Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans

Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A.

Sex : Australian lifestyle show

This is an entry in an encyclopedia of television by John Hartley.It is a short description of the Australian TV show "Sex" which was hosted by Sophie Lee and subsequently Pamela Stevenson in 1992 - 1993.

Raising the Standards: An Integrated Approach to Promoting Professional Standards and Avoiding Professional Criminality

Crime in the Professions critically examines the nature and extent of crime and deviance in the professions and how it should be dealt with. The increasing professionalization of the work force and the changes in the way in which professionals carry out their work, such as through the use of computing and communications technology, have created new opportunities for professionals to break the law. Looking in detail at the nature and extent of crime committed by professionals such as doctors, accountants and nurses the book offers some innovative solutions on preventing and controlling professional crime. In addition to examining the nature and extent of crime in the professions, it also addresses some critical issues of regulation for the future, concerning new and emerging professional groups and issues relating to emerging technologies.

Combining expert opinions in prior elicitation

A method of eliciting prior distributions for Bayesian models using expert knowledge is proposed. Elicitation is a widely studied problem, from a psychological perspective as well as from a statistical perspective. Here, we are interested in combining opinions from more than one expert using an explicitly model-based approach so that we may account for various sources of variation affecting elicited expert opinions. We use a hierarchical model to achieve this. We apply this approach to two problems. The first problem involves a food risk assessment problem involving modelling dose-response for Listeria monocytogenes contamination of mice. The second concerns the time taken by PhD students to submit their thesis in a particular school.

CDKN2A mutation in a non-FAMMM kindred with cancers at multiple sites results in a functionally abnormal protein

The CDKN2A gene encodes p16 (CDKN2A), a cell-cycle inhibitor protein which prevents inappropriate cell cycling and, hence, proliferation. Germ-line mutations in CDKN2A predispose to the familial atypical multiple-mole melanoma (FAMMM) syndrome but also have been seen in rare families in which only 1 or 2 individuals are affected by cutaneous malignant melanoma (CMM). We therefore sequenced exons 1alpha and 2 of CDKN2A using lymphocyte DNA isolated from index cases from 67 families with cancers at multiple sites, where the patterns of cancer did not resemble those attributable to known genes such as hMLH1, hMLH2, BRCA1, BRCA2, TP53 or other cancer susceptibility genes. We found one mutation, a mis-sense mutation resulting in a methionine to isoleucine change at codon 53 (M531) of exon 2. The individual tested had developed 2 CMMs but had no dysplastic nevi and lacked a family history of dysplastic nevi or CMM. Other family members had been diagnosed with oral cancer (2 persons), bladder cancer (1 person) and possibly gall-bladder cancer. While this mutation has been reported in Australian and North American melanoma kindreds, we did not observe it in 618 chromosomes from Scottish and Canadian controls. Functional studies revealed that the CDKN2A variant carrying the M531 change was unable to bind effectively to CDK4, showing that this mutation is of pathological significance. Our results have confirmed that CDKN2A mutations are not limited to FAMMM kindreds but also demonstrate that multi-site cancer families without melanoma are very unlikely to contain CDKN2A mutations.

Three-dimensional geological modelling and multivariate statistical analysis of water chemistry data to analyse and visualise aquifer structure and groundwater composition in the Wairau Plain, Marlborough District, New Zealand

Concerns regarding groundwater contamination with nitrate and the long-term sustainability of groundwater resources have prompted the development of a multi-layered three dimensional (3D) geological model to characterise the aquifer geometry of the Wairau Plain, Marlborough District, New Zealand. The 3D geological model which consists of eight litho-stratigraphic units has been subsequently used to synthesise hydrogeological and hydrogeochemical data for different aquifers in an approach that aims to demonstrate how integration of water chemistry data within the physical framework of a 3D geological model can help to better understand and conceptualise groundwater systems in complex geological settings. Multivariate statistical techniques(e.g. Principal Component Analysis and Hierarchical Cluster Analysis) were applied to groundwater chemistry data to identify hydrochemical facies which are characteristic of distinct evolutionary pathways and a common hydrologic history of groundwaters. Principal Component Analysis on hydrochemical data demonstrated that natural water-rock interactions, redox potential and human agricultural impact are the key controls of groundwater quality in the Wairau Plain. Hierarchical Cluster Analysis revealed distinct hydrochemical water quality groups in the Wairau Plain groundwater system. Visualisation of the results of the multivariate statistical analyses and distribution of groundwater nitrate concentrations in the context of aquifer lithology highlighted the link between groundwater chemistry and the lithology of host aquifers. The methodology followed in this study can be applied in a variety of hydrogeological settings to synthesise geological, hydrogeological and hydrochemical data and present them in a format readily understood by a wide range of stakeholders. This enables a more efficient communication of the results of scientific studies to the wider community.

