Critical Nodes In Directed Networks

Critical nodes or "middlemen" have an essential place in both social and economic networks when considering the flow of information and trade. This paper extends the concept of critical nodes to directed networks. We identify strong and weak middlemen. Node contestability is introduced as a form of competition in networks; a duality between uncontested intermediaries and middlemen is established. The brokerage power of middlemen is formally expressed and a general algorithm is constructed to measure the brokerage power of each node from the networks adjacency matrix. Augmentations of the brokerage power measure are discussed to encapsulate relevant centrality measures. We use these concepts to identify and measure middlemen in two empirical socio-economic networks, the elite marriage network of Renaissance Florence and Krackhardt's advice network.Comment: 28 pages, 6 figures, 2 table

The freeze on mass media campaigns in England: a natural experiment of the impact of tobacco control campaigns on quitting behaviour

Aims To measure the impact of the suspension of tobacco control mass media campaigns in England in April 2010 on measures of smoking cessation behaviour. Design Interrupted time series design using routinely collected population-level data. Analysis of use of a range of types of smoking cessation support using segmented negative binomial regression. Setting England. Measurements Use of non-intensive support: monthly calls to the National Health Service (NHS) quitline (April 2005–September 2011), text requests for quit support packs (December 2007–10) and web hits on the national smoking cessation website (January 2009–March 2011). Use of intensive cessation support: quarterly data on the number of people setting a quit date and 4-week quitters at the NHS Stop Smoking Services (SSS) (quarter 1, 2001 and quarter 3, 2011). Findings During the suspension of tobacco control mass media spending, literature requests fell by 98% [95% confidence interval (CI) = 96–99], and quitline calls and web hits fell by 65% (95% CI = 43–79) and 34% (95% CI: 11–50), respectively. The number of people setting a quit date and 4-week quitters at the SSS increased throughout the study period. Conclusions The suspension of tobacco control mass media campaigns in England in 2012 appeared to markedly reduce the use of smoking cessation literature, quitline calls and hits on the national smoking cessation website, but did not affect attendance at the Stop Smoking Services. Within a comprehensive tobacco control programme, mass media campaigns can play an important role in maximizing quitting activity

Who They Are and How to Engage Them:A Summary of the REACT Systematic Literature Review of the 'Hard to Reach' in Higher Education

This article reports upon the systematic literature review of hard to reach students carried out as part of the REACT (Realising Engagement through Active Culture Transformation) project. The review has been undertaken in order to critically assess the concept of hard to reach and attempt to bring some clarity to the use of the term, as well as to add empirical rigour and much-needed context to discussion in this area. The review also explores methods that have been used to explicitly engage the hard to reach, thereby providing a resource for policy makers, researchers and also practitioners who are working to increase inclusivity or better engage their students. The article presents a summary of the initial findings of the review

Next-generation sequencing of advanced prostate cancer treated with androgen-deprivation therapy

<b>Background:</b> Androgen-deprivation therapy (ADT) is standard treatment for locally advanced or metastatic prostate cancer (PCa). Many patients develop castration resistance (castration-resistant PCa [CRPC]) after approximately 2–3 yr, with a poor prognosis. The molecular mechanisms underlying CRPC progression are unclear.<p></p> <b>Objective:</b> To undertake quantitative tumour transcriptome profiling prior to and following ADT to identify functionally important androgen-regulated pathways or genes that may be reactivated in CRPC.<p></p> <b>Design, setting, and participants:</b> RNA sequencing (RNA-seq) was performed on tumour-rich, targeted prostatic biopsies from seven patients with locally advanced or metastatic PCa before and approximately 22 wk after ADT initiation. Differentially regulated genes were identified in treatment pairs and further investigated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on cell lines and immunohistochemistry on a separate CRPC patient cohort. Functional assays were used to determine the effect of pathway modulation on cell phenotypes.<p></p> <b>Outcome measurements and statistical analysis:</b> We searched for gene expression changes affecting key cell signalling pathways that may be targeted as proof of principle in a CRPC in vitro cell line model.<p></p> <b>Results and limitations:</b> We identified ADT-regulated signalling pathways, including the Wnt/β-catenin signalling pathway, and observed overexpression of β-catenin in a subset of CRPC by immunohistochemistry. We validated 6 of 12 (50%) pathway members by qRT-PCR on LNCaP/LNCaP-AI cell RNAs, of which 4 (67%) demonstrated expression changes consistent with RNA-seq data. We show that the tankyrase inhibitor XAV939 (which promotes β-catenin degradation) reduced androgen-independent LNCaP-AI cell line growth compared with androgen-responsive LNCaP cells via an accumulation of cell proportions in the G0/G1 phase and reduction in the S and G2/M phases. Our biopsy protocol did not account for tumour heterogeneity, and pathway inhibition was limited to pharmacologic approaches.<p></p> <b>Conclusions:</b> RNA-seq of paired PCa samples revealed ADT-regulated signalling pathways. Proof-of-principle inhibition of the Wnt/β-catenin signalling pathway specifically delays androgen-independent PCa cell cycle progression and proliferation and warrants further investigation as a potential target for therapy for CRPC.<p></p&gt

