Final Measurement of the

This Letter reports one of the most precise measurements to date of the antineutrino spectrum from a purely ^{235}U-fueled reactor, made with the final dataset from the PROSPECT-I detector at the High Flux Isotope Reactor. By extracting information from previously unused detector segments, this analysis effectively doubles the statistics of the previous PROSPECT measurement. The reconstructed energy spectrum is unfolded into antineutrino energy and compared with both the Huber-Mueller model and a spectrum from a commercial reactor burning multiple fuel isotopes. A local excess over the model is observed in the 5-7 MeV energy region. Comparison of the PROSPECT results with those from commercial reactors provides new constraints on the origin of this excess, disfavoring at 2.0 and 3.7 standard deviations the hypotheses that antineutrinos from ^{235}U are solely responsible and noncontributors to the excess observed at commercial reactors, respectively.

Joint Measurement of the

The PROSPECT and STEREO collaborations present a combined measurement of the pure ^{235}U antineutrino spectrum, without site specific corrections or detector-dependent effects. The spectral measurements of the two highest precision experiments at research reactors are found to be compatible with χ^{2}/ndf=24.1/21, allowing a joint unfolding of the prompt energy measurements into antineutrino energy. This ν[over ¯]_{e} energy spectrum is provided to the community, and an excess of events relative to the Huber model is found in the 5-6 MeV region. When a Gaussian bump is fitted to the excess, the data-model χ^{2} value is improved, corresponding to a 2.4σ significance.

Nonfuel Antineutrino Contributions in the High Flux Isotope Reactor.

Reactor neutrino experiments have seen major improvements in precision in recent years. With the experimental uncertainties becoming lower than those from theory, carefully considering all sources of ν ¯ e is important when making theoretical predictions. One source of ν ¯ e that is often neglected arises from the irradiation of the nonfuel materials in reactors. The ν ¯ e rates and energies from these sources vary widely based on the reactor type, configuration, and sampling stage during the reactor cycle and have to be carefully considered for each experiment independently. In this article, we present a formalism for selecting the possible ν ¯ e sources arising from the neutron captures on reactor and target materials. We apply this formalism to the High Flux Isotope Reactor (HFIR) at Oak Ridge National Laboratory, the ν ¯ e source for the the Precision Reactor Oscillation and Spectrum Measurement (PROSPECT) experiment. Overall, we observe that the nonfuel ν ¯ e contributions from HFIR to PROSPECT amount to 1% above the inverse beta decay threshold with a maximum contribution of 9% in the 1.8-2.0 MeV range. Nonfuel contributions can be particularly high for research reactors like HFIR because of the choice of structural and reflector material in addition to the intentional irradiation of target material for isotope production. We show that typical commercial pressurized water reactors fueled with low-enriched uranium will have significantly smaller nonfuel ν ¯ e contribution.

Contemporary x-ray wavelength metrology and traceability.

We report recent advances in absolute x-ray wavelength metrology in the context of producing modern standard reference data. Primary x-ray wavelength standards are produced today using diffraction spectrometers using crystal optics arranged to be operated in dispersive and non-dispersive geometries, giving natural-line-width limited profiles with high resolution and accuracy. With current developments, measurement results can be made traceable to the Système internationale definition of the meter by using diffraction crystals that have absolute lattice-spacing provenance through x-ray-optical interferometry. Recent advances in goniometry, innovation of electronic x-ray area detectors, and new in situ alignment and measurement methods now permit robust measurement and quantification of previously-elusive systematic uncertainties. This capability supports infrastructures like the NIST Standard Reference Data programs and the International Initiative on X-ray Fundamental Parameters and their contributions to science and industry. Such data projects are further served by employing complementary wavelength-and energy-dispersive spectroscopic techniques. This combination can provide, among other things, new tabulations of less-intense x-ray lines that need to be identified in x-ray fluorescence investigation of uncharacterized analytes. After delineating the traceability chain for primary x-ray wavelength standards, and NIST efforts to produce standard reference data and materials in particular, this paper posits the new opportunities for x-ray reference data tabulation that modern methods now afford.

Measurement of the Antineutrino Spectrum from

This Letter reports the first measurement of the ^{235}U ν[over ¯]_{e} energy spectrum by PROSPECT, the Precision Reactor Oscillation and Spectrum experiment, operating 7.9 m from the 85 MW_{th} highly enriched uranium (HEU) High Flux Isotope Reactor. With a surface-based, segmented detector, PROSPECT has observed 31678±304(stat) ν[over ¯]_{e}-induced inverse beta decays, the largest sample from HEU fission to date, 99% of which are attributed to ^{235}U. Despite broad agreement, comparison of the Huber ^{235}U model to the measured spectrum produces a χ^{2}/ndf=51.4/31, driven primarily by deviations in two localized energy regions. The measured ^{235}U spectrum shape is consistent with a deviation relative to prediction equal in size to that observed at low-enriched uranium power reactors in the ν[over ¯]_{e} energy region of 5-7 MeV.

Expression of a Constitutively Active Human Insulin Receptor in Hippocampal Neurons Does Not Alter VGCC Currents.

Memory and cognitive decline are the product of numerous physiological changes within the aging brain. Multiple theories have focused on the oxidative, calcium, cholinergic, vascular, and inflammation hypotheses of brain aging, with recent evidence suggesting that reductions in insulin signaling may also contribute. Specifically, a reduction in insulin receptor density and mRNA levels has been implicated, however, overcoming these changes remains a challenge. While increasing insulin receptor occupation has been successful in offsetting cognitive decline, alternative molecular approaches should be considered as they could bypass the need for brain insulin delivery. Moreover, this approach may be favorable to test the impact of continued insulin receptor signaling on neuronal function. Here we used hippocampal cultures infected with lentivirus with or without IRß, a constitutively active, truncated form of the human insulin receptor, to characterize the impact continued insulin receptor signaling on voltage-gated calcium channels. Infected cultures were harvested between DIV 13 and 17 (48 h after infection) for Western blot analysis on pAKT and AKT. These results were complemented with whole-cell patch-clamp recordings of individual pyramidal neurons starting 96 h post-infection. Results indicate that while a significant increase in neuronal pAKT/AKT ratio was seen at the time point tested, effects on voltage-gated calcium channels were not detected. These results suggest that there is a significant difference between constitutively active insulin receptors and the actions of insulin on an intact receptor, highlighting potential alternate mechanisms of neuronal insulin resistance and mode of activation.

A Phase II Study of Pembrolizumab in EGFR-Mutant, PD-L1+, Tyrosine Kinase Inhibitor Naïve Patients With Advanced NSCLC.

BACKGROUND: Despite the significant antitumor activity of pembrolizumab in NSCLC, clinical benefit has been less frequently observed in patients whose tumors harbor EGFR mutations compared to EGFR wild-type patients. Our single-center experience on the KEYNOTE-001 trial suggested that pembrolizumab-treated EGFR-mutant patients, who were tyrosine kinase inhibitor (TKI) naïve, had superior clinical outcomes to those previously treated with a TKI. As TKI naïve EGFR-mutants have generally been excluded from pembrolizumab studies, data to guide treatment decisions in this patient population is lacking, particularly in patients with programmed death ligand 1 (PD-L1) expression ≥50%. METHODS: We conducted a phase II trial (NCT02879994) of pembrolizumab in TKI naive patients with EGFR mutation-positive, advanced NSCLC and PD-L1-positive (≥1%, 22C3 antibody) tumors. Pembrolizumab was administered 200 mg every 3 weeks. The primary endpoint was objective response rate. Secondary endpoints included safety of pembrolizumab, additional pembrolizumab efficacy endpoints, and efficacy and safety of an EGFR TKI after pembrolizumab. RESULTS: Enrollment was ceased due to lack of efficacy after 11 of 25 planned patients were treated. Eighty-two percent of trial patients were treatment naïve, 64% had sensitizing EGFR mutations, and 73% had PD-L1 expression ≥50%. Only 1 patient had an objective response (9%), but repeat analysis of this patient's tumor definitively showed the original report of an EGFR mutation to be erroneous. Observed treatment-related adverse events were similar to prior experience with pembrolizumab, but two deaths within 6 months of enrollment, including one attributed to pneumonitis, were of concern. CONCLUSIONS: Pembrolizumab's lack of efficacy in TKI naïve, PD-L1+, EGFR-mutant patients with advanced NSCLC, including those with PD-L1 expression ≥50%, suggests that it is not an appropriate therapeutic choice in this setting.

aCORN: An experiment to measure the electron-antineutrino correlation coefficient in free neutron decay.

We describe an apparatus used to measure the electron-antineutrino angular correlation coefficient in free neutron decay. The apparatus employs a novel measurement technique in which the angular correlation is converted into a proton time-of-flight asymmetry that is counted directly, avoiding the need for proton spectroscopy. Details of the method, apparatus, detectors, data acquisition, and data reduction scheme are presented, along with a discussion of the important systematic effects.

The aCORN Backscatter-Suppressed Beta Spectrometer.

Backscatter of electrons from a beta spectrometer, with incomplete energy deposition, can lead to undesirable effects in many types of experiments. We present and discuss the design and operation of a backscatter-suppressed beta spectrometer that was developed as part of a program to measure the electronantineutrino correlation coefficient in neutron beta decay (aCORN). An array of backscatter veto detectors surrounds a plastic scintillator beta energy detector. The spectrometer contains an axial magnetic field gradient, so electrons are efficiently admitted but have a low probability for escaping back through the entrance after backscattering. The design, construction, calibration, and performance of the spectrometer are discussed.

Measurement of the Electron-Antineutrino Angular Correlation in Neutron ß Decay.

We report the first result for the electron-antineutrino angular correlation (a coefficient) in free neutron ß decay from the aCORN experiment. aCORN uses a novel method in which the a coefficient is proportional to an asymmetry in proton time of flight for events where the ß electron and recoil proton are detected in delayed coincidence. Data are presented from a 15 month run at the NIST Center for Neutron Research. We obtained a=-0.1090±0.0030(stat)±0.0028(sys), the most precise measurement of the neutron a coefficient reported to date.

Standardizing the influenza neuraminidase inhibition assay among United States public health laboratories conducting virological surveillance.

BACKGROUND: Monitoring influenza virus susceptibility to neuraminidase (NA) inhibitors (NAIs) is vital for detecting drug-resistant variants, and is primarily assessed using NA inhibition (NI) assays, supplemented by NA sequence analysis. However, differences in NI testing methodologies between surveillance laboratories results in variability of 50% inhibitory concentration (IC50) values, which impacts data sharing, reporting and interpretation. In 2011, the Centers for Disease Control and Prevention (CDC), in collaboration with the Association for Public Health Laboratories (APHL) spearheaded efforts to standardize fluorescence-based NI assay testing in the United States (U.S.), with the goal of achieving consistency of IC50 data. METHODS: For the standardization process, three participating state public health laboratories (PHLs), designated as National Surveillance Reference Centers for Influenza (NSRC-Is), assessed the NAI susceptibility of the 2011-12 CDC reference virus panel using stepwise procedures, with support from the CDC reference laboratory. Next, the NSRC-Is assessed the NAI susceptibility of season 2011-12 U.S. influenza surveillance isolates (n = 940), with a large subset (n = 742) tested in parallel by CDC. Subsequently, U.S. influenza surveillance isolates (n = 9629) circulating during the next three influenza seasons (2012-15), were independently tested by the three NSRC-Is (n = 7331) and CDC (n = 2298). RESULTS: The NI assay IC50s generated by respective NSRC-Is using viruses and drugs prepared by CDC were similar to those obtained with viruses and drugs prepared in-house, and were uniform between laboratories. IC50s for U.S. surveillance isolates tested during four consecutive influenza seasons (2011-15) were consistent from season to season, within and between laboratories. CONCLUSION: These results show that the NI assay is robust enough to be standardized, marking the first time IC50 data have been normalized across multiple laboratories, and used for U.S. national NAI susceptibility surveillance.

Performance of the Los Alamos National Laboratory spallation-driven solid-deuterium ultra-cold neutron source.

In this paper, we describe the performance of the Los Alamos spallation-driven solid-deuterium ultra-cold neutron (UCN) source. Measurements of the cold neutron flux, the very low energy neutron production rate, and the UCN rates and density at the exit from the biological shield are presented and compared to Monte Carlo predictions. The cold neutron rates compare well with predictions from the Monte Carlo code MCNPX and the UCN rates agree with our custom UCN Monte Carlo code. The source is shown to perform as modeled. The maximum delivered UCN density at the exit from the biological shield is 52(9) UCN/cc with a solid deuterium volume of ~1500 cm(3).

