Uncertainty evaluation associated with versatile automated gauging influenced by process variations through design of experiments approach

Recent advances in versatile automated gauging have enabled accurate geometric tolerance assessment on the shop floor. This paper is concerned with the uncertainty evaluation associated with comparative coordinate measurement using the design of experiments (DOE) approach. It employs the Renishaw Equator which is a software-driven comparative gauge based on the traditional comparison of production parts to a reference master part. The fixturing requirement of each production part to the master part is approximately ±1 mm for a comparison process with an uncertainty of ±2 μm. Therefore, a number of experimental designs are applied with the main focus on the influence of part misalignment from rotation between master and measure coordinate frames on the comparator measurement uncertainty. Other factors considered include measurement mode mainly in scanning and touch-trigger probing (TTP) and alignment procedure used to establish the coordinate reference frame (CRF) with respect to the number of contact points used for each geometric feature measured. The measurement uncertainty analysis of the comparator technique used by the Equator gauge commences with a simple measurement task using a gauge block to evaluate the three-dimensional (3D) uncertainty of length comparative coordinate measurement influenced by an offset by tilt in one direction (two-dimensional angular misalignment). Then, a specific manufactured measurement object is employed so that the comparator measurement uncertainty can be assessed for numerous measurement tasks within a satisfactory range of the working volume of the versatile gauge. Furthermore, in the second case study, different types of part misalignment including both 2D and 3D angular misalignments are applied. The time required for managing the re-mastering process is also examined. A task specific uncertainty evaluation is completed using DOE. Also, investigating the effects of process variations that might be experienced by such a device in workshop environments. It is shown that the comparator measurement uncertainties obtained by all the experiments agree with system features under specified conditions. It is also demonstrated that when the specified conditions are exceeded, the comparator measurement uncertainty is associated with the measurement task, the measurement strategy used, the feature size, and the magnitude and direction of offset angles in relation to the reference axes of the machine. In particular, departures from the specified part fixturing requirement of Equator have a more significant effect on the uncertainty of length measurement in comparator mode and a less significant effect on the diameter measurement uncertainty for the specific Equator and test conditions

A scanning electron microscopic study of hypercementosis

The purpose of this study was to evaluate morphological characteristics of teeth with hypercementosis that are relevant to endodontic practice. Twenty-eight extracted teeth with hypercementosis had their root apexes analyzed by scanning electron microscopy (SEM). The teeth were divided according to tooth groups and type of hypercementosis. The following aspects were examined under SEM: the contour and regularity of the root surface; presence of resorption; presence and number of apical foramina, and the diameter of the main foramen. The progression of club shape hypercementosis was directly associated with the presence of foramina and apical foramen obstruction. Cases of focal hypercementosis presented foramina on the surface, even when sidelong located in the root. Circular cementum hyperplasia form was present in 2 out of 3 residual roots, which was the highest proportion among the tooth types. The detection of a large number of foramina in the apical third of teeth with hypercementosis or even the possible existence of apical foramen obliteration contributes to understand the difficulties faced during endodontic treatment of these cases

Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression

Depression is a highly prevalent and recurrent neuropsychiatric disorder associated with alterations in emotional and cognitive domains. Neuroplastic phenomena are increasingly considered central to the etiopathogenesis of and recovery from depression. Nevertheless, a high number of remitted patients experience recurrent episodes of depression, remaining unclear how previous episodes impact on behavior and neuroplasticity and/or whether modulation of neuroplasticity is important to prevent recurrent depression. Through re-exposure to an unpredictable chronic mild stress protocol in rats, we observed the re-appearance of emotional and cognitive deficits. Furthermore, treatment with the antidepressants fluoxetine and imipramine was effective to promote sustained reversion of a depressive-like phenotype; however, their differential impact on adult hippocampal neuroplasticity triggered a distinct response to stress re-exposure: while imipramine re-established hippocampal neurogenesis and neuronal dendritic arborization contributing to resilience to recurrent depressive-like behavior, stress re-exposure in fluoxetine-treated animals resulted in an overproduction of adult-born neurons along with neuronal atrophy of granule neurons, accounting for an increased susceptibility to recurrent behavioral changes typical of depression. Strikingly, cell proliferation arrest compromised the behavior resilience induced by imipramine and buffered the susceptibility to recurrent behavioral changes promoted by fluoxetine. This study shows that previous exposure to a depressive-like episode impacts on the behavioral and neuroanatomical changes triggered by subsequent re-exposure to similar experimental conditions and reveals that the proper control of adult hippocampal neuroplasticity triggered by antidepressants is essential to counteract recurrent depressive-like episodes.FCT (IF/01079/2014). This article has been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the FCT, under the scope of the project POCI-01-0145-FEDER-007038info:eu-repo/semantics/publishedVersio

