492 research outputs found
Second-generation PLINK: rising to the challenge of larger and richer datasets
PLINK 1 is a widely used open-source C/C++ toolset for genome-wide
association studies (GWAS) and research in population genetics. However, the
steady accumulation of data from imputation and whole-genome sequencing studies
has exposed a strong need for even faster and more scalable implementations of
key functions. In addition, GWAS and population-genetic data now frequently
contain probabilistic calls, phase information, and/or multiallelic variants,
none of which can be represented by PLINK 1's primary data format.
To address these issues, we are developing a second-generation codebase for
PLINK. The first major release from this codebase, PLINK 1.9, introduces
extensive use of bit-level parallelism, O(sqrt(n))-time/constant-space
Hardy-Weinberg equilibrium and Fisher's exact tests, and many other algorithmic
improvements. In combination, these changes accelerate most operations by 1-4
orders of magnitude, and allow the program to handle datasets too large to fit
in RAM. This will be followed by PLINK 2.0, which will introduce (a) a new data
format capable of efficiently representing probabilities, phase, and
multiallelic variants, and (b) extensions of many functions to account for the
new types of information.
The second-generation versions of PLINK will offer dramatic improvements in
performance and compatibility. For the first time, users without access to
high-end computing resources can perform several essential analyses of the
feature-rich and very large genetic datasets coming into use.Comment: 2 figures, 1 additional fil
High-order discrete ordinate transport in hexagonal geometry: A new capability in ERANOS
This paper presents the implementation of an arbitrary order discontinuous Galerkin scheme within the framework of a discrete ordinate solver of the neutron transport equation for nuclear reactor calculations. More precisely, it deals with non-conforming spatial meshes for the 2D and 3D modeling of core geometries based on hexagonal assemblies. This work aims at improving the capabilities of
the ERANOS code system dedicated to fast reactor analysis and design. Both the angular quadrature and spatial scheme peculiarities for hexagonal geometries are presented. A particular focus is set on the spatial non-conforming mesh and variable order capabilities of this scheme in anticipation to the development of spatial adaptiveness algorithms. These features are illustrated on a 3D numerical benchmark with comparison to a Monte Carlo reference and a 2D benchmark that shows the potential of this scheme for both h- and p-adaptation
A new pear scab resistance gene Rvp1 from the European pear cultivar âNavaraâ maps in a genomic region syntenic to an apple scab resistance gene cluster on linkage group 2
Scab, caused by the ascomycete fungus Venturia pirina, leads to severe damage on European pear varieties resulting in a loss of commercial value and requiring frequent use of fungicides. Identifying scab resistance genes, developing molecular markers linked to these genes and establishing marker-assisted selection would be an effective way to improve European pear breeding for scab resistance. Most of the European pear cultivars (Pyrus communis) are currently reported to be sensitive. The pear cultivar âNavaraâ was shown to carry a major scab resistance gene whose phenotypic expression in seedling progenies was a typical stellate necrosis symptom. The resistance gene was called Rvp1, for resistance to V. pirina, and was mapped on linkage group 2 of the pear genome close to microsatellite marker CH02b10. This genomic region is known to carry a cluster of scab resistance genes in apple indicating a first functional synteny for scab resistance between apple and pear
Challenge pools of hepatitis C virus genotypes 1-6 prototype strains: replication fitness and pathogenicity in chimpanzees and human liver-chimeric mouse models
Chimpanzees represent the only animal model for studies of the natural history of hepatitis C virus (HCV). To generate virus stocks of important HCV variants, we infected chimpanzees with HCV strains of genotypes 1-6 and determined the infectivity titer of acute-phase plasma pools in additional animals. The courses of first- and second-passage infections were similar, with early appearance of viremia, HCV RNA titers of >10(4.7) IU/mL, and development of acute hepatitis; the chronicity rate was 56%. The challenge pools had titers of 10(3)-10(5) chimpanzee infectious doses/mL. Human liver-chimeric mice developed high-titer infections after inoculation with the challenge viruses of genotypes 1-6. Inoculation studies with different doses of the genotype 1b pool suggested that a relatively high virus dose is required to consistently infect chimeric mice. The challenge pools represent a unique resource for studies of HCV molecular virology and for studies of pathogenesis, protective immunity, and vaccine efficacy in vivo
Effects of the dual TP receptor antagonist and thromboxane synthase inhibitor EV-077 on human endothelial and vascular smooth muscle cells
AbstractThe prothrombotic mediator thromboxane A2 is derived from arachidonic acid metabolism through the cyclooxygenase and thromboxane synthase pathways, and transduces its effect through the thromboxane prostanoid (TP) receptor. The aim of this study was to determine the effect of the TP receptor antagonist and thromboxane synthase inhibitor EV-077 on inflammatory markers in human umbilical vein endothelial cells and on human coronary artery smooth muscle cell proliferation. To this end, mRNA levels of different proinflammatory mediators were studied by real time quantitative PCR, supernatants were analyzed by enzyme immune assay, and cell proliferation was assessed using WST-1. EV-077 significantly decreased mRNA levels of ICAM-1 and PTX3 after TNFα incubation, whereas concentrations of 6-keto PGF1α in supernatants of endothelial cells incubated with TNFα were significantly increased after EV-077 treatment. Although U46619 did not alter coronary artery smooth muscle cell proliferation, this thromboxane mimetic enhanced the proliferation induced by serum, insulin and growth factors, which was significantly inhibited by EV-077. In conclusion, EV-077 inhibited TNFα-induced endothelial inflammation and reduced the enhancement of smooth muscle cell proliferation induced by a thromboxane mimetic, supporting that the thromboxane pathway may be associated with early atherosclerosis in terms of endothelial dysfunction and vascular hypertrophy
