Transducin is a prototypic heterotrimeric G-protein mediating visual signaling in vertebrate photoreceptor cells. Despite its central role in phototransduction, little is known about the mechanisms that regulate its expression and maintain approximately stoichiometric levels of the ␣-and ␥-subunits. Here we demonstrate that the knock-out of transducin ␥-subunit leads to a major downregulation of both ␣-and -subunit proteins, despite nearly normal levels of the corresponding transcripts, and fairly rapid photoreceptor degeneration. Significant fractions of the remaining ␣-and -subunits were mislocalized from the light-sensitive outer segment compartment of the rod. Yet, the tiny amount of the ␣-subunit present in the outer segments of knock-out rods was sufficient to support light signaling, although with a markedly reduced sensitivity. These data indicate that the ␥-subunit controls the expression level of the entire transducin heterotrimer and that heterotrimer formation is essential for normal transducin localization. They further suggest that the production of transducin -subunit without its constitutive ␥-subunit partner sufficiently stresses the cellular biosynthetic and/or chaperone machinery to induce cell death.
The rate of synaptic transmission between photoreceptors and bipolar cells has been long known to depend on conditions of ambient illumination. However, the molecular mechanisms that mediate and regulate transmission at this ribbon synapse are poorly understood. We conducted electroretinographic recordings from dark-and light-adapted mice lacking the abundant photoreceptor-specific protein phosducin and found that the ON-bipolar cell responses in these animals have a reduced light sensitivity in the dark-adapted state. Additional desensitization of their responses, normally caused by steady background illumination, was also diminished compared with wild-type animals. This effect was observed in both rod-and cone-driven pathways, with the latter affected to a larger degree. The underlying mechanism is likely to be photoreceptor specific because phosducin is not expressed in other retina neurons and transgenic expression of phosducin in rods of phosducin knock-out mice rescued the rod-specific phenotype. The underlying mechanism functions downstream from the phototransduction cascade, as evident from the sensitivity of phototransduction in phosducin knock-out rods being affected to a much lesser degree than b-wave responses. These data indicate that a major regulatory component responsible for setting the sensitivity of signal transmission between photoreceptors and ON-bipolar cells is confined to photoreceptors and that phosducin participates in the underlying molecular mechanism.
BackgroundThis paper presents a case study that demonstrates the evolution of a project entitled "Enhancing QUality-of-care In Psychosis" (EQUIP) that began approximately when the U.S. Department of Veterans Affairs' Quality Enhancement Research Initiative (QUERI), and implementation science were emerging. EQUIP developed methods and tools to implement chronic illness care principles in the treatment of schizophrenia, and evaluated this implementation using a small-scale controlled trial. The next iteration of the project, EQUIP-2, was further informed by implementation science and the use of QUERI tools.MethodsThis paper reports the background, development, results and implications of EQUIP, and also describes ongoing work in the second phase of the project (EQUIP-2). The EQUIP intervention uses implementation strategies and tools to increase the adoption and implementation of chronic illness care principles. In EQUIP-2, these strategies and tools are conceptually grounded in a stages-of-change model, and include clinical and delivery system interventions and adoption/implementation tools. Formative evaluation occurs in conjunction with the intervention, and includes developmental, progress-focused, implementation-focused, and interpretive evaluation.ResultsEvaluation of EQUIP provided an understanding of quality gaps and how to address related problems in schizophrenia. EQUIP showed that solutions to quality problems in schizophrenia differ by treatment domain and are exacerbated by a lack of awareness of evidence-based practices. EQUIP also showed that improving care requires creating resources for physicians to help them easily implement practice changes, plus intensive education as well as product champions who help physicians use these resources. Organizational changes, such as the addition of care managers and informatics systems, were shown to help physicians with identifying problems, making referrals, and monitoring follow-up. In EQUIP-2, which is currently in progress, these initial findings were used to develop a more comprehensive approach to implementing and evaluating the chronic illness care model.DiscussionIn QUERI, small-scale projects contribute to the development and enhancement of hands-on, action-oriented service-directed projects that are grounded in current implementation science. This project supports the concept that QUERI tools can be useful in implementing complex care models oriented toward evidence-based improvement of clinical care.
This report is a replication of a study conducted 10 years ago by Person et al., investigating gender differences in sexual behaviors and fantasies in a college population. We found that men continue to fantasize more than women, but the gender differences have narrowed. Recent sexual experiences of our population show a trend toward an increase in gender differences, and there is a greater correlation between sexual fantasy and experiences in women than in men. As in Person's study, we did not find that men had more aggressive/sadistic fantasies than women.
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