Nuclear Receptor Signaling Atlas: Opening Access to the Biology of Nuclear Receptor Signaling Pathways.

Signaling pathways involving nuclear receptors (NRs), their ligands and coregulators, regulate tissue-specific transcriptomes in diverse processes, including development, metabolism, reproduction, the immune response and neuronal function, as well as in their associated pathologies. The Nuclear Receptor Signaling Atlas (NURSA) is a Consortium focused around a Hub website (www.nursa.org) that annotates and integrates diverse 'omics datasets originating from the published literature and NURSA-funded Data Source Projects (NDSPs). These datasets are then exposed to the scientific community on an Open Access basis through user-friendly data browsing and search interfaces. Here, we describe the redesign of the Hub, version 3.0, to deploy "Web 2.0" technologies and add richer, more diverse content. The Molecule Pages, which aggregate information relevant to NR signaling pathways from myriad external databases, have been enhanced to include resources for basic scientists, such as post-translational modification sites and targeting miRNAs, and for clinicians, such as clinical trials. A portal to NURSA's Open Access, PubMed-indexed journal Nuclear Receptor Signaling has been added to facilitate manuscript submissions. Datasets and information on reagents generated by NDSPs are available, as is information concerning periodic new NDSP funding solicitations. Finally, the new website integrates the Transcriptomine analysis tool, which allows for mining of millions of richly annotated public transcriptomic data points in the field, providing an environment for dataset re-use and citation, bench data validation and hypothesis generation. We anticipate that this new release of the NURSA database will have tangible, long term benefits for both basic and clinical research in this field.

The National Institutes of Health's Big Data to Knowledge (BD2K) initiative: capitalizing on biomedical big data.

Biomedical research has and will continue to generate large amounts of data (termed 'big data') in many formats and at all levels. Consequently, there is an increasing need to better understand and mine the data to further knowledge and foster new discovery. The National Institutes of Health (NIH) has initiated a Big Data to Knowledge (BD2K) initiative to maximize the use of biomedical big data. BD2K seeks to better define how to extract value from the data, both for the individual investigator and the overall research community, create the analytic tools needed to enhance utility of the data, provide the next generation of trained personnel, and develop data science concepts and tools that can be made available to all stakeholders.

Transporting integrated primary care to the private sector: addressing the business challenges.

The primary care literature provides some useful information and several project examples for clinicians attempting to develop an integrated care practice, but prior discussion has been based largely on projects developed in government-funded or HMO systems. The current paper focuses on the business challenges of establishing an integrated care practice in a private, fee-for-service setting. Despite increasing commitment to the concept of the medical home, which embraces behavioral health care, physicians in the private sector remain cautious about proposed practice changes such as integrated care. There are additional obstacles that can impede successful implementation of integrated primary care in the private sector. The authors identify five major challenges and suggest potential strategies to address these challenges, drawing, in part, on their experience with a 4-year integrated primary care demonstration project.

Psychometric properties of the primary care behavioral health screen.

The Primary Care Behavioral Health Screen (PCBHS) is a self-report instrument developed to screen for behavioral health problems in primary care settings. The present paper describes development of the PCBHS and reports findings from item analyses and studies examining the instrument's convergent validity and test-retest reliability. Results suggest the PCBHS is a useful and valid method for screening a variety of behavioral health problems in a busy primary care practice. Recommendations for further research on the PCBHS are provided.

Commentary: Parallel evolution of Molecular Endocrinology as a journal and a discipline: convergence of interests with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK/NIH).

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) celebrates in 2010 its 60(th) year as an institute of the National Institutes of Health. NIDDK has been fundamental in providing support for research in endocrinology, fostering research to elucidate basic principles of endocrine signaling leading to understanding of diseases and disorders of hormone action. Over this time span, a move to a more molecular level in understanding of the basis of hormone action has emerged and been supported by NIDDK, with many advances finding their way into a new journal, Molecular Endocrinology. The merging of disciplines that has made this possible constitutes a major force for further progress as NIDDK moves forward over the next 60 yr. Together, NIDDK and Molecular Endocrinology have served as catalysts for advancing knowledge in the field, energizing new paradigms that have led to advances in the clinic.

No time to lose: workshop on circadian rhythms and metabolic disease.

The objective of the workshop was to gain a better understanding of the link between circadian rhythms and human health and disease. The impacts of circadian rhythms on metabolic gene regulation, as well as the effect of nutrient uptake and balance on the molecular components of the clock, were discussed. Topics included the neural circuitry underlying the central clock; the effect of the environment and diet on the central clock as well as peripheral, tissue-specific clocks; and the transcriptional, post-transcriptional, and post-translational (e.g., epigenomic) mechanisms through which these signals are transduced. Evidence presented during the meeting demonstrated that circadian rhythms and metabolism are intricately linked, and that disruption in these rhythms have profound consequences-many times leading to metabolic disease. The mechanisms by which circadian rhythms are maintained and the cross-talk with metabolic signaling are just beginning to be elucidated. However, the interactions between these fields and the knowledge learned will clearly have a profound impact on our understanding of metabolic disease and lead to novel therapeutic approaches in the future.

