Characterization of three vasopressin receptor 2 variants: an apparent polymorphism (V266A) and two loss-of-function mutations (R181C and M311V).

Arginine vasopressin (AVP) is released from the posterior pituitary and controls water homeostasis. AVP binding to vasopressin V2 receptors (V2Rs) located on kidney collecting duct epithelial cells triggers activation of Gs proteins, leading to increased cAMP levels, trafficking of aquaporin-2 water channels, and consequent increased water permeability and antidiuresis. Typically, loss-of-function V2R mutations cause nephrogenic diabetes insipidus (NDI), whereas gain-of-function mutations cause nephrogenic syndrome of inappropriate antidiuresis (NSIAD). Here we provide further characterization of two mutant V2Rs, R181C and M311V, reported to cause complete and partial NDI respectively, together with a V266A variant, in a patient diagnosed with NSIAD. Our data in HEK293FT cells revealed that for cAMP accumulation, AVP was about 500- or 30-fold less potent at the R181C and M311V mutants than at the wild-type receptor respectively (and about 4000- and 60-fold in COS7 cells respectively). However, in contrast to wild type V2R, the R181C mutant failed to increase inositol phosphate production, while with the M311V mutant, AVP exhibited only partial agonism in addition to a 37-fold potency decrease. Similar responses were detected in a BRET assay for β-arrestin recruitment, with the R181C receptor unresponsive to AVP, and partial agonism with a 23-fold decrease in potency observed with M311V in both HEK293FT and COS7 cells. Notably, the V266A V2R appeared functionally identical to the wild-type receptor in all assays tested, including cAMP and inositol phosphate accumulation, β-arrestin interaction, and in a BRET assay of receptor ubiquitination. Each receptor was expressed at comparable levels. Hence, the M311V V2R retains greater activity than the R181C mutant, consistent with the milder phenotype of NDI associated with this mutant. Notably, the R181C mutant appears to be a Gs protein-biased receptor incapable of signaling to inositol phosphate or recruiting β-arrestin. The etiology of NSIAD in the patient with V266A V2R remains unknown

Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.

The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes

Increased serum levels of TGFβ1 in children with localized scleroderma

scleroderm

HST/STIS Ultraviolet Imaging of Polar Aurora on Ganymede

We report new observations of the spectrum of Ganymede in the spectral range 1160 - 1720 A made with the Space Telescope Imaging Spectrograph (STIS) on HST on 1998 October 30. The observations were undertaken to locate the regions of the atomic oxygen emissions at 1304 and 1356 A, previously observed with the GHRS on HST, that Hall et al. (1998) claimed indicated the presence of polar aurorae on Ganymede. The use of the 2" wide STIS slit, slightly wider than the disk diameter of Ganymede, produced objective spectra with images of the two oxygen emissions clearly separated. The OI emissions appear in both hemispheres, at latitudes above 40 degrees, in accordance with recent Galileo magnetometer data that indicate the presence of an intrinsic magnetic field such that Jovian magnetic field lines are linked to the surface of Ganymede only at high latitudes. Both the brightness and relative north-south intensity of the emissions varied considerably over the four contiguous orbits (5.5 hours) of observation, presumably due to the changing Jovian plasma environment at Ganymede. However, the observed longitudinal non-uniformity in the emission brightness at high latitudes, particularly in the southern hemisphere, and the lack of pronounced limb brightening near the poles are difficult to understand with current models. In addition to observed solar HI Lyman-alpha reflected from the disk, extended Lyman-alpha emission resonantly scattered from a hydrogen exosphere is detected out to beyond two Ganymede radii from the limb, and its brightness is consistent with the Galileo UVS measurements of Barth et al. (1997).Comment: 7 pages, 4 figures, accepted for publication in ApJ, June 1, 200

Representative Farms Economic Outlook for the December 2005 FAPRI/AFPC Baseline

The Agricultural and Food Policy Center (AFPC) at Texas A&M University develops and maintains data to simulate 102 representative crop and livestock operations in major production areas in 28 states. The chief purpose of this analysis is to project those farms’ economic viability for 2005 through 2011. The data necessary to simulate the economic activity of these operations is developed through ongoing cooperation with panels of agricultural producers in each of these states. The Food and Agricultural Policy Research Institute (FAPRI) provided projected prices, policy variables, and input inflation rates in their December 2005 Baseline. Under the December 2005 Baseline, 12 of the 66 crop farms are considered in good liquidity condition (less than a 25 percent chance of negative ending cash during 2005-2011). Five crop farms have between a 25 percent and a 50 percent likelihood of negative ending cash. The remaining 49 crop farms have greater than a 50 percent of negative ending cash. Additionally, 22 of the 66 crop farms are considered in good equity position (less than a 25 percent chance of decreasing real net worth during 2005-2011). Ten crop farms have between a 25 percent and 50 percent likelihood of losing real net worth, and 34 crop farms have greater than a 50 percent probability of decreasing real net worth.Agribusiness, Agricultural and Food Policy, Crop Production/Industries, Livestock Production/Industries,

