C3G mediated suppression of malignant transformation involves activation of PP2A phosphatases at the subcortical actin cytoskeleton

In previous work, we demonstrated that C3G suppresses Ras oncogenic transformation by a mechanism involving inhibition of ERK phosphorylation. Here we present evidences indicating that this suppression mechanism is mediated, at least in part, by serine/threonine phosphatases of the PP2A family. Thus: (i) ectopic expression of C3G or C3GΔCat (mutant lacking the GEF activity) increases specific ERK-associated PP2A phosphatase activities; (ii) C3G and PP2A interact, as demonstrated by immunofluorescence and co-immunoprecipitation experiments; (iii) association between PP2A and MEK or ERK increases in C3G overexpressing cells; (iv) phosphorylated-inactive PP2A level decreases in C3G expressing clones and, most importantly, (v) okadaic acid reverts the inhibitory effect of C3G on ERK phosphorylation. Moreover, C3G interacts with Ksr-1, a scaffold protein of the Ras-ERK pathway that also associates with PP2A. The fraction of C3G involved in transformation suppression is restricted to the subcortical actin cytoskeleton where it interacts with actin. Furthermore, the association between C3G and PP2A remains stable even after cytoskeleton disruption with cytochalasin D, suggesting that the three proteins form a complex at this subcellular compartment. Finally, C3G- and C3GΔCat-mediated inhibition of ERK phosphorylation is reverted by incubation with cytochalasin D. We hypothesize that C3G triggers PP2A activation and binding to MEK and ERK at the subcortical actin cytoskeleton, thus favouring ERK dephosphorylation. © 2007 Elsevier Inc. All rights reserved.This work was supported by grants SAF2003-04177 andGEN2003- 20239-C06-02 from MEC, Spain, FIS-FEDERPI030651, PI041324 and PI061274 from ISCIII,MSC, Spain, as well as institutional support from Redes Temáticas (C03/10 and RD06/0020/0000) de investigación en cáncer from ISCIII, MSC, Spain. S. M-E is a postodoctoral fellow supported by grant GEN2003-20239-C06-02. C.G. was supported by the Ramón y Cajal Program from the Spanish Ministry of Education.Peer Reviewe

Shared Service Delivery Can Increase Client Engagement: A Study of Shared Medical Appointments

Problem definition: Clients and service providers alike often consider one-on-one service delivery to be ideal, assuming, perhaps unquestioningly, that devoting individualized attention best improves client outcomes. In contrast, in shared service delivery, clients are served in batches and the dynamics of group interaction could lead to increased client engagement, which could improve outcomes. However, the loss of privacy and personal connection might undermine engagement. The engagement dynamics in one-on-one and shared delivery models have not been rigorously studied. To the extent that shared delivery may result in comparable or better engagement than one-on-one delivery, service providers in a broad array of contexts may be able to create more value for clients by delivering service in batches. Methodology/results: We conducted a randomized controlled trial with 1,000 patients who were undergoing glaucoma treatment over a three-year period at a large eye hospital. Using verbatim and behavioral transcripts from more than 20,000 minutes of video recorded during our trial, we examine how shared medical appointments (SMAs), in which patients are served in batches, impact engagement. On average, a patient who experienced SMAs asked 33.3% more questions per minute and made 8.6% more nonquestion comments per minute. Because there were multiple patients in an SMA, this increase in engagement at the individual patient level resulted in patients hearing far more comments in the group setting. Patients in SMAs also exhibited higher levels of nonverbal engagement across a wide array of measures (attentiveness, positivity, head wobbling, or “thalai aattam” in Tamil: a South Indian gesture to signal agreement or understanding, eye contact, and end-of-appointment happiness), relative to patients who attended one-on-one appointments. Managerial implications: These results shed light on the potential for shared service delivery models to increase client engagement and thus enhance service performance

Betatrophin levels are related to the early histological findings in nonalcoholic fatty liver disease

Betatrophin, a liver hormone, regulates glucose and lipid metabolism. We investigated the betatrophin levels in nonalcoholic fatty liver disease (NAFLD) and searched for any relationship with histological severity and metabolic parameters. Fifty males with NAFLD [Nonalcoholic Steatohepati-tis (NASH) (n = 32); non-NASH (n = 18)] and 30 healthy controls were included. Plasma betatrophin was measured by ELISA method. Insulin sensitivity was assessed by HOMA-IR index. Histological features were scored by the semi quantitative classification and combined as the NAFLD activity score (NAS). Betatrophin levels in the non-NASH group were significantly higher than the controls. Betatrophin was positively correlated to the age, waist circumference, total cholesterol, triglycerides, LDL cholesterol, glucose, insulin, HOMA-IR index and gamma glutamyl transpeptidase levels, and negatively correlated to the steatosis and NAS. In the stepwise linear regression analysis, the triglyceride (β = 0.457, p < 0.001), glucose (β = 0.281, p = 0.02) and NAS (β = −0.260, p = 0.03) were the independent determinants of betatrophin. Betatrophin levels are higher in the early stages of NAFLD and tend to decrease when the disease progresses. This could be an important preliminary mechanistic finding to explain the increased frequency of glucose intolerance during the course of NAFLD

