Wykorzystanie satelitów w rozsiewczej radiofonii i telewizji. Przegląd Zagadnień Łączności, 1971, nr 3 (102)

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Pharmacological Evaluation of the Long-Term Effects of Xanomeline on the M1 Muscarinic Acetylcholine Receptor

Xanomeline is a unique agonist of muscarinic receptors that possesses functional selectivity at the M1 and M4 receptor subtypes. It also exhibits wash-resistant binding to and activation of the receptor. In the present work we investigated the consequences of this type of binding of xanomeline on the binding characteristics and function of the M1 muscarinic receptor. Pretreatment of CHO cells that stably express the M1 receptor for 1 hr with increasing concentrations of xanomeline followed by washing and waiting for an additional 23 hr in control culture media transformed xanomeline-induced inhibition of [3H]NMS binding from monophasic to biphasic. The high-affinity xanomeline binding site exhibited three orders of magnitude higher affinity than in the case of xanomeline added directly to the binding assay medium containing control cells. These effects were associated with a marked decrease in maximal radioligand binding and attenuation of agonist-induced increase in PI hydrolysis and were qualitatively similar to those caused by continuous incubation of cells with xanomeline for 24 hr. Attenuation of agonist-induced PI hydrolysis by persistently-bound xanomeline developed with a time course that parallels the return of receptor activation by prebound xanomeline towards basal levels. Additional data indicated that blockade of the receptor orthosteric site or the use of a non-functional receptor mutant reversed the long-term effects of xanomeline, but not its persistent binding at an allosteric site. Furthermore, the long-term effects of xanomeline on the receptor are mainly due to receptor down-regulation rather than internalization

OSSOS. V. Diffusion in the Orbit of a High-perihelion Distant Solar System Object

We report the discovery of the minor planet 2013 SY$_{99}$, on an exceptionally distant, highly eccentric orbit. With a perihelion of 50.0 au, 2013 SY$_{99}$'s orbit has a semi-major axis of $730 \pm 40$ au, the largest known for a high-perihelion trans-Neptunian object (TNO), well beyond those of (90377) Sedna and 2012 VP$_{113}$. Yet, with an aphelion of $1420 \pm 90$ au, 2013 SY$_{99}$'s orbit is interior to the region influenced by Galactic tides. Such TNOs are not thought to be produced in the current known planetary architecture of the Solar System, and they have informed the recent debate on the existence of a distant giant planet. Photometry from the Canada-France-Hawaii Telescope, Gemini North and Subaru indicate 2013 SY$_{99}$ is $\sim 250$ km in diameter and moderately red in colour, similar to other dynamically excited TNOs. Our dynamical simulations show that Neptune's weak influence during 2013 SY$_{99}$'s perihelia encounters drives diffusion in its semi-major axis of hundreds of astronomical units over 4 Gyr. The overall symmetry of random walks in semi-major axis allow diffusion to populate 2013 SY$_{99}$'s orbital parameter space from the 1000-2000 au inner fringe of the Oort cloud. Diffusion affects other known TNOs on orbits with perihelia of 45 to 49 au and semi-major axes beyond 250 au, providing a formation mechanism that implies an extended population, gently cycling into and returning from the inner fringe of the Oort cloud.Comment: First reviewer report comments incorporated. Comments welcom

The Role of Innate APOBEC3G and Adaptive AID Immune Responses in HLA-HIV/SIV Immunized SHIV Infected Macaques

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

OSSOS. IV. DISCOVERY OF A DWARF PLANET CANDIDATE IN THE 9 : 2 RESONANCE WITH NEPTUNE

We report the discovery and orbit of a new dwarf planet candidate, 2015 RR245, by the Outer Solar System Origins Survey (OSSOS). The orbit of 2015 RR245 is eccentric (e = 0.586), with a semimajor axis near 82 au, yielding a perihelion distance of 34 au. 2015 RR245 has g - r = 0.59 +/- 0.11 and absolute magnitude H-r = 3.6 +/- 0.1; for an assumed albedo of p(V) = 12%, the object has a diameter of similar to 670. km. Based on astrometric measurements from OSSOS and Pan-STARRS1, we find that 2015 RR245 is securely trapped on ten-megayear timescales in the 9: 2 mean-motion resonance with Neptune. It is the first trans-Neptunian object (TNO) identified in this resonance. On hundred-megayear. timescales, particles in 2015 RR245-like orbits depart and sometimes return to the resonance, indicating that 2015 RR245 likely forms part of the long-lived metastable population of distant TNOs that drift between resonance sticking and actively scattering via gravitational encounters with Neptune. The discovery of a 9: 2 TNO stresses the role of resonances in the long-term evolution of objects in the scattering disk. and reinforces the view that distant resonances are heavily populated in the current solar system. This object further motivates detailed modeling of the transient sticking population.Peer reviewe

Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer

BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.United States. Dept. of Defense (Grant W81-XWH-13-1-0323)National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051