Mechanically induced current and quantum evaporation from Luttinger liquids

We investigate transport through a tunnelling junction between an uncorrelated metallic lead and a Luttinger liquid when the latter is subjected to a time dependent perturbation. The tunnelling current as well as the electron energy distribution function are found to be strongly affected by the perturbation due to generation of harmonics in the density oscillations. Using a semiconducting lead instead of a metallic one results in electrons being injected into the lead even without applied voltage. Some applications to carbon nanotubes are discussed.Comment: 7 pages, 2 figures (eps files

The role of EZH2 and DNA methylation in the silencing of the tumour suppressor RUNX3 in colorectal cancer

In gastric cancer, a new epigenetic mechanism of tumour suppressor loss has been suggested where the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is responsible for loss of expression of RUNX3. This is consistent with EZH2 upregulation in multiple cancer types being associated with poor prognosis. We investigated whether EZH2 influences the expression of RUNX3 in colorectal cancer (CRC) and whether this is independent of methylation. We determined protein and messenger RNA (mRNA) levels of EZH2 and RUNX3 and assessed RUNX3 methylation with methylation-specific polymerase chain reaction using 72 human CRCs and 8 CRC cell lines. We assessed the effect of efficient RNA interference-mediated knockdown of EZH2 on RUNX3 levels, cell viability and H3K27 trimethylation of the RUNX3 promoter using chromatin immunoprecipitation. Despite higher levels of EZH2 and lower levels of RUNX3 in CRC specimens in general, no inverse correlation between EZH2 and RUNX3 in paired samples was found arguing against a major role for histone methylation in silencing RUNX3 in CRC. Conversely, downregulation of RUNX3 mRNA in the same tumours was associated with RUNX3 DNA methylation (P < 0.05). In cell lines, knockdown of EZH2 removed the repressive chromatin marks from RUNX3 but did not result in RUNX3 re-expression. However, it prevented the re-silencing of RUNX3 after the removal of demethylating agents. In conclusion, DNA methylation is primarily responsible for the transcriptional silencing of RUNX3 in CRC, but EZH2 and histone methylation are necessary for its methylation-dependent re-silencing after the removal of demethylating agents. These results would predict that inhibitors of EZH2 and histone methylation would enhance the effects of demethylating agents in cancer therapy

Origin of the Local Bubble

We present a new unbiased search for OB associations in the Solar neighbourhood which have hosted the progenitor stars of the core collapse supernovae responsible for the Local Bubble in the interstellar gas. For this purpose we have analyzed a volume complete set (with a diameter of 400 pc) of B stars drawn from the Hipparcos catalogue and the Arivel data base, from which candidate members were selected by a kinematical criterion. After careful dereddening the star colours we have constructed a colour-magnitude diagram and confirmed that the Upper Scorpius, Upper Centaurus Lupus, and Lower Centaurus Crux subgroups of the Sco OB2 association are the youngest nearby OB associations. We dated their ages with theoretical isochrones in the range of 20–30 Myr, in agreement with previous work. We have traced backwards in time the paths of the stars and found that they entered the volume of the present bubble at 10 to 15 Myr ago. We argue that the Local Bubble began to form then and estimate that 14 to 20 supernovae have exploded since. The implied energy input into the ambient medium can be shown to be sufficient to excavate a bubble of the presently observed size

ELF5 suppresses estrogen sensitivity and underpins the acquisition of antiestrogen resistance in luminal breast cancer

We have previously shown that during pregnancy the E-twenty-six (ETS) transcription factor ELF5 directs the differentiation of mammary progenitor cells toward the estrogen receptor (ER)-negative and milk producing cell lineage, raising the possibility that ELF5 may suppress the estrogen sensitivity of breast cancers. To test this we constructed inducible models of ELF5 expression in ER positive luminal breast cancer cells and interrogated them using transcript profiling and chromatin immunoprecipitation of DNA followed by DNA sequencing (ChIP-Seq). ELF5 suppressed ER and FOXA1 expression and broadly suppressed ER-driven patterns of gene expression including sets of genes distinguishing the luminal molecular subtype. Direct transcriptional targets of ELF5, which included FOXA1, EGFR, and MYC, accurately classified a large cohort of breast cancers into their intrinsic molecular subtypes, predicted ER status with high precision, and defined groups with differential prognosis. Knockdown of ELF5 in basal breast cancer cell lines suppressed basal patterns of gene expression and produced a shift in molecular subtype toward the claudin-low and normal-like groups. Luminal breast cancer cells that acquired resistance to the antiestrogen Tamoxifen showed greatly elevated levels of ELF5 and its transcriptional signature, and became dependent on ELF5 for proliferation, compared to the parental cells. Thus ELF5 provides a key transcriptional determinant of breast cancer molecular subtype by suppression of estrogen sensitivity in luminal breast cancer cells and promotion of basal characteristics in basal breast cancer cells, an action that may be utilised to acquire antiestrogen resistance

