Evidence for a nuclear compartment of transcription and splicing located at chromosome domain boundaries

The nuclear topography of splicing snRNPs, mRNA transcripts and chromosome domains in various mammalian cell types are described. The visualization of splicing snRNPs, defined by the Sm antigen, and coiled bodies, revealed distinctly different distribution patterns in these cell types. Heat shock experiments confirmed that the distribution patterns also depend on physiological parameters. Using a combination of fluorescencein situ hybridization and immunodetection protocols, individual chromosome domains were visualized simultaneously with the Sm antigen or the transcript of an integrated human papilloma virus genome. Three-dimensional analysis of fluorescence-stained target regions was performed by confocal laser scanning microscopy. RNA transcripts and components of the splicing machinery were found to be generally excluded from the interior of the territories occupied by the individual chromosomes. Based on these findings we present a model for the functional compartmentalization of the cell nucleus. According to this model the space between chromosome domains, including the surface areas of these domains, defines a three-dimensional network-like compartment, termed the interchromosome domain (ICD) compartment, in which transcription and splicing of mRNA occurs

The celebrity entrepreneur on television: profile, politics and power

This article examines the rise of the ‘celebrity entrepreneur’ on television through the emergence of the ‘business entertainment format’ and considers the ways in which regular television exposure can be converted into political influence. Within television studies there has been a preoccupation in recent years with how lifestyle and reality formats work to transform ‘ordinary’ people into celebrities. As a result, the contribution of vocationally skilled business professionals to factual entertainment programming has gone almost unnoticed. This article draws on interviews with key media industry professionals and begins by looking at the construction of entrepreneurs as different types of television personalities and how discourses of work, skill and knowledge function in business shows. It then outlines how entrepreneurs can utilize their newly acquired televisual skills to cultivate a wider media profile and secure various forms of political access and influence. Integral to this is the centrality of public relations and media management agencies in shaping media discourses and developing the individual as a ‘brand identity’ that can be used to endorse a range of products or ideas. This has led to policy makers and politicians attempting to mobilize the media profile of celebrity entrepreneurs to reach out and connect with the public on business and enterprise-related issues

The landscape of viral associations in human cancers

Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, for which whole-genome and—for a subset—whole-transcriptome sequencing data from 2,658 cancers across 38 tumor types was aggregated, we systematically investigated potential viral pathogens using a consensus approach that integrated three independent pipelines. Viruses were detected in 382 genome and 68 transcriptome datasets. We found a high prevalence of known tumor-associated viruses such as Epstein–Barr virus (EBV), hepatitis B virus (HBV) and human papilloma virus (HPV; for example, HPV16 or HPV18). The study revealed significant exclusivity of HPV and driver mutations in head-and-neck cancer and the association of HPV with APOBEC mutational signatures, which suggests that impaired antiviral defense is a driving force in cervical, bladder and head-and-neck carcinoma. For HBV, HPV16, HPV18 and adeno-associated virus-2 (AAV2), viral integration was associated with local variations in genomic copy numbers. Integrations at the TERT promoter were associated with high telomerase expression evidently activating this tumor-driving process. High levels of endogenous retrovirus (ERV1) expression were linked to a worse survival outcome in patients with kidney cancer

Elastic SCAD as a novel penalization method for SVM classification tasks in high-dimensional data

<p>Abstract</p> <p>Background</p> <p>Classification and variable selection play an important role in knowledge discovery in high-dimensional data. Although Support Vector Machine (SVM) algorithms are among the most powerful classification and prediction methods with a wide range of scientific applications, the SVM does not include automatic feature selection and therefore a number of feature selection procedures have been developed. Regularisation approaches extend SVM to a feature selection method in a flexible way using penalty functions like LASSO, SCAD and Elastic Net.</p> <p>We propose a novel penalty function for SVM classification tasks, Elastic SCAD, a combination of SCAD and ridge penalties which overcomes the limitations of each penalty alone.</p> <p>Since SVM models are extremely sensitive to the choice of tuning parameters, we adopted an interval search algorithm, which in comparison to a fixed grid search finds rapidly and more precisely a global optimal solution.</p> <p>Results</p> <p>Feature selection methods with combined penalties (Elastic Net and Elastic SCAD SVMs) are more robust to a change of the model complexity than methods using single penalties. Our simulation study showed that Elastic SCAD SVM outperformed LASSO (<it>L</it>₁) and SCAD SVMs. Moreover, Elastic SCAD SVM provided sparser classifiers in terms of median number of features selected than Elastic Net SVM and often better predicted than Elastic Net in terms of misclassification error.</p> <p>Finally, we applied the penalization methods described above on four publicly available breast cancer data sets. Elastic SCAD SVM was the only method providing robust classifiers in sparse and non-sparse situations.</p> <p>Conclusions</p> <p>The proposed Elastic SCAD SVM algorithm provides the advantages of the SCAD penalty and at the same time avoids sparsity limitations for non-sparse data. We were first to demonstrate that the integration of the interval search algorithm and penalized SVM classification techniques provides fast solutions on the optimization of tuning parameters.</p> <p>The penalized SVM classification algorithms as well as fixed grid and interval search for finding appropriate tuning parameters were implemented in our freely available R package 'penalizedSVM'.</p> <p>We conclude that the Elastic SCAD SVM is a flexible and robust tool for classification and feature selection tasks for high-dimensional data such as microarray data sets.</p

