Regulated Inositol‐Requiring Protein 1‐Dependent Decay as a Mechanism of Corin RNA and Protein Deficiency in Advanced Human Systolic Heart Failure

BACKGROUND: The compensatory actions of the endogenous natriuretic peptide system require adequate processing of natriuretic peptide pro‐hormones into biologically active, carboxyl‐terminal fragments. Natriuretic peptide pro‐peptide processing is accomplished by corin, a transmembrane serine protease expressed by cardiomyocytes. Brain natriuretic peptide (BNP) processing is inadequate in advanced heart failure and is independently associated with adverse outcomes; however, the molecular mechanisms causing impaired BNP processing are not understood. We hypothesized that the development of endoplasmic reticulum stress in cardiomyocytes in advanced heart failure triggers inositol‐requiring protein 1 (IRE1)‐dependent corin mRNA decay, which would favor a molecular substrate favoring impaired natriuretic peptide pro‐peptide processing. METHODS AND RESULTS: Two independent samples of hearts obtained from patients with advanced heart failure at transplant demonstrated that corin RNA was reduced as Atrial natriuretic peptide (ANP)/BNP RNA increased. Increases in spliced X‐box protein 1, a marker for IRE1‐endoribonuclease activity, were associated with decreased corin RNA. Moreover, ≈50% of the hearts demonstrated significant reductions in corin RNA and protein as compared to the nonfailing control sample. In vitro experiments demonstrated that induction of endoplasmic reticulum stress in cultured cardiomyocytes with thapsigargin activated IRE1s endoribonuclease activity and time‐dependent reductions in corin mRNA. In HL‐1 cells, overexpression of IRE1 activated IRE1 endoribonuclease activity and caused corin mRNA decay, whereas IRE1‐RNA interference with shRNA attenuated corin mRNA decay after induction of endoplasmic reticulum stress with thapsigargin. Pre‐treatment of cells with Actinomycin D to inhibit transcription did not alter the magnitude or time course of thapsigargin‐induced corin mRNA decline, supporting the hypothesis that this was the result of IRE1‐mediated corin mRNA degradation. CONCLUSIONS: These data support the hypothesis that endoplasmic reticulum stress‐mediated, IRE1‐dependent targeted corin mRNA decay is a mechanism leading to corin mRNA resulting in corresponding corin protein deficiency may contribute to the pathophysiology of impaired natriuretic peptide pro‐hormone processing in humans processing in humans with advanced systolic heart failure

Unification of Radio Galaxies and Their Accretion/Jet Properties

We investigate the relation between black hole mass, M_bh, and jet power, Q_jet, for a sample of BL Lacs and radio quasars. We find that BL Lacs are separated from radio quasars by the FR I/II dividing line in M_bh-Q_jet plane, which strongly supports the unification scheme of FR I/BL Lac and FR II/radio quasar. The Eddington ratio distribution of BL Lacs and radio quasars exhibits a bimodal nature with a rough division at L_bol/L_Edd~0.01, which imply that they may have different accretion modes. We calculate the jet power extracted from advection dominated accretion flow (ADAF), and find that it require dimensionless angular momentum of black hole j~0.9-0.99 to reproduce the dividing line between FR I/II or BL Lac/radio quasar if dimensionless accretion rate mdot=0.01 is adopted, which is required by above bimodal distribution of Eddington ratios. Our results suggest that black holes in radio galaxies are rapidly spinning.Comment: To appear JAA in Jun

Chromosome location and characterization of genes for grain protein content in Triticum dicoccoides

Dissertação de Mestrado em História, apresentada à Faculdade de Letras da Universidade de Coimbra.No início do século XX, com a instalação da República portuguesa, surgiu a oportunidade de se construir um lar judaico num território português de além-mar. Angola foi uma forte possibilidade. Vários fatores contribuíram para que tal oportunidade fosse possível. Os constantes massacres feitos ao povo judaico em variadíssimos países europeus, nomeadamente nos países de leste, e as dificuldades encontradas por Theodor Herzl, fundador do movimento sionista, para a edificação do desejado Estado judaico na Palestina, levou a que alguns líderes judaicos começassem a estudar outras hipóteses para o estabelecimento da comunidade judaica para além da Palestina. Era urgente encontrar uma solução para que o sofrimento dos judeus terminasse. Por outro lado, é preciso não esquecer que Portugal se debatia com uma grande questão, a necessidade de ocupar efetivamente as suas colónias, a fim de contrariar as pretensões alemãs e inglesas. A hipótese de criar uma colónia judaica em Angola, como forma de enfrentar as aspirações alheias, e a necessidade de valorizar aquele território, faziam da colonização judaica uma boa solução para Portugal. Tendo em conta as dificuldades de um povoamento de Angola com elementos naturais da metrópole, devido à fraca capacidade financeira do Estado português e a razões sociais e mentais, a colonização judaica aparecia como uma alternativa viável. No entanto, este projeto não se concretizaria. Serão identificados os fatores internos e externos que levaram a que este projeto não fosse posto em prática e tratar-se-á da posterior criação do Estado de Israel na Palestina, depois da Segunda Guerra Mundial.In the early XXth century, with the establishment of Portuguese Republic, arises an opportunity of setting a jewish home in a portuguese land overseas. Angola was a strong possibility. Several factors contributed for the possibility of such opportunity. The constant massacres the Jewish people suffered in numerous different European countries, mainly in Eastern countries, and the difficulties encountered by Theodor Herlz, founder of the Zionist movement, in order to build the desired Jewish State in Palestine, drove some of jewish leaders to study other options to establish the home of Jewish people beyond Palestine. It was urgent to find a solution for the suffering of the Jews to end. On the other hand, it’s important not to forget that Portugal was struggling with a big question, the necessity of effectively settling its colonies, in order to fight back the German and English pretensions. The possibility of creating a jewish colony in Angola as a way to prevent third-parties aspirations and the need of increase the value of Angola land turned the jewish settlement into a good solution to Portugal. As the colonization of Angola with natives from the metropolis appeared hard to reach, due to a poor financial capacity of the portuguese State as well as social and mental factors, the Jewish colonization appeared as a viable alternative. However, this project wasn’t meant to achieve the goal. We’ll describe the internal and external factors that caused the failure of this project and we’ll talk about the creation, later on, of the Jewish State in Palestine, after Second World Wa

Biological impacts of 'hot-spot' mutations of hepatitis B virus X proteins are genotype B and C differentiated

AIM: To investigate the biological impacts of “hot-spot” mutations on genotype B and C HBV X proteins (HBx). METHODS: Five types of “hot-spot” mutations of genotype B or C HBV X genes, which sequentially lead to the amino acid substitutions of HBx as I127T, F132Y, K130M+V131I, I127T+K130M+V131I, or K130M+V131I+F132Y, respectively, were generated by means of site-directed mutagenesis. To evaluate the anti-proliferative effects, HBx or related mutants’ expression vectors were transfected separately to the Chang cells by lipofectamine, and the cells were cultured in hygromycin selective medium for 14 d, drug-resistant colonies were fixed with cold methanol, stained with Giemsa dyes and scored (increase of the colonies indicated the reduction of the anti-proliferation activity, and vice versa). Different types of HBx expression vectors were co-transfected separately with the reporter plasmid pCMVβ to Chang cells, which were lysed 48 h post-transfection and the intra-cellular β-galactosidase activities were monitored (increase of the β-galactosidase activities indicated the reduction of the transactivation activity, and vice versa). All data obtained were calculated by paired-samples t-test. RESULTS: As compared to standard genotype B HBx, mutants of I127T and I127T+K130M+V131I showed higher transactivation and anti-proliferative activities, while the mutants of F132Y, K130M+V131I, and K130M+V131I+F132Y showed lower activities. As compared to standard genotype C HBx, I127T mutant showed higher transactivation activity, while the other four types of mutants showed no differences. With regard to anti-proliferative activity, compared to standard genotype C HBx, F132Y and K130M+V131I mutants showed lower activities, and K130M+V131I +F132Y mutant, on the other hand, showed higher activity, while the mutants of I127T and I127T+K130M+V131I showed no differences. CONCLUSION: “Hot-spot” mutations affect the anti-proliferation and transactivation activities of genotype B and/or C HBx, and the biological impacts of most “hot-spot” mutations on HBx are genotype B and C differentiated.published_or_final_versio

