Epigenetic stability of repressed states involving the histone variant macroH2A revealed by nuclear transfer to Xenopus oocytes

How various epigenetic mechanisms restrict chromatin plasticity to determine the stability of repressed genes is poorly understood. Nuclear transfer to Xenopus oocytes induces the transcriptional reactivation of previously silenced genes. Recent work suggests that it can be used to analyze the epigenetic stability of repressed states. The notion that the epigenetic state of genes is an important determinant of the efficiency of nuclear reprogramming is supported by the differential reprogramming of given genes from different starting epigenetic configurations. After nuclear transfer, transcription from the inactive X chromosome of post-implantation-derived epiblast stem cells is reactivated. However, the same chromosome is resistant to reactivation when embryonic fibroblasts are used. Here, we discuss different kinds of evidence that link the histone variant macroH2A to the increased stability of repressed states. We focus on developmentally regulated X chromosome inactivation and repression of autosomal pluripotency genes, where macroH2A may help maintain the long-term stability of the differentiated state of somatic cells

学生の授業評価から見えてきた教員の授業改善

　福岡県立大学人間社会学部で2002年に行われた、78授業に対する延べ2980名の学生による授業評価を元に、授業をどのように改善すればよいかについて検討した。各授業（78授業）について、評価項目（19項目、５件法）の平均得点を求め、因子分析を行った結果、４つの因子（わかりやすさ、授業の組み立て、シラバス、環境）から構成されることが示された。78授業について、各因子に因子負荷量の高い項目から、尺度を構成し、これに各教科を受講している学生の授業に対する全体評価と学生自身の自己評価（出席、熱意）と各授業の受講生数を加えて、相互の相関を求めた。その結果、「わかりやすさ」・「授業の組み立て」と「全体評価」・「学生の熱意」に強い相関（r＞0.7）が見られ、「出席」と「授業の組み立て」・「学生の熱意」に中程度の相関（0.7＞r＞0.4）が見られた。これらのことから、授業評価は「わかりやすさ」と「授業の組み立て」からなっており、これらが高ければ全体評価も高くなり、学生の熱意も増し、出席も増えることが示唆された。授業をどのようにすればわかりやすくできるのか、どのように授業を組み立てるのかについて考察した

Histone variant macroH2A confers resistance to nuclear reprogramming

Gurdon and collaborators report reversible X chromosome inactivation in epiblast stem cells (EpiSCs) that seems to be determined by macroH2A1 deposition. These findings are of rather general interest as they highlight the epigenetic state of repressed loci as determinant for reprogramming efficiency

Functional illness in primary care: dysfunction versus disease

<p>Abstract</p> <p>Background</p> <p>The Biopsychosocial Model aims to integrate the biological, psychological and social components of illness, but integration is difficult in practice, particularly when patients consult with medically unexplained physical symptoms or functional illness.</p> <p>Discussion</p> <p>This Biopsychosocial Model was developed from General Systems Theory, which describes nature as a dynamic order of interacting parts and processes, from molecular to societal. Despite such conceptual progress, the biological, psychological, social and spiritual components of illness are seldom managed as an integrated whole in conventional medical practice. This is because the biomedical model can be easier to use, clinicians often have difficulty relinquishing a disease-centred approach to diagnosis, and either dismiss illness when pathology has been excluded, or explain all undifferentiated illness in terms of psychosocial factors. By contrast, traditional and complementary treatment systems describe reversible functional disturbances, and appear better at integrating the different components of illness. Conventional medicine retains the advantage of scientific method and an expanding evidence base, but needs to more effectively integrate psychosocial factors into assessment and management, notably of 'functional' illness. As an aid to integration, pathology characterised by structural change in tissues and organs is contrasted with dysfunction arising from disordered physiology or psychology that may occur independent of pathological change.</p> <p>Summary</p> <p>We propose a classification of illness that includes orthogonal dimensions of pathology and dysfunction to support a broadly based clinical approach to patients; adoption of which may lead to fewer inappropriate investigations and secondary care referrals and greater use of cognitive behavioural techniques, particularly when managing functional illness.</p

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

A Multicenter, Randomized, Placebo‐Controlled Trial of Atorvastatin for the Primary Prevention of Cardiovascular Events in Patients With Rheumatoid Arthritis

Objective: Rheumatoid arthritis (RA) is associated with increased cardiovascular event (CVE) risk. The impact of statins in RA is not established. We assessed whether atorvastatin is superior to placebo for the primary prevention of CVEs in RA patients. Methods: A randomized, double‐blind, placebo‐controlled trial was designed to detect a 32% CVE risk reduction based on an estimated 1.6% per annum event rate with 80% power at P 50 years or with a disease duration of >10 years who did not have clinical atherosclerosis, diabetes, or myopathy received atorvastatin 40 mg daily or matching placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, or any arterial revascularization. Secondary and tertiary end points included plasma lipids and safety. Results: A total of 3,002 patients (mean age 61 years; 74% female) were followed up for a median of 2.51 years (interquartile range [IQR] 1.90, 3.49 years) (7,827 patient‐years). The study was terminated early due to a lower than expected event rate (0.70% per annum). Of the 1,504 patients receiving atorvastatin, 24 (1.6%) experienced a primary end point, compared with 36 (2.4%) of the 1,498 receiving placebo (hazard ratio [HR] 0.66 [95% confidence interval (95% CI) 0.39, 1.11]; P = 0.115 and adjusted HR 0.60 [95% CI 0.32, 1.15]; P = 0.127). At trial end, patients receiving atorvastatin had a mean ± SD low‐density lipoprotein (LDL) cholesterol level 0.77 ± 0.04 mmoles/liter lower than those receiving placebo (P < 0.0001). C‐reactive protein level was also significantly lower in the atorvastatin group than the placebo group (median 2.59 mg/liter [IQR 0.94, 6.08] versus 3.60 mg/liter [IQR 1.47, 7.49]; P < 0.0001). CVE risk reduction per mmole/liter reduction in LDL cholesterol was 42% (95% CI −14%, 70%). The rates of adverse events in the atorvastatin group (n = 298 [19.8%]) and placebo group (n = 292 [19.5%]) were similar. Conclusion: Atorvastatin 40 mg daily is safe and results in a significantly greater reduction of LDL cholesterol level than placebo in patients with RA. The 34% CVE risk reduction is consistent with the Cholesterol Treatment Trialists’ Collaboration meta‐analysis of statin effects in other populations

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations