247 research outputs found
Soluble RAGE: a hot new biomarker for the hot joint?
The receptor for advanced glycation endproducts (RAGE) interacts with distinct ligand families linked to the inflammatory response. Studies in animal models suggest that RAGE is upregulated in the inflamed joint and that blockade of the receptor, using a ligand decoy soluble form of RAGE (sRAGE), attenuates joint inflammation and expression of inflammatory and tissue-destructive mediators. In this issue of Arthritis Research & Therapy, Rille Pullerits and colleagues reported that plasma levels of sRAGE were reduced in subjects with rheumatoid arthritis compared with healthy controls or subjects with non-inflammatory joint disease. These findings suggest the possibility that levels of sRAGE might be a biomarker of inflammation. Not resolved by these studies, however, is the intriguing possibility that endogenously higher levels of sRAGE might be linked to a lower incidence of arthritis or to the extent of inflammation. Nevertheless, although 'cause or effect' relationships may not be established in this report, fascinating insights into RAGE, inflammation and human arthritis emerge from these studies
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Percutaneous Cell Delivery Into the Heart Using Hydrogels Polymerizing In Situ
Heart disease is the leading cause of death in the US. Following an acute myocardial infarction, a fibrous, noncontractile scar develops, and results in congestive heart failure in more than 500,000 patients in the US each year. Muscle regeneration and the induction of new vascular growth to treat ischemic disorders of the heart can have significant therapeutic implications. Early studies in patients with chronic ischemic systolic left ventricular dysfunction (SLVD) using skeletal myoblasts or bone marrow-derived cells report improvement in left ventricular ejection function (LVEF) and clinical status, without notable safety issues. Nonetheless, the efficacy of cell transfer for cardiovascular disease is not established, in part due to a lack of control over cell retention, survival, and function following delivery. We studied the use of biocompatible hydrogels polymerizable in situ as a cell delivery vehicle, to improve cell retention, survival, and function following delivery into the ischemic myocardium. The study was conducted using human bone marrow-derived mesenchymal stem cells and fibrin glue, but the methods are applicable to any human stem cells (adult or embryonic) and a wide range of hydrogels. We first evaluated the utility of several commercially available percutaneous catheters for delivery of viscous cell/hydrogel suspensions. Next we characterized the polymerization kinetics of fibrin glue solutions to define the ranges of concentrations compatible with catheter delivery. We then demonstrate the in vivo effectiveness of this preparation and its ability to increase cell retention and survival in a nude rat model of myocardial infarction
Glycation and diabetes: The RAGE connection
The hyperglycaemic state seen in diabetes mellitus is associated with the development of diabetes-specific microvascular complications and accelerated macrovascular disease. Evidence implicates the formation and subsequent effects of advanced glycation endproducts (AGEs) as a contributing cause. AGEs exert their effects through interaction with the Receptor for AGE (RAGE) which upregulates expression of the receptor and induces a cascade of cytotoxic pathways. Accumulation of AGE/RAGE can be seen at sites of vascular disease in both animal models of diabetes and human diabetic subjects. Blockade of RAGE in animal models of diabetes suppresses development of dysfunction in the vasculature and atherosclerosis development. Genetic studies of RAGE reveal that a number of allelic variants of RAGE occur in key protein and regulatory domains. A Gly to Ser change at position 82 and two 5¢¢ flanking polymorphisms at position –374 and –429 lead to altered function and expression of RAGE which may impact on diabetic vascular disease development. Therapy aimed to block RAGE upregulation may prove to be useful in treating individuals with diabetic vascular disease
The Extragalactic Distance Scale Key Project XXVII. A Derivation of the Hubble Constant Using the Fundamental Plane and Dn-Sigma Relations in Leo I, Virgo, and Fornax
Using published photometry and spectroscopy, we construct the fundamental
plane and D_n-Sigma relations in Leo I, Virgo and Fornax. The published Cepheid
P-L relations to spirals in these clusters fixes the relation between angular
size and metric distance for both the fundamental plane and D_n-Sigma
relations. Using the locally calibrated fundamental plane, we infer distances
to a sample of clusters with a mean redshift of cz \approx 6000 \kms, and
derive a value of H_0=78+- 5+- 9 km/s/Mpc (random, systematic) for the local
expansion rate. This value includes a correction for depth effects in the
Cepheid distances to the nearby clusters, which decreased the deduced value of
the expansion rate by 5% +- 5%. If one further adopts the metallicity
correction to the Cepheid PL relation, as derived by the Key Project, the value
of the Hubble constant would decrease by a further 6%+- 4%. These two sources
of systematic error, when combined with a +- 6% error due to the uncertainty in
the distance to the Large Magellanic Cloud, a +- 4% error due to uncertainties
in the WFPC2 calibration, and several small sources of uncertainty in the
fundamental plane analysis, combine to yield a total systematic uncertainty of
+- 11%. We find that the values obtained using either the CMB, or a flow-field
model, for the reference frame of the distant clusters, agree to within 1%. The
Dn-Sigma relation also produces similar results, as expected from the
correlated nature of the two scaling relations. A complete discussion of the
sources of random and systematic error in this determination of the Hubble
constant is also given, in order to facilitate comparison with the other
secondary indicators being used by the Key Project.Comment: 21 pages, 3 figures, Accepted for publication in Ap
The Buffer Gas Beam: An Intense, Cold, and Slow Source for Atoms and Molecules
Beams of atoms and molecules are stalwart tools for spectroscopy and studies
of collisional processes. The supersonic expansion technique can create cold
