Voluntary Exercise Reduces Alzheimer’s-like Pathology After Inflammation in Mice

Current global statistics estimate that 44.4 million people are afflicted with dementia, and that 50%-75% of these patients suffer from Alzheimer’s disease (AD; Prince et al. 2013). AD, a progressive disorder categorized by neuronal and behavioral deterioration, is the 6th leading cause of death in America (Alz facts and figure 2012). One hallmark pathology of AD is the presence of amyloid-beta (Aβ) in the brain, which can limit cell-to-cell communication, leading to cognitive deficits, and neuronal cell death. Although the exact origins of this disease still remain unknown, one possible catalyst of AD pathology is inflammation. Our lab has previously shown that 7 consecutive peripheral injections of a bacterial mimetic led to systemic inflammation, increased levels of Ab in the brain, and cognitive dysfunction (Kahn et al., 2012; Weintraub et al., 2013). Currently there are very few effective treatments that diminish AD symptomology. One documented way to decrease inflammation without the use of pharmaceuticals is through regular physical exercise (Cho et al., 2003; Cotman & Berchtold, 2002; Cotman et al., 2007). The present study tested the hypothesis that voluntary exercise would decrease the level of brain Ab following inflammation. Interestingly, we found that two weeks of voluntary wheel running after inflammation led to a reduction of Ab when compared to sedentary recovery. These results indicate that exercise may be an effective modality to reduce AD-like pathology, and that these effects appear to be facilitated by higher versus lower levels of exercise, as measured by total distance run

Tradespace and Affordability – Phase 2

MOTIVATION AND CONTEXT: One of the key elements of the SERC’s research strategy is transforming the practice of systems engineering – “SE Transformation.” The Grand Challenge goal for SE Transformation is to transform the DoD community’s current systems engineering and management methods, processes, and tools (MPTs) and practices away from sequential, single stovepipe system, hardware-first, outside-in, document-driven, point-solution, acquisition-oriented approaches; and toward concurrent, portfolio and enterprise-oriented, hardware-software-human engineered, balanced outside-in and inside-out, model-driven, set-based, full life cycle approaches.This material is based upon work supported, in whole or in part, by the U.S. Department of Defense through the Office of the Assistant Secretary of Defense for Research and Engineering (ASD(R&E)) under Contract H98230-08- D-0171 (Task Order 0031, RT 046).This material is based upon work supported, in whole or in part, by the U.S. Department of Defense through the Office of the Assistant Secretary of Defense for Research and Engineering (ASD(R&E)) under Contract H98230-08- D-0171 (Task Order 0031, RT 046)

The Victorian Newsletter (Spring 2006)

The Victorian Newsletter is sponsored for the Victorian Group of the Modern Language Association by Western Kentucky University and is published twice annually.Scandalous Sensations: The Woman in White on the Victorian Stage / Maria K. Bachman -- Nostalgia to Amnesia: Charles Dickens, Marcus Clarke and Narratives of Australia's Convict Origins / Beth A. Boehm -- The Epigraph to Henley's In Hospital / Edward H. Cohen -- Emily Brontë's Pedagogy of Desire in Wuthering Heights / Amy Carol Reeves -- Kate Field and Anthony Trollope: The Gaps in the Record / Gary Scharnhorst -- Metaphoric Mules: Dickens's Tom Gradgrind and Dante's Vanni Fucci / Ernest Fontana -- A Husband's Tragedy: The Relationship between Art and Life in Oscar Wilde's An Ideal Husband / Carol Schnitzer -- Coming In Victorian Newsletter -- Books Receive

Tradespace and Affordability – Phase 1

One of the key elements of the SERC’s research strategy is transforming the practice of systems engineering – “SE Transformation.” The Grand Challenge goal for SE Transformation is to transform the DoD community’s current systems engineering and management methods, processes, and tools (MPTs) and practices away from sequential, single stovepipe system, hardware-first, outside-in, document-driven, point-solution, acquisition-oriented approaches; and toward concurrent, portfolio and enterprise-oriented, hardware-software-human engineered, balanced outside-in and inside-out, model-driven, set-based, full life cycle approaches.This material is based upon work supported, in whole or in part, by the U.S. Department of Defense through the Office of the Assistant Secretary of Defense for Research and Engineering (ASD(R&E)) under Contract H98230-08- D-0171 (Task Order 0031, RT 046).This material is based upon work supported, in whole or in part, by the U.S. Department of Defense through the Office of the Assistant Secretary of Defense for Research and Engineering (ASD(R&E)) under Contract H98230-08- D-0171 (Task Order 0031, RT 046)

Reexamining the frustration effect in rats: Aftereffects of surprising reinforcement and nonreinforcement.

