26 research outputs found

    Development and Analytical Validation of a Radioimmunoassay for the Measurement of Trypsin-like Immunoreactivity in Ferret Serum

    Get PDF
    Ferrets are valuable animal models for the study of many human diseases. Cystic fibrosis (CF) and pancreatitis are two such human diseases that could benefit from a ferret model. The pancreatic disease processes that occur in the ferret animal model may allow researchers to investigate the pathophysiology of these diseases and help to develop new therapeutics for them. Trypsin-like immunoreactivity (TLI) is a noninvasive diagnostic tool used to assess exocrine pancreatic function in humans, dogs, and cats. Therefore, the major objective of this project was to purify trypsin from ferret pancreas and to set up and analytically validate a radioimmunoassay (RIA) for the measurement of TLI in ferret serum. Ferrets euthanized for unrelated projects had their pancreata removed and frozen at -80⁰C for further purification. Ferret trypsin was purified from pancreatic tissue and antiserum against ferret trypsin was raised in rabbits. Tracer was produced by the chloramine-T method. A radioimmunoassay was set up and analytically validated by determination of dilutional parallelism, spiking recovery, intra-assay variability, interassay variability, and sensitivity. A reference interval was established from 35 healthy ferret serum samples. A small group of ferrets with acute pancreatitis (AP; n = 3) and healthy controls (HC; n = 4) were analyzed by the new TLI RIA. We conclude that the ferret TLI RIA is analytically sensitive, accurate, precise, reproducible, and sufficiently linear for the measurement of TLI in serum samples from ferrets. All AP ferrets had higher serum TLI concentrations than HC ferrets, although the sample size was small. Further studies evaluating the usefulness of measuring serum ferret TLI concentrations in animal models with AP and CF are underway

    Testing SOAR Tools in Use

    Full text link
    Modern security operation centers (SOCs) rely on operators and a tapestry of logging and alerting tools with large scale collection and query abilities. SOC investigations are tedious as they rely on manual efforts to query diverse data sources, overlay related logs, and correlate the data into information and then document results in a ticketing system. Security orchestration, automation, and response (SOAR) tools are a new technology that promise to collect, filter, and display needed data; automate common tasks that require SOC analysts' time; facilitate SOC collaboration; and, improve both efficiency and consistency of SOCs. SOAR tools have never been tested in practice to evaluate their effect and understand them in use. In this paper, we design and administer the first hands-on user study of SOAR tools, involving 24 participants and 6 commercial SOAR tools. Our contributions include the experimental design, itemizing six characteristics of SOAR tools and a methodology for testing them. We describe configuration of the test environment in a cyber range, including network, user, and threat emulation; a full SOC tool suite; and creation of artifacts allowing multiple representative investigation scenarios to permit testing. We present the first research results on SOAR tools. We found that SOAR configuration is critical, as it involves creative design for data display and automation. We found that SOAR tools increased efficiency and reduced context switching during investigations, although ticket accuracy and completeness (indicating investigation quality) decreased with SOAR use. Our findings indicated that user preferences are slightly negatively correlated with their performance with the tool; overautomation was a concern of senior analysts, and SOAR tools that balanced automation with assisting a user to make decisions were preferred

    AI ATAC 1: An Evaluation of Prominent Commercial Malware Detectors

    Full text link
    This work presents an evaluation of six prominent commercial endpoint malware detectors, a network malware detector, and a file-conviction algorithm from a cyber technology vendor. The evaluation was administered as the first of the Artificial Intelligence Applications to Autonomous Cybersecurity (AI ATAC) prize challenges, funded by / completed in service of the US Navy. The experiment employed 100K files (50/50% benign/malicious) with a stratified distribution of file types, including ~1K zero-day program executables (increasing experiment size two orders of magnitude over previous work). We present an evaluation process of delivering a file to a fresh virtual machine donning the detection technology, waiting 90s to allow static detection, then executing the file and waiting another period for dynamic detection; this allows greater fidelity in the observational data than previous experiments, in particular, resource and time-to-detection statistics. To execute all 800K trials (100K files ×\times 8 tools), a software framework is designed to choreographed the experiment into a completely automated, time-synced, and reproducible workflow with substantial parallelization. A cost-benefit model was configured to integrate the tools' recall, precision, time to detection, and resource requirements into a single comparable quantity by simulating costs of use. This provides a ranking methodology for cyber competitions and a lens through which to reason about the varied statistical viewpoints of the results. These statistical and cost-model results provide insights on state of commercial malware detection

    Large-scale detector testing for the GAPS Si(Li) Tracker

    Full text link
    Lithium-drifted silicon [Si(Li)] has been used for decades as an ionizing radiation detector in nuclear, particle, and astrophysical experiments, though such detectors have frequently been limited to small sizes (few cm2^2) and cryogenic operating temperatures. The 10-cm-diameter Si(Li) detectors developed for the General Antiparticle Spectrometer (GAPS) balloon-borne dark matter experiment are novel particularly for their requirements of low cost, large sensitive area (~10 m2^2 for the full 1440-detector array), high temperatures (near -40\,^\circC), and energy resolution below 4 keV FWHM for 20--100-keV x-rays. Previous works have discussed the manufacturing, passivation, and small-scale testing of prototype GAPS Si(Li) detectors. Here we show for the first time the results from detailed characterization of over 1100 flight detectors, illustrating the consistent intrinsic low-noise performance of a large sample of GAPS detectors. This work demonstrates the feasibility of large-area and low-cost Si(Li) detector arrays for next-generation astrophysics and nuclear physics applications.Comment: Updated to version accepted in IEEE Trans Nucl Sci. Minor changes to text, fixed plotting error on Fig. 5. Conclusions unchange

    Fexofenadine Brain Exposure and the Influence of Blood-Brain Barrier P-Glycoprotein After Fexofenadine and Terfenadine Administration

    Get PDF
    P-glycoprotein (P-gp) plays an important role in determining net brain uptake of fexofenadine. Initial in vivo experiments with 24-h subcutaneous osmotic minipump administration demonstrated that fexofenadine brain penetration was 48-fold higher in mdr1a(–/–) mice than in mdr1a(+/+) mice. In contrast, the P-gp efflux ratio at the blood-brain barrier (BBB) for fexofenadine was only ∼4 using an in situ brain perfusion technique. Pharmacokinetic modeling based on the experimental results indicated that the apparent fexofenadine P-gp efflux ratio is time-dependent due to low passive permeability at the BBB. Fexofenadine brain penetration after terfenadine administration was ∼25- to 27-fold higher than after fexofenadine administration in both mdr1a(+/+) and mdr1a(–/–) mice, consistent with terfenadine metabolism to fexofenadine in murine brain tissue. The fexofenadine formation rate after terfenadine in situ brain perfusion was comparable with that in a 2-h brain tissue homogenate in vitro incubation. The fexofenadine formation rate increased ∼5-fold during a 2-h brain tissue homogenate incubation with hydroxyl-terfenadine, suggesting that the hydroxylation of terfenadine is the rate-limiting step in fexofenadine formation. Moreover, regional brain metabolism seems to be an important factor in terfenadine brain disposition and, consequently, fexofenadine brain exposure. Taken together, these results indicate that the fexofenadine BBB P-gp efflux ratio has been underestimated previously due to the lack of complete equilibration of fexofenadine across the blood-brain interface under typical experimental paradigms

    The Rational Design of Highly Potent and Selective Covalent MAP2K7 Inhibitors

    No full text
    The mitogen-activated protein kinase signaling cascade is conserved across eukaryotes from yeast to humans, where it plays a central role regulating activities including proliferation, differentiation, and stress responses. This pathway propagates external stimuli through a series of phosphorylation events, allowing external signals to influence metabolic and transcriptional activities. Within the cascade, MEK, or MAP2K, enzymes occupy a molecular crossroads situated immediately upstream to significant signal divergence and cross-talk. One such kinase, MAP2K7, also known as MEK7 and MKK7, is a protein of great interest in the molecular pathophysiology underlying pediatric T-cell acute lymphoblastic leukemia. Herein, we describe the rational design, synthesis, evaluation, and optimization of a novel class of irre-versible MAP2K7 inhibitors. With a streamlined one-pot synthesis, favorable in vitro potency and selectivity, as well as promising cellular activity, this novel class of compounds wields promise as a powerful tool in the study of pediatric T-AL
    corecore