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DOE OSTI2018

Plaster: An Integration, Benchmark and Development Framework for Heterogeneous Metadata Normalization Methods

The recent advances in the automation of metadata normalization and the invention of a unified schema — Brick — alleviate the metadata normalization challenge for deploying portable applications across buildings. Yet, the lack of compatibility between existing metadata normalization methods precludes the possibility of comparing and combining them. While generic machine learning (ML) frameworks, such as MLJAR and OpenML, provide versatile interfaces for standard ML problems, they cannot easily accommodate the metadata normalization tasks for buildings due to the heterogeneity in the inference scope, type of data required as input, evaluation metric, and the building-specific human-in-the-loop learning procedure. We propose Plaster, an open and modular framework that incorporates existing advances in building metadata normalization. It provides unified programming interfaces for various types of learning methods for metadata normalization and defines standardized data models for building metadata and timeseries data. Thus, it enables the integration of different methods via a workflow, benchmarking of different methods via unified interfaces, and rapid prototyping of new algorithms. With Plaster, we 1) show three examples of the workflow integration, delivering better performance than individual algorithms, 2) benchmark/analyze five algorithms over five common buildings, and 3) exemplify the process of developing a new algorithm involving time series features. We believe Plaster will facilitate the development of new algorithms and expedite the adoption of standard metadata schema such as Brick, in order to enable seamless smart building applications in the future.

99 GENERAL AND MISCELLANEOUS↗

DOE OSTI2020

Regional Tau Effects on Prospective Cognitive Change in Cognitively Normal Older Adults

Studies suggest that tau deposition starts in the anterolateral entorhinal cortex (EC) with normal aging, and that the presence of β-amyloid (Aβ) facilitates its spread to neocortex, which may reflect the beginning of Alzheimer's disease (AD). Functional connectivity between the anterolateral EC and the anterior-temporal (AT) memory network appears to drive higher tau deposition in AT than in the posterior-medial (PM) memory network. Here, we investigated whether this differential vulnerability to tau deposition may predict different cognitive consequences of EC, AT, and PM tau. Using 18 F-flortaucipir (FTP) and 11 C-Pittsburgh compound-B (PiB) positron emission tomography (PET) imaging, we measured tau and Aβ in 124 cognitively normal human older adults (74 females, 50 males) followed for an average of 2.8 years for prospective cognition. We found that higher FTP in all three regions was individually related to faster memory decline, and that the effects of AT and PM FTP, but not EC, were driven by Aβ+ individuals. Moreover, when we included all three FTP measures competitively in the same model, only AT FTP significantly predicted memory decline. Our data support a model whereby tau, facilitated by Aβ, transits from EC to cortical regions that are most closely associated with the anterolateral EC, which specifically affects memory in the initial stage of AD. Memory also appears to be affected by EC tau in the absence of Aβ, which may be less clinically consequential. These findings may provide clarification of differences between normal aging and AD, and elucidate the transition between the two stages. SIGNIFICANCE STATEMENT Tau and β-amyloid (Aβ) are hallmarks of Alzheimer's disease (AD) but are also found in cognitively normal people. It is unclear whether, and how, this early deposition of tau and Aβ may affect cognition in normal aging and the asymptomatic stage of AD. We show that tau deposition in the entorhinal cortex (EC), which is common in advanced age, predicts memory decline in older adults independent of Aβ, likely reflecting normal, age-related memory loss. In contrast, tau in anterior-temporal (AT) regions is most predictive of memory decline in Aβ+ individuals. These data support the idea that tau preferentially spreads to specific cortical regions, likely through functional connections, which plays a primary role in memory decline in the early stage of AD.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

File format for normalizing radiological concentration exposure rate and dose rate data for the effects of radioactive decay and weathering processes

This report specifies the electronic file format that was agreed upon to be used as the file format for normalized radiological data produced by the software tool developed under this TI project. The NA-84 Technology Integration (TI) Program project (SNL17-CM-635, Normalizing Radiological Data for Analysis and Integration into Models) investigators held a teleconference on December 7, 2017 to discuss the tasks to be completed under the TI program project. During this teleconference, the TI project investigators determined that the comma-separated values (CSV) file format is the most suitable file format for the normalized radiological data that will be outputted from the normalizing tool developed under this TI project. The CSV file format was selected because it provides the requisite flexibility to manage different types of radiological data (i.e., activity concentration, exposure rate, dose rate) from other sources [e.g., Radiological Assessment and Monitoring System (RAMS), Aerial Measuring System (AMS), Monitoring and Sampling). The CSV file format also is suitable for the file format of the normalized radiological data because this normalized data can then be ingested by other software [e.g., RAMS, Visual Sampling Plan (VSP)] used by the NA-84’s Consequence Management Program.

97 MATHEMATICS AND COMPUTING↗

DOE OSTI2017

Log-normal Star Formation Histories in Simulated and Observed Galaxies

Gladders et al. have recently suggested that the star formation histories (SFHs) of individual galaxies are characterized by a log-normal function in time, implying a slow decline rather than rapid quenching. We test their conjecture on theoretical SFHs from the cosmological simulation Illustris and on observationally inferred SFHs. While the log-normal form necessarily ignores short-lived features such as starbursts, it fits the overall shape of the majority of SFHs very well. In particular, 85% of the cumulative SFHs are fitted to within a maximum error of 5% of the total stellar mass formed, and 99% to within 10%. The log-normal performs systematically better than the commonly used delayed-τ model, and is superseded only by functions with more than three free parameters. Poor fits are mostly found in galaxies that were rapidly quenched after becoming satellites. We explore the log-normal parameter space of normalization, peak time, and full width at half maximum, and find that the simulated and observed samples occupy similar regions, though Illustris predicts wider, later-forming SFHs on average. The ensemble of log-normal fits correctly reproduces complex metrics such as the evolution of Illustris galaxies across the star formation main sequence, but overpredicts their quenching timescales. SFHs in Illustris are a diverse population not determined by any one physical property of galaxies, but follow a tight relation, where width ∝ (peaktime){sup 3/2}. We show that such a relation can be explained qualitatively (though not quantitatively) by a close connection between the growth of dark matter halos and their galaxies.

79 ASTRONOMY AND ASTROPHYSICS↗

NASA NTRS1981

Energy normalization of TV viewed optical correlation (automated correlation plane analyzer for an optical processor)

An automatic correlation plane processor that can rapidly acquire, identify, and locate the autocorrelation outputs of a bank of multiple optical matched filters is described. The read-only memory (ROM) stored digital silhouette of each image associated with each matched filter allows TV video to be used to collect image energy to provide accurate normalization of autocorrelations. The resulting normalized autocorrelations are independent of the illumination of the matched input. Deviation from unity of a normalized correlation can be used as a confidence measure of correct image identification. Analog preprocessing circuits permit digital conversion and random access memory (RAM) storage of those video signals with the correct amplitude, pulse width, rising slope, and falling slope. TV synchronized addressing of 3 RAMs permits on-line storage of: (1) the maximum unnormalized amplitude, (2) the image x location, and (3) the image y location of the output of each of up to 99 matched filters. A fourth RAM stores all normalized correlations. A normalization approach, normalization for cross correlations, a system's description with block diagrams, and system's applications are discussed.

Grumet, A.↗

NASA NTRS1985

Low-angle normal faults-low differential stress at mid crustal levels

A simple model for frictional slip on pre-existing faults that considers the local stress state near the fault and the effect of non-hydrostatic fluid pressures predicts that low-angle normal faulting is restricted to areas of the crust characterized by low differential stress and nearly lithostatic fluid pressures. The model considers frictional slip on a cohesionless low-angle normal fault governed by the failure criterion tau = mu sub f (sigma (*) sub n) =mu sub f (sigma sub n - P sub f) where tau and sigma sub n are the shear and normal stresses across the fault plane, mu sub f is the static coefficient of friction, and P sub f is the pore fluid pressure. As a first approximation, the model considers a vertical greatest principal compressive stress, sigma sub 1. It is apparent that if slip on low-angle normal faults is governed by the avove frictional failure criterion, slip on the low-angle normal fault occurs only if the least effective principal stress, sigma (*) sub 3 = sigma sub 3 - P sub f, is tensile, whenever tan superscrip -1(mu sub f d, where d is the dip of the fault. If detachment faulting occurs at any significant depth in the crust, P sub f sigma sub 3 is required. In light of this conclusion I allow P sub f to vary as necessary to allow slip on the low-angle normal fault.

