RINGdb: An integrated database for G protein-coupled receptors and regulators of G protein signaling

BACKGROUND: Many marketed therapeutic agents have been developed to modulate the function of G protein-coupled receptors (GPCRs). The regulators of G-protein signaling (RGS proteins) are also being examined as potential drug targets. To facilitate clinical and pharmacological research, we have developed a novel integrated biological database called RINGdb to provide comprehensive and organized RGS protein and GPCR information. RESULTS: RINGdb contains information on mutations, tissue distributions, protein-protein interactions, diseases/disorders and other features, which has been automatically collected from the Internet and manually extracted from the literature. In addition, RINGdb offers various user-friendly query functions to answer different questions about RGS proteins and GPCRs such as their possible contribution to disease processes, the putative direct or indirect relationship between RGS proteins and GPCRs. RINGdb also integrates organized database cross-references to allow users direct access to detailed information. The database is now available at . CONCLUSION: RINGdb is the only integrated database on the Internet to provide comprehensive RGS protein and GPCR information. This knowledgebase will be useful for clinical research, drug discovery and GPCR signaling pathway research

DSENT - A Tool Connecting Emerging Photonics with Electronics for Opto-Electronic Networks-on-Chip Modeling

With the advent of many-core chips that place substantial demand on the NoC, photonics has been investigated as a promising alternative to electrical NoCs. While numerous opto-electronic NoCs have been proposed, their evaluations tend to be based on fixed numbers for both photonic and electrical components, making it difficult to co-optimize. Through our own forays into opto-electronic NoC design, we observe that photonics and electronics are very much intertwined, reflecting a strong need for a NoC modeling tool that accurately models parameterized electronic and photonic components within a unified framework, capturing their interactions faithfully. In this paper, we present a tool, DSENT, for design space exploration of electrical and opto-electrical networks. We form a framework that constructs basic NoC building blocks from electrical and photonic technology parameters. To demonstrate potential use cases, we perform a network case study illustrating data-rate tradeoffs, a comparison with scaled electrical technology, and sensitivity to photonics parameters

BMP4 Activation and Secretion Are Negatively Regulated by an Intracellular Gremlin-BMP4 Interaction

Bone morphogenetic protein 4 (BMP4) is a potent growth factor that is involved in many important biological processes. Regulation of the level of secreted mature BMP4 determines the biological effects of BMP4 on cells in the local microenvironment. Previous studies suggested that Gremlin, a member of DAN family proteins, antagonizes BMP4 activity by sequestering extracellular BMP4. Herein, we report a novel intracellular regulatory mechanism by which Gremlin interacts with BMP4 precursor, prevents secretion of mature BMP4, and therefore inhibits BMP4 activity more efficiently. Furthermore, we also defined a 30-amino acid peptide sequence within the Gremlin DAN domain that is essential for BMP4 interaction. This novel Gremlin-mediated BMP4 posttranslational regulatory mechanism implies that the level of BMP4 mRNA expression does not truly reflect BMP4 activity when Gremlin and BMP4 are coexpressed within the same cell. Similar regulatory mechanisms may be utilized by other DAN family proteins

Non-invasive and transdermal measurement of blood uric acid level in human by electroporation and reverse iontophoresis

The aim of this study was to find out the optimum combination of electroporation (EP) and reverse iontophoresis (RI) on noninvasive and transdermal determination of blood uric acid level in humans. EP is the use of high-voltage electric pulse to create nano-channels on the stratum corneum, temporarily and reversibly. RI is the use of small current to facilitate both charged and uncharged molecule transportation across the skin. It is believed that the combination of these two techniques has additional benefits on the molecules’ extraction across the human skin. In vitro studies using porcine skin and diffusion cell have indicated that the optimum mode for transdermal uric acid extraction is the combination of RI with symmetrical biphasic direct current (current density = 0.3 mA/cm2; phase duration = 180 s) and EP with 10 pulses per second (voltage = 100 V/cm2; pulse width = 1 ms). This optimum mode was applied to six human subjects. Uric acid was successfully extracted through the subjects’ skin into the collection solution. A good correlation (r2 = 0.88) between the subject’s blood uric acid level and uric acid concentrations in collection solutions was observed. The results suggest that it may be possible to noninvasively and transdermally determine blood uric acid levels

