1,3,4,6-Tetramethyl-1,4-dihydro-1,2,4,5-tetrazine, C_6H_(12)N_4

M_r =140∙19, monoclinic, P2_1/n, a = 10∙612(3), b=6∙820(1), c= 10∙975 (2) Å, β=95∙31(2)°, V=790.9(5) Å^3, Z=4, D_m=1.13(5) (flotation), D_x = 1∙177 g cm^(-3), Mo Kα, λ = 0.71073 Å, μ= 0.848 cm^(-1), F(000) = 304, T= 295 K, R = 0∙077 for 704 observed reflections. This potentially antiaromatic or homoaromatic ring system has a flattened boat conformation with both N-methyls in equatorial positions. Bond angles and distances (excluding H's) predicted to be symmetry equivalent exhibit variations of 0.002-0.014 Å and 0.0-2.0°. Substantial delocalization of the electron lone pairs of N(1) and N(4) is found

Performance of a 229 Thorium solid-state nuclear clock

The 7.8 eV nuclear isomer transition in 229 Thorium has been suggested as an etalon transition in a new type of optical frequency standard. Here we discuss the construction of a "solid-state nuclear clock" from Thorium nuclei implanted into single crystals transparent in the vacuum ultraviolet range. We investigate crystal-induced line shifts and broadening effects for the specific system of Calcium fluoride. At liquid Nitrogen temperatures, the clock performance will be limited by decoherence due to magnetic coupling of the Thorium nucleus to neighboring nuclear moments, ruling out the commonly used Rabi or Ramsey interrogation schemes. We propose a clock stabilization based on counting of flourescence photons and present optimized operation parameters. Taking advantage of the high number of quantum oscillators under continuous interrogation, a fractional instability level of 10^{-19} might be reached within the solid-state approach.Comment: 28 pages, 9 figure

ATLASGAL: 3-mm class I methanol masers in high-mass star formation regions

We analyzed the 3-mm wavelength spectral line survey of 408 ATLASGAL clumps observed with the IRAM 30m-telescope, focusing on the class I methanol masers with frequencies near 84, 95 and 104.3 GHz. We detect narrow, maser-like features towards 54, 100 and 4 sources in the maser lines near 84, 95 and 104.3 GHz, respectively. Among them, fifty 84 GHz masers, twenty nine 95 GHz masers and four rare 104.3 GHz masers are new discoveries. The new detections increase the number of known 104.3 GHz masers from 5 to 9. The 95 GHz class I methanol maser is generally stronger than the 84 GHz maser counterpart. We find 9 sources showing class I methanol masers but no SiO emission, indicating that class I methanol masers might be the only signpost of protostellar outflow activity in extremely embedded objects at the earliest evolutionary stage. Class I methanol masers that are associated with sources that show SiO line wings are more numerous and stronger than those without such wings. The total integrated intensity of class I methanol masers is well correlated with the integrated intensity and velocity coverage of the SiO (2--1) emission. The properties of class I methanol masers are positively correlated with the bolometric luminosity, clump mass, peak H$_2$ column density of their associated clumps but uncorrelated with the luminosity-to-mass ratio, dust temperature, and mean H$_2$ volume density. We suggest that the properties of class I masers are related to shocks traced by SiO. Based on our observations, we conclude that class I methanol masers at 84 and 95 GHz can trace a similar evolutionary stage as H$_2$O maser, and appear prior to 6.7 and 12.2 GHz methanol and OH masers. Despite their small number, the 104.3 GHz class I masers appear to trace a short and more evolved stage compared to the other class I masers. [abridged]Comment: 23 pages, 27 figures, 8 tables, accepted for publication in A&

Heightened Levels of Antimicrobial Response Factors in Patients With Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease leading to considerable disability over time. The disease can be characterized by the presence of multiple autoantibodies in the serum and synovial fluid. Microbial dysbiosis is proposed to play a role in the pathogenesis of RA. Increased systemic bacterial exposure leads to elevated levels of antimicrobial response factors (ARFs) in the circulation. In the present study, we tested whether RA patients have increased levels of ARFs by analyzing the levels of multiple ARFs in serum from RA patients and healthy age and sex-matched controls. The levels of soluble CD14 (sCD14), lysozyme, and CXCL16 were significantly elevated in RA patients compared to healthy controls. Lipopolysaccharide binding protein (LBP) levels remained unchanged in RA patients compared to healthy controls. A positive correlation of LBP with rheumatoid factor (RF) was also found in RA subjects. Interestingly, the levels of anti-endotoxin core antibodies (EndoCAb) IgM, total IgM, EndoCAb IgA, and total IgA were significantly elevated in RA patients compared to healthy controls. No significant changes in the levels of EndoCAb IgG and total IgG were observed in RA patients compared to healthy controls. Furthermore, lysozyme and CXCL16 levels were positively correlated with disease severity among RA subjects. Increases in the levels of several ARFs and their correlations with clinical indices suggest systemic microbial exposure in the RA cohort. Modulation of microbial exposure may play an important role in disease pathogenesis in individuals with RA

