Solution and displacement in monolayer and multilayer binary films of SF6 and CF4 on graphite.

Infrared reflection absorption spectroscopy is used to study the evolution of binary physisorbed films on graphite. A predeposited monolayer of SF6 is exposed to slowly increasing pressure of CF4 at constant temperature between 80 and 113 K. Shifts in the frequencies of the dominant vibrational mode of each species due to resonant dipole-dipole coupling serve as proxies for the areal density of each species in the monolayer. If the initial SF6 film is far below saturation (coexistence with bulk solid), the SF6 can be largely displaced by continuous solution of CF4. However, if the initial SF6 layer is at or near saturation, a layer of CF4 condenses on top at a well defined CF4 pressure after only 2%-3% dilution of the SF6 layer. Simultaneously, most of the dissolved CF4 is withdrawn from the SF6 layer. With further increase in CF4 pressure, the CF4 layer is compressed and additional layers condense, while the SF6 layer is again diluted. Still, the SF6 layer retains about 90% concentration until the CF4 pressure is very close to saturation, at which point the SF6 is rapidly displaced, apparently going into dilute solution in the rapidly growing CF4 multilayer. Monte Carlo simulations are used to quantitatively relate measured frequency shifts to concentrations in the binary monolayer.

Effect of vector asymmetry of radially polarized beams in solid immersion microscopy.

We theoretically and experimentally investigate the effect of imperfect vector symmetry on radially polarized beams focused by an aplanatic solid immersion lens at a numerical aperture of 3.3. We experimentally achieve circularly symmetric focused spot with a full-width-half-maximum of ~λ0/5.7 at λ0 = 1,310 nm, free-space wavelength. The tight spatial confinement and overall circular symmetry of the focused radially polarized beam are found to be sensitive to perturbations of its cylindrical polarization symmetry. The addition of a liquid crystal based variable retarder to the optical path can effectively ensure the vector symmetry and achieve circularly symmetric focused spots at such high numerical aperture conditions.

Radially polarized Bessel-Gauss beams: decentered Gaussian beam analysis and experimental verification.

We derive solutions for radially polarized Bessel-Gauss beams in free-space by superimposing decentered Gaussian beams with differing polarization states. We numerically show that the analytical result is applicable even for large semi-aperture angles, and we experimentally confirm the analytical expression by employing a fiber-based mode-converter.

The pre-clinical absorption, distribution, metabolism and excretion properties of IPI-926, an orally bioavailable antagonist of the hedgehog signal transduction pathway.

1. IPI-926 is a novel semisynthetic cyclopamine derivative that is a potent and selective Smoothened inhibitor that blocks the hedgehog signal transduction pathway. 2. The in vivo clearance of IPI-926 is low in mouse and dog and moderate in monkey. The volume of distribution is high across species. Oral bioavailability ranges from moderate in monkey to high in mouse and dog. Predicted human clearance using simple allometry is low (24 L h(-1)), predicted volume of distribution is high (469 L) and predicted half-life is long (20 h). 3. IPI-926 is highly bound to plasma proteins and has minimal interaction with human α-1-acid glycoprotein. 4. In vitro metabolic stability ranges from stable to moderately stable. Twelve oxidative metabolites were detected in mouse, rat, dog, monkey and human liver microsome incubations and none were unique to human. 5. IPI-926 is not a potent reversible inhibitor of CYP1A2, 2C8, 2C9 or 3A4 (testosterone). IPI-926 is a moderate inhibitor of CYP2C19, 2D6 and 3A4 (midazolam) with KI values of 19, 16 and 4.5 µM, respectively. IPI-926 is both a substrate and inhibitor (IC50 = 1.9 µM) of P-glycoprotein. 6. In summary, IPI-926 has desirable pre-clinical absorption, distribution, metabolism and excretion properties.

Acetylene frequency references in gas-filled hollow optical fiber and photonic microcells.