The nuclear receptor superfamily of steroid hormones and vitamin D gene regulation. An update.

Nuclear receptors bind to chromatin and seed formation of complexes comprising coregulators at the hormone response element. Nuclear receptors and coregulators can mediate chromatin remodeling, epigenetic modification, and ultimately gene expression. Chromatin immunoprecipitation has shown that nuclear receptors bind to chromatin throughout the genome, often at locations distant from the transcription start site. New findings related to the regulation of key vitamin D target genes in intestine and bone as well as nonclassical actions of 1,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)], including effects on breast cancer cells and on the immune system, are discussed. These studies will form the basis for future studies examining global networks regulated by the vitamin D receptor. It is becoming increasingly recognized that the actions of 1,25(OH)(2)D(3), similar to those of other steroids, is complex, involving regulation of gene activity at a range of locations.

Chemical approaches to nuclear receptors in metabolism.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a workshop, "Chemical Approaches to Nuclear Receptors and Metabolism," in April 2009 to explore how chemical and molecular biology and physiology can be exploited to further our understanding of nuclear receptor structure, function, and role in disease. Signaling cascades involving nuclear receptors are more complex and interrelated than once thought. Nuclear receptors continue to be attractive targets for drug discovery. The overall goal of this workshop was to identify gaps in our understanding of the complexity of ligand activities and begin to address them by (i) increasing the collaboration of investigators from different disciplines, (ii) developing a better understanding of chemical modulation of nuclear receptor action, and (iii) identifying opportunities and roadblocks in the path of translating basic research to discovery of new therapeutics.

Minireview: Evolution of NURSA, the Nuclear Receptor Signaling Atlas.

Nuclear receptors and coregulators are multifaceted players in normal metabolic and homeostatic processes in addition to a variety of disease states including cancer, inflammation, diabetes, obesity, and atherosclerosis. Over the past 7 yr, the Nuclear Receptor Signaling Atlas (NURSA) research consortium has worked toward establishing a discovery-driven platform designed to address key questions concerning the expression, organization, and function of these molecules in a variety of experimental model systems. By applying powerful technologies such as quantitative PCR, high-throughput mass spectrometry, and embryonic stem cell manipulation, we are pursuing these questions in a series of transcriptomics-, proteomics-, and metabolomics-based research projects and resources. The consortium's web site (www.nursa.org) integrates NURSA datasets and existing public datasets with the ultimate goal of furnishing the bench scientist with a comprehensive framework for hypothesis generation, modeling, and testing. We place a strong emphasis on community input into the development of this resource and to this end have published datasets from academic and industrial laboratories, established strategic alliances with Endocrine Society journals, and are developing tools to allow web site users to act as data curators. With the ongoing support of the nuclear receptor and coregulator signaling communities, we believe that NURSA can make a lasting contribution to research in this dynamic field.

Teaching integrated behavioral health in a primary care clerkship.

BACKGROUND: Most behavioral health care is actually delivered by primary care physicians. Primary care clerkship students have a unique opportunity to learn about behavioral health and the integrated care model. Integrated care is an effective multidisciplinary model for delivering high quality care. PURPOSE: Evaluate the efficacy of a brief curriculum in increasing students' knowledge regarding common behavioral health issues. METHODS: We designed an interactive, 90-minute curriculum to introduce students to the unique model of integrated care, and to build skills in addressing a number of common behavioral health issues. Each problem is presented from both the medical and behavioral perspective. We evaluated this intervention with a pre- and post-clerkship test assessing knowledge regarding behavioral health care. RESULTS: There was significant improvement on the overall score and on seven of eight individual questions. CONCLUSIONS: This curriculum is an effective intervention for introducing integrated care and increasing knowledge of several common behavioral problems.

The Nuclear Receptor Signaling Atlas: catalyzing understanding of thyroid hormone signaling and metabolic control.

The Nuclear Receptor Signaling Atlas (NURSA) was established as a trans-National Institutes of Health resource to develop, accrue, and communicate information about the nuclear receptor (NR) superfamily of ligand-dependent and -independent transcription factors. NRs have broad involvement in the regulation of development, reproduction, and metabolism. Receptors for thyroid hormones represent important members of the NR superfamily with key roles in development and homeostasis. NURSA has attempted to create a resource for information on NRs, associated coregulators, and ligands. The Web portal (www.NURSA.org) creates a window through which the general research community can gain access to data generated by NURSA investigators and linked from other sources. The molecule pages provide detailed curated information about the NR superfamily and allow the user to search for information useful to their own specific research problems. With the application of bioinformatics solutions, analyses of large amounts of data can be utilized to validate and/or create hypotheses that will ultimately lead to translational opportunities to take information about NRs, in general, and thyroid receptors, in particular to potential clinical applications.

Nuclear receptors and bone.

