Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study

We performed a prospective genotype-phenotype study using molecular screening and clinical assessment to compare the severity of disease and the risk of sarcoma in 172 individuals (78 families) with hereditary multiple exostoses. We calculated the severity of disease including stature, number of exostoses, number of surgical procedures that were necessary, deformity and functional parameters and used molecular techniques to identify the genetic mutations in affected individuals. Each arm of the genotype-phenotype study was blind to the outcome of the other. Mutations EXT1 and EXT2 were almost equally common, and were identified in 83% of individuals. Non-parametric statistical tests were used. There was a wide variation in the severity of disease. Children under ten years of age had fewer exostoses, consistent with the known age-related penetrance of this condition. The severity of the disease did not differ significantly with gender and was very variable within any given family. The sites of mutation affected the severity of disease with patients with EXT1 mutations having a significantly worse condition than those with EXT2 mutations in three of five parameters of severity (stature, deformity and functional parameters). A single sarcoma developed in an EXT2 mutation carrier, compared with seven in EXT1 mutation carriers. There was no evidence that sarcomas arose more commonly in families in whom the disease was more severe. The sarcoma risk in EXT1 carriers is similar to the risk of breast cancer in an older population subjected to breast-screening, suggesting that a role for regular screening in patients with hereditary multiple exostoses is justifiable. ©2004 British Editorial Society of Bone and Joint Surgery

Chlorine isotope composition in chlorofluorocarbons CFC-11, CFC-12 and CFC-113 in firn, stratospheric and tropospheric air

The stratospheric degradation of chlorofluorocarbons (CFCs) releases chlorine, which is a major contributor to the destruction of stratospheric ozone (O3). A recent study reported strong chlorine isotope fractionation during the breakdown of the most abundant CFC (CFC-12, CCl2F2, Laube et al., 2010a), similar to effects seen in nitrous oxide (N2O). Using air archives to obtain a long-term record of chlorine isotope ratios in CFCs could help to identify and quantify their sources and sinks. We analyse the three most abundant CFCs and show that CFC-11 (CCl3F) and CFC-113 (CClF2CCl2F) exhibit significant stratospheric chlorine isotope fractionation, in common with CFC-12. The apparent isotope fractionation (εapp) for mid- and high-latitude stratospheric samples are (-2.4±0.5) ‰ and (-2.3±0.4) ‰ for CFC-11, (-12.2±1.6) ‰ and (-6.8±0.8) ‰ for CFC-12 and (-3.5±1.5) ‰ and (-3.3±1.2) ‰ for CFC-113, respectively. Assuming a constant isotope composition of emissions, we calculate the expected trends in the tropospheric isotope signature of these gases based on their stratospheric 37Cl enrichment and stratosphere-troposphere exchange. We compare these projections to the long-term δ(37Cl) trends of all three CFCs, measured on background tropospheric samples from the Cape Grim air archive (Tasmania, 1978 – 2010) and tropospheric firn air samples from Greenland (NEEM site) and Antarctica (Fletcher Promontory site). From 1970 to the present-day, projected trends agree with tropospheric measurements, suggesting that within analytical uncertainties a constant average emission isotope delta is a compatible scenario. The measurement uncertainty is too high to determine whether the average emission isotope delta has been affected by changes in CFC manufacturing processes, or not. Our study increases the suite of trace gases amenable to direct isotope ratio measurements in small air volumes (approximately 200 ml), using a single-detector gas chromatography-mass spectrometry system

Fractal-like Distributions over the Rational Numbers in High-throughput Biological and Clinical Data

Recent developments in extracting and processing biological and clinical data are allowing quantitative approaches to studying living systems. High-throughput sequencing, expression profiles, proteomics, and electronic health records are some examples of such technologies. Extracting meaningful information from those technologies requires careful analysis of the large volumes of data they produce. In this note, we present a set of distributions that commonly appear in the analysis of such data. These distributions present some interesting features: they are discontinuous in the rational numbers, but continuous in the irrational numbers, and possess a certain self-similar (fractal-like) structure. The first set of examples which we present here are drawn from a high-throughput sequencing experiment. Here, the self-similar distributions appear as part of the evaluation of the error rate of the sequencing technology and the identification of tumorogenic genomic alterations. The other examples are obtained from risk factor evaluation and analysis of relative disease prevalence and co-mordbidity as these appear in electronic clinical data. The distributions are also relevant to identification of subclonal populations in tumors and the study of the evolution of infectious diseases, and more precisely the study of quasi-species and intrahost diversity of viral populations

