The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.     

Impaired amylase release from the parotid gland of rats treated with reserpine.

Using an automated system for the analysis of amylase, the release of this enzyme was compared in superfused parotid gland segments from control and reserpine treated rats. Stimulant-evoked amylase release was delayed and of smaller magnitude in the glands of the treated animals and a reduction of the transmembrane K+ gradient caused a smaller and short lasting reduction in Ach-evoked release of amylase in the glands from these animals.     

14-3-3sigma controls mitotic translation to facilitate cytokinesis

14-3-3 proteins are crucial in a wide variety of cellular responses including cell cycle progression, DNA damage checkpoints and apoptosis. One particular 14-3-3 isoform, sigma, is a p53-responsive gene, the function of which is frequently lost in human tumours, including breast and prostate cancers as a result of either hypermethylation of the 14-3-3sigma promoter or induction of an oestrogen-responsive ubiquitin ligase that specifically targets 14-3-3sigma for proteasomal degradation. Loss of 14-3-3sigma protein occurs not only within the tumours themselves but also in the surrounding pre-dysplastic tissue (so-called field cancerization), indicating that 14-3-3sigma might have an important tumour suppressor function that becomes lost early in the process of tumour evolution. The molecular basis for the tumour suppressor function of 14-3-3sigma is unknown. Here we report a previously unknown function for 14-3-3sigma as a regulator of mitotic translation through its direct mitosis-specific binding to a variety of translation/initiation factors, including eukaryotic initiation factor 4B in a stoichiometric manner. Cells lacking 14-3-3sigma, in marked contrast to normal cells, cannot suppress cap-dependent translation and do not stimulate cap-independent translation during and immediately after mitosis. This defective switch in the mechanism of translation results in reduced mitotic-specific expression of the endogenous internal ribosomal entry site (IRES)-dependent form of the cyclin-dependent kinase Cdk11 (p58 PITSLRE), leading to impaired cytokinesis, loss of Polo-like kinase-1 at the midbody, and the accumulation of binucleate cells. The aberrant mitotic phenotype of 14-3-3sigma-depleted cells can be rescued by forced expression of p58 PITSLRE or by extinguishing cap-dependent translation and increasing cap-independent translation during mitosis by using rapamycin. Our findings show how aberrant mitotic translation in the absence of 14-3-3sigma impairs mitotic exit to generate binucleate cells and provides a potential explanation of how 14-3-3sigma-deficient cells may progress on the path to aneuploidy and tumorigenesis.     

Human metabolic individuality in biomedical and pharmaceutical research

Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.     

The importance of extracellular calcium for acetylcholine-evoked salivary secretion

Zusammenfassung 5 min nach Beginn der Perfusion der Submandibularisdrüse der Katze mit einer kalziumfreien Flüssigkeit ist die Acetylcholin-induzierte Sekretionsrate nich reduziert, während dieselbe 5 min nach Einführen einer Na-freien Saccharoselösung blockiert ist. Dies zeigt, dass der Sekretionsprozess nicht durch Einströmen von Ca aus dem Extrazellulär- in den Intrazellulärraum ausgelöst wird.

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The technical assistance ofB. Lynderup andG. Pedersen is gratefully acknowledged.     

Influence of dormancy on the chemical composition ofStrophocheilus (Strophocheilidae,Pulmonata, Mollusca)

Résumé Pendant l'hibernation, leStrophocheilus (Pulmoné, Mollusque) perd de l'eau, du sodium, du calciun, du magnésium, du soufre, du cuivre, du fer et des carbohydrates totaux, mais son taux de potassium et d'iode augmente. En état d'estivation, il y en a perte d'eau, de sodium, de magnésium, de cuivre, de fer et de carbohydrates totaux, mais accumulation de calcium.     

Variations in nitrogenous compounds in the urine ofStrophocheilus (pulmonata,mollusca) with different diets

Résumé La composition de l'urine du pulmoné terrestreStrophocheilus oblongus musculus, spécialement le taux de l'urée, est un reflet des différences du contenu protéique des aliments. Ce fait confirme que le fonctionnement du rein des mollusques et des vertébrés est semblable.     

The importance of extracellular sodium and potassium for acetylcholine-evoked salivary secretion

Zusammenfassung Es wird gezeigt, dass die Speichelsekretionsrate der perfundierten SubmandibulardrÜse der Katze stark von der Natriumkonzentration im Perfusat abhängt. Die Sekretionsrate wird erhöht bei Perfusion mit kaliumfreier Lösung und reduziert während der Perfusion mit Lösungen erhöhter Kaliumkonzentrationen. Es ist möglich, dass ein durch Acetylcholin induzierter Natriumstrom in die Azinarzellen hinein den Sekretions mechanismus aktiviert.

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With the technical assistance of G.Pedersen.     

Progenitor cell maintenance requires numb and numblike during mouse neurogenesis

Neurons in most regions of the mammalian nervous system are generated over an extended period of time during development. Maintaining sufficient numbers of progenitors over the course of neurogenesis is essential to ensure that neural cells are produced in correct numbers and diverse types. The underlying molecular mechanisms, like those governing stem-cell self-renewal in general, remain poorly understood. We report here that mouse numb and numblike (Nbl), two highly conserved homologues of Drosophila numb, play redundant but critical roles in maintaining neural progenitor cells during embryogenesis, by allowing their progenies to choose progenitor over neuronal fates. In Nbl mutant embryos also conditionally mutant for mouse numb in the nervous system, early neurons emerge in the expected spatial and temporal pattern, but at the expense of progenitor cells, leading to a nearly complete depletion of dividing cells shortly after the onset of neurogenesis. Our findings show that a shared molecular mechanism, with mouse Numb and Nbl as key components, governs the self-renewal of all neural progenitor cells, regardless of their lineage or regional identities.