Abstract The reinforcement-omission effect (ROE; also called frustration effect), or greater response strength immediately after nonreinforcement (N) than reinforcement (R), has been traditionally interpreted in terms of one of two factors: transient facilitation after N induced by primary frustration or transient suppression after R induced by postconsummatory processes. Three instrumental lever-pressing experiments with rats demonstrated that the ROE can be caused by either factor in isolation, or by both acting simultaneously. The distribution of trials and the interval between N or R and the target response determine which factor would cause the ROE. Both aftereffects decay in time, but the after-N process decays at a slower rate than the after-R factor. Ó 2003 Elsevier Inc. All rights reserved. In 1952 Amsel and Roussel reported a runway experiment that demonstrated (or so they thought) that the surprising omission of an appetitive reinforcer was followed by behavioral invigoration. In that experiment, rats received training in a double Learning and Motivation 34 (2003

System Qualities Ontology, Tradespace and Affordability (SQOTA) Project – Phase 4

This task was proposed and established as a result of a pair of 2012 workshops sponsored by the DoD Engineered Resilient Systems technology priority area and by the SERC. The workshops focused on how best to strengthen DoD’s capabilities in dealing with its systems’ non-functional requirements, often also called system qualities, properties, levels of service, and –ilities. The term –ilities was often used during the workshops, and became the title of the resulting SERC research task: “ilities Tradespace and Affordability Project (iTAP).” As the project progressed, the term “ilities” often became a source of confusion, as in “Do your results include considerations of safety, security, resilience, etc., which don’t have “ility” in their names?” Also, as our ontology, methods, processes, and tools became of interest across the DoD and across international and standards communities, we found that the term “System Qualities” was most often used. As a result, we are changing the name of the project to “System Qualities Ontology, Tradespace, and Affordability (SQOTA).” Some of this year’s university reports still refer to the project as “iTAP.”This material is based upon work supported, in whole or in part, by the U.S. Department of Defense through the Office of the Assistant of Defense for Research and Engineering (ASD(R&E)) under Contract HQ0034-13-D-0004.This material is based upon work supported, in whole or in part, by the U.S. Department of Defense through the Office of the Assistant of Defense for Research and Engineering (ASD(R&E)) under Contract HQ0034-13-D-0004

Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells

An alternative to therapeutic targeting of oncogenes is to perform “synthetic lethality” screens for genes that are essential only in the context of specific cancer-causing mutations. We used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring mutant KRAS, the most commonly mutated human oncogene. We find that cells that are dependent on mutant KRAS exhibit sensitivity to suppression of the serine/threonine kinase STK33 irrespective of tissue origin, whereas STK33 is not required by KRAS-independent cells. STK33 promotes cancer cell viability in a kinase activity-dependent manner by regulating the suppression of mitochondrial apoptosis mediated through S6K1-induced inactivation of the death agonist BAD selectively in mutant KRAS-dependent cells. These observations identify STK33 as a target for treatment of mutant KRAS-driven cancers and demonstrate the potential of RNAi screens for discovering functional dependencies created by oncogenic mutations that may enable therapeutic intervention for cancers with “undruggable” genetic alterations.National Institutes of Health (U.S.) (grant R33 CA128625)National Institutes of Health (U.S.) (grant NIH U54 CA112962)National Institutes of Health (U.S.) (grant P01 CA095616)National Institutes of Health (U.S.) (grant P01 CA66996)Starr Cancer ConsortiumDoris Duke Charitable FoundationMPN Research FoundationDeutsche Forschungsgemeinschaft (grant SCHO 1215/1-1)Deutsche Forschungsgemeinschaft (grant FR 2113/1-1)Brain Science FoundationLeukemia & Lymphoma Society of Americ

Computational simulation of Haidinger's brushes

Haidinger's brushes (HB) are entoptic phenomena resulting from differential absorption of linear polarized light by the human macula. Computational models have assisted in understanding the behavior of these subjective phenomena but have been limited in their application. This study presents a revised computational model that incorporates known determinants of the form and behavior of HB. The model generates both static and animated simulations of HB that can be quantified by their density, contrast, and radial/circumferential extent. Measured physiological parameters are used to demonstrate the dependency of HB on macular pigment (MP) density, MP distribution, and ocular retardation. Physiological variations in these parameters explain the reported variations in the perception of HB

Satellite observations of banded VLF emissions in conjunction with energy‐banded ions during very large geomagnetic storms

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95489/1/jgra22114.pd

Genetic determinants of gut microbiota composition and bile acid profiles in mice.

The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct mice derived from eight founder strains. We characterized the fecal microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we identified several genomic regions associated with variations in both bacterial and BA profiles. Notably, we found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped to a locus containing the gene for the ileal bile acid transporter, Slc10a2. Mediation analysis and subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression associated with the different strains influences levels of both traits and revealed novel interactions between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to generate testable hypotheses and provide insight into host-microbe interactions