Synthesis of (+)-Cortistatin A

Steroids have historically elicited attention from the chemical sciences owing to their utility in living systems, as well as their intrinsic and diverse beauty.1 The cortistatin family (Figure 1, 1-7 and others),2 a collection of unusual, marine 9-(10,19)-abeo-androstane steroids, is certainly no exception; aside from challenging stereochemistry and an odd bricolage of functional groups, the salient feature of these sponge metabolites is, inescapably, their biological activity. Cortistatin A, the most potent member of the small family, inhibits the proliferation of human umbilical vein endothelial cells (HUVECs, IC50) 1.8 nM), evidently with no general toxicity toward either healthy or cancerous cell lines (IC50(testing cells)/IC50(HUVECs) g 3300).2a From initial pharmacological studies, binding appears to occur reversibly, but to an unknown target, inhibiting the phosphorylation of an unidentified 110 kDa protein, and implying a pathway that may be unique to know

Adaptive thermal compensation of test masses in advanced LIGO

As the first generation of laser interferometric gravitational wave detectors near operation, research and development has begun on increasing the instrument's sensitivity while utilizing the existing infrastructure. In the Laser Interferometer Gravitational Wave Observatory (LIGO), significant improvements are being planned for installation in ~2007, increasing strain sensitivity through improved suspensions and test mass substrates, active seismic isolation, and higher input laser power. Even with the highest quality optics available today, however, finite absorption of laser power within transmissive optics, coupled with the tremendous amount of optical power circulating in various parts of the interferometer, result in critical wavefront deformations which would cripple the performance of the instrument. Discussed is a method of active wavefront correction via direct thermal actuation on optical elements of the interferometer. A simple nichrome heating element suspended off the face of an affected optic will, through radiative heating, remove the gross axisymmetric part of the original thermal distortion. A scanning heating laser will then be used to remove any remaining non-axisymmetric wavefront distortion, generated by inhomogeneities in the substrate's absorption, thermal conductivity, etc. A proof-of-principle experiment has been constructed at MIT, selected data of which are presented.Comment: 11 pages, 7 figures, submitted to Classical and Quantum Gravit

Alkali doping leads to charge-transfer salt formation in a two-dimensional metal–organic framework

Efficient charge transfer across metal–organic interfaces is a key physical process in modern organic electronics devices, and characterization of the energy level alignment at the interface is crucial to enable a rational device design. We show that the insertion of alkali atoms can significantly change the structure and electronic properties of a metal–organic interface. Coadsorption of tetracyanoquinodimethane (TCNQ) and potassium on a Ag(111) surface leads to the formation of a two-dimensional charge transfer salt, with properties quite different from those of the two-dimensional Ag adatom TCNQ metal–organic framework formed in the absence of K doping. We establish a highly accurate structural model by combination of quantitative X-ray standing wave measurements, scanning tunnelling microscopy, and density-functional theory (DFT) calculations. Full agreement between the experimental data and the computational prediction of the structure is only achieved by inclusion of a charge-transfer-scaled dispersion correction in the DFT, which correctly accounts for the effects of strong charge transfer on the atomic polarizability of potassium. The commensurate surface layer formed by TCNQ and K is dominated by strong charge transfer and ionic bonding and is accompanied by a structural and electronic decoupling from the underlying metal substrate. The consequence is a significant change in energy level alignment and work function compared to TCNQ on Ag(111). Possible implications of charge-transfer salt formation at metal–organic interfaces for organic thin-film devices are discussed

Anti-inflammatory effects of a casein hydrolysate and its peptide-enriched fractions on TNFα-challenged Caco-2 cells and LPS-challenged porcine colonic explants

