tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia

Pontocerebellar hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or hypoplasia of the cerebellum, hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders.     

Genome-wide association study of prostate cancer identifies a second risk locus at 8q24

Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting a genome-wide association study in the Cancer Genetic Markers of Susceptibility project with 550,000 SNPs in a nested case-control study (1,172 cases and 1,157 controls of European origin), we identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal is 70 kb centromeric to the previously reported SNP, rs1447295, but shows little evidence of linkage disequilibrium with it. A combined analysis with four additional studies (total: 4,296 cases and 4,299 controls) confirms association with prostate cancer for rs6983267 in the centromeric locus (P = 9.42 x 10(-13); heterozygote odds ratio (OR): 1.26, 95% confidence interval (c.i.): 1.13-1.41; homozygote OR: 1.58, 95% c.i.: 1.40-1.78). Each SNP remained significant in a joint analysis after adjusting for the other (rs1447295 P = 1.41 x 10(-11); rs6983267 P = 6.62 x 10(-10)). These observations, combined with compelling evidence for a recombination hotspot between the two markers, indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. We estimate that the population attributable risk of the new locus, marked by rs6983267, is higher than the locus marked by rs1447295 (21% versus 9%).     

A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (P(trend) for the most strongly associated SNP (rs1219648) = 1.1 x 10(-10); population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.     

Mechanism of variations in environmental magnetic proxies of lake sediments from Nam Co, Tibet during the Holocene

High-resolution environmental records from the Tibetan Plateau are essential to understand past global climatic and environmental changes. Magnetic minerals in lake sediments are important proxies to reconstruct environmental and climatic changes. Nam Co (lake) is a typical great lake in the transitional region of southwest monsoon in the Tibetan Plateau. Previous studies have extensively focused on geochemistry, microfossils, sedimentology and biochemistry analysis of Nam Co, which provides sound interpretation of paleoclimatic and paleoenvironmental changes. However, up to now, no systematic environmental magnetic studies have been carried out. Therefore, high-resolution and systematic magnetic studies combined with geochemical parameters were carried on lake sediments of core NC 08/01 from Nam Co for the Holocene period (11.3 cal ka BP) in order to explore how magnetic properties of the sediments respond to climatic changes. Based on variations of magnetic proxies, the sequence can be separated into 3 units. Unit 1 (236-199 cm, 11.3-7.8 cal ka BP) contains dominantly coarse-grained magnetite with homogeneous grain size. A positive correlation between magnetite and Ti strongly suggests that these coarse-grained detrital magnetites reflect detrital input signals due to insignificant effects of postdepositional dissolution processes on these coarse-grained magnetite particles. For Unit 2 (198-102 cm, 7.8-2.1 cal ka BP), magnetic grain size is finer and the corresponding concentration of magnetite is also reduced. This is mainly due to significant dissolution of these fine-grained detrital magnetite particles, which were transported under reduced water flow conditions during this period. For Unit 3 (101-0 cm, 2.1-0 cal ka BP), the bulk magnetic properties are dominated by a mixture of single domain biogenic magnetite and detrital magnetite. The concentration of magnetic minerals is not correlated with the Ti content. In conclusion, the preservation of magnetic minerals in the lake sediment and thus the corresponding magnetic properties are related to the initial grain size. Combination of magnetic properties (including variation of grain size and concentration) and other proxies of detrital inputs (e.g. Ti) can be used to infer the variation of redox conditions in Nam Co. These results provide a viable framework for reconstructing the paleoenvironmental changes of this lake.     

WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion

A key question in systems biology is how diverse physiologic processes are integrated to produce global homeostasis. Genetic analysis can contribute by identifying genes that perturb this integration. One system orchestrates renal NaCl and K+ flux to achieve homeostasis of blood pressure and serum K+ concentration. Positional cloning implicated the serine-threonine kinase WNK4 in this process; clustered mutations in PRKWNK4, encoding WNK4, cause hypertension and hyperkalemia (pseudohypoaldosteronism type II, PHAII) by altering renal NaCl and K+ handling. Wild-type WNK4 inhibits the renal Na-Cl cotransporter (NCCT); mutations that cause PHAII relieve this inhibition. This explains the hypertension of PHAII but does not account for the hyperkalemia. By expression in Xenopus laevis oocytes, we show that WNK4 also inhibits the renal K+ channel ROMK. This inhibition is independent of WNK4 kinase activity and is mediated by clathrin-dependent endocytosis of ROMK, mechanisms distinct from those that characterize WNK4 inhibition of NCCT. Most notably, the same mutations in PRKWNK4 that relieve NCCT inhibition markedly increase inhibition of ROMK. These findings establish WNK4 as a multifunctional regulator of diverse ion transporters; moreover, they explain the pathophysiology of PHAII. They also identify WNK4 as a molecular switch that can vary the balance between NaCl reabsorption and K+ secretion to maintain integrated homeostasis.     

Die Reizbewegungen der Mimosoideen und ihre Hormone

Summary The irritation substances of various plants of the family of Mimosoideae are highly sensitive to oxygen, and their chemical behaviour is that of reductones. Just the same substances were also found in non-sensitive plants. Meso-inositol is perhaps one of the original compounds leading to the active substances. It became possible to explain some characteristics of the irritation-process ofMimosa pudica by regarding known properties of reductones, i.e. the irritation reaction, the restitution, the influence of sun-light and their sleeping in darkness.

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Herrn Prof.Arthur Stoll zum 70. Geburtstag gewidmet.

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Aus dem chemischen Institut der Universität Freiburg i. Br. und dem Institut für organische Chemie an der Universität Erlangen.

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Mein lieber Freund Dr.B. Banerjee hat die Fortsetzung dieser Untersuchung nicht mehr erlebt. Noch während seines Aufenthalts in Deutschland überfiel ihn die tückische Krankheit, der er kurz nach seiner Heimkehr erlag.     

Ancient, highly heterogeneous mantle beneath Gakkel ridge, Arctic Ocean

The Earth's mantle beneath ocean ridges is widely thought to be depleted by previous melt extraction, but well homogenized by convective stirring. This inference of homogeneity has been complicated by the occurrence of portions enriched in incompatible elements. Here we show that some refractory abyssal peridotites from the ultraslow-spreading Gakkel ridge (Arctic Ocean) have very depleted 187Os/188Os ratios with model ages up to 2 billion years, implying the long-term preservation of refractory domains in the asthenospheric mantle rather than their erasure by mantle convection. The refractory domains would not be sampled by mid-ocean-ridge basalts because they contribute little to the genesis of magmas. We thus suggest that the upwelling mantle beneath mid-ocean ridges is highly heterogeneous, which makes it difficult to constrain its composition by mid-ocean-ridge basalts alone. Furthermore, the existence of ancient domains in oceanic mantle suggests that using osmium model ages to constrain the evolution of continental lithosphere should be approached with caution.