Research priorities in pediatric rheumatology: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus

<p>Abstract</p> <p>Background</p> <p>North American pediatric rheumatologists have created an investigator-initiated research network (the Childhood Arthritis and Rheumatology Research Alliance – CARRA) to facilitate multi-centre studies. One of the first projects undertaken by this network was to define, by consensus, research priorities for the group, and if possible a first group-sponsored clinical trial in which all members could participate.</p> <p>Methods</p> <p>We determined consensus using the Delphi approach. This approach has been used extensively in health research to reach consensus in large groups. It uses several successive iterations of surveys eliciting ideas and opinions from specialists in the field. Three surveys were designed based on this method and were distributed to members of CARRA to elicit and rank-order research priorities.</p> <p>Results</p> <p>A response rate of 87.6% was achieved in the final survey. The most highly ranked research suggestion was to study infliximab treatment of uveitis unresponsive to methotrexate. Other highly ranked suggestions were to study i) the treatment of systemic arthritis with anakinra and ii) the treatment of pediatric systemic lupus erythematosus with mycophenolate mofetil.</p> <p>Conclusion</p> <p>The Delphi approach was an effective and practical method to define research priorities in this group. Ongoing discussion and cooperation among pediatric rheumatologists in CARRA and others world-wide will help in developing further research priorities and to facilitate the execution of clinical trials in the future.</p

Representative Farms Economic Outlook for the January 2005 FAPRI/AFPC Baseline

The farm level economic impacts of the Farm Security and Rural Investment Act of 2002 on representative crop and livestock operations are projected in this report. The analysis was conducted over the 2002-2009 planning horizon using FLIPSIM, AFPC’s whole farm simulation model. Data to simulate farming operations in the nation’s major production regions came from two sources:•Producer panel cooperation to develop economic information to describe and simulate representative crop, livestock, and dairy farms, and•Projected prices, policy variables, and input inflation rates from the Food and Agricultural Policy Research Institute (FAPRI) January 2005 Baseline. The FLIPSIM policy simulation model incorporates the historical risk faced by farmers for prices and production. This report presents the results of the January 2005 Baseline in a risk context using selected simulated probabilities and ranges for annual net cash farm income values. The probability of a farm experiencing negative ending cash reserves and the probability of a farm losing real net worth are included as indicators of the cash flow and equity risks facing farms through the year 2009.Agribusiness, Agricultural and Food Policy, Crop Production/Industries, Livestock Production/Industries,

Representative Farms Economic Outlook for the August 2005 FAPRI/AFPC Baseline

The farm level economic impacts of the Farm Security and Rural Investment Act of 2002 on representative crop and livestock operations are projected in this report. The analysis was conducted over the 2002-2009 planning horizon using FLIPSIM, AFPC’s whole farm simulation model. Data to simulate farming operations in the nation’s major production regions came from two sources: • Producer panel cooperation to develop economic information to describe and simulate representative crop, livestock, and dairy farms, and • Projected prices, policy variables, and input inflation rates from the Food and Agricultural Policy Research Institute (FAPRI) August 2005 Baseline. The FLIPSIM policy simulation model incorporates the historical risk faced by farmers for prices and production. This report presents the results of the August 2005 Baseline in a risk context using selected simulated probabilities and ranges for annual net cash farm income values. The probability of a farm experiencing negative ending cash reserves and the probability of a farm losing real net worth are included as indicators of the cash flow and equity risks facing farms through the year 2009.Agribusiness, Agricultural and Food Policy, Crop Production/Industries, Livestock Production/Industries,

Proceedings of the 2019 Canadian Inflammatory Myopathy Study Symposium: Clinical Trial Readiness in Myositis.

The Canadian Inflammatory Myopathy Study (CIMS) is a multicenter prospective cohort recruiting in 8 centers across Canada. One of the aims of CIMS is to conduct and participate in clinical trials in autoimmune inflammatory myopathies (AIM). Conducting clinical trials in rare diseases such as AIM presents challenges. During this symposium, experts in the field presented different solutions to successfully conduct clinical trials in AIM, including the importance of collaboration and careful trial design, as well as training and mentoring of young investigators