Cervical cancer screening: target age bracket, screening frequency and screening method: review of recent evidence and comparison with the Portuguese performance indicator

Esta revisão teve por objetivo avaliar a força de evidência do indicador de desempenho português relativo ao rastreio do Câncer do Colo do Útero (CCU): (1) limites etários das mulheres da população geral que o devem realizar, a (2) periodicidade com que deve ser realizado e (3) qual o melhor exame de rastreio. Foram pesquisados os seguintes termos MeSH: vaginal smears, age groups, periodicity, methods, uterine cervical cancer. Foram excluídos os artigos que não abordavam o objetivo da investigação ou que não fossem redigidos em Inglês, Português ou Espanhol. Para interpretar os artigos selecionados foi utilizada a classificação SORT. Foram encontrados 197 artigos, dos quais seleccionados 9: 1 revisão sistemática (RS), 1 estudo clínico controlado aleatorizado, 2 estudos observacionais retrospectivos e 5 normas de orientação clínica (NOC). Os autores optaram por incluir nesta revisão mais 4 NOCs e 2 RSs por considerarem ser relevantes para a população Portuguesa, apesar de não resultarem da pesquisa efectuada. Os estudos sugerem realização do rastreio entre os 21 e 25 até aos 65 anos, com uma periodicidade trienal usando a citologia convencional. Existe ainda controvérsia no que toca aos 3 objetivos deste artigo (limites etários, frequência e método).The scope of this review was to assess the strength of evidence of Portuguese performance indicators on Cervical Cancer screening: (1) age group of the women that should be screened for cervical cancer; (2) frequency of screening; and (3) the best method for screening. The following MeSH terms were searched: vaginal smears, age groups, periodicity, methods, uterine cervical cancer. Articles not reflecting the study objectives or not available in English, Portuguese or Spanish were excluded. The SORT classification was used to rate the articles selected.Of the 197 articles found, 9 that met all study criteria were selected for inclusion in this review. These included 1 systematic review, 1 randomized controlled clinical trial, 2 retrospective studies and 5 clinical guidelines. The authors also chose to include 4 clinical guidelines and two systematic reviews relevant to the Portuguese population even though they did not appear in the initial search of the literature. The studies suggest screening women between the ages of 21 to 25 years and 65 years of age, once every three years using conventional cytology. There is still controversy regarding the three objectives of this study (target age bracket, screening frequency and screening method)

Differential and converging molecular mechanisms of antidepressants' action in the hippocampal dentate gyrus

Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited, and relapse rates are high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompany depression and its amelioration with ADs. In this study, the unpredictable chronic mild stress (uCMS) rat model of depression was used to determine the molecular mediators of chronic stress and the targets of four ADs with different pharmacological profiles (fluoxetine, imipramine, tianeptine, and agomelatine) in the hippocampal DG. All ADs, except agomelatine, reversed the depression-like behavior and neuroplastic changes produced by uCMS. Chronic stress induced significant molecular changes that were generally reversed by fluoxetine, imipramine, and tianeptine. Fluoxetine primarily acted on neurons to reduce the expression of pro-inflammatory response genes and increased a set of genes involved in cell metabolism. Similarities were found between the molecular actions and targets of imipramine and tianeptine that activated pathways related to cellular protection. Agomelatine presented a unique profile, with pronounced effects on genes related to Rho-GTPase-related pathways in oligodendrocytes and neurons. These differential molecular signatures of ADs studied contribute to our understanding of the processes implicated in the onset and treatment of depression-like symptoms.Patricia Patricio, Antonio Mateus-Pinheiro, Monica Morais, and Nuno Dinis Alves received fellowships from the Portuguese Foundation for Science and Technology (FCT). Michal Korostynski and Marcin Piechota were funded by the POIG De-Me-Ter 3.1 and NCN 2011/03/D/NZ3/01686 grants. This study was co-funded by the Life and Health Sciences Research Institute (ICVS) and ON. 2-O NOVO NORTE-North Portugal Regional Operational Programme 2007/2013, of the National Strategic Reference Framework (NSRF) 2007/ 2013, through the European Regional Development Fund (ERDF) and by the SwitchBox Consortium (Contract FP7-Health-F2-2010-259772 from the European Union). The authors declare no conflict of interest

Detection and quantitation of copy number variation in the voltage-gated sodium channel gene of the mosquito Culex quinquefasciatus

Insecticide resistance is typically associated with alterations to the insecticidal target-site or with gene expression variation at loci involved in insecticide detoxification. In some species copy number variation (CNV) of target site loci (e.g. the Ace-1 target site of carbamate insecticides) or detoxification genes has been implicated in the resistance phenotype. We show that field-collected Ugandan Culex quinquefasciatus display CNV for the voltage-gated sodium channel gene (Vgsc), target-site of pyrethroid and organochlorine insecticides. In order to develop field-applicable diagnostics for Vgsc CN, and as a prelude to investigating the possible association of CN with insecticide resistance, three assays were compared for their accuracy in CN estimation in this species. The gold standard method is droplet digital PCR (ddPCR), however, the hardware is prohibitively expensive for widespread utility. Here, ddPCR was compared to quantitative PCR (qPCR) and pyrosequencing. Across all platforms, CNV was detected in ≈10% of mosquitoes, corresponding to three or four copies (per diploid genome). ddPCR and qPCR-Std-curve yielded similar predictions for Vgsc CN, indicating that the qPCR protocol developed here can be applied as a diagnostic assay, facilitating monitoring of Vgsc CN in wild populations and the elucidation of association between the Vgsc CN and insecticide resistance

Tau-dependent suppression of adult neurogenesis in the stressed hippocampus

uncorrected proofStress, a well-known sculptor of brain plasticity, is shown to suppress hippocampal neurogenesis in the adult brain; yet, the underlying cellular mechanisms are poorly investigated. Previous studies have shown that chronic stress triggers hyperphosphorylation and accumulation of the cytoskeletal protein Tau, a process that may impair the cytoskeleton-regulating role (s) of this protein with impact on neuronal function. Here, we analyzed the role of Tau on stress-driven suppression of neurogenesis in the adult dentate gyrus (DG) using animals lacking Tau (Tau-knockout; Tau-KO) and wild-type (WT) littermates. Unlike WTs, Tau-KO animals exposed to chronic stress did not exhibit reduction in DG proliferating cells, neuroblasts and newborn neurons; however, newborn astrocytes were similarly decreased in both Tau-KO and WT mice. In addition, chronic stress reduced phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/glycogen synthase kinase-3 beta (GSK3 beta)/beta-catenin signaling, known to regulate cell survival and proliferation, in the DG of WT, but not Tau-KO, animals. These data establish Tau as a critical regulator of the cellular cascades underlying stress deficits on hippocampal neurogenesis in the adult brain.Portuguese Foundation for Science and Technology (FCT) Investigator grants (IF/01799/2013, IF/00883/2013, IF/01079/2014, respectively). This work was funded by FCT research grants 'PTDC/SAU-NMC/113934/2009' (IS), the Portuguese North Regional Operational Program (ON.2) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER), the Project Estratégico co-funded by FCT (PEst-C/SAU/LA0026/2013) and the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037298) as well as the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER)info:eu-repo/semantics/publishedVersio

