Signal peptide peptidases and gamma-secretase: Cousins of the same protease family?

Signal peptide peptidase (SPIP) is an unusual aspartyl protease, which mediates clearance of signal peptides by proteolysis within the endoplasmic reticulum (ER). Like presenilins, which provide the proteolytically active subunit of the,gamma-secretase complex, SPP contains a conserved GxGD motif in its C-terminal domain which is critical for its activity. While SPIP is known to be an aspartyl protease of the GxGD type, several presenilin homologues/SPP-like proteins (PSHs/ SPPL) of unknown function have been identified by database searches. In contrast to SPP and SPPL3, which are both restricted to the endoplasmic reticulum, SPPL2b is targeted through the secretory pathway to endosomes/lysosomes. As suggested by the differential subcellular localization of SPPL2b and SPPL3 distinct phenotypes were found upon antisense gripNA-mediated knockdown in zebrafish. spp and sppl3 knockdowns in zebrafish result in cell death within the central nervous system, whereas reduction of sppl2b expression causes erythrocyte accumulation in an enlarged caudal vein. Moreover, expression of D/A mutants of the putative C-terminal active sites of spp, sppl2, and spp13 produced phenocopies of the respective knockdown phenotypes. These data suggest that all investigated PSHs/SPPLs are members of the novel family of GxGD aspartyl proteases. More recently, it was shown that SPPL2b utilizes multiple intramembrane cleavages to liberate the TNF(x intracellular domain into the cytosol and to release the C-terminal counterpart into the lumen. These findings suggest common principles of intramembrane proteolysis by GxGD type aspartyl proteases. In this article,we will review the similarities of SPPs and gamma-secretase based on recent findings by us and others

High frequency diffraction of an electromagnetic plane wave by an imperfectly conducting rectangular cylinder

Copyright @ 2011 IEEEWe shall consider the the problem of determining the scattered far wave field produced when a plane E-polarized wave is incident on an imperfectly conducting rectangular cylinder. By using the the uniform asymptotic solution for the problem of the diffraction of a plane wave by a right-angled impedance wedge, in conjunction with Keller's method, the a high frequency far field solution to the problem is given

Effects of simultaneously performed dual-task training with aerobic exercise and working memory training on cognitive functions and neural systems in the elderly

Working memory (WM) training (WMT), aerobic exercise training (AET), and dual-task training improve cognitive functions and alter neural systems in older adults. In particular, the effects have been investigated of dual-task training that combines a walking or standing activity (balance exercise) simultaneously performed with cognitive training (which is ecologically difficult for the elderly). In this study, we investigated the effects of simultaneously performed dual-task training incorporating both AET and WMT (SDAEWMT), using a recumbent ergocycle bicycle and a WMT program that provided a portable console and made the training ecologically easy for the elderly. Older adults ( years old) participated in 3 months of SDAEWMT, WMT, or AET after random allocation, and the effects of SDAEWMT were compared with those of WMT and AET. Prior to and after training, all the subjects underwent cognitive testing, magnetic resonance imaging (MRI) involving diffusion tensor imaging (DTI), and functional MRI during performance of an N-back WM task. SDAEWMT improved executive function (performance of a frontal assessment battery); however, there was no evidence of broader transfer effects or enhanced learning with WMT. SDAEWMT resulted in mean diffusivity changes in brain areas involving the dopaminergic system, suggesting that neural tissue changes occurred in these areas. SDAEWMT also resulted in an increase in brain activity during the 2-back working memory task in brain areas involved in attentional reorientation. These results suggest that SDAEWMT is effective for improving cognitive functions and inducing beneficial neural changes in older adults

Improved measurement of the K+->pi+nu(nu)over-bar branching ratio

An additional event near the upper kinematic limit for K+-->pi(+)nu(nu) over bar has been observed by experiment E949 at Brookhaven National Laboratory. Combining previously reported and new data, the branching ratio is B(K+-->pi(+)nu(nu) over bar)=(1.47(-0.89)(+1.30))x10(-10) based on three events observed in the pion momentum region 211<P<229 MeV/c. At the measured central value of the branching ratio, the additional event had a signal-to-background ratio of 0.9

