Dual Mechanisms of Regulation of Type I lodothyronine 5'-Deiodinase in the Rat Kidney, Liver, and Thyroid Gland Implications for the Treatment of Hyperthyroidism with Radiographic Contrast Agents

Abstract Introduction Alterations in thyroid hormone status and the administration of radiographic contrast agents can markedly influence iodothyronine metabolism and, in particular, the activity of type I 5'-deiodinase (51I). In the present studies, the mechanisms responsible for these effects have been reassessed. As previously reported, the addition of iopanoic acid (1OP) to broken cell preparations resulted in a competitive pattern of 5DI inhibition. However, the in vivo administration to rats of IOP or 3,3',5'-triiodothyronine (rT3) resulted in a noncompetitive pattern of inhibition of 51)I in the liver, kidney, and thyroid gland, whereby marked decreases in maximal enzyme velocity (Vx) were noted, with no change in the value of the Michaelis-Menten constant. In rats rendered hyperthyroid by the injection of 3,5,3'-triiodothyronine (T3), 5DI activity was significantly increased in the liver and the kidney. Alterations in thyroid hormone status also have important and direct "autoregulatory" effects on the cellular processes that metabolize these hormones (2). In the rat, hyperthyroidism results in a marked increase in the rate of "local" T3 production in the liver (3, 4). This effect is secondary, in part, to an increase in activity of type I 5'-deiodinase (51DI), the principal enzymatic process responsible for hepatic thyroxine (T4) to T3 conversion (5). In contrast to this activating effect of thyroid hormones on 5'DI in the liver (and kidney Radiographic contrast agents such as iopanoic acid (IOP) and sodium ipodate (NaIp) inhibit T4 to T3 conversion in man (7-9) and experimental animals (10-12), and offer an alternative to the thionamides in the treatment ofGraves' disease In tissue homogenates, IOP and NaIp act as competitive inhibitors of both 5D

Performance analysis integration in the Uintah software development cycle

ManuscriptThe increasing complexity of high-performance computing environments and programming methodologies presents challenges for empirical performance evaluation. Evolving parallel and distributed systems require performance technology that can be flexibly configured to observe different events and associated performance data of interest. It must also be possible to integrate performance evaluation techniques with the programming paradigms and software engineering methods. This is particularly important for tracking performance on parallel software projects involving many code teams over many stages of development. This paper describes the integration of the TAU and XPARE tools in the Uintah Computational Framework (UCF). Discussed is the use of performance mapping techniques to associate low-level performance data to higher levels of abstraction in UCF and the use of performance regression testing to provides a historical portfolio of the evolution of application performance. A scalability study shows the benefits of integrating performance technology in building large-scale parallel applications

Isolation and characterization of the mouse gene for the type 3 iodothyronine deiodinase

The type 3 iodothyronine deiodinase (D3) is a selenoenzyme that inactivates thyroid hormones by removing a iodine from the 5-position of the tyrosyl ring. D3 is highly expressed in many tissues during the early stages of development, and its activity is regulated by selected growth factors and various hormones. To gain further insights into the structure, functional role, and regulation of this enzyme, we screened a mouse liver genomic library with a rat D3 complementary DNA probe and isolated a 12-kb clone coding for the Dio3. Restriction analysis followed by Southern blotting and nucleotide sequencing demonstrated that the Dio3 contains a single exon, 1853 bp in length, that encodes the entire length of the messenger RNA expressed in murine placenta and neonatal skin. Primer extension experiments identified two potential transcriptional start sites located 77 and 60 nt upstream of the ATG translational start codon. The region immediately 5' to the start sites contains consensus TATA, CAAT, and GC elements. Furthermore, a 526-nucleotide genomic fragment from this region was demonstrated to efficiently drive a luciferase reporter construct when transfected into COS-7, XTC-2, or XL-2 cells or into primary cultures of rat preadipocytes derived from neonatal brown fat. In conclusion, D3 transcripts in the placenta and skin are encoded by the Dio3 gene from a single exon whose expression is regulated by an upstream region that contains several consensus promoter elements. Further characterization of this gene will provide new insights into the factors regulating the unique pattern of D3 expression during development

