Theoretical studies of steroid hormones and related compounds

A theoretical study of steroidal inhibitors of the enzymes Glucose-6-Phosphate Dehydrogenase and Aromatase is presented. Both enzyme systems are of interest in the study of cancer, the latter being the final step in the biosynthesis of oestrogens which are involved in certain types of breast cancer. Two levels of theory are employed in the study, namely, Ab Initio and Semi Empirical methods. Structures and charges have been calculated using the MOPAC and GAUSSIAN programs and these have been used to model the efficacy of various inhibitors. The major tool in comparing these steroids has been the molecular electrostatic potential (MEP). Maps of the MEP and an analysis of the similarity between the MEP s of different molecules have led both to a method of assessing the activities of steroids as enzyme inhibitors and requirements for the electronic structure of the steroid binding sites within these enzymes. A molecular graphics display program has been developed to facilitate this work. It has been designed to make full use of the facilities available. The quality of the resulting display has improved greatly on what was previously available and has been of value in studies of large molecular systems. The program is written in VAX FORTRAN and uses the Graphics Kernel System (GKS) to produce graphical output and should be reasonably easy to transfer to other systems. Finally, to determine whether PM3 really is a significant advance on AM1, a comparison of the two semi empirical methods is presented. The calculated properties of steroid hormones are compared to those of both Ab Initio calculations and experimental determinations, allowing the quality of the semi empirical predictions to be assessed

A multi-institutional experience in adventitial cystic disease

AbstractBackgroundAdventitial cystic disease (ACD) is an unusual arteriopathy; case reports and small series constitute the available literature regarding treatment. We sought to examine the presentation, contemporary management, and long-term outcomes using a multi-institutional database.MethodsUsing a standardized database, 14 institutions retrospectively collected demographics, comorbidities, presentation/symptoms, imaging, treatment, and follow-up data on consecutive patients treated for ACD during a 10-year period, using Society for Vascular Surgery reporting standards for limb ischemia. Univariate and multivariate analyses were performed comparing treatment methods and factors associated with recurrent intervention. Life-table analysis was performed to estimate the freedom from reintervention in comparing the various treatment modalities.ResultsForty-seven patients (32 men, 15 women; mean age, 43 years) were identified with ACD involving the popliteal artery (n = 41), radial artery (n = 3), superficial/common femoral artery (n = 2), and common femoral vein (n = 1). Lower extremity claudication was seen in 93% of ACD of the leg arteries, whereas patients with upper extremity ACD had hand or arm pain. Preoperative diagnosis was made in 88% of patients, primarily using cross-sectional imaging of the lower extremity; mean lower extremity ankle-brachial index was 0.71 in the affected limb. Forty-one patients with lower extremity ACD underwent operative repair (resection with interposition graft, 21 patients; cyst resection, 13 patients; cyst resection with bypass graft, 5 patients; cyst resection with patch, 2 patients). Two patients with upper extremity ACD underwent cyst drainage without resection or arterial reconstruction. Complications, including graft infection, thrombosis, hematoma, and wound dehiscence, occurred in 12% of patients. Mean lower extremity ankle-brachial index at 3 months postoperatively improved to 1.07 (P < .001), with an overall mean follow-up of 20 months (range, 0.33-9 years). Eight patients (18%) with lower extremity arterial ACD required reintervention (redo cyst resection, one; thrombectomy, three; redo bypass, one; balloon angioplasty, three) after a mean of 70 days with symptom relief in 88%. Lower extremity patients who underwent cyst resection and interposition or bypass graft were less likely to require reintervention (P = .04). One patient with lower extremity ACD required an above-knee amputation for extensive tissue loss.ConclusionsThis multi-institutional, contemporary experience of ACD examines the treatment and outcomes of ACD. The majority of patients can be identified preoperatively; surgical repair, consisting of cyst excision with arterial reconstruction or bypass alone, provides the best long-term symptomatic relief and reduced need for intervention to maintain patency

From Sacred to Scientific: Epic Religion, Spectacular Science, and Charlton Heston’s Science Fiction Cinema

This paper analyses how long-1960s cinema responded to and framed public discourses surrounding religion and science. This approach allows for a discussion that extends beyond a critical study of the scholarly debates that surround the place of religion in science during a transitional period. Charlton Heston was an epic actor who went from literally playing God in The Ten Commandments (1956) to playing “god” as a messianic scientist in The Omega Man (1971). Best known for playing Moses, Heston became an unlikely science-based cinema star during the early 1970s. He was re-imagined as a scientist, but the religiosity of his established persona was inescapable. Heston and the science-based films he starred in capitalized upon the utopian promises of real science, and also the fears of the vocal activist counterculture. Planet of the Apes (1968), Omega Man (1971), Soylent Green (1973), and other science-based films made between 1968-1977 were bleak countercultural warnings about excessive consumerism, uncontrolled science, nuclear armament, irreversible environmental damage, and eventual human extinction. In this paper I argue that Heston’s transition from biblical epic star to science-fiction anti-hero represents the way in which the role and interpretation of science changed in post-classical cinema. Despite the shift from religious epic to science-based spectacle, religion remained a faithful component of Hollywood output indicating the ongoing connection between science and religion in US culture. I will consider the transition from sacred to science-based narratives and how religion was utilised across the production process of films that commented upon scientific advances

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice