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The presence of latent human immunodeficiency virus 1 (HIV-1) in quiescent memory CD4 + T cells represents a major barrier to viral eradication. Proliferation of memory CD4 + T cells is the primary mechanism that leads to persistence of the latent reservoir, despite effective antiretroviral therapy (ART). Memory CD4 + T cells are long-lived and can proliferate through two mechanisms: homeostatic proliferation via γc-cytokine stimulation or antigen-driven proliferation. Therefore, therapeutic modalities that perturb homeostatic and antigen-driven proliferation, combined with ART, represent promising strategies to reduce the latent reservoir. In this study, we investigated a library of FDA-approved oncology drugs to determine their ability to inhibit homeostatic and/or antigen-driven proliferation. We confirmed potential hits by evaluating their effects on proliferation in memory CD4 + T cells from people living with HIV-1 on ART (PLWH) and interrogated downstream signaling of γc-cytokine stimulation. We found that dasatinib and ponatinib, tyrosine kinase inhibitors, and trametinib, a MEK inhibitor, reduced both homeostatic and antigen-driven proliferationby >65%, with a reduction in viability <45%, ex vivo. In memory CD4 + T cells from PLWH, only dasatinib restricted both homeostatic and antigen-driven proliferation and prevented spontaneous rebound, consistent with promoting a smaller reservoir size. We show that dasatinib restricts IL-7 induced proliferation through STAT5 phosphorylation inhibition. Our results establish that the anti-cancer agent dasatinib is an exciting candidate to be used as an anti-proliferative drug in a clinical trial, since it efficiently blocks proliferation and iswell tolerated in patients with chronic myeloid leukemia (CML).

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The nuclei below lead but with more than 126 neutrons are crucial to an understanding of the astrophysical r process in producing nuclei heavier than A∼190. Despite their importance, the structure and properties of these nuclei remain experimentally untested as they are difficult to produce in nuclear reactions with stable beams. In a first exploration of the shell structure of this region, neutron excitations in ^{207}Hg have been probed using the neutron-adding (d,p) reaction in inverse kinematics. The radioactive beam of ^{206}Hg was delivered to the new ISOLDE Solenoidal Spectrometer at an energy above the Coulomb barrier. The spectroscopy of ^{207}Hg marks a first step in improving our understanding of the relevant structural properties of nuclei involved in a key part of the path of the r process.

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Triacylglycerol lipases have recently been shown to be transferred from the ocean to the atmosphere in atmospheric sea spray aerosol (SSA). Lipases have the potential to alter the composition of SSA; however, the structure and properties of enzymes in the high salt, high ionic strength, and low pH conditions found in SSA have never been explored. Here, we study the dynamics of Burkholderia cepacia triacylglycerol lipase (BCL) at SSA model surfaces comprised of palmitic acid and dipalmitoylphosphatidic acid (DPPA), two commonly found lipids at SSA surfaces. Surface adsorption Langmuir isotherm experiments and all-atom explicit solvent molecular dynamics simulations together illuminate how and why BCL expands the ordering of lipids at palmitic acid surfaces the most at pH < 4 and the least in DPPA surfaces at pH 6. Taken together, these results represent a first glimpse into the complex interplay between lipid surface structure and protein dynamics within enzyme-containing aerosols.

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A beam containing a substantial component of both the J^{π}=5^{+}, T_{1/2}=162 ns isomeric state of ^{18}F and its 1^{+}, 109.77-min ground state is utilized to study members of the ground-state rotational band in ^{19}F through the neutron transfer reaction (d,p) in inverse kinematics. The resulting spectroscopic strengths confirm the single-particle nature of the 13/2^{+} band-terminating state. The agreement between shell-model calculations using an interaction constructed within the sd shell, and our experimental results reinforces the idea of a single-particle-collective duality in the descriptions of the structure of atomic nuclei.

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Anthrax vaccine adsorbed (AVA, BioThrax) was recently approved by the Food and Drug Administration (FDA) for a post-exposure prophylaxis (PEP) indication in adults 18-65years of age. The schedule is three doses administered subcutaneous (SC) at 2-week intervals (0, 2, and 4weeks), in conjunction with a 60-day course of antimicrobials. The Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) developed an animal model to support assessment of a shortened antimicrobial PEP duration following Bacillus anthracis exposure. A nonhuman primate (NHP) study was completed to evaluate the efficacy of a two dose anthrax vaccine absorbed (AVA) schedule (0, 2weeks) aerosol challenged with high levels of B. anthracis spores at week4- the time point at which humans would receive the third vaccination of the approved PEP schedule. Here we use logistic regression models to combine the survival data from the NHP study along with serum anthrax lethal toxin neutralizing activity (TNA) and anti-PA IgG measured by enzyme linked immunosorbent assay (ELISA) data to perform a cross-species analysis to estimate survival probabilities in vaccinated human populations at this time interval (week4 of the PEP schedule). The bridging analysis demonstrated that high levels of NHP protection also yield high predicted probability of human survival just 2weeks after the second dose of vaccine with the full or half antigen dose regimen. The absolute difference in probability of human survival between the full and half antigen dose was estimated to be at most approximately 20%, indicating that more investigation of the half-antigen dose for vaccine dose sparing strategies may be warranted.

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Anthrax Vaccine Adsorbed (AVA, BioThrax) is approved by the US Food and Drug Administration for post-exposure prophylaxis (PEP) of anthrax in adults. The PEP schedule is 3 subcutaneous (SC) doses (0, 14 and 28 days), in conjunction with a 60 day course of antimicrobials. The objectives of this study were to understand the onset of protection from AVA PEP vaccination and to assess the potential for shortening the duration of antimicrobial treatment (http://www.phe.gov/Preparedness/mcm/phemce/Documents/2014-phemce-sip.pdf). We determined the efficacy against inhalation anthrax in nonhuman primates (NHP) of the first two doses of the PEP schedule by infectious challenge at the time scheduled for receipt of the third PEP dose (Day 28). Forty-eight cynomolgus macaques were randomized to five groups and vaccinated with serial dilutions of AVA on Days 0 and 14. NHP were exposed to Bacillus anthracis Ames spores on Day 28 (target dose 200 LD50 equivalents). Anti-protective antigen (PA) IgG and toxin neutralizing antibody (TNA) responses to vaccination and in post-challenge survivors were determined. Post-challenge blood and selected tissue samples were assessed for B. anthracis at necropsy or end of study (Day 56). Pre-challenge humoral immune responses correlated with survival, which ranged from 24 to 100% survival depending on vaccination group. Surviving, vaccinated animals had elevated anti-PA IgG and TNA levels for the duration of the study, were abacteremic, exhibited no apparent signs of infection, and had no gross or microscopic lesions. However, survivors had residual spores in lung tissues. We conclude that the first two doses of the PEP schedule provide high levels of protection by the scheduled timing of the third dose. These data may also support consideration of a shorter duration PEP antimicrobial regimen.

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Cross sections for proton knockout observed in (e,e'p) reactions are apparently quenched by a factor of ∼0.5, an effect attributed to short-range correlations between nucleons. Here we demonstrate that such quenching is not restricted to proton knockout, but a more general phenomenon associated with any nucleon transfer. Measurements of absolute cross sections on a number of targets between 16O and 208Pb were analyzed in a consistent way, with the cross sections reduced to spectroscopic factors through the distorted-wave Born approximation with global optical potentials. Across the 124 cases analyzed here, induced by various proton- and neutron-transfer reactions and with angular momentum transfer ℓ=0-7, the results are consistent with a quenching factor of 0.55. This is an apparently uniform quenching of single-particle motion in the nuclear medium. The effect is seen not only in (d,p) reactions but also in reactions with A=3 and 4 projectiles, when realistic wave functions are used for the projectiles.

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The quantitative consistency of nucleon transfer reactions as a probe of the occupancy of valence orbits in nuclei is tested. Neutron-adding, neutron-removal, and proton-adding transfer reactions were measured on the four stable even Ni isotopes, with particular attention to the cross section determinations. The data were analyzed consistently in terms of the distorted wave Born approximation to yield spectroscopic factors. Valence-orbit occupancies were extracted, utilizing the Macfarlane-French sum rules. The deduced occupancies are consistent with the changing number of valence neutrons, as are the vacancies for protons, both at the level of <5%. While there has been some debate regarding the true "observability" of spectroscopic factors, the present results indicate that empirically they yield self-consistent results.

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Accurate, reliable and standardized quantification of anti-protective antigen (PA) IgG antibody levels is essential for comparative analyses of anti-toxin immune responses in anthrax cases, recipients of PA-based anthrax vaccines and for evaluation of anti-PA based immunotherapies. We have previously reported the early performance characteristics and application of a quantitative anti-PA IgG enzyme linked immunosorbent assay. The principal application of this assay was in a Phase 4 human clinical trial of anthrax vaccine adsorbed (AVA, BioThrax), the central component of the CDC Anthrax Vaccine Research Program (AVRP) and in humans following bioterrorism associated Bacillus anthracis infection (Quinn et al., 2002; Quinn et al., 2004; Marano et al., 2008). The objective of the AVRP was to determine the feasibility of reducing the number of priming series and booster doses of the licensed Anthrax Vaccine Adsorbed (AVA) (BioThrax®; Emergent BioSolutions, Lansing, MI) and changing the route of administration from subcutaneous (SC) to intramuscular (IM) (Marano et al., 2008). In this paper we report the validation and long term performance characteristics of the assay during its six year application in the AVRP (2002-2008). The critical features are 1) extensive validation of the assay using two standard reference sera; 2) long term stability and 3) consistency of the data for quantitative analysis of human long term anti-PA IgG responses. The reportable value (RV) of the assay was expressed as anti-PA IgG concentration (µg/ml). Accuracy of the assay was high with a percent error (%ER) range of 1.6-11.4%. Overall intra-operator and intermediate precision were high with Coefficients of Variation (%CVs) of 2.5-15.4% and 6.3-13.2%, respectively. The assay demonstrated excellent dilutional linearity for human sera using log(10) transformed data with the slope=0.95 to 0.99, intercept=0.02 to 0.06 and r(2)=0.980-0.987. The assay was robust, tolerating changes in serum incubation temperatures from 35 to 39°C, serum incubation times from 55 to 65min and changes in key reagents. The long-term assay stability over 6years using consecutive reference sera AVR414 and AVR801 demonstrated sustained high accuracy and precision for the assay, confirming its suitability for long term studies of PA protein-based anthrax vaccines.

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A first experiment is reported that makes use of a new kind of spectrometer uniquely suited to the study of reactions with radioactive beams in inverse kinematics, the helical orbit spectrometer, HELIOS. The properties of some low-lying states in the neutron-rich N=8 nucleus 13B were studied with good resolution. From the measured angular distributions of the (d,p) reaction and the relative spectroscopic factors, spin and configuration assignments of the first- and third-excited states of this nucleus can be constrained.

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We have studied the ¹5C(d,p)¹6C reaction in inverse kinematics using the Helical Orbit Spectrometer at Argonne National Laboratory. Prior studies of electromagnetic-transition rates in ¹6C suggested an exotic decoupling of the valence neutrons from the core in that nucleus. Neutron-adding spectroscopic factors give a different probe of the wave functions of the relevant states in ¹6C. Shell-model calculations reproduce both the present transfer data and the previously measured transition rates, suggesting that ¹6C may be described without invoking very exotic phenomena.

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The possibility of observing neutrinoless double beta decay offers the opportunity of determining the effective neutrino mass if the nuclear matrix element were known. Theoretical calculations are uncertain, and measurements of the occupations of valence orbits by nucleons active in the decay can be important. The occupation of valence neutron orbits in the ground states of 76Ge (a candidate for such decay) and 76Se (the daughter nucleus) were determined by precisely measuring cross sections for both neutron-adding and removing transfer reactions. Our results indicate that the Fermi surface is much more diffuse than in theoretical calculations. We find that the populations of at least three orbits change significantly between these two ground states while in the calculations, the changes are confined primarily to one orbit.

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A new measurement of the beta-delayed alpha decay of 16N has been performed using a set of high efficiency ionization chambers. Sources were made by implantation of a 16N beam, yielding very clean alpha spectra down to energies as low as 400 keV. Our data are in good agreement with earlier results. For the S factor S(E1), we obtain a value of 74 +/- 21 keV b. In spite of improvements in the measurement, the error in S(E1) remains relatively large because of the correlations among the fit parameters and the uncertainties inherent to the extrapolation.

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We have studied the 2H(8Li,p)9Li reaction to obtain information on the spins, parities, and single-neutron spectroscopic factors for states in 9Li, using a radioactive 8Li beam. The deduced properties of the lowest three states are compared to the predictions of a number of calculations for the structure of 9Li. The results of ab initio quantum Monte Carlo calculations are in good agreement with the observed properties.

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We have performed precision laser spectroscopy on individual 6He (t(1/2)=0.8 s) atoms confined and cooled in a magneto-optical trap, and measured the isotope shift between 6He and 4He to be 43 194.772+/-0.056 MHz for the 2(3)S1-3(3)P2 transition. Based on this measurement and atomic theory, the nuclear charge radius of 6He is determined for the first time in a method independent of nuclear models to be 2.054+/-0.014 fm. The result is compared with the values predicted by a number of nuclear structure calculations and tests their ability to characterize this loosely bound halo nucleus.

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The difference in the energies of the lowest states corresponding to the two nodeless single-particle orbitals outside the Z=50 closed proton shell, h(11/2) and g(7/2), increases with neutron excess. We have measured the Sn(alpha,t) reaction for all seven stable even Sn isotopes and found that the spectroscopic factors are constant for these two states, confirming their characterization as single-particle states. The trend in energies is consistent with a decrease in the nuclear spin-orbit interaction. A similar trend, also suggesting a decreasing spin-orbit splitting, is seen in the energies of the neutron single-particle states outside the N=82 core, i(13/2) and h(9/2).

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Our knowledge of the possible existence in nature of stable exotic particles depends solely upon experimental observation. Using a sensitive laser spectroscopy technique, we searched for a doubly charged particle accompanied by two electrons as an anomalously heavy isotope of helium in the Earth's atmosphere. The concentration of noble-gas-like atoms in the atmosphere and the subsequent very large depletion of the light (3,4)He isotopes allow stringent upper limits to be set on the abundance: 10(-12)-10(-17) per atom in the solar system over the mass range of 20-10 000 amu.

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OBJECTIVE: To evaluate the breathing and sleep patterns in patients with brain tumors before and after operation, and assess their relation to the location and size of the tumor, as well as to the post-operative outcome. METHODS: Polysomnographic studies were performed in 11 patients with intracranial tumors (nine supra- and two infratentorial) before and after surgery. RESULTS: Pre-operatively, the mean apnea-hypopnea index (AHI) was 23.3. Six patients demonstrated signs of obstructive sleep apnea (SA) and one had mixed obstructive and central type SA. After operation, the mean AHI decreased to 8.1(P < 0.05). The duration of random eye movement sleep stage increased after tumor removal (P < 0.04). No relation was found between the characteristics of the tumor, nor the post-operative outcome and SA. CONCLUSIONS: Patients with brain tumors often suffer from SA and this can further worsen their symptoms related to increased intracranial pressure. Removal of the tumor results in a substantial decrease in sleep-related disturbances and may thus play a role in clinical recovery.

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