A vivid and exciting account of royal
collectors, art dealers, connoisseurs
, and the rise of old master paintings Old master
paintings are among the most valuable and prestigious of the visual
arts, ...and the best examples command the highest prices of any
luxury commodity. In Kings and Connoisseurs , Jonathan
Brown tells the story of how painting rose to this exalted status.
The transformation of painting from an inexpensive to a costly art
form reached a crucial stage in the royal courts of Europe in the
seventeenth century, where rulers and aristocrats assembled huge
collections, often in short periods of time. By comparing
collecting and collectors at these courts, Brown explains the
formation of new attitudes toward pictures, as well as the
mechanisms that supported the enterprise of collecting, including
the emergence of the art dealer, the development of
connoisseurship, and the publication of sumptuous picture books of
various collections. The result is an exciting narrative of greed
and passion, played out against a background of international
politics and intrigue.
Heart failure (HF) is driven by the interplay between regulatory transcription factors and dynamic alterations in chromatin structure. Pathologic gene transactivation in HF is associated with ...recruitment of histone acetyl-transferases and local chromatin hyperacetylation. We therefore assessed the role of acetyl-lysine reader proteins, or bromodomains, in HF. Using a chemical genetic approach, we establish a central role for BET family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to expression of genes that are central to HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers as essential effectors of transcriptional pause release during HF pathogenesis and identifies BET coactivator proteins as therapeutic targets in the heart.
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•BET bromodomains coactivate cardiac gene expression programs•BET inhibition blocks pathologic cardiac remodeling in vitro and in vivo•BRD4 occupies active cardiac enhancers and promoters•BET inhibition blocks pathologic transcriptional elongation in the adult heart
Small-molecule inhibition of BET bromodomain proteins that recognize acetylated histones blocks release of paused polymerase at genes induced during cardiac stress. This inhibition protects against heart failure.
The spread of the SARS-CoV-2 into a global pandemic within a few months of onset motivates the development of a rapidly scalable vaccine. Here, we present a self-amplifying RNA encoding the ...SARS-CoV-2 spike protein encapsulated within a lipid nanoparticle (LNP) as a vaccine. We observe remarkably high and dose-dependent SARS-CoV-2 specific antibody titers in mouse sera, as well as robust neutralization of both a pseudo-virus and wild-type virus. Upon further characterization we find that the neutralization is proportional to the quantity of specific IgG and of higher magnitude than recovered COVID-19 patients. saRNA LNP immunizations induce a Th1-biased response in mice, and there is no antibody-dependent enhancement (ADE) observed. Finally, we observe high cellular responses, as characterized by IFN-γ production, upon re-stimulation with SARS-CoV-2 peptides. These data provide insight into the vaccine design and evaluation of immunogenicity to enable rapid translation to the clinic.
AMP-activated protein kinase (AMPK) is a conserved serine/threonine kinase with a critical function in the regulation of metabolic pathways in eukaryotic cells. Recently, AMPK has been shown to play ...an additional role as a regulator of inflammatory activity in leukocytes. Treatment of macrophages with chemical AMPK activators, or forced expression of a constitutively active form of AMPK, results in polarization to an anti-inflammatory phenotype. In addition, we reported previously that stimulation of macrophages with anti-inflammatory cytokines such as IL-10, IL-4, and TGF-β results in rapid activation of AMPK, suggesting that AMPK contributes to the suppressive function of these cytokines. In this study, we investigated the role of AMPK in IL-10-induced gene expression and anti-inflammatory function. IL-10-stimulated wild-type macrophages displayed rapid activation of PI3K and its downstream targets Akt and mammalian target of rapamycin complex (mTORC1), an effect that was not seen in macrophages generated from AMPKα1-deficient mice. AMPK activation was not impacted by treatment with either the PI3K inhibitor LY294002 or the JAK inhibitor CP-690550, suggesting that IL-10-mediated activation of AMPK is independent of PI3K and JAK activity. IL-10 induced phosphorylation of both Tyr(705) and Ser(727) residues of STAT3 in an AMPKα1-dependent manner, and these phosphorylation events were blocked by inhibition of Ca(2+)/calmodulin-dependent protein kinase kinase β, an upstream activator of AMPK, and by the mTORC1 inhibitor rapamycin, respectively. The impaired STAT3 phosphorylation in response to IL-10 observed in AMPKα1-deficient macrophages was accompanied by reduced suppressor of cytokine signaling 3 expression and an inadequacy of IL-10 to suppress LPS-induced proinflammatory cytokine production. Overall, our data demonstrate that AMPKα1 is required for IL-10 activation of the PI3K/Akt/mTORC1 and STAT3-mediated anti-inflammatory pathways regulating macrophage functional polarization.
Proinflammatory stimuli elicit rapid transcriptional responses via transduced signals to master regulatory transcription factors. To explore the role of chromatin-dependent signal transduction in the ...atherogenic inflammatory response, we characterized the dynamics, structure, and function of regulatory elements in the activated endothelial cell epigenome. Stimulation with tumor necrosis factor alpha prompted a dramatic and rapid global redistribution of chromatin activators to massive de novo clustered enhancer domains. Inflammatory super enhancers formed by nuclear factor-kappa B accumulate at the expense of immediately decommissioned, basal endothelial super enhancers, despite persistent histone hyperacetylation. Mass action of enhancer factor redistribution causes momentous swings in transcriptional initiation and elongation. A chemical genetic approach reveals a requirement for BET bromodomains in communicating enhancer remodeling to RNA Polymerase II and orchestrating the transition to the inflammatory cell state, demonstrated in activated endothelium and macrophages. BET bromodomain inhibition abrogates super enhancer-mediated inflammatory transcription, atherogenic endothelial responses, and atherosclerosis in vivo.
