Search

SUMMARY: Multiplexed assays of variant effect (MAVEs) are capable of experimentally testing all possible single nucleotide or amino acid variants in selected genomic regions, generating 'variant effect maps', which provide biochemical insight and functional evidence to enable more rapid and accurate clinical interpretation of human variation. Because the international community applying MAVE approaches is growing rapidly, we developed the online MaveRegistry platform to catalyze collaboration, reduce redundant efforts, allow stakeholders to nominate targets and enable tracking and sharing of progress on ongoing MAVE projects. AVAILABILITY AND IMPLEMENTATION: MaveRegistry service: https://registry.varianteffect.org. MaveRegistry source code: https://github.com/kvnkuang/maveregistry-front-end.

Using a combination of tandem affinity purification tagging and mass spectrometry, we characterized a novel, evolutionarily conserved protein phosphatase 4 (PP4)-containing complex (PP4cs, protein phosphatase 4, cisplatin-sensitive complex) that plays a critical role in the eukaryotic DNA damage response. PP4cs is comprised of the catalytic subunit PP4C; a known regulatory subunit, PP4R2; and a novel protein that we termed PP4R3. The Saccharomyces cerevisiae PP4R3 ortholog Psy2 was identified previously in a screen for sensitivity to the DNA-damaging agent and anticancer drug cisplatin. We demonstrated that deletion of any of the PP4cs complex orthologs in S. cerevisiae elicited cisplatin hypersensitivity. Furthermore human PP4R3 complemented the yeast psy2 deletion, and Drosophila melanogaster lacking functional PP4R3 (flfl) exhibited cisplatin hypersensitivity, suggesting a highly conserved role for PP4cs in DNA damage repair. Finally we found that PP4R3 may target PP4cs to the DNA damage repair machinery at least in part via an interaction with Rad53 (CHK2).

Item does not contain fulltext, Comprehensive protein protein interaction maps promise to reveal many aspects of the complex regulatory network underlying cellular function. Recently, large-scale approaches have predicted many new protein interactions in yeast. To measure their accuracy and potential as well as to identify biases, strengths and weaknesses, we compare the methods with each other and with a reference set of previously reported protein interactions.

The problem of gain scheduling LPV systems is studied and applied to missile autopilot design. Necessary and sufficient conditions for determining the Quadratic stabilizing of LPV systems are given. A stabilizing LPV controller is found if one exists. The necessary and sufficient conditions are realistically computable with reduced dimension and with only the elements of the Lyapunov matrix P as the unknown variables. The quadratic Stability results are then extended to the more general case of General Lyapunov stability. The derivation is the same as for Quadratic stability, except there is an additional term that is a function of the derivative of the Lyapunov function. An algorithm is presented that will solve these new conditions. Finally two methods for finding minimal/near minimal realizations for 2-D systems is presented. The first method requires extracting any greatest common divisors out of a nonminimal realization and then returning the realization back to state-space form. This method does not extend to N-D systems. However the second method, the System Equivalent Based method, can be extended to N-D systems. This method begins with the LPV system description being converted to Rosenbreock's system matrix form. Then the system matrix form is systematically manipulated until it is in state-space form.

Topotecan, a topoisomerase I inhibitor, was evaluated in a multicenter, phase II study of women with epithelial ovarian carcinoma who relapsed after one or two prior regimens that included platinum and paclitaxel.

Topotecan (SK&F 104864-A, NSC 609699) is a water-soluble, semi-synthetic analog of camptothecin which is an inhibitor of topoisomerase I. Since topoisomerase I is cell specific for S phase, we undertook a phase I study to determine the maximum tolerated dose and toxicities of continuous infusion (CI) topotecan. This phase I trial first explored a 5 day CI every 21 day schedule. Doses of topotecan included 0.17, 0.34 and 0.68 mg/m2/day. Fourteen patients [median age 60; median performance status (PS) of 1] with refractory malignancies received 59 courses of drug. Hematologic toxicities occurred only at the highest dose level; NCI grade 3-4 granulocytopenia and thrombocytopenia occurred in 4/8 and 3/8 patients, respectively. The protocol was amended to a 3 day infusion in an effort to ameliorate toxicity and obtain greater dose intensity (DI). Doses of 0.68, 0.85, 1.05, 1.3 and 1.6 mg/m2/day were evaluated. Thirty-two patients (median age 60; median PS of 1) received a total of 115 courses. The major toxicity seen was hematologic with 9/32 and 5/32 patients demonstrating grade 3-4 granulocytopenia and thrombocytopenia, respectively. Non-hematologic toxicities were mild (grade 1-2) in the two schedules and included nausea, vomiting, fatigue and alopecia. At the maximum tolerated dose (MTD) on the 5 day schedule, patients received 0.87 mg/m2/week, whereas they received 1.08 mg/m2/week at the MTD on the 3 day schedule (24% increase in relative dose intensity). A steady-state plasma lactone concentration of 5.5 mg/ml of topotecan was achieved at the phase II recommended dose of 1.6 ng/m2/day as a 3 day continuous infusion.(ABSTRACT TRUNCATED AT 250 WORDS), Clinical Trial, Clinical Trial, Phase I, Journal Article, info:eu-repo/semantics/published

S.M. Fields writes to President Roosevelt regarding statements made by Jeff Davis, Governor of Arkansas and imprisonment of women.

Wind tunnel tests were carried out using models of fallout shelters to determine correlations between shelter ventilation rate, area and distribution of wall openings, wind speed and its direction relative to the orientation of the shelter. Models of bermed shelters with five different opening configurations were used. A simple correlation was formulated between the shelter ventilation rate, the total area of windward openings, the ratio of leeward to windward opening areas and the velocity of the approach wind. Results were compared with those projected from available correlations for general type buildings. Originator provided keywords include: Flow visualization and Relative wind angle., Includes detachable summary. See also AD-A137 230 and AD- A126 765.

Wind-induced ventilation rates that could be achieved in a 100-man below-ground shelter with simple designs of passive flow enhancement devices (FEDs) were estimated by scale model tests in a low-speed wind tunnel. Air volume flow rates through the model were determined by using bubble flow tracers and motion photography. Test results indicate that adequate ventilation can be achieved in the type of shelter considered by the use of FEDs even at relatively low wind speeds. The study also generated guidelines for the relatively low speeds. The study also generated guidelines for the design of FEDs and their placement around stairway openings. In addition, estimates of reductions in ventilation rates due to an obstruction upstream of the windward FED and due to a decrease in the area of wall openings were made., Update to report dated Mar 83, AD-A126 765. Includes summary dated Sep 1983.

The overall objective of this program was to investigate experimentally the mixing processes occuring in in-flight ballons of the 'bar-bell' or ballonet type in which initially separate gases (methane and oxygen) are allowed to mix to form a detonable gas mixture during ascent to cruise or test altitude. This investigation has been carried out by testing appropriately scaled model balloons in the Ballistic Research Laboratories' Blast Sphere Facility. During two weeks of tests in the Blast Sphere, a range of simulated altitudes from sea level to 50,000 feet. In addition, a series of seven balloon detonations was performed at a simulated altitude of approximately 35,000 feet. (Modified author abstract)

The digitization of this collection was funded by a gift from EBSCO Industries.