RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule ...inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.
Climate change induced by anthropogenic warming of the earth's atmosphere is a daunting problem. This review examines one of the consequences of climate change that has only recently attracted ...attention: namely, the effects of climate change on the environmental distribution and toxicity of chemical pollutants. A review was undertaken of the scientific literature (original research articles, reviews, government and intergovernmental reports) focusing on the interactions of toxicants with the environmental parameters, temperature, precipitation, and salinity, as altered by climate change. Three broad classes of chemical toxicants of global significance were the focus: air pollutants, persistent organic pollutants (POPs), including some organochlorine pesticides, and other classes of pesticides. Generally, increases in temperature will enhance the toxicity of contaminants and increase concentrations of tropospheric ozone regionally, but will also likely increase rates of chemical degradation. While further research is needed, climate change coupled with air pollutant exposures may have potentially serious adverse consequences for human health in urban and polluted regions. Climate change producing alterations in: food webs, lipid dynamics, ice and snow melt, and organic carbon cycling could result in increased POP levels in water, soil, and biota. There is also compelling evidence that increasing temperatures could be deleterious to pollutant-exposed wildlife. For example, elevated water temperatures may alter the biotransformation of contaminants to more bioactive metabolites and impair homeostasis. The complex interactions between climate change and pollutants may be particularly problematic for species living at the edge of their physiological tolerance range where acclimation capacity may be limited. In addition to temperature increases, regional precipitation patterns are projected to be altered with climate change. Regions subject to decreases in precipitation may experience enhanced volatilization of POPs and pesticides to the atmosphere. Reduced precipitation will also increase air pollution in urbanized regions resulting in negative health effects, which may be exacerbated by temperature increases. Regions subject to increased precipitation will have lower levels of air pollution, but will likely experience enhanced surface deposition of airborne POPs and increased run-off of pesticides. Moreover, increases in the intensity and frequency of storm events linked to climate change could lead to more severe episodes of chemical contamination of water bodies and surrounding watersheds. Changes in salinity may affect aquatic organisms as an independent stressor as well as by altering the bioavailability and in some instances increasing the toxicity of chemicals. A paramount issue will be to identify species and populations especially vulnerable to climate–pollutant interactions, in the context of the many other physical, chemical, and biological stressors that will be altered with climate change. Moreover, it will be important to predict tipping points that might trigger or accelerate synergistic interactions between climate change and contaminant exposures.
Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for ...promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53-driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport β₁ integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53-driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.
Several developmental pathways contribute to processes that regulate tissue growth and organ size. The Hippo pathway has emerged as one such critical regulator. However, how Hippo signaling is ...integrated with other pathways to coordinate these processes remains unclear. Here, we show that the Hippo pathway restricts Wnt/β-Catenin signaling by promoting an interaction between TAZ and DVL in the cytoplasm. TAZ inhibits the CK1δ/ɛ-mediated phosphorylation of DVL, thereby inhibiting Wnt/β-Catenin signaling. Abrogation of TAZ levels or Hippo signaling enhances Wnt3A-stimulated DVL phosphorylation, nuclear β-Catenin, and Wnt target gene expression. Mice lacking
Taz develop polycystic kidneys with enhanced cytoplasmic and nuclear β-Catenin. Moreover, in
Drosophila, Hippo signaling modulates Wg target gene expression. These results uncover a cytoplasmic function of TAZ in regulating Wnt signaling and highlight the role of the Hippo pathway in coordinating morphogenetic signaling with growth control.
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► This work identifies a cytoplasmic role for the transcriptional coactivator TAZ ► TAZ, a Hippo pathway mediator, binds Dishevelled and inhibits Wnt signaling ► β-catenin is mislocalized in polycystic kidneys of TAZ null mice ► Disrupting the Hippo pathway in cell lines and flies modulates Wnt signaling
We present the analysis of 61 nucleated dwarf galaxies in the central regions ( Rvir/4) of the Fornax galaxy cluster. The galaxies and their nuclei are studied as part of the Next Generation Fornax ...Survey using optical imaging obtained with the Dark Energy Camera mounted at Blanco/Cerro Tololo Inter-American Observatory and near-infrared data obtained with VIRCam at VISTA/ESO. We decompose the nucleated dwarfs in nucleus and spheroid, after subtracting the surface brightness profile of the spheroid component and studying the nucleus using point source photometry. In general, nuclei are consistent with colors of confirmed metal-poor globular clusters, but with significantly smaller dispersion than other confirmed compact stellar systems in Fornax. We find a bimodal nucleus mass distribution with peaks located at and ∼6.3. These two nucleus subpopulations have different stellar population properties: the more massive nuclei are older than ∼2 Gyr and have metal-poor stellar populations (Z ≤ 0.02 Z ), while the less massive nuclei are younger than ∼2 Gyr with metallicities in the range 0.02 < Z/Z ≤ 1. We find that the nucleus mass ( ) versus galaxy mass ( ) relation becomes shallower for less massive galaxies starting around 108 M , and the mass ratio shows a clear anticorrelation with for the lowest masses, reaching 10%. We test current theoretical models of nuclear cluster formation and find that they cannot fully reproduce the observed trends. A likely mixture of in situ star formation and star cluster mergers seems to be acting during nucleus growth over cosmic time.
