Interaction Between Allelic Variations in Vitamin D Receptor and Retinoid X Receptor Genes on Metabolic Traits

Low vitamin D status has been shown to be a risk factor for several metabolic traits such as obesity, diabetes and cardiovascular disease. The biological actions of 1, 25-dihydroxyvitamin D, are mediated through the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptor, gamma (RXRG). Hence, we examined the potential interactions between the tagging polymorphisms in the VDR (22 tag SNPs) and RXRG (23 tag SNPs) genes on metabolic outcomes such as body mass index, waist circumference, waist-hip ratio (WHR), high- and low-density lipoprotein (LDL) cholesterols, serum triglycerides, systolic and diastolic blood pressures and glycated haemoglobin in the 1958 British Birth Cohort (1958BC, up to n = 5,231). We used Multifactor- dimensionality reduction (MDR) program as a non-parametric test to examine for potential interactions between the VDR and RXRG gene polymorphisms in the 1958BC. We used the data from Northern Finland Birth Cohort 1966 (NFBC66, up to n = 5,316) and Twins UK (up to n = 3,943) to replicate our initial findings from 1958BC

Targeting Cislunar Near Rectilinear Halo Orbits for Human Space Exploration

Part of the challenge of charting a human exploration space architecture is finding locations to stage missions to multiple destinations. To that end, a specific subset of Earth-Moon halo orbits, known as Near Rectilinear Halo Orbits (NRHOs) are evaluated. In this paper, a systematic process for generating full ephemeris based ballistic NRHOs is outlined, different size NRHOs are examined for their favorability to avoid eclipses, the performance requirements for missions to and from NRHOs are calculated, and disposal options are evaluated. Combined, these studies confirm the feasibility of cislunar NRHOs to enable human exploration in the cislunar proving ground

Comparison of stainless and mild steel welding fumes in generation of reactive oxygen species

<p>Abstract</p> <p>Background</p> <p>Welding fumes consist of a wide range of complex metal oxide particles which can be deposited in all regions of the respiratory tract. The welding aerosol is not homogeneous and is generated mostly from the electrode/wire. Over 390,000 welders were reported in the U.S. in 2008 while over 1 million full-time welders were working worldwide. Many health effects are presently under investigation from exposure to welding fumes. Welding fume pulmonary effects have been associated with bronchitis, metal fume fever, cancer and functional changes in the lung. Our investigation focused on the generation of free radicals and reactive oxygen species from stainless and mild steel welding fumes generated by a gas metal arc robotic welder. An inhalation exposure chamber located at NIOSH was used to collect the welding fume particles.</p> <p>Results</p> <p>Our results show that hydroxyl radicals (^.OH) were generated from reactions with H₂O₂and after exposure to cells. Catalase reduced the generation of <b>^.</b>OH from exposed cells indicating the involvement of H₂O₂. The welding fume suspension also showed the ability to cause lipid peroxidation, effect O₂consumption, induce H₂O₂generation in cells, and cause DNA damage.</p> <p>Conclusion</p> <p>Increase in oxidative damage observed in the cellular exposures correlated well with <b>^.</b>OH generation in size and type of welding fumes, indicating the influence of metal type and transition state on radical production as well as associated damage. Our results demonstrate that both types of welding fumes are able to generate ROS and ROS-related damage over a range of particle sizes; however, the stainless steel fumes consistently showed a significantly higher reactivity and radical generation capacity. The chemical composition of the steel had a significant impact on the ROS generation capacity with the stainless steel containing Cr and Ni causing more damage than the mild steel. Our results suggest that welding fumes may cause acute lung injury. Since type of fume generated, particle size, and elapsed time after generation of the welding exposure are significant factors in radical generation and particle deposition these factors should be considered when developing protective strategies.</p

The streptococcal collagen-like protein-1 (Scl1) is a significant determinant for biofilm formation by group a Streptococcus

<p>Abstract</p> <p>Background</p> <p>Group A <it>Streptococcus </it>(GAS) is a human-specific pathogen responsible for a number of diseases characterized by a wide range of clinical manifestations. During host colonization GAS-cell aggregates or microcolonies are observed in tissues. GAS biofilm, which is an <it>in vitro </it>equivalent of tissue microcolony, has only recently been studied and little is known about the specific surface determinants that aid biofilm formation. In this study, we demonstrate that surface-associated streptococcal collagen-like protein-1 (Scl1) plays an important role in GAS biofilm formation.</p> <p>Results</p> <p>Biofilm formation by M1-, M3-, M28-, and M41-type GAS strains, representing an intraspecies breadth, were analyzed spectrophotometrically following crystal violet staining, and characterized using confocal and field emission scanning electron microscopy. The M41-type strain formed the most robust biofilm under static conditions, followed by M28- and M1-type strains, while the M3-type strains analyzed here did not form biofilm under the same experimental conditions. Differences in architecture and cell-surface morphology were observed in biofilms formed by the M1- and M41-wild-type strains, accompanied by varying amounts of deposited extracellular matrix and differences in cell-to-cell junctions within each biofilm. Importantly, all Scl1-negative mutants examined showed significantly decreased ability to form biofilm <it>in vitro</it>. Furthermore, the Scl1 protein expressed on the surface of a heterologous host, <it>Lactococcus lactis</it>, was sufficient to induce biofilm formation by this organism.</p> <p>Conclusions</p> <p>Overall, this work (i) identifies variations in biofilm formation capacity among pathogenically different GAS strains, (ii) identifies GAS surface properties that may aid in biofilm stability and, (iii) establishes that the Scl1 surface protein is an important determinant of GAS biofilm, which is sufficient to enable biofilm formation in the heterologous host <it>Lactococcus</it>. In summary, the GAS surface adhesin Scl1 may have an important role in biofilm-associated pathogenicity.</p

