Hyperproliferation and Dysregulation ofIL-4 Expression in NF-ATp-Deficient Mice

AbstractNF-ATp is a member of a family of genes that encodes the cytoplasmic component of the nuclear factor of activated T cells (NF-AT). In this study, we show that mice with a null mutation in the NF-ATp gene have splenomegaly with hyperproliferation of both B and T cells. They also display early defects in the transcription of multiple genes encoding cytokines and cell surface receptors, including CD40L and FasL. A striking defect in early IL-4 production was observed after ligation of the TCR complex by treatment with anti-CD3 in vivo. The transcription of other cytokines including IL-13, GM–CSF, and TNFα was also affected, though to a lesser degree. Interestingly, the cytokines IL-2 and IFNγ were minimally affected. Despite this early defect in IL-4 transcription, Th2 development was actually enhanced at later timepoints as evidenced by increased IL-4 production and IgE levels in situations that favor the formation of Th2 cells both in vitro and in vivo. These data suggest that NF-ATp may be involved in cell growth, and that it is important for the balanced transcription of the IL-4 gene during the course of an immune response.BDY

Visualizing the Needle in the Haystack: In Situ Hybridization With Fluorescent Dendrimers

In situ hybridization with 3DNA™ dendrimers is a novel tool for detecting low levels of mRNA in tissue sections and whole embryos. Fluorescently labeled dendrimers were used to identify cells that express mRNA for the skeletal muscle transcription factor MyoD in the early chick embryo. A small population of MyoD mRNA positive cells was found in the epiblast prior to the initiation of gastrulation, two days earlier than previously detected using enzymatic or radiolabeled probes for mRNA. When isolated from the epiblast and placed in culture, the MyoD mRNA positive cells were able to differentiate into skeletal muscle cells. These results demonstrate that DNA dendrimers are sensitive and precise tools for identifying low levels of mRNA in single cells and tissues

DNA Dendrimers Localize Myod mRNA in Presomitic Tissues of the Chick Embryo

MyoD expression is thought to be induced in somites in response to factors released by surrounding tissues; however, reverse transcription-PCR and cell culture analyses indicate that myogenic cells are present in the embryo before somite formation. Fluorescently labeled DNA dendrimers were used to identify MyoD expressing cells in presomitic tissues in vivo. Subpopulations of MyoD positive cells were found in the segmental plate, epiblast, mesoderm, and hypoblast. Directly after laying, the epiblast of the two layered embryo contained ∼20 MyoD positive cells. These results demonstrate that dendrimers are precise and sensitive reagents for localizing low levels of mRNA in tissue sections and whole embryos, and that cells with myogenic potential are present in the embryo before the initiation of gastrulation

Disruption of the β1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner

TERT promoter mutations reactivate telomerase, allowing for indefinite telomere maintenance and enabling cellular immortalization. These mutations specifically recruit the multimeric ETS factor GABP, which can form two functionally independent transcription factor species: a dimer or a tetramer. We show that genetic disruption of GABPβ1L (β1L), a tetramer-forming isoform of GABP that is dispensable for normal development, results in TERT silencing in a TERT promoter mutation-dependent manner. Reducing TERT expression by disrupting β1L culminates in telomere loss and cell death exclusively in TERT promoter mutant cells. Orthotopic xenografting of β1L-reduced, TERT promoter mutant glioblastoma cells rendered lower tumor burden and longer overall survival in mice. These results highlight the critical role of GABPβ1L in enabling immortality in TERT promoter mutant glioblastoma.This work was supported by a generous gift from the Dabbiere family (J.F.C.), the Hana Jabsheh Research Initiative (J.F.C.), NIH grant NCI P50CA097257 (J.F.C. and J.A.D.), NCI P01CA118816-06 (J.F.C.), T32 GM008568 and T32 CA151022 (A.M.), and NCI R01CA163336 (J.S.S.), and the Sontag Foundation Distinguished Scientist Award (J.S.S.). C.F. is supported by a US NIH K99/R00 Pathway to Independence Award (K99GM118909) from the National Institute of General Medical Sciences. Additional support was provided by Fundação para a Ciência e Tecnologia SFRH/BD/88220/2012 (A.X.-M.) and IF/00601/2012 (B.M.C.). J.A.D. is an investigator of the Howard Hughes Medical Institute.info:eu-repo/semantics/publishedVersio

State of the art. Overview of concepts, indicators and methodologies used for analyzing the social OMC.

