Radon and skin cancer in southwest England: an ecologic study

This is the author's post peer review version of the article. The final version is published in Epidemiology. 2012 Jan;23(1):44-52. doi: 10.1097/EDE.0b013e31823b6139.Radon, a naturally occurring radioactive gas, is a carcinogen that causes a small proportion of lung cancers among exposed populations. Theoretical models suggest that radon may also be a risk factor for skin cancer, but epidemiologic evidence for this relationship is weak. In this study, we investigated ecologic associations between environmental radon concentration and the incidence of various types of skin cancer

Effect of carbohydrate feeding on the bone metabolic response to running

Bone resorption is increased after running, with no change in bone formation. Feeding during exercise might attenuate this increase, preventing associated problems for bone. This study investigated the immediate and short-term bone metabolic responses to carbohydrate (CHO) feeding during treadmill running. Ten men completed two 7-day trials, once being fed CHO (8% glucose immediately before, every 20 min during, and immediately after exercise at a rate of 0.7 g CHO·kg body mass-1·h-1) and once being fed placebo (PBO). On day 4 of each trial, participants completed a 120-min treadmill run at 70% of maximal oxygen consumption (VO2 max). Blood was taken at baseline (BASE), immediately after exercise (EE), after 60 (R1) and 120 (R2) min of recovery, and on three follow-up days (FU1-FU3). Markers of bone resorption [COOH-terminal telopeptide region of collagen type 1 (β-CTX)] and formation [NH2-terminal propeptides of procollagen type 1 (P1NP)] were measured, along with osteocalcin (OC), parathyroid hormone (PTH), albumin-adjusted calcium (ACa), phosphate, glucagon-like peptide-2 (GLP-2), interleukin-6 (IL-6), insulin, cortisol, leptin, and osteoprotogerin (OPG). Area under the curve was calculated in terms of the immediate (BASE, EE, R1, and R2) and short-term (BASE, FU1, FU2, and FU3) responses to exercise. β-CTX, P1NP, and IL-6 responses to exercise were significantly lower in the immediate postexercise period with CHO feeding compared with PBO (β-CTX: P=0.028; P1NP: P=0.021; IL-6: P=0.036), although there was no difference in the short-term response (β-CTX: P=0.856; P1NP: P=0.721; IL-6: P=0.327). No other variable was significantly affected by CHO feeding during exercise. We conclude that CHO feeding during exercise attenuated the β-CTX and P1NP responses in the hours but not days following exercise, indicating an acute effect of CHO feeding on bone turnover

IL-4Rα Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis.

Dupilumab is a fully human antibody to interleukin-4 receptor α that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S. aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S. aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S. aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor α inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S. aureus

Walk on the wild side: estimating the global magnitude of visits to protected areas.

How often do people visit the world's protected areas (PAs)? Despite PAs covering one-eighth of the land and being a major focus of nature-based recreation and tourism, we don't know. To address this, we compiled a globally-representative database of visits to PAs and built region-specific models predicting visit rates from PA size, local population size, remoteness, natural attractiveness, and national income. Applying these models to all but the very smallest of the world's terrestrial PAs suggests that together they receive roughly 8 billion (8 x 109) visits/y-of which more than 80% are in Europe and North America. Linking our region-specific visit estimates to valuation studies indicates that these visits generate approximately US $600 billion/y in direct in-country expenditure and US$250 billion/y in consumer surplus. These figures dwarf current, typically inadequate spending on conserving PAs. Thus, even without considering the many other ecosystem services that PAs provide to people, our findings underscore calls for greatly increased investment in their conservation.This study was supported by The Natural Capital Project (http://www.naturalcapitalproject.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final published version. It first appeared at http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002074

The neurogenic basic helix–loop–helix transcription factor NeuroD6 confers tolerance to oxidative stress by triggering an antioxidant response and sustaining the mitochondrial biomass

Preserving mitochondrial mass, bioenergetic functions and ROS (reactive oxygen species) homoeostasis is key to neuronal differentiation and survival, as mitochondria produce most of the energy in the form of ATP to execute and maintain these cellular processes. In view of our previous studies showing that NeuroD6 promotes neuronal differentiation and survival on trophic factor withdrawal, combined with its ability to stimulate the mitochondrial biomass and to trigger comprehensive antiapoptotic and molecular chaperone responses, we investigated whether NeuroD6 could concomitantly modulate the mitochondrial biomass and ROS homoeostasis on oxidative stress mediated by serum deprivation. In the present study, we report a novel role of NeuroD6 as a regulator of ROS homoeostasis, resulting in enhanced tolerance to oxidative stress. Using a combination of flow cytometry, confocal fluorescence microscopy and mitochondrial fractionation, we found that NeuroD6 sustains mitochondrial mass, intracellular ATP levels and expression of specific subunits of respiratory complexes upon oxidative stress triggered by withdrawal of trophic factors. NeuroD6 also maintains the expression of nuclear-encoded transcription factors, known to regulate mitochondrial biogenesis, such as PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α), Tfam (transcription factor A, mitochondrial) and NRF-1 (nuclear respiratory factor-1). Finally, NeuroD6 triggers a comprehensive antioxidant response to endow PC12-ND6 cells with intracellular ROS scavenging capacity. The NeuroD6 effect is not limited to the classic induction of the ROS-scavenging enzymes, such as SOD2 (superoxide dismutase 2), GPx1 (glutathione peroxidase 1) and PRDX5 (peroxiredoxin 5), but also to the recently identified powerful ROS suppressors PGC-1α, PINK1 (phosphatase and tensin homologue-induced kinase 1) and SIRT1. Thus our collective results support the concept that the NeuroD6–PGC-1α–SIRT1 neuroprotective axis may be critical in co-ordinating the mitochondrial biomass with the antioxidant reserve to confer tolerance to oxidative stress

Structural basis for the RING catalyzed synthesis of K63 linked ubiquitin chains

This work was supported by grants from Cancer Research UK (C434/A13067), the Wellcome Trust (098391/Z/12/Z) and Biotechnology and Biological Sciences Research Council (BB/J016004/1).The RING E3 ligase catalysed formation of lysine 63 linked ubiquitin chains by the Ube2V2–Ubc13 E2 complex is required for many important biological processes. Here we report the structure of the RING domain dimer of rat RNF4 in complex with a human Ubc13~Ub conjugate and Ube2V2. The structure has captured Ube2V2 bound to the acceptor (priming) ubiquitin with Lys63 in a position that could lead to attack on the linkage between the donor (second) ubiquitin and Ubc13 that is held in the active “folded back” conformation by the RING domain of RNF4. The interfaces identified in the structure were verified by in vitro ubiquitination assays of site directed mutants. This represents the first view of the synthesis of Lys63 linked ubiquitin chains in which both substrate ubiquitin and ubiquitin-loaded E2 are juxtaposed to allow E3 ligase mediated catalysis.PostprintPeer reviewe

Cell-free (RNA) and cell-associated (DNA) HIV-1 and postnatal transmission through breastfeeding

<p>Introduction - Transmission through breastfeeding remains important for mother-to-child transmission (MTCT) in resource-limited settings. We quantify the relationship between cell-free (RNA) and cell-associated (DNA) shedding of HIV-1 virus in breastmilk and the risk of postnatal HIV-1 transmission in the first 6 months postpartum.</p> <p>Materials and Methods - Thirty-six HIV-positive mothers who transmitted HIV-1 by breastfeeding were matched to 36 non-transmitting HIV-1 infected mothers in a case-control study nested in a cohort of HIV-infected women. RNA and DNA were quantified in the same breastmilk sample taken at 6 weeks and 6 months. Cox regression analysis assessed the association between cell-free and cell-associated virus levels and risk of postnatal HIV-1 transmission.</p> <p>Results - There were higher median levels of cell-free than cell-associated HIV-1 virus (per ml) in breastmilk at 6 weeks and 6 months. Multivariably, adjusting for antenatal CD4 count and maternal plasma viral load, at 6 weeks, each 10-fold increase in cell-free or cell-associated levels (per ml) was significantly associated with HIV-1 transmission but stronger for cell-associated than cell-free levels [2.47 (95% CI 1.33–4.59) vs. aHR 1.52 (95% CI, 1.17–1.96), respectively]. At 6 months, cell-free and cell-associated levels (per ml) in breastmilk remained significantly associated with HIV-1 transmission but was stronger for cell-free than cell-associated levels [aHR 2.53 (95% CI 1.64–3.92) vs. 1.73 (95% CI 0.94–3.19), respectively].</p> <p>Conclusions - The findings suggest that cell-associated virus level (per ml) is more important for early postpartum HIV-1 transmission (at 6 weeks) than cell-free virus. As cell-associated virus levels have been consistently detected in breastmilk despite antiretroviral therapy, this highlights a potential challenge for resource-limited settings to achieve the UNAIDS goal for 2015 of eliminating vertical transmission. More studies would further knowledge on mechanisms of HIV-1 transmission and help develop more effective drugs during lactation.</p&gt

