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.
It is widely accepted, based on data from the last few decades and on model simulations, that anthropogenic climate change will cause increased fire activity. However, less attention has been paid to ...the relationship between abrupt climate changes and heightened fire activity in the paleorecord. We use 35 charcoal and pollen records to assess how fire regimes in North America changed during the last glacial-interglacial transition (15 to 10 ka), a time of large and rapid climate changes. We also test the hypothesis that a comet impact initiated continental-scale wildfires at 12.9 ka; the data do not support this idea, nor are continent-wide fires indicated at any time during deglaciation. There are, however, clear links between large climate changes and fire activity. Biomass burning gradually increased from the glacial period to the beginning of the Younger Dryas. Although there are changes in biomass burning during the Younger Dryas, there is no systematic trend. There is a further increase in biomass burning after the Younger Dryas. Intervals of rapid climate change at 13.9, 13.2, and 11.7 ka are marked by large increases in fire activity. The timing of changes in fire is not coincident with changes in human population density or the timing of the extinction of the megafauna. Although these factors could have contributed to fire-regime changes at individual sites or at specific times, the charcoal data indicate an important role for climate, and particularly rapid climate change, in determining broad-scale levels of fire activity.
We present the PMAS/PPak Integral-field Supernova hosts COmpilation (PISCO), which comprises integral field spectroscopy (IFS) of 232 supernova (SN) host galaxies that hosted 272 SNe, observed over ...several semesters with the 3.5 m telescope at the Calar Alto Observatory (CAHA). PISCO is the largest collection of SN host galaxies observed with wide-field IFS, totaling 466,347 individual spectra covering a typical spatial resolution of ∼380 pc. Focused studies regarding specific SN Ia-related topics will be published elsewhere; this paper aims to present the properties of the SN environments, using stellar population (SP) synthesis, and the gas-phase interstellar medium, providing additional results separating stripped-envelope SNe into their subtypes. With 11,270 H ii regions detected in all galaxies, we present for the first time a statistical analysis of H ii regions, which puts H ii regions that have hosted SNe in context with all other star-forming clumps within their galaxies. SNe Ic are associated with environments that are more metal-rich and have higher EW(H ) and higher star formation rate within their host galaxies than the mean of all H ii regions detected within each host. This in contrast to SNe IIb, which occur in environments that are very different compared to other core-collapse SNe types. We find two clear components of young and old SPs at SNe IIn locations. We find that SNe II fast decliners tend to explode at locations where the SFR is more intense. Finally, we outline how a future dedicated IFS survey of galaxies in parallel to an untargeted SN search would overcome the biases in current environmental studies.
Wave attenuation by vegetation is a highly dynamic process and its quantification is important for understanding shore protection potential and modeling coastal hydrodynamics. Data documenting the ...interactions of Spartina alterniflora, represented by polyolefin tubing, and single- and double-peaked irregular waves were collected in a large-scale laboratory flume. The laboratory provided a controlled environment to evaluate wave attenuation, including the parameters of stem density, submergence, wave height, and peak period. Wave attenuation appeared to be most dependent on stem density and the ratio of stem length to water depth. Wave attention increased slightly with wave height while no clear trend with respect to wave period was seen. Treating double-peaked spectra as superimposed wave systems revealed a preferential dissipation of the higher-frequency wave system relative to the lower-frequency wave system under emergent conditions. Wave energy loss occurred at all frequencies of both spectral types, with dissipation increasing with frequency above the spectral peak. Parameterizing the spectral equilibrium range as a function of frequency showed a steepening of the spectral tail compared to the −4 power law under emergent conditions. An empirical relationship defining the bulk drag coefficient for S. alterniflora as a function of the stem Reynolds number is found to serve as a first estimate for engineering applications.
•Laboratory studies show the wave attenuation potential of salt marsh vegetation.•Explores the effects of stem density and varied hydrodynamics on wave attenuation.•Considers the attenuation of double-peaked spectra through vegetation.•Explores deviations from the f-4equlibrium range parameterization.•Presents an empirical formula for a bulk drag coefficient for S. alterniflora.
We examine a sample of ∼250 000 ‘locally brightest galaxies’ selected from the Sloan Digital Sky Survey to be central galaxies within their dark matter haloes. We stack the X-ray emission from these ...haloes, as a function of the stellar mass of the central galaxy, using data from the ROSAT All-Sky Survey. We detect emission across almost our entire sample, including emission which we attribute to hot gas around galaxies spanning a range of 1.2 dex in stellar mass (corresponding to nearly two orders of magnitude in halo mass) down to M
* = 1010.8 M⊙ (M
500 ≈ 1012.6 M⊙). Over this range, the X-ray luminosity can be fit by a power law, either of stellar mass or of halo mass. From this, we infer a single unified scaling relation between mass and L
X which applies for galaxies, groups, and clusters. This relation has a slope steeper than expected for self-similarity, showing the importance of non-gravitational heating. Assuming this non-gravitational heating is predominately due to AGN feedback, the lack of a break in the relation shows that AGN feedback is tightly self-regulated and fairly gentle, in agreement with the predictions of recent high-resolution simulations. Our relation is consistent with established measurements of the L
X–L
K
relation for elliptical galaxies as well as the L
X–M
500 relation for optically selected galaxy clusters. However, our L
X–M
500 relation has a normalization more than a factor of 2 below most previous relations based on X-ray-selected cluster samples. We argue that optical selection offers a less biased view of the L
X–M
500 relation for mass-selected clusters.
Interferon regulatory factor 4 (IRF4) is an attractive therapeutic target in multiple myeloma (MM). We here report that expression of IRF4 mRNA inversely correlates with microRNA (miR)-125b in MM ...patients. Moreover, we provide evidence that miR-125b is downregulated in TC2/3 molecular MM subgroups and in established cell lines. Importantly, constitutive expression of miR-125b-5p by lentiviral vectors or transfection with synthetic mimics impaired growth and survival of MM cells and overcame the protective role of bone marrow stromal cells in vitro. Apoptotic and autophagy-associated cell death were triggered in MM cells on miR-125b-5p ectopic expression. Importantly, we found that the anti-MM activity of miR-125b-5p was mediated via direct downregulation of IRF4 and its downstream effector BLIMP-1. Moreover, inhibition of IRF4 translated into downregulation of c-Myc, caspase-10 and cFlip, relevant IRF4-downstream effectors. Finally, in vivo intra-tumor or systemic delivery of formulated miR-125b-5p mimics against human MM xenografts in severe combined immunodeficient/non-obese diabetic mice induced significant anti-tumor activity and prolonged survival. Taken together, our findings provide evidence that miR-125b, differently from other hematologic malignancies, has tumor-suppressor activity in MM. Furthermore, our data provide proof-of-concept that synthetic miR-125b-5p mimics are promising anti-MM agents to be validated in early clinical trials.
Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has ...exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.
Breast cancer is a heterogeneous disease, divisible into a variable number of clinical subtypes. A fundamental question is how many etiological classes underlie the clinical spectrum of breast ...cancer? An etiological subtype reflects a grouping with a common set of causes, whereas a clinical subtype represents a grouping with similar prognosis and/or prediction. Herein, we review the evidence for breast cancer etiological heterogeneity. We then evaluate the etiological evidence with mRNA profiling data. A bimodal age distribution at diagnosis with peak frequencies near ages 50 and 70 years is a fundamental characteristic of breast cancer for important tumor features, clinical characteristics, risk factor profiles, and molecular subtypes. The bimodal peak frequencies at diagnosis divide breast cancer overall into a "mixture" of two main components in varying proportions in different cancer populations. The first breast cancer tends to arise early in life with modal age-at-diagnosis near 50 years and generally behaves aggressively. The second breast cancer occurs later in life with modal age near 70 years and usually portends a more indolent clinical course. These epidemiological and molecular data are consistent with a two-component mixture model and compatible with a hierarchal view of breast cancers arising from two main cell types of origin. Notwithstanding the potential added value of more detailed categorizations for personalized breast cancer treatment, we suggest that the development of better criteria to identify the two proposed etiologic classes would advance breast cancer research and prevention.
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