Genetic factors in systemic sclerosis

A number of genetic loci have been identified that appear to be associated with systemic sclerosis (SSc; scleroderma). There is mounting evidence suggesting that these genetic associations may in fact be associated with distinct phenotypes in SSc based on autoantibody pattern rather than with SSc as a single disease entity. This may ultimately have implications for approaches to therapy as well as responses to therapy. The most promising candidate genes are those involved in pathways that lead to the vascular damage and fibrosis that are the hallmarks of this disease. There is uncertainty, however, regarding the nature of the key pathological mechanisms that link these two disease processes. Recent studies have focused on Fli1 (friend leukaemia integration 1), a transcription factor that is found in immune cells, fibroblasts, and endothelial cells that regulates collagen gene function and angiogenesis. Fli1 is dysregulated in SSc skin and dermal blood vessels, and appears to play a pathological role in SSc skin fibrosis and vessel degeneration. Whether this dysregulation is due to genetic polymorphisms in the Fli1 pathway or to epigenetic mechanisms is not clear

Vaccination for children- when parents doubts are a challenge for doctors

Most doctors strongly believe that vaccinations are one of the greatest goods in medicine. Obviously, vaccination is a procedure which, results like no other in a decrease in mortality. Vaccinations have significantly reduced the incidence of the infectious disease and even some of them, such as smallpox and polio, have been almost completely eliminated. The widespread implementation of vaccinations considerably improved the individual’s health, regardless of gender and age. A question arises why every year a growing number of parents is choosing not to vaccinate their children, despite the obvious benefits from the procedure

Autocrine Transforming Growth Factor β Signaling Regulates Extracellular Signal-regulated Kinase 1/2 Phosphorylation via Modulation of Protein Phosphatase 2A Expression in Scleroderma Fibroblasts

BACKGROUND. During scleroderma (SSc) pathogenesis, fibroblasts acquire an activated phenotype characterized by enhanced production of extracellular matrix (ECM) and constitutive activation of several major signaling pathways including extracellular signal-related kinase (ERK1/2). Several studies have addressed the role of ERK1/2 in SSc fibrosis however the mechanism of its prolonged activation in SSc fibroblasts is still unknown. Protein phosphatase 2A (PP2A) is a key serine threonine phosphatase responsible for dephosphorylation of a wide array of signaling molecules. Recently published microarray data from cultured SSc fibroblasts suggests that the catalytic subunit (C-subunit) of PP2A is downregulated in SSc. In this study we examined the role and regulation of PP2A in SSc fibroblasts in the context of ERK1/2 phosphorylation and matrix production. RESULTS. We show for the first time that PP2A mRNA and protein expression are significantly reduced in SSc fibroblasts and correlate with an increase in ERK1/2 phosphorylation and collagen expression. Furthermore, transforming growth factor β (TGFβ), a major profibrotic cytokine implicated in SSc fibrosis, downregulates PP2A expression in healthy fibroblasts. PP2A-specific small interfering RNA (siRNA) was utilized to confirm the role of PP2A in ERK1/2 dephosphorylation in dermal fibroblasts. Accordingly, blockade of autocrine TGFβ signaling in SSc fibroblasts using soluble recombinant TGFβ receptor II (SRII) restored PP2A levels and decreased ERK1/2 phosphorylation and collagen expression. In addition, we observed that inhibition of ERK1/2 in SSc fibroblasts increased PP2A expression suggesting that ERK1/2 phosphorylation also contributes to maintaining low levels of PP2A, leading to an even further amplification of ERK1/2 phosphorylation. CONCLUSIONS. Taken together, these studies suggest that decreased PP2A levels in SSc is a result of constitutively activated autocrine TGFβ signaling and could contribute to enhanced phosphorylation of ERK1/2 and matrix production in SSc fibroblasts.National Institutes of Health (AR-44883

Application of lean approaches and techniques in an automotive company

In this paper are applied lean approaches and techniques in an industrial environment at Preh Portugal, Lda., a Company involved in the automotive sector located in Trofa, Portugal. This work makes use of the action-research methodology, aiming to diagnose the production system and to implement lean production procedures in order to optimize the Mizusumashi that supplies several production sections, about plastic Injection, cutting and painting. The results obtained enabled to obtain significant improvements on this Company at several factory management and operational levels.This work was supported by FCT “Fundação para a Ciência e a Tecnologia” under the program: PEst20152020.info:eu-repo/semantics/publishedVersio

The tool supporting decision making process in area of job-shop scheduling

Today most manufacturing companies from machine building industry are operating in single unit or short-run production which is very complex in terms of decision making processes in production planning area. The difficulty in decision making in the area of scheduling is caused by the necessity of analy sing multiple factors and evaluating various scheduling options due to numerous criteria. The article presents the author’s tool supporting decision making in the area of job-shop scheduling. The tool introduced in the article enables scheduling based on author’s priority rule allowing maximum usage of the most loaded resource (known as critical resource), which determines efficiency of the produc tion system. The tool has been designed and verified as a part of PhD dissertation research.This work has been supported by COMPETE: POCI-01-0145-FEDER-007043 and FCT – Fundação para a Ciência e Tecnologia within the Project Scope: UID/CEC/00319/2013.info:eu-repo/semantics/publishedVersio