Understanding hydrochemical processes using 3D models and hydrochemical facies in Wairau Plain groundwater, Marlborough

Three dimensional models and groundwater quality are combined to better understand and conceptualise groundwater systems in complex geological settings in the Wairau Plain, Marlborough. Hydrochemical facies, which are characteristic of distinct evolutionary pathways and a common hydrologic history of groundwaters, are identified within geological formations to assess natural water-rock interactions, redox potential and human agricultural impact on groundwater quality in the Wairau Plain.

Preliminary Design and Performance Estimation of Radial Inflow Turbines: An Automated Approach

A comprehensive one-dimensional meanline design approach for radial inflow turbines is described in the present work. An original code was developed in Python that takes a novel approach to the automatic selection of feasible machines based on pre-defined performance or geometry characteristics for a given application. It comprises a brute-force search algorithm that traverses the entire search space based on key non-dimensional parameters and rotational speed. In this study, an in-depth analysis and subsequent implementation of relevant loss models as well as selection criteria for radial inflow turbines is addressed. Comparison with previously published designs, as well as other available codes, showed good agreement. Sample (real and theoretical) test cases were trialed and results showed good agreement when compared to other available codes. The presented approach was found to be valid and the model was found to be a useful tool with regards to the preliminary design and performance estimation of radial inflow turbines, enabling its integration with other thermodynamic cycle analysis and three-dimensional blade design codes.

Candidate radial-inflow turbines and high-density working fluids for geothermal power systems

Optimisation of Organic Rankine Cycle (ORCs) for binary-cycle geothermal applications could play a major role in determining the competitiveness of low to moderate temperature geothermal resources. Part of this optimisation process is matching cycles to a given resource such that power output can be maximised. Two major and largely interrelated components of the cycle are the working fluid and the turbine. Both components need careful consideration: the selection of working fluid and appropriate operating conditions as well as optimisation of the turbine design for those conditions will determine the amount of power that can be extracted from a resource. In this paper, we present the rationale for the use of radial-inflow turbines for ORC applications and the preliminary design of several radial-inflow machines based on a number of promising ORC systems that use five different working fluids: R134a, R143a, R236fa, R245fa and n-Pentane. Preliminary meanline analysis lead to the generation of turbine designs for the various cycles with similar efficiencies (77%) but large differences in dimensions (139–289 mm rotor diameter). The highest performing cycle, based on R134a, was found to produce 33% more net power from a 150 °C resource flowing at 10 kg/s than the lowest performing cycle, based on n-Pentane.

Near-Wall Turbulent Pressure Diffusion Modeling and Influence in Three-Dimensional Secondary Flows

The purpose of this paper is to develop a second-moment closure with a near-wall turbulent pressure diffusion model for three-dimensional complex flows, and to evaluate the influence of the turbulent diffusion term on the prediction of detached and secondary flows. A complete turbulent diffusion model including a near-wall turbulent pressure diffusion closure for the slow part was developed based on the tensorial form of Lumley and included in a re-calibrated wall-normal-free Reynolds-stress model developed by Gerolymos and Vallet. The proposed model was validated against several one-, two, and three-dimensional complex flows.