Hazy Blue Worlds:A Holistic Aerosol Model for Uranus and Neptune, Including Dark Spots

We present a reanalysis (using the Minnaert limb-darkening approximation) of visible/near-infrared (0.3 - 2.5 micron) observations of Uranus and Neptune made by several instruments. We find a common model of the vertical aerosol distribution that is consistent with the observed reflectivity spectra of both planets, consisting of: 1) a deep aerosol layer with a base pressure > 5-7 bar, assumed to be composed of a mixture of H2S ice and photochemical haze; 2) a layer of photochemical haze/ice, coincident with a layer of high static stability at the methane condensation level at 1-2 bar; and 3) an extended layer of photochemical haze, likely mostly of the same composition as the 1-2-bar layer, extending from this level up through to the stratosphere, where the photochemical haze particles are thought to be produced. For Neptune, we find that we also need to add a thin layer of micron-sized methane ice particles at ~0.2 bar to explain the enhanced reflection at longer methane-absorbing wavelengths. We suggest that methane condensing onto the haze particles at the base of the 1-2-bar aerosol layer forms ice/haze particles that grow very quickly to large size and immediately 'snow out' (as predicted by Carlson et al. 1988), re-evaporating at deeper levels to release their core haze particles to act as condensation nuclei for H2S ice formation. In addition, we find that the spectral characteristics of 'dark spots', such as the Voyager-2/ISS Great Dark Spot and the HST/WFC3 NDS-2018, are well modelled by a darkening or possibly clearing of the deep aerosol layer only.Comment: 58 pages, 23 figures, 4 table

Hazy Blue Worlds:A Holistic Aerosol Model for Uranus and Neptune, Including Dark Spots

We present a reanalysis (using the Minnaert limb-darkening approximation) of visible/near-infrared (0.3 - 2.5 micron) observations of Uranus and Neptune made by several instruments. We find a common model of the vertical aerosol distribution that is consistent with the observed reflectivity spectra of both planets, consisting of: 1) a deep aerosol layer with a base pressure > 5-7 bar, assumed to be composed of a mixture of H2S ice and photochemical haze; 2) a layer of photochemical haze/ice, coincident with a layer of high static stability at the methane condensation level at 1-2 bar; and 3) an extended layer of photochemical haze, likely mostly of the same composition as the 1-2-bar layer, extending from this level up through to the stratosphere, where the photochemical haze particles are thought to be produced. For Neptune, we find that we also need to add a thin layer of micron-sized methane ice particles at ~0.2 bar to explain the enhanced reflection at longer methane-absorbing wavelengths. We suggest that methane condensing onto the haze particles at the base of the 1-2-bar aerosol layer forms ice/haze particles that grow very quickly to large size and immediately 'snow out' (as predicted by Carlson et al. 1988), re-evaporating at deeper levels to release their core haze particles to act as condensation nuclei for H2S ice formation. In addition, we find that the spectral characteristics of 'dark spots', such as the Voyager-2/ISS Great Dark Spot and the HST/WFC3 NDS-2018, are well modelled by a darkening or possibly clearing of the deep aerosol layer only.Comment: 58 pages, 23 figures, 4 table

In situ epitaxial MgB2 thin films for superconducting electronics

A thin film technology compatible with multilayer device fabrication is critical for exploring the potential of the 39-K superconductor magnesium diboride for superconducting electronics. Using a Hybrid Physical-Chemical Vapor Deposition (HPCVD) process, it is shown that the high Mg vapor pressure necessary to keep the MgB$_2$ phase thermodynamically stable can be achieved for the {\it in situ} growth of MgB$_2$ thin films. The films grow epitaxially on (0001) sapphire and (0001) 4H-SiC substrates and show a bulk-like $T_c$ of 39 K, a $J_c$(4.2K) of $1.2 \times 10^7$ A/cm$^2$ in zero field, and a $H_{c2}(0)$ of 29.2 T in parallel magnetic field. The surface is smooth with a root-mean-square roughness of 2.5 nm for MgB$_2$ films on SiC. This deposition method opens tremendous opportunities for superconducting electronics using MgB$_2$