Expression of PEG11 and PEG11AS transcripts in normal and callipyge sheep

BACKGROUND: The callipyge mutation is located within an imprinted gene cluster on ovine chromosome 18. The callipyge trait exhibits polar overdominant inheritance due to the fact that only heterozygotes inheriting a mutant paternal allele (paternal heterozygotes) have a phenotype of muscle hypertrophy, reduced fat and a more compact skeleton. The mutation is a single A to G transition in an intergenic region that results in the increased expression of several genes within the imprinted cluster without changing their parent-of-origin allele-specific expression. RESULTS: There was a significant effect of genotype (p < 0.0001) on the transcript abundance of DLK1, PEG11, and MEG8 in the muscles of lambs with the callipyge allele. DLK1 and PEG11 transcript levels were elevated in the hypertrophied muscles of paternal heterozygous animals relative to animals of the other three genotypes. The PEG11 locus produces a single 6.5 kb transcript and two smaller antisense strand transcripts, referred to as PEG11AS, in skeletal muscle. PEG11AS transcripts were detectable over a 5.5 kb region beginning 1.2 kb upstream of the PEG11 start codon and spanning the entire open reading frame. Analysis of PEG11 expression by quantitative PCR shows a 200-fold induction in the hypertrophied muscles of paternal heterozygous animals and a 13-fold induction in homozygous callipyge animals. PEG11 transcripts were 14-fold more abundant than PEG11AS transcripts in the gluteus medius of paternal heterozygous animals. PEG11AS transcripts were expressed at higher levels than PEG11 transcripts in the gluteus medius of animals of the other three genotypes. CONCLUSIONS: The effect of the callipyge mutation has been to alter the expression of DLK1, GTL2, PEG11 and MEG8 in the hypertrophied skeletal muscles. Transcript abundance of DLK1 and PEG11 was highest in paternal heterozygous animals and exhibited polar overdominant gene expression patterns; therefore, both genes are candidates for causing skeletal muscle hypertrophy. There was unique relationship of PEG11 and PEG11AS transcript abundance in the paternal heterozygous animals that suggests a RNA interference mechanism may have a role in PEG11 gene regulation and polar overdominance in callipyge sheep

Learning to become an online editor: the editathon as a learning environment

This study explores Wikipedia as a site for learning. In particular it traces how people learn to become Wikipedia editors through engagement in an editathon, a training event for people who want to become a volunteer editor. The study is original in its emphasis on the various types of knowledge editors acquire as they develop expertise. Determining the knowledge needed to contribute to Wikipedia is significant in terms of understanding Wikipedia as a site for learning. Data was gathered from nine participants who took part in an ‘editathon’ event on the theme of the Edinburgh Seven. The study used a rigorous methodology, combining quantitative social network analysis, documenting the online activity of participants as they created and edited Wikipedia pages, with qualitative interviews, which recorded participants reflections on their participation in the editathon. A key finding is that conceptual and procedural knowledge are representative of the foundational knowledge needed to contribute to Wikipedia actively as an editor. However, this knowledge on its own is not sufficient. Editors also develop socio-cultural and relational knowledge forms of knowledge to enable them to operate and problem-solve effectively. The relationship between the physical and the digital is important, since socio-cultural and relational knowledge are developed through active experimentation as the editathon engage with physical objects to create the online wiki pages

Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut

Bile acids (BAs) mediate the crosstalk between human and microbial cells and influence diseases including Clostridioides difficile infection (CDI). While bile salt hydrolases (BSHs) shape the BA pool by deconjugating conjugated BAs, the basis for their substrate selectivity and impact on C. difficile remain elusive. Here we survey the diversity of BSHs in the gut commensals Lactobacillaceae, which are commonly used as probiotics, and other members of the human gut microbiome. We structurally pinpoint a loop that predicts BSH preferences for either glycine or taurine substrates. BSHs with varying specificities were shown to restrict C. difficile spore germination and growth in vitro and colonization in pre-clinical in vivo models of CDI. Furthermore, BSHs reshape the pool of microbial conjugated bile acids (MCBAs) in the murine gut, and these MCBAs can further restrict C. difficile virulence in vitro. The recognition of conjugated BAs by BSHs defines the resulting BA pool, including the expansive MCBAs. This work provides insights into the structural basis of BSH mechanisms that shape the BA landscape and promote colonization resistance against C. difficile

Comparing and contrasting the νμ→ντ\nu_{\mu} \to \nu_{\tau} and νμ→νs\nu_{\mu} \to \nu_s solutions to the atmospheric neutrino problem with SuperKamiokande data

The $\nu_{\mu} \to \nu_{\tau}$ and $\nu_{\mu} \to \nu_s$ solutions to the atmospheric neutrino problem are compared with SuperKamiokande data. The differences between these solutions due to matter effects in the Earth are calculated for the ratio of $\mu$-like to $e$-like events and for up-down flux asymmetries. These quantities are chosen because they are relatively insensitive to theoretical uncertainties in the overall neutrino flux normalisation and detection cross-sections and efficiencies. A $\chi^2$ analysis using these quantities is performed yielding $3\sigma$ ranges which are approximately given by $(0.725 - 1.0, 4 \times 10^{-4} - 2 \times 10^{-2} eV^2)$ and $(0.74 - 1.0, 1 \times 10^{-3} - 2 \times 10^{-2} eV^2)$ for $(\sin^2 2\theta,\Delta m^2)$ for the $\nu_{\mu} \to \nu_{\tau}$ and $\nu_{\mu} \to \nu_s$ solutions, respectively. Values of $\Delta m^2$ smaller than about $2 \times 10^{-3}$ eV$^2$ are disfavoured for the $\nu_{\mu} \to \nu_s$ solution, suggesting that future long baseline experiments should see a positive signal if this scenario is the correct one.Comment: revtex, 22 pages, 12 figure

