877 research outputs found
A protocol for amide bond formation with electron deficient amines and sterically hindered substrates
Probe-dependent negative allosteric modulators of the long-chain free fatty acid receptor FFA4
High-affinity and selective antagonists that are able to block the actions of both endogenous and synthetic agonists of G protein–coupled receptors are integral to analysis of receptor function and to support suggestions of therapeutic potential. Although there is great interest in the potential of free fatty acid receptor 4 (FFA4) as a novel therapeutic target for the treatment of type II diabetes, the broad distribution pattern of this receptor suggests it may play a range of roles beyond glucose homeostasis in different cells and tissues. To date, a single molecule, 4-methyl-N-9H-xanthen-9-yl-benzenesulfonamide (AH-7614), has been described as an FFA4 antagonist; however, its mechanism of antagonism remains unknown. We synthesized AH-7614 and a chemical derivative and demonstrated these to be negative allosteric modulators (NAMs) of FFA4. Although these NAMs did inhibit FFA4 signaling induced by a range of endogenous and synthetic agonists, clear agonist probe dependence in the nature of allosteric modulation was apparent. Although AH-7614 did not antagonize the second long-chain free fatty acid receptor, free fatty acid receptor 1, the simple chemical structure of AH-7614 containing features found in many anticancer drugs suggests that a novel close chemical analog of AH-7614 devoid of FFA4 activity, 4-methyl-N-(9H-xanthen-9-yl)benzamide (TUG-1387), will also provide a useful control compound for future studies assessing FFA4 function. Using TUG-1387 alongside AH-7614, we show that endogenous activation of FFA4 expressed by murine C3H10T1/2 mesenchymal stem cells is required for induced differentiation of these cells toward a more mature, adipocyte-like phenotype
A primordial star in the heart of the Lion
Context: The discovery and chemical analysis of extremely metal-poor stars
permit a better understanding of the star formation of the first generation of
stars and of the Universe emerging from the Big Bang. aims: We report the study
of a primordial star situated in the centre of the constellation Leo (SDSS
J102915+172027). method: The star, selected from the low resolution-spectrum of
the Sloan Digital Sky Survey, was observed at intermediate (with X-Shooter at
VLT) and at high spectral resolution (with UVES at VLT). The stellar parameters
were derived from the photometry. The standard spectroscopic analysis based on
1D ATLAS models was completed by applying 3D and non-LTE corrections. results:
An iron abundance of [Fe/H]=--4.89 makes SDSS J102915+172927 one of the lowest
[Fe/H] stars known. However, the absence of measurable C and N enhancements
indicates that it has the lowest metallicity, Z<= 7.40x10^{-7} (metal-mass
fraction), ever detected. No oxygen measurement was possible. conclusions: The
discovery of SDSS J102915+172927 highlights that low-mass star formation
occurred at metallicities lower than previously assumed. Even lower metallicity
stars may yet be discovered, with a chemical composition closer to the
composition of the primordial gas and of the first supernovae.Comment: To be published in A&
High Mobility Group Box 1 (HMGB1) Induces Toll-Like Receptor 4-Mediated Production of the Immunosuppressive Protein Galectin-9 in Human Cancer Cells
High mobility group box 1 (HMGB1) is a non-histone protein which is predominantly localised in the cell nucleus. However, stressed, dying, injured or dead cells can release this protein into the extracellular matrix passively. In addition, HMGB1 release was observed in cancer and immune cells where this process can be triggered by various endogenous as well as exogenous stimuli. Importantly, released HMGB1 acts as a so-called “danger signal” and could impact on the ability of cancer cells to escape host immune surveillance. However, the molecular mechanisms underlying the functional role of HMGB1 in determining the capability of human cancer cells to evade immune attack remain unclear. Here we report that the involvement of HMGB1 in anti-cancer immune evasion is determined by Toll-like receptor (TLR) 4, which recognises HMGB1 as a ligand. We found that HGMB1 induces TLR4-mediated production of transforming growth factor beta type 1 (TGF-β), displaying autocrine/paracrine activities. TGF-β induces production of the immunosuppressive protein galectin-9 in cancer cells. In TLR4-positive cancer cells, HMGB1 triggers the formation of an autocrine loop which induces galectin-9 expression. In malignant cells lacking TLR4, the same effect could be triggered by HMGB1 indirectly through TLR4-expressing myeloid cells present in the tumour microenvironment (e. g. tumour-associated macrophages)
Emerging methods and tools for environmental risk assessment, decision-making, and policy for nanomaterials: summary of NATO Advanced Research Workshop
