Stability analysis of non-autonomous reaction-diffusion systems: the effects of growing domains

By using asymptotic theory, we generalise the Turing diffusively-driven instability conditions for reaction-diffusion systems with slow, isotropic domain growth. There are two fundamental biological differences between the Turing conditions on fixed and growing domains, namely: (i) we need not enforce cross nor pure kinetic conditions and (ii) the restriction to activator-inhibitor kinetics to induce pattern formation on a growing biological system is no longer a requirement. Our theoretical findings are confirmed and reinforced by numerical simulations for the special cases of isotropic linear, exponential and logistic growth profiles. In particular we illustrate an example of a reaction-diffusion system which cannot exhibit a diffusively-driven instability on a fixed domain but is unstable in the presence of slow growth

Proinflammatory Phenotype and Increased Caveolin-1 in Alveolar Macrophages with Silenced CFTR mRNA

The inflammatory milieu in the respiratory tract in cystic fibrosis (CF) has been linked to the defective expression of the cystic transmembrane regulator (CFTR) in epithelial cells. Alveolar macrophages (AM), important contibutors to inflammatory responses in the lung, also express CFTR. The present study analyzes the phenotype of human AM with silenced CFTR. Expression of CFTR mRNA and the immature form of the CFTR protein decreased 100-fold and 5.2-fold, respectively, in AM transfected with a CFTR specific siRNA (CFTR-siRNA) compared to controls. Reduction of CFTR expression in AM resulted in increased secretion of IL-8, increased phosphorylation of NF-κB, a positive regulator of IL-8 expression, and decreased expression of IκB-α, the inhibitory protein of NF-κB activation. AM with silenced CFTR expression also showed increased apoptosis. We hypothesized that caveolin-1 (Cav1), a membrane protein that is co-localized with CFTR in lipid rafts and that is related to inflammation and apoptosis in macrophages, may be affected by decreased CFTR expression. Messenger RNA and protein levels of Cav1 were increased in AM with silenced CFTR. Expression and transcriptional activity of sterol regulatory element binding protein (SREBP), a negative transcriptional regulator of Cav1, was decreased in AM with silenced CFTR, but total and free cholesterol mass did not change. These findings indicate that silencing of CFTR in human AM results in an inflammatory phenotype and apoptosis, which is associated to SREBP-mediated regulation of Cav1

A Comparative Approach Linking Molecular Dynamics of Altered Peptide Ligands and MHC with In Vivo Immune Responses

The recognition of peptide in the context of MHC by T lymphocytes is a critical step in the initiation of an adaptive immune response. However, the molecular nature of the interaction between peptide and MHC and how it influences T cell responsiveness is not fully understood.We analyzed the immunological consequences of the interaction of MHC class II (I-Au) restricted 11-mer peptides of myelin basic protein with amino acid substitutions at position 4. These mutant peptides differ in MHC binding affinity, CD4+ T cell priming, and alter the severity of peptide-induced experimental allergic encephalomyelitis. Using molecular dynamics, a computational method of quantifying intrinsic movements of proteins at high resolution, we investigated conformational changes in MHC upon peptide binding. We found that irrespective of peptide binding affinity, MHC deformation appears to influence costimulation, which then leads to effective T cell priming and disease induction. Although this study compares in vivo and molecular dynamics results for three altered peptide ligands, further investigation with similar complexes is essential to determine whether spatial rearrangement of peptide-MHC and costimulatory complexes is an additional level of T cell regulation

Recommended level of physical activity and health-related quality of life among Japanese adults

<p>Abstract</p> <p>Background</p> <p>The benefits of a recommended level of physical activity on physiological health indicators such as morbidity and mortality are well-accepted, but less research has addressed whether or not the association between the recommended level of physical activity and a health-related quality of life (HRQOL) exists in the Japanese population. Thus, the present study examined whether the recommended physical activity would be associated with HRQOL in the general Japanese middle-aged population.</p> <p>Methods</p> <p>Data were obtained from 1211 male and female respondents (39.4 ± 10.9 year, mean ± SD) from an Internet-based survey of registrants of an Internet research service. Physical activity level was estimated from the short form of the International Physical Activity Questionnaire. HRQOL was assessed with the Medical Outcomes Survey Short Form-8 questionnaire (SF-8). Based on the current national guidelines for exercise in Japan, respondents were divided into a recommended group, an insufficient group, and an inactive group according to their estimated weekly physical activity level. Multivariate analyses of covariance were utilized.</p> <p>Results</p> <p>Across both genders, the recommended group had significantly higher physical functioning (PF) scores than the inactive group (p < .05). Additionally, across both genders, the recommended group had significantly higher general health perception scores than the insufficient and inactive groups (p < .05). The recommended group had significantly higher vitality scores than the insufficient and inactive groups in males, and higher than only the inactive group in females (p < .05). The insufficient group had significantly higher PF scores than the inactive group across both genders (p < .05). The recommended group had significantly higher physical component scores than the inactive group (p = .001).</p> <p>Conclusion</p> <p>Individuals who attained the recommended level of physical activity had better scores on some dimensions of HRQOL than those who did not, suggesting that the recommended level of physical activity may be applicable not only to the physiological objective outcomes but also to some dimensions in both the physical and mental aspects of HRQOL.</p

Active Site Mutations Change the Cleavage Specificity of Neprilysin

Neprilysin (NEP), a member of the M13 subgroup of the zinc-dependent endopeptidase family is a membrane bound peptidase capable of cleaving a variety of physiological peptides. We have generated a series of neprilysin variants containing mutations at either one of two active site residues, Phe563 and Ser546. Among the mutants studied in detail we observed changes in their activity towards leucine5-enkephalin, insulin B chain, and amyloid β1–40. For example, NEPF563I displayed an increase in preference towards cleaving leucine5-enkephalin relative to insulin B chain, while mutant NEPS546E was less discriminating than neprilysin. Mutants NEPF563L and NEPS546E exhibit different cleavage site preferences than neprilysin with insulin B chain and amyloid ß1–40 as substrates. These data indicate that it is possible to alter the cleavage site specificity of neprilysin opening the way for the development of substrate specific or substrate exclusive forms of the enzyme with enhanced therapeutic potential

Importance of salt fingering for new nitrogen supply in the oligotrophic ocean.