Audiologic Features of Norrie Disease

Artículo científico -- Instituto de Investigaciones en Salud. 2005Objectives: Norrie disease is an X-linked recessive disorder in which patients are born blind and develop sensory hearing loss in adolescence. The hearing loss associated with Norrie disease has been shown in a genetically altered knockout mouse to involve dysfunction of the stria vascularis; most other structures are preserved until the later stages of the disease. The objective of this study was to characterize the audiologic phenotype of Nark disease for comparison with the pathophysiologic mechanism. Methods: The design combined two series of clinical audiologic evaluations, with special attention to speech intelligibility. Results: The audiologic results for 12 affected individuals and 10 carriers show that patients with Norrie disease retain high speech intelligibility scores even when the threshold loss is severe. Conclusions: The cochlear mechanism — failure of the stria vascularis — accounts for some of the higher values in the wide distribution of speech scores in cases with similar pure tone and iograms.Universidad de Costa Rica, Instituto de Investigaciones en SaludUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA

The DNA-binding domain of the Chd1 chromatin-remodelling enzyme contains SANT and SLIDE domains

The ATP-dependent chromatin-remodelling enzyme Chd1 is a 168-kDa protein consisting of a double chromodomain, Snf2-related ATPase domain, and a C-terminal DNA-binding domain. Here, we show the DNA-binding domain is required for Saccharomyces cerevisiae Chd1 to bind and remodel nucleosomes. The crystal structure of this domain reveals the presence of structural homology to SANT and SLIDE domains previously identified in ISWI remodelling enzymes. The presence of these domains in ISWI and Chd1 chromatin-remodelling enzymes may provide a means of efficiently harnessing the action of the Snf2-related ATPase domain for the purpose of nucleosome spacing and provide an explanation for partial redundancy between these proteins. Site directed mutagenesis was used to identify residues important for DNA binding and generate a model describing the interaction of this domain with DNA. Through inclusion of Chd1 sequences in homology searches SLIDE domains were identified in CHD6–9 proteins. Point mutations to conserved amino acids within the human CHD7 SLIDE domain have been identified in patients with CHARGE syndrome

Interpreting Soft Sediment Deformation and Mass Transport Deposits as Seismites in the Dead Sea Depocenter

Peer reviewedPublisher PD

The response of stromatolites to seismic shocks: Tomboliths from the Palaeoproterozoic Chaibasa Formation, E India

It is demonstrated here for the first time how Palaeoproterozoic stromatolites survived seismic disturbance of their substrate. The stromatolites under study could have been cyanobacteria or any other photoautotrophic microbes, which formed mats that covered a substrate of very fine-grained sandstones and mudstones of the Chaibasa Fm. in eastern India. The sediments represent a shelf environment. The local abundance of the stromatolites suggests that the low-energy environment formed a suitable habitat. The common phases of tectonic quiescence were, however, occasionally interrupted by seismic shocks. These were sufficiently strong to deform the mat layers, the lower parts of which might already have been (semi-) consolidated. The mats became partly folded, partly faulted, and already consolidated parts of the stromatolite layers broke off. This can be deduced from the angular shapes of part of the broken-off fragments. It appears, however, that part of these fragments were still sufficiently soft to become rounded and deformed by rolling over the seafloor, probably under the influence of tidal currents. When come to rest, these fragments served as a new substrate for new generations of the micro-organisms. These micro-organisms thus survived by continued growth on the reworked fragments and built up new stromatolites that may show an ‘angular disconformity’ with the stromatolites of their substrate. It thus is shown that stromatolites have an adequate response to a sudden disturbance of their habitat, and that they survive earthquakes by colonization of broken-off fragments. We call the ‘healed’ fragments ‘tomboliths’ (tumbled stones)