Murine models of Alzheimer's disease and their use in developing immunotherapies

AbstractAlzheimer's disease (AD) is one of the categories of neurodegenerative diseases characterized by a conformational change of a normal protein into a pathological conformer with a high β-sheet content that renders it resistant to degradation and neurotoxic. In AD, the normal soluble amyloid β (sAβ) peptide is converted into oligomeric/fibrillar Aβ. The oligomeric forms of Aβ are thought to be the most toxic, while fibrillar Aβ becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. An additional important feature of AD is the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles. Many therapeutic interventions are under investigation to prevent and treat AD. The testing of these diverse approaches to ameliorate AD pathology has been made possible by the existence of numerous transgenic mouse models which each mirror specific aspects of AD pathology. None of the current murine models is a perfect match of the human disease. Perhaps the most exciting of the therapeutic approaches being developed is immunomodulation targeting the aggregating proteins, Aβ and tau. This type of AD therapy is currently being assessed in many transgenic mouse models, and promising findings have led to clinical trials. However, there is a discrepancy between results in murine models and ongoing clinical trials, which highlight the limitations of these models and also of our understanding of the underlying etiology and pathogenesis of AD. Because of these uncertainties, Tg models for AD are continuously being refined with the aim to better understand the disease and to enhance the predictive validity of potential treatments such as immunotherapies

Asymptotically Tight Bounds for Performing BMMC Permutations on Parallel Disk Systems

This paper presents asymptotically equal lower and upper bounds for the number of parallel I/O operations required to perform bit-matrix-multiply/complement (BMMC) permutations on the Parallel Disk Model proposed by Vitter and Shriver. A BMMC permutation maps a source index to a target index by an affine transformation over GF(2), where the source and target indices are treated as bit vectors. The class of BMMC permutations includes many common permutations, such as matrix transposition (when dimensions are powers of 2), bit-reversal permutations, vector-reversal permutations, hypercube permutations, matrix reblocking, Gray-code permutations, and inverse Gray-code permutations. The upper bound improves upon the asymptotic bound in the previous best known BMMC algorithm and upon the constant factor in the previous best known bit-permute/complement (BPC) permutation algorithm. The algorithm achieving the upper bound uses basic linear-algebra techniques to factor the characteristic matrix for the BMMC permutation into a product of factors, each of which characterizes a permutation that can be performed in one pass over the data. The factoring uses new subclasses of BMMC permutations: memoryload-dispersal (MLD) permutations and their inverses. These subclasses extend the catalog of one-pass permutations. Although many BMMC permutations of practical interest fall into subclasses that might be explicitly invoked within the source code, this paper shows how to quickly detect whether a given vector of target addresses specifies a BMMC permutation. Thus, one can determine efficiently at run time whether a permutation to be performed is BMMC and then avoid the general-permutation algorithm and save parallel I/Os by using the BMMC permutation algorithm herein

Dissolution of Pre-Existing Platelet Thrombus by Synergistic Administration of Low Concentrations of Bifunctional Antibodies against β3 Integrin

Most antithrombotic approaches target prevention rather than the more clinically relevant issue of resolution of an existing thrombus. In this study, we describe a novel and effective therapeutic strategy for ex vivo clearance of pre-existing platelet thrombus by the combination of two bifunctional platelet GPIIIa49-66 ligands that target different parts of the arterial thrombus. We produced an additional GPIIIa49-66 agent (named APAC), which homes to activated platelets. Like our previously described SLK (which targets newly deposited fibrin strands surrounding the platelet thrombus), APAC destroys platelet aggregates ex vivo in an identical fashion with 85% destruction of platelet aggregates at 2 hours. The combined application of APAC and SLK demonstrated a ∼2 fold greater platelet thrombus dissolution than either agent alone at a low concentration (0.025 µM). Platelet-rich clot lysis experiments demonstrated the time required for 50% platelet-rich fibrin clot lysis (T50%) by APAC (95±6.1 min) or SLK (145±7.1 min) was much longer than that by combined APAC+SLK (65±7.6 min) at the final concentration of 0.025 µM (APAC+SLK vs APAC, p<0.05; APAC+SLK vs SLK, p<0.01). Thus these low concentrations of a combination of both agents are likely to be more effective and less toxic when used therapeutically in vivo