Shortening Changeover Time - An Industrial Study

This paper presents the results of the use of the Single Minute Exchange of Die method to shorten changeover time on machines in a polish production company. This project has been developed for a manufacturing company, whose products are fiberboard, hardboard and softboard products manufactured by a highly specialized industry using only pure wood fibers. Long changeover times used to conduct to bad results in timely delivery of orders. Therefore, in this work each element of the changeover time was analyzed to understand if it could be eliminated, moved or simplified. Implemented solutions significantly reduce setup time and improve the Company's competitiveness.This work is supported by Portuguese National Funds through FCT “Fundação para a Ciência e a Tecnologia” under the projects: “Projeto Estratégico–UI 252–2011–2012”, reference PEst-OE/EME/UI0252/2014, and FCOMP-01-0124FEDER-PEst-OE/EEI/UI0760/2014.info:eu-repo/semantics/publishedVersio

Innate immune modulation induced by EBV lytic infection promotes endothelial cell inflammation and vascular injury in scleroderma

Microvascular injury is considered an initial event in the pathogenesis of scleroderma and endothelial cells are suspected of being the target of the autoimmune process seen in the disease. EBV has long been proposed as a trigger for autoimmune diseases, including scleroderma. Nevertheless, its contribution to the pathogenic process remains poorly understood. In this study, we report that EBV lytic antigens are detected in scleroderma dermal vessels, suggesting that endothelial cells might represent a target for EBV infection in scleroderma skin. We show that EBV DNA load is remarkably increased in peripheral blood, plasma and circulating monocytes from scleroderma patients compared to healthy EBV carriers, and that monocytes represent the prominent subsets of EBV-infected cells in scleroderma. Given that monocytes have the capacity to adhere to the endothelium, we then investigated whether monocyte-associated EBV could infect primary human endothelial cells. We demonstrated that endothelial cells are infectable by EBV, using human monocytes bound to recombinant EBV as a shuttle, even though cell-free virus failed to infect them. We show that EBV induces activation of TLR9 innate immune response and markers of vascular injury in infected endothelial cells and that up-regulation is associated with the expression of EBV lytic genes in infected cells. EBV innate immune modulation suggests a novel mechanism mediating inflammation, by which EBV triggers endothelial cell and vascular injury in scleroderma. In addition, our data point to up-regulation of EBV DNA loads as potential biomarker in developing vasculopathy in scleroderma. These findings provide the framework for the development of novel therapeutic interventions to shift the scleroderma treatment paradigm towards antiviral therapies

Integrated platform for real-time control and production and productivity monitoring and analysis

In this paper is proposed the IndustSystems, which is an integrated platform that aims at controlling and monitoring of production and evaluation of productivity in real time, via web access, using hybrid and scheduling algorithms that allow management and optimized use of production resources and perfect synchronization of production flows.This work was supported by FCT “Fundação para a Ciência e a Tecnologia” under the program: PEst20152020.info:eu-repo/semantics/publishedVersio

Stimulation of Type I Collagen Transcription in Human Skin Fibroblasts by TGF-β: Involvement of Smad 3

Transforming growth factor-β (TGF-β) stimulates the transcription of the α2(I) procollagen gene (COL1A2). The intracellular mediators involved in this response remain poorly understood. In this study, we demonstrate that primary human skin fibroblasts express Smads, a novel family of signaling molecules, in vitro in the absence of TGF-β. The levels of Smad 7 mRNA was rapidly and transiently increased by TGF-β. Transient overexpression of Smad 3 and Smad 4, but not Smad 1 or Smad 2, caused trans-activation of a CAT reporter gene driven by a 772 bp segment of the human COL1A2 promoter containing putative TGF-β response elements. Smad stimulation of promoter activity was ligand independent, but was further enhanced by TGF-β. Overexpression of a phosphorylation-deficient Smad 3 mutant or wild-type Smad 7, which lacks the carboxy-terminal phosphorylation motif, specifically inhibited TGF-β-induced activation of COL1A2 promoter. A CAGACA sequence shown to be a functional Smad-binding element in the plasminogen activator inhibitor-1 gene promoter was found within the TGF-β-response region of the proximal COL1A2 promoter. Gel mobility shift assays showed protein phosphorylation-dependent binding activity in fibroblast nuclear extracts specific for this sequence; TGF-β treatment strongly stimulated the formation of this DNA-protein complex. Smad was identified as a component of the CAGACA-binding transcription complex in TGF-β-treated fibroblasts by antibody supershifting. These results demonstrate that (i) Smad 3 transmits TGF-β signals from the receptor to the COL1A2 promoter in human fibroblasts, and is likely to play an important role in stimulation of COL1A2 promoter activity elicited by TGF-β; (ii) in fibroblasts, Smads appear to function as inducible DNA-binding transcription factors; and (iii) Smad 7 may be involved in autocrine negative feedback in the regulation of COL1A2 promoter activity by TGF-β