Towards More Precise Photometric Redshifts: Calibration Via CCD Photometry

We present the initial results from a deep, multi-band photometric survey of selected high Galactic latitude redshift fields. Previous work using the photographic data of Koo and Kron demonstrated that the distribution of galaxies in the multi-dimensional flux space U B R I is nearly planar. The position of a galaxy within this plane is determined by its redshift, luminosity and spectral type. Using recently acquired deep CCD photometry in existing, published redshift fields, we have redetermined the distribution of galaxies in this four-dimensional magnitude space. Furthermore, from our CCD photometry and the published redshifts, we have quantified the photometric-redshift relation within the standard AB magnitude system. This empirical relation has a measured dispersion of approximately 0.02 for z < 0.4. With this work we are reaching the asymptotic intrinsic dispersions that were predicted from simulated distributions of galaxy colors.Comment: submitted to the Astrophysical Journal Letter

In vitro activity profiling of Cumyl-PEGACLONE variants at the CB1 receptor : fluorination versus isomer exploration

Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest groups of new psychoactive substances monitored in Europe. SCRAs are known to typically exert higher cannabinoid activity than tetrahydrocannabinol from cannabis, thereby entailing a greater health risk. Both Cumyl-PEGACLONE and 5F-Cumyl-PEGACLONE were not controlled by the national legislation upon their first detection in Germany in 2016 and 2017, respectively, and have been linked to several fatalities. In this study, the CB1 receptor activity of these compounds, together with two newly synthesized structural isomers (Cumyl-PEGACLONE ethylbenzyl isomer and npropylphenyl isomer), was assessed using two different in vitro receptor-proximal bioassays, monitoring the recruitment of either β-arrestin2 (β-arr2) or a modified G protein (mini-Gαi) to the activated CB1 receptor. In terms of both potency and relative efficacy, Cumyl-PEGACLONE and 5F-Cumyl-PEGACLONE were found to exert strong CB1 activation, with sub-nanomolar EC50 values and efficacy values exceeding those of the reference agonist JWH-018 threefold (β-arr2 assay) or almost twofold (mini-Gαi assay). The ethylbenzyl and n-propylphenyl isomers exhibited a strongly reduced CB1 activity (EC50 values >100 nM; efficacy <40% relative to JWH-018), which is hypothesized to originate from steric hindrance in the ligand-binding pocket. None of the evaluated compounds exhibited significant biased agonism. In conclusion, the functional assays applied here allowed us to demonstrate that 5-fluorination of Cumyl-PEGACLONE is not linked to an intrinsically higher CB1 activation potential and that the ethylbenzyl and n-propylphenyl isomers yield a strongly reduced CB1 activation

Analyses of the oncogenic BRAFD594G variant reveal a kinase-independent function of BRAF in activating MAPK signaling

Class 3 mutations in B-Raf proto-oncogene, Ser/Thr kinase (BRAF), that result in kinase-impaired or kinase-dead BRAF have the highest mutation frequency in BRAF gene in lung adenocarcinoma. Several studies have reported that kinase-dead BRAF variants amplify mitogen-activated protein kinase (MAPK) signaling by dimerizing with and activating WT C-Raf proto-oncogene, Ser/Thr kinase (CRAF). However, the structural and functional principles underlying their activation remain elusive. Herein, using cell biology and various biochemical approaches, we established that variant BRAFD594G, a kinase-dead representative of class 3 mutation-derived BRAF variants, has a higher dimerization potential as compared with WT BRAF. Molecular dynamics simulations uncovered that the D594G substitution orients the αC-helix toward the IN position and extends the activation loop within the kinase domain, shifting the equilibrium toward the active, dimeric conformation, thus priming BRAFD594G as an effective allosteric activator of CRAF. We found that B/CRAF heterodimers are the most thermodynamically stable RAF dimers, suggesting that RAF heterodimers, and not homodimers, are the major players in determining the amplitude of MAPK signaling in cells. Additionally, we show that BRAFD594G:CRAF heterodimers bypass autoinhibitory P-loop phosphorylation, which might contribute to longer duration of MAPK pathway signaling in cancer cells. Last, we propose that the dimer interface of the BRAFD594G:CRAF heterodimer may represent a promising target in the design of novel anticancer therapeutics