Insights into Chinese perspectives on do-not-resuscitate (DNR) orders from an examination of DNR order form completeness for cancer patients

PURPOSE: Discussing end-of-life care with patients is often considered taboo, and signing a do-not-resuscitate (DNR) order is difficult for most patients, especially in Chinese culture. This study investigated distributions and details related to the signing of DNR orders, as well as the completeness of various DNR order forms. METHODS: Retrospective chart reviews were performed. We screened all charts from a teaching hospital in Taiwan for patients who died of cancer during the period from January 2010 to December 2011. A total of 829 patient records were included in the analysis. The details of the DNR order forms were recorded. RESULTS: The DNR order signing rate was 99.8 %. The percentage of DNR orders signed by patients themselves (DNR-P) was 22.6 %, while the percentage of orders signed by surrogates (DNR-S) was 77.2 %. The percentage of signed DNR forms that were completely filled out was 78.4 %. The percentage of DNR-S forms that were completed was 81.7 %, while the percentage of DNR-P forms that were completely filled out was only 67.6 %. CONCLUSION: Almost all the cancer patients had a signed DNR order, but for the majority of them, the order was signed by a surrogate. Negative attitudes of discussing death from medical professionals and/or the family members of patients may account for the higher number of signed DNR-S orders than DNR-P orders. Moreover, early obtainment of signed DNR orders should be sought, as getting the orders earlier could promote the quality of end-of-life care, especially in non-oncology wards

Expression and function of proton-sensing G-protein-coupled receptors in inflammatory pain

<p>Abstract</p> <p>Background</p> <p>Chronic inflammatory pain, when not effectively treated, is a costly health problem and has a harmful effect on all aspects of health-related quality of life. Despite the availability of pharmacologic treatments, chronic inflammatory pain remains inadequately treated. Understanding the nociceptive signaling pathways of such pain is therefore important in developing long-acting treatments with limited side effects. High local proton concentrations (tissue acidosis) causing direct excitation or modulation of nociceptive sensory neurons by proton-sensing receptors are responsible for pain in some inflammatory pain conditions. We previously found that all four proton-sensing G-protein-coupled receptors (GPCRs) are expressed in pain-relevant loci (dorsal root ganglia, DRG), which suggests their possible involvement in nociception, but their functions in pain remain unclear.</p> <p>Results</p> <p>In this study, we first demonstrated differential change in expression of proton-sensing GPCRs in peripheral inflammation induced by the inflammatory agents capsaicin, carrageenan, and complete Freund's adjuvant (CFA). In particular, the expression of TDAG8, one proton-sensing GPCR, was increased 24 hours after CFA injection because of increased number of DRG neurons expressing TDAG8. The number of DRG neurons expressing both TDAG8 and transient receptor potential vanilloid 1 (TRPV1) was increased as well. Further studies revealed that TDAG8 activation sensitized the TRPV1 response to capsaicin, suggesting that TDAG8 could be involved in CFA-induced chronic inflammatory pain through regulation of TRPV1 function.</p> <p>Conclusion</p> <p>Each subtype of the OGR1 family was expressed differently, which may reflect differences between models in duration and magnitude of hyperalgesia. Given that TDAG8 and TRPV1 expression increased after CFA-induced inflammation and that TDAG8 activation can lead to TRPV1 sensitization, it suggests that high concentrations of protons after inflammation may not only directly activate proton-sensing ion channels (such as TRPV1) to cause pain but also act on proton-sensing GPCRs to regulate the development of hyperalgesia.</p