26 research outputs found
Development and Analytical Validation of a Radioimmunoassay for the Measurement of Trypsin-like Immunoreactivity in Ferret Serum
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
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
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 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
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 cm) 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 m 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
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
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