Power, W. L.↗

NASA NTRS1989

Flow-field characteristics and normal-force correlations for delta wings from Mach 2.4 to 4.6

An experimental investigation has been conducted to determine the upper-surface flowfield types and the normal-force characteristics of a series of delta wing models at supersonic speeds. Flow-visualization data were used to classify the flowfields into seven primary types: shockless attached flow, separation bubble, classical vortex, vortex with shock, shock with no separation, shock-induced separation, and separation bubble with shock. The pressure distributions were integrated to obtain upper and lower surface normal-force loadings. A minimal effect of sweep was observed on the upper-surface normal force at constant Mach number and a minimal effect of Mach number was noted for the 75 deg delta wing lower-surface normal force. The normal-force coefficients for all test conditions were correlated, and a single empirical equation was formulated from which the normal-force coefficient could be calculated as a function of Mach number, angle of attack, and wing aspect ratio.

Covell, Peter F.↗

NASA NTRS1995

The COBE normalization for standard cold dark matter

The Cosmic Background Explorer Satellite (COBE) detection of microwave anisotropies provides the best way of fixing the amplitude of cosmological fluctuations on the largest scales. This normalization is usually given for an n = 1 spectrum, including only the anisotropy caused by the Sachs-Wolfe effect. This is certainly not a good approximation for a model containing any reasonable amount of baryonic matter. In fact, even tilted Sachs-Wolfe spectra are not a good fit to models like cold dark matter (CDM). Here, we normalize standard CDM (sCDM) to the two-year COBE data and quote the best amplitude in terms of the conventionally used measures of power. We also give normalizations for some specific variants of this standard model, and we indicate how the normalization depends on the assumed values on n, Omega(sub B) and H(sub 0). For sCDM we find the mean value of Q = 19.9 +/- 1.5 micro-K, corresponding to sigma(sub 8) = 1.34 +/- 0.10, with the normalization at large scales being B = (8.16 +/- 1.04) x 10(exp 5)(Mpc/h)(exp 4), and other numbers given in the table. The measured rms temperature fluctuation smoothed on 10 deg is a little low relative to this normalization. This is mainly due to the low quadrupole in the data: when the quadrupole is removed, the measured value of sigma(10 deg) is quite consistent with the best-fitting the mean value of Q. The use of the mean value of Q should be preferred over sigma(10 deg), when its value can be determined for a particular theory, since it makes full use of the data.

Bunn, Emory F.↗

NASA NTRS1958

Flight Investigation of a Normal-Acceleration Automatic Longitudinal Control System in a Fighter Airplane

A flight investigation was made to obtain experimental information on the handling qualities of a normal-acceleration type of automatic longitudinal control system. The control system was installed in a subsonic fighter-type airplane. In hands-off (stick-free) flight the normal-acceleration control system attempted to regulate the normal acceleration to a constant value which is dependent on the automatic-control-system trim setting. In maneuvering flight a given pilot's stick deflection produced a proportional change in normal acceleration, the change in acceleration being independent of flight condition. A small side-located controller stick was used by the pilot to introduce signals into the automatic control system. In the flight program emphasis was placed on the acceleration-limiting capabilities of the control system. The handling qualities were investigated in maneuvers such as slow and rapid pull-ups and turns and also in flight operations such as cruising, stalls, landings, aerobatics, and air-to-air tracking. Good acceleration limiting was obtained with the normal-acceleration control system by limiting the magnitude of the input signal that the pilot could introduce into the control system. The same values of control-system gain settings could be used from an acceleration-limiting stand-point at both 10,000 and 30,000 feet for the complete speed range of the airplane. The response characteristics of the airplane-control system combination were also satisfactory at both high and low altitude with these same values of control-system gain setting. In the pilot's opinion, the normal-acceleration control system provided good stability and control characteristics in flight operations such as cruising, stalls, landings, aerobatics, and air-to-air tracking.

