We present an up-to-date, comprehensive summary of the rates for all types of compact binary coalescence sources detectable by the Initial and Advanced versions of the ground-based gravitational-wave ...detectors LIGO and Virgo. Astrophysical estimates for compact-binary coalescence rates depend on a number of assumptions and unknown model parameters, and are still uncertain. The most confident among these estimates are the rate predictions for coalescing binary neutron stars which are based on extrapolations from observed binary pulsars in our Galaxy. These yield a likely coalescence rate of 100 per Myr per Milky Way Equivalent Galaxy (MWEG), although the rate could plausibly range from 1 per Myr per MWEG to 1000 per Myr per MWEG. We convert coalescence rates into detection rates based on data from the LIGO S5 and Virgo VSR2 science runs and projected sensitivities for our Advanced detectors. Using the detector sensitivities derived from these data, we find a likely detection rate of 0.02 per year for Initial LIGO-Virgo interferometers, with a plausible range between 0.0002 and 0.2 per year. The likely binary neutron-star detection rate for the Advanced LIGO-Virgo network increases to 40 events per year, with a range between 0.4 and 400 per year.
Boomerang dysplasia (BD) is a perinatal lethal osteochondrodysplasia, characterised by absence or underossification of the limb bones and vertebrae. The BD phenotype is similar to a group of ...disorders including atelosteogenesis I, atelosteogenesis III, and dominantly inherited Larsen syndrome that we have recently shown to be associated with mutations in FLNB, the gene encoding the actin binding cytoskeletal protein, filamin B. We report the identification of mutations in FLNB in two unrelated individuals with boomerang dysplasia. The resultant substitutions, L171R and S235P, lie within the calponin homology 2 region of the actin binding domain of filamin B and occur at sites that are evolutionarily well conserved. These findings expand the phenotypic spectrum resulting from mutations in FLNB and underline the central role this protein plays during skeletogenesis in humans.
Extremophilic organisms require specialized enzymes for their exotic metabolisms. Acid-loving thermophilic Archaea that live in the mudpots of volcanic solfataras obtain their energy from reduced ...sulphur compounds such as hydrogen sulphide (H(2)S) and carbon disulphide (CS(2)). The oxidation of these compounds into sulphuric acid creates the extremely acidic environment that characterizes solfataras. The hyperthermophilic Acidianus strain A1-3, which was isolated from the fumarolic, ancient sauna building at the Solfatara volcano (Naples, Italy), was shown to rapidly convert CS(2) into H(2)S and carbon dioxide (CO(2)), but nothing has been known about the modes of action and the evolution of the enzyme(s) involved. Here we describe the structure, the proposed mechanism and evolution of a CS(2) hydrolase from Acidianus A1-3. The enzyme monomer displays a typical β-carbonic anhydrase fold and active site, yet CO(2) is not one of its substrates. Owing to large carboxy- and amino-terminal arms, an unusual hexadecameric catenane oligomer has evolved. This structure results in the blocking of the entrance to the active site that is found in canonical β-carbonic anhydrases and the formation of a single 15-Å-long, highly hydrophobic tunnel that functions as a specificity filter. The tunnel determines the enzyme's substrate specificity for CS(2), which is hydrophobic. The transposon sequences that surround the gene encoding this CS(2) hydrolase point to horizontal gene transfer as a mechanism for its acquisition during evolution. Our results show how the ancient β-carbonic anhydrase, which is central to global carbon metabolism, was transformed by divergent evolution into a crucial enzyme in CS(2) metabolism.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We report on results of a measurement of meson production in central Pb-Au collisions at E(lab) = 158A GeV. For the first time in the history of high energy heavy-ion collisions, phi mesons were ...reconstructed both in the K+K- and the dilepton decay channels in the same experiment. This measurement yields rapidity densities near midrapidity, from the two decay channels, of 2.05 +/- 0.14(stat) +/- 0.25(syst) and 2.04 +/- 0.49(stat) +/- 0.32(syst), respectively. The shape of the measured transverse momentum spectrum is also in close agreement in both decay channels. The data rule out a possible enhancement of the phi yield in the leptonic over the hadronic decay channel of a factor 1.6 or larger at the 95% C.L. This rules out the discrepancy reported in the literature between measurements of the hadronic and dimuon decay channels by two different experiments.
