An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100kb), rare copy number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1,564 cases and 1,748 controls all from Ireland, and further extended the analysis to include an additional 5,196 UK controls. We found association with duplications at chr20p12.2 (P=0.007) and evidence of replication in large independent European schizophrenia (P=0.052) and UK bipolar disorder case-control cohorts (P=0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11,707 cases and 10 carriers in 21,204 controls (meta-analysis CMH P value=2x10(-4) (odds ratio (OR)=11.3, 95% CI=3.7, ∞)). Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68Mb with similar breakpoints across samples. By haplotype analysis and sequencing we identified a tandem ∼149kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P=2.5x10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

Web Psychosocial Surveys in Cancer Survivorship— A Methodological Note

The number of Internet surveys is increasing, and there is a need to examine critically their value in psychosocial cancer care research. This study explored the use of an online method of recruiting and surveying people affected by cancer. An online survey was designed to measure the health status and service needs of adult cancer survivors and caregivers. The online survey received 491 page visits; only 5% of visitors (13 survivors and 14 cancer caregivers) completed the online questionnaire. The average age of survivors and caregivers was 43 and 42 years, respectively. The majority of survivor and caregiver online respondents were female (23/27, 85%) and had been affected by cancer between 1 and 3 years previously (16/27, 59%). Our online research did not appear to be an effective method for recruiting and surveying the psychosocial health of cancer survivors. This study identified potential pitfalls and obstacles of online cancer care surveys particularly in relation to the age of cancer survivors, access to the Internet and the need to ensure surveys are easily and immediately accessible. Future Internet surveys should pay particular attention to the need to advertise and improve survey access via targeted and tailored techniques.

A Non-Inferiority Randomized Controlled Trial Comparing the Clinical Effectiveness of Anesthesia Obtained by Application of a Novel Topical Anesthetic Putty With the Infiltration of Lidocaine for the Treatment of Lacerations in the Emergency Department

We test the hypothesis that anesthesia, measured as pain scores, induced by a novel topical anesthetic putty is non-inferior (margin=1.3) to that provided by conventional lidocaine infiltration for the repair of lacerations.

Development of a method to quantify the DNA content in DNA- cationic peptide nanoparticles

Gene therapy has the potential to provide safe and targeted therapies for a variety of diseases. A range of intracellular gene delivery vehicles have been proposed for this purpose. Non-viral vectors are a particularly attractive option and among them cationic peptides have emerged as promising candidates. For the pharmaceutical formulation and application to clinical studies it is necessary to quantify the amount of pDNA condensed with the delivery system. There is a severe deficiency in this area, thus far no methods have been reported specifically for pDNA condensed with cationic peptide to form nanoparticles. The current study seeks to address this and describes the evaluation of a range of disruption agents to extract DNA from nanoparticles formed by condensation with cationic fusogenic peptides RALA and KALA. Only proteinase K exhibited efficient and reproducible results and compatibility with the PicoGreen reagent based quantification assay. Thus we report for the first time a simple and reliable method that can quantify the pDNA content in pDNA cationic peptide nanoparticles.

Spitzer Space Telescope spectra of post-AGB stars in the large magellanic Cloud-polycyclic aromatic hydrocarbons at low metallicities

This paper reports variations of polycyclic aromatic hydrocarbons (PAHs) features that were found in Spitzer Space Telescope spectra of carbon-rich post-asymptotic giant branch (post-AGB) stars in the Large Magellanic Cloud (LMC). The paper consists of two parts. The first part describes our Spitzer spectral observing programme of 24 stars including post-AGB candidates. The latter half of this paper presents the analysis of PAH features in 20 carbon-rich post-AGB stars in the LMC, assembled from the Spitzer archive as well as from our own programme.We found that five post-AGB stars showed a broad feature with a peak at 7.7 μm, that had not been classified before. Further, the 10-13 μm PAH spectra were classified into four classes, one of which has three broad peaks at 11.3, 12.3 and 13.3 μm rather than two distinct sharp peaks at 11.3 and 12.7 μm, as commonly found in HII regions. Our studies suggest that PAHs are gradually processed while the central stars evolve from post-AGB phase to planetary nebulae, changing their composition before PAHs are incorporated into the interstellar medium. Although some metallicity dependence of PAH spectra exists, the evolutionary state of an object is more significant than its metallicity in determining the spectral characteristics of PAHs for LMC and Galactic post-AGB stars. © 2014 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.

