Benzo-fused Lactams from a Diversity-oriented Synthesis (DOS) Library as Inhibitors of Scavenger Receptor BI (SR-BI)-mediated Lipid Uptake

We report a new series of 8-membered benzo-fused lactams that inhibit cellular lipid uptake from HDL particles mediated by Scavenger Receptor, Class B, Type I (SR-BI). The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR), measuring the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is part of a previously reported diversity-oriented synthesis (DOS) library prepared via a build-couple-pair approach. Detailed structure–activity relationship (SAR) studies were performed with a selection of the original library, as well as additional analogs prepared via solution phase synthesis. These studies demonstrate that the orientation of the substituents on the aliphatic ring have a critical effect on activity. Additionally, a lipophilic group is required at the western end of the molecule, and a northern hydroxyl group and a southern sulfonamide substituent also proved to be optimal. Compound 2p was found to possess a superior combination of potency (av IC50 = 0.10 μM) and solubility (79 μM in PBS), and it was designated as probe ML312

Discovery of Bisamide-heterocycles as Inhibitors of Scavenger Receptor BI (SR-BI)-mediated Lipid Uptake

A new series of potent inhibitors of cellular lipid uptake from HDL particles mediated by scavenger receptor, class B, type I (SR-BI) was identified. The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) that measured the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is characterized by a linear peptidomimetic scaffold with two adjacent amide groups, as well as an aryl-substituted heterocycle. Analogs of the initial hit were rapidly prepared via Ugi 4-component reaction, and select enantiopure compounds were prepared via a stepwise sequence. Structure–activity relationship (SAR) studies suggest an oxygenated arene is preferred at the western end of the molecule, as well as highly lipophilic substituents on the central and eastern nitrogens. Compound 5e, with (R)-stereochemistry at the central carbon, was designated as probe ML279. Mechanistic studies indicate that ML279 stabilizes the interaction of HDL particles with SR-BI, and its effect is reversible. It shows good potency (IC50 = 17 nM), is non-toxic, plasma stable, and has improved solubility over our alternative probe ML278

Indolinyl-Thiazole Based Inhibitors of Scavenger Receptor-BI (SR-BI)-Mediated Lipid Transport

A potent class of indolinyl-thiazole based inhibitors of cellular lipid uptake mediated by scavenger receptor, class B, type I (SR-BI) was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) in an assay measuring the uptake of the fluorescent lipid DiI from HDL particles. This class of compounds is represented by ML278 (17–11), a potent (average IC50 = 6 nM) and reversible inhibitor of lipid uptake via SR-BI. ML278 is a plasma-stable, noncytotoxic probe that exhibits moderate metabolic stability, thus displaying improved properties for in vitro and in vivo studies. Strikingly, ML278 and previously described inhibitors of lipid transport share the property of increasing the binding of HDL to SR-BI, rather than blocking it, suggesting there may be similarities in their mechanisms of action

Hydrogen-related 3.8 eV UV luminescence in α-Ga2O3

Temperature-dependent photoluminescence was used to investigate the impact of H on the optical properties of α-Ga2O3 films grown by halide vapor phase epitaxy. An additional UV luminescence line centered at 3.8 eV is observed at low temperatures, which strongly correlates with the concentration of H in the films. This luminescence line is assigned to donor–acceptor pair recombination involving an H-related shallow donor and H-decorated Ga vacancy (VGa-nH) as the acceptor, where n = 1, 2, 3. Previous reports have already suggested the impact of H on the electrical properties of Ga2O3, and the present study shows its clear impact on the optical properties of α-Ga2O3

From inclusion to independence – Training consumers to review research

Health and medical research invariably impacts on the lives of everyday people. Organisations in the developed world are increasingly involving the public in health research projects, and research governance structures and processes. The form the involvement takes varies, as does the level of involvement, from individuals, to groups, to the wider community. Lay community members can be trained to independently review health and medical research, and wider societal involvement in funding decisions, can be effectively fostered. The theoretical foundation, design and development of a task based consumer-training program, including a number of enabling factors to support the success of such training are presented. This work is likely to be of value to those planning to train consumers in technical or complex areas

Impact of Excess Auditor Remuneration on the Cost of Equity Capital around the World

This study examines the relation between excess auditor remuneration and the implied required rate of return (IRR hereafter) on equity capital in global markets. We conjecture that when auditor remuneration is excessively large, investors may perceive the auditor to be economically bonded to the client, leading to a lack of independence. This perceived lack of independence increases the information risk associated with the credibility of financial statements, thereby increasing IRR. Consistent with this notion, we find that IRR is increasing in excess auditor remuneration, but only in countries with stronger investor protection. Finding evidence of a relation only in stronger investor protection countries is consistent with the more prominent role of audited financial statements for investors' decisions in these countries. In settings in which investors are less likely to rely on audited financial statements and instead rely on alternative sources of information (i.e., in countries with weaker investor protection), the impact of client-auditor bonding should have less of an effect on investors' decisions.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Sex-specific differences in the synaptonemal complex in the genus Oreochromis (Cichlidae)

