Structure-function analysis of amino acid 74 of human RAMP1 and RAMP3 and its role in peptide interactions with adrenomedullin and calcitonin gene-related peptide receptors

The receptors for calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are complexes of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying proteins (RAMP). The CGRP receptor is a CLR/RAMP1 pairing whereas CLR/RAMP2 and CLR/RAMP3 constitute two subtypes of AM receptor: AM(1) and AM(2), respectively. Previous studies identified Glu74 in RAMP3 to be important for AM binding and potency. To further understand the importance of this residue and its equivalent in RAMP1 (Trp74) we substituted the native amino acids with several others. In RAMP3, these were Trp, Phe, Tyr, Ala, Ser, Thr, Arg and Asn; in RAMP1, Glu, Phe, Tyr, Ala and Asn substitutions were made. The mutant RAMPs were co-expressed with CLR in Cos7 cells; receptor function in response to AM, AM(2)/intermedin and CGRP was measured in a cAMP assay and cell surface expression was determined by ELISA. Phe reduced AM potency in RAMP3 but had no effect in RAMP1. In contrast, Tyr had no effect in RAMP3 but enhanced AM potency in RAMP1. Most other substitutions had a small effect on AM potency in both receptors whereas there was little impact on CGRP or AM(2) potency. Overall, these data suggest that the geometry and charge of the residue at position 74 contribute to how AM interacts with the AM(2) and CGRP receptors and confirms the role of this position in dictating differential AM pharmacology at the AM(2) and CGRP receptors.

Lack of association between glucocorticoid use and presence of the metabolic syndrome in patients with rheumatoid arthritis:a cross-sectional study

Introduction - Rheumatoid arthritis (RA) associates with excessive cardiovascular morbidity and mortality, attributed to both traditional and novel cardiovascular risk factors. The metabolic syndrome, a cluster of classical cardiovascular risk factors, including hypertension, obesity, glucose intolerance, and dyslipidaemia, is highly prevalent in RA. Reports suggest that long-term glucocorticoid (GC) use may exacerbate individual cardiovascular risk factors, but there have been no studies in RA to assess whether it associates with the metabolic syndrome. We examined whether GC exposure associates with the presence of metabolic syndrome in patients with RA. Methods - RA patients (n = 398) with detailed clinical and laboratory assessments were categorised into three groups according to GC exposure: no/limited (<3 months) exposure (NE), low-dose (<7.5 mg/day) long-term exposure (LE), and medium-dose (greater than or equal to 7.5 mg to 30 mg/day) long-term exposure (ME). The metabolic syndrome was defined using the National Cholesterol Education Programme III guidelines. The association of GC exposure with the metabolic syndrome was evaluated using binary logistic regression. Results - The metabolic syndrome was present in 40.1% of this population and its prevalence did not differ significantly between the GC exposure groups (NE 37.9% versus LE 40.7% versus ME 50%, P = 0.241). Binary logistic regression did not demonstrate any increased odds for the metabolic syndrome when comparing ME with LE (odds ratio = 1.64, 95% confidence interval 0.92 to 2.92, P = 0.094) and remained non significant after adjusting for multiple potential confounders. Conclusions - Long-term GC exposure does not appear to associate with a higher prevalence of the metabolic syndrome in patients with RA. The components of the metabolic syndrome may already be extensively modified by other processes in RA (including chronic inflammation and treatments other than GCs), leaving little scope for additive effects of GCs.

Assessment of physical and hydrological properties of biological soil crusts using x-ray microtomography and modelling

Biological soil crusts (BSCs) are formed by aggregates of soil particles and communities of microbial organisms and are common in all drylands. The role of BSCs on infiltration remains uncertain due to the lack of data on their role in affecting soil physical properties such as porosity and structure. Quantitative assessment of these properties is primarily hindered by the fragile nature of the crusts. Here we show how the use of a combination of non-destructive imaging X-ray microtomography (XMT) and Lattice Boltzmann method (LBM) enables quantification of key soil physical parameters and the modeling of water flow through BSCs samples from Kalahari Sands, Botswana. We quantify porosity and flow changes as a result of mechanical disturbance of such a fragile cyanobacteria-dominated crust. Results show significant variations in porosity between different types of crusts and how they affect the flow and that disturbance of a cyanobacteria-dominated crust results in the breakdown of larger pore spaces and reduces flow rates through the surface layer. We conclude that the XMT–LBM approach is well suited for study of fragile surface crust samples where physical and hydraulic properties cannot be easily quantified using conventional methods.

