Inhibitors of oestrogen biosynthesis: preclinical studies with CGS 16949A, a new nonsteroidal aromatase inhibitor

Inhibitors of the aromatase enzyme represent a class of therapeutic agents which potently inhibit oestrogen biosynthesis in vivo. This inhibition of oestrogen biosynthesis is well established as effective therapy in the treatment of oestrogen-dependent breast cancer. CGS 16949A [4-(5,6,7,8-tetrahydroimidazo-[l,5-a]pyridin-5-yl)-benzonitrile hydrochloride] is a non-steroidal imidazole derivative which is a potent competitive aromatase inhibitor in vitro. At a maximally effective concentration, it selectively inhibits aromatase and does not affect glucocorticoid production from the adrenal in vitro. In vivo in the rat, CGS 16949A effectively reduces ovarian oestrogen content and potently inhibits an aromatase-mediated androgen-induced uterine hypertrophy. Oral treatment of adult, cyclic female rats with CGS 16949A disrupts cyclicity, inhibits ovulation, reduces uterine weight and suppresses serum oestradiol, all expected sequelae of oestrogen deprivation. At maximally effective doses, there is no evidence of adrenal hypertrophy, indicating that adrenal steroidogenesis is unaffected. In the DMBA-induced mammary carcinoma model in the rat, CGS 16949A caused almost complete regression of palpable tumours and significantly suppressed the appearance of new tumours at a maximally effective oral dose. Thus, CGS 16949A is a potent and selective inhibitor of the aromatase enzyme. In the rat, it is very efficacious in inhibiting oestrogen biosynthesis and in suppressing the growth of DMBA-induced mammary tumour

Identification and quantification of microplastics in wastewater using focal plane array-based reflectance micro-FT-IR imaging

Microplastics (<5 mm) have been documented in environmental samples on a global scale. While these pollutants may enter aquatic environments via wastewater treatment facilities, the abundance of microplastics in these matrices has not been investigated. Although efficient methods for the analysis of microplastics in sediment samples and marine organisms have been published, no methods have been developed for detecting these pollutants within organic-rich wastewater samples. In addition, there is no standardized method for analyzing microplastics isolated from environmental samples. In many cases, part of the identification protocol relies on visual selection before analysis, which is open to bias. In order to address this, a new method for the analysis of microplastics in wastewater was developed. A pretreatment step using 30% hydrogen peroxide (H2O2) was employed to remove biogenic material, and focal plane array (FPA)-based reflectance micro-Fourier-transform (FT-IR) imaging was shown to successfully image and identify different microplastic types (polyethylene, polypropylene, nylon-6, polyvinyl chloride, polystyrene). Microplastic-spiked wastewater samples were used to validate the methodology, resulting in a robust protocol which was nonselective and reproducible (the overall success identification rate was 98.33%). The use of FPA-based micro-FT-IR spectroscopy also provides a considerable reduction in analysis time compared with previous methods, since samples that could take several days to be mapped using a single-element detector can now be imaged in less than 9 h (circular filter with a diameter of 47 mm). This method for identifying and quantifying microplastics in wastewater is likely to provide an essential tool for further research into the pathways by which microplastics enter the environment.This work is funded by a NERC (Natural Environment Research Council) CASE studentship (NE/K007521/1) with contribution from industrial partner Fera Science Ltd., United Kingdom. The authors would like to thank Peter Vale, from Severn Trent Water Ltd, for providing access to and additionally Ashley Howkins (Brunel University London) for providing travel and assistance with the sampling of the Severn Trent wastewater treatment plant in Derbyshire, UK. We are grateful to Emma Bradley and Chris Sinclair for providing helpful suggestions for our research

Independent measurement of the total active B8 solar neutrino flux using an array of He3 proportional counters at the Sudbury Neutrino Observatory

The Sudbury Neutrino Observatory (SNO) used an array of 3He proportional counters to measure the rate of neutral-current interactions in heavy water and precisely determined the total active (νx) 8B solar neutrino flux. This technique is independent of previous methods employed by SNO. The total flux is found to be 5.54-0.31+0.33(stat)-0.34+0.36(syst)×106  cm-2 s-1, in agreement with previous measurements and standard solar models. A global analysis of solar and reactor neutrino results yields Δm2=7.59-0.21+0.19×10-5  eV2 and θ=34.4-1.2+1.3 degrees. The uncertainty on the mixing angle has been reduced from SNO’s previous results

Measurement of the rate of nu_e + d --> p + p + e^- interactions produced by 8B solar neutrinos at the Sudbury Neutrino Observatory