Averaging bias correction for the future space-borne methane IPDA lidar mission MERLIN
The CNES (French Space
Agency) and DLR (German Space Agency) project MERLIN is a future integrated
path differential absorption (IPDA) lidar satellite mission that aims at
measuring methane dry-air mixing ratio columns (XCH4) in order
to improve surface flux estimates of this key greenhouse gas. To reach a
1 % relative random error on XCH4 measurements, MERLIN
signal processing performs an averaging of data over 50 km along the
satellite trajectory. This article discusses how to process this horizontal
averaging in order to avoid the bias caused by the non-linearity of the
measurement equation and measurements affected by random noise and horizontal
geophysical variability. Three averaging schemes are presented: averaging of
columns of XCH4, averaging of columns of differential absorption
optical depth (DAOD) and averaging of signals. The three schemes are affected
both by statistical and geophysical biases that are discussed and compared,
and correction algorithms are developed for the three schemes. These
algorithms are tested and their biases are compared on modelled scenes from
real satellite data. To achieve the accuracy requirements that are limited to
0.2 % relative systematic error (for a reference value of 1780 ppb), we
recommend performing the averaging of signals corrected from the statistical
bias due to the measurement noise and from the geophysical bias mainly due to
variations of methane optical depth and surface reflectivity along the
averaging track. The proposed method is compliant with the mission relative
systematic error requirements dedicated to averaging algorithms of 0.06 %
(±1 ppb for XCH4â=â1780âppb) for all tested scenes
and all tested ground reflectivity values.</p
A new method to quantify and compare the multiple components of fitness-A study case with kelp niche partition by divergent microstage adaptations to Temperature
Point 1 Management of crops, commercialized or protected species, plagues or life-cycle evolution are subjects requiring comparisons among different demographic strategies. The simpler methods fail in relating changes in vital rates with changes in population viability whereas more complex methods lack accuracy by neglecting interactions among vital rates. Point 2 The difference between the fitness (evaluated by the population growth rate.) of two alternative demographies is decomposed into the contributions of the differences between the pair-wised vital rates and their interactions. This is achieved through a full Taylor expansion (i.e. remainder = 0) of the demographic model. The significance of each term is determined by permutation tests under the null hypothesis that all demographies come from the same pool. Point 3 An example is given with periodic demographic matrices of the microscopic haploid phase of two kelp cryptic species observed to partition their niche occupation along the Chilean coast. The method provided clear and synthetic results showing conditional differentiation of reproduction is an important driver for their differences in fitness along the latitudinal temperature gradient. But it also demonstrated that interactions among vital rates cannot be neglected as they compose a significant part of the differences between demographies. Point 4 This method allows researchers to access the effects of multiple effective changes in a life-cycle from only two experiments. Evolutionists can determine with confidence the effective causes for changes in fitness whereas population managers can determine best strategies from simpler experimental designs.CONICYT-FRENCH EMBASSADY Ph.D. gran
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Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signaling pathway.
iRhoms are pseudoprotease members of the rhomboid-like superfamily and are cardinal regulators of inflammatory and growth factor signaling; they function primarily by recognizing transmembrane domains of their clients. Here, we report a mechanistically distinct nuclear function of iRhoms, showing that both human and mouse iRhom2 are non-canonical substrates of signal peptidase complex (SPC), the protease that removes signal peptides from secreted proteins. Cleavage of iRhom2 generates an N-terminal fragment that enters the nucleus and modifies the transcriptome, in part by binding C-terminal binding proteins (CtBPs). The biological significance of nuclear iRhom2 is indicated by elevated levels in skin biopsies of patients with psoriasis, tylosis with oesophageal cancer (TOC), and non-epidermolytic palmoplantar keratoderma (NEPPK); increased iRhom2 cleavage in a keratinocyte model of psoriasis; and nuclear iRhom2 promoting proliferation of keratinocytes. Overall, this work identifies an unexpected SPC-dependent ER-to-nucleus signaling pathway and demonstrates that iRhoms can mediate nuclear signaling
Mutant Ras and inflammation-driven skin tumorigenesis is suppressed via a JNK-iASPP-AP1 axis
Concurrent mutation of a RAS oncogene and the tumor suppressor p53 is common in tumorigenesis, and inflammation can promote RAS-driven tumorigenesis without the need to mutate p53. Here, we show, using a well-established mutant RAS and an inflammation-driven mouse skin tumor model, that loss of the p53 inhibitor iASPP facilitates tumorigenesis. Specifically, iASPP regulates expression of a subset of p63 and AP1 targets, including genes involved in skin differentiation and inflammation, suggesting that loss of iASPP in keratinocytes supports a tumor-promoting inflammatory microenvironment. Mechanistically, JNK-mediated phosphorylation regulates iASPP function and inhibits iASPP binding with AP1 components, such as JUND, via PXXP/SH3 domain-mediated interaction. Our results uncover a JNK-iASPP-AP1 regulatory axis that is crucial for tissue homeostasis. We show that iASPP is a tumor suppressor and an AP1 coregulator
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