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•Activated NF-κB prompts rapid formation of super enhancers in endothelial cells•Super enhancer-bound BRD4 coactivates inflammatory genes•Redistribution of BRD4 results in eviction from basal super enhancers•BET bromodomain inhibition attenuates atherogenic responses and atherosclerosis
Activation of NF-κB underlies many chronic diseases including atherosclerosis. Brown et al. show that TNFα-mediated activation of NF-κB forms de novo super enhancers in endothelial cells by reallocation of the BET bromodomain protein BRD4 away from basal super enhancers. In a preclinical model of atherosclerosis, BET bromodomain inhibition can suppress atherogenesis.
This study examined the availability of primary care and wellness services in community mental health centers (CMHCs) and outpatient mental health facilities (OMHFs).
This study used data from the ...2016 National Mental Health Services Survey to examine the proportion of facilities that reported offering integrated primary care and wellness services (smoking and tobacco cessation counseling, diet and exercise counseling, and chronic disease and illness management). The study used logistic regression to model the odds that a facility offered integrated primary care as a function of facility characteristics.
Across states, 23% of CMHCs and 19% of OMHFs offered integrated primary care. The odds of offering integrated primary care were significantly higher among facilities that reported more quality improvement practices, prohibited smoking, or offered wellness services. Less than one third offered smoking and tobacco cessation counseling or other wellness services.
Integrated primary care remains uncommon in CMHCs and OMHFs and is more likely among facilities with certain characteristics.
We use direct method oxygen abundances in combination with strong optical emission lines, stellar masses (M
⋆), and star formation rates (SFRs) to recalibrate the N2, O3N2, and N2O2 oxygen abundance ...diagnostics. We stack spectra of ∼200 000 star-forming galaxies from the Sloan Digital Sky Survey in bins of M
⋆ and SFR offset from the star-forming main sequence (
$ {\Delta \log (SSFR)}$
) to measure the weak emission lines needed to apply the direct method. All three new calibrations are reliable to within ±0.10 dex from log (M
⋆/M⊙) ∼ 7.5–10.5 and up to at least 200 M⊙ yr−1 in SFR. The N2O2 diagnostic is the least subject to systematic biases. We apply the diagnostics to galaxies in the local Universe and investigate the M
⋆–Z–SFR relation. The N2 and O3N2 diagnostics suggest the SFR dependence of the M
⋆–Z–SFR relation varies with both M
⋆ and
${\Delta \log (SSFR)}$
, whereas the N2O2 diagnostic suggests a nearly constant dependence on SFR. We apply our calibrations to a sample of high-redshift galaxies from the literature, and find them to be metal-poor relative to local galaxies with similar M
⋆ and SFR. The calibrations do reproduce direct method abundances of the local analogues. We conclude that the M
⋆–Z–SFR relation evolves with redshift.
Hutchinson-Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that encodes nuclear lamin A. This ...mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and shortens the lifespan of children with progeria to approximately 14 years
. Adenine base editors (ABEs) convert targeted A•T base pairs to G•C base pairs with minimal by-products and without requiring double-strand DNA breaks or donor DNA templates
. Here we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured fibroblasts derived from children with progeria and in a mouse model of HGPS. Lentiviral delivery of the ABE to fibroblasts from children with HGPS resulted in 87-91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. Unbiased off-target DNA and RNA editing analysis did not detect off-target editing in treated patient-derived fibroblasts. In transgenic mice that are homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (around 20-60% across various organs six months after injection), restoration of normal RNA splicing and reduction of progerin protein levels. In vivo base editing rescued the vascular pathology of the mice, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days. These findings demonstrate the potential of in vivo base editing as a possible treatment for HGPS and other genetic diseases by directly correcting their root cause.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in the transcriptional regulation of key metabolic pathways such as lipid metabolism, ...adipogenesis, and insulin sensitivity. More recent work implicates all 3 PPAR isotypes (alpha, gamma, and delta, also known as beta or beta/delta) in inflammatory and atherosclerotic pathways. Because these nuclear receptors are activated by extracellular signals and control multiple gene targets, PPARs can be seen as nodes that control multiple inputs and outputs involved in energy balance, providing insight into how metabolism and the vasculature may be integrated. The ongoing clinical use of fibrates, which activate PPARalpha, and thiazolidinediones, which activate PPARgamma, establishes these receptors as viable drug targets, whereas considerable in vitro animal model and human surrogate marker studies suggest that PPAR activation may limit inflammation and atherosclerosis. Together, these various observations have stimulated intense interest in PPARs as therapeutic targets and led to large-scale cardiovascular end-point trials with PPAR agonists. The first of these studies has generated mixed results that require careful review, especially in anticipation of additional clinical trial data and ongoing attempts to develop novel PPAR modulators. Such analysis of the existing PPAR data, the appropriate use of currently approved PPAR agonists, and continued progress in PPAR therapeutics will be predicated on a better understanding of PPAR biology.
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