Identification of a Serum-Induced Transcriptional Signature Associated With Type 1 Diabetes in the BioBreeding Rat

OBJECTIVE - Inflammatory mediators associated with type 1 diabetes are dilute and difficult to measure in the periphery, necessitating development of more sensitive and informative biomarkers for studying diabetogenic mechanisms, assessing preonset risk, and monitoring therapeutic interventions. RESEARCH DESIGN AND METHODS - We previously utilized a novel bioassay in which human type 1 diabetes sera were used to induce a disease-specific transcriptional signature in unrelated, healthy peripheral blood mononuclear cells (PBMCs). Here, we apply this strategy to investigate the inflammatory state associated with type 1 diabetes in biobreeding (BB) rats. RESULTS - Consistent with their common susceptibility, sera of both spontaneously diabetic BB DRlyp/lyp and diabetes inducible BB DR+/+ rats induced transcription of cytokines, immune receptors, and signaling molecules in PBMCs of healthy donor rats compared with control sera. Like the human type 1 diabetes signature, the DRlyp/lyp signature, which is associated with progression to diabetes, was differentiated from that of the DR+/+ by induction of many interleukin (IL)-1-regulated genes. Supplementing cultures with an IL-1 receptor antagonist (IL-1Ra) modulated the DRlyp/lyp signature (P < 10-6), while administration of IL-1Ra to DRlyp/lyp rats delayed onset (P = 0.007), and sera of treated animals did not induce the characteristic signature. Consistent with the presence of immunoregulatory cells in DR+/+ rats was induction of a signature possessing negative regulators of transcription and inflammation. CONCLUSIONS - Paralleling our human studies, serum signatures in BB rats reflect processes associated with progression to type 1 diabetes. Furthermore, these studies support the potential utility of this approach to detect changes in the inflammatory state during therapeutic intervention

Identification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humans

The genetic basis of type 2 diabetes remains incompletely defined despite the use of multiple genetic strategies. Multiparental populations such as heterogeneous stocks (HS) facilitate gene discovery by allowing fine mapping to only a few megabases, significantly decreasing the number of potential candidate genes compared to traditional mapping strategies. In the present work, we employed expression and sequence analysis in HS rats (Rattus norvegicus) to identify Tpcn2 as a likely causal gene underlying a 3.1-Mb locus for glucose and insulin levels. Global gene expression analysis on liver identified Tpcn2 as the only gene in the region that is differentially expressed between HS rats with glucose intolerance and those with normal glucose regulation. Tpcn2 also maps as a cis-regulating expression QTL and is negatively correlated with fasting glucose levels. We used founder sequence to identify variants within this region and assessed association between 18 variants and diabetic traits by conducting a mixed-model analysis, accounting for the complex family structure of the HS. We found that two variants were significantly associated with fasting glucose levels, including a nonsynonymous coding variant within Tpcn2. Studies in Tpcn2 knockout mice demonstrated a significant decrease in fasting glucose levels and insulin response to a glucose challenge relative to those in wild-type mice. Finally, we identified variants within Tpcn2 that are associated with fasting insulin in humans. These studies indicate that Tpcn2 is a likely causal gene that may play a role in human diabetes and demonstrate the utility of multiparental populations for positionally cloning genes within complex loci

The Gene Ontology knowledgebase in 2023

The Gene Ontology (GO) knowledgebase (http://geneontology.org) is a comprehensive resource concerning the functions of genes and gene products (proteins and noncoding RNAs). GO annotations cover genes from organisms across the tree of life as well as viruses, though most gene function knowledge currently derives from experiments carried out in a relatively small number of model organisms. Here, we provide an updated overview of the GO knowledgebase, as well as the efforts of the broad, international consortium of scientists that develops, maintains, and updates the GO knowledgebase. The GO knowledgebase consists of three components: (1) the GO-a computational knowledge structure describing the functional characteristics of genes; (2) GO annotations-evidence-supported statements asserting that a specific gene product has a particular functional characteristic; and (3) GO Causal Activity Models (GO-CAMs)-mechanistic models of molecular "pathways" (GO biological processes) created by linking multiple GO annotations using defined relations. Each of these components is continually expanded, revised, and updated in response to newly published discoveries and receives extensive QA checks, reviews, and user feedback. For each of these components, we provide a description of the current contents, recent developments to keep the knowledgebase up to date with new discoveries, and guidance on how users can best make use of the data that we provide. We conclude with future directions for the project

