Plasma Magnetohydrodynamics and Energy Conversion

Contains research objectives and reports on four research projects.U.S. Air Force (Aeronautical Systems Division) under Contract AF33(616)-7624 with the Aeronautical Accessories Laboratory, Wright-Patterson Air Force Base, OhioNational Science Foundation under Grant G-24073National Institutes of Health (Grant HTS-5550

Integrated genomic analyses of ovarian carcinoma

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.National Institutes of Health (U.S.) (Grant U54HG003067)National Institutes of Health (U.S.) (Grant U54HG003273)National Institutes of Health (U.S.) (Grant U54HG003079)National Institutes of Health (U.S.) (Grant U24CA126543)National Institutes of Health (U.S.) (Grant U24CA126544)National Institutes of Health (U.S.) (Grant U24CA126546)National Institutes of Health (U.S.) (Grant U24CA126551)National Institutes of Health (U.S.) (Grant U24CA126554)National Institutes of Health (U.S.) (Grant U24CA126561)National Institutes of Health (U.S.) (Grant U24CA126563)National Institutes of Health (U.S.) (Grant U24CA143882)National Institutes of Health (U.S.) (Grant U24CA143731)National Institutes of Health (U.S.) (Grant U24CA143835)National Institutes of Health (U.S.) (Grant U24CA143845)National Institutes of Health (U.S.) (Grant U24CA143858)National Institutes of Health (U.S.) (Grant U24CA144025)National Institutes of Health (U.S.) (Grant U24CA143866)National Institutes of Health (U.S.) (Grant U24CA143867)National Institutes of Health (U.S.) (Grant U24CA143848)National Institutes of Health (U.S.) (Grant U24CA143843)National Institutes of Health (U.S.) (Grant R21CA135877

Visual Stability and the Motion Aftereffect: A Psychophysical Study Revealing Spatial Updating

Eye movements create an ever-changing image of the world on the retina. In particular, frequent saccades call for a compensatory mechanism to transform the changing visual information into a stable percept. To this end, the brain presumably uses internal copies of motor commands. Electrophysiological recordings of visual neurons in the primate lateral intraparietal cortex, the frontal eye fields, and the superior colliculus suggest that the receptive fields (RFs) of special neurons shift towards their post-saccadic positions before the onset of a saccade. However, the perceptual consequences of these shifts remain controversial. We wanted to test in humans whether a remapping of motion adaptation occurs in visual perception

Expression of VEGF and semaphorin genes define subgroups of triple negative breast cancer.

PMC3648524Triple negative breast cancers (TNBC) are difficult to treat due to a lack of targets and heterogeneity. Inhibition of angiogenesis is a promising therapeutic strategy, but has had limited effectiveness so far in breast cancer. To quantify heterogeneity in angiogenesis-related gene expression in breast cancer, we focused on two families--VEGFs and semaphorins--that compete for neuropilin co-receptors on endothelial cells. We compiled microarray data for over 2,600 patient tumor samples and analyzed the expression of VEGF- and semaphorin-related ligands and receptors. We used principal component analysis to identify patterns of gene expression, and clustering to group samples according to these patterns. We used available survival data to determine whether these clusters had prognostic as well as therapeutic relevance. TNBC was highly associated with dysregulation of VEGF- and semaphorin-related genes; in particular, it appeared that expression of both VEGF and semaphorin genes were altered in a pro-angiogenesis direction. A pattern of high VEGFA expression with low expression of secreted semaphorins was associated with 60% of triple-negative breast tumors. While all TNBC groups demonstrated poor prognosis, this signature also correlated with lower 5-year survival rates in non-TNBC samples. A second TNBC pattern, including high VEGFC expression, was also identified. These pro-angiogenesis signatures may identify cancers that are more susceptible to VEGF inhibition.JH Libraries Open Access Fun

Multi-scale genomic, transcriptomic and proteomic analysis of colorectal cancer cell lines to identify novel biomarkers

This work was partially funded by the Strategic Educational Pathways Scholarship (Malta). The scholarship is part-financed by the European Union – European Social Fund (ESF) under Operational Programme II – Cohesion Policy 2007-2013, “Empowering People for More Jobs and a Better Quality of Life”. This project was additionally funded by Medical Research Scotland.Selecting colorectal cancer (CRC) patients likely to respond to therapy remains a clinical challenge. The objectives of this study were to establish which genes were differentially expressed with respect to treatment sensitivity and relate this to copy number in a panel of 15 CRC cell lines. Copy number variations of the identified genes were assessed in a cohort of CRCs. IC50’s were measured for 5-fluorouracil, oxaliplatin, and BEZ-235, a PI3K/mTOR inhibitor. Cell lines were profiled using array comparative genomic hybridisation, Illumina gene expression analysis, reverse phase protein arrays, and targeted sequencing of KRAS hotspot mutations. Frequent gains were observed at 2p, 3q, 5p, 7p, 7q, 8q, 12p, 13q, 14q, and 17q and losses at 2q, 3p, 5q, 8p, 9p, 9q, 14q, 18q, and 20p. Frequently gained regions contained EGFR, PIK3CA, MYC, SMO, TRIB1, FZD1, and BRCA2, while frequently lost regions contained FHIT and MACROD2. TRIB1 was selected for further study. Gene enrichment analysis showed that differentially expressed genes with respect to treatment response were involved in Wnt signalling, EGF receptor signalling, apoptosis, cell cycle, and angiogenesis. Stepwise integration of copy number and gene expression data yielded 47 candidate genes that were significantly correlated. PDCD6 was differentially expressed in all three treatment responses. Tissue microarrays were constructed for a cohort of 118 CRC patients and TRIB1 and MYC amplifications were measured using fluorescence in situ hybridisation. TRIB1 and MYC were amplified in 14.5% and 7.4% of the cohort, respectively, and these amplifications were significantly correlated (p≤0.0001). TRIB1 protein expression in the patient cohort was significantly correlated with pERK, Akt, and Caspase 3 expression. In conclusion, a set of candidate predictive biomarkers for 5-fluorouracil, oxaliplatin, and BEZ235 are described that warrant further study. Amplification of the putative oncogene TRIB1 has been described for the first time in a cohort of CRC patients.Publisher PDFPeer reviewe

Meat and Nicotinamide:A Causal Role in Human Evolution, History, and Demographics

Hunting for meat was a critical step in all animal and human evolution. A key brain-trophic element in meat is vitamin B 3 /nicotinamide. The supply of meat and nicotinamide steadily increased from the Cambrian origin of animal predators ratcheting ever larger brains. This culminated in the 3-million-year evolution of Homo sapiens and our overall demographic success. We view human evolution, recent history, and agricultural and demographic transitions in the light of meat and nicotinamide intake. A biochemical and immunological switch is highlighted that affects fertility in the ‘de novo’ tryptophan-to-kynurenine-nicotinamide ‘immune tolerance’ pathway. Longevity relates to nicotinamide adenine dinucleotide consumer pathways. High meat intake correlates with moderate fertility, high intelligence, good health, and longevity with consequent population stability, whereas low meat/high cereal intake (short of starvation) correlates with high fertility, disease, and population booms and busts. Too high a meat intake and fertility falls below replacement levels. Reducing variances in meat consumption might help stabilise population growth and improve human capital