Total synaptonemal complex (SC) lengths were estimated from Oreochromis aureus Steindachner (which has a WZ/ZZ sex determination system), O. mossambicus Peters and O. niloticus L. (both of which have XX/XY sex determination systems). The total SC length in oocytes was greater than that in spermatocytes in all three species (194±30 μm and 134±13 μm, 187±22 μm and 127±17 μm, 193±37 μm and 144±19 μm, respectively). These sex-specific differences did not appear to be influenced by the type of sex determination system (the female/male total SC length ratio was 1.45 in O. aureus, 1.47 in O. mossambicus and 1.34 in O. niloticus) and do not correlate with the lack of any overall sex-specific length differences in the current Oreochromis linkage map. Although based on data from relatively few species, there appears to be no consistent relationship between sex-specific SC lengths and linkage map lengths in fish. Neomale (hormonally masculinized genetic female) O. aureus and O. mossambicus had total SC lengths of 138±13 μm and 146±13 μm respectively, more similar to normal males than to normal females. These findings agree with data from other vertebrate species that suggest that phenotypic sex, rather than genotype, determines traits such as total SC length, chiasmata position and recombination pattern, at least for the autosomes

Identification of upper thermal thresholds during development in the endangered Nechako white sturgeon with management implications for a regulated river

Climate change-induced warming effects are already evident in river ecosystems, and projected increases in temperature will continue to amplify stress on fish communities. In addition, many rivers globally are impacted by dams, which have many negative effects on fishes by altering flow, blocking fish passage, and changing sediment composition. However, in some systems, dams present an opportunity to manage river temperature through regulated releases of cooler water. For example, there is a government mandate for Kenney dam operators in the Nechako river, British Columbia, Canada, to maintain river temperature <20°C in July and August to protect migrating sockeye salmon (Oncorhynchus nerka). However, there is another endangered fish species inhabiting the same river, Nechako white sturgeon (Acipenser transmontanus), and it is unclear if these current temperature regulations, or timing of the regulations, are suitable for spawning and developing sturgeon. In this study, we aimed to identify upper thermal thresholds in white sturgeon embryos and larvae to investigate if exposure to current river temperatures are playing a role in recruitment failure. We incubated embryos and yolk-sac larvae in three environmentally relevant temperatures (14, 18 and 21°C) throughout development to identify thermal thresholds across different levels of biological organization. Our results demonstrate upper thermal thresholds at 21°C across physiological measurements in embryo and yolk-sac larvae white sturgeon. Before hatch, both embryo survival and metabolic rate were reduced at 21°C. After hatch, sublethal consequences continued at 21°C because larval sturgeon had decreased thermal plasticity and a dampened transcriptional response during development. In recent years, the Nechako river has reached 21°C by the end of June, and at this temperature, a decrease in sturgeon performance is evident in most of the traits measured. As such, the thermal thresholds identified here suggest current temperature regulations may not be suitable for developing white sturgeon and future recruitment

Evapotranspiration estimation considering anthropogenic heat based on remote sensing in urban area

Urbanization influences hydrologic cycle significantly on local, regional even global scale. With urbanization the water resources demand for dense population sharpened, thus it is a great challenge to ensure water supply for some metropolises such as Beijing. Urban area is traditionally considered as the area with lower evapotranspiration (ET) on account of the impervious surface and the lower wind speed. For most remote sensing models, the ET, defined as latent heat in energy budget, is estimated as the difference between net radiation and sensible heat. The sensible heat is generally higher in urban area due to the high surface temperature caused by heat island, therefore the latent heat (i.e. the ET) in urban area is lower than that in other region. We estimated water consumption from 2003 to 2012 in Beijing based on water balance method and found that the annual mean ET in urban area was about 654 mm. However, using Surface Energy Balance System (SEBS) model, the annual mean ET in urban area was only 348 mm. We attributed this inconsistence to the impact of anthropogenic heat and quantified this impact on the basis of the night-light maps. Therefore, a new model SEBS-Urban, coupling SEBS model and anthropogenic heat was developed to estimate the ET in urban area. The ET in urban area of Beijing estimated by SEBS-Urban showed a good agreement with the ET from water balance method. The findings from this study highlighted that anthropogenic heat should be included in the surface energy budget for a highly urbanized area

Terminal valuations, growth rates and the implied cost of capital

This article is published with open access at Springerlink.comWe develop a model based on the notion that prices lead earnings, allowing for a simultaneous estimation of the implied growth rate and the cost of equity capital for US industrial sectors. The major difference between our approach and that in prior literature is that ours avoids the necessity to make assumptions about terminal values and consequently about future growth rates. In fact, growth rates are an endogenous variable, which is estimated simultaneously with the implied cost of equity capital. Since we require only 1-year-ahead forecasts of earnings and no assumptions about dividend payouts, our methodology allows us to estimate ex ante aggregate growth and risk premia over a larger sample of firms than has previously been possible. Our estimate of the risk premium being between 3.1 and 3.9 % is at the lower end of recent estimates, reflecting the inclusion of these short-lived companies. Our estimate of the long run growth is from 4.2 to 4.7 %