Unraveling the role of forgiveness in family relationships

Testing the idea that the process of forgiveness is intrinsically different across diverse relationships, this study examined the role of forgiveness in different family relationships. In 2 laboratory sessions 1 year apart, 114 families (each including 2 parents and 1 child) completed a new measure of family forgiveness and many individual-level, relationship-level, and family-level variables that have been previously linked with forgiveness. After validating the measure of family forgiveness in cross-sectional analyses, investigators performed longitudinal analyses to examine the role of forgiveness in each family relationship over the 1-year interval. Results indicated many important positive consequences of forgiveness on individual traits, aspects of each family relationship, and general family environment. However, there were also important asymmetries in associates of forgiveness across parent-child and parent-parent relationships, demonstrating the relationship-bound nature of forgiveness.

Exercise Training Reduces Liver Fat and Increases Rates of VLDL Clearance, but not VLDL Production in NAFLD

Context Randomised controlled trials in non-alcoholic fatty liver disease (NAFLD) have shown that regular exercise, even without calorie restriction, reduces liver steatosis. A previous study has shown that 16 weeks supervised exercise training in NAFLD did not affect total VLDL kinetics. Objective To determine the effect of exercise training on intrahepatocellular fat (IHCL) and the kinetics of large triglyceride-(TG)-rich VLDL1 and smaller denser VLDL2 which has a lower TG content. Design A 16 week randomised controlled trial. Patients 27 sedentary patients with NAFLD. Intervention Supervised exercise with moderate-intensity aerobic exercise or conventional lifestyle advice (control). Main outcome Very low density lipoprotein1 (VLDL1) and VLDL2-TG and apolipoproteinB (apoB) kinetics investigated using stable isotopes before and after the intervention. Results In the exercise group VO2max increased by 31±6% (mean±SEM) and IHCL decreased from 19.6% (14.8, 30.0) to 8.9% (5.4, 17.3) (median (IQR)) with no significant change in VO2max or IHCL in the control group (change between groups p<0.001 and p=0.02, respectively). Exercise training increased VLDL1-TG and apoB fractional catabolic rates, a measure of clearance, (change between groups p=0.02 and p=0.01, respectively), and VLDL1-apoB production rate (change between groups p=0.006), with no change in VLDL1 -TG production rate. Plasma TG did not change in either group. Conclusion An increased clearance of VLDL1 may contribute to the significant decrease in liver fat following 16 weeks of exercise in NAFLD. A longer duration or higher intensity exercise interventions may be needed to lower plasma TG and VLDL production rate.

FcγRIIa and FcγRIIIa polymorphisms and cetuximab benefit in the microscopic disease

Purpose: FcγR polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early-stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomized phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX ± cetuximab in high-risk, locally advanced rectal cancer.r/>r/>Experimental Design: FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Kaplan–Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.r/>r/>Results: Genotyping was successfully performed in 105 of 164 (64%) patients (CAPOX = 54, CAPOX-C = 51). No deviation from the Hardy–Weinberg equilibrium or association of these polymorphisms with tumor RAS status was observed. FcγRIIa-131R (HR, 0.38; P = 0.058) and FcγRIIIa-158F alleles (HR, 0.21; P = 0.007) predicted improved progression-free survival (PFS) in patients treated with cetuximab. In the CAPOX-C arm, carriers of both 131R and 158F alleles had a statistically significant improvement in PFS (5 years: 78.4%; HR, 0.22; P = 0.002) and overall survival (OS; 5 years: 86.4%; HR, 0.24; P = 0.018) when compared with patients homozygous for 131H and/or 158V (5-year PFS: 35.7%; 5-year OS: 57.1%). An interaction between cetuximab benefit and 131R and 158F alleles was found for PFS (P = 0.017) and remained significant after adjusting for prognostic variables (P = 0.003).r/>r/>Conclusion: This is the first study investigating FcγRIIa and FcγRIIIa polymorphisms in patients with early-stage colorectal cancer treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.