beams of many species of atoms and molecules. However, the resulting beam is
typically moving at a speed of 300-600 m/s in the lab frame, and for a large
class of species has insufficient flux (i.e. brightness) for important
applications. In contrast, buffer gas beams can be a superior method in many
cases, producing cold and relatively slow molecules in the lab frame with high
brightness and great versatility. There are basic differences between
supersonic and buffer gas cooled beams regarding particular technological
advantages and constraints. At present, it is clear that not all of the
possible variations on the buffer gas method have been studied. In this review,
we will present a survey of the current state of the art in buffer gas beams,
and explore some of the possible future directions that these new methods might
take
Molecules cooled below the Doppler limit
The ability to cool atoms below the Doppler limit -- the minimum temperature reachable by Doppler cooling -- has been essential to most experiments with quantum degenerate gases, optical lattices and atomic fountains, among many other applications. A broad set of new applications await ultracold molecules, and the extension of laser cooling to molecules has begun. A molecular magneto-optical trap has been demonstrated, where molecules approached the Doppler limit. However, the sub-Doppler temperatures required for most applications have not yet been reached. Here we cool molecules to 50 uK, well below the Doppler limit, using a three-dimensional optical molasses. These ultracold molecules could be loaded into optical tweezers to trap arbitrary arrays for quantum simulation, launched into a molecular fountain for testing fundamental physics, and used to study ultracold collisions and ultracold chemistry
Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds
The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and KrĂĽppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting
Computational and Serologic Analysis of Novel and Known Viruses in Species Human Adenovirus D in Which Serology and Genomics Do Not Correlate
In November of 2007 a human adenovirus (HAdV) was isolated from a bronchoalveolar lavage (BAL) sample recovered from a biopsy of an AIDS patient who presented with fever, cough, tachycardia, and expiratory wheezes. To better understand the isolated virus, the genome was sequenced and analyzed using bioinformatic and phylogenomic analysis. The results suggest that this novel virus, which is provisionally named HAdV-D59, may have been created from multiple recombination events. Specifically, the penton, hexon, and fiber genes have high nucleotide identity to HAdV-D19C, HAdV-D25, and HAdV-D56, respectively. Serological results demonstrated that HAdV-D59 has a neutralization profile that is similar yet not identical to that of HAdV-D25. Furthermore, we observed a two-fold difference between the ability of HAdV-D15 and HAdV-D25 to be neutralized by reciprocal antiserum indicating that the two hexon proteins may be more similar in epitopic conformation than previously assumed. In contrast, hexon loops 1 and 2 of HAdV-D15 and HAdV-D25 share 79.13 and 92.56 percent nucleotide identity, respectively. These data suggest that serology and genomics do not always correlate
Wide-Field InfrarRed Survey Telescope-Astrophysics Focused Telescope Assets WFIRST-AFTA 2015 Report
This report describes the 2014 study by the Science Definition Team (SDT) of
the Wide-Field Infrared Survey Telescope (WFIRST) mission. It is a space
observatory that will address the most compelling scientific problems in dark
energy, exoplanets and general astrophysics using a 2.4-m telescope with a
wide-field infrared instrument and an optical coronagraph. The Astro2010
Decadal Survey recommended a Wide Field Infrared Survey Telescope as its top
priority for a new large space mission. As conceived by the decadal survey,
WFIRST would carry out a dark energy science program, a microlensing program to
determine the demographics of exoplanets, and a general observing program
utilizing its ultra wide field. In October 2012, NASA chartered a Science
Definition Team (SDT) to produce, in collaboration with the WFIRST Study Office
at GSFC and the Program Office at JPL, a Design Reference Mission (DRM) for an
implementation of WFIRST using one of the 2.4-m, Hubble-quality telescope
assemblies recently made available to NASA. This DRM builds on the work of the
earlier WFIRST SDT, reported by Green et al. (2012) and the previous WFIRST-2.4
DRM, reported by Spergel et. (2013). The 2.4-m primary mirror enables a mission
with greater sensitivity and higher angular resolution than the 1.3-m and 1.1-m
designs considered previously, increasing both the science return of the
primary surveys and the capabilities of WFIRST as a Guest Observer facility.
The addition of an on-axis coronagraphic instrument to the baseline design
enables imaging and spectroscopic studies of planets around nearby stars.Comment: This report describes the 2014 study by the Science Definition Team
of the Wide-Field Infrared Survey Telescope mission. 319 pages; corrected a
misspelled name in the authors list and a typo in the abstrac
Quantum cascade laser frequency stabilisation at the sub-Hz level
Quantum Cascade Lasers (QCL) are increasingly being used to probe the
mid-infrared "molecular fingerprint" region. This prompted efforts towards
improving their spectral performance, in order to reach ever-higher resolution
and precision. Here, we report the stabilisation of a QCL onto an optical
frequency comb. We demonstrate a relative stability and accuracy of 2x10-15 and
10-14, respectively. The comb is stabilised to a remote near-infrared
ultra-stable laser referenced to frequency primary standards, whose signal is
transferred via an optical fibre link. The stability and frequency traceability
of our QCL exceed those demonstrated so far by two orders of magnitude. As a
demonstration of its capability, we then use it to perform high-resolution
molecular spectroscopy. We measure absorption frequencies with an 8x10-13
relative uncertainty. This confirms the potential of this setup for ultra-high
precision measurements with molecules, such as our ongoing effort towards
testing the parity symmetry by probing chiral species
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