R/BHC: fast Bayesian hierarchical clustering for microarray data

BACKGROUND: Although the use of clustering methods has rapidly become one of the standard computational approaches in the literature of microarray gene expression data analysis, little attention has been paid to uncertainty in the results obtained. RESULTS: We present an R/Bioconductor port of a fast novel algorithm for Bayesian agglomerative hierarchical clustering and demonstrate its use in clustering gene expression microarray data. The method performs bottom-up hierarchical clustering, using a Dirichlet Process (infinite mixture) to model uncertainty in the data and Bayesian model selection to decide at each step which clusters to merge. CONCLUSION: Biologically plausible results are presented from a well studied data set: expression profiles of A. thaliana subjected to a variety of biotic and abiotic stresses. Our method avoids several limitations of traditional methods, for example how many clusters there should be and how to choose a principled distance metric

Hormonal contraceptive use and smoking as risk factors for high-grade cervical intraepithelial neoplasia in unvaccinated women aged 30–44 years: A case-control study in New South Wales, Australia

Background Human papillomavirus (HPV) vaccines protect against HPV types 16/18, but do not eliminate the need to detect pre-cancerous lesions. Australian women vaccinated as teenage girls are now entering their mid-thirties. Since other oncogenic HPV types have been shown to be more prevalent in women ≥30 years old, understanding high grade cervical lesions in older women is still important. Hormonal contraceptives (HC) and smoking are recognised cofactors for the development of pre-malignant lesions. Methods 886 cases with cervical intraepithelial neoplasia (CIN) 2/3 and 3636 controls with normal cytology were recruited from the Pap Test Register of NSW, Australia. All women were aged 30–44 years. Conditional logistic regression was used to quantify the relationship of HC and smoking to CIN 2/3 adjusted for various factors. Results Current-users of HC were at higher risk for CIN 2/3 than never-users [odds ratio (OR) = 1.50, 95%CI = 1.03–2.17] and risk increased with increasing duration of use [ORs:1.13 (0.73–1.75), 1.51 (1.00–2.72), 1.82 (1.22–2.72) for <10, 10–14, ≥15 years of use; p-trend = 0.04]. Ex-users had risks similar to never-users (OR 1.08, 95%CI = 0.75–1.57) regardless of duration of use. Current smoking was significantly associated with CIN 2/3 (OR = 1.43, 95%CI = 1.14–1.80) and risk increased with increasing number of cigarettes/day (p-trend = 0.02). Among ex-smokers, the risk of CIN 2/3 decreased with increasing time since quitting (p-trend = 0.04). Conclusions In this benchmark study, current, long term users of HC and current smokers of ≥5 cigarettes/day were each at increased risk of developing CIN 2/3. Findings support smoking cessation in relation to decreasing the risk of pre-cancerous lesions and reinforce the continuing need for cervical screening for cancer prevention in vaccinated and unvaccinated populations

Mathematical Modelling of Optical Coherence Tomography

In this chapter a general mathematical model of Optical Coherence Tomography (OCT) is presented on the basis of the electromagnetic theory. OCT produces high resolution images of the inner structure of biological tissues. Images are obtained by measuring the time delay and the intensity of the backscattered light from the sample considering also the coherence properties of light. The scattering problem is considered for a weakly scattering medium located far enough from the detector. The inverse problem is to reconstruct the susceptibility of the medium given the measurements for different positions of the mirror. Different approaches are addressed depending on the different assumptions made about the optical properties of the sample. This procedure is applied to a full field OCT system and an extension to standard (time and frequency domain) OCT is briefly presented.Comment: 28 pages, 5 figures, book chapte