FXN promoter silencing in the humanized mouse model of Friedreich Ataxia

Background - Friedreich ataxia is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene that results in epigenetic silencing of the FXN promoter. This silencing mechanism is seen in patient-derived lymphoblastoid cells but it remains unknown if it is a widespread phenomenon affecting multiple cell types and tissues. Methodology / Principal Findings - The humanized mouse model of Friedreich ataxia (YG8sR), which carries a single transgenic insert of the human FXN gene with an expanded GAA triplet-repeat in intron 1, is deficient for FXN transcript when compared to an isogenic transgenic mouse lacking the expanded repeat (Y47R). We found that in YG8sR the deficiency of FXN transcript extended both upstream and downstream of the expanded GAA triplet-repeat, suggestive of deficient transcriptional initiation. This pattern of deficiency was seen in all tissues tested, irrespective of whether they are known to be affected or spared in disease pathogenesis, in both neuronal and non-neuronal tissues, and in cultured primary fibroblasts. FXN promoter function was directly measured via metabolic labeling of newly synthesized transcripts in fibroblasts, which revealed that the YG8sR mouse was significantly deficient in transcriptional initiation compared to the Y47R mouse. Conclusions / Significance- Deficient transcriptional initiation accounts for FXN transcriptional deficiency in the humanized mouse model of Friedreich ataxia, similar to patient-derived cells, and the mechanism underlying promoter silencing in Friedreich ataxia is widespread across multiple cell types and tissues.This research was supported by grants from the National Institutes of Health (R01 NS072418), and the Muscular Dystrophy Association to S.I.B. Y.K.C. is supported by a postdoctoral research fellowship from the Million Dollar Bike Ride Grant Program of the Orphan Disease Center at University of Pennsylvania. T.T.H. was supported by the American College of Medical Genetics Foundation. A.C.P. and M.G.M. were supported by the SURE and OSCTR programs at OUHSC, respectively

Decreased level of recent thymic emigrants in CD4+ and CD8+T cells from CML patients

<p>Abstract</p> <p>Background</p> <p>T-cell immunodeficiency is a common feature in cancer patients, which may relate to initiation and development of tumor. Based on our previous finding, to further characterize the immune status, T cell proliferative history was analyzed in CD4+ and CD8+ T cells from chronic myeloid leukemia (CML) patients.</p> <p>Methods</p> <p>Quantitative analysis of δRec-ψJα signal joint T cell receptor excision circles (sjTRECs) was performed in PBMCs, CD3+, CD4+ and CD8+T cells by real-time PCR, and the analysis of 23 <it>TRBV-D1 </it>sjTRECs was performed by semi-nested PCR. Forty eight CML cases in chronic phase (CML-CP) were selected for this study and 17 healthy individuals served as controls.</p> <p>Results</p> <p>The levels of δRec-ψJα sjTRECs in PBMCs, CD3+, CD4+, and CD8+ T cells were significantly decreased in CML patients, compared with control groups. Moreover, the numbers of detectable <it>TRBV </it>subfamily sjTRECs, as well as the frequency of particular <it>TRBV-BD</it>1 sjTRECs in patients with CML were significantly lower than those from healthy individuals.</p> <p>Conclusions</p> <p>We observed decreased levels of recent thymic emigrants in CD4+ and CD8+ T cells that may underlay the persistent immunodeficiency in CML patients.</p

Linking habitat quality with genetic diversity: a lesson from great bustards in Spain

P. 411-419The effects of habitat loss and fragmentation on the genetic structure and variability of wild populations have received wide empirical support and theoretical formalization. By contrast, the effects of habitat quality seem largely underinvestigated, partly due to technical difficulties in properly assessing habitat quality. In this study, we combine geographic information system (GIS)-based habitat-quality modelling with a landscape genetics approach based on mitochondrial DNA markers to evaluate the possible influence of habitat quality on the levels and distribution of genetic diversity in a range of natural populations (n = 15) of Otis tarda throughout Spain. Ninety-three percent of the population represented by our countrywide sample lives in good-quality habitats, while 4.5% and 2.5% occur respectively in intermediate and poor habitats. Habitat quality was highly correlated with patch size, population size and population density, indicating the reliability and predictive power of the habitat suitability model. Genetic diversity was significantly correlated with habitat quality, size and density of the population, but not with patch size. Three of a total of 20 existing matrilineages from the species’ current genetic pool are restricted to poor-quality habitats. This study therefore highlights the importance of considering both population genetics and habitat quality in a species of high conservation priority.S

Deep-Sea Fish Distribution Varies between Seamounts: Results from a Seamount Complex off New Zealand

