Antagonism between Ca and Na ions at neurohypophysial nerve terminals

Résumé La secrétion hormonale de neurohypophyses isolées de rat a été estimée à l'aide d'un test d'éjection du lait. Au moment de la dépolarisation des terminaisons neurosecrétrices, il y a compétition entre le sodium et le calcium externes pour d'hypothétiques sites membranaires. Pour des concentrations de calcium inférieures ou égales à la concentration physiologique, la libération hormonale est fonction du rapport [Ca²⁺]/[Na⁺]² dans le milieu externe.

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This work was supported by grants from the Swiss National Science Foundation No. 5340.3 and 3.556.71 and the F. Hoffmann-La-Roche Foundation No. 117.     

On the storage and mobilization of organic resources in the hepatopancreas of a crab (Paratelphusa hydrodromus)

Résumé Etude des changements cycliques observés dans les hydrates de carbone et les lipides contenus dans l'hépatopancreas du crabeParatelphusa hydrodromus pendant le cycle de mue.     

Recovery and identification of interferon in the rabbit urine

Riassunto È stato dimostrato che l'inoculazione endovenosa di virus Sindbis nel coniglio provoca formazione di interferone che viene liberato nel sangue ed escreto con le urine. L'interferone urinario sembra derivare quasi completamente dal siero, ha alti titoli ed ha le stesse proprietà fisico-chimiche e biologiche dell'interferone sierico.     

Effects of continued pentaerythritol tetranitrate administration on myocardial circulation and metabolism

Zusammenfassung Die Untersuchungsergebnisse stützen die Vorstellung, dass die gute Wirkung der prophylaktischen Anwendung von Pentaerythritol-tetranitrat bei Patienten mit Coronarinsuffizienz auf Abnahme der Herztätigkeit und Zunahme der Herzmuskelleistung, nicht aber auf eine Zunahme des Coronarkreislaufes zurückzuführen ist.     

Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies

Muscle eye brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD) are congenital muscular dystrophies with associated, similar brain malformations. The FCMD gene, fukutin, shares some homology with fringe-like glycosyltransferases, and the MEB gene, POMGnT1, seems to be a new glycosyltransferase. Here we show, in both MEB and FCMD patients, that alpha-dystroglycan is expressed at the muscle membrane, but similar hypoglycosylation in the diseases directly abolishes binding activity of dystroglycan for the ligands laminin, neurexin and agrin. We show that this post-translational biochemical and functional disruption of alpha-dystroglycan is recapitulated in the muscle and central nervous system of mutant myodystrophy (myd) mice. We demonstrate that myd mice have abnormal neuronal migration in cerebral cortex, cerebellum and hippocampus, and show disruption of the basal lamina. In addition, myd mice reveal that dystroglycan targets proteins to functional sites in brain through its interactions with extracellular matrix proteins. These results suggest that at least three distinct mammalian genes function within a convergent post-translational processing pathway during the biosynthesis of dystroglycan, and that abnormal dystroglycan-ligand interactions underlie the pathogenic mechanism of muscular dystrophy with brain abnormalities.     

Isolation of pathogenic treponemes from hare.

A presumably new species of pathogenic treponemes was isolated from a lesion on the male organs of hare (Lepus sp.) and the scrotum of a rabbit (Oryctolagus sp.) was infected with this treponeme. Lesion developed on the scrotum after a 110-day incubation.     

Variations in DNA elucidate molecular networks that cause disease

Identifying variations in DNA that increase susceptibility to disease is one of the primary aims of genetic studies using a forward genetics approach. However, identification of disease-susceptibility genes by means of such studies provides limited functional information on how genes lead to disease. In fact, in most cases there is an absence of functional information altogether, preventing a definitive identification of the susceptibility gene or genes. Here we develop an alternative to the classic forward genetics approach for dissecting complex disease traits where, instead of identifying susceptibility genes directly affected by variations in DNA, we identify gene networks that are perturbed by susceptibility loci and that in turn lead to disease. Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. Our analysis provides direct experimental support that complex traits such as obesity are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors.     

Genome-wide association analysis identifies three new breast cancer susceptibility loci

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ～8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ～70,000 cases and ～68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.     

PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene

PALB2 interacts with BRCA2, and biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia. We identified monoallelic truncating PALB2 mutations in 10/923 individuals with familial breast cancer compared with 0/1,084 controls (P = 0.0004) and show that such mutations confer a 2.3-fold higher risk of breast cancer (95% confidence interval (c.i.) = 1.4-3.9, P = 0.0025). The results show that PALB2 is a breast cancer susceptibility gene and further demonstrate the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition.     

Celiac disease patient IgA antibodies induce endothelial adhesion and cell polarization defects via extracellular transglutaminase 2

We have recently found that celiac disease patient serum-derived autoantibodies targeted against transglutaminase 2 interfere with several steps of angiogenesis, including endothelial sprouting and migration, though the mechanism involved remained to be fully characterized. This study now investigated the processes underlying the antiangiogenic effects exerted by celiac disease patient antibodies on endothelial cells, with particular regard to the adhesion, migration, and polarization signaling pathway. We observed that celiac IgA reduced endothelial cell numbers by affecting adhesion without increasing apoptosis. Endothelial cells in the presence of celiac IgA showed weak attachment, a high susceptibility to detach from fibronectin, and a disorganized extracellular matrix due to a reduction of protein cross-links. Furthermore, celiac patient IgA led to secretion of active transglutaminase 2 from endothelial cells into the culture supernatants. Additionally, cell surface transglutaminase 2 mediated integrin clustering in the presence of celiac IgA was coupled to augmented expression of β1-integrin. We also observed that celiac patient IgA-treated endothelial cells had migratory defects and a less polarized phenotype when compared to control groups, and this was associated with the RhoA signaling pathway. These biological effects mediated by celiac IgA on endothelial cells were partially influenced but not completely abolished by R281, an irreversible extracellular transglutaminase 2 enzymatic activity inhibitor. Taken together, our results imply that celiac patient IgA antibodies disturb the extracellular protein cross-linking function of transglutaminase 2, thus altering cell-extracellular matrix interactions and thereby affecting endothelial cell adhesion, polarization, and motility.