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

What was lost in translation in the DHA trial is whom you should intend to treat

The results of a randomized double-blind placebocontrolled trial with docosahexaenoic acid (DHA) supplementation in mild to moderate Alzheimer's disease (AD) published by Quinn and colleagues in JAMA argues against overall efficacy of DHA in slowing progression. However, certain caveats in the results caution against discarding DHA altogether, raising questions about oxidation, dosage, pharmacogenomics and stage of intervention

Effective learning and teaching of reading

This was the largest study in Britain to date of the strategies used to teach reading in adult literacy classes (some classes were integrated with ICT and financial literacy for example), and the first attempt to correlate that evidence with measures of change in learners' reading attainment and attitudes to literacy. We observed and recorded (in writing) over 472 hours of teaching and learning. Our sample of learners is broadly representative of the national distribution, and the data gathered on 454 learners in 59 classes represents a wealth of information: about teaching and learning, effective and promising practices, and also areas where it is a priority for teachers and teacher trainers to engage in further training and development

Seagrass Loss in Belize: Studies of Turtlegrass (Thalassia testudinum) Habitat Using Remote Sensing and Ground-Truth Data

Spatial and temporal change in turtlegrass (Thalassia testudinum) habitat of the South Water Caye Marine Reserve (SWCMR) in Belize were analyzed using satellite images backed up with ground-truth data. We had two pri-mary objectives. First, we wanted to determine areal expanse of seagrass across a large area (~12 km by 3 km) of the SWCMR, and address its change over time. We used paired satellite images taken during 2001 and 2005 to determine coverage by seagrass and measure temporal variables. These analyses recorded an overall seagrass loss of 1.8% (52.3 ha) during the 4 yr period. Secondly, we wanted to determine whether seagrass gains or losses were consistent across the study area. Replicate sampling was used as a statistical basis and confirmed a significant loss of seagrass across the region. It also helped identify two regions of significant seagrass loss; one 600 ha area lost 12.4% of its seagrass; another 240 ha area lost nearly 40%. These components helped us assess seagrass habitat in an area perceived as critical to Belize fisheries, and provided the scale and statistical rigor necessary to adequately assess a broad region of study. The salient results from our study were not the magnitude of seagrass loss per se, but the loss in seagrass habitat from an area that is thought to be relatively pristine. Seagrass-habitat loss in this region of the Caribbean Sea may be evidence that even near-pristine areas can be impacted by anthropogenic factors. Determining the causes of habitat loss may help prevent loss of productivity, habitat, and livelihood for the associated human and nonhuman communities

Electrostatic considerations affecting the calculated HOMO-LUMO gap in protein molecules.

A detailed study of energy differences between the highest occupied and lowest unoccupied molecular orbitals (HOMO-LUMO gaps) in protein systems and water clusters is presented. Recent work questioning the applicability of Kohn-Sham density-functional theory to proteins and large water clusters (E. Rudberg, J. Phys.: Condens. Mat. 2012, 24, 072202) has demonstrated vanishing HOMO-LUMO gaps for these systems, which is generally attributed to the treatment of exchange in the functional used. The present work shows that the vanishing gap is, in fact, an electrostatic artefact of the method used to prepare the system. Practical solutions for ensuring the gap is maintained when the system size is increased are demonstrated. This work has important implications for the use of large-scale density-functional theory in biomolecular systems, particularly in the simulation of photoemission, optical absorption and electronic transport, all of which depend critically on differences between energies of molecular orbitals.Comment: 13 pages, 4 figure

Nevanlinna-Pick interpolation on distinguished varieties in the bidisk

This article treats Nevanlinna-Pick interpolation in the setting of a special class of algebraic curves called distinguished varieties. An interpolation theorem, along with additional operator theoretic results, is given using a family of reproducing kernels naturally associated to the variety. The examples of the Neil parabola and doubly connected domains are discussed.Comment: 31 pages. The question left open at the end of version 1 has been answered in the affirmative; see Theorem 1.12 and Corollary 1.13 in version

Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines

BackgroundImatinib mesylate is currently the drug of choice to treat chronic myeloid leukemia. However, patient resistance and cytotoxicity make secondary lines of treatment, such as omacetaxine mepesuccinate, a necessity. Given that drug cytotoxicity represents a major problem during treatment, it is essential to understand the biological pathways affected to better predict poor drug response and prioritize a treatment regime.MethodsWe conducted cell viability and gene expression assays to determine heritability and gene expression changes associated with imatinib and omacetaxine treatment of 55 non-cancerous lymphoblastoid cell lines, derived from 17 pedigrees. In total, 48,803 transcripts derived from Illumina Human WG-6 BeadChips were analyzed for each sample using SOLAR, whilst correcting for kinship structure.ResultsCytotoxicity within cell lines was highly heritable following imatinib treatment (h2&thinsp;=&thinsp;0.60-0.73), but not omacetaxine treatment. Cell lines treated with an IC20 dose of imatinib or omacetaxine showed differential gene expression for 956 (1.96%) and 3,892 transcripts (7.97%), respectively; 395 of these (0.8%) were significantly influenced by both imatinib and omacetaxine treatment. k-means clustering and DAVID functional annotation showed expression changes in genes related to kinase binding and vacuole-related functions following imatinib treatment, whilst expression changes in genes related to cell division and apoptosis were evident following treatment with omacetaxine. The enrichment scores for these ontologies were very high (mostly &gt;10).ConclusionsInduction of gene expression changes related to different pathways following imatinib and omacetaxine treatment suggests that the cytotoxicity of such drugs may be differentially tolerated by individuals based on their genetic background.<br /