This paper is a detailed analysis about the literature on the Social OMC from 2006-2010, focusing on how OMC research has been carried out. It specifically points to which theoretical framework/concepts are used, and how change is conceptualised and measured. It is organised in five sections. The first concerns visibility and awareness about the OMC; the second analyses research on the EU level coordination process; the third scrutinizes how features of the OMC have been analysed. The fourth and fifth sections, addressing how national integration of the OMC has been researched, respectively address substantive policy change as well as national policy-making. Strikingly, virtually all OMC research adopts theoretical frameworks derived from literature on Europeanisation and/or institutionalisation. Also, as the OMC is voluntary and sanction-free, it depends heavily on how and the the extent to which actors use it (agenda-setting, conflict resolution, maintaining focus on a policy issue, developing a policy dialogue, etc). OMC research has become nuanced and does highlight how, for which purpose and with which outcome actors engage with the OMC. Another finding is that there is data on policy issues addressed through the OMC, learning does take place and there is knowledge about domestic policy problems. However, the linkage between knowledge of an issue and direct use of the OMC for policy change in social policy is weak, but that may change with EU2020, where social policy has received a higher profile. Most research covers the EU-15, much more research needs to be undertaken in newer EU member states

The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in Europe. Data from real-world registries are necessary, as clinical trials do not represent the full spectrum of VTE patients seen in clinical practice. We aimed to document the epidemiology, management and outcomes of VTE using data from a large, observational database. PREFER in VTE was an international, non-interventional disease registry conducted between January 2013 and July 2015 in primary and secondary care across seven European countries. Consecutive patients with acute VTE were documented and followed up over 12 months. PREFER in VTE included 3,455 patients with a mean age of 60.8 ± 17.0 years. Overall, 53.0 % were male. The majority of patients were assessed in the hospital setting as inpatients or outpatients (78.5 %). The diagnosis was deep-vein thrombosis (DVT) in 59.5 % and pulmonary embolism (PE) in 40.5 %. The most common comorbidities were the various types of cardiovascular disease (excluding hypertension; 45.5 %), hypertension (42.3 %) and dyslipidaemia (21.1 %). Following the index VTE, a large proportion of patients received initial therapy with heparin (73.2 %), almost half received a vitamin K antagonist (48.7 %) and nearly a quarter received a DOAC (24.5 %). Almost a quarter of all presentations were for recurrent VTE, with >80 % of previous episodes having occurred more than 12 months prior to baseline. In conclusion, PREFER in VTE has provided contemporary insights into VTE patients and their real-world management, including their baseline characteristics, risk factors, disease history, symptoms and signs, initial therapy and outcomes

Predicting Recovery Rates of Defaulted Bonds Using a Neural Network

In this study we implement a neural network to forecast recovery rates of defaulted bonds using bond-specific, firm-specific and macroeconomic variables. We benchmark the model with a simple linear regression and a random forest. The network is composed of one hidden layer and a sigmoid activation function to guarantee a prediction in the unit interval. The relative importance of the network's inputs is computed using Garson's and Olden's algorithm. The performance of each model is assessed with and without overestimation penalties. The results suggest that neural networks do not have better predictive abilities given the data and the parameters. Finally, we compare the impact of each model on the Value-at-Risk by simulating 20,000 portfolios. The results show the linear regression computes the highest VaR, followed by the neural network and the random forest.Master [120] en Ingénieur de gestion, Université catholique de Louvain, 201