Performance evaluation of discrete event systems involving Henstock-Kurzweil integral

This paper presents a study on the performance of flexible manufacturing systems (FMSs), by using discrete event system (DES) models, considering resource losses modelled by a parameter entitled coverage factor. We conclude that the resources cell loss distribution between the tasks of a FSM is a real function that cannot be integrated, in order to calculate its primitive, in the classical sense of Riemann or Lebesgue, but only in the sense of Henstock-Kurzweil integral. Our result allows one to study more general processes where highly oscillatory functions occur. The method used to deduce the function describing the resources cell loss distribution is compared with a classical method related in the literature, respectively rational interpolants. An example has been constructed to emphasize what we believe to be, new approaches.     

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10(-10)) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.     

Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk

To identify risk variants for multiple myeloma, we conducted a genome-wide association study of 1,675 individuals with multiple myeloma and 5,903 control subjects. We identified risk loci for multiple myeloma at 3p22.1 (rs1052501 in ULK4; odds ratio (OR) = 1.32; P = 7.47 × 10(-9)) and 7p15.3 (rs4487645, OR = 1.38; P = 3.33 × 10(-15)). In addition, we observed a promising association at 2p23.3 (rs6746082, OR = 1.29; P = 1.22 × 10(-7)). Our study identifies new genomic regions associated with multiple myeloma risk that may lead to new etiological insights.     

Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33

Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10?1? and rs6687758, OR = 1.09, P = 2.27 × 10??, 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10??), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10?1? and rs7136702, OR = 1.06, P = 4.02 × 10??) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10?1?). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.     

A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3)

To identify susceptibility loci for classical Hodgkin's lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10(-8)), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10(-13)) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10(-8)). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10(-50)). These data provide new insight into the pathogenesis of cHL.     

The Role of Formalisation, Participation and Context in the Success of Public Involvement Mechanisms in Resource Management

In the face of complex and uncertain issues, one important goal of public participation in resource management and research is to foster communication and the inclusion of non-expert knowledge—thus the effective flow of information between project organisers and stakeholders. We compare different methods (instruments, tools) that were employed in the German–Austrian ‘PartizipA’ project to structure information flows in participatory processes. Depending on their goals and context, more or less ‘formalised’ and ‘participatory’ methods were applied, the most important being guided interviews, focus groups, agent-based modelling, nutrient modelling, cognitive mapping and group model building as well as the development of a common document. Two regional case studies, both concerned with European-induced institutional change, are portrayed in which the specific participatory methods were embedded. The Austrian case study involved the analysis and modelling of agricultural land use in the region of St. Pölten against the background of the reform of the Common Agricultural Policy, while the implementation of recent European water policy was the issue in the German agricultural region north of Osnabrück. Presenting both cases in their regional context, the applied methods are first described according to the logic of the entire respective process. Subsequently, the specific methods are systematically analysed and compared according to their objective, context and degrees of participation and formalisation. Finally, we evaluate all methods regarding their effectiveness in terms of goal attainment and their potential generalisation, seeking to respond to the question of when a particular method might best be used.     

Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance

G proteins are an important class of regulatory switches in all living systems. They are activated by guanine nucleotide exchange factors (GEFs), which facilitate the exchange of GDP for GTP. This activity makes GEFs attractive targets for modulating disease-relevant G-protein-controlled signalling networks. GEF inhibitors are therefore of interest as tools for elucidating the function of these proteins and for therapeutic intervention; however, only one small molecule GEF inhibitor, brefeldin A (BFA), is currently available. Here we used an aptamer displacement screen to identify SecinH3, a small molecule antagonist of cytohesins. The cytohesins are a class of BFA-resistant small GEFs for ADP-ribosylation factors (ARFs), which regulate cytoskeletal organization, integrin activation or integrin signalling. The application of SecinH3 in human liver cells showed that insulin-receptor-complex-associated cytohesins are required for insulin signalling. SecinH3-treated mice show increased expression of gluconeogenic genes, reduced expression of glycolytic, fatty acid and ketone body metabolism genes in the liver, reduced liver glycogen stores, and a compensatory increase in plasma insulin. Thus, cytohesin inhibition results in hepatic insulin resistance. Because insulin resistance is among the earliest pathological changes in type 2 diabetes, our results show the potential of chemical biology for dissecting the molecular pathogenesis of this disease.