Newborns are at increased risk of overwhelming infection, yet the mechanisms underlying this susceptibility are incompletely defined. In this study we report a striking 1- to 3-log decrease in ...sensitivity of monocytes in human neonatal cord blood, compared with monocytes in adult peripheral blood, to the TNF-alpha-inducing effect of multiple TLR ligands, including bacterial lipopeptides (BLPs), LPS, and the imidazoquinoline compound, imiquimod. In marked contrast, TNF-alpha release in response to R-848, a TLR ligand that is a congener of imiquimod, was equivalent in newborn and adult blood. Differences in ligand-induced TNF-alpha release correlated with divergent ligand-induced changes in monocyte TNF-alpha mRNA levels. Newborn and adult monocytes did not differ in basal mRNA or protein expression of TLRs or mRNA expression of functionally related molecules. Newborn monocytes demonstrated diminished LPS-induced, but equivalent R-848-induced, phosphorylation of p38 mitogen-activated protein kinase and altered BLP- and LPS-induced acute modulation of cognate receptors, suggesting that the mechanism accounting for the observed differences may be localized proximal to ligand recognition by surface TLRs. Remarkably, newborn plasma conferred substantially reduced BLP-, LPS-, and imiquimod-induced TNF-alpha release on adult monocytes without any effect on R-848-induced TNF-alpha release, reflecting differences in a plasma factor(s) distinct from soluble CD14. Impaired response to multiple TLR ligands may significantly contribute to immature neonatal immunity. Conversely, relative preservation of responses to R-848 may present unique opportunities for augmenting innate and acquired immunity in the human newborn.
Echinocandins are a valuable addition for the treatment of invasive fungal infections, as they are efficacious, demonstrate low toxicity, and have limited drug-drug interactions. In specific clinical ...situations when altered pharmacokinetics can be expected or dosing guidelines are conflicting, it may be useful to measure concentrations. For this purpose, a liquid chromatography tandem mass-spectrometric method to measure anidulafungin and caspofungin in ethylenediaminetetraacetic acid plasma was developed.
The method was developed on a Thermo Fisher TSQ Quantum LC-MS/MS. For separation, a BetaBasic C4 (100 mm × 3.0 mm; 5 μm) analytical column was used. Sample preparation consisted of protein precipitation directly in the autosampler vial. The internal standard aculeacin A is structurally related, not used in humans, and commercially available. The method was validated according to the guidelines for bioanalytical method validation of the Food and Drug Administration.
The method was accurate (bias ranging from -3.0% to 1.9%) and precise (within-run and between-run coefficients of variation of 2.2% to 7.7% and 1.6% to 9.0%, respectively). All calibration curves were linear over a range of 0.5-10.0 mg/L for anidulafungin and 0.1-20.0 mg/L for caspofungin, and if necessary, samples can be diluted 10-fold. The samples were stable for 3 freeze-thaw cycles, with a bias ranging from 0.6% to 11%. The maximum bias from the worst storage condition, 72 hours at room temperature, was -14.7%. In patient samples, anidulafungin peak concentrations ranged from 2.8 to 8.6 mg/L (n = 20) and trough concentrations ranged from 1.0 to 4.7 mg/L (n = 79). The measured caspofungin concentrations ranged from 1.9 to 7.3 mg/L (n = 20).
The method developed has a straightforward sample preparation and uses a structural analog as the internal standard. This method has been applied successfully for the measurement of anidulafungin and caspofungin concentrations in patient samples, both for clinical practice and for research.
Mammographic screening programmes are now established in developing countries. We present an analysis of the first screening programme in sub-Saharan Africa.
Women aged > or = 40 years were ...identified at three primary healthcare centres in the Western Cape Province, South Africa, and after giving informed consent underwent mammography at a mobile unit. After a single reading, patients with American College of Radiology Breast Imaging Reporting and Data System (BIRADS) 3 - 5 lesions were referred to a tertiary centre for further management.
Between 1 February 2011 and 31 August 2012, 2 712 screening mammograms were performed. A total of 261 screening mammograms were reported as BIRADS 3 - 5 (recall rate 9.6%). Upon review of the 250 available screening mammograms, 58 (23%) were rated benign or no abnormalities (BIRADS 1 and 2) and no further action was taken. In 32 women, tissue was acquired (biopsy rate for the series 1.2%); 10 cancers were diagnosed (biopsy malignancy rate 31%). For the entire series of 2 712 screening mammograms, the cancer diagnosis rate was 3.7/1 000 examinations. Of 10 cancers diagnosed at screening, 5 were TNM clinical stage 0, 2 stage I and 3 stage II.
The low cancer detection rate achieved, and the technical and multiple administrative problems experienced do not justify installation of a screening programme using the model utilised in this series.
The goal of the present study was to improve prediction of outcome after chemoradiation in advanced head and neck cancer using gene expression analysis.