Atmospheric neutrino oscillations with three neutrinos and a mass hierarchy

A comprehensive formalism for the description of neutrino oscillations in the Earth in a general scheme with three massive neutrinos and the mass hierarchy m_1<<m_2<<m_3 is presented. Using this formalism, which is valid both in vacuum and in a medium, the matter effect on the oscillations of low-energy neutrinos is discussed, pointing out the existence of very long oscillations which are independent of the neutrino masses and the neutrino energy, and are very sensitive to the matter density along the neutrino trajectory. As an example of application of the formulation, a fit of the Kamiokande atmospheric neutrino data with the matter effect taken into account for neutrinos propagating in the Earth is presented. The results of the fit indicate that 4*10^{-3} eV^2 < m_3^2 nu_e, nu_munu_tau, nu_enu_tau) could be large. Hence, long-baseline experiments with reactor (CHOOZ and Palo Verde) and accelerator (K2K, MINOS and ICARUS) neutrinos could observe neutrino oscillations in all channels with a relatively large statistics.Comment: 42 pages, including 7 figure

Re-sampling strategy to improve the estimation of number of null hypotheses in FDR control under strong correlation structures

<p>Abstract</p> <p>Background</p> <p>When conducting multiple hypothesis tests, it is important to control the number of false positives, or the False Discovery Rate (FDR). However, there is a tradeoff between controlling FDR and maximizing power. Several methods have been proposed, such as the q-value method, to estimate the proportion of true null hypothesis among the tested hypotheses, and use this estimation in the control of FDR. These methods usually depend on the assumption that the test statistics are independent (or only weakly correlated). However, many types of data, for example microarray data, often contain large scale correlation structures. Our objective was to develop methods to control the FDR while maintaining a greater level of power in highly correlated datasets by improving the estimation of the proportion of null hypotheses.</p> <p>Results</p> <p>We showed that when strong correlation exists among the data, which is common in microarray datasets, the estimation of the proportion of null hypotheses could be highly variable resulting in a high level of variation in the FDR. Therefore, we developed a re-sampling strategy to reduce the variation by breaking the correlations between gene expression values, then using a conservative strategy of selecting the upper quartile of the re-sampling estimations to obtain a strong control of FDR.</p> <p>Conclusion</p> <p>With simulation studies and perturbations on actual microarray datasets, our method, compared to competing methods such as q-value, generated slightly biased estimates on the proportion of null hypotheses but with lower mean square errors. When selecting genes with controlling the same FDR level, our methods have on average a significantly lower false discovery rate in exchange for a minor reduction in the power.</p

The Electron-Ring Accelerator Program at Lrl

A progress report is presented on the activities at LRL in connection with electron-ring accelerators. A two-stage compressor unit (employing only low-intensity beams) has been built, and operated with a 4-MeV 100-mA linac as an injector. Electron rings have been formed and compressed from 20 cm radius to 7 cm radius. A three-stage compression unit has been constructed and is now under test with the high intensity (200 A) 3.3-MeV beam of the Astron injector. The apparatus is described. Design work on a magnetic expansion unit is reported

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Lives saved with vaccination for 10 pathogens across 112 countries in a pre-COVID-19 world.

BackgroundVaccination is one of the most effective public health interventions. We investigate the impact of vaccination activities for Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, rotavirus, rubella, Streptococcus pneumoniae, and yellow fever over the years 2000-2030 across 112 countries.MethodsTwenty-one mathematical models estimated disease burden using standardised demographic and immunisation data. Impact was attributed to the year of vaccination through vaccine-activity-stratified impact ratios.ResultsWe estimate 97 (95%CrI[80, 120]) million deaths would be averted due to vaccination activities over 2000-2030, with 50 (95%CrI[41, 62]) million deaths averted by activities between 2000 and 2019. For children under-5 born between 2000 and 2030, we estimate 52 (95%CrI[41, 69]) million more deaths would occur over their lifetimes without vaccination against these diseases.ConclusionsThis study represents the largest assessment of vaccine impact before COVID-19-related disruptions and provides motivation for sustaining and improving global vaccination coverage in the future.FundingVIMC is jointly funded by Gavi, the Vaccine Alliance, and the Bill and Melinda Gates Foundation (BMGF) (BMGF grant number: OPP1157270 / INV-009125). Funding from Gavi is channelled via VIMC to the Consortium's modelling groups (VIMC-funded institutions represented in this paper: Imperial College London, London School of Hygiene and Tropical Medicine, Oxford University Clinical Research Unit, Public Health England, Johns Hopkins University, The Pennsylvania State University, Center for Disease Analysis Foundation, Kaiser Permanente Washington, University of Cambridge, University of Notre Dame, Harvard University, Conservatoire National des Arts et Métiers, Emory University, National University of Singapore). Funding from BMGF was used for salaries of the Consortium secretariat (authors represented here: TBH, MJ, XL, SE-L, JT, KW, NMF, KAMG); and channelled via VIMC for travel and subsistence costs of all Consortium members (all authors). We also acknowledge funding from the UK Medical Research Council and Department for International Development, which supported aspects of VIMC's work (MRC grant number: MR/R015600/1).JHH acknowledges funding from National Science Foundation Graduate Research Fellowship; Richard and Peggy Notebaert Premier Fellowship from the University of Notre Dame. BAL acknowledges funding from NIH/NIGMS (grant number R01 GM124280) and NIH/NIAID (grant number R01 AI112970). The Lives Saved Tool (LiST) receives funding support from the Bill and Melinda Gates Foundation.This paper was compiled by all coauthors, including two coauthors from Gavi. Other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication