lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs.

Although recent studies have indicated roles of long non-coding RNAs (lncRNAs) in physiological aspects of cell-type determination and tissue homeostasis, their potential involvement in regulated gene transcription programs remains rather poorly understood. The androgen receptor regulates a large repertoire of genes central to the identity and behaviour of prostate cancer cells, and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy. Here we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 (also known as PCAT8) and PCGEM1, bind successively to the androgen receptor and strongly enhance both ligand-dependent and ligand-independent androgen-receptor-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the carboxy-terminally acetylated androgen receptor on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the androgen receptor amino terminus that is methylated by DOT1L. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited pygopus 2 PHD domain enhances selective looping of androgen-receptor-bound enhancers to target gene promoters in these cells. In 'resistant' prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full-length androgen receptor, causing ligand-independent activation of the androgen receptor transcriptional program and cell proliferation. Conditionally expressed short hairpin RNA targeting these lncRNAs in castration-resistant prostate cancer cell lines strongly suppressed tumour xenograft growth in vivo. Together, these results indicate that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumours

Correlation between centrality metrics and their application to the opinion model

In recent decades, a number of centrality metrics describing network properties of nodes have been proposed to rank the importance of nodes. In order to understand the correlations between centrality metrics and to approximate a high-complexity centrality metric by a strongly correlated low-complexity metric, we first study the correlation between centrality metrics in terms of their Pearson correlation coefficient and their similarity in ranking of nodes. In addition to considering the widely used centrality metrics, we introduce a new centrality measure, the degree mass. The m order degree mass of a node is the sum of the weighted degree of the node and its neighbors no further than m hops away. We find that the B_{n}, the closeness, and the components of x_{1} are strongly correlated with the degree, the 1st-order degree mass and the 2nd-order degree mass, respectively, in both network models and real-world networks. We then theoretically prove that the Pearson correlation coefficient between x_{1} and the 2nd-order degree mass is larger than that between x_{1} and a lower order degree mass. Finally, we investigate the effect of the inflexible antagonists selected based on different centrality metrics in helping one opinion to compete with another in the inflexible antagonists opinion model. Interestingly, we find that selecting the inflexible antagonists based on the leverage, the B_{n}, or the degree is more effective in opinion-competition than using other centrality metrics in all types of networks. This observation is supported by our previous observations, i.e., that there is a strong linear correlation between the degree and the B_{n}, as well as a high centrality similarity between the leverage and the degree.Comment: 20 page

Critical animal and media studies: Expanding the understanding of oppression in communication research

Critical and communication studies have traditionally neglected the oppression conducted by humans towards other animals. However, our (mis)treatment of other animals is the result of public consent supported by a morally speciesist-anthropocentric system of values. Speciesism or anthroparchy, as much as any other mainstream ideologies, feeds the media and at the same time is perpetuated by them. The goal of this article is to remedy this neglect by introducing the subdiscipline of Critical Animal and Media Studies. Critical Animal and Media Studies takes inspiration both from critical animal studies – which is so far the most consolidated critical field of research in the social sciences addressing our exploitation of other animals – and from the normative-moral stance rooted in the cornerstones of traditional critical media studies. The authors argue that the Critical Animal and Media Studies approach is an unavoidable step forward for critical media and communication studies to engage with the expanded circle of concerns of contemporary ethical thinking

PPAR? Downregulation by TGF in Fibroblast and Impaired Expression and Function in Systemic Sclerosis: A Novel Mechanism for Progressive Fibrogenesis

The nuclear orphan receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) is expressed in multiple cell types in addition to adipocytes. Upon its activation by natural ligands such as fatty acids and eicosanoids, or by synthetic agonists such as rosiglitazone, PPAR-γ regulates adipogenesis, glucose uptake and inflammatory responses. Recent studies establish a novel role for PPAR-γ signaling as an endogenous mechanism for regulating transforming growth factor-ß (TGF-ß)- dependent fibrogenesis. Here, we sought to characterize PPAR-γ function in the prototypic fibrosing disorder systemic sclerosis (SSc), and delineate the factors governing PPAR-γ expression. We report that PPAR-γ levels were markedly diminished in skin and lung biopsies from patients with SSc, and in fibroblasts explanted from the lesional skin. In normal fibroblasts, treatment with TGF-ß resulted in a time- and dose-dependent down-regulation of PPAR-γ expression. Inhibition occurred at the transcriptional level and was mediated via canonical Smad signal transduction. Genome-wide expression profiling of SSc skin biopsies revealed a marked attenuation of PPAR-γ levels and transcriptional activity in a subset of patients with diffuse cutaneous SSc, which was correlated with the presence of a ''TGF-ß responsive gene signature'' in these biopsies. Together, these results demonstrate that the expression and function of PPAR-γ are impaired in SSc, and reveal the existence of a reciprocal inhibitory cross-talk between TGF-ß activation and PPAR-γ signaling in the context of fibrogenesis. In light of the potent anti-fibrotic effects attributed to PPAR-γ, these observations lead us to propose that excessive TGF-ß activity in SSc accounts for impaired PPAR-γ function, which in turn contributes to unchecked fibroblast activation and progressive fibrosis. © 2010 Wei et al

Writing in Britain and Ireland, c. 400 to c. 800

No abstract available

Neonatal severe bacterial infection impairment estimates in South Asia, sub-Saharan Africa, and Latin America for 2010.

BACKGROUND: Survivors of neonatal infections are at risk of neurodevelopmental impairment (NDI), a burden not previously systematically quantified and yet important for program priority setting. Systematic reviews and meta-analyses were undertaken and applied in a three-step compartmental model to estimate NDI cases after severe neonatal bacterial infection in South Asia, sub-Saharan Africa, and Latin America in neonates of >32 wk gestation (or >1,500 g). METHODS: We estimated cases of sepsis, meningitis, pneumonia, or no severe bacterial infection from among estimated cases of possible severe bacterial infection ((pSBI) step 1). We applied respective case fatality risks ((CFRs) step 2) and the NDI risk among survivors (step 3). For neonatal tetanus, incidence estimates were based on the estimated deaths, CFRs, and risk of subsequent NDI. RESULTS: For 2010, we estimated 1.7 million (uncertainty range: 1.1-2.4 million) cases of neonatal sepsis, 200,000 (21,000-350,000) cases of meningitis, 510,000 cases (150,000-930,000) of pneumonia, and 79,000 cases (70,000-930,000) of tetanus in neonates >32 wk gestation (or >1,500 g). Among the survivors, we estimated moderate to severe NDI after neonatal meningitis in 23% (95% confidence interval: 19-26%) of survivors, 18,000 (2,700-35,000) cases, and after neonatal tetanus in 16% (6-27%), 4,700 cases (1,700-8,900). CONCLUSION: Data are lacking for impairment after neonatal sepsis and pneumonia, especially among those of >32 wk gestation. Improved recognition and treatment of pSBI will reduce neonatal mortality. Lack of follow-up data for survivors of severe bacterial infections, particularly sepsis, was striking. Given the high incidence of sepsis, even minor NDI would be of major public health importance. Prevention of neonatal infection, improved case management, and support for children with NDI are all important strategies, currently receiving limited policy attention

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

An enhanced thrombotic environment and premature atherosclerosis are key factors for the increased cardiovascular risk in diabetes. The occlusive vascular thrombus, formed secondary to interactions between platelets and coagulation proteins, is composed of a skeleton of fibrin fibres with cellular elements embedded in this network. Diabetes is characterised by quantitative and qualitative changes in coagulation proteins, which collectively increase resistance to fibrinolysis, consequently augmenting thrombosis risk. Current long-term therapies to prevent arterial occlusion in diabetes are focussed on anti-platelet agents, a strategy that fails to address the contribution of coagulation proteins to the enhanced thrombotic milieu. Moreover, antiplatelet treatment is associated with bleeding complications, particularly with newer agents and more aggressive combination therapies, questioning the safety of this approach. Therefore, to safely control thrombosis risk in diabetes, an alternative approach is required with the fibrin network representing a credible therapeutic target. In the current review, we address diabetes-specific mechanistic pathways responsible for hypofibrinolysis including the role of clot structure, defects in the fibrinolytic system and increased incorporation of anti-fibrinolytic proteins into the clot. Future anti-thrombotic therapeutic options are discussed with special emphasis on the potential advantages of modulating incorporation of the anti-fibrinolytic proteins into fibrin networks. This latter approach carries theoretical advantages, including specificity for diabetes, ability to target a particular protein with a possible favourable risk of bleeding. The development of alternative treatment strategies to better control residual thrombosis risk in diabetes will help to reduce vascular events, which remain the main cause of mortality in this condition

Male and female meiotic behaviour of an intrachromosomal insertion determined by preimplantation genetic diagnosis