Nonlinear Localization in Metamaterials

Metamaterials, i.e., artificially structured ("synthetic") media comprising weakly coupled discrete elements, exhibit extraordinary properties and they hold a great promise for novel applications including super-resolution imaging, cloaking, hyperlensing, and optical transformation. Nonlinearity adds a new degree of freedom for metamaterial design that allows for tuneability and multistability, properties that may offer altogether new functionalities and electromagnetic characteristics. The combination of discreteness and nonlinearity may lead to intrinsic localization of the type of discrete breather in metallic, SQUID-based, and ${\cal PT}-$symmetric metamaterials. We review recent results demonstrating the generic appearance of breather excitations in these systems resulting from power-balance between intrinsic losses and input power, either by proper initialization or by purely dynamical procedures. Breather properties peculiar to each particular system are identified and discussed. Recent progress in the fabrication of low-loss, active and superconducting metamaterials, makes the experimental observation of breathers in principle possible with the proposed dynamical procedures.Comment: 19 pages, 14 figures, Invited (Review) Chapte

Lung Cancer in Pulmonary Fibrosis: Tales of Epithelial Cell Plasticity

Lung epithelial cells exhibit a high degree of plasticity. Alterations to lung epithelial cell function are critically involved in several chronic lung diseases such as pulmonary fibrosis. Pulmonary fibrosis is characterized by repetitive injury and subsequent impaired repair of epithelial cells, which leads to aberrant growth factor activation and fibroblast accumulation. Increased proliferation and hyper- and metaplasia of epithelial cells upon injury have also been observed in pulmonary fibrosis; this epithelial cell activation might represent the basis for lung cancer development. Indeed, several studies have provided histopathological evidence of an increased incidence of lung cancer in pulmonary fibrosis. The mechanisms involved in the development of cancer in pulmonary fibrosis, however, remain poorly understood. This review highlights recently uncovered molecular mechanisms shared between lung cancer and fibrosis, which extend the current evidence of a common trait of cancer and fibrosis, as provided by histopathological observations. Copyright (C) 2011 S. Karger AG, Base

Prevention of type 2 diabetes in a primary healthcare setting: Three-year results of lifestyle intervention in Japanese subjects with impaired glucose tolerance

<p>Abstract</p> <p>Background</p> <p>A randomized control trial was performed to test whether a lifestyle intervention program, carried out in a primary healthcare setting using existing resources, can reduce the incidence of type 2 diabetes in Japanese with impaired glucose tolerance (IGT). The results of 3 years' intervention are summarized.</p> <p>Methods</p> <p>Through health checkups in communities and workplaces, 304 middle-aged IGT subjects with a mean body mass index (BMI) of 24.5 kg/m²were recruited and randomized to the intervention group or control group. The lifestyle intervention was carried out for 3 years by public health nurses using the curriculum and educational materials provided by the study group.</p> <p>Results</p> <p>After 1 year, the intervention had significantly improved body weight (-1.5 ± 0.7 vs. -0.7 ± 2.5 kg in the control; p = 0.023) and daily non-exercise leisure time energy expenditure (25 ± 113 vs. -3 ± 98 kcal; p = 0.045). Insulin sensitivity assessed by the Matsuda index was improved by the intervention during the 3 years. The 3-year cumulative incidence tended to be lower in the intervention group (14.8% vs.8.2%, log-rank test: p = 0.097). In a sub-analysis for the subjects with a BMI > 22.5 kg/m², a significant reduction in the cumulative incidence was found (p = 0.027).</p> <p>Conclusions</p> <p>The present lifestyle intervention program using existing healthcare resources is beneficial in preventing diabetes in Japanese with IGT. This has important implications for primary healthcare-based diabetes prevention.</p> <p>Trial registration number</p> <p><b>UMIN000003136</b></p

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition