Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer\u27s disease pathogenesis

Background The greatest genetic risk factor for late-onset Alzheimer\u27s disease (AD) is the ϵ4 allele of Apolipoprotein E (ApoE). ApoE regulates secretion of the potent neuroprotective signaling lipid Sphingosine 1-phosphate (S1P). S1P is derived by phosphorylation of sphingosine, catalysed by sphingosine kinases 1 and 2 (SphK1 and 2), and SphK1 positively regulates glutamate secretion and synaptic strength in hippocampal neurons. S1P and its receptor family have been subject to intense pharmacological interest in recent years, following approval of the immunomodulatory drug Fingolimod, an S1P mimetic, for relapsing multiple sclerosis. Results We quantified S1P levels in six brain regions that are differentially affected by AD pathology, in a cohort of 34 post-mortem brains, divided into four groups based on Braak neurofibrillary tangle staging. S1P declined with increasing Braak stage, and this was most pronounced in brain regions most heavily affected by AD pathology. The S1P/sphingosine ratio was 66% and 64% lower in Braak stage III/IV hippocampus (p = 0.010) and inferior temporal cortex (p = 0.014), respectively, compared to controls. In accordance with this change, both SphK1 and SphK2 activity declined with increasing Braak pathology in the hippocampus (p = 0.032 and 0.047, respectively). S1P/sphingosine ratio was 2.5-fold higher in hippocampus of ApoE2 carriers compared to ApoE4 carriers, and multivariate regression showed a significant association between APOE genotype and hippocampal S1P/sphingosine (p = 0.0495), suggesting a new link between APOE genotype and pre-disposition to AD. Conclusions This study demonstrates loss of S1P and sphingosine kinase activity early in AD pathogenesis, and prior to AD diagnosis. Our findings establish a rationale for further exploring S1P receptor pharmacology in the context of AD therapy

Prediction, dynamics, and visualization of antigenic phenotypes of seasonal influenza viruses

Human seasonal influenza viruses evolve rapidly, enabling the virus population to evade immunity and reinfect previously infected individuals. Antigenic properties are largely determined by the surface glycoprotein hemagglutinin (HA), and amino acid substitutions at exposed epitope sites in HA mediate loss of recognition by antibodies. Here, we show that antigenic differences measured through serological assay data are well described by a sum of antigenic changes along the path connecting viruses in a phylogenetic tree. This mapping onto the tree allows prediction of antigenicity from HA sequence data alone. The mapping can further be used to make predictions about the makeup of the future A(H3N2) seasonal influenza virus population, and we compare predictions between models with serological and sequence data. To make timely model output readily available, we developed a web browser-based application that visualizes antigenic data on a continuously updated phylogeny

Measuring affective well-being at work using short-form scales : implications for affective structures and participant instructions

Measuring affective well-being in organizational studies has become increasingly widespread, given its association with key work-performance and other markers of organizational functioning. As such, researchers and policy-makers need to be confident that well-being measures are valid, reliable and robust. To reduce the burden on participants in applied settings, short-form measures of affective well-being are proving popular. However, these scales are seldom validated as standalone, comprehensive measures in their own right. In this article, we used a short-form measure of affective well-being with 10 items: the Daniels five-factor measure of affective well-being (D-FAW). In Study 1, across six applied sample groups (N = 2624), we found that the factor structure of the short-form D-FAW is robust when issued as a standalone measure, and that it should be scored differently depending on the participant instruction used. When participant instructions focus on now or today, then affect is best represented by five discrete emotion factors. When participant instructions focus on the past week, then affect is best represented by two or three mood-based factors. In Study 2 (N = 39), we found good construct convergent validity of short-form D-FAW with another widely used scale (PANAS). Implications for the measurement and structure of affect are discussed

Radiometric Stability of the SABER Instrument

The SABER instrument on the National Aeronautics and Space Administration Thermosphere‐Ionosphere‐Mesosphere Energetics and Dynamics satellite continues to provide a long‐term record of Earth\u27s stratosphere, mesosphere, and lower thermosphere. The SABER data are being used to examine long‐term changes and trends in temperature, water vapor, and carbon dioxide. A tacit, central assumption of these analyses is that the SABER instrument radiometric calibration is not changing with time; that is, the instrument is stable. SABER stratospheric temperatures and those derived from Global Positioning System Radio Occultation measurements are compared to examine SABER\u27s stability. Global Positioning System Radio Occultation measurements are inherently stable due to the accuracy and traceability of the measured phase delay rate to the Système Internationale definition of the second. Differences in global annual mean SABER and COSMIC lower stratospheric temperatures show little significant change with time in the 11 years spanning 2007–2017. From this analysis we infer that SABER temperatures are stable to better than 0.1 to 0.2 K per decade

Genomic signatures of population decline in the malaria mosquito Anopheles gambiae

Population genomic features such as nucleotide diversity and linkage disequilibrium are expected to be strongly shaped by changes in population size, and might therefore be useful for monitoring the success of a control campaign. In the Kilifi district of Kenya, there has been a marked decline in the abundance of the malaria vector Anopheles gambiae subsequent to the rollout of insecticide-treated bed nets. To investigate whether this decline left a detectable population genomic signature, simulations were performed to compare the effect of population crashes on nucleotide diversity, Tajima's D, and linkage disequilibrium (as measured by the population recombination parameter ρ). Linkage disequilibrium and ρ were estimated for An. gambiae from Kilifi, and compared them to values for Anopheles arabiensis and Anopheles merus at the same location, and for An. gambiae in a location 200 km from Kilifi. In the first simulations ρ changed more rapidly after a population crash than the other statistics, and therefore is a more sensitive indicator of recent population decline. In the empirical data, linkage disequilibrium extends 100-1000 times further, and ρ is 100-1000 times smaller, for the Kilifi population of An. gambiae than for any of the other populations. There were also significant runs of homozygosity in many of the individual An. gambiae mosquitoes from Kilifi. These results support the hypothesis that the recent decline in An. gambiae was driven by the rollout of bed nets. Measuring population genomic parameters in a small sample of individuals before, during and after vector or pest control may be a valuable method of tracking the effectiveness of interventions

Search for Neutrinoless Double-Beta Decay in 136^{136}Xe with EXO-200

We report on a search for neutrinoless double-beta decay of $^{136}$Xe with EXO-200. No signal is observed for an exposure of 32.5 kg-yr, with a background of ~1.5 x 10^{-3} /(kg yr keV) in the $\pm 1\sigma$ region of interest. This sets a lower limit on the half-life of the neutrinoless double-beta decay $T_{1/2}^{0\nu\beta\beta}$($^{136}$Xe) > 1.6 x 10$^{25}$ yr (90% CL), corresponding to effective Majorana masses of less than 140-380 meV, depending on the matrix element calculation

Investigation of radioactivity-induced backgrounds in EXO-200

The search for neutrinoless double-beta decay (0{\nu}{\beta}{\beta}) requires extremely low background and a good understanding of their sources and their influence on the rate in the region of parameter space relevant to the 0{\nu}{\beta}{\beta} signal. We report on studies of various {\beta}- and {\gamma}-backgrounds in the liquid- xenon-based EXO-200 0{\nu}{\beta}{\beta} experiment. With this work we try to better understand the location and strength of specific background sources and compare the conclusions to radioassay results taken before and during detector construction. Finally, we discuss the implications of these studies for EXO-200 as well as for the next-generation, tonne-scale nEXO detector.Comment: 9 pages, 7 figures, 3 table