Genotypes and phenotypes for apolipoprotein E and Alzheimer disease in the Honolulu-Asia aging study

BACKGROUND: The utility of apolipoprotein E (ApoE) type as an indicator of genetic susceptibility to Alzheimer disease (AD) depends on the reliability of typing. Although ApoE protein isoform phenotyping is generally assumed equivalent to genotyping from DNA, phenotype-genotype differences have been reported. METHODS: ApoE genotype and phenotype results were examined for 3564 older (ages 71-93 years) Japanese-American male participants of the Honolulu-Asia Aging Study, an ongoing population-based study of aging and dementia. RESULTS: Both methods demonstrated similar associations of ApoE type with AD: a direct association with ApoE4 and a less dramatic inverse association ApoE2. Advanced age did not appear to influence the ApoE4-AD association. The association with AD among ApoE4 homozygotes [odds ratio (OR) = 14.7] was higher than expected based on an observed OR of 2.0 in heterozygotes. Phenotype-genotype nonconcordance was more frequent for ApoE2 than for ApoE4. The ApoE2 phenotype occurred at a frequency of 7.9% vs a genotype frequency of 4.9%, corresponding to a probability of 56% that an individual with ApoE2 phenotype had the same genotype. CONCLUSIONS: Whereas E4 and E2 phenotypes and genotypes were comparably associated with AD, neither method would be expected to substantially improve the efficiency of case finding in the context of population screening beyond prediction based on age and education. Nonconcordance of phenotype and genotype was substantial for E2 and modest for E4 in this population. The ApoE4-AD association was independent of age

Peptide mimics selected from immune sera using phage display technology can replace native antigens in the diagnosis of Epstein–Barr virus infection

There is an expanding area of small molecule discovery, especially in the area of peptide mimetics. Peptide sequences can be used to substitute for the entire native antigen for use in diagnostic assays. Our approach is to select peptides that mimic epitopes of the natural immune response to Epstein–Barr virus (EBV) that may be recognised by antibodies typically produced after infection with EBV. We screened a random peptide library on sera from rabbits immunised with a crude preparation of EBV and serum antibodies from a patient with a high titer of EBV antibodies. We selected four peptides (Eb1–4) with the highest relative binding affinity with immune rabbit sera and a single peptide with high affinity to human serum antibodies. The peptides were coupled to the carrier molecule BSA and the recognition of the peptides by IgM antibodies in clinical samples after infection with EBV was measured. The sensitivities were Eb1 94%, Eb2, 3, 4 88%, H1 81% and all had 100% specificity. This study illustrates that the phage display approach to select epitope mimics can be applied to polyclonal antibodies and peptides that represent several diagnostically important epitopes can be selected simultaneously. This panel of EBV peptides representing a wide coverage of immunodominant epitopes could replace crude antigen preparations currently used for capture in commercial diagnostic tests for EBV

Displaying the Heterogeneity of the SN 2002cx-like Subclass of Type Ia Supernovae with Observations of the Pan-STARRS-1 Discovered SN2009ku

SN2009ku, discovered by Pan-STARRS-1, is a Type Ia supernova (SNIa), and a member of the distinct SN2002cx-like class of SNeIa. Its light curves are similar to the prototypical SN2002cx, but are slightly broader and have a later rise to maximum in g. SN2009ku is brighter (~0.6 mag) than other SN2002cx-like objects, peaking at M_V = -18.4 mag - which is still significantly fainter than typical SNeIa. SN2009ku, which had an ejecta velocity of ~2000 kms^-1 at 18 days after maximum brightness is spectroscopically most similar to SN2008ha, which also had extremely low-velocity ejecta. However, SN2008ha had an exceedingly low luminosity, peaking at M_V = -14.2 mag, ~4 mag fainter than SN2009ku. The contrast of high luminosity and low ejecta velocity for SN2009ku is contrary to an emerging trend seen for the SN2002cx class. SN2009ku is a counter-example of a previously held belief that the class was more homogeneous than typical SNeIa, indicating that the class has a diverse progenitor population and/or complicated explosion physics. As the first example of a member of this class of objects from the new generation of transient surveys, SN2009ku is an indication of the potential for these surveys to find rare and interesting objects.Comment: 7 pages, 3 figure

Pliocene Model Intercomparison Project Phase 3 (PlioMIP3) – Science plan and experimental design

