PAK in Alzheimer disease, Huntington disease and X-linked mental retardation.

Developmental cognitive deficits including X-linked mental retardation (XLMR) can be caused by mutations in P21-activated kinase 3 (PAK3) that disrupt actin dynamics in dendritic spines. Neurodegenerative diseases such as Alzheimer disease (AD), where both PAK1 and PAK3 are dysregulated, may share final common pathways with XLMR. Independent of familial mutation, cognitive deficits emerging with aging, notably AD, begin after decades of normal function. This prolonged prodromal period involves the buildup of amyloid-β (Aβ) extracellular plaques and intraneuronal neurofibrillary tangles (NFT). Subsequently region dependent deficits in synapses, dendritic spines and cognition coincide with dysregulation in PAK1 and PAK. Specifically proximal to decline, cytoplasmic levels of actin-regulating Rho GTPase and PAK1 kinase are decreased in moderate to severe AD, while aberrant activation and translocation of PAK1 appears around the onset of cognitive deficits. Downstream to PAK1, LIM kinase inactivates cofilin, contributing to cofilin pathology, while the activation of Rho-dependent kinase ROCK increases Aβ production. Aβ activation of fyn disrupts neuronal PAK1 and ROCK-mediated signaling, resulting in synaptic deficits. Reductions in PAK1 by the anti-amyloid compound curcumin suppress synaptotoxicity. Similarly other neurological disorders, including Huntington disease (HD) show dysregulation of PAKs. PAK1 modulates mutant huntingtin toxicity by enhancing huntingtin aggregation, and inhibition of PAK activity protects HD as well as fragile X syndrome (FXS) symptoms. Since PAK plays critical roles in learning and memory and is disrupted in many cognitive disorders, targeting PAK signaling in AD, HD and XLMR may be a novel common therapeutic target for AD, HD and XLMR

In vitro and in vivo modification of Neisseria gonorrhoeae lipooligosaccharide epitope structure by sialylation.

After growth of gonococci in the presence of cytidine monophospho-N-acetyl-neuraminic acid (CMP-NANA), their 4.5-kD lipooligosaccharide (LOS) component was increased by approximately 400 daltons, whereas the LOS of strains lacking the 4.5-kD component were unaffected. Expression of mAb-defined epitopes on the 4.5-kD component was decreased on LOS of strains grown in CMP-NANA, and treatment of the LOS with neuraminidase reversed this affect. Gonococci incubated with human PMNs also had decreased expression of the 4.5-kD+ epitopes. A detergent extract of gonococci incorporated radiolabeled NANA in the LOS, suggesting the presence of a sialyltransferase in gonococci. Exogenous sialyltransferases also could use LOS as an acceptor

Household waste management practices in Charnwood borough, England

Household waste recycling rates vary between 20-60% across the UK. Legislative and financial measures introduced to reduce landfill disposal of waste in the UK, have impacted on the way Local Authorities operate their household waste and recycling collection services. This paper reports on the performance of Charnwood Borough Council (CBC), a Local Authority in England, it is responsible for the collection and recycling of waste from 67,000 households. This service is carried out by a private company, Serco, who operate household waste collections for 15 UK Local Authorities. To improve recycling performance CBC has changed the collection frequency and increased the number of materials segregated from residual waste for recovery. There have also been actions and campaigns to raise public awareness. Together these have improved recycling and composting rates in the CBC area from 16% in 2002/03 to 46.1% in 2010/11. This paper is a case study and progress report on the details of how this was achieved. It compares performance with other Local Authorities, explores the impact of local operational and policy issues on the amount of household waste collected for recycling. The research has concluded that differences in how the household waste services were provided and local policies influenced the amount of recyclates recovered. Local decision making and the ability to tailor services to suit different demographic areas, together with partnerships between neighbouring Authorities supported better sustainable waste management

Innovative Connectivity Ensuring Education (I.-C.E.E.)

This is the critical design review for the Telepresence/Telerobotic Technology for Children with Disabilities Project by team I.- C.E.E. (Innovative Connectivity Ensuring Education). This report details our telepresence system design for our client (Nathan Stilts) including design choices/justification, testing verification and procedures, and chosen components for implementation. There are seven chapters in total starting with introductory/background information followed by hardware and software design, verification, and testing and concludes with the current status of the project and what future work may need to be included

