Both Ligand- and Cell-Specific Parameters Control Ligand Agonism in a Kinetic Model of G Protein–Coupled Receptor Signaling

G protein–coupled receptors (GPCRs) exist in multiple dynamic states (e.g., ligand-bound, inactive, G protein–coupled) that influence G protein activation and ultimately response generation. In quantitative models of GPCR signaling that incorporate these varied states, parameter values are often uncharacterized or varied over large ranges, making identification of important parameters and signaling outcomes difficult to intuit. Here we identify the ligand- and cell-specific parameters that are important determinants of cell-response behavior in a dynamic model of GPCR signaling using parameter variation and sensitivity analysis. The character of response (i.e., positive/neutral/inverse agonism) is, not surprisingly, significantly influenced by a ligand's ability to bias the receptor into an active conformation. We also find that several cell-specific parameters, including the ratio of active to inactive receptor species, the rate constant for G protein activation, and expression levels of receptors and G proteins also dramatically influence agonism. Expressing either receptor or G protein in numbers several fold above or below endogenous levels may result in system behavior inconsistent with that measured in endogenous systems. Finally, small variations in cell-specific parameters identified by sensitivity analysis as significant determinants of response behavior are found to change ligand-induced responses from positive to negative, a phenomenon termed protean agonism. Our findings offer an explanation for protean agonism reported in β2-adrenergic and α2A-adrenergic receptor systems

History of Speech Communication and Communication Studies at Utah State University 1890-2000

This history of the Communications Department at USU, written by Emeritus Professor Harold J. Kinzer, covers early speech instruction at the University, the involvement of women in speech instructions, and the development of the Communications Department throughout University history. Biographies of select faculty are also included.https://digitalcommons.usu.edu/ua_faculty/1002/thumbnail.jp

A Cryogenic Infrared Calibration Target

A compact cryogenic calibration target is presented that has a peak diffuse reflectance, $R \le 0.003$, from $800-4,800\,{\rm cm}^{-1}$ $(12-2\,\mu$m). Upon expanding the spectral range under consideration to $400-10,000\,{\rm cm}^{-1}$ $(25-1\,\mu$m) the observed performance gracefully degrades to $R \le 0.02$ at the band edges. In the implementation described, a high-thermal-conductivity metallic substrate is textured with a pyramidal tiling and subsequently coated with a thin lossy dielectric coating that enables high absorption and thermal uniformity across the target. The resulting target assembly is lightweight, has a low-geometric profile, and has survived repeated thermal cycling from room temperature to $\sim4\,$K. Basic design considerations, governing equations, and test data for realizing the structure described are provided. The optical properties of selected absorptive materials -- Acktar Fractal Black, Aeroglaze Z306, and Stycast 2850 FT epoxy loaded with stainless steel powder -- are characterized and presented

Spectrum of the gamma-ray diffuse component observed from HEAO-1

The spectrum of the diffuse X and gamma ray background was measured between 15 keV and 4 MeV with the scintillation detectors aboard the HEAO 1 satellite. The apertures of the detectors were modulated on time scales of hours and the difference in counting rates measured the diffuse component flux. The observed spectrum is presented and compared with other measurements. At least two components are indicated, one below -100 keV and the other above. Possible origins are discussed

A Comparative Study of Educators\u27 Perceptions and Use of Mandated Reading Assessments

With the increasing emphasis on minimum competency testing has come a corresponding increase in mandated, district-wide testing programs. Results of such testing are oftn highly publicized, though perhaps not always completely understood. Yet, even though mandated tests have become an integral part of schooling in many areas of this country, we know little about specific testing practices

Search for gamma ray lines from SS433

Data obtained with the Gamma Ray Spectrometer (0.3 to 9 MeV) aboard the Solar Maximum Mission satellite from 1980 to 1985 for evidence of the reported Doppler shifted lines from SS433 were examined. The data base covers a total of 468 days when SS433 was in the field of view and includes times of quiescent and flaring radio activity. In 9 day integrations of the SMM data no evidence is found for gamma ray line emission from SS433. The 99% confidence upper limits for 9 day integrations of the shifted 1.37 and 6.1 MeV lines are 0.0013 gamma/sq cm-s and 0.0007 gamma/sq cm-s, respectively. The 360 day time averaged upper limits are 0.0002 gamma/sq cm-s x 0.0001 gamma/sq cm-s for both lines

