Probability of Causation for Lung Cancer After Exposure to Radon Progeny: A Comparison of Models and Data

The estimates of lung cancer risk due to the exposure to radon decay products are based on different data sets from underground mining and on different mathematical models that are used to fit the data. Diagrams of the excess relative rate per 100 working level months in its dependence on age at exposure and age attained are shown to be a useful tool to elucidate the influence that is due to the choice of the model, and to assess the differences between the data from the major western cohorts and those from the Czech uranium miners. It is seen that the influence of the choice of the model is minor compared to the difference between the data sets. The results are used to derive attributable lifetime risks and probabilities of causation for lung cancer following radon progeny exposures

A Survey of the Czechoslovak Follow-up of Lung Cancer Mortality in Uranium Miners

The major Czechoslovak cohort of uranium miners (S-cohort) is surveyed in terms of diagrams illustrating dependences on calendar year, age, and exposure to radon and radon progeny. An analysis of the dose dependence of lung cancer mortality is performed by nonparametric and, subsequently, by parametric methods. In the first step, two-dimensional isotonic regression is employed to derive the lung cancer mortality rate and the relative excess risk as functions of age attained and of lagged cumulated exposure. In a second step, analytical fits in terms of relative risk models are derived. The treatment is largely analogous to the methods applied by the BEIR IV Committee to other major cohorts of uranium miners. There is a marked dependence of the excess risk on age attained and on time since exposure. A specific characteristic of the Czechoslovak data is the nonlinearity of the dependence of the lung cancer excess risk on the cumulated exposure; exposures on the order of 100 working level months or less appear to be more effective per working level month than larger exposures but, in the absence of an internal control group, this cannot be excluded to be due to confounders such as smoking or environmental exposures. A further notable observation is the association of larger excess risks with longer protraction of the exposures

Classical interventions in quantum systems. I. The measuring process

The measuring process is an external intervention in the dynamics of a quantum system. It involves a unitary interaction of that system with a measuring apparatus, a further interaction of both with an unknown environment causing decoherence, and then the deletion of a subsystem. This description of the measuring process is a substantial generalization of current models in quantum measurement theory. In particular, no ancilla is needed. The final result is represented by a completely positive map of the quantum state $\rho$ (possibly with a change of the dimensions of $\rho$). A continuous limit of the above process leads to Lindblad's equation for the quantum dynamical semigroup.Comment: Final version, 14 pages LaTe

The Intrinsic Antiviral Defense to Incoming HSV-1 Genomes Includes Specific DNA Repair Proteins and Is Counteracted by the Viral Protein ICP0

Cellular restriction factors responding to herpesvirus infection include the ND10 components PML, Sp100 and hDaxx. During the initial stages of HSV-1 infection, novel sub-nuclear structures containing these ND10 proteins form in association with incoming viral genomes. We report that several cellular DNA damage response proteins also relocate to sites associated with incoming viral genomes where they contribute to the cellular front line defense. We show that recruitment of DNA repair proteins to these sites is independent of ND10 components, and instead is coordinated by the cellular ubiquitin ligases RNF8 and RNF168. The viral protein ICP0 targets RNF8 and RNF168 for degradation, thereby preventing the deposition of repressive ubiquitin marks and counteracting this repair protein recruitment. This study highlights important parallels between recognition of cellular DNA damage and recognition of viral genomes, and adds RNF8 and RNF168 to the list of factors contributing to the intrinsic antiviral defense against herpesvirus infection

Transient Reversal of Episome Silencing Precedes VP16-Dependent Transcription during Reactivation of Latent HSV-1 in Neurons

Herpes simplex virus type-1 (HSV-1) establishes latency in peripheral neurons, creating a permanent source of recurrent infections. The latent genome is assembled into chromatin and lytic cycle genes are silenced. Processes that orchestrate reentry into productive replication (reactivation) remain poorly understood. We have used latently infected cultures of primary superior cervical ganglion (SCG) sympathetic neurons to profile viral gene expression following a defined reactivation stimulus. Lytic genes are transcribed in two distinct phases, differing in their reliance on protein synthesis, viral DNA replication and the essential initiator protein VP16. The first phase does not require viral proteins and has the appearance of a transient, widespread de-repression of the previously silent lytic genes. This allows synthesis of viral regulatory proteins including VP16, which accumulate in the cytoplasm of the host neuron. During the second phase, VP16 and its cellular cofactor HCF-1, which is also predominantly cytoplasmic, concentrate in the nucleus where they assemble an activator complex on viral promoters. The transactivation function supplied by VP16 promotes increased viral lytic gene transcription leading to the onset of genome amplification and the production of infectious viral particles. Thus regulated localization of de novo synthesized VP16 is likely to be a critical determinant of HSV-1 reactivation in sympathetic neurons