<p>Abstract</p> <p>Background</p> <p>Two related family members, a female and a male balanced carrier of an intrachromosomal insertion on chromosome 7 were referred to our centre for preimplantation genetic diagnosis. This presented a rare opportunity to investigate the behaviour of the insertion chromosome during meiosis in two related carriers. The aim of this study was to carry out a detailed genetic analysis of the preimplantation embryos that were generated from the three treatment cycles for the male and two for the female carrier.</p> <p>Patients underwent <it>in vitro </it>fertilization and on day 3, 22 embryos from the female carrier and 19 embryos from the male carrier were biopsied and cells analysed by fluorescent in situ hybridization. Follow up analysis of 29 untransferred embryos was also performed for confirmation of the diagnosis and to obtain information on meiotic and mitotic outcome.</p> <p>Results</p> <p>In this study, the female carrier produced more than twice as many chromosomally balanced embryos as the male (76.5% vs. 36%), and two pregnancies were achieved for her. Follow up analysis showed that the male carrier had produced more highly abnormal embryos than the female (25% and 15% respectively) and no pregnancies occurred for the male carrier and his partner.</p> <p>Conclusion</p> <p>This study compares how an intrachromosomal insertion has behaved in the meiotic and preimplantation stages of development in sibling male and female carriers. It confirms that PGD is an appropriate treatment in such cases. Reasons for the differing outcome for the two carriers are discussed.</p

Diagnostic performance of image navigated coronary CMR angiography in patients with coronary artery disease

BACKGROUND: The use of coronary MR angiography (CMRA) in patients with coronary artery disease (CAD) remains limited due to the long scan times, unpredictable and often non-diagnostic image quality secondary to respiratory motion artifacts. The purpose of this study was to evaluate CMRA with image-based respiratory navigation (iNAV CMRA) and compare it to gold standard invasive x-ray coronary angiography in patients with CAD.METHODS: Consecutive patients referred for CMR assessment were included to undergo iNAV CMRA on a 1.5 T scanner. Coronary vessel sharpness and a visual score were assigned to the coronary arteries. A diagnostic reading was performed on the iNAV CMRA data, where a lumen narrowing &gt;50% was considered diseased. This was compared to invasive x-ray findings.RESULTS: Image-navigated CMRA was performed in 31 patients (77% male, 56 ± 14 years). The iNAV CMRA scan time was 7 min:21 s ± 0 min:28 s. Out of a possible 279 coronary segments, 26 segments were excluded from analysis due to stents or diameter less than 1.5 mm, resulting in a total of 253 coronary segments. Diagnostic image quality was obtained for 98% of proximal coronary segments, 94% of middle segments, and 91% of distal coronary segments. The sensitivity and specificity was 86% and 83% per patient, 80% and 92% per vessel and 73% and 95% per segment.CONCLUSION: In this study, iNAV CMRA offered a very good diagnostic performance when compared against invasive x-ray angiography. Due to the short and predictable scan time it can add clinical value as a part of a comprehensive CAD assessment protocol.</p

Políticas e legislação ambiental em São Tomé e Príncipe

DEUS, Delmar Joy D’assunção Da Silva Madre. Políticas e legislação ambiental em São Tomé e Príncipe. 2021. 74 f. Monografia (Graduação) - Curso de Graduação presencial em Administração Pública, Instituto de Ciências Exatas Sociais Aplicadas- (ICSA). Universidade da Integração Internacional da Lusofonia Afro-brasileira, Redenção-Ceara, 2021O presente trabalho versa sobre as políticas e legislação ambiental em São Tomé e Príncipe, cujo o objetivo consiste em analisar a implementação das políticas e legislação ambiental em S.T.P, com o intuito de facilitar no entendimento da proteção, preservação e conservação dos seus recursos naturais. Para a consecução deste objetivo determinamos os seguintes objetivos específicos, tais como: identificar na legislação as políticas públicas ambientais, políticas de proteção, preservação e conservação ambiental implementada no país nas ultimas 3 décadas; determinar os períodos em que ocorreram as atualizações da legislação ambiental em decorrências das consequências dos problemas ambientais e por último verificar se o desenvolvimento econômico e social está em consonância com a proposta da preservação da qualidade do meio ambiente e do equilíbrio ecológico. Diante disso, fez-se um levantamento teórico sobre a gestão ambiental e desenvolvimento sustentável buscando assim compreender os seus conceitos e sua evolução. Metodologicamente trata-se de uma pesquisa de caráter exploratório descritiva, com técnica de coleta de análise documental e bibliográfica de conteúdo oficiais de governo como diplomas legais, sobretudo em legislação, normas, decretos, planos e relatórios nacionais. Através disso, pôde-se fazer uma apresentação desses conjuntos de políticas e documentos oficiais ligadas a conservação dos recursos naturais e também constatamos que a legislação ambiental implementada no país carece de informações sobre o processo de políticas de controle e fiscalização para a proteção, preservação e conservação dos ecossistemas. Sob essa ótica, ressalta-se a importância das políticas públicas ambientais no processo de conservação dos recursos naturais, como o papel do Estado e a sociedades na sua promoção, sensibilização e conscientização de forma a poluir menos e respeitando o ciclo de recomposição do meio ambiente no processo da sustentabilidade