3,849 research outputs found
Fast Genome-Wide QTL Association Mapping on Pedigree and Population Data
Since most analysis software for genome-wide association studies (GWAS)
currently exploit only unrelated individuals, there is a need for efficient
applications that can handle general pedigree data or mixtures of both
population and pedigree data. Even data sets thought to consist of only
unrelated individuals may include cryptic relationships that can lead to false
positives if not discovered and controlled for. In addition, family designs
possess compelling advantages. They are better equipped to detect rare
variants, control for population stratification, and facilitate the study of
parent-of-origin effects. Pedigrees selected for extreme trait values often
segregate a single gene with strong effect. Finally, many pedigrees are
available as an important legacy from the era of linkage analysis.
Unfortunately, pedigree likelihoods are notoriously hard to compute. In this
paper we re-examine the computational bottlenecks and implement ultra-fast
pedigree-based GWAS analysis. Kinship coefficients can either be based on
explicitly provided pedigrees or automatically estimated from dense markers.
Our strategy (a) works for random sample data, pedigree data, or a mix of both;
(b) entails no loss of power; (c) allows for any number of covariate
adjustments, including correction for population stratification; (d) allows for
testing SNPs under additive, dominant, and recessive models; and (e)
accommodates both univariate and multivariate quantitative traits. On a typical
personal computer (6 CPU cores at 2.67 GHz), analyzing a univariate HDL
(high-density lipoprotein) trait from the San Antonio Family Heart Study
(935,392 SNPs on 1357 individuals in 124 pedigrees) takes less than 2 minutes
and 1.5 GB of memory. Complete multivariate QTL analysis of the three
time-points of the longitudinal HDL multivariate trait takes less than 5
minutes and 1.5 GB of memory
Identification And Characterization Of A Second Encephalitogenic Determinant Of Myelin Proteolipid Protein (Residues 178-191) For SJL Mice
We previously described a synthetic peptide of myelin proteolipid protein (PLP), peptide 139-151, which induces experimental allergic encephalomyelitis in SJL/J (H-2s) mice. We have now identified an additional determinant, PLP residues 178-191, that is also a potent encephalitogen in this strain. When PLP peptide 178-191 was compared with peptide 139-151 on an equimolar basis, the day of onset of disease induced by PLP 178-191 was earlier, but the incidence, severity, and histologic features were indistinguishable. Lymph node cells from animals immunized with the whole PLP molecule responded to both PLP 178-191 and 139-151, suggesting immunologic codominance of the two epitopes. PLP 178-191 elicited stronger proliferative responses and this may relate to the earlier onset of disease induced with this peptide. Two CD4+, peptide-specific, I-A(s)-restricted T cell lines, selected by stimulation of lymph node cells with either PLP 178-191 or 139-151, were each encephalitogenic in naive syngeneic mice. The presence of multiple encephalitogenic codominant PLP epitopes within a single mouse strain emphasizes the complexity of the immune response to PLP and its potential as a target Ag in autoimmune demyelinating diseases
Motivating news audiences: Shock them or provide them with solutions?
Despite the well-established power of the media to shape public perceptions of social problems, compassion fatigue is believed to remain prevalent. So what does it take for someone to be compelled to act after reading a story or seeing an image of a prominent issue? This study, a 3-by-2 between subjects experiment, examined the effects of two journalistic techniques — shocking audiences into action with offensive stories or inspiring them to act with solution-based stories – in the context of sex trafficking. Results revealed that neither shock nor solutions stories led to increased empathy for trafficked individuals, greater understanding of the issue, increased desire to share the story or increased desire to act, but that readers of solutions stories felt more positive and were more likely to read similar stories about the issue. This suggests that solution-focused news stories might be at least somewhat more engaging than shocking and offensive stories
Neutrino-induced deuteron disintegration experiment
Cross sections for the disintegration of the deuteron via neutral-current
(NCD) and charged-current (CCD) interactions with reactor antineutrinos are
measured to be 6.08 +/- 0.77 x 10^(-45) cm-sq and 9.83 +/- 2.04 x 10^(-45)
cm-sq per neutrino, respectively, in excellent agreement with current
calculations. Since the experimental NCD value depends upon the CCD value, if
we use the theoretical value for the CCD reaction, we obtain the improved value
of 5.98 +/- 0.54 x 10^(-45) for the NCD cross section. The neutral-current
reaction allows a unique measurement of the isovector-axial vector coupling
constant in the hadronic weak interaction (beta). In the standard model, this
constant is predicted to be exactly 1, independent of the Weinberg angle. We
measure a value of beta^2 = 1.01 +/- 0.16. Using the above improved value for
the NCD cross section, beta^2 becomes 0.99 +/- 0.10.Comment: 22pages, 9 figure
The mitochondrial tRNA-derived fragment, mt-tRF-Leu<sup>TAA</sup>, couples mitochondrial metabolism to insulin secretion.
