Comparative measurements of air quality monitoring between RIVM, GGD Amsterdam and DCMR : Results 2010

Alleen digitaal beschikbaarIn het kader van de samenwerking tussen de luchtkwaliteits-meetnetten van het RIVM, de GGD Amsterdam en de DCMR Milieudienst Rijnmond vinden sinds enkele jaren tussen RIVM en de beide organisaties vergelijkende metingen plaats op meetlocaties in Amsterdam (RIVM-GGD) en Rotterdam (RIVM-DCMR): - Amsterdam: stikstofdioxide op locatie Overtoom - Rotterdam: stikstofdioxide en PM10 op locatie Bentinckplein/Statenweg. Deze hebben tot doel de vergelijkbaarheid van de resultaten van de verschillende meetinstanties vast te stellen; bij voldoende vergelijkbaarheid kunnen de instanties wederzijds gebruik maken van elkaars resultaten. Evaluatie van de resultaten van de vergelijkingen verricht in 2010 toont aan dat de resulterende meetonzekerheden in alle gevallen te voldoen aan de criteria gesteld in EU Richtlijn 2008/50/EC. Aangezien alle instanties een ISO 17025 accreditatie voeren voor de betreffende metingen mag ervan worden uitgegaan dat het kwaliteitsniveau en de vergelijkbaarheid zoals bepaald in deze vergelijkingen representatief zijn voor de andere meetlocaties van de netwerken. Dit impliceert dat de instanties in principe gebruik kunnen maken van elkaars meetgegevens voor de componenten waarvoor resultaten zijn vergeleken (DCMR en RIVM voor stikstofdioxide en PM10; GGD en RIVM voor stikstofdioxide).Within the frame of the cooperation between the air quality monitoring networks of RIVM, GGD Amsterdam and DCMR Environmental Protection Agency comparative measurements are performed between RIVM and both regional networks at locations in Amsterdam (RIVM-GGD) and Rotterdam (RIVM-DCMR): - Amsterdam: nitrogen dioxide at location Overtoom - Rotterdam: nitrogen dioxide and PM10 at location Bentinckplein/Statenweg. The purpose of these comparisons is demonstrating comparability of results obtained by the different networks. In case of sufficient comparability mutual use can be made of their results. All networks use the European Union reference methods for nitrogen dioxide and PM10. The evaluation involves comparison of hourly average results for nitrogen dioxide and of daily average results for PM10 by applying orthogonal regression analysis and by examination of differences between results as a function of measurement period and concentration level. Evaluation of the comparison between RIVM and DCMR for the year 2010 shows that for PM10 results agree almost on a "1 to 1" basis. The comparisons for nitrogen dioxide reveal an overall agreement of results averaged over the whole year to within ±1,6%. However, distinct differences can be observed in the relationships over the first and second half of 2010, with ratios of RIVM's results to those of the other networks increasing. Further, the relationship between results for DCMR and RIVM deviates markedly from the expected relationship y=x. Reasons for this may be differences in applied calibration procedures and handling of low measurement values. Evaluation further shows that the resulting measurement uncertainties in all cases are well within the criteria given in EU Directive 2008/50/EC. As all networks have an ISO 17025 accreditation for the measurements compared it may be assumed that the quality levels and, consequently, the comparability of the results determined in these comparisons are representative for the networks as a whole. Consequently, it should be possible for networks to make mutual use of results for the components compared (DCMR and RIVM for nitrogen dioxide and PM10; GGD and RIVM for nitrogen dioxide).Rijksinstituut voor Volksgezondheid en Milieu RIV

A type I IFN-dependent DNA damage response regulates the genetic program and inflammasome activation in macrophages

