A search for muon neutrinos from neutralino annihilations in the Sun has been performed with the IceCube 22-string neutrino detector using data collected in 104.3 days of live time in 2007. No excess ...over the expected atmospheric background has been observed. Upper limits have been obtained on the annihilation rate of captured neutralinos in the Sun and converted to limits on the weakly interacting massive particle (WIMP) proton cross sections for WIMP masses in the range 250-5000 GeV. These results are the most stringent limits to date on neutralino annihilation in the Sun.
Interferon γ (IFN-γ) plays an important physiological role during inflammation by down-regulating collagen gene expression and activating major histocompatibility II (MHC-II) complex. The activation ...of MHC-II by IFN-γ requires activation of a trimeric DNA binding transcriptional complex, RFX5 complex, containing RFXB (also called RFXANK or Tvl-1), RFXAP, as well as RFX5 protein. Previously, we demonstrated that RFX5 binds to the collagen transcription start site and represses collagen gene expression (Sengupta, P. K., Fargo, J., Smith, B. D. (2002) J. Biol. Chem. 277, 24926–24937). In this report, we have examined the role of RFXB and RFXAP proteins within the RFX5 complex to regulate collagen gene expression. The data show that all three RFX5 complex proteins are required for maximum repression. Expression of proteins with mutations known to be important for RFX5 complex formation does not repress collagen promoter activity. Two mutated forms of RFX5 act as dominant negative proteins activating collagen expression and reversing IFN-γ down-regulation of collagen expression in human lung fibroblasts. IFN-γ increases expression and nuclear translocation of RFX5. RFXB has a naturally occurring splice variant isoform (RFX SV). Interferon increases expression of the long form of RFXB and decreases expression of RFX SV with the same kinetics as collagen gene expression. Overexpression of the splice variant form reverses the IFN-γ induced collagen repression in human lung fibroblasts. Finally, all three RFX5 complex proteins increase at the collagen transcription start site with IFN-γ treatment using chromatin immunoprecipitation analysis. Thus, these studies suggest an important role for RFX5 complex in collagen repression.
Current ambiguity concerning the related issues of optimal means for measurement of odor sensitivity and the functional properties of the olfactory system hinders progress in basic and applied ...research on the human sense of smell. To address these needs, we selected n-amyl acetate (nAA) as a test odorant and developed a methodology in which participants (Ps) receive multiple presentations each session of several concentrations. Yes–no responses as to whether odor was detected are analyzed using binomial statistics, with the probability that a given proportion of yes responses (or greater) would occur by chance alone being treated as the inverse of detectability. Over the course of multiple sessions, this information is also used to maximize the collection of data in the peri-threshold region. Surprisingly, data collected over as many as 14 sessions were fit well by a single logistic regression model relating probability and concentration. Threshold concentrations, defined as those corresponding to a probability of 0.05, varied from 7.11 to 167.53 p.p.b. (v/v) for 11 Ps. Our approach and findings, if shown to be representative of other combinations of Ps and odorants, could accelerate the pace of research in human olfaction by providing a comprehensive operational definition of the limit of the olfactory system to detect odorant molecules.
The tumor suppressor gene CDKN2A (MTS1/p16), located on chromosome 9p21, is inactivated in a variety of tumors including melanomas and tumors of the biliary tract, pancreas, and stomach. The aim of ...the present study was to determine whether this gene is inactivated in hepatocellular carcinoma (HCC). Twenty‐three primary HCCs and four HCC cell lines were examined. Loss of heterozygosity (LOH) analysis was performed using eight polymorphic markers immediately surrounding CDKN2A, and showed a contiguous region of loss, with the two most commonly deleted markers being D9S1604, located between the p16 and p15 genes, at which 7 of 13 informative tumors (54%) showed loss, and D9S171, with 4 of 14 LOH (29%). Exons 1, 2, and 3 of CDKN2A were amplified by polymerase chain reaction to detect homozygous deletions, and single‐strand conformation polymorphism (SSCP) analysis was performed to screen for mutations. No homozygous deletions were detected in any sample. SSCP and sequence analysis showed the same nucleotide change at codon 148 in four tumors. This has been reported elsewhere as a polymorphism. One of these four tumors also contained a mutation at codon 119, resulting in the substitution of an acidic amino acid for a basic one. It is concluded that CDKN2A is infrequently deleted or mutated in HCC. The region of allelic loss upstream from CDKN2A might result in inactivation of regulatory sequences important in the expression of this gene; alternatively, a second tumor suppressor gene may be present in the region 9p21‐22, proximal to CDKN2A. These possibilities require further investigation.