Emulating a trial of joint dynamic strategies: An application to monitoring and treatment of HIV-positive individuals

Decisions about when to start or switch a therapy often depend on the frequency with which individuals are monitored or tested. For example, the optimal time to switch antiretroviral therapy depends on the frequency with which HIV-positive individuals have HIV RNA measured. This paper describes an approach to use observational data for the comparison of joint monitoring and treatment strategies and applies the method to a clinically relevant question in HIV research: when can monitoring frequency be decreased and when should individuals switch from a first-line treatment regimen to a new regimen?. We outline the target trial that would compare the dynamic strategies of interest and then describe how to emulate it using data from HIV-positive individuals included in the HIV-CAUSAL Collaboration and the Centers for AIDS Research Network of Integrated Clinical Systems. When, as in our example, few individuals follow the dynamic strategies of interest over long periods of follow-up, we describe how to leverage an additional assumption: no direct effect of monitoring on the outcome of interest. We compare our results with and without the “no direct effect†assumption. We found little differences on survival and AIDS-free survival between strategies where monitoring frequency was decreased at a CD4 threshold of 350 cells/μl compared with 500 cells/μl and where treatment was switched at an HIV-RNA threshold of 1000 copies/ml compared with 200 copies/ml. The “no direct effect†assumption resulted in efficiency improvements for the risk difference estimates ranging from an 7- to 53-fold increase in the effective sample size

Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

Anaerobic oxidation of methane and its impact on iron and phosphorus cycling in marine sediments

Methane (CH4) represents one of the key compounds in the global carbon (C) cycle. A major proportion of the CH4 in the Earth system is produced in marine sediments by methanogenesis, the final step in the gradual fermentation of organic matter deposited on the seafloor. Once emitted to the atmosphere, CH4 acts as a powerful greenhouse gas. Despite high rates of methanogenesis in continental shelf and slope environments, the ocean today contributes only a relatively small amount of this potent greenhouse gas to the global atmospheric budget. The low atmospheric CH4 efflux from the ocean is largely due to the effective biological removal of dissolved CH4 through anaerobic oxidation with sulfate (SO42-) in marine sediments. This removal of pore water CH4 occurs within a distinct sulfate/methane transition zone (SMTZ), preventing the large amounts of CH4 generated in marine sediments from escaping to the water column. The relevant pathways and the environmental factors that control the rates of CH4 oxidation in marine sediments are, however, still incompletely understood. In some settings, for example, pore water CH4 is found throughout the SO42--bearing zone, pointing towards an inefficient CH4 oxidation by SO42- in certain marine environments. Other more recent findings further indicate that nitrate and nitrite, as well as metal oxides (e.g. manganese and iron (Fe) oxides) can enhance the conversion of CH4 to CO2 in the absence of oxygen. Sulfate may thus not be the only electron acceptor used by microorganisms to oxidize CH4 in anoxic sediments, but knowledge about the significance of additional electron acceptors for the global CH4 cycle is still lacking. In addition, little is known about how CH4 oxidation may impact the marine cycling of Fe and phosphorus (P), both key nutrients for oceanic phytoplankton. This thesis aims to refine our understanding of the potential impacts and controls of CH4 oxidation in marine sediments. In particular, it discusses how anaerobic oxidation of CH4 affects the sequestration and sedimentary records of Fe and P, using a wide range of geochemical tools. The results presented here also demonstrate that climate change and anthropogenic nutrient loading may alter the position and efficiency of the CH4 oxidation barrier in coastal sediments, which in turn could lead to increased atmospheric CH4 emissions from the coastal ocean

Civiele en fiscale bedrijfsopvolgingsfaciliteiten. Een praktijkonderzoek

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