Temporary labour migration to United Arab Emirates: a complex story

In this study, we take a point of departure in two recently available large quantitative sources of data from the United Arab Emirates(UAE) in order to analyse social and economic aspects of temporary labour migration to the country. We attempt to present a nuanced and broad-scale description of social and economic situation of labour immigrants in the UAE. The results paint a rather complex picture. On one hand, immigrant workers are often low-paid and harshly treated, on the other there are opportunities for economic advancement for many of them. We conclude that, although far from being a neo-liberal utopia, the UAE does provide better opportunities for millions of immigrants. Life in the country is harsh for many of immigrants but it is less harsh than the alternatives they have in home countries. Regarding the UAE citizens, they surely are or will be facing economic challenges due to massive immigration, but the country has experienced the levels of economic development that would be unimaginable without a large-scale immigration. Thus, the immigration experience of the UAE has so far largely been a win-win situation, for both natives and immigrants

Role of Chemerin in Cardiovascular Diseases

(1) Background: Obesity is closely connected to the pathophysiology of cardiovascular diseases (CVDs). Excess fat accumulation is associated with metabolic malfunctions that disrupt cardiovascular homeostasis by activating inflammatory processes that recruit immune cells to the site of injury and reduce nitric oxide levels, resulting in increased blood pressure, endothelial cell migration, proliferation, and apoptosis. Adipose tissue produces adipokines, such as chemerin, that may alter immune responses, lipid metabolism, vascular homeostasis, and angiogenesis. (2) Methods: We performed PubMed and MEDLINE searches for articles with English abstracts published between 1997 (when the first report on chemerin identification was published) and 2022. The search retrieved original peer-reviewed articles analyzed in the context of the role of chemerin in CVDs, explicitly focusing on the most recent findings published in the past five years. (3) Results: This review summarizes up-to-date findings related to mechanisms of chemerin action, its role in the development and progression of CVDs, and novel strategies for developing chemerin-targeting therapeutic agents for treating CVDs. (4) Conclusions: Extensive evidence points to chemerin’s role in vascular inflammation, angiogenesis, and blood pressure modulation, which opens up exciting perspectives for developing chemerin-targeting therapeutic agents for the treatment of CVDs

A global optimization approach applied to structural dynamic updating

In this paper, the application of stochastic global optimization tech- niques, in particular the GlobalSearch and MultiStart solvers from MatLab®, to improve the updating of a structural dynamic model, are presented. For com- parative purposes, the efficiency of these global methods relatively to the local search method previously used in a Finite Element Model Updating program is evaluated. The obtained solutions showed that the GlobalSearch and MultiStart solvers are able to achieve a better solution than the local solver previously used, in the updating of a structural dynamic model. The results show also that the GlobalSearch solver is more efficient than the MultiStart, since requires less computational effort to obtain the global solution.Fundação para a Ciência e a Tecnologia (FCT

Evolutionary Sequence Modeling for Discovery of Peptide Hormones

There are currently a large number of “orphan” G-protein-coupled receptors (GPCRs) whose endogenous ligands (peptide hormones) are unknown. Identification of these peptide hormones is a difficult and important problem. We describe a computational framework that models spatial structure along the genomic sequence simultaneously with the temporal evolutionary path structure across species and show how such models can be used to discover new functional molecules, in particular peptide hormones, via cross-genomic sequence comparisons. The computational framework incorporates a priori high-level knowledge of structural and evolutionary constraints into a hierarchical grammar of evolutionary probabilistic models. This computational method was used for identifying novel prohormones and the processed peptide sites by producing sequence alignments across many species at the functional-element level. Experimental results with an initial implementation of the algorithm were used to identify potential prohormones by comparing the human and non-human proteins in the Swiss-Prot database of known annotated proteins. In this proof of concept, we identified 45 out of 54 prohormones with only 44 false positives. The comparison of known and hypothetical human and mouse proteins resulted in the identification of a novel putative prohormone with at least four potential neuropeptides. Finally, in order to validate the computational methodology, we present the basic molecular biological characterization of the novel putative peptide hormone, including its identification and regional localization in the brain. This species comparison, HMM-based computational approach succeeded in identifying a previously undiscovered neuropeptide from whole genome protein sequences. This novel putative peptide hormone is found in discreet brain regions as well as other organs. The success of this approach will have a great impact on our understanding of GPCRs and associated pathways and help to identify new targets for drug development

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE

Azimuthal anisotropy of charged particles at high transverse momenta in PbPb collisions at sqrt(s[NN]) = 2.76 TeV

The azimuthal anisotropy of charged particles in PbPb collisions at nucleon-nucleon center-of-mass energy of 2.76 TeV is measured with the CMS detector at the LHC over an extended transverse momentum (pt) range up to approximately 60 GeV. The data cover both the low-pt region associated with hydrodynamic flow phenomena and the high-pt region where the anisotropies may reflect the path-length dependence of parton energy loss in the created medium. The anisotropy parameter (v2) of the particles is extracted by correlating charged tracks with respect to the event-plane reconstructed by using the energy deposited in forward-angle calorimeters. For the six bins of collision centrality studied, spanning the range of 0-60% most-central events, the observed v2 values are found to first increase with pt, reaching a maximum around pt = 3 GeV, and then to gradually decrease to almost zero, with the decline persisting up to at least pt = 40 GeV over the full centrality range measured.Comment: Replaced with published version. Added journal reference and DO