Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10(-8) to P = 2.7 × 10(-24)). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ～25% of the familial risk in this disease, have now been identified.     

THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia

Characterization of previously described intraflagellar transport (IFT) mouse mutants has led to the proposition that normal primary cilia are required for mammalian cells to respond to the sonic hedgehog (SHH) signal. Here we describe an N-ethyl-N-nitrosourea-induced mutant mouse, alien (aln), which has abnormal primary cilia and shows overactivation of the SHH pathway. The aln locus encodes a novel protein, THM1 (tetratricopeptide repeat-containing hedgehog modulator-1), which localizes to cilia. aln-mutant cilia have bulb-like structures at their tips in which IFT proteins (such as IFT88) are sequestered, characteristic of Chlamydomonas reinhardtii and Caenorhabditis elegans retrograde IFT mutants. RNA-interference knockdown of Ttc21b (which we call Thm1 and which encodes THM1) in mouse inner medullary collecting duct cells expressing an IFT88-enhanced yellow fluorescent protein fusion recapitulated the aln-mutant cilial phenotype, and live imaging of these cells revealed impaired retrograde IFT. In contrast to previously described IFT mutants, Smoothened and full-length glioblastoma (GLI) proteins localize to aln-mutant cilia. We hypothesize that the aln retrograde IFT defect causes sequestration of IFT proteins in aln-mutant cilia and leads to the overactivated SHH signaling phenotype. Specifically, the aln mutation uncouples the roles of anterograde and retrograde transport in SHH signaling, suggesting that anterograde IFT is required for GLI activation and that retrograde IFT modulates this event.     

Marine biodiversity on the Algerian Continental Shelf (Mediterranean Sea)

The Mediterranean Sea is known as a biodiversity hot spot, with 16,848 species reported. Biodiversity is higher in coastal areas and decreases with depth. However, knowledge about the southwestern sector remains scarce. For the last three decades, sampling of soft-bottom communities along the 1180 km of the shallow Algerian coast (0–136 m) has recorded 1642 macrobenthic species. There is a decreasing west–east species-richness gradient, especially for the total species richness and the amphipods. In addition, quantitative sampling in Bou Ismail Bay in summer 1988 (98 sampling sites for a total of 841 species) shows that diversity indices (i.e. species richness, >100 species for 0.2 m^?2; Shannon diversity, >6.0; and ES₅₀, >34) are among the highest for similar sand and muddy-fine sand communities in the Mediterranean Sea and the northeastern Atlantic Ocean. Bou Ismail Bay appears to have the highest species richness among Algerian bays, probably because of its variety of benthic habitats and the absence of significant pollution in this area. Monitoring must be undertaken to survey this high biodiversity, and a national strategy should be proposed to preserve high diversity zones.     

Bimodal processing of olfactory information in an amphibian nose: odor responses segregate into a medial and a lateral stream

In contrast to the single sensory surface present in teleost fishes, several spatially segregated subsystems with distinct molecular and functional characteristics define the mammalian olfactory system. However, the evolutionary steps of that transition remain unknown. Here we analyzed the olfactory system of an early diverging tetrapod, the amphibian Xenopus laevis, and report for the first time the existence of two odor-processing streams, sharply segregated in the main olfactory bulb and partially segregated in the olfactory epithelium of pre-metamorphic larvae. A lateral odor-processing stream is formed by microvillous receptor neurons and is characterized by amino acid responses and Gα_o/Gα_i as probable signal transducers, whereas a medial stream formed by ciliated receptor neurons is characterized by responses to alcohols, aldehydes, and ketones, and Gα_olf/cAMP as probable signal transducers. To reveal candidates for the olfactory receptors underlying these two streams, the spatial distribution of 12 genes from four olfactory receptor gene families was determined. Several class II and some class I odorant receptors (ORs) mimic the spatial distribution observed for the medial stream, whereas a trace amine-associated receptor closely parallels the spatial pattern of the lateral odor-processing stream. Other olfactory receptors (some class I odorant receptors and vomeronasal type 1 receptors) and odor responses (to bile acids, amines) were not lateralized, the latter not even in the olfactory bulb, suggesting an incomplete segregation. Thus, the olfactory system of X. laevis exhibits an intermediate stage of segregation and as such appears well suited to investigate the molecular driving forces behind olfactory regionalization.     

New evidence on the robust identification of news shocks: Role of revisions in utilization‐adjusted TFP series and term structure data

Data revisions and selections of appropriate forwarding‐looking variables have a major impact on true identification of news shocks and quality of research findings derived from structural vector autoregression (SVAR) estimation. This paper revisits news shocks to identify the role of different vintages of total factor productivity (TFP) series and term structure of interest rates as major prognosticators of future economic growth. There is a growing strand of literature regarding the use of utilization‐adjusted TFP series, provided by Fernald (Federal Reserve Bank of San Francisco, Working Paper Series, 2014) for identification of news shocks. We reestimate Barsky and Sims' (Journal of Monetary Economics, 2011, 58, 273–289) empirical analysis by employing 2007 and 2015 vintages of TFP data. We find substantial quantitative as well as qualitative differences among impulse response functions when using 2007 and 2015 vintages of TFP data. Output and hours initially decline, followed by quick reversal of both variables. In sharp contrast to results achieved by the 2007 vintage of TFP data, results achieved by the 2015 vintage of TFP data depict that output and hours will increase in response to positive TFP shock. By including term structure data in our VAR specification, total surprise technology shock and news shock account for 97% and 92% of the forecast error variance in total TFP and total output respectively. We find that revisions in TFP series over time ultimately impact the conclusion regarding news shocks on business cycles. Our results support the notion that term structure data help in better identification of news shock as compared to other forward‐looking variables.     

Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection

Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.