257 research outputs found
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
Deep Inelastic Scattering from off-Shell Nucleons
We derive the general structure of the hadronic tensor required to describe
deep-inelastic scattering from an off-shell nucleon within a covariant
formalism. Of the large number of possible off-shell structure functions we
find that only three contribute in the Bjorken limit. In our approach the usual
ambiguities encountered when discussing problems related to off-shellness in
deep-inelastic scattering are not present. The formulation therefore provides a
clear framework within which one can discuss the various approximations and
assumptions which have been used in earlier work. As examples, we investigate
scattering from the deuteron, nuclear matter and dressed nucleons. The results
of the full calculation are compared with those where various aspects of the
off-shell structure are neglected, as well as with those of the convolution
model.Comment: 36 pages RevTeX, 9 figures (available upon request), ADP-93-210/T128,
PSI-PR-93-13, accepted for publication in Physical Review
Crebinostat: A novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity
Long-term memory formation is known to be critically dependent upon de novo gene expression in the brain. As a consequence, pharmacological enhancement of the transcriptional processes mediating long-term memory formation provides a potential therapeutic strategy for cognitive disorders involving aberrant neuroplasticity. Here we focus on the identification and characterization of small molecule inhibitors of histone deacetylases (HDACs) as enhancers of CREB (cAMP response element-binding protein)-regulated transcription and modulators of chromatin-mediated neuroplasticity. Using a CREB reporter gene cell line, we screened a library of small molecules structurally related to known HDAC inhibitors leading to the identification of a probe we termed crebinostat that produced robust activation of CREB-mediated transcription. Further characterization of crebinostat revealed its potent inhibition of the deacetylase activity of recombinant class I HDACs 1, 2, 3, and class IIb HDAC6, with weaker inhibition of the class I HDAC8 and no significant inhibition of the class IIa HDACs 4, 5, 7, and 9. In cultured mouse primary neurons, crebinostat potently induced acetylation of both histone H3 and histone H4 as well as enhanced the expression of the CREB target gene Egr1 (early growth response 1). Using a hippocampus-dependent, contextual fear conditioning paradigm, mice systemically administered crebinostat for a ten day time period exhibited enhanced memory. To gain insight into the molecular mechanisms of memory enhancement by HDAC inhibitors, whole genome transcriptome profiling of cultured mouse primary neurons treated with crebinostat, combined with bioinformatic analyses of CREB-target genes, was performed revealing a highly connected protein–protein interaction network reflecting modules of genes important to synaptic structure and plasticity. Consistent with these findings, crebinostat treatment increased the density of synapsin-1 punctae along dendrites in cultured neurons. Finally, crebinostat treatment of cultured mouse primary neurons was found to upregulate Bdnf (brain-derived neurotrophic factor) and Grn (granulin) and downregulate Mapt (tau) gene expression—genes implicated in aging-related cognitive decline and cognitive disorders. Taken together, these results demonstrate that crebinostat provides a novel probe to modulate chromatin-mediated neuroplasticity and further suggests that pharmacological optimization of selective of HDAC inhibitors may provide an effective therapeutic approach for human cognitive disorders.National Institutes of Health (U.S.) (R01DA028301)National Institutes of Health (U.S.) (R01NS051874)Stanley Medical Research InstituteHoward Hughes Medical Institut
Coherent matter wave inertial sensors for precision measurements in space
We analyze the advantages of using ultra-cold coherent sources of atoms for
matter-wave interferometry in space. We present a proof-of-principle experiment
that is based on an analysis of the results previously published in [Richard et
al., Phys. Rev. Lett., 91, 010405 (2003)] from which we extract the ratio h/m
for 87Rb. This measurement shows that a limitation in accuracy arises due to
atomic interactions within the Bose-Einstein condensate
The effects of pressure, temperature, and concentration on the reactivity of alkanes: Experiments and modeling in a rapid compression machine
Decomposition of operator semigroups on W*-algebras
We consider semigroups of operators on a W-algebra and prove, under
appropriate assumptions, the existence of a Jacobs-DeLeeuw-Glicksberg type
decomposition. This decomposition splits the algebra into a "stable" and
"reversible" part with respect to the semigroup and yields, among others, a
structural approach to the Perron-Frobenius spectral theory for completely
positive operators on W-algebras.Comment: referee's comments incorporated. To appear in Semigroup Foru
Fitting the integrated Spectral Energy Distributions of Galaxies
Fitting the spectral energy distributions (SEDs) of galaxies is an almost
universally used technique that has matured significantly in the last decade.
Model predictions and fitting procedures have improved significantly over this
time, attempting to keep up with the vastly increased volume and quality of
available data. We review here the field of SED fitting, describing the
modelling of ultraviolet to infrared galaxy SEDs, the creation of
multiwavelength data sets, and the methods used to fit model SEDs to observed
galaxy data sets. We touch upon the achievements and challenges in the major
ingredients of SED fitting, with a special emphasis on describing the interplay
between the quality of the available data, the quality of the available models,
and the best fitting technique to use in order to obtain a realistic
measurement as well as realistic uncertainties. We conclude that SED fitting
can be used effectively to derive a range of physical properties of galaxies,
such as redshift, stellar masses, star formation rates, dust masses, and
metallicities, with care taken not to over-interpret the available data. Yet
there still exist many issues such as estimating the age of the oldest stars in
a galaxy, finer details ofdust properties and dust-star geometry, and the
influences of poorly understood, luminous stellar types and phases. The
challenge for the coming years will be to improve both the models and the
observational data sets to resolve these uncertainties. The present review will
be made available on an interactive, moderated web page (sedfitting.org), where
the community can access and change the text. The intention is to expand the
text and keep it up to date over the coming years.Comment: 54 pages, 26 figures, Accepted for publication in Astrophysics &
Space Scienc
Towards Ontologies of Functionality and Semantic Annotation for Technical Knowledge Management
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