The contribution of the mitochondrial electron transfer system to insulin secretion involves more than just energy provision. We identified a small RNA fragment (mt-tRF-Leu <sup>TAA</sup> ) derived from the cleavage of a mitochondrially-encoded tRNA that is conserved between mice and humans. The role of mitochondrially-encoded tRNA-derived fragments remains unknown. This study aimed to characterize the impact of mt-tRF-Leu <sup>TAA</sup> , on mitochondrial metabolism and pancreatic islet functions.
We used antisense oligonucleotides to reduce mt-tRF-Leu <sup>TAA</sup> levels in primary rat and human islet cells, as well as in insulin-secreting cell lines. We performed a joint transcriptome and proteome analysis upon mt-tRF-Leu <sup>TAA</sup> inhibition. Additionally, we employed pull-down assays followed by mass spectrometry to identify direct interactors of the fragment. Finally, we characterized the impact of mt-tRF-Leu <sup>TAA</sup> silencing on the coupling between mitochondrial metabolism and insulin secretion using high-resolution respirometry and insulin secretion assays.
Our study unveils a modulation of mt-tRF-Leu <sup>TAA</sup> levels in pancreatic islets in different Type 2 diabetes models and in response to changes in nutritional status. The level of the fragment is finely tuned by the mechanistic target of rapamycin complex 1. Located within mitochondria, mt-tRF-Leu <sup>TAA</sup> interacts with core subunits and assembly factors of respiratory complexes of the electron transfer system. Silencing of mt-tRF-Leu <sup>TAA</sup> in islet cells limits the inner mitochondrial membrane potential and impairs mitochondrial oxidative phosphorylation, predominantly by affecting the Succinate (via Complex II)-linked electron transfer pathway. Lowering mt-tRF-Leu <sup>TAA</sup> impairs insulin secretion of rat and human pancreatic β-cells.
Our findings indicate that mt-tRF-Leu <sup>TAA</sup> interacts with electron transfer system complexes and is a pivotal regulator of mitochondrial oxidative phosphorylation and its coupling to insulin secretion
Remodeling of the interstitial extracellular matrix in white matter multiple sclerosis lesions:Implications for remyelination (failure)
The extracellular matrix (ECM) provides protection, rigidity, and structure toward cells. It consists, among others, of a wide variety of glycoproteins and proteoglycans, which act together to produce a complex and dynamic environment, most relevant in transmembrane events. In the brain, the ECM occupies a notable proportion of its volume and maintains the homeostasis of central nervous system (CNS). In addition, remodeling of the ECM, that is transient changes in ECM proteins regulated by matrix metalloproteinases (MMPs), is an important process that modulates cell behavior upon injury, thereby facilitating recovery. Failure of ECM remodeling plays an important role in the pathogenesis of multiple sclerosis (MS), a neurodegenerative demyelinating disease of the CNS with an inflammatory response against protective myelin sheaths that surround axons. Remyelination of denuded axons improves the neuropathological conditions of MS, but this regeneration process fails over time, leading to chronic disease progression. In this review, we uncover abnormal ECM remodeling in MS lesions by discussing ECM remodeling in experimental demyelination models, that is when remyelination is successful, and compare alterations in ECM components to the ECM composition and MMP expression in the parenchyma of demyelinated MS lesions, that is when remyelination fails. Inter- and intralesional differences in ECM remodeling in the distinct white matter MS lesions are discussed in terms of consequences for oligodendrocyte behavior and remyelination (failure). Hence, the review will aid to understand how abnormal ECM remodeling contributes to remyelination failure in MS lesions and assists in developing therapeutic strategies to promote remyelination
Majorana Neutrinos and Gravitational Oscillation
We analyze the possibility of encountering resonant transitions of high
energy Majorana neutrinos produced in Active Galactic Nuclei (AGN). We consider
gravitational, electromagnetic and matter effects and show that the latter are
ignorable. Resonant oscillations due to the gravitational interactions are
shown to occur at energies in the PeV range for magnetic moments in the
range. Coherent precession will dominate for larger magnetic
moments. The alllowed regions for gravitational resonant transitions are
obtained.Comment: 11 pages, 8 figures, Latex; requires revtex and epsf.tex submitted to
Physical Review
Observation of the east-west anisotropy of the atmospheric neutrino flux
The east-west anisotropy, caused by the deflection of primary cosmic rays in
the Earth's magnetic field, is observed for the first time in the flux of
atmospheric neutrinos. Using a 45 kt-year exposure of the
Super-Kamiokande detector, 552 e-like and 633 mu-like horizontally-going
events are selected in the momentum range between 400 and 3000 MeV/c.
The azimuthal distribution of e-like and mu-like events agrees with the
expectation from atmospheric neutrino flux calculations that account for the
geomagnetic field, verifying that the geomagnetic field effects in the
production of atmospheric neutrinos in the GeV energy range are well
understood.Comment: 8 pages,3 figures revtex, submitted to PR
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