Performance Evaluation of Adaptive Scientific Applications using TAU

Fueled by increasing processor speeds and high speed interconnection networks, advances in high performance computer architectures have allowed the development of increasingly complex large scale parallel systems. For computational scientists, programming these systems efficiently is a challenging task. Understanding the performance of their parallel applications i

Radiometric measurements of the microwave emissivity of foam

Includes bibliographical references.Radiometric measurements of the microwave emissivity of foam were conducted during May 2000 at the Naval Research Laboratory's Chesapeake Bay Detachment using radiometers operating at 10.8 and 36.5 GHz. Horizontal and vertical polarization measurements were performed at 36.5 GHz; horizontal, vertical, +45°, ­45°, left-circular, and right-circular polarization measurements were obtained at 10.8 GHz. These measurements were carried out over a range of incidence angles from 30° to 60°. Surface foam was generated by blowing compressed air through a matrix of gas-permeable tubing supported by an aluminum frame and floats. Video micrographs of the foam were used to measure bubble size distribution and foam layer thickness. A video camera was boresighted with the radiometers to determine the beam-fill fraction of the foam generator. Results show emissivities that were greater than 0.9 and approximately constant in value over the range of incidence angles for vertically polarized radiation at both 10.8 and 36.5 GHz, while emissivities of horizontally polarized radiation showed a gradual decrease in value as incidence angle increased. Emissivities at +45°, ­45°, left-circular, and right-circular polarizations were all very nearly equal to each other and were in turn approximately equal to the average values of the horizontal and vertical emissivities in each case.This work was sponsored by the Department of the Navy, Office of Naval Research under Award N0014-00-1-280 to the University of Massachusetts, Award N00014-00-0152 to the University of Washington, and Award N0001400WX21032 to the Naval Research Laboratory

The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability

Neurolysin (NLN) is a zinc metallopeptidase whose mitochondrial function is unclear. We found that NLN was overexpressed in almost half of patients with acute myeloid leukemia (AML), and inhibition of NLN was selectively cytotoxic to AML cells and stem cells while sparing normal hematopoietic cells. Mechanistically, NLN interacted with the mitochondrial respiratory chain. Genetic and chemical inhibition of NLN impaired oxidative metabolism and disrupted the formation of respiratory chain supercomplexes (RCS). Furthermore, NLN interacted with the known RCS regulator, LETM1, and inhibition of NLN disrupted LETM1 complex formation. RCS were increased in patients with AML and positively correlated with NLN expression. These findings demonstrate that inhibiting RCS formation selectively targets AML cells and stem cells and highlights the therapeutic potential of pharmacologically targeting NLN in AML

Flight Development for Cryogenic Fluid Management in Support of Exploration Missions

This paper describes the results of the "Experimentation for the Maturation of Deep Space Cryogenic Refueling Technology" study. The purposes of this study were to identify cryogenic fluids management technologies requiring low gravity flight experiments to bring to technology readiness level (TRL) 5-6; to study many possible flight experiment options; and to develop near-term low-cost flight experiment concepts to mature core technologies of refueling. A total of twenty-five white papers were prepared in the course of this study. Each white paper is briefly summarized and relevant references cited. A total of 90 references are cited

Patient free text reporting of symptomatic adverse events in cancer clinical research using the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