Sjoberg, S. A.↗

NASA NTRS2011

Chromosomal Aberrations in Normal and AT Cells Exposed to High Dose of Low Dose Rate Irradiation

Ataxia telangiectasia (A-T) is a human autosomally recessive syndrome characterized by cerebellar ataxia, telangiectases, immune dysfunction, and genomic instability, and high rate of cancer incidence. A-T cell lines are abnormally sensitive to agents that induce DNA double strand breaks, including ionizing radiation. The diverse clinical features in individuals affected by A-T and the complex cellular phenotypes are all linked to the functional inactivation of a single gene (AT mutated). It is well known that cells deficient in ATM show increased yields of both simple and complex chromosomal aberrations after high-dose-rate irradiation, but, less is known on how cells respond to low-dose-rate irradiation. It has been shown that AT cells contain a large number of unrejoined breaks after both low-dose-rate irradiation and high-dose-rate irradiation, however sensitivity for chromosomal aberrations at low-dose-rate are less often studied. To study how AT cells respond to low-dose-rate irradiation, we exposed confluent normal and AT fibroblast cells to up to 3 Gy of gamma-irradiation at a dose rate of 0.5 Gy/day and analyzed chromosomal aberrations in G0 using fusion PCC (Premature Chromosomal Condensation) technique. Giemsa staining showed that 1 Gy induces around 0.36 unrejoined fragments per cell in normal cells and around 1.35 fragments in AT cells, whereas 3Gy induces around 0.65 fragments in normal cells and around 3.3 fragments in AT cells. This result indicates that AT cells can rejoin breaks less effectively in G0 phase of the cell cycle? compared to normal cells. We also analyzed chromosomal exchanges in normal and AT cells after exposure to 3 Gy of low-dose-rate rays using a combination of G0 PCC and FISH techniques. Misrejoining was detected in the AT cells only? When cells irradiated with 3 Gy were subcultured and G2 chromosomal aberrations were analyzed using calyculin-A induced PCC technique, the yield of unrejoined breaks decreased in both normal and AT cells and misrejoined breaks increased in both cell lines. The present study suggests that AT cells begin to rejoin breaks when a certain number of breaks are accumulated and an increased number of exchanges were observed in G0 AT cells, which is similar situation after high-dose-rate irradiation.

Kawata, T.↗

NASA NTRS2016

Evaluation of the Hinge Moment and Normal Force Aerodynamic Loads from a Seamless Adaptive Compliant Trailing Edge Flap in Flight

A seamless adaptive compliant trailing edge (ACTE) flap was demonstrated in flight on a Gulfstream III aircraft at the NASA Armstrong Flight Research Center. The trailing edge flap was deflected between minus 2 deg up and plus 30 deg down in flight. The safety-of-flight parameters for the ACTE flap experiment require that flap-to-wing interface loads be sensed and monitored in real time to ensure that the structural load limits of the wing are not exceeded. The attachment fittings connecting the flap to the aircraft wing rear spar were instrumented with strain gages and calibrated using known loads for measuring hinge moment and normal force loads in flight. The safety-of-flight parameters for the ACTE flap experiment require that flap-to-wing interface loads be sensed and monitored in real time to ensure that the structural load limits of the wing are not exceeded. The attachment fittings connecting the flap to the aircraft wing rear spar were instrumented with strain gages and calibrated using known loads for measuring hinge moment and normal force loads in flight. The interface hardware instrumentation layout and load calibration are discussed. Twenty-one applied calibration test load cases were developed for each individual fitting. The 2-sigma residual errors for the hinge moment was calculated to be 2.4 percent, and for normal force was calculated to be 7.3 percent. The hinge moment and normal force generated by the ACTE flap with a hinge point located at 26-percent wing chord were measured during steady state and symmetric pitch maneuvers. The loads predicted from analysis were compared to the loads observed in flight. The hinge moment loads showed good agreement with the flight loads while the normal force loads calculated from analysis were over-predicted by approximately 20 percent. Normal force and hinge moment loads calculated from the pressure sensors located on the ACTE showed good agreement with the loads calculated from the installed strain gages.