Selective Protein Labelling to Visualize Cellular Differentiation

Protein post-translational modifications serve to give proteins new cellular function, spatial localization, or enzymatic activity. Myristoylation is a common post-translational modification where the enzyme N-myristoyltransferase adds myristic acid onto the N-terminus of a variety of proteins. In this work we use a myristic acid analog, 12-azidododecanoic acid (12ADA) to facilitate the implementation of azide-alkyne cycloaddition reactions on myristoylated proteins. Selective protein labeling methods such as these are useful in research because they can be used to help determine the biological function of this protein lipid modification and can be extended to study disregulated protein myristoylation in disease states. To validate 12ADA incorporation onto proteins, C2C12 myoblast cell lysates were reacted with an alkyne functionalized fluorophore and analyzed via SDS-PAGE. In order to visualize 12ADA tagged proteins in vivo, fixed C2C12 cells were reacted with an alkyne functionalized fluorophore and were imaged with a fluorescent microscope. The results clearly indicate selective protein tagging in in vitro lysates and in vivo. There is a distinct difference in the patterning of 12ADA protein tagging between differentiated and non-differentiated cells. The purpose of this research is to develop a selective protein labeling method. In our research, this selective protein labeling method is used to studying cellular differentiation in the context of developmental biology. Currently, there is not a clear understanding of the proteins associated with cellular differentiation related to development. Understanding this can allow scientists to track development progress and understand unique proteins associated with differentiating cells

Monte Carlo calibration of the SMM gamma ray spectrometer for high energy gamma rays and neutrons

The Gamma Ray Spectrometer (GRS) on the Solar Maximum Mission spacecraft was primarily designed and calibrated for nuclear gamma ray line measurements, but also has a high energy mode which allows the detection of gamma rays at energies above 10 MeV and solar neutrons above 20 MeV. The GRS response has been extrapolated until now for high energy gamma rays from an early design study employing Monte Carlo calculations. The response to 50 to 600 MeV solar neutrons was estimated from a simple model which did not consider secondary charged particles escaping into the veto shields. In view of numerous detections by the GRS of solar flares emitting high energy gamma rays, including at least two emitting directly detectable neutrons, the calibration of the high energy mode in the flight model has been recalculated by the use of more sophisticated Monte Carlo computer codes. New results presented show that the GRS response to gamma rays above 20 MeV and to neutrons above 100 MeV is significantly lower than the earlier estimates

Vertical distribution and feeding patterns of midwater fish in the central equatorial Atlantic

Fishes and zooplankton were obtained (March-April 1979 and partly in August 1974) from 45 hauls taken during the day and at night in the central equatorial Atlantic between Latitude 3 ~ and 2 ~ from the surface to 1250-m depth, using the RMT 1+8, a combined opening-closing plankton and micronekton trawl. The vertical distribution of 30 myctophid species is described. All species migrate in a diel pattern, Ceratoscopelus warmingii and Lampanyctus photonotus down to at least 1250 m. During daytime most species aggregated at 400- to 700-m depth, therefore only partly occupying the depth of the Deep Scattering Layer (400 to 500 m at 15 kHz). The feeding patterns of seven of the most abundant species were compared, with a total of 1 905 stomach contents being analysed. All seven species are regarded as opportunistic predators, which feed predominantly during the night on calanoid copepods. A total of 66 species of calanoid copepods were identified among the prey items, with smaller species definitely being in the minority. Stomachs of C. warmingii (700 to 1 250 m depth) and Lepidophanes guentheri (500 to 900 m depth) from daytime samples contained copepod species restricted to the upper 150 m of the water column, including Undinula vulgaris, Nannocalanus minor, and Euchaeta marina, thereby confirming an extended vertical migration of predators. Differences in diet and preferences between species in their total food spectrum are described