MicroRNA deregulation and chemotaxis and phagocytosis impairment in Alzheimer's disease

AbstractIntroductionMononuclear phagocytes play a critical role during Alzheimer's disease (AD) pathogenesis due to their contribution to innate immune responses and amyloid beta (Aβ) clearance mechanisms.MethodsBlood-derived monocytes (BDMs) and monocyte-derived macrophages (MDMs) were isolated from blood of AD, mild cognitive impairment (MCI) patients, and age-matched healthy controls for molecular and phenotypic comparisons.ResultsThe chemokine/chemokine receptor CCL2/CCR2 axis was impaired in BDMs from AD and MCI patients, causing a deficit in cell migration. Changes were also observed in MDM-mediated phagocytosis of Aβ fibrils, correlating with alterations in the expression and processing of the triggering receptor expressed on myeloid cells 2 (TREM2). Finally, immune-related microRNAs (miRNAs), including miR-155, -154, -200b, -27b, and -128, were found to be differentially expressed in these cells.DiscussionThis work provides evidence that chemotaxis and phagocytosis, two crucial innate immune functions, are impaired in AD and MCI patients. Correlations with miRNA levels suggest an epigenetic contribution to systemic immune dysfunction in AD

Model-based user interface testing with Spec Explorer and ConcurTaskTrees

Analytic usability analysis methods have been proposed as an alternative to user testing in early phases of development due to the cost of the latter approach. By working with models of the systems, analytic models are not capable of identifying implementation related problems that might have an impact on usability. Model-based testing enables the testing of an implemented software artefact against a model of what it should be (the oracle). In the case of model-based user interface testing, the models should be expressed at an adequate level of abstraction, adequately modelling the interaction process. This paper describes an effort to develop tool support enabling the use of task models as oracles for model-based testing of user interfaces.FCT -Fuel Cell Technologies Program(POSC/EIA/56646/2004

Co-Authorship of scientists in the energy field: an exploratory study of the ETDE World Energy Database (ETDEWEB) using Social Network Analysis

Paper presented at the 5th European Conference Economics and Management of Energy in Industry, Vilamoura, Algarve. Apr. 14-17, 2009, 11p. URL: http:// www.cenertec.pt/ecemei/This paper presents a preliminary exploratory study, using a social network analysis (SNA) approach to examine the structure of co-authorship collaboration within the research community in the energy field from 1995 to 2008. The domain of the study is Portuguese scientists, working either in Portugal or abroad; by foreign scientists working in Portugal or by scientists who have co-authored with either of these groups. The study uses the most common measures of macro (whole network) and micro (actor-centered) structures of this collaboration. The data used to design the social network was obtained from the Energy Technology Data Exchange (ETDE)’s Energy Database, which is the largest collection of energy research and technology literature in the world created under the umbrella of the International Energy Agency/Organisation for Economic Co- operation and Development (IEA/OEC

Loss of proteostasis induced by amyloid beta peptide in brain endothelial cells

AbstractAbnormal accumulation of amyloid-β (Aβ) peptide in the brain is a pathological hallmark of Alzheimer's disease (AD). In addition to neurotoxic effects, Aβ also damages brain endothelial cells (ECs) and may thus contribute to the degeneration of cerebral vasculature, which has been proposed as an early pathogenic event in the course of AD and is able to trigger and/or potentiate the neurodegenerative process and cognitive decline. However, the mechanisms underlying Aβ-induced endothelial dysfunction are not completely understood. Here we hypothesized that Aβ impairs protein quality control mechanisms both in the secretory pathway and in the cytosol in brain ECs, leading cells to death. In rat brain RBE4 cells, we demonstrated that Aβ1–40 induces the failure of the ER stress-adaptive unfolded protein response (UPR), deregulates the ubiquitin–proteasome system (UPS) decreasing overall proteasome activity with accumulation of ubiquitinated proteins and impairs the autophagic protein degradation pathway due to failure in the autophagic flux, which culminates in cell demise. In conclusion, Aβ deregulates proteostasis in brain ECs and, as a consequence, these cells die by apoptosis

Co-Authorship of scientists in the energy field: an exploratory study of the ETDE World Energy Database (ETDEWEB) using Social Network Analysis

Paper presented at the 5th European Conference Economics and Management of Energy in Industry, Vilamoura, Algarve. Apr. 14-17, 2009, 11p. URL: http:// www.cenertec.pt/ecemei/This paper presents a preliminary exploratory study, using a social network analysis (SNA) approach to examine the structure of co-authorship collaboration within the research community in the energy field from 1995 to 2008. The domain of the study is Portuguese scientists, working either in Portugal or abroad; by foreign scientists working in Portugal or by scientists who have co-authored with either of these groups. The study uses the most common measures of macro (whole network) and micro (actor-centered) structures of this collaboration. The data used to design the social network was obtained from the Energy Technology Data Exchange (ETDE)’s Energy Database, which is the largest collection of energy research and technology literature in the world created under the umbrella of the International Energy Agency/Organisation for Economic Co- operation and Development (IEA/OEC

Activation of the endoplasmic reticulum stress response by the amyloid-beta 1–40 peptide in brain endothelial cells

Neurovascular dysfunction arising from endothelial cell damage is an early pathogenic event that contributes to the neurodegenerative process occurring in Alzheimer's disease (AD). Since the mechanisms underlying endothelial dysfunction are not fully elucidated, this study was aimed to explore the hypothesis that brain endothelial cell death is induced upon the sustained activation of the endoplasmic reticulum (ER) stress response by amyloid-beta (Aβ) peptide, which deposits in the cerebral vessels in many AD patients and transgenic mice. Incubation of rat brain endothelial cells (RBE4 cell line) with Aβ1–40 increased the levels of several markers of ER stress-induced unfolded protein response (UPR), in a time-dependent manner, and affected the Ca2 + homeostasis due to the release of Ca2 + from this intracellular store. Finally, Aβ1–40 was shown to activate both mitochondria-dependent and -independent apoptotic cell death pathways. Enhanced release of cytochrome c from mitochondria and activation of the downstream caspase-9 were observed in cells treated with Aβ1–40 concomitantly with caspase-12 activation. Furthermore, Aβ1–40 activated the apoptosis effectors' caspase-3 and promoted the translocation of apoptosis-inducing factor (AIF) to the nucleus demonstrating the involvement of caspase-dependent and -independent mechanisms during Aβ-induced endothelial cell death. In conclusion, our data demonstrate that ER stress plays a significant role in Aβ1–40-induced apoptotic cell death in brain endothelial cells suggesting that ER stress-targeted therapeutic strategies might be useful in AD to counteract vascular defects and ultimately neurodegeneration

β2-adrenergic agonists do not improve physical performance in healthy individuals

All beta-2 agonists are prohibited by the World Anti-Doping Agency (WADA, www.wada-ama.org). However, its use may be permitted in athletes who are granted a therapeutic use exemption (TUE). [...]info:eu-repo/semantics/publishedVersio

β2-adrenergic agonists and doping: Where do we stand?

Hostrup et al1 kindly commented on our previous paper related to the enhancement of physical performance by β2-agonists.2 First, we would like to thank the authors for their review and acknowledge that our title and conclusions may have been misleading because, in fact, they only refer to endurance/aerobic-dominated performances [...]info:eu-repo/semantics/publishedVersio