Objective: The study sought to describe patient-entered supplemental information on symptomatic adverse events (AEs) in cancer clinical research reported via a National Cancer Institute software system and examine the feasibility of mapping these entries to established terminologies. Materials and Methods: Patients in 3 multicenter trials electronically completed surveys during cancer treatment. Each survey included a prespecified subset of items from the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Upon completion of the survey items, patients could add supplemental symptomatic AE information in a free text box. As patients typed into the box, structured dropdown terms could be selected from the PRO-CTCAE item library or Medical Dictionary for Regulatory Activities (MedDRA), or patients could type unstructured free text for submission. Results: Data were pooled from 1760 participants (48% women; 78% White) who completed 8892 surveys, of which 2387 (26.8%) included supplemental symptomatic AE information. Overall, 1024 (58%) patients entered supplemental information at least once, with an average of 2.3 per patient per study. This encompassed 1474 of 8892 (16.6%) dropdowns and 913 of 8892 (10.3%) unstructured free text entries. One-third of the unstructured free text entries (32%) could be mapped post hoc to a PRO-CTCAE term and 68% to a MedDRA term. Discussion: Participants frequently added supplemental information beyond study-specific survey items. Almost half selected a structured dropdown term, although many opted to submit unstructured free text entries. Most free text entries could be mapped post hoc to PRO-CTCAE or MedDRA terms, suggesting opportunities to enhance the system to perform real-time mapping for AE reporting. Conclusions: Patient reporting of symptomatic AEs using a text box functionality with mapping to existing terminologies is both feasible and informative

VLT/FORS1 spectrophotometry of the first planetary nebula discovered in the Phoenix dwarf galaxy

Context: A planetary nebula (PN) candidate was discovered during FORS imaging of the Local Group dwarf galaxy Phoenix. Aims: We use this PN to complement abundances from red-giant stars. Methods: FORS spectroscopy was used to confirm the PN classification. Empirical methods and photoionization modeling were used to derive elemental abundances from the emission line fluxes and to characterize the central star. Results: For the elements deemed most reliable for measuring the metallicity of the interstellar medium (ISM) from which the PN formed, [O/H] ∼ −0.46 and [Ar/H] ∼ −1.03. [O/H] has lower measurement errors but greater uncertainties due to the unresolved issue of oxygen enrichment in the PN precursor star. Conclusions: Earlier than 2 Gyr ago (the lower limit of the derived age for the central star) the ISM had Z = 0.002–0.008, a range slightly more metal-rich than the one provided by stars. Comparing our PN-to-stellar values to surveys of other dwarf Local Group galaxies, Phoenix appears to be an outlier

Software for administering the National Cancer Institute’s patient-reported outcomes version of the common terminology criteria for adverse events: Usability study

Background: The US National Cancer Institute (NCI) developed software to gather symptomatic adverse events directly from patients participating in clinical trials. The software administers surveys to patients using items from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) through Web-based or automated telephone interfaces and facilitates the management of survey administration and the resultant data by professionals (clinicians and research associates). Objective: The purpose of this study was to iteratively evaluate and improve the usability of the PRO-CTCAE software. Methods: Heuristic evaluation of the software functionality was followed by semiscripted, think-aloud protocols in two consecutive rounds of usability testing among patients with cancer, clinicians, and research associates at 3 cancer centers. We conducted testing with patients both in clinics and at home (remotely) for both Web-based and telephone interfaces. Furthermore, we refined the software between rounds and retested. Results: Heuristic evaluation identified deviations from the best practices across 10 standardized categories, which informed initial software improvement. Subsequently, we conducted user-based testing among 169 patients and 47 professionals. Software modifications between rounds addressed identified issues, including difficulty using radio buttons, absence of survey progress indicators, and login problems (for patients) as well as scheduling of patient surveys (for professionals). The initial System Usability Scale (SUS) score for the patient Web-based interface was 86 and 82 (P=.22) before and after modifications, respectively, whereas the task completion score was 4.47, which improved to 4.58 (P=.39) after modifications. Following modifications for professional users, the SUS scores improved from 71 to 75 (P=.47), and the mean task performance improved significantly (4.40 vs 4.02; P=.001). Conclusions: Software modifications, informed by rigorous assessment, rendered a usable system, which is currently used in multiple NCI-sponsored multicenter cancer clinical trials