concentrations due to stiff chemical reactions. The coupled solver is applied to several challenging test problems including multi-component shocked flows as well as chemically reacting detonations, deflagrations, and shear flows with detailed kinetics. We demonstrate that the discretization does not produce unphysical pressure oscillations and, when applicable, we verify that it maintains discrete conservation. The solver is also shown to reproduce the expected temperature and species profiles throughout a detonation as well as the expected two-dimensional cellular detonation structure. We also demonstrate that the solver can produce accurate, high-order, approximations of temperature and species profiles without artificial stabilization for the case of a one-dimensional pre-mixed flame. Finally, high-order solutions of two- and three-dimensional multi-component chemically reacting shear flows, computed without any additional stabilization, are presented.
Parasite dispersal can shape host–parasite interactions at both deep and shallow timescales. One approach to understanding the effects of dispersal is to study parasite lineages that differ in ...dispersal capability but are from the same group of hosts. In this study, we compared phylogenetic and population genetic patterns of wing and body lice from ground‐doves. Wing lice are more capable of dispersal than body lice. We sequenced full genomes of individual lice for multiple representatives of several wing and body louse species. From these data, we assembled genes for phylogenetic analysis and called SNPs for population genetic analysis. At the phylogenetic level, body lice showed more codivergence with their hosts than did wing lice. However, both wing and body lice exhibited some phylogenetic congruence with their hosts. Within species, body lice showed more population genetic structure than wing lice, although both types of lice showed some structure according to biogeography. Body lice also had significantly lower heterozygosity than wing lice, suggesting more inbreeding. Our results demonstrate that dispersal can shape a host–parasite system across evolutionary time, but also that other factors (e.g., host association and biogeography) can have varying degrees of influence on different groups of parasites and at different evolutionary scales.
Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) ...may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.
Abstract
The insect order Psocodea is a diverse lineage comprising both parasitic (Phthiraptera) and nonparasitic members (Psocoptera). The extreme age and ecological diversity of the group may be ...associated with major genomic changes, such as base compositional biases expected to affect phylogenetic inference. Divergent morphology between parasitic and nonparasitic members has also obscured the origins of parasitism within the order. We conducted a phylogenomic analysis on the order Psocodea utilizing both transcriptome and genome sequencing to obtain a data set of 2370 orthologous genes. All phylogenomic analyses, including both concatenated and coalescent methods suggest a single origin of parasitism within the order Psocodea, resolving conflicting results from previous studies. This phylogeny allows us to propose a stable ordinal level classification scheme that retains significant taxonomic names present in historical scientific literature and reflects the evolution of the group as a whole. A dating analysis, with internal nodes calibrated by fossil evidence, suggests an origin of parasitism that predates the K-Pg boundary. Nucleotide compositional biases are detected in third and first codon positions and result in the anomalous placement of the Amphientometae as sister to Psocomorpha when all nucleotide sites are analyzed. Likelihood-mapping and quartet sampling methods demonstrate that base compositional biases can also have an effect on quartet-based methods.Illumina; Phthiraptera; Psocoptera; quartet sampling; recoding methods.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Loop-mediated isothermal amplification (LAMP) has proven to be easier to implement than PCR for point-of-care diagnostic tests. However, the underlying mechanism of LAMP is complicated and the ...kinetics of the major steps in LAMP have not been fully elucidated, which prevents rational improvements in assay development. Here we present our work to characterize the kinetics of the elementary steps in LAMP and show that: (i) strand invasion / initiation is the rate-limiting step in the LAMP reaction; (ii) the loop primer plays an important role in accelerating the rate of initiation and does not function solely during the exponential amplification phase and (iii) strand displacement synthesis by Bst-LF polymerase is relatively fast (125 nt/s) and processive on both linear and hairpin templates, although with some interruptions on high GC content templates. Building on these data, we were able to develop a kinetic model that relates the individual kinetic experiments to the bulk LAMP reaction. The assays developed here provide important insights into the mechanism of LAMP, and the overall model should be crucial in engineering more sensitive and faster LAMP reactions. The kinetic methods we employ should likely prove useful with other isothermal DNA amplification methods.
A placebo-controlled study of idelalisib in patients with relapsed chronic lymphocytic leukemia who were receiving rituximab was stopped early because of significant improvement in rates of response, ...progression-free survival, and overall survival with idelalisib.
Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia among adults. Standard treatments include combinations of purine analogues, alkylating agents, and monoclonal antibodies. In younger patients without major coexisting illnesses, these regimens can provide high response rates of durable length but have substantial toxic effects. As a result, these treatments often have unacceptable side effects in older patients and those with coexisting illnesses.
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Patients with relapsed CLL often have limited options because of the development of resistance to, or persisting toxic effects of, previous therapies. This is particularly true for elderly patients and those with coexisting illnesses.
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For these patients, . . .
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