Substrate stiffness and VE-cadherin mechano-transduction coordinate to regulate endothelial monolayer integrity.

The vascular endothelium is subject to diverse mechanical cues that regulate vascular endothelial barrier function. In addition to rigidity sensing through integrin adhesions, mechanical perturbations such as changes in fluid shear stress can also activate force transduction signals at intercellular junctions. This study investigated how extracellular matrix rigidity and intercellular force transduction, activated by vascular endothelial cadherin, coordinate to regulate the integrity of endothelial monolayers. Studies used complementary mechanical measurements of endothelial monolayers grown on patterned substrates of variable stiffness. Specifically perturbing VE-cadherin receptors activated intercellular force transduction signals that increased integrin-dependent cell contractility and disrupted cell-cell and cell-matrix adhesions. Further investigations of the impact of substrate rigidity on force transduction signaling demonstrated how cells integrate extracellular mechanics cues and intercellular force transduction signals, to regulate endothelial integrity and global tissue mechanics. VE-cadherin specific signaling increased focal adhesion remodeling and cell contractility, while sustaining the overall mechanical equilibrium at the mesoscale. Conversely, increased substrate rigidity exacerbates the disruptive effects of intercellular force transduction signals, by increasing heterogeneity in monolayer stress distributions. The results provide new insights into how substrate stiffness and intercellular force transduction coordinate to regulate endothelial monolayer integrity

Isolation of Plasmodium berghei ookinetes in culture using Nycodenz density gradient columns and magnetic isolation

BACKGROUND: Large scale in vitro production of the mosquito stages of malaria parasites remains elusive, with only limited success for complete sporogonic development and only one report of development through to infective sporozoites. The initial step in this process is the production, in vitro, of ookinetes from gametocytaemic blood. Methods for isolation of these ookinetes from blood cells have been described; however, in addition to yield often being low, processing time and potential for contamination by erythrocytes remain high. METHODS: This study compares two procedures for retaining mature ookinetes from blood stage cultures, whilst removing red blood cells and other contaminants prior to further culture of the parasite. The well established method of isolation on Nycodenz cushions is compared with a novel method utilizing the innate magnetic properties of the haem pigment crystals found in the cytoplasm of ookinetes. RESULTS: Yield and viability of ookinetes were similar with both isolation methods. However, in our hands magnetic isolation produced a cleaner ookinete preparation much more quickly. Moreover, decreasing the flow rate through the magnetic column could further enhance the yield. CONCLUSION: We recommend the enrichment of an ookinete preparation prior to further culture being performed using the magnetic properties of Plasmodium berghei ookinetes as an alternative to their density. The former technique is faster, removes more erythrocytes, but day-to-day costs are greater

Reorganization of mental health services: from institutional to community-based models of care.

Mental health services in the Eastern Mediterranean Region are predominantly centralized and institutionalized, relying on scarce specialist manpower. This creates a major treatment gap for patients with common and disabling mental disorders and places an unnecessary burden on the individual, their family and society. Six steps for reorganization of mental health services in the Region can be outlined: (1) integrate delivery of interventions for priority mental disorders into primary health care and existing priority programmes; (2) systematically strengthen the capacity of non-specialized health personnel for providing mental health care; (3) scale up community-based services (community outreach teams for defined catchment, supported residential facilities, supported employment and family support); (4) establish mental health services in general hospitals for outpatient and acute inpatient care; (5) progressively reduce the number of long-stay beds in mental hospitals through restricting new admissions; and (6) provide transitional/bridge funding over a period of time to scale up community-based services and downsize mental institutions in parallel

Constraining Disk Parameters of Be Stars using Narrowband H-alpha Interferometry with the NPOI

Interferometric observations of two well-known Be stars, gamma Cas and phi Per, were collected and analyzed to determine the spatial characteristics of their circumstellar regions. The observations were obtained using the Navy Prototype Optical Interferometer equipped with custom-made narrowband filters. The filters isolate the H-alpha emission line from the nearby continuum radiation, which results in an increased contrast between the interferometric signature due to the H-alpha-emitting circumstellar region and the central star. Because the narrowband filters do not significantly attenuate the continuum radiation at wavelengths 50 nm or more away from the line, the interferometric signal in the H-alpha channel is calibrated with respect to the continuum channels. The observations used in this study represent the highest spatial resolution measurements of the H-alpha-emitting regions of Be stars obtained to date. These observations allow us to demonstrate for the first time that the intensity distribution in the circumstellar region of a Be star cannot be represented by uniform disk or ring-like structures, whereas a Gaussian intensity distribution appears to be fully consistent with our observations.Comment: 23 pages, 14 figures, accepted for publication in A

Determining the Physical Properties of the B Stars I. Methodology and First Results