Gas-filled hollow optical fiber references based on the P(13) transition of the ν1+ν3 band of 12C2H2 promise portability with moderate accuracy and stability. Previous realizations are corrected (<1σ) by using proper modeling of a shift due to line-shape. To improve portability, a sealed photonic microcell is characterized on the 12C2H2 ν1+ν3 P(23) transition with somewhat reduced accuracy and stability. Effects of the photonic crystal fiber, including surface modes, are explored. Both polarization-maintaining (PM) and non-PM 7-cell photonic bandgap fiber are shown to be unsuitable for kilohertz-level frequency references.

Structure of plasmonic aerogel and the breakdown of the effective medium approximation.

A method for making aerogel doped with gold nanoparticles (GNPs) produces a composite material with a well-defined localized surface plasmon resonance peak at 520 nm. The width of the extinction feature indicates the GNPs are well dispersed in the aerogel, making it suited to optical study. A simple effective medium approximation cannot explain the peak extinction wavelengths. The plasmonic field extends on a scale where aerogel cannot be considered isotropic, so a new model is required: a 5 nm glass coating on the GNPs models the extinction spectrum of the composite material, with air (aerogel), methanol (alcogel), or toluene filling the pores.

Large-core acetylene-filled photonic microcells made by tapering a hollow-core photonic crystal fiber.

We report on kagomé-lattice photonic microcells with low losses, large outer diameters, and large cores. The large (40-70microm) cores are accommodated by tapering the fibers and splicing the reduced ends to a single-mode fiber. We demonstrate the repeatability of this process and obtain splice losses of 0.6dB by optimizing the taper transition length. Narrow electromagnetically induced transparencies and saturable absorption are demonstrated in an acetylene-filled photonic microcell.

Tapered fibers embedded in silica aerogel.

We have embedded thin tapered fibers (with diameters down to 1 microm) in silica aerogel with low loss. The aerogel is rigid but behaves refractively like air, protecting the taper without disturbing light propagation along it. This enables a new class of fiber devices exploiting volume evanescent interactions with the aerogel itself or with dopants or gases in the pores.

LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with Antitumor Activity.

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the formation of symmetric dimethylarginine in a number of nuclear and cytoplasmic proteins. Although the cellular functions of PRMT5 have not been fully unraveled, it has been implicated in a number of cellular processes like RNA processing, signal transduction, and transcriptional regulation. PRMT5 is ubiquitously expressed in most tissues and its expression has been shown to be elevated in several cancers including breast cancer, gastric cancer, glioblastoma, and lymphoma. Here, we describe the identification and characterization of a novel and selective PRMT5 inhibitor with potent in vitro and in vivo activity. Compound 1 (also called LLY-283) inhibited PRMT5 enzymatic activity in vitro and in cells with IC50 of 22 ± 3 and 25 ± 1 nM, respectively, while its diastereomer, compound 2 (also called LLY-284), was much less active. Compound 1 also showed antitumor activity in mouse xenografts when dosed orally and can serve as an excellent probe molecule for understanding the biological function of PRMT5 in normal and cancer cells.

Stereoselective synthesis of myo-inositol via ring-closing metathesis: a building block for glycosylphosphatidylinositol (GPI) anchor synthesis.

Here we report a concise stereoselective synthesis of myo-inositol via ring-closing metathesis. A readily available bis-Weinreb amide of D-tartrate served as a key intermediate. [reaction: see text]

The disruptive physician: a legal perspective.

RATIONALE AND OBJECTIVES: This article addresses the medical and legal implications of disruptive physician behavior. In addition, this article will address the appropriate use of due process in peer review of disruptive physician behavior. CONCLUSIONS: While most hospitals and even national organizations, like the American Medical Association, have definitions for what constitutes disruptive physician behavior, these definitions have been further examined and clarified in court rulings. These court rulings not only further clarify what constitutes disruptive behavior but also establish a threshold for revocation/nonrenewal of a physician's hospital privileges.

Emission and nonradiative decay of nanodiamond NV centers in a low refractive index environment.