Solar neutrinos from the decay of $^8$B have been detected at the Sudbury Neutrino Observatory (SNO) via the charged current (CC) reaction on deuterium and by the elastic scattering (ES) of electrons. The CC reaction is sensitive exclusively to nu_e's, while the ES reaction also has a small sensitivity to nu_mu's and nu_tau's. The flux of nu_e's from ^8B decay measured by the CC reaction rate is \phi^CC(nu_e) = 1.75 +/- 0.07 (stat)+0.12/-0.11 (sys.) +/- 0.05(theor) x 10^6 /cm^2 s. Assuming no flavor transformation, the flux inferred from the ES reaction rate is \phi^ES(nu_x) = 2.39+/-0.34 (stat.)+0.16}/-0.14 (sys) x 10^6 /cm^2 s. Comparison of \phi^CC(nu_e) to the Super-Kamiokande Collaboration's precision value of \phi^ES(\nu_x) yields a 3.3 sigma difference, providing evidence that there is a non-electron flavor active neutrino component in the solar flux. The total flux of active ^8B neutrinos is thus determined to be 5.44 +/-0.99 x 10^6/cm^2 s, in close agreement with the predictions of solar models.Comment: 6 pages (LaTex), 3 figures, submitted to Phys. Rev. Letter

First Neutrino Observations from the Sudbury Neutrino Observatory

The first neutrino observations from the Sudbury Neutrino Observatory are presented from preliminary analyses. Based on energy, direction and location, the data in the region of interest appear to be dominated by 8B solar neutrinos, detected by the charged current reaction on deuterium and elastic scattering from electrons, with very little background. Measurements of radioactive backgrounds indicate that the measurement of all active neutrino types via the neutral current reaction on deuterium will be possible with small systematic uncertainties. Quantitative results for the fluxes observed with these reactions will be provided when further calibrations have been completed.Comment: Latex, 7 pages, 10 figures, Invited paper at Neutrino 2000 Conference, Sudbury, Canada, June 16-21, 2000 to be published in the Proceeding

Unique Interplay between Sugar and Lipid in Determining the Antigenic Potency of Bacterial Antigens for NKT Cells

Structural and biophysical studies reveal the induced-fit mechanism underlying the stringent specificity of invariant natural killer T cells for unique glycolipid antigens from the pathogen Streptococcus pneumoniae

The Impact of Advocacy Organizations on Low-Income Housing Policy in U.S. Cities

Financial support for affordable housing competes with many other municipal priorities. This work seeks to explain the variation in support for affordable housing among U.S. cities with populations of 100,000 or more. Using multivariate statistical analysis, this research investigates political explanations for the level of city expenditures on housing and community with a particular interest in the influence of housing advocacy organizations (AOs). Data for the model were gathered from secondary sources, including the U.S. Census and the National Center for Charitable Statistics. Among other results, the analysis indicates that, on average, the political maturity of AOs has a statistically significant, positive effect on local housing and community development expenditures

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs.

SeSAME/EAST syndrome is a multisystemic disorder in humans, characterised by seizures, sensorineural deafness, ataxia, developmental delay and electrolyte imbalance. It is exclusively caused by homozygous or compound heterozygous variations in the KCNJ10 gene. Here we describe a similar syndrome in two families belonging to the Malinois dog breed, based on clinical, neurological, electrodiagnostic and histopathological examination. Genetic analysis detected a novel pathogenic KCNJ10 c.986T>C (p.(Leu329Pro)) variant that is inherited in an autosomal recessive way. This variant has an allele frequency of 2.9% in the Belgian Malinois population, but is not found in closely related dog breeds or in dog breeds where similar symptoms have been already described. The canine phenotype is remarkably similar to humans, including ataxia and seizures. In addition, in half of the dogs clinical and electrophysiological signs of neuromyotonia were observed. Because there is currently no cure and treatment is nonspecific and unsatisfactory, this canine translational model could be used for further elucidating the genotype/phenotype correlation of this monogenic multisystem disorder and as an excellent intermediate step for drug safety testing and efficacy evaluations before initiating human studies

Genetic and Structural Basis for Selection of a Ubiquitous T Cell Receptor Deployed in Epstein-Barr Virus Infection

Despite the ∼1018 αβ T cell receptor (TCR) structures that can be randomly manufactured by the human thymus, some surface more frequently than others. The pinnacles of this distortion are public TCRs, which exhibit amino acid-identical structures across different individuals. Public TCRs are thought to result from both recombinatorial bias and antigen-driven selection, but the mechanisms that underlie inter-individual TCR sharing are still largely theoretical. To examine this phenomenon at the atomic level, we solved the co-complex structure of one of the most widespread and numerically frequent public TCRs in the human population. The archetypal AS01 public TCR recognizes an immunodominant BMLF1 peptide, derived from the ubiquitous Epstein-Barr virus, bound to HLA-A*0201. The AS01 TCR was observed to dock in a diagonal fashion, grasping the solvent exposed peptide crest with two sets of complementarity-determining region (CDR) loops, and was fastened to the peptide and HLA-A*0201 platform with residue sets found only within TCR genes biased in the public response. Computer simulations of a random V(D)J recombination process demonstrated that both TCRα and TCRβ amino acid sequences could be manufactured easily, thereby explaining the prevalence of this receptor across different individuals. Interestingly, the AS01 TCR was encoded largely by germline DNA, indicating that the TCR loci already comprise gene segments that specifically recognize this ancient pathogen. Such pattern recognition receptor-like traits within the αβ TCR system further blur the boundaries between the adaptive and innate immune systems