Neural Substrates of Insulin-Mediated Memory Facilitation in Early Alzheimer's Disease; The Impact of the Apolipoprotein E-Epsilon-4 Allele on Hippocampal Insulin Responses

Background: Several studies have demonstrated that insulin delivered by nasal spray acutely improves cognitive performance in early Alzheimer's disease. Furthermore, the apolipoprotein E-episilon-4 allele, a known AD risk factor, appears to influence those cognitive responses in a dose dependent manner, with carriers exhibiting impaired cognitive performance at higher insulin doses. The neural correlates of this phenomenon are however presently undefined. Hippocampal neurons are known to express insulin receptors in high densities, and neuronal insulin signaling is thought to modulate long-term potentiation mechanisms, suggesting that insulin might act at the hippocampus to generate cognitive enhancement. How the apolipoprotein E-epsilon-4 allele might interact with hippocampal insulin responses is not clear however. Methods: We studied the effects of a single 40IU dose of insulin aspart on hippocampal activation in 10 cognitively intact and 18 early AD subjects in a double-blind, counterbalanced, crossover memory encoding BOLD-based functional MRI study. We also assessed the effects of insulin on non-cognitive brain function with an fMRI motor task, and mean cerebral blood flow with arterial spin-labeled MRI. Last, insulin's effect on cognitive performance was assessed. We hypothesized AD subjects would demonstrate insulin-related increases in hippocampal activation, and that insulin-related changes would be greatest in apolipoprotein E-epsilon-4 negative AD. We further hypothesized insulin-related increases in mean cerebral blood flow in all subjects. Results: We observed an apolipoprotein E-epsilon-4 based interaction in insulin-related changes in hippocampal activation in AD, with carriers exhibiting decreased activation with insulin. Mean cerebral blood flow did not change significantly with insulin administration. Cognitive performance increased in the apolipoprotein E-epsilon-4 negative AD subjects after insulin administration. Conclusions: There is growing body of research indicating that faulty insulin signaling might be a component of AD neuropathology. The results herein are the first description of the neural correlates of insulin-related cognitive enhancement in AD, and provide direct evidence that insulin might serve an important neuromodulatory role in AD. Insulin also appears to modulate non-cognitive functions in a manner similar to hippocampal activity, suggesting that insulin might have wide spread effects on brain physiology, while the arterial spin-labeled MRI results suggest that insulin's effects are independent of cerebral blood flow. Our results furthermore underscore the importance of the apolipoprotein E-epsilon-4 allele in brain insulin responses

Cardiorespiratory fitness and preserved medial temporal lobe volume in Alzheimer's Disease

This is not the final published version.Exercise and cardiorespiratory (CR) fitness may moderate age-related regional brain changes in nondemented older adults (ND). The relationship of fitness to Alzheimer's disease (AD) related brain change is understudied, particularly in the hippocampus which is disproportionately affected in early AD. The role of apolipoprotein E4 (apoE4) genotype in modulating this relationship is also unknown. Nondemented (n=56) and early-stage AD subjects (n=61) over age 65 had MRI and CR fitness assessments. Voxel-based morphometry (VBM) techniques were utilized to identify AD-related atrophy. We analyzed the relationship of CR fitness with white and gray matter within groups, assessed fitness-related brain volume change in areas most affected by AD-related atrophy, and then analyzed differential fitness-brain relationships between apoE4 carriers. Atrophy was present in the medial temporal, temporal, and parietal cortices in subjects with mild AD. There was a significant positive correlation of CR fitness with parietal and medial temporal volume in AD subjects. ND subjects did not have a significant relationship between brain volume and CR fitness in the global or SVC analyses. There was not a significant interaction for fitness × apoE4 genotype in either group. In early-stage AD, cardiorespiratory fitness is associated with regional brain volumes in the medial temporal and parietal cortices suggesting that maintaining cardiorespiratory fitness may modify AD-related brain atrophy

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families.

BACKGROUND: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. METHODS: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. RESULTS: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. CONCLUSIONS: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

The Sloan Digital Sky Survey: Technical Summary

The Sloan Digital Sky Survey (SDSS) will provide the data to support detailed investigations of the distribution of luminous and non- luminous matter in the Universe: a photometrically and astrometrically calibrated digital imaging survey of pi steradians above about Galactic latitude 30 degrees in five broad optical bands to a depth of g' about 23 magnitudes, and a spectroscopic survey of the approximately one million brightest galaxies and 10^5 brightest quasars found in the photometric object catalog produced by the imaging survey. This paper summarizes the observational parameters and data products of the SDSS, and serves as an introduction to extensive technical on-line documentation.Comment: 9 pages, 7 figures, AAS Latex. To appear in AJ, Sept 200

The Third Data Release of the Sloan Digital Sky Survey

This paper describes the Third Data Release of the Sloan Digital Sky Survey (SDSS). This release, containing data taken up through June 2003, includes imaging data in five bands over 5282 deg^2, photometric and astrometric catalogs of the 141 million objects detected in these imaging data, and spectra of 528,640 objects selected over 4188 deg^2. The pipelines analyzing both images and spectroscopy are unchanged from those used in our Second Data Release.Comment: 14 pages, including 2 postscript figures. Submitted to AJ. Data available at http://www.sdss.org/dr

Molecular and pathological signatures of epithelial–mesenchymal transitions at the cancer invasion front

Reduction of epithelial cell–cell adhesion via the transcriptional repression of cadherins in combination with the acquisition of mesenchymal properties are key determinants of epithelial–mesenchymal transition (EMT). EMT is associated with early stages of carcinogenesis, cancer invasion and recurrence. Furthermore, the tumor stroma dictates EMT through intensive bidirectional communication. The pathological analysis of EMT signatures is critically, especially to determine the presence of cancer cells at the resection margins of a tumor. When diffusion barriers disappear, EMT markers may be detected in sera from cancer patients. The detection of EMT signatures is not only important for diagnosis but can also be exploited to enhance classical chemotherapy treatments. In conclusion, further detailed understanding of the contextual cues and molecular mediators that control EMT will be required in order to develop diagnostic tools and small molecule inhibitors with potential clinical implications

Expanding the diversity of mycobacteriophages: insights into genome architecture and evolution.

Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists

Les droits disciplinaires des fonctions publiques : « unification », « harmonisation » ou « distanciation ». A propos de la loi du 26 avril 2016 relative à la déontologie et aux droits et obligations des fonctionnaires

The production of tt‾ , W+bb‾ and W+cc‾ is studied in the forward region of proton–proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98±0.02 fb−1 . The W bosons are reconstructed in the decays W→ℓν , where ℓ denotes muon or electron, while the b and c quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions.The production of $t\overline{t}$, $W+b\overline{b}$ and $W+c\overline{c}$ is studied in the forward region of proton-proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98 $\pm$ 0.02 \mbox{fb}^{-1}. The $W$ bosons are reconstructed in the decays $W\rightarrow\ell\nu$, where $\ell$ denotes muon or electron, while the $b$ and $c$ quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions