Control of Cavity-Induced Drag Using Steady Jets

Separated shear layer oscillations in open cavities can induce drag, noise and vibration. This issue has many aerospace applications such as Landing gears and control surfaces [1]. Recently, phase-cancellation [1] and offinstability frequency excitation [2] & [3] approaches have been incorporated in different open-loop and feedback control systems. Despite the high control performance of these systems, further enhancement is still possible. In this study, steady jets, as shown in fig. 1, are forced through 2mm, two-dimensional slots at the leading and trailing edges of the cavity. In order to study the performance of this novel approach, different cases will be examined, including: jet combination (blowing from cavity leading edge, suction from cavity leading edge and blowing-suction), jet angle (parallel or deflected jet) and jet-to-free stream velocity factor /.

Control of Cavity-Induced Drag Using Steady Jets

Separated shear layer oscillations in open cavities can induce drag, noise and vibration. This issue has many aerospace applications such as Landing gears and control surfaces [1]. Recently, phase-cancellation [1] and offinstability frequency excitation [2] & [3] approaches have been incorporated in different open-loop and feedback control systems. Despite the high control performance of these systems, further enhancement is still possible. In this study, steady jets, as shown in fig. 1, are forced through 2mm, two-dimensional slots at the leading and trailing edges of the cavity. In order to study the performance of this novel approach, different cases will be examined, including: jet combination (blowing from cavity leading edge, suction from cavity leading edge and blowing-suction), jet angle (parallel or deflected jet) and jet-to-free stream velocity factor /.

Proximity ligation assay reveals both pre- A nd postsynaptic localization of the APP-processing enzymes ADAM10 and BACE1 in rat and human adult brain

Background: Synaptic degeneration and accumulation of amyloid \u3b2-peptides (A\u3b2) are hallmarks of the Alzheimer diseased brain. A\u3b2 is synaptotoxic and produced by sequential cleavage of the amyloid precursor protein (APP) by the \u3b2-secretase BACE1 and by \u3b3-secretase. If APP is instead cleaved by the \u3b1-secretase ADAM10, A\u3b2 will not be generated. Although BACE1 is considered to be a presynaptic protein and ADAM10 has been reported to mainly localize to the postsynaptic density, we have previously shown that both ADAM10 and BACE1 are highly enriched in synaptic vesicles of rat brain and mouse primary hippocampal neurons. Results: Here, using brightfield proximity ligation assay, we expanded our previous result in primary neurons and investigated the in situ synaptic localization of ADAM10 and BACE1 in rat and human adult brain using both pre- A nd postsynaptic markers. We found that ADAM10 and BACE1 were in close proximity with both the presynaptic marker synaptophysin and the postsynaptic marker PSD-95. The substrate APP was also detected both pre- A nd postsynaptically. Subcellular fractionation confirmed that ADAM10 and BACE1 are enriched to a similar degree in synaptic vesicles and as well as in the postsynaptic density. Conclusions: We show that the \u3b1-secretase ADAM10 and the \u3b2-secretase BACE1 are located in both the pre- A nd postsynaptic compartments in intact brain sections. These findings increase our understanding of the regulation of APP processing, thereby facilitating development of more specific treatment strategies

APP mouse models for Alzheimer's disease preclinical studies

Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first-generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD Second-generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD In this review, we evaluate different APP mouse models of AD, and review recent studies using the second-generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study

The assess facility descriptor module

The Facility Descriptor (Facility) module is part of the Analytic System and Software for Evaluating Safeguards and Security (ASSESS). Facility is the foundational software application in the ASSESS system for modelling a nuclear facility's safeguards and security system to determine the effectiveness against theft of special nuclear material. The Facility module provides the tools for an analyst to define a complete description of a facility's physical protection system which can then be used by other ASSESS software modules to determine vulnerability to a spectrum of insider and outsider threats. The analyst can enter a comprehensive description of the protection system layout including all secured areas, target locations, and detailed safeguards specifications. An extensive safeguard component catalog provides the reference data for calculating delay and detection performance. Multiple target locations within the same physical area may be specified, and the facility may be defined for two different operational states such as dayshift and nightshift. 6 refs., 5 figs

Changes in cognitive domains during three years in patients with Alzheimer's disease treated with donepezil