The input of new nitrogen into the euphotic zone constrains the export of organic carbon to the deep ocean and thereby the biologically mediated long-term CO2 exchange between the ocean and atmosphere. In low-latitude open-ocean regions, turbulence-driven nitrate diffusion from the ocean’s interior and biological fixation of atmospheric N2 are the main sources of new nitrogen for phytoplankton productivity. With measurements across the tropical and subtropical Atlantic, Pacific and Indian oceans, we show that nitrate diffusion (171±190 mmolm 2 d 1) dominates over N2 fixation (9.0±9.4 mmolm 2 d 1) at the time of sampling. Nitrate diffusion mediated by salt fingers is responsible for ca. 20% of the new nitrogen supply in several provinces of the Atlantic and Indian Oceans. Our results indicate that salt finger diffusion should be considered in present and future ocean nitrogen budgets, as it could supply globally 0.23–1.00 TmolNyr 1 to the euphotic zone.MALASPINA (CSD2008-00077)Versión del editor10,015

Dendrimer-Based Fluorescent Indicators: In Vitro and In Vivo Applications

BACKGROUND: The development of fluorescent proteins and synthetic molecules whose fluorescence properties are controlled by the environment makes it possible to monitor physiological and pathological events in living systems with minimal perturbation. A large number of small organic dyes are available and routinely used to measure biologically relevant parameters. Unfortunately their application is hindered by a number of limitations stemming from the use of these small molecules in the biological environment. PRINCIPAL FINDINGS: We present a novel dendrimer-based architecture leading to multifunctional sensing elements that can overcome many of these problems. Applications in vitro, in living cells and in vivo are reported. In particular, we image for the first time extracellular pH in the brain in a mouse epilepsy model. CONCLUSION: We believe that the proposed architecture can represent a useful and novel tool in fluorescence imaging that can be widely applied in conjunction with a broad range of sensing dyes and experimental setups

Effects of the protein kinase inhibitors wortmannin and KN62 on cellular radiosensitivity and radiation-activated S phase and G1/S checkpoints in normal human fibroblasts

Wortmannin is a potent inhibitor of phosphatidylinositol (PI) 3-kinase and PI 3-kinase-related proteins (e.g. ATM), but it does not inhibit the activity of purified calmodulin-dependent protein kinase II (CaMKII). In the present study, we compared the effects of wortmannin and the CaMKII inhibitor KN62 on the response of normal human dermal fibroblast cultures to γ radiation. We demonstrate that wortmannin confers a phenotype on normal fibroblasts remarkably similar to that characteristic of cells homozygous for the ATM mutation. Thus wortmannin-treated normal fibroblasts exhibit increased sensitivity to radiation-induced cell killing, lack of temporary block in transition from G1 to S phase following irradiation (i.e. impaired G1/S checkpoint), and radioresistant DNA synthesis (i.e. impaired S phase checkpoint). Wortmannin-treated cultures display a diminished capacity for radiation-induced up-regulation of p53 protein and expression of p21WAF1, a p53-regulated gene involved in cell cycle arrest at the G1/S border; the treated cultures also exhibit decreased capacity for enhancement of CaMKII activity post-irradiation, known to be necessary for triggering the S phase checkpoint. We further demonstrate that KN62 confers a radioresistant DNA synthesis phenotype on normal fibroblasts and moderately potentiates their sensitivity to killing by γ rays, without modulating G1/S checkpoint, p53 up-regulation and p21WAF1 expression following radiation exposure. We conclude that CaMKII is involved in the radiation responsive signalling pathway mediating S phase checkpoint but not in the p53-dependent pathway controlling G1/S checkpoint, and that a wortmannin-sensitive kinase functions upstream in both pathways. © 1999 Cancer Research Campaig

A Bayesian assessment of an approximate model for unconfined water flow in sloping layered porous media

The prediction of water table height in unconfined layered porous media is a difficult modelling problem that typically requires numerical simulation. This paper proposes an analytical model to approximate the exact solution based on a steady-state Dupuit–Forchheimer analysis. The key contribution in relation to a similar model in the literature relies in the ability of the proposed model to consider more than two layers with different thicknesses and slopes, so that the existing model becomes a special case of the proposed model herein. In addition, a model assessment methodology based on the Bayesian inverse problem is proposed to efficiently identify the values of the physical parameters for which the proposed model is accurate when compared against a reference model given by MODFLOW-NWT, the open-source finite-difference code by the U.S. Geological Survey. Based on numerical results for a representative case study, the ratio of vertical recharge rate to hydraulic conductivity emerges as a key parameter in terms of model accuracy so that, when appropriately bounded, both the proposed model and MODFLOW-NWT provide almost identical results