Blockade of GABAB receptors accelerates amygdala kindling development.

The aim of this study was to investigate the putative role of GABAB receptors in the development of amygdala kindling in rats. The effects of the GABAB blocker CGP 35348 and the GABAB agonist baclofen on the progressive development of behavioural seizure symptoms (stages 1-5 classified by Racine) and duration of after-discharges (AD) were studied. CGP 35348 at a dose of 300 mg/kg i.p., which blocks central GABAB receptors, moderately but consistently accelerated the development of behavioural seizure symptoms. CGP 35348 had no marked effect on the duration of ADs corresponding to the different seizure stages. L-baclofen (6 mg/kg i.p.) had a dual effect on kindling development. It retarded the development of the behavioural symptoms, but increased the duration of AD. In conclusion, the results suggest that synaptically-released GABA activated GABAB receptors and thereby exerted a depressant effect on kindling development.     

The effect of diasone® sodium on the iodide uptake in the rat thyroid

Zusammenfassung Diasone® Sodium hemmt die Aufnahme von Radiojod in der Schilddrüse der Ratte. Diese Wirkung entsteht wahrscheinlich durch Hemmung der Jodid-Peroxydase.     

A stellar relic from the early Milky Way

The chemical composition of the most metal-deficient stars largely reflects the composition of the gas from which they formed. These old stars provide crucial clues to the star formation history and the synthesis of chemical elements in the early Universe. They are the local relics of epochs otherwise observable only at very high redshifts; if totally metal-free ('population III') stars could be found, this would allow the direct study of the pristine gas from the Big Bang. Earlier searches for such stars found none with an iron abundance less than 1/10,000 that of the Sun, leading to the suggestion that low-mass stars could form from clouds above a critical iron abundance. Here we report the discovery of a low-mass star with an iron abundance as low as 1/200,000 of the solar value. This discovery suggests that population III stars could still exist--that is, that the first generation of stars also contained long-lived low-mass objects. The previous failure to find them may be an observational selection effect.     

KIR expression on self-reactive CD8+ T cells is controlled by T-cell receptor engagement

Natural killer cell tolerance is maintained by the interaction of killer inhibitory receptors (KIRs) with self-major histocompatibility complex class I gene products. A subset of T cells also expresses inhibitory receptors, but the functional significance of these receptors on T cells is unclear. Here we show that, in the absence of T-cell receptor (TCR) engagement, KIRs expressed on CD8+ T cells are slowly downregulated by KIR ligands expressed on antigen-presenting cells. The resulting expression levels of KIR are no longer able to inhibit T-cell function. In contrast, TCR engagement sustains KIR expression, and re-induces functional levels of KIR expression after ligand-induced downregulation of KIR. Our data indicate that KIR expression on CD8+ T cells in vivo may be maintained through continuous encounters with antigen. As KIR-mediated inhibition of T-cell activation can be bypassed at high antigen concentrations, dynamic KIR expression may mediate T-cell tolerance to self-antigens by sparing self-reactive T cells, thus enabling them to mediate potentially useful immune functions to quantitatively or qualitatively different antigens.     

Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo- and a Cys-His domain.

The activity of the rat insulin I gene enhancer is mainly dependent on two cis-acting protein-binding domains. Here we report the isolation of a complementary DNA encoding a protein, Isl-1, that binds to one of these domains. Isl-1 contains a homeodomain with greatest similarity to those of the Caenorhabditis elegans proteins encoded by mec-3 and lin-11. In addition, Isl-1, like the lin-11 and mec-3 gene products, contains a novel Cys-His domain which is reminiscent of known metal-binding regions. Together these proteins define a novel class of proteins containing both a homeo- and a Cys His-domain. Isl-1 is preferentially expressed in cells of pancreatic endocrine origin. If the structural homologies between Isl-1 and the C. elegans gene products reflect functional similarities, a role for Isl-1 in the development of pancreatic endocrine cells could be envisaged.     

Efficient mapping of mendelian traits in dogs through genome-wide association

With several hundred genetic diseases and an advantageous genome structure, dogs are ideal for mapping genes that cause disease. Here we report the development of a genotyping array with approximately 27,000 SNPs and show that genome-wide association mapping of mendelian traits in dog breeds can be achieved with only approximately 20 dogs. Specifically, we map two traits with mendelian inheritance: the major white spotting (S) locus and the hair ridge in Rhodesian ridgebacks. For both traits, we map the loci to discrete regions of <1 Mb. Fine-mapping of the S locus in two breeds refines the localization to a region of approximately 100 kb contained within the pigmentation-related gene MITF. Complete sequencing of the white and solid haplotypes identifies candidate regulatory mutations in the melanocyte-specific promoter of MITF. Our results show that genome-wide association mapping within dog breeds, followed by fine-mapping across multiple breeds, will be highly efficient and generally applicable to trait mapping, providing insights into canine and human health.     

IL-18 in inflammatory and autoimmune disease

Inflammation serves as the first line of defense in response to tissue injury, guiding the immune system to ensure preservation of the host. The inflammatory response can be divided into a quick initial phase mediated mainly by innate immune cells including neutrophils and macrophages, followed by a late phase that is dominated by lymphocytes. Early in the new millennium, a key component of the inflammatory reaction was discovered with the identification of a number of cytosolic sensor proteins (Nod-like receptors) that assembled into a common structure, the ‘inflammasome’. This structure includes an enzyme, caspase-1, which upon activation cleaves pro-forms of cytokines leading to subsequent release of active IL-1 and IL-18. This review focuses on the role of IL-18 in inflammatory responses with emphasis on autoimmune diseases.     

MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer

Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker alpha-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy.     

Separate and simultaneous effects of ethanol,hypertonic saline and insulin on the function of the subcommissural organ

Zusammenfassung Das sogenannte Subkommissuralorgan, welches sich aus Ependymzellen am Anfang des Aquaeductus cerebri aufbaut, zeigt sekretorische Elemente. Es handelt sich dabei um Mucopolysaccharide. Diese sind vergleichbar dem neurosekretorischen Material im Hinterlappen der Hypophyse. Diese Massen lassen sich durch eine Fuchsinfärbung darstellen. Männlichen Ratten wurden 10%ige und 5%ige Äthylalkohol- und Salzlösungen mit Insulin verabreicht. Insulin-Alkohol- und Insulin-Wassergruppen wiesen eine Verminderung der Fuchsin-positiven Stoffe auf. Sowohl Alkohol wie Salz, einzeln verabreicht, führen zu einer Verminderung des Zellvolumens.