In this study, we investigated the use of a single-shot fast spin-echo-based sequence to perform diffusion tensor imaging (DTI) with improved anatomic fidelity through the entire brain and the ...cervical spine. Traditionally, diffusion tensor images have been acquired by single-shot echo-planar imaging (EPI) methods in which large distortions result from magnetic susceptibility effects, especially near air-tissue interfaces. These distortions can be problematic, especially in anterior and inferior portions of the brain, and they also can severely limit applications in the spine. At higher magnetic fields these magnetic susceptibility artifacts are increased. The single-shot fast spin-echo (SSFSE) method used in this study utilizes radiofrequency rephasing in the transverse plane and thus provides diffusion images with negligible distortion even at 3 Tesla. In addition, the SSFSE sequence does not require multiple fast-receivers, which are not available on many magnetic resonance (MR) systems. Phased array coils were used to increase the signal-to-noise ratio of the images, offering a major inherent advantage in diffusion tensor imaging of the spine and brain. The mean diffusion measurements obtained with the SSFSE acquisition were not statistically different (
p > 0.05) from EPI-based acquisitions. Compared to routine T
2-weighted MR images, the DTI-EPI sequence showed up to 20% in elongation of the brain in the anterior-posterior direction on a sagittal image due to magnetic susceptibility distortions, whereas in the DTI-SSFSE, the image distortions were negligible. The diffusion tensor SSFSE method was also able to assess diffusion abnormalities in a brain stem hemorrhage, unaffected by the spatial distortions that limited conventional EPI acquisition.
Ca 2+ binding to cardiac troponin C (cTnC) triggers contraction in heart muscle. In heart failure, myofilaments response to Ca 2+ are often altered and compounds that sensitize the myofilaments to Ca ...2+ possess therapeutic value in this syndrome. One of the most potent and selective Ca 2+ sensitizers is the thiadiazinone derivative EMD 57033, which increases myocardial contractile function both in vivo and in vitro and interacts with cTnC in vitro . We have determined the NMR structure of the 1:1 complex between Ca 2+ -saturated C-domain of human cTnC (cCTnC) and EMD 57033. Favorable hydrophobic interactions between the drug and the protein
position EMD 57033 in the hydrophobic cleft of the protein. The drug molecule is orientated such that the chiral group of
EMD 57033 fits deep in the hydrophobic pocket and makes several key contacts with the protein. This stereospecific interaction
explains why the (â)-enantiomer of EMD 57033 is inactive. Titrations of the cCTnC·EMD 57033 complex with two regions of cardiac
troponin I (cTnI 34â71 and cTnI 128â147 ) reveal that the drug does not share a common binding epitope with cTnI 128â147 but is completely displaced by cTnI 34â71 . These results have important implications for elucidating the mechanism of the Ca 2+ sensitizing effect of EMD 57033 in cardiac muscle contraction.
To determine HIV-1-specific T cell responses in clade B infected individuals recognizing the clade A, B and C consensus sequences in order to assess the degree of inter-clade cross-reactivity of ...these immune responses at the single epitope level.
HIV-1-specific T cell responses were assessed cross-sectionally in 27 chronically HIV-1-infected individuals from a population infected mainly with clade B viral strains, using an interferon-gamma Elispot assay with a total of 1230 overlapping peptides spanning the entire amino acid sequence of the clade A, B and C 2001 consensus sequences.
No significant difference was observed between the total magnitude or breadth of T cell responses recognizing either the clade A, B or C consensus sequences. However, at the single peptide level, 194 T cell responses were identified that recognized only one of the three different clade-specific peptide variants (A: B: C, 34: 105: 55), 125 T cell responses recognized two of the three peptide variants (AB: AC: BC, 71: 15: 39) and 166 T cell responses (34%) were cross-reactive with all three different peptide variants. Peptides recognized in all three consensus sequence variants had a significantly lower entropy (P < 0.0001) and a significantly higher inter-clade homology (P < 0.0001).
Viral epitopes within regions of low HIV-1 clade B diversity and high inter-clade homology can be recognized in the clade A, B and C variants and indicate a wide degree of cross-isolate and cross-clade recognition by HIV-1-specific T cells. These regions may therefore be of particular relevance for the design of HIV-1 vaccines.
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