<p>Abstract</p> <p>Background</p> <p>The objective was to identify separate cognitive domains in the standard assessment tools (MMSE, ADAS-Cog) and analyze the process of decline within domains during three years in Alzheimer's disease (AD) patients with donepezil treatment.</p> <p>Method</p> <p>AD patients (n = 421) were recruited from a clinical multi-centre study program in Sweden. Patients were assessed every six months during three years. All patients received donepezil starting directly after study entry. After dropouts, 158 patients remained for analyses over three years. Data for the other patients were analysed until they dropped out (4 groups based on length in study).</p> <p>Results</p> <p>Factor analyses of all items suggested that there were three intercorrelated factors: a General, a Memory and a Spatial factor for which we constructed corresponding domains. Overall there was a cognitive improvement at six months followed by a linear drop over time for the three domains. Some group and domain differences were identified. Patients who remained longer in the study had better initial performance and a slower deterioration rate. The early dropouts showed no improvement at six months and many dropped out due to side effects. The other groups displayed a performance improvement at six months that was less pronounced in the Memory domain. Before dropping out, deterioration accelerated, particularly in the Spatial domain.</p> <p>Conclusion</p> <p>The course of illness in the three domains was heterogeneous among the patients. We were not able to identify any clinically relevant correlates of this heterogeneity. As an aid we constructed three algorithms corresponding to the cognitive domains, which can be used to characterize patients initially, identify rapid decliners and follow the course of the disease.</p

γ-Secretase modulators show selectivity for γ-secretase–mediated amyloid precursor protein intramembrane processing

The aggregation of β-amyloid peptide 42 results in the formation of toxic oligomers and plaques, which plays a pivotal role in Alzheimer's disease pathogenesis. Aβ42 is one of several Aβ peptides, all of Aβ30 to Aβ43 that are produced as a result of γ-secretase–mediated regulated intramembrane proteolysis of the amyloid precursor protein. γ-Secretase modulators (GSMs) represent a promising class of Aβ42-lowering anti-amyloidogenic compounds for the treatment of AD. Gamma-secretase modulators change the relative proportion of secreted Aβ peptides, while sparing the γ-secretase–mediated processing event resulting in the release of the cytoplasmic APP intracellular domain. In this study, we have characterized how GSMs affect the γ-secretase cleavage of three γ-secretase substrates, E-cadherin, ephrin type A receptor 4 (EphA4) and ephrin type B receptor 2 (EphB2), which all are implicated in important contexts of cell signalling. By using a reporter gene assay, we demonstrate that the γ-secretase–dependent generation of EphA4 and EphB2 intracellular domains is unaffected by GSMs. We also show that γ-secretase processing of EphA4 and EphB2 results in the release of several Aβ-like peptides, but that only the production of Aβ-like proteins from EphA4 is modulated by GSMs, but with an order of magnitude lower potency as compared to Aβ modulation. Collectively, these results suggest that GSMs are selective for γ-secretase–mediated Aβ production

Glycan biomarkers for Alzheimer disease correlate with T-tau and P-tau in cerebrospinal fluid in subjective cognitive impairment

Alzheimer disease (AD) is a devastating disease and a global health problem, and current treatments are only symptomatic. A wealth of clinical studies support that the disease starts to develop decades before the first symptoms appear, emphasizing the importance of studying early changes for improving early diagnosis and guiding toward novel treatment strategies. Protein glycosylation is altered in AD but it remains to be clarified why these alterations occur and how they affect the disease development. Here, we used a glycomics approach to search for alterations in protein glycosylation in cerebrospinal fluid (CSF) in AD compared with nondemented controls. Using both matrix-assisted laser desorption ionization-time of flight and liquid chromatography–electrospray mass spectrometry, we observed an increase in N-glycans carrying bisecting N-acetylglucosamine in AD. Based on those findings, we designed an enzyme-linked multiwell plate assay to quantify N-glycans binding to the lectin Phaseolus vulgaris Erythroagglutinin (PHA-E), which is specific for N-glycans containing bisecting N-acetylglucosamine. Using this assay, we found a similar increase in CSF in AD compared with controls. Further analysis of CSF from 242 patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or AD dementia revealed significantly increased binding to PHA-E in MCI and AD compared to SCI. Interestingly, PHA-E binding correlated with CSF levels of phosphorylated tau and total tau and this correlation was most prominent in the SCI group (R = 0.53–0.54). This study supports a link between N-glycosylation, neurodegeneration, and tau pathology in AD and suggests that glycan biomarkers have potential to identify SCI cases at risk of developing AD