We collected 92 biopsies from untreated head ...and neck cancer patients subsequently given cisplatin-based chemoradiation (RADPLAT) for advanced squamous cell carcinomas (HNSCC). After RNA extraction and labeling, we performed dye swap experiments using 35k oligo-microarrays. Supervised analyses were performed to create classifiers to predict locoregional control and disease recurrence. Published gene sets with prognostic value in other studies were also tested.
Using supervised classification on the whole series, gene sets separating good and poor outcome could be found for all end points. However, when splitting tumors into training and validation groups, no robust classifiers could be found. Using Gene Set Enrichment analysis, several gene sets were found to be enriched in locoregional recurrences, although with high false-discovery rates. Previously published signatures for radiosensitivity, hypoxia, proliferation, "wound," stem cells, and chromosomal instability were not significantly correlated with outcome. However, a recently published signature for HNSCC defining a "high-risk" group was shown to be predictive for locoregional control in our dataset.
Gene sets can be found with predictive potential for locoregional control after combined radiation and chemotherapy in HNSCC. How treatment-specific these gene sets are needs further study.
Obesity is often associated with abnormalities in cardiac morphology and function. This study tested the hypothesis that obesity-related cardiomyopathy is caused by impaired cardiac energetics. In a ...mouse model of high-fat diet (HFD)-induced obesity, we applied in vivo cardiac 31P magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) to investigate cardiac energy status and function, respectively. The measurements were complemented by ex vivo determination of oxygen consumption in isolated cardiac mitochondria, the expression of proteins involved in energy metabolism, and markers of oxidative stress and calcium homeostasis. We also assessed whether HFD induced myocardial lipid accumulation using in vivo 1H MRS, and if this was associated with apoptosis and fibrosis. Twenty weeks of HFD feeding resulted in early stage cardiomyopathy, as indicated by diastolic dysfunction and increased left ventricular mass, without any effects on systolic function. In vivo cardiac phosphocreatine-to-ATP ratio and ex vivo oxygen consumption in isolated cardiac mitochondria were not reduced after HFD feeding, suggesting that the diastolic dysfunction was not caused by impaired cardiac energetics. HFD feeding promoted mitochondrial adaptations for increased utilization of fatty acids, which was however not sufficient to prevent the accumulation of myocardial lipids and lipid intermediates. Myocardial lipid accumulation was associated with oxidative stress and fibrosis, but not apoptosis. Furthermore, HFD feeding strongly reduced the phosphorylation of phospholamban, a prominent regulator of cardiac calcium homeostasis and contractility. In conclusion, HFD-induced early stage cardiomyopathy in mice is associated with lipotoxicity-associated oxidative stress, fibrosis, and disturbed calcium homeostasis, rather than impaired cardiac energetics.
•We study the effect of high-fat diet (HFD) feeding on cardiac energetics in mice.•We assess cardiac energy status in vivo using 31P MRS.•HFD induces diastolic dysfunction, without impairing in vivo cardiac energy status.•HFD leads to accumulation of cardiac lipids and lipid intermediates.•HFD induces oxidative stress, fibrosis, and impaired calcium handling in the heart.
Gravitational waves from a variety of sources are predicted to superpose to create a stochastic background. This background is expected to contain unique information from throughout the history of ...the Universe that is unavailable through standard electromagnetic observations, making its study of fundamental importance to understanding the evolution of the Universe. We carry out a search for the stochastic background with the latest data from the LIGO and Virgo detectors. Consistent with predictions from most stochastic gravitational-wave background models, the data display no evidence of a stochastic gravitational-wave signal. Assuming a gravitational-wave spectrum of Ω_{GW}(f)=Ω_{α}(f/f_{ref})^{α}, we place 95% confidence level upper limits on the energy density of the background in each of four frequency bands spanning 41.5-1726 Hz. In the frequency band of 41.5-169.25 Hz for a spectral index of α=0, we constrain the energy density of the stochastic background to be Ω_{GW}(f)<5.6×10^{-6}. For the 600-1000 Hz band, Ω_{GW}(f)<0.14(f/900 Hz)^{3}, a factor of 2.5 lower than the best previously reported upper limits. We find Ω_{GW}(f)<1.8×10^{-4} using a spectral index of zero for 170-600 Hz and Ω_{GW}(f)<1.0(f/1300 Hz)^{3} for 1000-1726 Hz, bands in which no previous direct limits have been placed. The limits in these four bands are the lowest direct measurements to date on the stochastic background. We discuss the implications of these results in light of the recent claim by the BICEP2 experiment of the possible evidence for inflationary gravitational waves.
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