Near-infrared line identification in type Ia supernovae during the transitional phase

We present near-infrared synthetic spectra of a delayed-detonation hydrodynamical model and compare them to observed spectra of four normal type Ia supernovae ranging from day +56.5 to day +85. This is the epoch during which supernovae are believed to be undergoing the transition from the photospheric phase, where spectra are characterized by line scattering above an optically thick photosphere, to the nebular phase, where spectra consist of optically thin emission from forbidden lines. We find that most spectral features in the near-infrared can be accounted for by permitted lines of Fe II and Co II. In addition, we find that [Ni II] fits the emission feature near 1.98 {\mu}m, suggesting that a substantial mass of 58Ni exists near the center of the ejecta in these objects, arising from nuclear burning at high density. A tentative identification of Mn II at 1.15 {\mu}m may support this conclusion as well.Comment: accepted to Ap

The HR 4796A Debris System: Discovery of Extensive Exo-Ring Dust Material

The optically and IR bright, and starlight-scattering, HR 4796A ring-like debris disk is one of the most (and best) studied exoplanetary debris systems. The presence of a yet-undetected planet has been inferred (or suggested) from the narrow width and inner/outer truncation radii of its r = 1.05" (77 au) debris ring. We present new, highly sensitive, Hubble Space Telescope (HST) visible-light images of the HR 4796A circumstellar debris system and its environment over a very wide range of stellocentric angles from 0.32" (23 au) to ~ 15" (1100 au). These very high contrast images were obtained with the Space Telescope Imaging Spectrograph (STIS) using 6-roll PSF-template subtracted coronagraphy suppressing the primary light of HR 4796A and using three image plane occulters and simultaneously subtracting the background light from its close angular proximity M2.5V companion. The resulting images unambiguously reveal the debris ring embedded within a much larger, morphologically complex, and bi-axially asymmetric exoring scattering structure. These images at visible wavelengths are sensitive to, and map, the spatial distribution, brightness, and radial surface density of micron size particles over 5 dex in surface brightness. These particles in the exo-ring environment may be unbound from the system and interacting with the local ISM. Herein we present a new morphological and photometric view of the larger than prior seen HR 4796A exoplanetary debris system with sensitivity to small particles at stellocentric distances an order of magnitude greater than has previously been observed.Comment: 28 pages, 17 figures, accepted for publication in the Astronomical Journal 21 December 201

Switch-independent task representations in frontal and parietal cortex

Alternating between two tasks is effortful and impairs performance. Previous fMRI studies have found increased activity in frontoparietal cortex when task switching is required. One possibility is that the additional control demands for switch trials are met by strengthening task representations in the human brain. Alternatively, on switch trials, the residual representation of the previous task might impede the buildup of a neural task representation. This would predict weaker task representations on switch trials, thus also explaining the performance costs. To test this, male and female participants were cued to perform one of two similar tasks, with the task being repeated or switched between successive trials. Multivoxel pattern analysis was used to test which regions encode the tasks and whether this encoding differs between switch and repeat trials. As expected, we found information about task representations in frontal and parietal cortex, but there was no difference in the decoding accuracy of task-related information between switch and repeat trials. Using cross-classification, we found that the frontoparietal cortex encodes tasks using a generalizable spatial pattern in switch and repeat trials. Therefore, task representations in frontal and parietal cortex are largely switch independent. We found no evidence that neural information about task representations in these regions can explain behavioral costs usually associated with task switching

Do Safety Culture Scores in Nursing Homes Depend on Job Role and Ownership? Results from a National Survey

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138839/1/jgs15030.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138839/2/jgs15030_am.pd