The nitrogen vacancy (NV) center is the most widely studied single optical defect in diamond with great potential for applications in quantum technologies. Development of practical single-photon devices requires an understanding of the emission under a range of conditions and environments. In this work, we study the properties of a single NV center in nanodiamonds embedded in an air-like silica aerogel environment which provides a new domain for probing the emission behavior of NV centers in nanoscale environments. In this arrangement, the emission rate is governed primarily by the diamond crystal lattice with negligible contribution from the surrounding environment. This is in contrast to the conventional approach of studying nanodiamonds on a glass coverslip. We observe an increase in the mean lifetime due to the absence of a dielectric interface near the emitting dipoles and a distribution arising from the irregularities in the nanodiamond geometry. Our approach results in the estimation of the mean quantum efficiency (~0.7) of the nanodiamond NV emitters.

Porous silicon nanocrystals in a silica aerogel matrix.

Silicon nanoparticles of three types (oxide-terminated silicon nanospheres, micron-sized hydrogen-terminated porous silicon grains and micron-size oxide-terminated porous silicon grains) were incorporated into silica aerogels at the gel preparation stage. Samples with a wide range of concentrations were prepared, resulting in aerogels that were translucent (but weakly coloured) through to completely opaque for visible light over sample thicknesses of several millimetres. The photoluminescence of these composite materials and of silica aerogel without silicon inclusions was studied in vacuum and in the presence of molecular oxygen in order to determine whether there is any evidence for non-radiative energy transfer from the silicon triplet exciton state to molecular oxygen adsorbed at the silicon surface. No sensitivity to oxygen was observed from the nanoparticles which had partially H-terminated surfaces before incorporation, and so we conclude that the silicon surface has become substantially oxidised. Finally, the FTIR and Raman scattering spectra of the composites were studied in order to establish the presence of crystalline silicon; by taking the ratio of intensities of the silicon and aerogel Raman bands, we were able to obtain a quantitative measure of the silicon nanoparticle concentration independent of the degree of optical attenuation.

Update on multidetector computed tomography angiography of the abdominal aorta.

Multidetector computed tomography angiography (MDCTA) allows high spatial resolution, including nearly isotropic submillimeter resolution in the X, Y, and Z planes, and rapid image acquisition in a single breath hold, with greatly enhanced diagnostic capabilities over conventional CT. MDCTA has largely replaced digital subtraction angiography because it is faster, less invasive, and provides more information. When technical parameters are optimized, it provides the radiologist with the information needed to diagnose life threatening diseases of the aortoiliac system, gives critical information for the vascular surgeon or interventional radiologist to treat that disease, and identifies subsequent complications related to therapy. This article briefly discusses the technical components and optimization of MDCTA of the abdominal aorta and iliac arteries (aortoiliac system) and examines the diseases of the aortoiliac system evaluated by MDCTA.

Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926).

Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.

Synthesis of lipidated green fluorescent protein and its incorporation in supported lipid bilayers.

Herein we report a semisynthetic method of producing membrane-anchored proteins. Ligation of synthetic lipids with designed anchor structures to proteins was performed using native chemical ligation (NCL) of a C-terminal peptide thioester and an N-terminal cysteine lipid. This strategy mimics the natural glycosylphosphatidylinositol (GPI) linkage found in many natural membrane-associated proteins; however, the synthetic method utilizes simple lipid anchors without glycans. Synthetically lipidated recombinant green fluorescent protein (GFP) was shown to be stably anchored to the membrane, and its lateral fluidity was quantitatively characterized by direct fluorescence imaging in supported membranes. Circumventing the steps of purification from native cell membranes, this methodology facilitates the reconstitution of membrane-associated proteins.

Homogeneous glycopeptides and glycoproteins for biological investigation.

Protein glycosylation is widely recognized as a modulator of protein structure, localization, and cell-cell recognition in multicellular systems. Glycoproteins are typically expressed as mixtures of glycoforms, their oligosaccharides being generated by a template-independent biosynthetic process. Investigation of their function has been greatly assisted by sources of homogeneous material. This review summarizes current efforts to obtain homogeneous glycopeptide and glycoprotein materials by a variety of methods that draw from the techniques of recombinant expression, chemical synthesis, enzymatic transformation, and chemoselective ligation. Some of these techniques remove obstacles to glycoprotein synthesis by installing nonnative linkages and other modifications for facilitated assembly. The end purpose of the described approaches is the production of glycosylated materials for experiments relevant to the biological investigation of glycoproteins, although the strategies presented apply to other posttranslational modifications as well.