Macrophages produce genotoxic agents, such as reactive oxygen and nitrogen species, that kill invading pathogens. Here we show that these agents activate the DNA damage response (DDR) kinases ATM and DNA-PKcs through the generation of double stranded breaks (DSBs) in murine macrophage genomic DNA. In contrast to other cell types, initiation of this DDR depends on signaling from the type I interferon receptor. Once activated, ATM and DNA-PKcs regulate a genetic program with diverse immune functions and promote inflammasome activation and the production of IL-1β and IL-18. Indeed, following infection with Listeria monocytogenes, DNA-PKcs-deficient murine macrophages produce reduced levels of IL-18 and are unable to optimally stimulate IFN-γ production by NK cells. Thus, genomic DNA DSBs act as signaling intermediates in murine macrophages, regulating innate immune responses through the initiation of a type I IFN-dependent DDR.</jats:p

DNA damage activates a complex transcriptional response in murine lymphocytes that includes both physiological and cancer-predisposition programs

BACKGROUND: Double strand (ds) DNA breaks are a form of DNA damage that can be generated from both genotoxic exposures and physiologic processes, can disrupt cellular functions and can be lethal if not repaired properly. Physiologic dsDNA breaks are generated in a variety of normal cellular functions, including the RAG endonuclease-mediated rearrangement of antigen receptor genes during the normal development of lymphocytes. We previously showed that physiologic breaks initiate lymphocyte development-specific transcriptional programs. Here we compare transcriptional responses to physiological DNA breaks with responses to genotoxic DNA damage induced by ionizing radiation. RESULTS: We identified a central lymphocyte-specific transcriptional response common to both physiologic and genotoxic breaks, which includes many lymphocyte developmental processes. Genotoxic damage causes robust alterations to pathways associated with B cell activation and increased proliferation, suggesting that genotoxic damage initiates not only the normal B cell maturation processes but also mimics activated B cell response to antigenic agents. Notably, changes including elevated levels of expression of Kras and mmu-miR-155 and the repression of Socs1 were observed following genotoxic damage, reflecting induction of a cancer-prone phenotype. CONCLUSIONS: Comparing these transcriptional responses provides a greater understanding of the mechanisms cells use in the differentiation between types of DNA damage and the potential consequences of different sources of damage. These results suggest genotoxic damage may induce a unique cancer-prone phenotype and processes mimicking activated B cell response to antigenic agents, as well as the normal B cell maturation processes

Nebraska Forest Service Annual Report 2012

Scorched and Burned..................................2 Saving Chadron State Park......................4 Tree Pests and Diseases Threaten Nebraska..........................................6 Tree Pests: A Proactive Approach.............................................8 From Adversity Rises Opportunity..................................................10 Mitigating Drought.............................12 Tribute to a Forester..........................................................................14 Survey Says........15 Refurbish and Repurpose...................................16 Contributors: Jeanne Andelt, Eric Berg, Dr. Mark Harrell, Casey McCoy, Dr. Scott J. Josiah, Doak Nickerson, Jeralyn Schluckebier, Lew Sieber, Adam Smith, Laurie Stepanek, Don Westove

ATM Deficiency -- A Multifaceted Defect in Lymphocyte Development

The generation of a functional antigen receptor gene in developing lymphocytes requires that the second exon be assembled through a process known as V(D)J recombination, a process that necessarily involves the generation and repair of DNA double-strand breaks made by the Rag endonuclease. Double strand breaks incurred during G1 of the cell cycle activate ATM, a PI3-kinase-like kinase that, in response to genotoxic DNA damage, is known to phosphorylate hundreds of proteins with unique and diverse functions. Notably, deficiencies in ATM lead to ataxia-telangiectasia, a syndrome characterized by lymphopenia, genomic instability and a predisposition to tumors involving antigen receptor loci suggesting that ATM likely plays a similar critical role downstream of Rag-mediated DNA DSBs during V(D)J recombination. In this body of work, I describe three distinct pathways activated by ATM in response to Rag DNA DSBs and how defects in these pathways would impair lymphocyte development and contribute to the phenotype of ATM-deficient mice and humans. First, ATM-deficient lymphocytes have a defect in the repair of Rag DNA DSBs characterized by an accumulation of unrepaired coding ends and an increase in aberrant hybrid joint formation during rearrangement by inversion. Furthermore, these coding ends drift apart and are frequently aberrantly resolved as translocations. We determine that ATM contributes to the repair of Rag DNA DSBs by maintaining the unrepaired ends in a stable post-cleavage complex possibly through the phosphorylation of components of the MRN complex. Secondly, in G1-phase lymphocytes, the ATM-dependent phosphorylation of histone H2AX inhibits the robust CtIP-dependent opening and resection of hairpin-sealed coding ends thereby preventing their aberrant resolution by alternative repair pathways. Finally, in response to Rag DSBs, through the activation of NFkB and other transcription factors, ATM activates a broad genetic program that transcends the canonical DNA damage response and includes genes whose known functions are integral to lymphocyte development. While this work has significantly increased our understanding of the cellular response to Rag DNA DSBs, given the diversity of the other known substrates of ATM, it seems likely that we have only begun to unravel the complexities of the ATM-deficient phenotype

