Akirin Links Twist-Regulated Transcription with the Brahma Chromatin Remodeling Complex during Embryogenesis

The activities of developmentally critical transcription factors are regulated via interactions with cofactors. Such interactions influence transcription factor activity either directly through protein–protein interactions or indirectly by altering the local chromatin environment. Using a yeast double-interaction screen, we identified a highly conserved nuclear protein, Akirin, as a novel cofactor of the key Drosophila melanogaster mesoderm and muscle transcription factor Twist. We find that Akirin interacts genetically and physically with Twist to facilitate expression of some, but not all, Twist-regulated genes during embryonic myogenesis. akirin mutant embryos have muscle defects consistent with altered regulation of a subset of Twist-regulated genes. To regulate transcription, Akirin colocalizes and genetically interacts with subunits of the Brahma SWI/SNF-class chromatin remodeling complex. Our results suggest that, mechanistically, Akirin mediates a novel connection between Twist and a chromatin remodeling complex to facilitate changes in the chromatin environment, leading to the optimal expression of some Twist-regulated genes during Drosophila myogenesis. We propose that this Akirin-mediated link between transcription factors and the Brahma complex represents a novel paradigm for providing tissue and target specificity for transcription factor interactions with the chromatin remodeling machinery

Generalisability and Cost-Impact of Antibiotic-Impregnated Central Venous Catheters for Reducing Risk of Bloodstream Infection in Paediatric Intensive Care Units in England

Background: We determined the generalisability and cost-impact of adopting antibiotic-impregnated CVCs in all paediatric intensive care units (PICUs) in England, based on results from a large randomised controlled trial (the CATCH trial; ISRCTN34884569). Methods: BSI rates using standard CVCs were estimated through linkage of national PICU audit data (PICANet) with laboratory surveillance data. We estimated the number of BSI averted if PICUs switched from standard to antibiotic-impregnated CVCs by applying the CATCH trial rate-ratio (0.40; 95% CI 0.17,0.97) to the BSI rate using standard CVCs. The value of healthcare resources made available by averting one BSI as estimated from the trial economic analysis was £10,975; 95% CI -£2,801,£24,751. Results: The BSI rate using standard CVCs was 4.58 (95% CI 4.42,4.74) per 1000 CVC-days in 2012. Applying the rate-ratio gave 232 BSI averted using antibiotic CVCs. The additional cost of purchasing antibiotic-impregnated compared with standard CVCs was £36 for each child, corresponding to additional costs of £317,916 for an estimated 8831 CVCs required in PICUs in 2012. Based on 2012 BSI rates, management of BSI in PICUs cost £2.5 million annually (95% uncertainty interval: -£160,986, £5,603,005). The additional cost of antibiotic CVCs would be less than the value of resources associated with managing BSI in PICUs with standard BSI rates >1.2 per 1000 CVC-days. Conclusions: The cost of introducing antibiotic-impregnated CVCs is less than the cost associated with managing BSIs occurring with standard CVCs. The long-term benefits of preventing BSI could mean that antibiotic CVCs are cost-effective even in PICUs with extremely low BSI rates

The IASLC Lung Cancer Staging Project: A Renewed Call to Participation

Over the past two decades, the International Association for the Study of Lung Cancer (IASLC) Staging Project has been a steady source of evidence-based recommendations for the TNM classification for lung cancer published by the Union for International Cancer Control and the American Joint Committee on Cancer. The Staging and Prognostic Factors Committee of the IASLC is now issuing a call for participation in the next phase of the project, which is designed to inform the ninth edition of the TNM classification for lung cancer. Following the case recruitment model for the eighth edition database, volunteer site participants are asked to submit data on patients whose lung cancer was diagnosed between January 1, 2011, and December 31, 2019, to the project by means of a secure, electronic data capture system provided by Cancer Research And Biostatistics in Seattle, Washington. Alternatively, participants may transfer existing data sets. The continued success of the IASLC Staging Project in achieving its objectives will depend on the extent of international participation, the degree to which cases are entered directly into the electronic data capture system, and how closely externally submitted cases conform to the data elements for the project

Akirin colocalizes with subunits of the SWI/SNF-class Brahma chromatin remodeling complex.

<p>(A–C) Detail of polytene chromosome squashes demonstrating immunocolocalization of Akirin with Brm complex subunits. See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002547#pgen.1002547.s009" target="_blank">Figure S9</a> for whole genome squash images. (A) To avoid cross-reactivity between Akirin and Brahma primary antibodies, polytene chromosomes were prepared from larvae expressing HA-tagged Akirin (<i>UAS</i>-Akirin-HA) under control of the <i>Sgs3-GAL4</i> driver, and immunostained with antibodies against HA (green) and Brahma (red). Extensive colocalization was observed between Akirin-HA and Brahma (white arrows). Examples of Akirin-HA immunostain without Brahma colocalization (white arrowhead), and Brahma signal without Akirin colocalization (black arrowhead) are indicated. See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002547#pgen.1002547.s008" target="_blank">Figure S8</a> for comparison of Akirin-HA and endogenous Akirin immunolocalization. (B,C) wild-type polytene chromosomes were immunostained with antibodies against Akirin (green) and Snr1 (B) or Osa (C). Examples of Akirin signal without corresponding Snr or Osa colocalization are indicated (white arrowhead), and Snr or Osa signal without corresponding Akirin immunostain (black arrowhead) are indicated. (D) Quantification of colocalization/non-overlap between Akirin and Brm complex subunits -positive polytene bands in (A–C). Scale bar in all images = 5 µm.</p