Characterising the Fermentation Capabilities of Gut Microbial Populations from Different Breeds of Cattle and Sheep Grazing Heathland

Previous studies have demonstrated differences in the diet composition of sheep and cattle when grazing heather moorland, and such differences may in turn lead to differences in rumen fermentation characteristics and associated adaptation to diet. To investigate this further an in vitro gas production experiment was conducted using inocula from different breeds of cattle and sheep grazing heathland

Formation and removal of alkylthiolate self-assembled monolayers on gold in aqueous solutions

We report the development of novel reagents and approaches for generating recyclable biosensors. The use of aqueous media for the formation of protein binding alkylthiolate monolayers on Au surfaces results in accelerated alkylthiolate monolayer formation and improvement in monolayer integrity as visualized by fluorescence microscopy and CV techniques. We have also developed an electrocleaning protocol that is compatible with microfluidics devices, and this technique serves as an on-chip method for cleaning Au substrates both before and after monolayer formation. The techniques for the formation and dissociation of biotinylated SAMs from aqueous solvents reported here may be applied towards the development of Au-based sensor devices and microfluidics chips in the future. A potential use of these devices includes the specific capture and triggered release of target cells, proteins, or small molecules from liquid samples

Inferential models: A framework for prior-free posterior probabilistic inference

Posterior probabilistic statistical inference without priors is an important but so far elusive goal. Fisher's fiducial inference, Dempster-Shafer theory of belief functions, and Bayesian inference with default priors are attempts to achieve this goal but, to date, none has given a completely satisfactory picture. This paper presents a new framework for probabilistic inference, based on inferential models (IMs), which not only provides data-dependent probabilistic measures of uncertainty about the unknown parameter, but does so with an automatic long-run frequency calibration property. The key to this new approach is the identification of an unobservable auxiliary variable associated with observable data and unknown parameter, and the prediction of this auxiliary variable with a random set before conditioning on data. Here we present a three-step IM construction, and prove a frequency-calibration property of the IM's belief function under mild conditions. A corresponding optimality theory is developed, which helps to resolve the non-uniqueness issue. Several examples are presented to illustrate this new approach.Comment: 29 pages with 3 figures. Main text is the same as the published version. Appendix B is an addition, not in the published version, that contains some corrections and extensions of two of the main theorem

The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy : a systematic review and economic evaluation

Peer reviewedPublisher PD

Estimating regional methane surface fluxes: the relative importance of surface and GOSAT mole fraction measurements

