Positional Cloning of “Lisch-like”, a Candidate Modifier of Susceptibility to Type 2 Diabetes in Mice

In 404 Lepob/ob F2 progeny of a C57BL/6J (B6) x DBA/2J (DBA) intercross, we mapped a DBA-related quantitative trait locus (QTL) to distal Chr1 at 169.6 Mb, centered about D1Mit110, for diabetes-related phenotypes that included blood glucose, HbA1c, and pancreatic islet histology. The interval was refined to 1.8 Mb in a series of B6.DBA congenic/subcongenic lines also segregating for Lepob. The phenotypes of B6.DBA congenic mice include reduced β-cell replication rates accompanied by reduced β-cell mass, reduced insulin/glucose ratio in blood, reduced glucose tolerance, and persistent mild hypoinsulinemic hyperglycemia. Nucleotide sequence and expression analysis of 14 genes in this interval identified a predicted gene that we have designated “Lisch-like” (Ll) as the most likely candidate. The gene spans 62.7 kb on Chr1qH2.3, encoding a 10-exon, 646–amino acid polypeptide, homologous to Lsr on Chr7qB1 and to Ildr1 on Chr16qB3. The largest isoform of Ll is predicted to be a transmembrane molecule with an immunoglobulin-like extracellular domain and a serine/threonine-rich intracellular domain that contains a 14-3-3 binding domain. Morpholino knockdown of the zebrafish paralog of Ll resulted in a generalized delay in endodermal development in the gut region and dispersion of insulin-positive cells. Mice segregating for an ENU-induced null allele of Ll have phenotypes comparable to the B.D congenic lines. The human ortholog, C1orf32, is in the middle of a 30-Mb region of Chr1q23-25 that has been repeatedly associated with type 2 diabetes

Constitutional dynamics and partisan conflict:A comparative assessment of multi-level systems in Europe

publication-status: Publishedtypes: ArticleThe case studies revealed that the constitutional nature of a multi-level system indeed shapes its modes of day-to-day intergovernmental coordination and, with it, the way competences are (re)allocated in the longer term. Both in federal arrangements and in confederations, the ‘subunits’ – whose status is constitutionally protected – could more easily defend their decision-making capacity within their areas of jurisdiction because they can veto changes in the allocation of competences, an advantage lower-level governments in regionalized systems do not enjoy. Similarly, in federal and confederal systems day-to-day interaction in Inter Governmental Relations (IGR) predominantly took place in multilateral structures, while in regionalized systems bilateralism was more pronounced. The relative influence of party-political (in)congruence on IGR, in contrast, was more varied than theoretically expected

Parliament vs. Supreme court: a veto player framework of the Indian constitutional experiment in the area of economic and civil rights

Indian constitution, Property rights, Civil rights, Basic structure doctrine, Public interest litigation, Veto bargaining model, Veto player framework, Supreme Court, Parliament, D-74, K-11, K-40,