A high-field adiabatic fast passage ultracold neutron spin flipper for the UCNA experiment.

The UCNA collaboration is making a precision measurement of the ß asymmetry (A) in free neutron decay using polarized ultracold neutrons (UCN). A critical component of this experiment is an adiabatic fast passage neutron spin flipper capable of efficient operation in ambient magnetic fields on the order of 1 T. The requirement that it operate in a high field necessitated the construction of a free neutron spin flipper based, for the first time, on a birdcage resonator. The design, construction, and initial testing of this spin flipper prior to its use in the first measurement of A with UCN during the 2007 run cycle of the Los Alamos Neutron Science Center's 800 MeV proton accelerator is detailed. These studies determined the flipping efficiency of the device, averaged over the UCN spectrum present at the location of the spin flipper, to be ̅ε=0.9985(4).

Determination of the axial-vector weak coupling constant with ultracold neutrons.

A precise measurement of the neutron decay ß asymmetry A0 has been carried out using polarized ultracold neutrons from the pulsed spallation ultracold neutron source at the Los Alamos Neutron Science Center. Combining data obtained in 2008 and 2009, we report A0 = -0.119 66±0.000 89{-0.001 40}{+0.001 23}, from which we determine the ratio of the axial-vector to vector weak coupling of the nucleon g{A}/g{V}=-1.275 90{-0.004 45}{+0.004 09}.

First measurement of the neutron beta asymmetry with ultracold neutrons.

We report the first measurement of an angular correlation parameter in neutron beta decay using polarized ultracold neutrons (UCN). We utilize UCN with energies below about 200 neV, which we guide and store for approximately 30 s in a Cu decay volume. The interaction of the neutron magnetic dipole moment with a static 7 T field external to the decay volume provides a 420 neV potential energy barrier to the spin state parallel to the field, polarizing the UCN before they pass through an adiabatic fast passage spin flipper and enter a decay volume, situated within a 1 T field in a 2x2pi solenoidal spectrometer. We determine a value for the beta-asymmetry parameter A_{0}=-0.1138+/-0.0046+/-0.0021.

Relevance-based feature extraction for hyperspectral images.

Hyperspectral imagery affords researchers all discriminating details needed for fine delineation of many material classes. This delineation is essential for scientific research ranging from geologic to environmental impact studies. In a data mining scenario, one cannot blindly discard information because it can destroy discovery potential. In a supervised classification scenario, however, the preselection of classes presents one with an opportunity to extract a reduced set of meaningful features without degrading classification performance. Given the complex correlations found in hyperspectral data and the potentially large number of classes, meaningful feature extraction is a difficult task. We turn to the recent neural paradigm of generalized relevance learning vector quantization (GRLVQ) [B. Hammer and T. Villmann, Neural Networks vol. 15, pp. 1059-1068, 2002], which is based on, and substantially extends, learning vector quantization (LVQ) [T. Kohonen, Self-Organizing Maps, Berlin, Germany: Springer-Verlag, 2001] by learning relevant input dimensions while incorporating classification accuracy in the cost function. By addressing deficiencies in GRLVQ, we produce an improved version, GRLVQI, which is an effective analysis tool for high-dimensional data such as remotely sensed hyperspectral data. With an independent classifier, we show that the spectral features deemed relevant by our improved GRLVQI result in a better classification for a predefined set of surface materials than using all available spectral channels.

Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication.

SCF ubiquitin ligases target phosphorylated substrates for ubiquitin-dependent proteolysis by means of adapter subunits called F-box proteins. The F-box protein Cdc4 captures phosphorylated forms of the cyclin-dependent kinase inhibitor Sic1 for ubiquitination in late G1 phase, an event necessary for the onset of DNA replication. The WD40 repeat domain of Cdc4 binds with high affinity to a consensus phosphopeptide motif (the Cdc4 phospho-degron, CPD), yet Sic1 itself has many sub-optimal CPD motifs that act in concert to mediate Cdc4 binding. The weak CPD sites in Sic1 establish a phosphorylation threshold that delays degradation in vivo, and thereby establishes a minimal G1 phase period needed to ensure proper DNA replication. Multisite phosphorylation may be a more general mechanism to set thresholds in regulated protein-protein interactions.

Functional cloning of Src-like adapter protein-2 (SLAP-2), a novel inhibitor of antigen receptor signaling.

In an effort to identify novel therapeutic targets for autoimmunity and transplant rejection, we developed and performed a large-scale retroviral-based functional screen to select for proteins that inhibit antigen receptor-mediated activation of lymphocytes. In addition to known regulators of antigen receptor signaling, we identified a novel adaptor protein, SLAP-2 which shares 36% sequence similarity with the known Src-like adaptor protein, SLAP. Similar to SLAP, SLAP-2 is predominantly expressed in hematopoietic cells. Overexpression of SLAP-2 in B and T cell lines specifically impaired antigen receptor-mediated signaling events, including CD69 surface marker upregulation, nuclear factor of activated T cells (NFAT) promoter activation and calcium influx. Signaling induced by phorbol myristate acetate (PMA) and ionomycin was not significantly reduced, suggesting SLAP-2 functions proximally in the antigen receptor signaling cascade. The SLAP-2 protein contains an NH2-terminal myristoylation consensus sequence and SH3 and SH2 Src homology domains, but lacks a tyrosine kinase domain. In antigen receptor-stimulated cells, SLAP-2 associated with several tyrosine phosphorylated proteins, including the ubiquitin ligase Cbl. Deletion of the COOH terminus of SLAP-2 blocked function and abrogated its association with Cbl. Mutation of the putative myristoylation site of SLAP-2 compromised its inhibitory activity and impaired its localization to the membrane compartment. Our identification of the negative regulator SLAP-2 demonstrates that a retroviral-based screening strategy may be an efficient way to identify and characterize the function of key components of many signal transduction systems.

Cytolethal distending toxin demonstrates genotoxic activity in a yeast model.

Cytolethal distending toxins (CDTs) are multisubunit proteins produced by a variety of bacterial pathogens that cause enlargement, cell cycle arrest, and apoptosis in mammalian cells. While their function remains uncertain, recent studies suggest that they can act as intracellular DNases in mammalian cells. Here we establish a novel yeast model for understanding CDT-associated disease. Expression of the CdtB subunit in yeast causes a G2/M arrest, as seen in mammalian cells. CdtB toxicity is not circumvented in yeast genetically altered to lack DNA damage checkpoint control or that constitutively promote cell cycle progression via mutant Cdk1, because CdtB causes a permanent type of damage that results in loss of viability. Finally, we establish that CDTs are likely to be potent genotoxins, as indicated by in vivo degradation of chromosomal DNA associated with expression of CdtB-suggesting that the varied distribution of CDT in bacteria implicates many human pathogens as possessors of genotoxic activity.

Histone deacetylase inhibitors promote apoptosis and differential cell cycle arrest in anaplastic thyroid cancer cells.

Little information exists concerning the response of anaplastic thyroid carcinoma (ATC) cells to histone deacetylase inhibitors (HDAIs). In this study, the cellular response to the histone deacetylase inhibitors, sodium butyrate and trichostatin A, was analyzed in cell lines derived from primary anaplastic thyroid carcinomas. HDAIs repress the growth (proliferation) of ATC cell lines, independent of p53 status, through the induction of apoptosis and differential cell cycle arrest (arrested in G1 and G2/M). Apoptosis increases in response to drug treatment and is associated with the appearance of the cleaved form of the caspase substrate, poly-(ADP-ribose) polymerase (PARP). Cell cycle arrest is associated with the reduced expression of cyclins A and B, the increased expression of the cyclin-dependent kinase inhibitors, p21(Cip1/WAF1) and p27Kip1, the reduced phosphorylation of the retinoblastoma protein (pRb), and a reduction in cdk2 and cdk1-associated kinase activities. In ATC cells overexpressing cyclin E, drug treatment failed to replicate these events. These results suggest that growth inhibition of ATC cells by HDAIs is due to the promotion of apoptosis through the activation of the caspase cascade and the induction of cell cycle arrest via a reduction in cdk2- and cdk1-associated kinase activities.