Fish species data from a complex of seamounts off New Zealand termed the “Graveyard Seamount Complex’ were analysed to investigate whether fish species composition varied between seamounts. Five seamount features were included in the study, with summit depths ranging from 748–891 m and elevation from 189–352 m. Measures of fish species dominance, rarity, richness, diversity, and similarity were examined. A number of factors were explored to explain variation in species composition, including latitude, water temperature, summit depth, depth at base, elevation, area, slope, and fishing effort. Depth at base and slope relationships were significant with shallow seamounts having high total species richness, and seamounts with a more gradual slope had high mean species richness. Species similarity was modelled and showed that the explanatory variables were driven primarily by summit depth, as well as by the intensity of fishing effort and elevation. The study showed that fish assemblages on seamounts can vary over very small spatial scales, in the order of several km. However, patterns of species similarity and abundance were inconsistent across the seamounts examined, and these results add to a growing literature suggesting that faunal communities on seamounts may be populated from a broad regional species pool, yet show considerable variation on individual seamounts

Методология синтеза архитектуры программно-технического комплекса автоматизированной системы мониторинга обстановки

Предложен подход к проектированию архитектуры программно-технического комплекса автоматизированной системы мониторинга обстановки в реальном времени, основанный на классификации решаемых функциональных задач на основе методов кластерного анализа и выбранного множества признаков подобия. Разработанный подход позволяет из множества функций системы выделить подобные (по определенным признакам) и объединить их в архитектурные компоненты (унифицированные функциональные модули).Запропоновано підхід до проектування архітектури центру обробки інформації автоматизованої системи моніторингу середовища в реальному часі, що заснований на класифікації функціональних задач на підставі методів кластерного аналізу і обраної множини ознак схожості. Розроблений підхід дозволяє вибрати із множини функцій системи схожі (за певними ознаками) і поєднати їх в архітектурні компоненти (уніфіковані функціональні модулі).The approach to designing architecture of the information processing complex of the automated real time conditions monitoring system based on classification of functional tasks on the basis of methods of cluster analysis and the chosen set of similarity attributes is offered. The developed approach allows to allocate from a set of functions the systems similar (on certain attributes) and to unite them in architectural components (unified functional modules)

Cancer: evolutionary, genetic and epigenetic aspects

There exist two paradigms about the nature of cancer. According to the generally accepted one, cancer is a by-product of design limitations of a multi-cellular organism (Greaves, Nat Rev Cancer 7:213–221, 2007). The essence of the second resides in the question “Does cancer kill the individual and save the species?” (Sommer, Hum Mutat 3:166–169, 1994). Recent data on genetic and epigenetic mechanisms of cell transformation summarized in this review support the latter point of view, namely that carcinogenesis is an evolutionary conserved phenomenon—a programmed death of an organism. It is assumed that cancer possesses an important function of altruistic nature: as a mediator of negative selection, it serves to preserve integrity of species gene pool and to mediate its evolutionary adjustment. Cancer fulfills its task due apparently to specific killer function, understanding mechanism of which may suggest new therapeutic strategy

Fostering coastal resilience to climate change vulnerability in Bangladesh, Brazil, Cameroon and Uruguay: a cross-country comparison

© 2017, Springer Science+Business Media B.V. This paper describes a comparative study of four different cases on vulnerability, hazards and adaptive capacity to climate threats in coastal areas and communities in four developing countries: Bangladesh, Brazil, Cameroon and Uruguay. Coastal areas are vulnerable to sea-level rise (SLR), storm surges and flooding due to their (i) exposure, (ii) concentration of settlements, many of which occupied by less advantaged groups and (iii) the concentration of assets and services seen in these areas. The objective of the paper is twofold: (i) to evaluate current evidence of coastal vulnerability and adaptive capacity and (ii) to compare adaptation strategies being implemented in a sample of developing countries, focusing on successful ones. The followed approach for the case evaluation is based on (i) documenting observed threats and damages, (ii) using indicators of physical and socioeconomic vulnerability and adaptive capacity status and (iii) selecting examples of successful responses. Major conclusions based on cross-case comparison are (a) the studied countries show different vulnerability, adaptive capacity and implementation of responses, (b) innovative community-based (CBA) and ecosystem-based adaptation (EbA) and (c) early warning systems are key approaches and tools to foster climate resilience. A recommendation to foster the resilience of coastal communities and services is that efforts in innovative adaptation strategies to sea-level rise should be intensified and integrated with climate risk management within the national adaption plans (NAPAs) in order to reduce the impacts of hazards