Hinge Moment Loads↗

DOE OSTI2019

ASSESSMENT OF NORMALITY FOR CRITICALITY SAFETY BIAS AND BIAS UNCERTAINTY CALCULATION

The single-sided lower tolerance factors frequently used for non-trending assessment of the validation bias and bias uncertainty are sensitive to departures from normality. When used properly, the tolerance limits ensure that an appropriate fraction of the true population of applicable critical experiments lies above the calculated lower tolerance limit with the required statistical confidence level. One condition necessary to ensure that the appropriate proportion of the true population of keff values in the validation suite lies above the lower tolerance limit is that the assumption that the normality of the underlying population of critical experiments is valid or conservative.This paper discusses various methods used to assess whether the assumption that the validation suite may be treated as a random sample drawn from a normal distribution is acceptable. Techniques for assessing the validity of this underlying assumption include common omnibus hypothesis tests for normality, assessment of sample skewness and kurtosis of the validation suite, and graphical techniques. These techniques are used to assess the nature and potential conservatism/nonconservatism imparted by various departures from normality where possible. A review of hypothesis testing is also presented to frame the discussion of omnibus normality tests. Additionally, two cases are analysed with these techniques to provide an example of how they should be implemented.

Clarity, Justin↗

DOE OSTI2014

J-R Curve Determination for Disk-shaped Compact Specimens Based on the Normalization Method and Direct Current Potential Drop Technique

Material ductile fracture toughness can be described by J-integral versus crack extension relationship (J-R curve). As a conventional J-R curve measurement method, unloading compliance (UC) becomes impractical in elevated temperature testing due to relaxation of the material and a friction induced back-up shape of the J-R curve. In addition, the UC method may underpredict the crack extension for standard disk-shaped compact (DC(T)) specimens. In order to address these issues, the normalization method and direct current potential drop (DCPD) technique were applied for determining J-R curves at 24 C and 500 C for 0.18T DC(T) specimens made from type 316L stainless steel. For comparison purchase, the UC method was also applied in 24 C tests. The normalization method was able to yield valid J-R curves in all tests. The J-R curves from the DCPD technique need adjustment to account for the potential drop induced by plastic deformation, crack blunting, etc. and after applying a newly-developed DCPD adjustment procedure, the post-adjusted DCPD J-R curves essentially matched J-R curves from the normalization method. In contrast, the UC method underpredicted the crack extension in all tests resulting in substantial deviation in the derived J-R curves manifested by high Jq values than the normalization or DCPD method. Only for tests where the UC method underpredicted the crack extension by a very small value, J-R curves determined by the UC method were similar to those determined by the normalization or DCPD method.

DCPD↗

DOE OSTI2019

Impact of non-specific normal databases on perfusion quantification of low-dose myocardial SPECT studies

Aim: To evaluate the impact of non-specific normal databases on the percent summed rest score (SR%) and stress score (SS%) from simulated low-dose SPECT studies by shortening the acquisition time/projection. Methods: Forty normal-weight and 40 overweight/obese patients underwent myocardial studies with a conventional gamma-camera (BrightView, Philips) using three different acquisition times/projection: 30, 15, and 8 s (100%-counts, 50%-counts, and 25%-counts scan, respectively) and reconstructed using the iterative algorithm with resolution recovery (IRR) Astonish{sup TM} (Philips). Three sets of normal databases were used: (1) full-counts IRR; (2) half-counts IRR; and (3) full-counts traditional reconstruction algorithm database (TRAD). The impact of these databases and the acquired count statistics on the SR% and SS% was assessed by ANOVA analysis and Tukey test (P < 0.05). Results: Significantly higher SR% and SS% values (> 40%) were found for the full-counts TRAD databases respect to the IRR databases. For overweight/obese patients, significantly higher SS% values for 25%-counts scans (+19%) are confirmed compared to those of 50%-counts scan, independently of using the half-counts or the full-counts IRR databases. Conclusions: Astonish{sup TM} requires the adoption of the own specific normal databases in order to prevent very high overestimation of both stress and rest perfusion scores. Conversely, the count statistics of the normal databases seems not to influence the quantification scores.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2016