The Pliocene Model Intercomparison Project (PlioMIP) was initiated in 2008. Over two phases PlioMIP has helped co-ordinate the experimental design and publication strategy of the community, which has included an increasing number of climate models and modelling groups from around the world. It has engaged with palaeoenvironmental scientists to foster new data synthesis supporting the construction of new model boundary conditions, as well as to facilitate new data-model comparisons. The work has advanced our understanding of Pliocene climates and environments, enhanced our knowledge regarding the ability of complex climate and Earth System models to accurately simulate climate change, and helped to refine our estimates of how sensitive the climate system is to forcing conditions. In this community protocol paper, we outline the scientific plan for PlioMIP Phase 3 (PlioMIP3). This plan provides the required guidance to participating modelling groups from around the world to successfully set up and perform PlioMIP3 climate model experiments. The project is open to new participants from the scientific community (both from the climate modelling and geosciences communities). In PlioMIP3, we retain the PlioMIP2 Core experiments (Eoi400, E280) and extend the Core requirements to include either an experiment focussed on the Early Pliocene or an alternative Late Pliocene simulation (or both). These additions (a) allow a comparison of Early and Late Pliocene warm intervals and help build research connections and synergy with the MioMIP (Miocene Model Intercomparison Project - also known as DeepMIP-Miocene) and PlioMioVAR projects (Pliocene-Miocene Variability Working Group), and (b) create an alternative time slice simulation for 3.205 Ma (MIS KM5c) through removal of some of the largest palaeogeographic differences introduced between PlioMIP1 and 2 resulting in minimal land-sea mask variations from the modern. In addition, we present ten optional experiments designed to enhance our assessment of climate sensitivity and to explore the uncertainty in greenhouse gas-related forcing. For the first time, we introduce orbital sensitivity experiments into the science plan, as well as simulations incorporating dynamic vegetation-climate feedbacks and an experiment designed to examine the potential significance of East Antarctic Ice Sheet boundary condition uncertainty. These changes enhance palaeo-to-future scientific connections and enable an exploration of the significance of palaeogeographic uncertainties on climate simulations

Avian Influenza H5N1 in Tigers and Leopards

Influenza virus is not known to affect wild felids. We demonstrate that avian influenza A (H5N1) virus caused severe pneumonia in tigers and leopards that fed on infected poultry carcasses. This finding extends the host range of influenza virus and has implications for influenza virus epidemiology and wildlife conservation

Models for Type Ia supernovae and related astrophysical transients

We give an overview of recent efforts to model Type Ia supernovae and related astrophysical transients resulting from thermonuclear explosions in white dwarfs. In particular we point out the challenges resulting from the multi-physics multi-scale nature of the problem and discuss possible numerical approaches to meet them in hydrodynamical explosion simulations and radiative transfer modeling. We give examples of how these methods are applied to several explosion scenarios that have been proposed to explain distinct subsets or, in some cases, the majority of the observed events. In case we comment on some of the successes and shortcoming of these scenarios and highlight important outstanding issues.Comment: 20 pages, 2 figures, review published in Space Science Reviews as part of the topical collection on supernovae, replacement corrects typos in the conclusions sectio

Synthetic Lethal Targeting of PTEN-Deficient Cancer Cells Using Selective Disruption of Polynucleotide Kinase/Phosphatase

A recent screen of 6,961 siRNAs to discover possible synthetic lethal partners of the DNA repair protein polynucleotide kinase/phosphatase (PNKP) led to the identification of the potent tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Here, we have confirmed the PNKP/PTEN synthetic lethal partnership in a variety of different cell lines including the PC3 prostate cancer cell line, which is naturally deficient in PTEN. We provide evidence that codepletion of PTEN and PNKP induces apoptosis. In HCT116 colon cancer cells, the loss of PTEN is accompanied by an increased background level of DNA double-strand breaks, which accumulate in the presence of an inhibitor of PNKP DNA 3'-phosphatase activity. Complementation of PC3 cells with several well-characterized mutated PTEN cDNAs indicated that the critical function of PTEN required to prevent toxicity induced by an inhibitor of PNKP is most likely associated with its cytoplasmic lipid phosphatase activity. Finally, we show that modest inhibition of PNKP in a PTEN knockout background enhances cellular radiosensitivity, suggesting that such a "synthetic sickness" approach involving the combination of PNKP inhibition with radiotherapy may be applicable to PTEN-deficient tumors

Kaon Production and Kaon to Pion Ratio in Au+Au Collisions at \snn=130 GeV

Mid-rapidity transverse mass spectra and multiplicity densities of charged and neutral kaons are reported for Au+Au collisions at \snn=130 GeV at RHIC. The spectra are exponential in transverse mass, with an inverse slope of about 280 MeV in central collisions. The multiplicity densities for these particles scale with the negative hadron pseudo-rapidity density. The charged kaon to pion ratios are $K^+/\pi^- = 0.161 \pm 0.002 {\rm (stat)} \pm 0.024 {\rm (syst)}$ and $K^-/\pi^- = 0.146 \pm 0.002 {\rm (stat)} \pm 0.022 {\rm (syst)}$ for the most central collisions. The $K^+/\pi^-$ ratio is lower than the same ratio observed at the SPS while the $K^-/\pi^-$ is higher than the SPS result. Both ratios are enhanced by about 50% relative to p+p and $\bar{\rm p}$+p collision data at similar energies.Comment: 6 pages, 3 figures, 1 tabl