Most inherited forms of blindness are caused by mutations that lead to photoreceptor cell death but spare second-and third-order retinal neurons. Expression of the light-gated excitatory mammalian ion channel light-gated ionotropic glutamate receptor (LiGluR) in retinal ganglion cells (RGCs) of the retina degeneration (rd1) mouse model of blindness was previously shown to restore some visual functions when stimulated by UV light. Here, we report restored retinal function in visible light in rodent and canine models of blindness through the use of a second-generation photoswitch for LiGluR, maleimide-azobenzene-glutamate 0 with peak efficiency at 460 nm (MAG0 460 ). In the blind rd1 mouse, multielectrode array recordings of retinal explants revealed robust and uniform lightevoked firing when LiGluR-MAG0 460 was targeted to RGCs and robust but diverse activity patterns in RGCs when LiGluR-MAG0 460 was targeted to ON-bipolar cells (ON-BCs). LiGluR-MAG0 460 in either RGCs or ON-BCs of the rd1 mouse reinstated innate light-avoidance behavior and enabled mice to distinguish between different temporal patterns of light in an associative learning task. In the rodcone dystrophy dog model of blindness, LiGluR-MAG0 460 in RGCs restored robust light responses to retinal explants and intravitreal delivery of LiGluR and MAG0 460 was well tolerated in vivo. The results in both large and small animal models of photoreceptor degeneration provide a path to clinical translation.retinal gene therapy | visual prosthetics | retinitis pigmentosa | optogenetic pharmacology | azobenzene photoswitches

Retinal disease is one of the most active areas of gene therapy, with clinical trials ongoing in the United States for five diseases. There are currently no treatments for patients with late-stage disease in which photoreceptors have been lost. Optogenetic gene therapies are in development, but, to date, have suffered from the low light sensitivity of microbial opsins, such as channelrhodopsin and halorhodopsin, and azobenzene-based photoswitches. Several groups have shown that photoreceptive G-protein-coupled receptors (GPCRs) can be expressed heterologously, and photoactivate endogenous Gi/o signaling. We hypothesized such a GPCR could increase sensitivity due to endogenous signal amplification. We targeted vertebrate rhodopsin to retinal ON-bipolar cells of blind rd1 mice and observed restoration of: (i) light responses in retinal explants, (ii) visually-evoked potentials in visual cortex in vivo, and (iii) two forms of visually-guided behavior: innate light avoidance and discrimination of temporal light patterns in the context of fear conditioning. Importantly, both the light responses of the retinal explants and the visually-guided behavior occurred reliably at light levels that were two to three orders of magnitude dimmer than required for channelrhodopsin. Thus, gene therapy with native light-gated GPCRs presents a novel approach to impart light sensitivity for visual restoration in a useful range of illumination.

Inherited and age-related retinal degenerative diseases cause progressive loss of rod and cone photoreceptors, leading to blindness, but spare downstream retinal neurons, which can be targeted for optogenetic therapy. However, optogenetic approaches have been limited by either low light sensitivity or slow kinetics, and lack adaptation to changes in ambient light, and not been shown to restore object vision. We find that the vertebrate medium wavelength cone opsin (MW-opsin) overcomes these limitations and supports vision in dim light. MW-opsin enables an otherwise blind retinitis pigmenotosa mouse to discriminate temporal and spatial light patterns displayed on a standard LCD computer tablet, displays adaption to changes in ambient light, and restores open-field novel object exploration under incidental room light. By contrast, rhodopsin, which is similar in sensitivity but slower in light response and has greater rundown, fails these tests. Thus, MW-opsin provides the speed, sensitivity and adaptation needed to restore patterned vision.

Retinitis pigmentosa results in blindness due to degeneration of photoreceptors, but spares other retinal cells, leading to the hope that expression of light-activated signaling proteins in the surviving cells could restore vision. We used a retinal G protein-coupled receptor, mGluR2, which we chemically engineered to respond to light. In retinal ganglion cells (RGCs) of blind rd1 mice, photoswitch-charged mGluR2 (“SNAG-mGluR2”) evoked robust OFF responses to light, but not in wild-type retinas, revealing selectivity for RGCs that have lost photoreceptor input. SNAG-mGluR2 enabled animals to discriminate parallel from perpendicular lines and parallel lines at varying spacing. Simultaneous viral delivery of the inhibitory SNAG-mGluR2 and excitatory light-activated ionotropic glutamate receptor LiGluR yielded a distribution of expression ratios, restoration of ON, OFF and ON-OFF light responses and improved visual acuity. Thus, SNAG-mGluR2 restores patterned vision and combinatorial light response diversity provides a new logic for enhanced-acuity retinal prosthetics.