Nanomaterials and their associated technologies hold promising opportunities for the development of new materials and applications in a wide variety of disciplines, including medicine, environmental remediation, waste treatment, and energy conservation. However, current information regarding the environmental effects and health risks associated with nanomaterials is limited and sometimes contradictory. This article summarizes the conclusions of a 2008 NATO workshop designed to evaluate the wide-scale implications (e.g., benefits, risks, and costs) of the use of nanomaterials on human health and the environment. A unique feature of this workshop was its interdisciplinary nature and focus on the practical needs of policy decision makers. Workshop presentations and discussion panels were structured along four main themes: technology and benefits, human health risk, environmental risk, and policy implications. Four corresponding working groups (WGs) were formed to develop detailed summaries of the state-of-the-science in their respective areas and to discuss emerging gaps and research needs. The WGs identified gaps between the rapid advances in the types and applications of nanomaterials and the slower pace of human health and environmental risk science, along with strategies to reduce the uncertainties associated with calculating these risks
Formation and Evolution of Supermassive Black Holes
The correlation between the mass of supermassive black holes in galaxy nuclei
and the mass of the galaxy spheroids or bulges (or more precisely their central
velocity dispersion), suggests a common formation scenario for galaxies and
their central black holes. The growth of bulges and black holes can commonly
proceed through external gas accretion or hierarchical mergers, and are both
related to starbursts. Internal dynamical processes control and regulate the
rate of mass accretion. Self-regulation and feedback are the key of the
correlation. It is possible that the growth of one component, either BH or
bulge, takes over, breaking the correlation, as in Narrow Line Seyfert 1
objects. The formation of supermassive black holes can begin early in the
universe, from the collapse of Population III, and then through gas accretion.
The active black holes can then play a significant role in the re-ionization of
the universe. The nuclear activity is now frequently invoked as a feedback to
star formation in galaxies, and even more spectacularly in cooling flows. The
growth of SMBH is certainly there self-regulated. SMBHs perturb their local
environment, and the mergers of binary SMBHs help to heat and destroy central
stellar cusps. The interpretation of the X-ray background yields important
constraints on the history of AGN activity and obscuration, and the census of
AGN at low and at high redshifts reveals the downsizing effect, already
observed for star formation. History appears quite different for bright QSO and
low-luminosity AGN: the first grow rapidly at high z, and their number density
decreases then sharply, while the density of low-luminosity objects peaks more
recently, and then decreases smoothly.Comment: 31 pages, 13 figures, review paper for Astrophysics Update
Transforming growth factor beta type 1 (TGF-B) and hypoxia-inducible factor 1 (HIF-1) transcription complex as master regulators of the immunosuppressive protein galectin-9 expression in human cancer and embryonic cells
Galectin-9 is one of the key proteins employed by a variety of human malignancies to suppress anti-cancer activities of cytotoxic lymphoid cells and thus escape immune surveillance. Human cancer cells in most cases express higher levels of galectin-9 compared to non-transformed cells. However, the biochemical mechanisms underlying this phenomenon remain unclear. Here we report for the first time that in human cancer as well as embryonic cells, the transcription factors hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP-1) are involved in upregulation of transforming growth factor beta 1 (TGF-β1) expression, leading to activation of the transcription factor Smad3 through autocrine action. This process triggers upregulation of galectin-9 expression in both malignant (mainly in breast and colorectal cancer as well as acute myeloid leukaemia (AML)) and embryonic cells. The effect, however, was not observed in mature non-transformed human cells. TGF-β1-activated Smad3 therefore displays differential behaviour in human cancer and embryonic vs non-malignant cells. This study uncovered a self-supporting biochemical mechanism underlying high levels of galectin-9 expression operated by the human cancer and embryonic cells employed in our investigations. Our results suggest the possibility of using the TGF-β1 signalling pathway as a potential highly efficient target for cancer immunotherapy
Masses, radii, and orbits of small Kepler planets : The transition from gaseous to rocky planets
We report on the masses, sizes, and orbits of the planets orbiting 22 Kepler stars. There are 49 planet candidates around these stars, including 42 detected through transits and 7 revealed by precise Doppler measurements of the host stars. Based on an analysis of the Kepler brightness measurements, along with high-resolution imaging and spectroscopy, Doppler spectroscopy, and (for 11 stars) asteroseismology, we establish low false-positive probabilities (FPPs) for all of the transiting planets (41 of 42 have an FPP under 1%), and we constrain their sizes and masses. Most of the transiting planets are smaller than three times the size of Earth. For 16 planets, the Doppler signal was securely detected, providing a direct measurement of the planet's mass. For the other 26 planets we provide either marginal mass measurements or upper limits to their masses and densities; in many cases we can rule out a rocky composition. We identify six planets with densities above 5 g cm-3, suggesting a mostly rocky interior for them. Indeed, the only planets that are compatible with a purely rocky composition are smaller than 2 R ⊕. Larger planets evidently contain a larger fraction of low-density material (H, He, and H2O).Peer reviewedFinal Accepted Versio
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