We use an ensemble Kalman filter (EnKF), together with the GEOS-Chem chemistry transport model, to estimate regional monthly methane (CH₄) fluxes for the period June 2009–December 2010 using proxy dry-air column-averaged mole fractions of methane (XCH₄) from GOSAT (Greenhouse gases Observing SATellite) and/or NOAA ESRL (Earth System Research Laboratory) and CSIRO GASLAB (Global Atmospheric Sampling Laboratory) CH₄ surface mole fraction measurements. Global posterior estimates using GOSAT and/or surface measurements are between 510–516 Tg yr⁻¹, which is less than, though within the uncertainty of, the prior global flux of 529 ± 25 Tg yr⁻¹. We find larger differences between regional prior and posterior fluxes, with the largest changes in monthly emissions (75 Tg yr⁻¹) occurring in Temperate Eurasia. In non-boreal regions the error reductions for inversions using the GOSAT data are at least three times larger (up to 45%) than if only surface data are assimilated, a reflection of the greater spatial coverage of GOSAT, with the two exceptions of latitudes >60° associated with a data filter and over Europe where the surface network adequately describes fluxes on our model spatial and temporal grid. We use CarbonTracker and GEOS-Chem XCO₂ model output to investigate model error on quantifying proxy GOSAT XCH₄ (involving model XCO₂) and inferring methane flux estimates from surface mole fraction data and show similar resulting fluxes, with differences reflecting initial differences in the proxy value. Using a series of observing system simulation experiments (OSSEs) we characterize the posterior flux error introduced by non-uniform atmospheric sampling by GOSAT. We show that clear-sky measurements can theoretically reproduce fluxes within 10% of true values, with the exception of tropical regions where, due to a large seasonal cycle in the number of measurements because of clouds and aerosols, fluxes are within 15% of true fluxes. We evaluate our posterior methane fluxes by incorporating them into GEOS-Chem and sampling the model at the location and time of surface CH₄ measurements from the AGAGE (Advanced Global Atmospheric Gases Experiment) network and column XCH₄ measurements from TCCON (Total Carbon Column Observing Network). The posterior fluxes modestly improve the model agreement with AGAGE and TCCON data relative to prior fluxes, with the correlation coefficients (<i>r</i>²) increasing by a mean of 0.04 (range: −0.17 to 0.23) and the biases decreasing by a mean of 0.4 ppb (range: −8.9 to 8.4 ppb)

Linking ice and gas in the Serpens low-mass star-forming region

The interaction between dust, ice, and gas during the formation of stars produces complex organic molecules. While observations indicate that several species are formed on ice-covered dust grains and are released into the gas phase, the exact chemical interplay between solid and gas phases and their relative importance remain unclear. Our goal is to study the interplay in regions of low-mass star formation through ice- and gas-mapping and by directly measuring gas-to-ice ratios. This provides constraints on the routes that lead to the chemical complexity that is observed in both phases. We present observations of gas-phase methanol (CH$_3$OH) and carbon monoxide at 1.3 mm towards ten low-mass young protostars in the Serpens SVS4 cluster from the SubMillimeter Array and the Atacama Pathfinder EXperiment telescope. We used archival data from the Very Large Telescope to derive abundances of ice H$_2$O, CO, and CH$_3$OH towards the same region. Finally, we constructed gas-ice maps of SVS4 and directly measured CO and CH$_3$OH gas-to-ice ratios. The CH$_3$OH gas-to-ice ratio agrees with values that were previously reported for embedded Class 0/I low-mass protostars. The CO gas-maps trace an extended gaseous component that is not sensitive to the effect of freeze-out. We find that there is no straightforward correlation between CO and CH$_3$OH gas with their ice counterparts in the cluster. This is likely related to the complex morphology of SVS4: the Class 0 protostar SMM4 and its envelope lie in the vicinity, and the outflow associated with SMM4 intersects the cluster. This study serves as a pathfinder for future observations with ALMA and the James Webb Space Telescope that will provide high-sensitivity gas-ice maps of molecules more complex than methanol. Such comparative maps will be essential to constrain the chemical routes that regulate the chemical complexity in star-forming regions.Comment: 25 pages, 20 figures, accepted for publication by A&

Quantum Kinks: Solitons at Strong Coupling

We examine solitons in theories with heavy fermions. These ``quantum'' solitons differ dramatically from semi-classical (perturbative) solitons because fermion loop effects are important when the Yukawa coupling is strong. We focus on kinks in a $(1+1)$--dimensional $\phi^4$ theory coupled to fermions; a large-$N$ expansion is employed to treat the Yukawa coupling $g$ nonperturbatively. A local expression for the fermion vacuum energy is derived using the WKB approximation for the Dirac eigenvalues. We find that fermion loop corrections increase the energy of the kink and (for large $g$) decrease its size. For large $g$, the energy of the quantum kink is proportional to $g$, and its size scales as $1/g$, unlike the classical kink; we argue that these features are generic to quantum solitons in theories with strong Yukawa couplings. We also discuss the possible instability of fermions to solitons.Comment: 21 pp. + 2 figs., phyzzx, JHU-TIPAC-92001