Enhancing composite Digital Documents Using XML-based Standoff Markup

Document representations can rapidly become unwieldy if they try to encapsulate all possible document properties, ranging from abstract structure to detailed rendering and layout. We present a composite document approach wherein an XMLbased document representation is linked via a shadow tree of bi-directional pointers to a PDF representation of the same document. Using a two-window viewer any material selected in the PDF can be related back to the corresponding material in the XML, and vice versa. In this way the treatment of specialist material such as mathematics, music or chemistry (e.g. via read aloud or play aloud ) can be activated via standard tools working within the XML representation, rather than requiring that application-specific structures be embedded in the PDF itself. The problems of textual recognition and tree pattern matching between the two representations are discussed in detail. Comparisons are drawn between our use of a shadow tree of pointers to map between document representations and the use of a code-replacement shadow tree in technologies such as XBL.

Horæ evangelicæ : or, the internal evidence of the Gospel history, being an inquiry into the structure and origin of the four Gospels, their historical consistency, and the characteristic design of each narrative /

Mode of access: Internet.

Actitudes de un grupo de directivos de empresa hacia la integración laboral de personas en proceso de reintegración en Colombia

Colombia atraviesa un proceso de desmovilización y una de las metas es la reintegración laboral, entendida como el proceso a través del cual las personas que han hecho parte de un grupo armado ilegal obtienen un empleo y se insertan definitivamente a la sociedad. El presente estudio tiene como objetivo fundamental comprender las actitudes de un grupo de tres directivos hacia la vinculación laboral de las personas en proceso de reintegración laboral (PPR), mediante un diseño cualitativo. Para ello, se llevó a cabo una serie de entrevistas semiestructuradas a una muestra de tres directivos del sector público y privado. La información obtenida se analizó mediante un proceso de codificación axial. Los resultados obtenidos evidencian que las actitudes de los tres empresarios frente a la contratación de personas en proceso de reintegración laboral, pueden ser positivas o negativas. Así mismo, una de las actitudes predominantes, son la evaluación de creencias y prejuicios de los empresarios frente al proceso de integración laboral, estos son: la incertidumbre frente al desempeño laboral del PPR, la falta de dedicación por parte del PPR, los posibles conflictos laborales y la dificultad de relacionamiento del PPR. En conclusión, el modelo del comportamiento organizacional juega un papel muy importante, dado que abarca los elementos que influyen y determinan la construcción de las actitudes. Estas guían la evaluación de conductas que pueden ser a favor o en contra, de diversos ámbitos del proceso de contratación de personas desmovilizadas.

An illustrated catalogue of engraved portraits and fancy subjects painted by Thomas Gainsborough, R.A., published between 1760 and 1820, and by George Romney, published between 1770 and 1830 : with the variations of the state of the plates /

Cover title: The engraved portraits & fancy subjects painted by Thomas Gainsborough, R.A., and George Romney.

Report on the scientific results of the voyage of H.M.S. Challenger during the years 1873-76 under the command of Captain George S. Nares ... and the late Captain Frank Tourle Thomson, R.N.

Botany v.2=pt.4 (1886)

Report on the scientific results of the voyage of H.M.S. Challenger during the years 1873-76 under the command of Captain George S. Nares ... and the late Captain Frank Tourle Thomson, R.N.

Zoology v.13=pt.35-37 (1884-1885)

Report on the scientific results of the voyage of H.M.S. Challenger during the years 1873-76 under the command of Captain George S. Nares ... and the late Captain Frank Tourle Thomson, R.N.

Zoology v.6=pt.15;17 (1881-1882)

Report on the scientific results of the voyage of H.M.S. Challenger during the years 1873-76 under the command of Captain George S. Nares ... and the late Captain Frank Tourle Thomson, R.N.

Zoology v.8=pt.23-25 (1882-1883)