TRPV1 antagonist activity of SB-705498 (
15) and its in vitro and in vivo activity are reported.
Small molecule antagonists of the vanilloid receptor TRPV1 (also known as VR1) are disclosed. ...Pyrrolidinyl ureas such as
8 and
15 (SB-705498) emerged as lead compounds following optimisation of the previously described urea SB-452533. Pharmacological studies using electrophysiological and FLIPR-Ca
2+-based assays showed that compounds such as
8 and
15 were potent antagonists versus the multiple chemical and physical modes of TRPV1 activation (namely capsaicin, acid and noxious heat). Furthermore,
15 possessed suitable developability properties to enable progression of this compound into in vivo studies and subsequently clinical development.
Nascap-2k is a modern spacecraft charging code, replacing the older codes NASA Charging Analyzer Program for GEosynchronous Orbit (NASCAP/GEO), NASA Charging Analyzer Program for Low-Earth Orbit ...(NASCAP/LEO), Potentials Of Large objects in the Auroral Region (POLAR), and Dynamic Plasma Analysis Code (DynaPAC). The code builds on the physical principles, mathematical algorithms, and user experience developed over three decades of spacecraft charging research. Capabilities include surface charging in geosynchronous and interplanetary orbits, sheath, and wake structure, and current collection in low-Earth orbits, and auroral charging. External potential structure and particle trajectories are computed using a finite element method on a nested grid structure and may be visualized within the Nascap-2k interface. Space charge can be treated either analytically, self-consistently with particle trajectories, or consistent with imported plume densities. Particle-in-cell (PIC) capabilities are available to study dynamic plasma effects. Auxiliary programs to Nascap-2k include Object Toolkit (for developing spacecraft surface models) and GridTool (for constructing nested grid structures around spacecraft models). The capabilities of the code are illustrated by way of four examples: charging of a geostationary satellite, self-consistent potentials for a negative probe in a low-Earth orbit spacecraft wake, potentials associated with thruster plumes, and PIC calculations of plasma effects on a very low frequency (about 1 to 20 kHz) antenna
VCAM-1 and ICAM-1 are endothelial adhesion molecules of the Ig gene superfamily that may participate in atherogenesis by promoting monocyte accumulation in the arterial intima. Both are expressed in ...regions predisposed to atherosclerosis and at the periphery of established lesions, while ICAM-1 is also expressed more broadly. To evaluate functions of VCAM-1 in chronic disease, we disrupted its fourth Ig domain, producing the murine Vcam1(D4D) allele. VCAM-1(D4D) mRNA and protein were reduced to 2-8% of wild-type allele (Vcam1(+)) levels but were sufficient to partially rescue the lethal phenotype of VCAM-1-null embryos. After crossing into the LDL receptor-null background, Vcam1(+/+) and Vcam1(D4D/D4D) paired littermates were generated from heterozygous intercrosses and fed a cholesterol-enriched diet for 8 weeks. The area of early atherosclerotic lesions in the aorta, quantified by en face oil red O staining, was reduced significantly in Vcam1(D4D/D4D) mice, although cholesterol levels, lipoprotein profiles, and numbers of circulating leukocytes were comparable to wild-type. In contrast, deficiency of ICAM-1 either alone or in combination with VCAM-1 deficiency did not alter nascent lesion formation. Therefore, although expression of both VCAM-1 and ICAM-1 is upregulated in atherosclerotic lesions, our data indicate that VCAM-1 plays a dominant role in the initiation of atherosclerosis.
Gene-environment interactions are important determinants of cancer risk. Traditionally, gene-environment interactions are thought to contribute to tumor-suppressor-gene penetrance by facilitating or ...inhibiting the acquisition of additional somatic mutations required for tumorigenesis. Here, we demonstrate that a distinctive type of gene-environment interaction can occur during development to enhance the penetrance of a tumor-suppressor-gene defect in the adult. Using rats carrying a germ-line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor-suppressor gene predisposed to uterine leiomyomas, we show that an early-life exposure to diethylstilbestrol during development of the uterus increased tumor-suppressor-gene penetrance from 65% to >90% and tumor multiplicity and size in genetically predisposed animals, but it failed to induce tumors in wild-type rats. This exposure was shown to impart a hormonal imprint on the developing uterine myometrium, causing an increase in expression of estrogen-responsive genes before the onset of tumors. Loss of function of the normal Tsc-2 allele remained the rate-limiting event for tumorigenesis; however, tumors that developed in exposed animals displayed an enhanced proliferative response to steroid hormones relative to tumors that developed in unexposed animals. These data suggest that exposure to environmental factors during development can permanently reprogram normal physiological tissue responses and thus lead to increased tumor-suppressor-gene penetrance in genetically susceptible individuals.
Measurements with coherent scattering of electromagnetic waves in plasmas of the National Spherical Torus Experiment indicate the existence of turbulent fluctuations in the range of wave numbers k ...perpendicular rho(e)=0.1-0.4, corresponding to a turbulence scale length nearly equal to the collisionless skin depth. Experimental observations and agreement with numerical results from a linear gyrokinetic stability code support the conjecture that the observed turbulence is driven by the electron-temperature gradient.