Halo bias in the excursion set approach with correlated steps

In the Excursion Set approach, halo abundances and clustering are closely related. This relation is exploited in many modern methods which seek to constrain cosmological parameters on the basis of the observed spatial distribution of clusters. However, to obtain analytic expressions for these quantities, most Excursion Set based predictions ignore the fact that, although different k-modes in the initial Gaussian field are uncorrelated, this is not true in real space: the values of the density field at a given spatial position, when smoothed on different real-space scales, are correlated in a nontrivial way. We show that when the excursion set approach is extended to include such correlations, then one must be careful to account for the fact that the associated prediction for halo bias is explicitly a real-space quantity. Therefore, care must be taken when comparing the predictions of this approach with measurements in simulations, which are typically made in Fourier-space. We show how to correct for this effect, and demonstrate that ignorance of this effect in recent analyses of halo bias has led to incorrect conclusions and biased constraints.Comment: 7 pages, 3 figures; v2 -- minor clarifications, accepted in MNRA

Evaluating Semi-Analytic Halo Merging Histories

We evaluate the accuracy of semi-analytic merger-trees by comparing them with the merging histories of dark-matter halos in N-body simulations, focusing on the joint distribution of the number of progenitors and their masses. We first confirm that the halo mass function as predicted directly by the Press-Schechter (PS) model deviates from the simulations by up to 50% depending on the mass scale and redshift, while the means of the projected distributions of progenitor number and mass for a halo of a given mass are more accurately predicted by the Extended PS model. We then use the full merger trees to study the joint distribution as a function of redshift and parent-halo mass. We find that while the deviation of the mean quantities due to the inaccuracy of the Extended PS model partly propagates into the higher moments of the distribution, the merger-tree procedure does not introduce a significant additional source of error. In particular, certain properties of the merging history such as the mass ratio of the progenitors and the total accretion rate are reproduced quite accurately for galaxy sized halos (\sim 10^{12}\msun), and less so for larger masses. We conclude that although there could be $\sim 50$ deviations in the absolute numbers and masses of progenitors and in the higher order moment of these distributions, the relative properties of progenitors for a given halo are reproduced fairly well by the merger trees. They can thus provide a useful framework for modelling galaxy formation once the above-mentioned limitations are taken into account.Comment: 10 pages including 9 figures, submitted to MNRA

Conditional Mass Functions and Merger Rates of Dark Matter Halos in the Ellipsoidal Collapse Model

Analytic models based on spherical and ellipsoidal gravitational collapse have been used to derive the mass functions of dark matter halos and their progenitors (the conditional mass function). The ellipsoidal model generally provides a better match to simulation results, but there has been no simple analytic expression in this model for the conditional mass function that is accurate for small time steps, a limit that is important for generating halo merger trees and computing halo merger rates. We remedy the situation by deriving accurate analytic formulae for the first-crossing distribution, the conditional mass function, and the halo merger rate in the ellipsoidal collapse model in the limit of small look-back times. We show that our formulae provide a closer match to the Millennium simulation results than those in the spherical collapse model and the ellipsoidal model of Sheth & Tormen (2002).Comment: 5 pages, 3 figures, accepted by MNRAS letter

A hybrid Bayesian hierarchical model combining cohort and case–control studies for meta-analysis of diagnostic tests: Accounting for partial verification bias

To account for between-study heterogeneity in meta-analysis of diagnostic accuracy studies, bivariate random effects models have been recommended to jointly model the sensitivities and specificities. As study design and population vary, the definition of disease status or severity could differ across studies. Consequently, sensitivity and specificity may be correlated with disease prevalence. To account for this dependence, a trivariate random effects model had been proposed. However, the proposed approach can only include cohort studies with information estimating study-specific disease prevalence. In addition, some diagnostic accuracy studies only select a subset of samples to be verified by the reference test. It is known that ignoring unverified subjects may lead to partial verification bias in the estimation of prevalence, sensitivities and specificities in a single study. However, the impact of this bias on a meta-analysis has not been investigated. In this paper, we propose a novel hybrid Bayesian hierarchical model combining cohort and case-control studies and correcting partial verification bias at the same time. We investigate the performance of the proposed methods through a set of simulation studies. Two case studies on assessing the diagnostic accuracy of gadolinium-enhanced magnetic resonance imaging in detecting lymph node metastases and of adrenal fluorine-18 fluorodeoxyglucose positron emission tomography in characterizing adrenal masses are presented

Are goal states represented during kinematic imitation?

A number of studies have shown that observation of another person's actions can modulate one's own actions, such as when 2 individuals cooperate in order to complete a joint task. However, little is known about whether or not direct matching of specific movements is modulated by the goals of the actions observed. In a series of 7 experiments, we employed an action observation paradigm in which 2 coactors sat opposite each other and took turns to reach out to targets presented on a shared workspace. Importantly, coactors performed either the same goal at the reached-to location or a different goal. Although results consistently showed that the reaching action of 1 individual slows the observer's reaching action to the same spatial location, the effect was not modulated according to the adopted goals of coactors. These findings challenge the notion that the processes involved in the imitation of specific movements code for the action goals of those movements