Introduction The introduction of phosphodiesterase type 5 inhibitors has revolutionized the armamentarium of clinicians in the field of sexual medicine. However, pharmacotherapy as a stand-alone treatment option has been criticized, particularly by psychosocial therapists, as incomplete. Specifically, it is widely argued that drug treatment alone often does not meet the standards of biopsychosocial (BPS) therapy. Aim A literature review was performed to explore the role of the biopsychosocial paradigm in the treatment of sexual dysfunction and outline some of the key challenges and possible shortcomings in the current application of biopsychosocial treatment. Main Outcome Measure Published treatment outcomes of integrative biopsychosocial clinical practice, including medical outcomes, psychological and relational factors, treatment of comorbid conditions, cost of treatment, and treatment efficacy, were investigated. Methods Using Medline, PubMed, and EMBASE databases, a literature search for articles published from January 1, 1980, to March 1, 2013, was performed, examining current approaches to the biopsychosocial model of sexual dysfunction and sexual medicine. Data were reviewed and combined, allowing characterization of current treatment approaches and recommendations for clinical practice and future research. Results The biopsychosocial model of treatment appears to have an intuitively obvious meaning (i.e., treatment of all three facets of the patient's biological–psychological–social condition). However, research suggests that clear treatment algorithms are still in development. By virtue of the ongoing development of biopsychosocial methods in sexual medicine, new models and research initiatives may be warranted. The evidence identified allows for characterization of some of the current clinical, professional, financial, and systemic challenges to biopsychosocial treatment, with the aim of helping identify possible directions for future research. Conclusion Implementation of biopsychosocial treatment, though mandated by process-of-care guidelines, may be limited in the field of sexual health owing to resource limitations, limitations in physician training curricula, and structural obstacles preventing interdisciplinary collaboration. Nonetheless, a number of current treatment developments are biopsychosocially integrative, and a number of established models are biopsychosocially informed. These models and concrete strategies may provide a way forward for developing further initiatives to advance BPS treatment.

ABSTRACT. This article presents an analysis of transportable biomass conversion facilities to evaluate the conceptual and economic viability of a highly mobile and modular biomass conversion supply chain in the Pacific

This study evolved out of an ethnographic approach to teaching, learning, and researching the different ways that business and cultural frames of reference can affect decision making in groups consisting of Austrian, Finnish, and Swedish business students. The data is based on videotaped and audio taped recordings, post-exercise debriefings and discussions, and post-exercise written reflections on two decision-making exercises. The business-related Carter Racing exercise, which imitates the developments leading to the space shuttle Challenger catastrophe, produced conclusion-driven groupthink in every multicultural group of students. The students' shared "business-is-taking-risks" frame of reference was salient, with few cultural differences within the groups. In contrast, an exercise requiring the same students to decide the appropriate degree of subordinate participation in decisionmaking when a nuclear power plant needed repair produced only one example of conclusion-driven discourse. Analyses of three groups illustrates (a) an example of groupthink (Austrians and Swedes) in both exercises, (b) an example of national culture interference (Austrians and Swedes) that paralyzed group decision-making and (c) an example of national culture interference (Austrians and Finns) that demonstrated the importance of a "cultural negotiator" in finding common ground for different national assumptions about social relationships and preferences for communication styles.

In retinal disease, despite the loss of light sensitivity as photoreceptors die, many retinal interneurons survive in a physiologically and metabolically functional state for long periods. This provides an opportunity for treatment by genetically adding a light sensitive function to these cells. Optogenetic therapies are in development, but, to date, they have suffered from low light sensitivity and narrow dynamic response range of microbial opsins. Expression of light-sensitive G protein coupled receptors (GPCRs), such as vertebrate rhodopsin , can increase sensitivity by signal amplification , as shown by several groups. Here, we describe the methods to (1) express light gated GPCRs in retinal neurons, (2) record light responses in retinal explants in vitro, (3) record cortical light responses in vivo, and (4) test visually guided behavior in treated mice.