MicroRNA-26a Is Strongly Downregulated in Melanoma and Induces Cell Death through Repression of Silencer of Death Domains (SODD)

Melanoma is an aggressive cancer that metastasizes rapidly and is refractory to conventional chemotherapies. Identifying microRNAs (miRNAs) that are responsible for this pathogenesis is therefore a promising means of developing new therapies. We identified miR-26a through microarray and quantitative reverse-transcription–PCR (qRT-PCR) experiments as an miRNA that is strongly downregulated in melanoma cell lines as compared with primary melanocytes. Treatment of cell lines with miR-26a mimic caused significant and rapid cell death compared with a negative control in most melanoma cell lines tested. In surveying targets of miR-26a, we found that protein levels of SMAD1 (mothers against decapentaplegic homolog 1) and BAG-4/SODD were strongly decreased in sensitive cells treated with miR-26a mimic as compared with the control. The luciferase reporter assays further demonstrated that miR-26a can repress gene expression through the binding site in the 3′ untranslated region (3′UTR) of SODD (silencer of death domains). Knockdown of these proteins with small interfering RNA (siRNA) showed that SODD has an important role in protecting melanoma cells from apoptosis in most cell lines sensitive to miR-26a, whereas SMAD1 may have a minor role. Furthermore, transfecting cells with a miR-26a inhibitor increased SODD expression. Our findings indicate that miR-26a replacement is a potential therapeutic strategy for metastatic melanoma, and that SODD, in particular, is a potentially useful therapeutic target

Pilots for Space Tourism

This article sheds light on the key player needed for any space tourism adventure: the pilot who flies the spacecraft. The paper addresses the potential benefits of including a pilot at the controls when designing a space tourism spacecraft. It examines the basic qualifications and advanced skills required of space tourism pilots and discusses key training requirements for selected pilots and space pilots’ pay and benefits. In addition, the research concludes that, just as the pioneers of passenger transport in aviation entertained and captured the interest of their passengers, the space pilot should have the skills of a tour guide

The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase

AbstractBackground: The p38 mitogen-activated protein (MAP) kinase regulates signal transduction in response to environmental stress. Pyridinylimidazole compounds are specific inhibitors of p38 MAP kinase that block the production of the cytokines interleukin-1 β and tumor necrosis factor α, and they are effective in animal models of arthritis, bone resorption and endotoxin shock. These compounds have been useful probes for studying the physiological functions of the p38-mediated MAP kinase pathway.Results: We report the crystal structure of a novel pyridinylimidazole compound complexed with p38 MAP kinase, and we demonstrate that this compound binds to the same site on the kinase as does ATP. Mutagenesis showed that a single residue difference between p38 MAP kinase and other MAP kinases is sufficient to confer selectivity among pyridinylimidazole compounds.Conclusions: Our results reveal how pyridinylimidazole compounds are potent and selective inhibitors of p38 MAP kinase but not other MAP kinases. It should now be possible to design other specific inhibitors of activated p38 MAP kinase using the structure of the nonphosphorylated enzyme

The Atlantic Ocean at the last glacial maximum: 1. Objective mapping of the GLAMAP sea-surface conditions

Recent efforts of the German paleoceanographic community have resulted in a unique data set of reconstructed sea-surface temperature for the Atlantic Ocean during the Last Glacial Maximum, plus estimates for the extents of glacial sea ice. Unlike prior attempts, the contributing research groups based their data on a common definition of the Last Glacial Maximum chronozone and used the same modern reference data for calibrating the different transfer techniques. Furthermore, the number of processed sediment cores was vastly increased. Thus the new data is a significant advance not only with respect to quality, but also to quantity. We integrate these new data and provide monthly data sets of global sea-surface temperature and ice cover, objectively interpolated onto a regular 1°x1° grid, suitable for forcing or validating numerical ocean and atmosphere models. This set is compared to an existing subjective interpolation of the same base data, in part by employing an ocean circulation model. For the latter purpose, we reconstruct sea surface salinity from the new temperature data and the available oxygen isotope measurements

Nanoscale Mechanical Characterisation of Amyloid Fibrils Discovered in a Natural Adhesive

Using the atomic force microscope, we have investigated the nanoscale mechanical response of the attachment adhesive of the terrestrial alga Prasiola linearis (Prasiolales, Chlorophyta). We were able to locate and extend highly ordered mechanical structures directly from the natural adhesive matrix of the living plant. The in vivo mechanical response of the structured biopolymer often displayed the repetitive sawtooth force-extension characteristics of a material exhibiting high mechanical strength at the molecular level. Mechanical and histological evidence leads us to propose a mechanism for mechanical strength in our sample based on amyloid fibrils. These proteinaceous, pleated β-sheet complexes are usually associated with neurodegenerative diseases. However, we now conclude that the amyloid protein quaternary structures detected in our material should be considered as a possible generic mechanism for mechanical strength in natural adhesives