Negative Effect of Smoking on the Performance of the QuantiFERON TB Gold in Tube Test.

False negative and indeterminate Interferon Gamma Release Assay (IGRA) results are a well documented problem. Cigarette smoking is known to increase the risk of tuberculosis (TB) and to impair Interferon-gamma (IFN-γ) responses to antigenic challenge, but the impact of smoking on IGRA performance is not known. The aim of this study was to evaluate the effect of smoking on IGRA performance in TB patients in a low and high TB prevalence setting respectively. Patients with confirmed TB from Denmark (DK, n = 34; 20 smokers) and Tanzania (TZ, n = 172; 23 smokers) were tested with the QuantiFERON-TB Gold In tube (QFT). Median IFN-γ level in smokers and non smokers were compared and smoking was analysed as a risk factor for false negative and indeterminate QFT results. Smokers from both DK and TZ had lower IFN-γ antigen responses (median 0.9 vs. 4.2 IU/ml, p = 0.04 and 0.4 vs. 1.6, p < 0.01), less positive (50 vs. 86%, p = 0.03 and 48 vs. 75%, p < 0.01) and more false negative (45 vs. 0%, p < 0.01 and 26 vs. 11%, p = 0.04) QFT results. In Tanzanian patients, logistic regression analysis adjusted for sex, age, HIV and alcohol consumption showed an association of smoking with false negative (OR 17.1, CI: 3.0-99.1, p < 0.01) and indeterminate QFT results (OR 5.1, CI: 1.2-21.3, p = 0.02). Cigarette smoking was associated with false negative and indeterminate IGRA results in both a high and a low TB endemic setting independent of HIV status

Precessional cyclicity of seawater Pb isotopes in the late Miocene Mediterranean

Astronomical tuning in the Mediterranean region is primarily based on organically‐mediated proxies, such as cyclicity of organic rich layers or changes in foraminiferal assemblages. Both during and post deposition, organic proxies can be affected by complex processes not immediately related to the changes in precession (insolation) they are assumed to reflect. Here we present an isotopic proxy which exhibits precessional cyclicity yet is inorganic. Seawater lead (Pb) isotope records over four precessional cycles between 6.6 and 6.5 Ma, from bulk sediment leachates of three Messinian, circum‐Mediterranean marginal locations, show variations consistent with precessional cyclicity. During insolation minima, the Pb isotope signatures from all three sites converge to similar values, suggesting a regional process is affecting all three locations at that time. Data from the marginal sites are compared with new data from ODP Site 978 and published data from a variety of geological archives from the Mediterranean region to determine the mechanism(s) causing the observed variability. While the comparisons are not fully conclusive, the timing of events suggest that increased dust production from North Africa during insolation minima is the most likely control. This hypothesis implies that authigenic marine Pb isotope records have the potential to provide a reliable inorganic tie point for Mediterranean cyclostratigraphy where sub‐precessional resolution is required. An inorganic tie point could also provide the means to resolve long‐standing problems in Mediterranean stratigraphy on precessional and sub‐precessional timescales which have been obscured due to post‐depositional changes (e.g., sapropel burn‐down) or suboptimal ecological conditions (e.g., the Messinian Salinity Crisis)

Southern Ocean bottom-water cooling and ice sheet expansion during the middle Miocene climate transition

The middle Miocene climate transition (MMCT), around 14 Ma, was associated with a significant climatic shift, but the mechanisms triggering the event remain enigmatic. We present a clumped isotope (Δ47) bottom-water temperature (BWT) record from 16.0 to 12.2 Ma from Ocean Drilling Program (ODP) Site 747 in the Southern Ocean and compare it to existing BWT records from different latitudes. We show that BWTs in the Southern Ocean reached 8–10 ∘C during the Miocene climatic optimum. These high BWT values indicate considerably warmer bottom-water conditions than today. Nonetheless, bottom-water δ18O (calculated from foraminiferal δ18O and Δ47) suggests substantial amounts of land ice throughout the interval of the study. Our dataset further demonstrates that BWTs at Site 747 were variable with an overall cooling trend across the MMCT. Notably, a cooling of around 3–5 ∘C preceded the stepped main increase in benthic δ18O, interpreted as global ice volume expansion, and appears to have been followed by a transient bottom-water warming starting during or slightly after the main ice volume increase. We speculate that a regional freshening of the upper water column at this time may have increased stratification and reduced bottom-water heat loss to the atmosphere, counteracting global cooling in the bottom waters of the Southern Ocean and possibly even at larger scales. Feedbacks required for substantial ice growth and/or tectonic processes may have contributed to the observed decoupling of global ice volume and Southern Ocean BWT.publishedVersio