Sigma phases in an 11%Cr ferritic/martensitic steel with the normalized and tempered condition

At the present time 9–12% Cr ferritic/martensitic (F/M) steels with target operating temperatures up to 650 °C and higher are being developed in order to further increase thermal efficiency so as to reduce coal consumption and air pollution. An 11% Cr F/M steel was prepared by reference to the nominal chemical composition of SAVE12 steel with an expected maximum use temperature of 650 °C. The precipitate phases of the 11% Cr F/M steel normalized at 1050 °C for 0.5 h and tempered at 780 °C for 1.5 h were investigated by transmission electron microscopy. Except for Cr-/Cr-Fe-Co-rich M{sub 23}C{sub 6}, Nb-/V-/Ta-Nb-/Nd-rich MX, Fe-rich M{sub 5}C{sub 2}, Co-rich M{sub 3}C and Fe-Co-rich M{sub 6}C phases previously identified in the steel, two types of sigma phases consisting of σ-FeCr and σ-FeCrW were found to be also present in the normalized and tempered steel. Identified σ-FeCr and σ-FeCrW phases have a simple tetragonal crystal structure with estimated lattice parameters a/c = 0.8713/0.4986 and 0.9119/0.5053 nm, respectively. The compositions in atomic pct of the observed sigma phases were determined to be approximately 50Fe-50Cr for the σ-FeCr, and 30Fe-55Cr-10W in addition to a small amount of Ta, Co and Mn for the σ-FeCrW. The sigma phases in the steel exhibit various blocky morphologies, and appear to have a smaller amount compared with the dominant phases Cr-rich M{sub 23}C{sub 6} and Nb-/V-/Ta-Nb-rich MX of the steel. The σ-FeCr phase in the steel was found to precipitate at δ-ferrite/martensite boundaries, suggesting that δ-ferrite may rapidly induce the formation of sigma phase at δ-ferrite/martensite boundaries in high Cr F/M steels containing δ-ferrite. The formation mechanism of sigma phases in the steel is also discussed in terms of the presence of δ-ferrite, M{sub 23}C{sub 6} precipitation, precipitation/dissolution of M{sub 2}X, and steel composition. - Highlights: •Precipitate phases in normalized and tempered 11%Cr F/M steel are presented in detail. • σ-FeCr phase, 50Fe50Cr (in at.%), was identified in normalized and tempered 11%Cr F/M steel. • σ-FeCrW phase, 30Fe55Cr10W (in at.%), was identified in normalized and tempered 11%Cr F/M steel. • Sigma phase in the 11%Cr F/M steel was found to precipitate at δ-ferrite/martensite boundaries. • δ-ferrite may rapidly induce the sigma phase formation at δ-ferrite/martensite boundaries.

36 MATERIALS SCIENCE↗

DOE OSTI2015

Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma

Dopamine (DA), a monoamine catecholamine neurotransmitter with antiangiogenic activity, stabilizes tumor vessels in colon, prostate and ovarian cancers, thus increases chemotherapeutic efficacy. Here, in the rat C6 glioma models, we investigated the vascular normalization effects of DA and its mechanisms of action. DA (25, 50 mg/kg) inhibited tumor growth, while a precursor of DA (levodopa) prolonged the survival time of rats bearing orthotopic C6 glioma. DA improved tumor perfusion, with significant effects from day 3, and a higher level at days 5 to 7. In addition, DA decreased microvessel density and hypoxia-inducible factor-1α expression in tumor tissues, while increasing the coverage of pericyte. Conversely, an antagonist of dopamine receptor 2 (DR2) (eticlopride) but not DR1 (butaclamol) abrogated DA-induced tumor regression and vascular normalization. Furthermore, DA improved the delivery and efficacy of temozolomide therapy. Importantly, DA increased representative M1 markers (iNOS, CXCL9, etc.), while decreasing M2 markers (CD206, arginase-1, etc.). Depletion of macrophages by clodronate or zoledronic acid attenuated the effects of DA. Notably, DA treatment induced M2-to-M1 polarization in RAW264.7 cells and mouse peritoneal macrophages, and enhanced the migration of pericyte-like cells (10T1/2), which was reversed by eticlopride or DR2-siRNA. Such changes were accompanied by the downregulation of VEGF/VEGFR2 signaling. In summary, DA induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages. Thus, targeting the tumor microvasculature by DA represents a promising strategy for human glioma therapy. - Highlights: • Dopamine induces tumor growth inhibition and vascular normalization in rat C6 glioma. • Dopamine switches macrophage phenotype from M2 to M1. • Dopamine-induced vascular normalization is mediated by macrophage polarization. • Dopamine is a promising agent targeting the microvasculature in tumor microenvironment.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Mechanism of TRIM25 mediated ubiquitination of metastasis associated protein (MTA) 1 in normal liver cells

Ninety percent of all cancer related deaths happen due to metastatic progression. One important protein facilitating metastatic progression in hepatocellular carcinoma (HCC) is the metastasis associated 1 protein (MTA-1). We have earlier shown that in the context of HCC and normal liver cell lines, HuH6 and THLE-2, respectively. MTA-1 protein is actively stabilized in HCC cell lines and actively degraded in normal liver cells. We had also shown that TRIM25 is the E3 ligase that interacts with and degrades MTA-1 protein in normal liver cells. However, the exact mechanism by which TRIM25 degrades MTA-1 protein has still not been elucidated. In the study, we used both in situ prediction algorithms and mass spectrometry based post-translational modification analysis to map the lysine residues in MTA-1 that are polyubiquitinated. Whereas UbPred algorithm revealed a combination of medium and low confidence sites, it revealed only one high confidence lysine (K98) residue. The hCKSAAP{sub U}bSite algorithm also predicted K98 site. Mass spectrometry analysis also showed that K98 has ubiquitin modification. Immunofluorescence analysis showed that in normal liver cell line, THLE-2, which has high expression of TRIM25, ectopically expressed FLAG-tagged wild-type MTA-1 was actively degraded, but the K98R mutant MTA-1 was not. In vitro ubiquitination assay using recombinant wild-type and K98R mutant MTA-1 confirmed that MTA-1 is poly-ubiquitinated at K98 residue by TRIM25. The K98R mutant had a longer half-life than wild-type MTA-1 protein in an in vitro protein stability assay. We establish that TRIM25 ubiquitinates MTA-1 at lysine 98 and degrades it normal liver cells.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

A compact fiber optics-based heterodyne combined normal and transverse displacement interferometer

While Photonic Doppler Velocimetry (PDV) has become a common diagnostic tool for the measurement of normal component of particle motion in shock wave experiments, this technique has not yet been modified for the measurement of combined normal and transverse motion, as needed in oblique plate impact experiments. In this study, we discuss the design and implementation of a compact fiber-optics-based heterodyne combined normal and transverse displacement interferometer. Like the standard PDV, this diagnostic tool is assembled using commercially available telecommunications hardware and uses a 1550 nm wavelength 2 W fiber-coupled laser, an optical focuser, and single mode fibers to transport light to and from the target. Two additional optical probes capture first-order beams diffracted from a reflective grating at the target free-surface and deliver the beams past circulators and a coupler where the signal is combined to form a beat frequency. The combined signal is then digitized and analyzed to determine the transverse component of the particle motion. The maximum normal velocity that can be measured by this system is limited by the equivalent transmission bandwidth (3.795 GHz) of the combined detector, amplifier, and digitizer and is estimated to be ~2.9 km/s. Finally, sample symmetric oblique plate-impact experiments are performed to demonstrate the capability of this diagnostic tool in the measurement of the combined normal and transverse displacement particle motion.

47 OTHER INSTRUMENTATION↗