We have derived nebular abundances for 10 dwarf galaxies belonging to the M81 Group, including several galaxies which do not have abundances previously reported in the literature. For each galaxy, ...multiple H II regions were observed with GMOS-N at the Gemini Observatory in order to determine abundances of several elements (oxygen, nitrogen, sulfur, neon, and argon). For seven galaxies, at least one H II region had a detection of the temperature sensitive O III Delta *l4363 line, allowing a 'direct' determination of the oxygen abundance. No abundance gradients were detected in the targeted galaxies, and the observed oxygen abundances are typically in agreement with the well-known metallicity-luminosity relation. However, three candidate 'tidal dwarf' galaxies lie well off this relation: UGC 5336, Garland, and KDG 61. The nature of these systems suggests that UGC 5336 and Garland are indeed recently formed systems, whereas KDG 61 is most likely a dwarf spheroidal galaxy which lies along the same line of sight as the M81 tidal debris field. We propose that these H II regions formed from previously enriched gas which was stripped from nearby massive galaxies (e.g., NGC 3077 and M81) during a recent tidal interaction.
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer‐related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer ...little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1‐Cre KrasG12D/+ Trp53R172H/+ (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor‐free survival in KPC mice with early‐stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease.
Synopsis
Lysyl oxidase (LOX) is identified as a therapeutic target in pancreatic ductal adenocarcinoma (PDAC). Inhibition of LOX resulted in increased drug efficacy and stromal changes and reduction in metastasis.
A signature of hazardous and protective genes in PDAC was defined. High expression of hypoxia‐associated genes, including LOX, was associated with poor patient prognosis.
Using transgenic mouse models of PDAC, LOX was found to be overexpressed in metastatic disease and its expression was required for PDAC cell invasion.
Inhibition of LOX in transgenic mice inhibited metastasis, while combination therapy with LOX inhibition and gemcitabine induced stromal alterations, immune cell infiltration and tumor necrosis and improved survival.
Lysyl oxidase (LOX) is identified as a therapeutic target in pancreatic ductal adenocarcinoma (PDAC). Inhibition of LOX resulted in increased drug efficacy and stromal changes and reduction in metastasis.
We report the discovery of 271 previously undetected dwarf galaxies in the outer Fornax cluster regions at radii rvir/4 < r < rvir/2 using data from the Next Generation Fornax Survey (NGFS) with deep ...coadded u′, g′, and i′ images obtained with Blanco/DECam at Cerro Tololo Interamerican Observatory. From the 271 dwarf candidates, we find 39 to be nucleated. Together with our previous study of the central Fornax region, the new dwarfs detected with NGFS data number 392, of which 56 are nucleated. The total Fornax dwarf galaxy population from NGFS and other catalogs rises, therefore, to a total of 643 with 181 being nucleated, yielding an overall nucleation fraction of 28%. The absolute i′-band magnitudes for the outer NGFS dwarfs are in the range −18.80 ≤ Mi′ ≤ −8.78 with effective radii reff,i′ = 0.18-2.22 kpc and an average Sérsic index . Nonnucleated dwarfs are found to be fainter and smaller by mag and than the nucleated dwarfs. We demonstrate a significant clustering of dwarf galaxies on scales 100 kpc, and projected surface number density profile estimates, N(r), show a concentration of dwarfs in the Fornax core region within r 350 kpc. N(r) has a flat distribution up to ∼350 kpc, beyond which it declines for the nonnucleated dwarfs. The nucleated dwarfs have a steeper N(r) distribution, are more concentrated toward NGC 1399, and are decreasing rapidly outwards. This is the first time the transition from cluster to field environment has been established for the very faint dwarf galaxy population with robust sample statistics.
ABSTRACT
We present the stellar kinematics of 48 representative elliptical and lenticular galaxies obtained with our custom‐built integral‐field spectrograph SAURON operating on the William Herschel ...Telescope. The data were homogeneously processed through a dedicated reduction and analysis pipeline. All resulting SAURON data cubes were spatially binned to a constant minimum signal‐to‐noise ratio. We have measured the stellar kinematics with an optimized (penalized pixel‐fitting) routine which fits the spectra in pixel space, via the use of optimal templates, and prevents the presence of emission lines to affect the measurements. We have thus generated maps of the mean stellar velocity V, the velocity dispersion σ, and the Gauss–Hermite moments h3 and h4 of the line‐of‐sight velocity distributions. The maps extend to approximately one effective radius. Many objects display kinematic twists, kinematically decoupled components, central stellar discs, and other peculiarities, the nature of which will be discussed in future papers of this series.
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