Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within ...resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.
ABSTRACT
We present observations of ASASSN-19dj, a nearby tidal disruption event (TDE) discovered in the post-starburst galaxy KUG 0810+227 by the All-Sky Automated Survey for Supernovae (ASAS-SN) at ...a distance of d ≃ 98 Mpc. We observed ASASSN-19dj from −21 to 392 d relative to peak ultraviolet (UV)/optical emission using high-cadence, multiwavelength spectroscopy and photometry. From the ASAS-SN g-band data, we determine that the TDE began to brighten on 2019 February 6.8 and for the first 16 d the rise was consistent with a flux ∝t2 power law. ASASSN-19dj peaked in the UV/optical on 2019 March 6.5 (MJD = 58548.5) at a bolometric luminosity of L = (6.2 ± 0.2) × 1044 erg s−1. Initially remaining roughly constant in X-rays and slowly fading in the UV/optical, the X-ray flux increased by over an order of magnitude ∼225 d after peak, resulting from the expansion of the X-ray emitting region. The late-time X-ray emission is well fitted by a blackbody with an effective radius of ∼1 × 1012 cm and a temperature of ∼6 × 105 K. The X-ray hardness ratio becomes softer after brightening and then returns to a harder state as the X-rays fade. Analysis of Catalina Real-Time Transient Survey images reveals a nuclear outburst roughly 14.5 yr earlier with a smooth decline and a luminosity of LV ≥ 1.4 × 1043 erg s−1, although the nature of the flare is unknown. ASASSN-19dj occurred in the most extreme post-starburst galaxy yet to host a TDE, with Lick HδA = 7.67 ± 0.17 Å.
The trapped-ion quantum charge-coupled device (QCCD) proposal
lays out a blueprint for a universal quantum computer that uses mobile ions as qubits. Analogous to a charge-coupled device (CCD) camera, ...which stores and processes imaging information as movable electrical charges in coupled pixels, a QCCD computer stores quantum information in the internal state of electrically charged ions that are transported between different processing zones using dynamic electric fields. The promise of the QCCD architecture is to maintain the low error rates demonstrated in small trapped-ion experiments
by limiting the quantum interactions to multiple small ion crystals, then physically splitting and rearranging the constituent ions of these crystals into new crystals, where further interactions occur. This approach leverages transport timescales that are fast relative to the coherence times of the qubits, the insensitivity of the qubit states of the ion to the electric fields used for transport, and the low crosstalk afforded by spatially separated crystals. However, engineering a machine capable of executing these operations across multiple interaction zones with low error introduces many difficulties, which have slowed progress in scaling this architecture to larger qubit numbers. Here we use a cryogenic surface trap to integrate all necessary elements of the QCCD architecture-a scalable trap design, parallel interaction zones and fast ion transport-into a programmable trapped-ion quantum computer that has a system performance consistent with the low error rates achieved in the individual ion crystals. We apply this approach to realize a teleported CNOT gate using mid-circuit measurement
, negligible crosstalk error and a quantum volume
of 2
= 64. These results demonstrate that the QCCD architecture provides a viable path towards high-performance quantum computers.
We present the discovery by the WASP-South survey of WASP-121 b, a new remarkable short-period transiting hot Jupiter. The planet has a mass of
$1.183_{-0.062}^{+0.064}$
M
Jup, a radius of 1.865 ± ...0.044 R
Jup, and transits every
$1.274\,9255_{-0.000\,0025}^{+0.000\,0020}$
days an active F6-type main-sequence star (V = 10.4,
$1.353_{-0.079}^{+0.080}$
M⊙, 1.458 ± 0.030 R⊙, T
eff = 6460 ± 140 K). A notable property of WASP-121 b is that its orbital semimajor axis is only ∼1.15 times larger than its Roche limit, which suggests that the planet is close to tidal disruption. Furthermore, its large size and extreme irradiation (∼7.1 109 erg s−1 cm−2) make it an excellent target for atmospheric studies via secondary eclipse observations. Using the TRAnsiting Planets and PlanetesImals Small Telescope, we indeed detect its emission in the z
′-band at better than ∼4σ, the measured occultation depth being 603 ± 130 ppm. Finally, from a measurement of the Rossiter–McLaughlin effect with the CORALIE spectrograph, we infer a sky-projected spin-orbit angle of
$257{^{\circ}_{.}} 8_{-5{^{\circ}_{.}} 5}^{+5{^{\circ}_{.}} 3}$
. This result may suggest a significant misalignment between the spin axis of the host star and the orbital plane of the planet. If confirmed, this high misalignment would favour a migration of the planet involving strong dynamical events with a third body.
Context.
High-precision pulsar timing requires accurate corrections for dispersive delays of radio waves, parametrized by the dispersion measure (DM), particularly if these delays are variable in ...time. In a previous paper, we studied the solar wind (SW) models used in pulsar timing to mitigate the excess of DM that is annually induced by the SW and found these to be insufficient for high-precision pulsar timing. Here we analyze additional pulsar datasets to further investigate which aspects of the SW models currently used in pulsar timing can be readily improved, and at what levels of timing precision SW mitigation is possible.
Aims.
Our goals are to verify: (a) whether the data are better described by a spherical model of the SW with a time-variable amplitude, rather than a time-invariant one as suggested in literature, and (b) whether a temporal trend of such a model’s amplitudes can be detected.
Methods.