Bioactive milk peptides are reported to illicit a range of physiological benefits and have been proposed as potential functional food ingredients. The objective of this study was to characterize the anti-inflammatory properties of sodium caseinate (NaCAS), its enzyme hydrolysate (EH) and peptide-enriched fractions (5 kDa retentate [R], 1 kDaR and 1 kDa permeate [P]), both in vitro using a Caco-2 cell line, and also ex vivo using a porcine colonic tissue explant system. Caco-2 cells were stimulated with tumour necrosis factor alpha (TNFα) and co-treated with casein hydrolysates for 24 h. Following this, interleukin (IL)-8 concentrations in the supernatant were measured using enzyme-linked immunosorbent assay. Porcine colonic tissue was stimulated with lipopolysaccharide and co-treated with casein hydrolysates for 3 h. The expression of a panel of inflammatory cytokines was measured using qPCR. While dexamethasone reduced the IL-8 concentration by 41.6%, the 1 kDaR and 1 kDaP fractions reduced IL-8 by 68.7% and 66.1%, respectively, relative to TNFα-stimulated Caco-2 cells (P < 0.05). In the ex vivo system, only the 1 kDaR fraction elicited a decrease in IL1-α, IL1-β, IL-8, TGF-β and IL-10 expression (P < 0.05). This study provides evidence that the bioactive peptides present in the 1 kDaR fraction of the NaCAS hydrolysate possess anti-inflammatory properties in vitro and ex vivo. Further in vivo analysis of the anti-inflammatory properties of the 1 kDaR is proposed

Direct experimental evidence for substrate adatom incorporation into a molecular overlayer

While the phenomenon of metal substrate adatom incorporation into molecular overlayers is generally believed to occur in several systems, the experimental evidence for this relies on the interpretation of scanning tunnelling microscopy (STM) images, which can be ambiguous and provides no quantitative structural information. We show that surface X- ray diffraction (SXRD) uniquely provides unambiguous identification of these metal adatoms. We present the results of a detailed structural study of the Au(111)-F4TCNQ system, combining surface characterisation by STM, low energy electron diffraction and soft X-ray photoelectron spectroscopy with quantitative experimental structural information from normal incidence X-ray standing waves (NIXSW) and SXRD, together with dispersion corrected density functional theory (DFT) calculations. Excellent agreement is found between the NIXSW data and the DFT calculations regarding the height and conformation of the adsorbed molecule, which has a twisted geometry rather than the previously supposed inverted bowl shape. SXRD measurements provide unequivocal evidence for the presence and location of Au adatoms, while the DFT calculations show this reconstruction to be strongly energetically favoured.Comment: 38 pages, 10 figure

Life cycle energy and carbon assessment of double skin façades for office refurbishments

In countries like the UK, the upkeep of existing buildings is where the greatest opportunities for achieving carbon reduction targets lie. Façades are the physical barriers between outdoors and indoors, and their upgrade can arguably be amongst the most effective interventions to improve the existing stock. Double Skin Façades (DSFs) represent a possible solution for low-carbon refurbishment due to their capability to reduce energy consumption, and the related carbon emissions, of the building they are applied to. Although much research exists on maximising the operational energy savings of DSFs, little is known about their life cycle performance. This article addresses such a knowledge gap through a comparative life cycle assessment between DSF refurbishments and an up-to-standard, single-skin alternative. This study adopts a parametric approach where 128 DSF configurations have been analysed through primary data. Energy and carbon (both operational and embodied) are the units assessed in this research. Results show that DSFs are more energy-efficient than single-skin in 98% of the cases, and more carbon-efficient in 85% of the cases. Not only does this study represent the first broad parametric approach to evaluating life cycle energy and carbon of DSFs within its given context, but it also informs environmentally-aware design and application of DSFs

Improved Imputation of Common and Uncommon Single Nucleotide Polymorphisms (SNPs) with a New Reference Set

Statistical imputation of genotype data is an important technique for analysis of genome-wide association studies (GWAS). We have built a reference dataset to improve imputation accuracy for studies of individuals of primarily European descent using genotype data from the Hap1, Omni1, and Omni2.5 human SNP arrays (Illumina). Our dataset contains 2.5-3.1 million variants for 930 European, 157 Asian, and 162 African/African-American individuals. Imputation accuracy of European data from Hap660 or OmniExpress array content, measured by the proportion of variants imputed with R^2^&#x3e;0.8, improved by 34%, 23% and 12% for variants with MAF of 3%, 5% and 10%, respectively, compared to imputation using publicly available data from 1,000 Genomes and International HapMap projects. The improved accuracy with the use of the new dataset could increase the power for GWAS by as much as 8% relative to genotyping all variants. This reference dataset is available to the scientific community through the NCBI dbGaP portal. Future versions will include additional genotype data as well as non-European populations