Precessional variability of 87 Sr/86 Sr in the late Miocene Sorbas Basin: An interdisciplinary study of drivers of interbasin exchange

We present the first subprecessional record of seawater 87Sr/86Sr isotope ratios for a marginal Mediterranean subbasin. The sediments contained in this interval (three precessional cycles between 6.60 and 6.55 Ma) are important because they record conditions during the transition to the Messinian Salinity Crisis (MSC; 5.97 to 5.33 Ma), an event for which many details are still poorly understood. The record, derived from planktic foraminifera of the late Miocene Sorbas Basin (SE Spain), shows brief excursions with precessional cyclicity to 87Sr/86Sr ratios higher than coeval ocean 87Sr/86Sr. The hydrologic conditions required to generate the observed record are investigated using box modeling, constrained using a new paleodepth estimate (150 to 250 m) based on benthic foraminiferal assemblages. The box model results highlight the role of climate‐driven interbasin density contrast as a significant driver of, or impediment to, exchange. The results are particularly significant in the context of the MSC, where 87Sr/86Sr excursions have been interpreted purely as a consequence of physical restriction. To replicate the observed temporal patterns of lithological variations and 87Sr/86Sr isotope excursions, the Sorbas Basin “box” must have a mainly positive hydrologic budget, in contrast with the Mediterranean's negative budget during the late Miocene. This result has implications for the assumption of synchronous deposition of specific sedimentary layers (sapropels) between marginal and open Mediterranean settings at subprecessional resolution. A net positive hydrologic budget in marginal Mediterranean subbasins may reconcile observations of freshwater inclusions in gypsum deposits

Profiles of Global Gene Expression in Ionizing-Radiation–Damaged Human Diploid Fibroblasts Reveal Synchronization behind the G(1) Checkpoint in a G(0)-like State of Quiescence

Cell cycle arrest and stereotypic transcriptional responses to DNA damage induced by ionizing radiation (IR) were quantified in telomerase-expressing human diploid fibroblasts. Analysis of cytotoxicity demonstrated that 1.5 Gy IR inactivated colony formation by 40–45% in three fibroblast lines; this dose was used in all subsequent analyses. Fibroblasts exhibited > 90% arrest of progression from G(2) to M at 2 hr post-IR and a similarly severe arrest of progression from G(1) to S at 6 and 12 hr post-IR. Normal rates of DNA synthesis and mitosis 6 and 12 hr post-IR caused the S and M compartments to empty by > 70% at 24 hr. Global gene expression was analyzed in IR-treated cells. A microarray analysis algorithm, EPIG, identified nine IR-responsive patterns of gene expression that were common to the three fibroblast lines, including a dominant p53-dependent G(1) checkpoint response. Many p53 target genes, such as CDKN1A, GADD45, BTG2, and PLK3, were significantly up-regulated at 2 hr post-IR. Many genes whose expression is regulated by E2F family transcription factors, including CDK2, CCNE1, CDC6, CDC2, MCM2, were significantly down-regulated at 24 hr post-IR. Numerous genes that participate in DNA metabolism were also markedly repressed in arrested fibroblasts apparently as a result of cell synchronization behind the G(1) checkpoint. However, cluster and principal component analyses of gene expression revealed a profile 24 hr post-IR with similarity to that of G(0) growth quiescence. The results reveal a highly stereotypic pattern of response to IR in human diploid fibroblasts that reflects primarily synchronization behind the G(1) checkpoint but with prominent induction of additional markers of G(0) quiescence such as GAS1

A multi-proxy stalagmite record indicates a shift in forcing of twentieth century drought events in Normandy

Drought events are increasingly impacting Europe. The study of past droughts helps disentangle the different factors that trigger hydrological drought, helping to forecast future drought severity. Here we identify the historical drought events of the twentieth and twenty-first centuries in geochemical records of a stalagmite from Caumont cave in Northern France and develop a mechanistic understanding of their root causes. Subannually-resolved stable carbon isotope (δ13C) and trace element data are directly compared with historical climatic records. δ13C, Mg, and Sr peaks align well with most of the historical drought events of the twentieth and twenty-first centuries. The comparison reveals a good correspondence between summer effective rainfall and δ13C, Mg, and Sr concentrations. Further comparison of geochemical records with the precipitation-evapotranspiration index (SPEI) reveals a change in the drought forcings for the past two decades. During most of the twentieth century, droughts appear driven by a pluvial regime, whereas since the late 1990s, drought was driven by higher evapotranspiration due to increased temperature