We use the pulsar timing technique on low-frequency pulsar observations to estimate the DM and quantify how this value changes as the Earth moves around the Sun. Specifically, we monitor the DM in weekly to monthly observations of 14 pulsars taken with parts of the LOw-Frequency ARray (LOFAR) across time spans of up to 6 years. We develop an informed algorithm to separate the interstellar variations in the DM from those caused by the SW and demonstrate the functionality of this algorithm with extensive simulations. Assuming a spherically symmetric model for the SW density, we derive the amplitude of this model for each year of observations.
Results.
We show that a spherical model with a time-variable amplitude models the observations better than a spherical model with a constant amplitude, but that both approaches leave significant SW-induced delays uncorrected in a number of pulsars in the sample. The amplitude of the spherical model is found to be variable in time, as opposed to what has been previously suggested.
The goal of this study was to determine the predictive value of cardiac T2* magnetic resonance for heart failure and arrhythmia in thalassemia major.
We analyzed cardiac and liver T2* magnetic ...resonance and serum ferritin in 652 thalassemia major patients from 21 UK centers with 1442 magnetic resonance scans. The relative risk for heart failure with cardiac T2* values <10 ms (compared with >10 ms) was 160 (95% confidence interval, 39 to 653). Heart failure occurred in 47% of patients within 1 year of a cardiac T2* <6 ms with a relative risk of 270 (95% confidence interval, 64 to 1129). The area under the receiver-operating characteristic curve for predicting heart failure was significantly greater for cardiac T2* (0.948) than for liver T2* (0.589; P<0.001) or serum ferritin (0.629; P<0.001). Cardiac T2* was <10 ms in 98% of scans in patients who developed heart failure. The relative risk for arrhythmia with cardiac T2* values <20 ms (compared with >20 ms) was 4.6 (95% confidence interval, 2.66 to 7.95). Arrhythmia occurred in 14% of patients within 1 year of a cardiac T2* of <6 ms. The area under the receiver-operating characteristic curve for predicting arrhythmia was significantly greater for cardiac T2* (0.747) than for liver T2* (0.514; P<0.001) or serum ferritin (0.518; P<0.001). The cardiac T2* was <20 ms in 83% of scans in patients who developed arrhythmia.
Cardiac T2* magnetic resonance identifies patients at high risk of heart failure and arrhythmia from myocardial siderosis in thalassemia major and is superior to serum ferritin and liver iron. Using cardiac T2* for the early identification and treatment of patients at risk is a logical means of reducing the high burden of cardiac mortality in myocardial siderosis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00520559.
•These ESMO Clinical Practice Guidelines provide recommendations for:○Fertility preservation strategies in post-pubertal cancer patients, including those with hereditary cancer syndromes.○The ...management of post-treatment pregnancies in cancer survivors, including those with hereditary cancer syndromes.•Management flowcharts for fertility preservation strategies are also provided.•Recommendations were compiled by the authors based on available scientific data and the authors' collective expert opinion.
Defensins contribute to host defense by disrupting the cytoplasmic membrane of microorganisms. This report shows that human β-defensins are also chemotactic for immature dendritic cells and memory T ...cells. Human β-defensin was selectively chemotactic for cells stably transfected to express human CCR6, a chemokine receptor preferentially expressed by immature dendritic cells and memory T cells. The β-defensin-induced chemotaxis was sensitive to pertussis toxin and inhibited by antibodies to CCR6. The binding of iodinated LARC, the chemokine ligand for CCR6, to CCR6-transfected cells was competitively displaced by β-defensin. Thus, β-defensins may promote adaptive immune responses by recruiting dendritic and T cells to the site of microbial invasion through interaction with CCR6.
Context.
Radio pulses from pulsars are affected by plasma dispersion, which results in a frequency-dependent propagation delay. Variations in the magnitude of this effect lead to an additional source ...of red noise in pulsar timing experiments, including pulsar timing arrays (PTAs) that aim to detect nanohertz gravitational waves.
Aims.
We aim to quantify the time-variable dispersion with much improved precision and characterise the spectrum of these variations.
Methods.
We use the pulsar timing technique to obtain highly precise dispersion measure (DM) time series. Our dataset consists of observations of 36 millisecond pulsars, which were observed for up to 7.1 yr with the LOw Frequency ARray (LOFAR) telescope at a centre frequency of ~150 MHz. Seventeen of these sources were observed with a weekly cadence, while the rest were observed at monthly cadence.
Results.
We achieve a median DM precision of the order of 10
−5
cm
−3
pc for a significant fraction of our sources. We detect significant variations of the DM in all pulsars with a median DM uncertainty of less than 2 × 10
−4
cm
−3
pc. The noise contribution to pulsar timing experiments at higher frequencies is calculated to be at a level of 0.1–10
μ
s at 1.4 GHz over a timespan of a few years, which is in many cases larger than the typical timing precision of 1
μ
s or better that PTAs aim for. We found no evidence for a dependence of DM on radio frequency for any of the sources in our sample.
Conclusions.
The DM time series we obtained using LOFAR could in principle be used to correct higher-frequency data for the variations of the dispersive delay. However, there is currently the practical restriction that pulsars tend to provide either highly precise times of arrival (ToAs) at 1.4 GHz or a high DM precision at low frequencies, but not both, due to spectral properties. Combining the higher-frequency ToAs with those from LOFAR to measure the infinite-frequency ToA and DM would improve the result.
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