We describe a new approach to fitting the UV-to-optical spectra of B stars to model atmospheres and present initial results. Using a sample of lightly reddened stars, we demonstrate that the Kurucz model atmospheres can produce excellent fits to either combined low dispersion IUE and optical photometry or HST FOS spectrophotometry, as long as the following conditions are fulfilled: 1) an extended grid of Kurucz models is employed, 2) the IUE NEWSIPS data are placed on the FOS absolute flux system using the Massa & Fitzpatrick (1999) transformation, and 3) all of the model parameters and the effects of interstellar extinction are solved for simultaneously. When these steps are taken, the temperatures, gravities, abundances and microturbulence velocities of lightly reddened B0-A0 V stars are determined to high precision. We also demonstrate that the same procedure can be used to fit the energy distributions of stars which are reddened by any UV extinction curve which can be expressed by the Fitzpatrick & Massa (1990) parameterization scheme. We present an initial set of results and verify our approach through comparisons with angular diameter measurements and the parameters derived for an eclipsing B star binary. We demonstrate that the metallicity derived from the ATLAS 9 fits to main sequence B stars is essentially the Fe abundance. We find that a near zero microturbulence velocity provides the best-fit to all but the hottest or most luminous stars (where it may become a surrogate for atmospheric expansion), and that the use of white dwarfs to calibrate UV spectrophotometry is valid.Comment: 17 pages, including 2 pages of Tables and 6 pages of Figures. Astrophysical Jounral, in pres

Weyl-Underhill-Emmrich quantization and the Stratonovich-Weyl quantizer

Weyl-Underhill-Emmrich (WUE) quantization and its generalization are considered. It is shown that an axiomatic definition of the Stratonovich-Weyl (SW) quantizer leads to severe difficulties. Quantization on the cylinder within the WUE formalism is discussed.Comment: 15+1 pages, no figure

Ancient Migratory Events in the Middle East: New Clues from the Y-Chromosome Variation of Modern Iranians

Knowledge of high resolution Y-chromosome haplogroup diversification within Iran provides important geographic context regarding the spread and compartmentalization of male lineages in the Middle East and southwestern Asia. At present, the Iranian population is characterized by an extraordinary mix of different ethnic groups speaking a variety of Indo-Iranian, Semitic and Turkic languages. Despite these features, only few studies have investigated the multiethnic components of the Iranian gene pool. In this survey 938 Iranian male DNAs belonging to 15 ethnic groups from 14 Iranian provinces were analyzed for 84 Y-chromosome biallelic markers and 10 STRs. The results show an autochthonous but non-homogeneous ancient background mainly composed by J2a sub-clades with different external contributions. The phylogeography of the main haplogroups allowed identifying post-glacial and Neolithic expansions toward western Eurasia but also recent movements towards the Iranian region from western Eurasia (R1b-L23), Central Asia (Q-M25), Asia Minor (J2a-M92) and southern Mesopotamia (J1-Page08). In spite of the presence of important geographic barriers (Zagros and Alborz mountain ranges, and the Dasht-e Kavir and Dash-e Lut deserts) which may have limited gene flow, AMOVA analysis revealed that language, in addition to geography, has played an important role in shaping the nowadays Iranian gene pool. Overall, this study provides a portrait of the Y-chromosomal variation in Iran, useful for depicting a more comprehensive history of the peoples of this area as well as for reconstructing ancient migration routes. In addition, our results evidence the important role of the Iranian plateau as source and recipient of gene flow between culturally and genetically distinct population

Narrative-based computational modelling of the Gp130/JAK/STAT signalling pathway.

BACKGROUND: Appropriately formulated quantitative computational models can support researchers in understanding the dynamic behaviour of biological pathways and support hypothesis formulation and selection by "in silico" experimentation. An obstacle to widespread adoption of this approach is the requirement to formulate a biological pathway as machine executable computer code. We have recently proposed a novel, biologically intuitive, narrative-style modelling language for biologists to formulate the pathway which is then automatically translated into an executable format and is, thus, usable for analysis via existing simulation techniques. RESULTS: Here we use a high-level narrative language in designing a computational model of the gp130/JAK/STAT signalling pathway and show that the model reproduces the dynamic behaviour of the pathway derived by biological observation. We then "experiment" on the model by simulation and sensitivity analysis to define those parameters which dominate the dynamic behaviour of the pathway. The model predicts that nuclear compartmentalisation and phosphorylation status of STAT are key determinants of the pathway and that alternative mechanisms of signal attenuation exert their influence on different timescales. CONCLUSION: The described narrative model of the gp130/JAK/STAT pathway represents an interesting case study showing how, by using this approach, researchers can model biological systems without explicitly dealing with formal notations and mathematical expressions (typically used for biochemical modelling), nevertheless being able to obtain simulation and analysis results. We present the model and the sensitivity analysis results we have obtained, that allow us to identify the parameters which are most sensitive to perturbations. The results, which are shown to be in agreement with existing mathematical models of the gp130/JAK/STAT pathway, serve us as a form of validation of the model and of the approach itself