The hydrogen effects on materials program at NIST-Boulder

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Strain-life testing in hydrogen; Adapting equipment for fully reversed loading of pressure vessel steels in hydrogen

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Highly trabeculated structure of the human endocardium underlies asymmetrical response to low-energy monophasic shocks

Novel low-energy defibrillation therapies are thought to be driven by virtual-electrodes (VEs), due to the interaction of applied monophasic electric shocks with fine-scale anatomical structures within the heart. Significant inter-species differences in the cardiac (micro)-anatomy exist, however, particularly with respect to the degree of endocardial trabeculations, which may underlie important differences in response to low-energy defibrillation protocols. Understanding the interaction of monophasic electric fields with the specific human micro-anatomy is therefore imperative in facilitating the translation and optimisation of these promising experimental therapies to the clinic. In this study, we sought to investigate how electric fields from implanted devices interact with the highly trabeculated human endocardial surface to better understand shock success in order to help optimise future clinical protocols. A bi-ventricular human computational model was constructed from high resolution (350 μm) ex-vivo MR data, including anatomically accurate endocardial structures. Monophasic shocks were applied between a basal right ventricular catheter and an exterior ground. Shocks of varying strengths were applied with both anodal [positive right ventricle (RV) electrode] and cathodal (negative RV electrode) polarities at different states of tissue refractoriness and during induced arrhythmias. Anodal shocks induced isolated positive VEs at the distal side of “detached” trabeculations, which rapidly spread into hyperpolarised tissue on the surrounding endocardial surfaces following the shock. Anodal shocks thus depolarised more tissue 10 ms after the shock than cathodal shocks where the propagation of activation from VEs induced on the proximal side of “detached” trabeculations was prevented due to refractory endocardium. Anodal shocks increased arrhythmia complexity more than cathodal shocks during failed anti-arrhythmia shocks. In conclusion, multiple detached trabeculations in the human ventricle interact with anodal stimuli to induce multiple secondary sources from VEs, facilitating more rapid shock-induced ventricular excitation compared to cathodal shocks. Such a mechanism may help explain inter-species differences in response to shocks and help to develop novel defibrillation strategies

Is microstructural homogeneity the answer to hydrogen embrittlement resistance?

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Combined high energy X-Ray diffraction and small-angle scattering measurements of strain, dislocation density and porosity near steel fatigue cracks grown in hydrogen

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A highly conserved complete accessory Escherichia coli type III secretion system 2 is widespread in bloodstream isolates of the ST69 lineage

The work was funded by the Scottish Executive via the Chief Scientists Office through the provision of a grant to establish the Scottish Healthcare Associated Infection Prevention Institute (SHAIPI). The funders had no role in the study design, data collection and interpretation, or the decision to submit the work for publication.Bacterial type III secretion systems (T3SSs) play an important role in pathogenesis of Gram-negative infections. Enteropathogenic and enterohemorrhagic Escherichia coli contain a well-defined T3SS but in addition a second T3SS termed E. coli T3SS 2 (ETT2) has been described in a number of strains of E. coli. The majority of pathogenic E. coli contain elements of a genetic locus encoding ETT2, but which has undergone significant mutational attrition rendering it without predicted function. Only a very few strains have been reported to contain an intact ETT2 locus. To investigate the occurrence of the ETT2 locus in strains of human pathogenic E. coli, we carried out genomic sequencing of 162 isolates obtained from patient blood cultures in Scotland. We found that 22 of 26 sequence type (ST) 69 isolates from this collection contained an intact ETT2 together with an associated eip locus which encodes putative secreted ETT2 effectors as well as eilA, a gene encoding a putative transcriptional regulator of ETT2 associated genes. Using a reporter gene for eilA activation, we defined conditions under which this gene was differentially activated. Analysis of published E. coli genomes with worldwide representation showed that ST69 contained an intact ETT2 in these strains as well. The conservation of the genes encoding ETT2 in human pathogenic ST69 strains strongly suggests it has importance in infection, although its exact functional role remains obscure.Publisher PDFPeer reviewe