The Gene Ontology knowledgebase in 2023

The Gene Ontology (GO) knowledgebase (http://geneontology.org) is a comprehensive resource concerning the functions of genes and gene products (proteins and noncoding RNAs). GO annotations cover genes from organisms across the tree of life as well as viruses, though most gene function knowledge currently derives from experiments carried out in a relatively small number of model organisms. Here, we provide an updated overview of the GO knowledgebase, as well as the efforts of the broad, international consortium of scientists that develops, maintains, and updates the GO knowledgebase. The GO knowledgebase consists of three components: (1) the GO-a computational knowledge structure describing the functional characteristics of genes; (2) GO annotations-evidence-supported statements asserting that a specific gene product has a particular functional characteristic; and (3) GO Causal Activity Models (GO-CAMs)-mechanistic models of molecular "pathways" (GO biological processes) created by linking multiple GO annotations using defined relations. Each of these components is continually expanded, revised, and updated in response to newly published discoveries and receives extensive QA checks, reviews, and user feedback. For each of these components, we provide a description of the current contents, recent developments to keep the knowledgebase up to date with new discoveries, and guidance on how users can best make use of the data that we provide. We conclude with future directions for the project

The Gene Ontology resource: enriching a GOld mine

The Gene Ontology Consortium (GOC) provides the most comprehensive resource currently available for computable knowledge regarding the functions of genes and gene products. Here, we report the advances of the consortium over the past two years. The new GO-CAM annotation framework was notably improved, and we formalized the model with a computational schema to check and validate the rapidly increasing repository of 2838 GO-CAMs. In addition, we describe the impacts of several collaborations to refine GO and report a 10% increase in the number of GO annotations, a 25% increase in annotated gene products, and over 9,400 new scientific articles annotated. As the project matures, we continue our efforts to review older annotations in light of newer findings, and, to maintain consistency with other ontologies. As a result, 20 000 annotations derived from experimental data were reviewed, corresponding to 2.5% of experimental GO annotations. The website (http://geneontology.org) was redesigned for quick access to documentation, downloads and tools. To maintain an accurate resource and support traceability and reproducibility, we have made available a historical archive covering the past 15 years of GO data with a consistent format and file structure for both the ontology and annotations

State Immunity and War Crimes: the Polish Supreme Court on the Natoniewski Case

The article critically assesses the decision of the Polish Supreme Court in Natoniewski v. Federal Republic of Germany. It argues that the decision as such reflects contemporary international law practice. Consequently, the holding of the Supreme Court that State immunity is applicable to acts de iure imperii committed on the territory of the forum State during an armed conflict even though they may amount to war crimes seems to be correct. This conclusion also means that the Court refused to engage in law-making activity by declining to endorse interpretation, which would permit to reject State immunity by attaching superior importance to human rights. Although the article recognizes that the reasoning of the Supreme Court as well as the choice of arguments is well-balanced and convincing, it also identifies certain instances in which the Court is not entirely persuasive. In the opinion of the author, one of the most important drawbacks in the reasoning relates to the characterization of State immunity as a procedural, rather than substantive, issue

Numerical analysis of the deep drawing process including the history of stress and strain

This paper discusses the results of a numerical study of circular cup drawing of steel sheets using finite element method. The drawing process is considered as a geometrical and physical nonlinear problem with unknown boundary conditions in the contact area of the system, such as the tool and the workpiece. The updated Lagrangian description is used to characterize these nonlinear phenomena on a typical incremental step time. Numerical results are obtained using an explicit method in Ansys/Ls-Dyna program. The constitutive Cowper-Symonds material model with linear hardening strain to predict material plasticity is used. The results of implementation of stresses and strains from a blanking operation flat disc of a sheet of metal for deep-drawing process are presented. After the blanking process simulation, an implicit springback analysis is performed. Then a numerical analysis of cup forming from this flat disc plate was carried out. The analysis results are compared with one another through reading of the sheet thickness in several characteristic points and the overall height of the product