Melody based tune retrieval over the World Wide Web

In this paper we describe the steps taken to develop a Web-based version of an existing stand-alone, single-user digital library application for melodical searching of a collection of music. For the three key components: input, searching, and output, we assess the suitability of various Web-based strategies that deal with the now distributed software architecture and explain the decisions we made. The resulting melody indexing service, known as MELDEX, has been in operation for one year, and the feed-back we have received has been favorable

Validation of evidence-Based Fall Prevention Programs for adults with intellectual and/or developmental disorders: a modified otago exercise Program

Introduction: Evidence-based fall prevention (EBFP) programs significantly decrease fall risk, falls, and fall-related injuries in community-dwelling older adults. To date, EBFP programs are only validated for use among people with normal cognition and, therefore, are not evidence-based for adults with intellectual and/or developmental disorders (IDD) such as Alzheimer’s disease and related dementias, cerebral vascular accident, or traumatic brain injury. Background: Adults with IDD experience not only a higher rate of falls than their community-dwelling, cognitively intact peers but also higher rates and earlier onset of chronic diseases, also known to increase fall risk. Adults with IDD experience many barriers to health care and health promotion programs. As the lifespan for people with IDD continues to increase, issues of aging (including falls with associated injury) are on the rise and require effective and efficient prevention. Methods: A modified group-based version of the Otago Exercise Program (OEP) was developed and implemented at a worksite employing adults with IDD in Montana. Participants were tested pre- and post-intervention using the Center for Disease Control and Prevention’s (CDC) Stopping Elderly Accidents Deaths and Injuries (STEADI) tool kit. Participants participated in progressive once weekly, 1-h group exercise classes and home programs over a 7-week period. Discharge planning with consumers and caregivers included home exercise, walking, and an optional home assessment. Results: Despite the limited number of participants (n = 15) and short length of participation, improvements were observed in the 30-s Chair Stand Test, 4-Stage Balance Test, and 2-Minute Walk Test. Additionally, three individuals experienced an improvement in ambulation independence. Participants reported no falls during the study period. Discussion: Promising results of this preliminary project underline the need for further study of this modified OEP among adults with IDD. Future multicenter study should include more participants in diverse geographic regions with longer lengths of participation and follow-up

Role of HIF1α and HIF2α in Cre Recombinase–Induced Retinal Pigment Epithelium Pathology and Its Secondary Effect on Choroidal Neovascularization

CreTrp1 mice are widely used for conditional retinal pigment epithelium (RPE) gene function studies. Like other Cre/LoxP models, phenotypes in CreTrp1 mice can be affected by Cre-mediated cellular toxicity, leading to RPE dysfunction, altered morphology and atrophy, activation of innate immunity, and consequent impairment of photoreceptor function. These effects are common among the age-related alterations of RPE that feature in early/intermediate forms of age-related macular degeneration. This article characterizes Cre-mediated pathology in the CreTrp1 line to elucidate the impact of RPE degeneration on both developmental and pathologic choroidal neovascularization. Nonredundant roles of the two major components of the hypoxia-inducible factor (HIF) family of transcription regulators, HIF1α and HIF2α, were identified. Genetic ablation of Hif1a protected against Cre-induced degeneration of RPE and choroid, whereas ablation of Hif2a exacerbated this degeneration. Furthermore, HIF1α deficiency protected CreTrp1 mice against laser-induced choroidal neovascularization, whereas HIF2α deficiency exacerbated the phenotype. Cre-mediated degeneration of the RPE in CreTrp1 mice offers an opportunity to investigate the impact of hypoxia signaling in the context of RPE degeneration. These findings indicate that HIF1α promotes Cre recombinase–mediated RPE degeneration and laser-induced choroidal neovascularization, whereas HIF2α is protective

Gene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179

The rd1 mouse with a mutation in the Pde6b gene was the first strain of mice identified with a retinal degeneration. However, AAV-mediated gene supplementation of rd1 mice only results in structural preservation of photoreceptors, and restoration of the photoreceptor-mediated a-wave, but not in restoration of the bipolar cell-mediated b-wave. Here we show that a mutation in Gpr179 prevents the full restoration of vision in rd1 mice. Backcrossing rd1 with C57BL6 mice reveals the complete lack of b-wave in a subset of mice, consistent with an autosomal recessive Mendelian inheritance pattern. We identify a mutation in the Gpr179 gene, which encodes for a G-protein coupled receptor localized to the dendrites of ON-bipolar cells. Gene replacement in rd1 mice that are devoid of the mutation in Gpr179 successfully restores the function of both photoreceptors and bipolar cells, which is maintained for up to 13 months. Our discovery may explain the failure of previous gene therapy attempts in rd1 mice, and we propose that Grp179 mutation status should be taken into account in future studies involving rd1 mice

Early-Onset Progressive Degeneration of the Area Centralis in RPE65-Deficient Dogs.

