Prion protein cleavage fragments regulate adult neural stem cell quiescence through redox modulation of mitochondrial fission and SOD2 expression

Neurogenesis continues in the post-developmental brain throughout life. The ability to stimulate the production of new neurones requires both quiescent and actively proliferating pools of neural stem cells (NSCs). Actively proliferating NSCs ensure that neurogenic demand can be met, whilst the quiescent pool makes certain NSC reserves do not become depleted. The processes preserving the NSC quiescent pool are only just beginning to be defined. Herein, we identify a switch between NSC proliferation and quiescence through changing intracellular redox signalling. We show that N-terminal post-translational cleavage products of the prion protein (PrP) induce a quiescent state, halting NSC cellular growth, migration, and neurite outgrowth. Quiescence is initiated by the PrP cleavage products through reducing intracellular levels of reactive oxygen species. First, inhibition of redox signalling results in increased mitochondrial fission, which rapidly signals quiescence. Thereafter, quiescence is maintained through downstream increases in the expression and activity of superoxide dismutase-2 that reduces mitochondrial superoxide. We further observe that PrP is predominantly cleaved in quiescent NSCs indicating a homeostatic role for this cascade. Our findings provide new insight into the regulation of NSC quiescence, which potentially could influence brain health throughout adult life.     

Common deletion polymorphisms in the human genome

The locations and properties of common deletion variants in the human genome are largely unknown. We describe a systematic method for using dense SNP genotype data to discover deletions and its application to data from the International HapMap Consortium to characterize and catalogue segregating deletion variants across the human genome. We identified 541 deletion variants (94% novel) ranging from 1 kb to 745 kb in size; 278 of these variants were observed in multiple, unrelated individuals, 120 in the homozygous state. The coding exons of ten expressed genes were found to be commonly deleted, including multiple genes with roles in sex steroid metabolism, olfaction and drug response. These common deletion polymorphisms typically represent ancestral mutations that are in linkage disequilibrium with nearby SNPs, meaning that their association to disease can often be evaluated in the course of SNP-based whole-genome association studies.     

Early brood-rearing habitat use and productivity of Greater Sage-Grouse in Wyoming

Populations of Greater Sage-Grouse ( Centrocercus urophasianus ) have been declining throughout their range since the 1960s. Productivity, which includes production and survival of young, is often cited as a factor in these declines. We monitored radio-equipped Greater Sage-Grouse at 3 sites in western Wyoming to assess early brood-rearing habitat use (through 14 days post-hatch) and productivity. Logistic and linear regression analyses with Akaike's Information Criterion were used to evaluate early brooding habitat use and to examine relationships between productivity and vegetation, insect size and abundance, and weather parameters. Females with broods were found in areas with greater sagebrush canopy and grass cover, and fewer invertebrates compared to random areas. The number of juveniles per female (estimated from wing barrel collections during fall harvest) was positively related to the abundance of medium-length Hymenoptera and grass cover, and the proportion of females with confirmed chicks 14 days post-hatch was positively related to abundance of medium-length Coleoptera and total herbaceous cover. Although the specific parameters varied slightly, Greater Sage-Grouse productivity in Wyoming appeared to be associated with a combination of insect and herbaceous cover elements. Managing for abundant and diverse insect communities within dense protective sagebrush stands should help ensure high-quality early brood-rearing habitat and increased Greater Sage-Grouse productivity.     

A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis

A20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-κB signaling in response to specific proinflammatory stimuli in different cell types and has been suggested as a susceptibility gene for rheumatoid arthritis. To define the contribution of A20 to rheumatoid arthritis pathology, we generated myeloid-specific A20-deficient mice and show that specific ablation of Tnfaip3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis. Myeloid-A20-deficient mice have high levels of inflammatory cytokines in their serum, consistent with a sustained NF-κB activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 and IL-6 dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. Together, these observations indicate a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis, supporting the idea of developing A20 modulatory drugs as cell-targeted therapies.     

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.     

Analysts’ Dynamic Decisions: Timeliness versus Accuracy

For analysts there is a tradeoff between the accuracy and the timeliness of their forecasts. Prior literature heavily investigates analyst forecast accuracy. Few papers investigate the importance of timeliness. To our best knowledge, there are no empirical papers to date to investigate the dynamic interplay between these key characteristics. We show that if analysts experience a period of high accuracy relative to their peers, they subsequently focus more on the timeliness of their forecasts in the subsequent period and thus issue their forecasts earlier than they did in the prior period. Copyright © 2016 John Wiley & Sons, Ltd.     

Distribution records and comments on fleas in southwestern South Dakota

From October 2003 through April 2006, we collected 565 fleas incidental to a distribution survey of mammals in southwestern South Dakota. Sixty-one specimens, representing 18 species of mammals, possessed 20 species of fleas. The geographic distributions of these flea species revealed 8 new records for the Black Hills and its adjacent grasslands. Four species— Megarthroglossus divisus, Stenoponia americana, Odontopsyllus dentatus, and Amaradix euphorbi —constitute new records for South Dakota, thus increasing the state’s known flea fauna to 42 species. Hunters, trappers, and field biologists should be aware that serosurveillance during the 1990s revealed the presence of sylvatic plague and tularemia in the Black Hills area. Desde octubre de 2003 hasta abril de 2006, colectamos 565 pulgas de manera incidental durante un estudio de la distribución de mamíferos en el suroeste del estado de Dakota del Sur. Los 61 especímenes, que representaban 18 especies de mamíferos, albergaban 20 especies de pulgas. Sus distribuciones geográficas revelaron 8 nuevos registros para las Colinas Negras (Black Hills) y las praderas adyacentes. Cuatro de estas especies ( Megarthroglossus divisus, Stenoponia americana, Odontopsyllus dentatus y Amaradix euphorbi ) constituyen nuevos registros para Dakota del Sur. Esto aumenta el número de especies de pulgas conocidas del estado a 42 especies. Los cazadores, tramperos y biólogos de campo deben estar conscientes de que la vigilancia serológica durante la década de los 1990 reveló la presencia de la plaga silvática y la tularemia en el área de las Colinas Negras.     

Can purchasing power parity help forecast the dollar?

This paper examines the information on future exchange rate movements provided by the doctrine of purchasing power parity (PPP). Previous research has studied this issue by analyzing the time-series properties of period-by-period levels of, or changes in, exchange rates. In contrast, the present study focuses on the durations of periods in which exchange rates deviate from their PPP levels. If PPP provides information about future exchange rate movements, these durations should exhibit positive duration dependence. That is, the probability of returning to PPP levels should increase as the period of deviation increases. Parametric hazard functions estimated using data from eighteen countries provide no evidence of positive duration dependence. These results are robust to alternative definitions of PPP and to alternative functional specifications. While exchange rates take prolonged swings away from their PPP levels and then eventually return, these movements apparently constitute Monte Carlo cycles in which, at any point in time, the probability of moving back toward PPP is the same as the probability of moving farther away. Thus, PPP provides no useful information on future exchange rate changes, a result consistent with market efficiency.