Nuclear receptors (NRs) represent a class of ligand-dependent and -independent transcription factors with importance to the regulation of development, reproduction, and metabolism. The emergence of new understanding of the structure, function, and role in disease of NRs provides new insights into the interaction between genetics and the environment, with NRs representing new targets for the development of therapeutic agents. NRs play key roles in bone health and contribute to our understanding of diseases and disorders that result in osteopenia and osteoporosis. The Nuclear Receptor Signaling Atlas (http://www.nursa.org) is an online repository of information about NRs and provides a community-wide resource designed to help catalyze new advances in biology and medicine.

Cystoid puncture for chronic cystoid macular oedema.

OBJECTIVE: To evaluate the new surgical technique of cystoid macular oedema puncture (CMOP) in patients with longstanding cystoid macular oedema refractory to standard treatments. DESIGN: Interventional, retrospective case series METHODS: Retrospective review of patients with chronic cystoid macular oedema from vascular retinopathy for whom maximal medical or surgical treatment failed and who underwent pars plana vitrectomy and CMOP. Clinical findings, best-corrected Snellen visual acuity, stereo colour fundus photography, intravenous fluorescein angiograms, and optical coherence tomography were obtained before and after treatment to evaluate the efficacy and safety of the treatment. RESULTS: Seven patients were included in the study. Cystoid macular oedema was due to diabetic retinopathy in five patients, central retinal vein occlusion in one patient and branch retinal vein occlusion in one patient. Preoperative intravitreal steroids failed for all patients, and three patients also had focal grid photocoagulation. Previous pars plana vitrectomy, with elevation of the posterior hyaloid, internal limiting membrane peeling, and intravitreal steroid injection, had failed in three patients. The median time to CMOP was 488 days. Resolution or improvement of cystoid oedema occurred in all patients as determined by fluorescein angiography or optical coherence tomography, or both. However, visual acuity was unchanged in five patients, declined in one patient and stable in one patient. CONCLUSIONS: Although cystoid macular oedema does improve quantitatively after CMOP, the technique fails to improve visual acuity in patients.

Novel targets and therapeutics for bone loss.

Advances in the treatment of osteoporosis over the past decade have resulted in the generation of novel therapeutic agents aimed at providing both anticatabolic and anabolic effects in bone. In-depth understanding of the biology of key factors regulating bone metabolism has begun to reveal new approaches to treating this costly and debilitating disease. During the next decade we will observe the development and evolution of several new classes of therapeutic targets and agents to combat this disease.

Nuclear Receptor Signaling Atlas (www.nursa.org): hyperlinking the nuclear receptor signaling community.

The nuclear receptor signaling (NRS) field has generated a substantial body of information on nuclear receptors, their ligands and coregulators, with the ultimate goal of constructing coherent models of the biological and clinical significance of these molecules. As a component of the Nuclear Receptor Signaling Atlas (NURSA)--the development of a functional atlas of nuclear receptor biology--the NURSA Bioinformatics Resource is developing a strategy to organize and integrate legacy and future information on these molecules in a single web-based resource (www.nursa.org). This entails parallel efforts of (i) developing an appropriate software framework for handling datasets from NURSA laboratories and (ii) designing strategies for the curation and presentation of public data relevant to NRS. To illustrate our approach, we have described here in detail the development of a web-based interface for the NURSA quantitative PCR nuclear receptor expression dataset, incorporating bioinformatics analysis which provides novel perspectives on functional relationships between these molecules. We anticipate that the free and open access of the community to a platform for data mining and hypothesis generation strategies will be a significant contribution to the progress of research in this field.

The Nuclear Receptor Signaling Atlas: development of a functional atlas of nuclear receptors.

The Nuclear Receptor Signaling Atlas (NURSA) was developed by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute on Aging (NIA), and the National Cancer Institute (NCI) of the National Institutes of Health (NIH); the aim of NURSA is to utilize classical approaches to validate existing hypotheses and exploit new and emerging technologies to formulate and test new hypotheses that might elucidate the program of nuclear receptor (NR) structure, function, and role in disease. The means for carrying out this ambitious program required development of interactions among investigators and the combined application of new high-throughput technologies and existing approaches to allow for both mechanistic studies and accrual of large datasets in a discovery-based research effort, all leading to advances with implications for the missions of the NIDDK, NIA, and NCI. A team-based multidisciplinary approach has allowed for both objectives to proceed simultaneously, tied together via a central bioinformatics resource and one web-accessible venue (www.nursa.org). The ultimate goals for the NURSA consortium are to: 1) establish the mechanistic principles of NR function, 2) characterize NR-coregulator complex formation and regulation, 3) map protein-protein interactions for coregulators, 4) identify candidate downstream target genes of NR action, 5) identify target tissue expression of NRs, 6) understand the regulation of NR expression and, 7) integrate existing and emerging information through NURSA bioinformatics tools.

Pain extent: relations with psychological state, pain severity, pain history, and disability.

The present study examined relationships between pain extent and measures of psychological state, pain-related disability, pain severity, and pain history in 416 patients with chronic pain. Previous research has examined the pain extent-psychological state relationship and has generally concluded that it is weak. Results of multiple regression analyses in this study indicated a moderate association between pain extent and psychosomatic symptoms. Weaker relationships were obtained for depression, pain severity, and length of time in pain. Results are discussed in light of prior studies of psychological state and pain extent.