Dengue Virus Infection of Aedes aegypti Requires a Putative Cysteine Rich Venom Protein

Citation: Londono-Renteria, B., Troupin, A., Conway, M. J., Vesely, D., Ledizet, M., Roundy, C. M., . . . Colpitts, T. M. (2015). Dengue Virus Infection of Aedes aegypti Requires a Putative Cysteine Rich Venom Protein. Plos Pathogens, 11(10), 23. doi:10.1371/journal.ppat.1005202Dengue virus (DENV) is a mosquito-borne flavivirus that causes serious human disease and mortality worldwide. There is no specific antiviral therapy or vaccine for DENV infection. Alterations in gene expression during DENV infection of the mosquito and the impact of these changes on virus infection are important events to investigate in hopes of creating new treatments and vaccines. We previously identified 203 genes that were >= 5-fold differentially upregulated during flavivirus infection of the mosquito. Here, we examined the impact of silencing 100 of the most highly upregulated gene targets on DENV infection in its mosquito vector. We identified 20 genes that reduced DENV infection by at least 60% when silenced. We focused on one gene, a putative cysteine rich venom protein (SeqID AAEL000379; CRVP379), whose silencing significantly reduced DENV infection in Aedes aegypti cells. Here, we examine the requirement for CRVP379 during DENV infection of the mosquito and investigate the mechanisms surrounding this phenomenon. We also show that blocking CRVP379 protein with either RNAi or specific antisera inhibits DENV infection in Aedes aegypti. This work identifies a novel mosquito gene target for controlling DENV infection in mosquitoes that may also be used to develop broad preventative and therapeutic measures for multiple flaviviruses

Edible bio-based nanostructures: delivery, absorption and potential toxicity

The development of bio-based nanostructures as nanocarriers of bioactive compounds to specific body sites has been presented as a hot topic in food, pharmaceutical and nanotechnology fields. Food and pharmaceutical industries seek to explore the huge potential of these nanostructures, once they can be entirely composed of biocompatible and non-toxic materials. At the same time, they allow the incorporation of lipophilic and hydrophilic bioactive compounds protecting them against degradation, maintaining its active and functional performance. Nevertheless, the physicochemical properties of such structures (e.g., size and charge) could change significantly their behavior in the gastrointestinal (GI) tract. The main challenges in the development of these nanostructures are the proper characterization and understanding of the processes occurring at their surface, when in contact with living systems. This is crucial to understand their delivery and absorption behavior as well as to recognize potential toxicological effects. This review will provide an insight into the recent innovations and challenges in the field of delivery via GI tract using bio-based nanostructures. Also, an overview of the approaches followed to ensure an effective deliver (e.g., avoiding physiological barriers) and to enhance stability and absorptive intestinal uptake of bioactive compounds will be provided. Information about nanostructures potential toxicity and a concise description of the in vitro and in vivo toxicity studies will also be given.Joana T. Martins, Oscar L. Ramos, Ana C. Pinheiro, Ana I. Bourbon, Helder D. Silva and Miguel A. Cerqueira (SFRH/BPD/89992/2012, SFRH/BPD/80766/2011, SFRH/BPD/101181/2014, SFRH/BD/73178/2010, SFRH/BD/81288/2011, and SFRH/BPD/72753/2010, respectively) are the recipients of a fellowship from the Fundacao para a Ciencia e Tecnologia (FCT, POPH-QREN and FSE, Portugal). The authors thank the FCT Strategic Project PEst-OE/EQB/LA0023/2013 and the project "BioInd-Biotechnology and Bioengineering for improved Industrial and Agro-Food processes," REF.NORTE-07-0124-FEDER-000028, co-funded by the Programa Operacional Regional do Norte (ON.2-O Novo Norte), QREN, FEDER. We also thank to the European Commission: BIOCAPS (316265, FP7/REGPOT-2012-2013.1) and Xunta de Galicia: Agrupamento INBIOMED (2012/273) and Grupo con potencial de crecimiento. The support of EU Cost Action FA1001 is gratefully acknowledged

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.