Fine grained process modelling: An experiment at British Airways

We report on the experimental application of process technology at British Airways (BA). We used SLANG to model BA's C++ class library management process, and we constructed an experimental process centred software engineering environment (PSEE) based on SPADE. BA required processes to be automated at a finer degree of granularity than tool invocation. We have demonstrated that SLANG and SPADE offer the basic mechanisms for modelling these fine grained processes. We have also shown that it is feasible to generate tools for dedicated processes and integrate them with a SLANG model so as to facilitate fine grained process automation. However, our experience highlighted some open problems. For instance, SLANG process models are tuned to efficient enactment, thus containing very detailed process fragments. These are not the most appropriate representation for humans trying to understand the process model. A more comprehensible notation is needed for design and documentation purposes. Although the airline did not deploy the PSEE in its production environment, the experiment proved beneficial for BA. The modelling uncovered serious flaws in the existing process, and the BA engineers improved their knowledge of process technology

How do psychiatrists address delusions in first meetings in acute care? A qualitative study

Licensed under the Creative Commons Attribution Licens

CCAAT-enhancer-binding protein-beta expression in vivo is associated with muscle strength

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Declining muscle strength is a core feature of aging. Several mechanisms have been postulated, including CCAAT/enhancer-binding protein-beta (C/EBP-β)-triggered macrophage-mediated muscle fiber regeneration after micro-injury, evidenced in a mouse model. We aimed to identify in vivo circulating leukocyte gene expression changes associated with muscle strength in the human adult population. We undertook a genome-wide expression microarray screen, using peripheral blood RNA samples from InCHIANTI study participants (aged 30 and 104). Logged expression intensities were regressed with muscle strength using models adjusted for multiple confounders. Key results were validated by real-time PCR. The Short Physical Performance Battery (SPPB) score tested walk speed, chair stand, and balance. CEBPB expression levels were associated with muscle strength (β coefficient = 0.20560, P = 1.03*10(-6), false discovery rate q = 0.014). The estimated handgrip strength in 70-year-old men in the lowest CEBPB expression tertile was 35.2 kg compared with 41.2 kg in the top tertile. CEBPB expression was also associated with hip, knee, ankle, and shoulder strength and the SPPB score (P = 0.018). Near-study-wide associations were also noted for TGF-β3 (P = 3.4*10(-5) , q = 0.12) and CEBPD expression (P = 9.7*10(-5) , q = 0.18) but not for CEBPA expression. We report here a novel finding that raised CEBPB expression in circulating leukocyte-derived RNA samples in vivo is associated with greater muscle strength and better physical performance in humans. This association may be consistent with mouse model evidence of CEBPB-triggered muscle repair: if this mechanism is confirmed, it may provide a target for intervention to protect and enhance aging muscle

The GOODSTEP project: General Object-Oriented Database for Software Engineering Processes

The goal of the GOODSTEP project is to enhance and improve the functionality of a fully object-oriented database management system to yield a platform suited for applications such as software development environments (SDEs). The baseline of the project is the O2 database management system (DBMS). The O2 DBMS already includes many of the features regulated by SDEs. The project has identified enhancements to O2 in order to make it a real software engineering DBMS. These enhancements are essentially upgrades of the existing O2 functionality, and hence require relatively easy extensions to the O2 system. They have been developed in the early stages of the project and are now exploited and validated by a number of software engineering tools built on top of the enhanced O2 DBMS. To ease tool construction, the GOODSTEP platform encompasses tool generation capabilities which allow for generation of integrated graphical and textual tools from high-level specifications. In addition, the GOODSTEP platform provides a software process toolset which enables modeling, analysis and enaction of software processes and is also built on top of the extended O2 database. The GOODSTEP platform is to be validated using two CASE studies carried out to develop an airline application and a business application

Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms

Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2V617F-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10−10) and rs2201862 (MECOM; meta-analysis P=1.96 × 10−9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10−7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ2 P=7.3 × 10−7). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype

Menopause accelerates biological aging

Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the “epigenetic clock”), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women's Health Initiative (n = 1,864); Invecchiare nel Chianti (n = 200); Parkinson's disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790). We find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (P = 0.00091), bilateral oophorectomy (P = 0.0018), and a longer time since menopause (P = 0.017). Conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (P = 0.0079), while a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078). Using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. Using Mendelian randomization analysis, we find that two SNPs that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. Overall, our Mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studies will be needed to dissect cause-and-effect relationships further

Leukocyte CCR2 expression is associated with mini-mental state examination score in older adults

This is a copy of an article published in Rejuvenation Research © 2012 Mary Ann Liebert, Inc.; Rejuvenation Research is available online at: http://online.liebertpub.com.Circulating inflammatory markers may play an important role in cognitive impairment at older ages. Mice deficient for the chemokine (C-C motif) receptor 2 (CCR2) develop an accelerated Alzheimer-like pathology. CCR2 is also important in neurogenesis. To identify human gene transcripts most closely associated with Mini-Mental State Examination (MMSE) scores, we undertook a genome-wide and inflammation specific transcriptome screen in circulating leukocytes from a population-based sample

Whole-genome sequencing to understand the genetic architecture of common gene expression and biomarker phenotypes.

Initial results from sequencing studies suggest that there are relatively few low-frequency (<5%) variants associated with large effects on common phenotypes. We performed low-pass whole-genome sequencing in 680 individuals from the InCHIANTI study to test two primary hypotheses: (i) that sequencing would detect single low-frequency-large effect variants that explained similar amounts of phenotypic variance as single common variants, and (ii) that some common variant associations could be explained by low-frequency variants. We tested two sets of disease-related common phenotypes for which we had statistical power to detect large numbers of common variant-common phenotype associations-11 132 cis-gene expression traits in 450 individuals and 93 circulating biomarkers in all 680 individuals. From a total of 11 657 229 high-quality variants of which 6 129 221 and 5 528 008 were common and low frequency (<5%), respectively, low frequency-large effect associations comprised 7% of detectable cis-gene expression traits [89 of 1314 cis-eQTLs at P < 1 × 10(-06) (false discovery rate ∼5%)] and one of eight biomarker associations at P < 8 × 10(-10). Very few (30 of 1232; 2%) common variant associations were fully explained by low-frequency variants. Our data show that whole-genome sequencing can identify low-frequency variants undetected by genotyping based approaches when sample sizes are sufficiently large to detect substantial numbers of common variant associations, and that common variant associations are rarely explained by single low-frequency variants of large effect

Occurrence of a Rabl-like telomere clustering in the holocentric chromosome of the peach potato aphid Myzus persicae (Hemiptera; Aphididae).

Several studies demonstrated that chromosome anchoring to nuclear structures is involved in the organization of the interphase nucleus. The Rabl configuration, a well-studied chromosome organization in the interphase nucleus, has been deeply studied in organisms with monocentric chromosomes but just slightly touched in species with holocentric chromosomes. In the present paper, by means of the isolation and chromosomal mapping of the C0t DNA fraction and chromatin immunoprecipitation with anti-LEM-2 antibodies, we evidenced the presence of few foci where telomeres and subtelomeric regions cluster in the aphid interphase nuclei, suggesting the occurrence of a Rabl-like chromosome configuration. The same experimental approaches also evidenced that most of the repetitive DNA of the 2 X chromosomes is located at the periphery of the nucleus, whereas the ribosomal genes, located at 1 telomere of each X chromosome, are present towards the inner portion of the nucleus, favoring their transcriptional activity