Should We Learn Probabilistic Models for Model Checking? A New Approach and An Empirical Study

Many automated system analysis techniques (e.g., model checking, model-based testing) rely on first obtaining a model of the system under analysis. System modeling is often done manually, which is often considered as a hindrance to adopt model-based system analysis and development techniques. To overcome this problem, researchers have proposed to automatically "learn" models based on sample system executions and shown that the learned models can be useful sometimes. There are however many questions to be answered. For instance, how much shall we generalize from the observed samples and how fast would learning converge? Or, would the analysis result based on the learned model be more accurate than the estimation we could have obtained by sampling many system executions within the same amount of time? In this work, we investigate existing algorithms for learning probabilistic models for model checking, propose an evolution-based approach for better controlling the degree of generalization and conduct an empirical study in order to answer the questions. One of our findings is that the effectiveness of learning may sometimes be limited.Comment: 15 pages, plus 2 reference pages, accepted by FASE 2017 in ETAP

A theory of normed simulations

In existing simulation proof techniques, a single step in a lower-level specification may be simulated by an extended execution fragment in a higher-level one. As a result, it is cumbersome to mechanize these techniques using general purpose theorem provers. Moreover, it is undecidable whether a given relation is a simulation, even if tautology checking is decidable for the underlying specification logic. This paper introduces various types of normed simulations. In a normed simulation, each step in a lower-level specification can be simulated by at most one step in the higher-level one, for any related pair of states. In earlier work we demonstrated that normed simulations are quite useful as a vehicle for the formalization of refinement proofs via theorem provers. Here we show that normed simulations also have pleasant theoretical properties: (1) under some reasonable assumptions, it is decidable whether a given relation is a normed forward simulation, provided tautology checking is decidable for the underlying logic; (2) at the semantic level, normed forward and backward simulations together form a complete proof method for establishing behavior inclusion, provided that the higher-level specification has finite invisible nondeterminism.Comment: 31 pages, 10figure

Polo-like kinase 3 regulates CtIP during DNA double-strand break repair in G1

DNA double-strand breaks (DSBs) are repaired by nonhomologous end joining (NHEJ) or homologous recombination (HR). The C terminal binding protein–interacting protein (CtIP) is phosphorylated in G2 by cyclin-dependent kinases to initiate resection and promote HR. CtIP also exerts functions during NHEJ, although the mechanism phosphorylating CtIP in G1 is unknown. In this paper, we identify Plk3 (Polo-like kinase 3) as a novel DSB response factor that phosphorylates CtIP in G1 in a damage-inducible manner and impacts on various cellular processes in G1. First, Plk3 and CtIP enhance the formation of ionizing radiation-induced translocations; second, they promote large-scale genomic deletions from restriction enzyme-induced DSBs; third, they are required for resection and repair of complex DSBs; and finally, they regulate alternative NHEJ processes in Ku−/− mutants. We show that mutating CtIP at S327 or T847 to nonphosphorylatable alanine phenocopies Plk3 or CtIP loss. Plk3 binds to CtIP phosphorylated at S327 via its Polo box domains, which is necessary for robust damage-induced CtIP phosphorylation at S327 and subsequent CtIP phosphorylation at T847