Interaction between allelic variations in vitamin D receptor and retinoid X receptor genes on metabolic traits

BACKGROUND: Low vitamin D status has been shown to be a risk factor for several metabolic traits such as obesity, diabetes and cardiovascular disease. The biological actions of 1, 25-dihydroxyvitamin D, are mediated through the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptor, gamma (RXRG). Hence, we examined the potential interactions between the tagging polymorphisms in the VDR (22 tag SNPs) and RXRG (23 tag SNPs) genes on metabolic outcomes such as body mass index, waist circumference, waist-hip ratio (WHR), high- and low-density lipoprotein (LDL) cholesterols, serum triglycerides, systolic and diastolic blood pressures and glycated haemoglobin in the 1958 British Birth Cohort (1958BC, up to n = 5,231). We used Multifactor- dimensionality reduction (MDR) program as a non-parametric test to examine for potential interactions between the VDR and RXRG gene polymorphisms in the 1958BC. We used the data from Northern Finland Birth Cohort 1966 (NFBC66, up to n = 5,316) and Twins UK (up to n = 3,943) to replicate our initial findings from 1958BC. RESULTS: After Bonferroni correction, the joint-likelihood ratio test suggested interactions on serum triglycerides (4 SNP - SNP pairs), LDL cholesterol (2 SNP - SNP pairs) and WHR (1 SNP - SNP pair) in the 1958BC. MDR permutation model testing analysis showed one two-way and one three-way interaction to be statistically significant on serum triglycerides in the 1958BC. In meta-analysis of results from two replication cohorts (NFBC66 and Twins UK, total n = 8,183), none of the interactions remained after correction for multiple testing (Pinteraction >0.17). CONCLUSIONS: Our results did not provide strong evidence for interactions between allelic variations in VDR and RXRG genes on metabolic outcomes; however, further replication studies on large samples are needed to confirm our findings

Raw Single-Wall Carbon Nanotubes Induce Oxidative Stress and Activate MAPKs, AP-1, NF-κB, and Akt in Normal and Malignant Human Mesothelial Cells

Background Single-wall carbon nanotubes (SWCNTs), with their unique physicochemical and mechanical properties, have many potential new applications in medicine and industry. There has been great concern subsequent to preliminary investigations of the toxicity, biopersistence, pathogenicity, and ability of SWCNTs to translocate to subpleural areas. These results compel studies of potential interactions of SWCNTs with mesothelial cells. Objective Exposure to asbestos is the primary cause of malignant mesothelioma in 80–90% of individuals who develop the disease. Because the mesothelial cells are the primary target cells of asbestos-induced molecular changes mediated through an oxidant-linked mechanism, we used normal mesothelial and malignant mesothelial cells to investigate alterations in molecular signaling in response to a commercially manufactured SWCNT. Methods In the present study, we exposed mesothelial cells to SWCNTs and investigated reactive oxygen species (ROS) generation, cell viability, DNA damage, histone H2AX phosphorylation, activation of poly(ADP-ribose) polymerase 1 (PARP-1), stimulation of extracellular signal-regulated kinase (ERKs), Jun N-terminal kinases (JNKs), protein p38, and activation of activator protein-1 (AP-1), nuclear factor κB (NF-κB), and protein serine-threonine kinase (Akt). Results Exposure to SWCNTs induced ROS generation, increased cell death, enhanced DNA damage and H2AX phosphorylation, and activated PARP, AP-1, NF-κB, p38, and Akt in a dose-dependent manner. These events recapitulate some of the key molecular events involved in mesothelioma development associated with asbestos exposure. Conclusions The cellular and molecular findings reported here do suggest that SWCNTs can cause potentially adverse cellular responses in mesothelial cells through activation of molecular signaling associated with oxidative stress, which is of sufficient significance to warrant in vivo animal exposure studies

Characterization of silver particles in the stratum corneum of healthy subjects and atopic dermatitis patients dermally exposed to a silver-containing garment

Silver is increasingly being used in garments to exploit its antibacterial properties. Information on the presence of silver nanoparticles (AgNPs) in garments and their in vivo penetration across healthy and impaired skin from use is limited. We investigated the presence of AgNPs in a silver containing garment and in the stratum corneum (SC) of healthy subjects (CTRLs) and individuals with atopic dermatitis (AD). Seven CTRLs and seven AD patients wore a silver sleeve (13% Ag w/w) 8 h/day for five days on a forearm and a placebo sleeve on the other forearm. After five days, the layers of the SC were collected by adhesive tapes. The silver particles in the garment and SC were characterized by scanning electron microscopy with energy dispersive X-ray analysis (SEM-EDX) and atomic force microscopy (AFM). AFM and SEM revealed the presence of sub-micrometre particles having a broad range of sizes (30\u2013500 nm) on the surface of the garment that were identified as silver. On the SC tapes collected from different depths, aggregates with a wide range of sizes (150 nm\u20132 \u3bcm) and morphologies were found. Most aggregates contained primarily silver, although some also contained chlorine and sulfur. There was no clear difference in the number or size of the aggregates observed in SC between healthy and AD subjects. After use, AgNPs and their aggregates were present in the SC at different depths of both healthy subjects and AD patients. Their micrometre size suggests that aggregation likely occurred in the SC

Definition of ambulatory blood pressure targets for diagnosis and treatment of hypertension in relation to clinic blood pressure: prospective cohort study

Background Twenty-four hour ambulatory blood pressure thresholds have been defined for the diagnosis of mild hypertension but not for its treatment or for other blood pressure thresholds used in the diagnosis of moderate to severe hypertension. We aimed to derive age and sex related ambulatory blood pressure equivalents to clinic blood pressure thresholds for diagnosis and treatment of hypertension