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Found 35038 matches. Displaying 91-100
Sakurai K
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Cutaneous p38 mitogen-activated protein kinase activation triggers

Background: Psoriasis is a chronic inflammatory skin disease
Li Y, Levran O, Kim J, Zhang TJ, Chen XD, Suo C
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Extreme sampling design in genetic association mapping of quantitative trait loci using balanced and unbalanced case-control samples

SCIENTIFIC REPORTS 2019 OCT 29; 9(?):? Article 15504
It is extremely expensive to conduct large sample size array- or sequencing based genome scale association studies. For a quantitative trait, an extreme case-control study design may improve the power and reduce the cost of variant calling. We investigated the performance of extreme study design when various proportions of samples are selected from the tails of phenotype distribution. Using simulations, we show that when risk genotypes become rare in the population and effect size is relatively small, it is beneficial to carry out an extreme sampling study. In particular, the number of selected cases and controls can even be unbalanced such that power is further increased, compared with a balanced selection. Our application to two data sets: methadone dose data and yearling weight data, demonstrated that similar results for full data analysis can be obtained using extreme sampling with only a fraction of the data. Using power analysis with simulated data and an experimental data application, we conclude that when full data is unavailable due to restricted budget, it is rewarding to employ an extreme sampling design in the sense that there can be immense cost reductions and qualitatively similar power as in the full data analysis.
Bal E, Lim AC, Shen M, Douangpanya J, Madrange M, Gazah R, Tauber M, Beghdadi W, Casanova JL, Bourrat E, Bachelez H, Towne JE, Smahi A
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Mutation in IL36RN impairs the processing and regulatory function of the interleukin-36-receptor antagonist and is associated with DITRA syndrome

The identification of loss-of-function mutations of the IL36RN gene encoding the interleukin-36 receptor antagonist (IL-36Ra) in generalized pustular psoriasis (GPP) emphasized the key role of this pathway in skin innate immunity and systemic inflammation. It has been previously shown in vitro that removal of the N-terminal amino acid IL36Ra (M1) is critical to its biological activity, but the in vivo contribution of this processing remains unknown. We report herein a new homozygous (c4G>T, pV2F) missense IL36RN mutation segregating in a family with three GPP-affected patients. The V2F mutation does not alter IL-36Ra protein expression but was devoid of any antagonist activity. Mass spectrometry showed that the V2F IL-36Ra mutant retains its first N-terminal methionine. These results provide the first in vivo demonstration that removal of N-terminal methionine of native IL-36Ra is a mandatory step to reach optimal antagonist activity and to prevent sustained skin and systemic inflammation in humans.
Fava GA
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Clinical characterization of allostatic overload

Allostatic load reflects the cumulative effects of stressful experiences
Billing AM
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A Systems-level Characterization of the Differentiation of Human

Mesenchymal stem/stromal cells (MSCs) are self-renewing multipotent
Kumari N, Abul Hassan M, Lu XD, Roeder RG, Biswas D
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AFF1 acetylation by p300 temporally inhibits transcription during genotoxic stress response

Soon after exposure to genotoxic reagents, mammalian cells inhibit transcription to prevent collisions with repair machinery and to mount a proper DNA damage response. However, mechanisms underlying early transcriptional inhibition are poorly understood. In this report, we show that site-specific acetylation of super elongation complex (SEC) subunit AFF1 by p300 reduces its interaction with other SEC components and impairs P-TEFb-mediated C-terminal domain phosphorylation of RNA polymerase II both in vitro and in vivo. Reexpression of wild-type AFF1, but not an acetylation mimic mutant, restores SEC component recruitment and target gene expression in AFF1 knockdown cells. Physiologically, we show that, upon genotoxic exposure, p300-mediated AFF1 acetylation is dynamic and strongly correlated with concomitant global down-regulation of transcription-and that this can be reversed by over-expression of an acetylation-defective AFF1 mutant. Therefore, we describe a mechanism of dynamic transcriptional regulation involving p300-mediated acetylation of a key elongation factor during genotoxic stress.
Liberatore RA, Mastrocola EJ, Cassella E, Schmidt F, Willen JR, Voronin D, Zang TM, Hatziioannou T, Bieniasz PD
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Rhabdo-immunodeficiency virus, a murine model of acute HIV-1 infection

ELIFE 2019 OCT 23; 8(?):? Article e49875
Numerous challenges have impeded HIV-1 vaccine development. Among these is the lack of a convenient small animal model in which to study antibody elicitation and efficacy. We describe a chimeric Rhabdo-Immunodeficiency virus (RhIV) murine model that recapitulates key features of HIV-1 entry, tropism and antibody sensitivity. RhIVs are based on vesicular stomatitis viruses (VSV), but viral entry is mediated by HIV-1 Env proteins from diverse HIV-1 strains. RhIV infection of transgenic mice expressing human CD4 and CCR5, exclusively on mouse CD4+ cells, at levels mimicking those on human CD4+ T-cells, resulted in acute, resolving viremia and CD4+ T-cell depletion. RhIV infection elicited protective immunity, and antibodies to HIV-1 Env that were primarily non-neutralizing and had modest protective efficacy following passive transfer. The RhIV model enables the convenient in vivo study of HIV-1 Env-receptor interactions, antiviral activity of antibodies and humoral responses against HIV-1 Env, in a genetically manipulatable host.
Gleicher N, Barad DH
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Not even noninvasive cell-free DNA can rescue preimplantation genetic testing

Zhang P, Itan Y
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Biological Network Approaches and Applications in Rare Disease Studies

GENES 2019 OCT; 10(10):? Article 797
Network biology has the capability to integrate, represent, interpret, and model complex biological systems by collectively accommodating biological omics data, biological interactions and associations, graph theory, statistical measures, and visualizations. Biological networks have recently been shown to be very useful for studies that decipher biological mechanisms and disease etiologies and for studies that predict therapeutic responses, at both the molecular and system levels. In this review, we briefly summarize the general framework of biological network studies, including data resources, network construction methods, statistical measures, network topological properties, and visualization tools. We also introduce several recent biological network applications and methods for the studies of rare diseases.
Saremi NF, Supple MA, Byrne A, Cahill JA, Coutinho LL, Dalen L, Figueiro HV, Johnson WE, Milne HJ, O'Brien SJ, O'Connell B, Onorato DP, Riley SPD, Sikich JA, Stahler DR, Villela PMS, Vollmers C, Wayne RK, Eizirik E, Corbett-Detig RB, Green RE, Wilmers CC, Shapiro B
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Puma genomes from North and South America provide insights into the genomic consequences of inbreeding

NATURE COMMUNICATIONS 2019 OCT 18; 10(?):? Article 4769
Pumas are the most widely distributed felid in the Western Hemisphere. Increasingly, however, human persecution and habitat loss are isolating puma populations. To explore the genomic consequences of this isolation, we assemble a draft puma genome and a geographically broad panel of resequenced individuals. We estimate that the lineage leading to present-day North American pumas diverged from South American lineages 300-100 thousand years ago. We find signatures of close inbreeding in geographically isolated North American populations, but also that tracts of homozygosity are rarely shared among these populations, suggesting that assisted gene flow would restore local genetic diversity. The genome of a Florida panther descended from translocated Central American individuals has long tracts of homozygosity despite recent outbreeding. This suggests that while translocations may introduce diversity, sustaining diversity in small and isolated populations will require either repeated translocations or restoration of landscape connectivity. Our approach provides a framework for genome-wide analyses that can be applied to the management of similarly small and isolated populations.