Use of the CONSIDER statement by eye health researchers when conducting and reporting research involving Indigenous peoples: an online survey

Background: Indigenous peoples experience worse eye health compared to non-Indigenous peoples. Service providers and researchers must avoid perpetuating this inequity. To help achieve this, researchers can use the CONSolIDated critERia for strengthening the reporting of health research involving Indigenous peoples (CONSIDER) statement. This study aimed to identify the degree to which the CONSIDER statement has been used by eye health researchers when conducting and reporting research with an Indigenous component, and how they perceive its relevance in their future research. Methods: We used purposive sampling to recruit eye health researchers from any country who have undertaken research with an Indigenous component. The online survey collected quantitative and qualitative data and was analysed using descriptive statistics and reflexive thematic analysis. Responses were gathered on a four-point Likert scale (1 to 4), with four being the most positive statement. Results: Thirty-nine eye health researchers from nine countries completed the survey (Aotearoa New Zealand, Argentina, Australia, Brazil, Canada, Colombia, Guatemala, Panama, Peru); almost two-thirds (n = 24) undertake epidemiological research. On average, participants disclosed only ‘sometimes’ previously reporting CONSIDER items (2.26 ± 1.14), but they thought the items were relevant to eye health research and were motivated to use these guidelines in their future research. Some participants requested clarity about how CONSIDER aligned with existing guidelines, and when and how to apply the statement. Others shared rich experiences of the benefits to their research of Indigenous leadership and collaboration. Conclusions: The CONSIDER statement is perceived as a valuable tool by these eye health researchers, and there are opportunities to maximise uptake and use, including increasing awareness of the statement, clarity about when it applies, and availability of institutional-level support

Rubinstein-Taybi Syndrome: spectrum of CREBBP mutations in Italian patients

BACKGROUND: Rubinstein-Taybi Syndrome (RSTS, MIM 180849) is a rare congenital disorder characterized by mental and growth retardation, broad and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms and increased risk of tumors. RSTS is caused by chromosomal rearrangements and point mutations in one copy of the CREB-binding protein gene (CREBBP or CBP) in 16p13.3. To date mutations in CREBBP have been reported in 56.6% of RSTS patients and an average figure of 10% has ascribed to deletions. METHODS: Our study is based on the mutation analysis of CREBBP in 31 Italian RSTS patients using segregation analysis of intragenic microsatellites, BAC FISH and direct sequencing of PCR and RT-PCR fragments. RESULTS: We identified a total of five deletions, two of the entire gene and three, all in a mosaic condition, involving either the 5' or the 3' region. By direct sequencing a total of 14 de novo mutations were identified: 10 truncating (5 frameshift and 5 nonsense), one splice site, and three novel missense mutations. Two of the latter affect the HAT domain, while one maps within the conserved nuclear receptor binding of (aa 1–170) and will probably destroy a Nuclear Localization Signal. Identification of the p.Asn1978Ser in the healthy mother of a patient also carrying a de novo frameshift mutation, questions the pathogenetic significance of the missense change reported as recurrent mutation. Thirteen additional polymorphisms, three as of yet unreported, were also detected. CONCLUSION: A high detection rate (61.3%) of mutations is confirmed by this Italian study which also attests one of the highest microdeletion rate (16%) documented so far

Common law marriage and couple formation

The Current Population Survey is used to investigate effects of Common Law Marriage (CLM) on whether young US-born adults live in couples in the U.S. CLM effects are identified through cross-state and time variation, as some states abolished CLM over the period examined. Analysis based on Gary Becker's marriage economics helps explain why CLM affects couple formation and does so differently depending on education, sex ratios and parent status. CLM reduces in-couple residence, and more so for childless whites and where there are fewer men per woman. Effects are larger for college-educated men and women without college

Framing the future for taxonomic monography: Improving recognition, support, and access

No abstract available

Active medulloblastoma enhancers reveal subgroup-specific cellular origins

Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins