Climatic control of riverine and seawater uranium-isotope ratios

The large variation in the ratio of uranium-234 to uranium-238 (234U/238U) in rivers is not well understood, but may provide information about past weathering and rainfall and is important because it controls seawater (234U/238U). Here, we demonstrate the importance of physical weathering and rainfall for (234U/238U), using rivers from South Island, New Zealand. These data allow interpretation of an existing speleothem (234U/238U) record and suggest that New Zealand glacier advance 13,000 years ago was influenced by increased rainfall rather than by Younger Dryas-like cooling. A model of seawater (234U/238U) during glacial cycles indicates that rejection of corals based on modern (234U/238U) +/- <0.01 is not merited and may reject the highest quality ages.     

Mutational inactivation of STAG2 causes aneuploidy in human cancer

Most cancer cells are characterized by aneuploidy, an abnormal number of chromosomes. We have identified a clue to the mechanistic origins of aneuploidy through integrative genomic analyses of human tumors. A diverse range of tumor types were found to harbor deletions or inactivating mutations of STAG2, a gene encoding a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Because STAG2 is on the X chromosome, its inactivation requires only a single mutational event. Studying a near-diploid human cell line with a stable karyotype, we found that targeted inactivation of STAG2 led to chromatid cohesion defects and aneuploidy, whereas in two aneuploid human glioblastoma cell lines, targeted correction of the endogenous mutant alleles of STAG2 led to enhanced chromosomal stability. Thus, genetic disruption of cohesin is a cause of aneuploidy in human cancer.     

Cross-linking cellular prion protein triggers neuronal apoptosis in vivo

Neuronal death is a prominent, but poorly understood, pathological hallmark of prion disease. Notably, in the absence of the cellular prion protein (PrPC), the disease-associated isoform, PrPSc, appears not to be intrinsically neurotoxic, suggesting that PrPC itself may participate directly in the prion neurodegenerative cascade. Here, cross-linking PrPC in vivo with specific monoclonal antibodies was found to trigger rapid and extensive apoptosis in hippocampal and cerebellar neurons. These findings suggest that PrPC functions in the control of neuronal survival and provides a model to explore whether cross-linking of PrPC by oligomeric PrPSc can promote neuronal loss during prion infection.     

A Burkholderia pseudomallei toxin inhibits helicase activity of translation factor eIF4A

The structure of BPSL1549, a protein of unknown function from Burkholderia pseudomallei, reveals a similarity to Escherichia coli cytotoxic necrotizing factor 1. We found that BPSL1549 acted as a potent cytotoxin against eukaryotic cells and was lethal when administered to mice. Expression levels of bpsl1549 correlate with conditions expected to promote or suppress pathogenicity. BPSL1549 promotes deamidation of glutamine-339 of the translation initiation factor eIF4A, abolishing its helicase activity and inhibiting translation. We propose to name BPSL1549 Burkholderia lethal factor 1.     

Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation

The canonical Wnt-beta-catenin signaling pathway is initiated by inducing phosphorylation of one of the Wnt receptors, low-density lipoprotein receptor-related protein 6 (LRP6), at threonine residue 1479 (Thr1479) and serine residue 1490 (Ser1490). By screening a human kinase small interfering RNA library, we identified phosphatidylinositol 4-kinase type II alpha and phosphatidylinositol-4-phosphate 5-kinase type I (PIP5KI) as required for Wnt3a-induced LRP6 phosphorylation at Ser1490 in mammalian cells and confirmed that these kinases are important for Wnt signaling in Xenopus embryos. Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [PtdIns (4,5)P2] through frizzled and dishevelled, the latter of which directly interacted with and activated PIP5KI. In turn, PtdIns (4,5)P2 regulated phosphorylation of LRP6 at Thr1479 and Ser1490. Therefore, our study reveals a signaling mechanism for Wnt to regulate LRP6 phosphorylation.     

Carotenogenesis up-regulation in Scenedesmus sp. using a targeted metabolomics approach by liquid chromatography-high-resolution mass spectrometry

Carotenoids have potent antioxidant activity as well as therapeutic value, and their formation has been seen to be induced in algae by stress, including high-salt culture conditions. A differential profiling of carotenoids was conducted using a targeted metabolomics approach with accurate mass data generated by liquid chromatography-electrospray-time-of-flight (LC-ESI-TOF) mass spectrometry followed by postacquisition filtering based on isotope patterns and mass defects to detect carotenoids up-regulated in Scenedesmus sp. exposed to high-salt conditions. Algal cultures treated with high concentrations of sodium acetate or sodium chloride were found to cause an increase in various carotenoids. On the basis of differential analysis, astaxanthin and canthaxanthin increased upon salt treatment. Astaxanthin, in its free form and as fatty acid esters, was seen to increase in Scenedesmus sp. using accurate mass MS. A few other carotenoid compounds increased upon salt treatment, including echinenone and adonirubin, involved in the pathway of astaxanthin biosynthesis from β-carotene, as well as isomers of astaxanthin and canthaxanthin. A time course study of acetate treatment was done to observe the time-dependent up-regulation of carotenogenesis.