Complex field mapping is a powerful tool to characterize the optical performance of astronomical instruments, and has become the standard for characterizing heterodyne array cameras. Recently, an ...adaptation of the heterodyne beam mapping technique was demonstrated on a single pixel of a direct detector instrument. We present a novel measurement apparatus and data acquisition techniques to efficiently reconstruct the complex field pattern of individual pixels across a direct detector focal plane array. These techniques are scalable to high pixel counts as the technology maturation and scientific requirements push to larger arrays. For this demonstration, we used an engineering model of the low-frequency band of the APEX microwave kinetic inductance detector camera with a center frequency of <inline-formula><tex-math notation="LaTeX">\nu = {\text{350}}</tex-math></inline-formula> GHz. Amplitude and phase radiation patterns were measured from all 880 pixels of the test array in two orthogonal polarizations. We also discuss an updated postprocessing pipeline using the complex field data to characterize the optical performance of the array. Using the measured complex field pattern, we extract the co- and cross-polarization patterns and Gaussian beam parameters, and propagate the beam from the measurement plane to additional planes of interest across all pixels in the test array. Complex field measurements of direct detectors allow more precise characterization of beam parameters when compared to thermal measurements, particularly for individualized fitting in postprocessing not reliant on the accuracy of the probe system alignment. These techniques enable high-precision characterization of individualized beam parameters as well as the overall optical system to very large format arrays with modest computational processing power. These results demonstrate the diagnostic power of the presented measurement and analysis techniques.
Aims. We uncover the H2 flows in the Corona Australis molecular cloud and in particular identify the flows from the Coronet cluster. Methods. A deep, near-infrared H2v = 1–0 S(1), 2.122 μm-line, ...narrow-band imaging survey of the R CrA cloud core was carried out. The nature of all candidate-driving sources in the region was evaluated using data available from the literature and also by fitting the spectral energy distributions (SED) of each source either with an extincted photosphere or YSO model. Archival Spitzer-IRAC and MIPS data was used to obtain photometry, which was combined with USNO, 2MASS catalogs and millimeter photometry from the literature, to build the SEDs. We identify the best candidate-driving source for each outflow by comparing the flow properties, available proper motions, and the known/estimated properties of the driving sources. We also adopted the thumbrule of outflow power as proportional to source luminosity and inversely proportional to the source age to reach a consensus. Results. Continuum-subtracted, narrow-band images reveal several new Molecular Hydrogen emission-line Objects (MHOs). Together with previously known MHOs and Herbig-Haro objects we catalog at least 14 individual flow components of which 11 appear to be driven by the R CrA aggregate members. The flows originating in the Coronet cluster have lengths of ~0.1–0.2 pc. Eight out of nine submillimeter cores mapped in the Coronet cluster region display embedded stars driving an outflow component. Roughly 80% of the youngest objects in the Coronet are associated with outflows. The MHO flows to the west of the Coronet display lobes moving to the west and vice-versa, resulting in nondetections of the counter lobe in our deep imaging. We speculate that these counter flows may be experiencing a stunting effect in penetrating the dense central core. Conclusions. Although this work has reduced the ambiguities for many flows in the Coronet region, one of the brightest H2 feature (MHO2014) and a few fainter features in the region remain unassociated with a clear driving source. The flows from Coronet, therefore, continue to be interesting targets for future studies.
Hepatitis C virus (HCV) is the main cause of parenteral non-A, non-B hepatitis and serum can be tested for the virus itself by reverse-transcription polymerase chain amplificaton. What of the level ...of this viraemia? To find out if quantitative study of H CV RNA might be useful clinically we took advantage of participation in trials of interferon-α in patients with chronic HCV infection and applied a new assay, branched DNA (bDNA) signal amplification.
Paired serum and liver biopsy specimens from 47 patients with confirmed chronic HCV infection and evidence of HCV RNA in their serum were studied. The quantitative bDNA assay (detection limit 350000 equivalents/mL eq/mL) was positive in 34 sera (sensitivity 72%). Patients who acquired HCV infection by blood transfusion had a higher viraemia (median 2701 000 eq/mL, n=29) than health workers and intravenous drug users (635 000 eq/mL, n=13; p<0·01). Patients with a sustained complete response to interferon-α therapy had lower pre-treatment viraemia levels (median at bDNA cut-off, n=11) than complete responders who relapsed after the drug was stopped (1613 000 eq/mL, n=15; p<0·01) and non-responders (3066 000 eq/mL, n=20; p<0·01). High viraemia levels were not related to the histological diagnosis but were associated with lobular inflammation, lymphoid aggregates, and bileduct lesions.
These findings indicate that mode of acquisition is an important determinant of HCV viraemia and that patients with low HCV viraemia levels are more likely to respond to interferon in a sustained fashion.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBJE, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Lightning data, collected using a Boltek Storm Tracker system installed at Chilton, UK, were used to investigate the mean response of the ionospheric sporadic‐E layer to lightning strokes in a ...superposed epoch study. The lightning detector can discriminate between positive and negative lightning strokes and between cloud‐to‐ground (CG) and inter‐cloud (IC) lightning. Superposed epoch studies carried out separately using these subsets of lightning strokes as trigger events have revealed that the dominant cause of the observed ionospheric enhancement in the Es layer is negative cloud‐to‐ground lightning.
ABSTRACT We present the results of a search for astrophysical sources of brief transient neutrino emission using IceCube and DeepCore data acquired between 2012 May 15 and 2013 April 30. While the ...search methods employed in this analysis are similar to those used in previous IceCube point source searches, the data set being examined consists of a sample of predominantly sub-TeV muon-neutrinos from the Northern Sky (−5 ) obtained through a novel event selection method. This search represents a first attempt by IceCube to identify astrophysical neutrino sources in this relatively unexplored energy range. The reconstructed direction and time of arrival of neutrino events are used to search for any significant self-correlation in the data set. The data revealed no significant source of transient neutrino emission. This result has been used to construct limits at timescales ranging from roughly 1 s to 10 days for generic soft-spectra transients. We also present limits on a specific model of neutrino emission from soft jets in core-collapse supernovae.
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