Summary of the Snowmastodon Project Special Volume: A high-elevation, multi-proxy biotic and environmental record of MIS 6-4 from the Ziegler Reservoir fossil site, Snowmass Village, Colorado, USA

In North America, terrestrial records of biodiversity and climate change that span Marine Oxygen Isotope Stage (MIS) 5 are rare. Where found, they provide insight into how the coupling of the ocean-atmosphere system is manifested in biotic and environmental records and how the biosphere responds to climate change. In 2010-2011, construction at Ziegler Reservoir near Snowmass Village, Colorado (USA) revealed a nearly continuous, lacustrine/wetland sedimentary sequence that preserved evidence of past plant communities between similar to 140 and 55 lea, including all of MIS 5. At an elevation of 2705 m, the Ziegler Reservoir fossil site also contained thousands of well-preserved bones of late Pleistocene megafauna, including mastodons, mammoths, ground sloths, horses, camels, deer, bison, black bear, coyotes, and bighorn sheep. In addition, the site contained more than 26,000 bones from at least 30 species of small animals including salamanders, otters, muskrats, minks, rabbits, beavers, frogs, lizards, snakes, fish, and birds. The combination of macro- and micro-vertebrates, invertebrates, terrestrial and aquatic plant macrofossils, a detailed pollen record, and a robust, directly dated stratigraphic framework shows that high-elevation ecosystems in the Rocky Mountains of Colorado are climatically sensitive and varied dramatically throughout MIS 5 

A fluorescence model of the C3 radical in comets

Theoretical resonance fluorescence calculations are presented of the triatomic C3 radical and are compared with observations of the C3 emission in comets Hale-Bopp and de Vico. A theoretical model of the C3 vibration-rotational structure in the A1Piu - X1Sigmag + electronic system is introduced. The model takes into account the detailed structure of the bending mode nu2 which is responsible for the emission of the 4050 Å group. A total of 1959 levels are considered, with 515 levels in the ground state. The main effort is to model high-resolution spectra of the 4050 Å emission in comets C/1995 O1 Hale-Bopp and 122P/1995 S1 de Vico. The agreement between observed and theoretical spectra is good for a value of the dipole moment derivative of dmu/dr ~ 2.5 Debye Å-1. The modeled C3 emission exhibits a pronounced Swings effect. Based on observations made with William Herschel Telescope operated on the island of La Palma by the Isaac Newton Group in the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofisica de Canarias, and on observations made at the McDonald Observatory, which is operated by the University of Texas at Austin, USA.

Hyperoxia Depletes (6R)-5,6,7,8-Tetrahydrobiopterin Levels in the Neonatal Retina: Implications for Nitric Oxide Synthase Function in Retinopathy

Retinopathy of prematurity is a sight-threatening complication of premature birth caused by nitrooxidativeinsult to the developing retinal vasculature during therapeutic hyperoxia exposure and laterischemia-induced neovascularization on supplemental oxygen withdrawal. In the vasodegenerativephase, during hyperoxia, defective endothelial nitric oxide synthase (NOS) produces reactive oxygenand nitrogen free radicals rather than vasoprotective nitric oxide for unclear reasons. More important,NOS critically depends on the availability of the cofactor (6R)-5,6,7,8-tetrahydrobiopterin (BH4).Because BH4 synthesis is controlled enzymatically by GTP cyclohydrolase (GTPCH), we used GTPCHdepletedmice [hyperphenylalanaemia strain Q4 (hph1)] to investigate the impact of hyperoxia on BH4bioavailability and retinal vascular pathology in the neonate. Hyperoxia decreased BH4 in retinas,lungs, and aortas in all experimental groups, resulting in a dose-dependent decrease in NOS activityand, in the wild-type group, elevated NOS-derived superoxide. Retinal dopamine levels were similarlydiminished, consistent with the dependence of tyrosine hydroxylase on BH4. Despite greater depletionof BH4, the hphþ/ and hph1/ groups did not show exacerbated hyperoxia-induced vessel closure,but exhibited greater vascular protection and reduced progression to neovascular disease. This vasoprotectiveeffect was independent of enhanced circulating vascular endothelial growth factor (VEGF),which was reduced by hyperoxia, but Q5 to local ganglion cell layerederived VEGF. A constitutively higherlevel of VEGF expression associated with retinal development protects GTPCH-deficient neonates fromoxygen-induced vascular damage.