PURPOSE: Retinal epithelium-specific protein 65 kDa (RPE65)-deficient dogs are a valuable large animal model species that have been used to refine gene augmentation therapy for Leber congenital amaurosis type-2 (LCA2). Previous studies have suggested that retinal degeneration in the dog model is slower than that observed in humans. However, the area centralis of the dog retina is a cone and rod photoreceptor rich region comparable to the human macula, and the effect of RPE65 deficiency specifically on this retinal region, important for high acuity vision, has not previously been reported. METHODS: Spectral-domain optical coherence tomography, fundus photography, and immunohistochemistry of retinal wholemounts and sagittal frozen sections were used to define the time-course and cell-types affected in degeneration of the area centralis in affected dogs. RESULTS: Area centralis photoreceptor degeneration was evident from 6 weeks of age, and progressed to involve the inner retina. Immunohistochemistry showed that RPE65-deficient dogs developed early loss of S-cone outer segments, with slower loss of L/M-cone outer segments and rods. CONCLUSIONS: Early-onset severe photoreceptor degeneration in the area centralis of dogs with RPE65-deficiency offers a model of the early foveal/perifoveal degeneration in some patients with LCA2. This model could be used to refine interventions aiming to improve function and halt the progression of foveal/perifoveal photoreceptor degeneration

Lightweight Interactions for Reciprocal Cooperation in a Social Network Game

The construction of reciprocal relationships requires cooperative interactions during the initial meetings. However, cooperative behavior with strangers is risky because the strangers may be exploiters. In this study, we show that people increase the likelihood of cooperativeness of strangers by using lightweight non-risky interactions in risky situations based on the analysis of a social network game (SNG). They can construct reciprocal relationships in this manner. The interactions involve low-cost signaling because they are not generated at any cost to the senders and recipients. Theoretical studies show that low-cost signals are not guaranteed to be reliable because the low-cost signals from senders can lie at any time. However, people used low-cost signals to construct reciprocal relationships in an SNG, which suggests the existence of mechanisms for generating reliable, low-cost signals in human evolution.Comment: 13 pages, 2 figure

Gene therapy for Leber congenital amaurosis

Introduction: Leber congenital amaurosis (LCA) is a group of recessively inherited, early infantile-onset, severe rod-cone dystrophies that can result from defects in at least 25 genes, including RPE65, CEP290, RDH12, AIPL1 and GUCY2D. The possibility of benefit is offered by therapeutic intervention to provide the functional gene that is otherwise lacking. Areas covered: We searched PubMed for publications using the relevant keywords. Expert commentary: Clinical trials of gene therapy for LCA owing to defects in RPE65 have demonstrated benefit with improved function of rod photoreceptor cells. A gene therapy for this condition has been approved by the FDA. Ongoing clinical trials aim to determine whether cone photoreceptor cell function can be protected by appropriate gene delivery at an early stage of the disease. Clinical trials of gene therapy for LCA owing to defects in 5 other genes are planned

Retinal gene therapy

INTRODUCTION: Inherited retinal diseases are the leading cause of sight impairment in people of working age in England and Wales, and the second commonest in childhood. Gene therapy offers the potential for benefit. SOURCES OF DATA: Pubmed and clinicaltrials.gov. Areas of agreement: Gene therapy can improve vision in RPE65-associated Leber Congenital Amaurosis (RPE65-LCA). Potential benefit depends on efficient gene transfer and is limited by the extent of retinal degeneration. AREAS OF CONTROVERSY: The magnitude of vision improvement from RPE65-LCA gene therapy is suboptimal, and its durability may be limited by progressive retinal degeneration. GROWING POINTS: The safety and potential benefit of gene therapy for inherited and acquired retinal diseases is being explored in a rapidly expanding number of trials. Areas timely for developing research: Developments in vector design and delivery will enable greater efficiency and safety of gene transfer. Optimization of trial design will accelerate reliable assessment of outcomes

Long-Term Preservation of Cones and Improvement in Visual Function Following Gene Therapy in a Mouse Model of Leber Congenital Amaurosis Caused by Guanylate Cyclase-1 Deficiency

Leber congenital amaurosis (LCA) is a severe retinal dystrophy manifesting from early infancy as poor vision or blindness. Loss-of-function mutations in GUCY2D cause LCA1 and are one of the most common causes of LCA, accounting for 20% of all cases. Human GUCY2D and mouse Gucy2e genes encode guanylate cyclase-1 (GC), which is responsible for restoring the dark state in photoreceptors after light exposure. The Glicy2e(-/-) mouse shows partially diminished rod function, but an absence of cone function before degeneration. Although the cones appear morphologically normal, they exhibit mislocalization of proteins involved in phototransduction. In this study we tested the efficacy of an rAAV2/8 vector containing the human rhodopsin kinase promoter and the human GUCY2D gene. Following subretinal delivery of the vector in Glicy2e(-/-) mice, GC1 protein was detected in the rod and cone outer segments, and in transduced areas of retina cone transducin was appropriately localized to cone outer segments. Moreover, we observed a dose-dependent restoration of rod and cone function and an improvement in visual behavior of the treated mice. Most importantly, cone preservation was observed in transduced areas up to 6 months post injection. To date, this is the most effective rescue of the Glicy2e(-/-) mouse model of LCA and we propose that a vector, similar to the one used in this study, could be suitable for use in a clinical trial of gene therapy for LCA1