EBV Tegument Protein BNRF1 Disrupts DAXX-ATRX to Activate Viral Early Gene Transcription

Productive infection by herpesviruses involve the disabling of host-cell intrinsic defenses by viral encoded tegument proteins. Epstein-Barr Virus (EBV) typically establishes a non-productive, latent infection and it remains unclear how it confronts the host-cell intrinsic defenses that restrict viral gene expression. Here, we show that the EBV major tegument protein BNRF1 targets host-cell intrinsic defense proteins and promotes viral early gene activation. Specifically, we demonstrate that BNRF1 interacts with the host nuclear protein Daxx at PML nuclear bodies (PML-NBs) and disrupts the formation of the Daxx-ATRX chromatin remodeling complex. We mapped the Daxx interaction domain on BNRF1, and show that this domain is important for supporting EBV primary infection. Through reverse transcription PCR and infection assays, we show that BNRF1 supports viral gene expression upon early infection, and that this function is dependent on the Daxx-interaction domain. Lastly, we show that knockdown of Daxx and ATRX induces reactivation of EBV from latently infected lymphoblastoid cell lines (LCLs), suggesting that Daxx and ATRX play a role in the regulation of viral chromatin. Taken together, our data demonstrate an important role of BNRF1 in supporting EBV early infection by interacting with Daxx and ATRX; and suggest that tegument disruption of PML-NB-associated antiviral resistances is a universal requirement for herpesvirus infection in the nucleus

The Genomic Distribution and Function of Histone Variant HTZ-1 during C. elegans Embryogenesis

In all eukaryotes, histone variants are incorporated into a subset of nucleosomes to create functionally specialized regions of chromatin. One such variant, H2A.Z, replaces histone H2A and is required for development and viability in all animals tested to date. However, the function of H2A.Z in development remains unclear. Here, we use ChIP-chip, genetic mutation, RNAi, and immunofluorescence microscopy to interrogate the function of H2A.Z (HTZ-1) during embryogenesis in Caenorhabditis elegans, a key model of metazoan development. We find that HTZ-1 is expressed in every cell of the developing embryo and is essential for normal development. The sites of HTZ-1 incorporation during embryogenesis reveal a genome wrought by developmental processes. HTZ-1 is incorporated upstream of 23% of C. elegans genes. While these genes tend to be required for development and occupied by RNA polymerase II, HTZ-1 incorporation does not specify a stereotypic transcription program. The data also provide evidence for unexpectedly widespread independent regulation of genes within operons during development; in 37% of operons, HTZ-1 is incorporated upstream of internally encoded genes. Fewer sites of HTZ-1 incorporation occur on the X chromosome relative to autosomes, which our data suggest is due to a paucity of developmentally important genes on X, rather than a direct function for HTZ-1 in dosage compensation. Our experiments indicate that HTZ-1 functions in establishing or maintaining an essential chromatin state at promoters regulated dynamically during C. elegans embryogenesis

Special cases : moons, rings, comets, trojans

Non-planetary bodies provide valuable insight into our current under- standing of planetary formation and evolution. Although these objects are challeng- ing to detect and characterize, the potential information to be drawn from them has motivated various searches through a number of techniques. Here, we briefly review the current status in the search of moons, rings, comets, and trojans in exoplanet systems and suggest what future discoveries may occur in the near future.Comment: Invited review (status August 2017

A systematic review of the health, social and financial impacts of welfare rights advice delivered in healthcare settings

BACKGROUND: Socio-economic variations in health, including variations in health according to wealth and income, have been widely reported. A potential method of improving the health of the most deprived groups is to increase their income. State funded welfare programmes of financial benefits and benefits in kind are common in developed countries. However, there is evidence of widespread under claiming of welfare benefits by those eligible for them. One method of exploring the health effects of income supplementation is, therefore, to measure the health effects of welfare benefit maximisation programmes. We conducted a systematic review of the health, social and financial impacts of welfare rights advice delivered in healthcare settings. METHODS: Published and unpublished literature was accessed through searches of electronic databases, websites and an internet search engine; hand searches of journals; suggestions from experts; and reference lists of relevant publications. Data on the intervention delivered, evaluation performed, and outcome data on health, social and economic measures were abstracted and assessed by pairs of independent reviewers. Results are reported in narrative form. RESULTS: 55 studies were included in the review. Only seven studies included a comparison or control group. There was evidence that welfare rights advice delivered in healthcare settings results in financial benefits. There was little evidence that the advice resulted in measurable health or social benefits. This is primarily due to lack of good quality evidence, rather than evidence of an absence of effect. CONCLUSION: There are good theoretical reasons why income supplementation should improve health, but currently little evidence of adequate robustness and quality to indicate that the impact goes beyond increasing income