Open design of high pressure ratio radial-inflow turbine for academic validation

Computational Fluid Dynamics (CFD) simulations are widely used in mechanical engineering. Although achieving a high level of confidence in numerical modelling is of crucial importance in the field of turbomachinery, verification and validation of CFD simulations are very tricky especially for complex flows encountered in radial turbines. Comprehensive studies of radial machines are available in the literature. Unfortunately, none of them include enough detailed geometric data to be properly reproduced and so cannot be considered for academic research and validation purposes. As a consequence, design improvements of such configurations are difficult. Moreover, it seems that well-developed analyses of radial turbines are used in commercial software but are not available in the open literature especially at high pressure ratios. It is the purpose of this paper to provide a fully open set of data to reproduce the exact geometry of the high pressure ratio single stage radial-inflow turbine used in the Sundstrand Power Systems T-100 Multipurpose Small Power Unit. First, preliminary one-dimensional meanline design and analysis are performed using the commercial software RITAL from Concepts-NREC in order to establish a complete reference test case available for turbomachinery code validation. The proposed design of the existing turbine is then carefully and successfully checked against the geometrical and experimental data partially published in the literature. Then, three-dimensional Reynolds-Averaged Navier-Stokes simulations are conducted by means of the Axcent-PushButton CFDR CFD software. The effect of the tip clearance gap is investigated in detail for a wide range of operating conditions. The results confirm that the 3D geometry is correctly reproduced. It also reveals that the turbine is shocked while designed to give a high-subsonic flow and highlight the importance of the diffuser.

Oblique-Shock-Wave/Boundary-Layer Interaction Using Near-Wall Reynolds-Stress Models

A synthesis is presented of the predictive capability of a family of near-wall wall-normal free Reynolds stress models (which are completely independent of wall topology, i.e., of the distance fromthe wall and the normal-to-thewall orientation) for oblique-shock-wave/turbulent-boundary-layer interactions. For the purpose of comparison, results are also presented using a standard low turbulence Reynolds number k–ε closure and a Reynolds stress model that uses geometric wall normals and wall distances. Studied shock-wave Mach numbers are in the range MSW = 2.85–2.9 and incoming boundary-layer-thickness Reynolds numbers are in the range Reδ0 = 1–2×106. Computations were carefully checked for grid convergence. Comparison with measurements shows satisfactory agreement, improving on results obtained using a k–ε model, and highlights the relative importance of redistribution and diffusion closures, indicating directions for future modeling work.

Influence of inflow turbulence in shock-wave/turbulent-boundary-layer interaction computations

The influence of inflow turbulence on the results of Favre–Reynolds-averaged Navier–Stokes computations of supersonic oblique-shock-wave/turbulent-boundary-layer interactions (shock-wave Mach-number MSW ∼2.9), using seven-equation Reynolds-stress model turbulence closures, is studied. The generation of inflow conditions (and the initialization of the flowfield) for mean flow, Reynolds stresses, and turbulence length scale, based on semi-analytic grid-independent boundary-layer profiles, is described in detail. Particular emphasis is given to freestream turbulence intensity and length scale. The influence of external-flow turbulence intensity is studied in detail both for flat-plate boundary-layer flow and for a compression-ramp interaction with large separation. It is concluded that the Reynolds-stress model correctly reproduces the effects of external flow turbulence.

Candidate radial-inflow turbines and high-density working fluids for geothermal power systems

Optimisation of Organic Rankine Cycles (ORCs) for binary-cycle geothermal applications could play a major role in the competitiveness of low to moderate temperature geothermal resources. Part of this optimisation process is matching cycles to a given resource such that power output can be maximised. Two major and largely interrelated components of the cycle are the working fluid and the turbine. Both components need careful consideration. Due to the temperature differences in geothermal resources a one-size-fits-all approach to surface power infrastructure is not appropriate. Furthermore, the traditional use of steam as a working fluid does not seem practical due to the low temperatures of many resources. A variety of organic fluids with low boiling points may be utilised as ORC working fluids in binary power cycle loops. Due to differences in thermodynamic properties, certain fluids are able to extract more heat from a given resource than others over certain temperature and pressure ranges. This enables the tailoring of power cycle infrastructure to best match the geothermal resource through careful selection of the working fluid and turbine design optimisation to yield the optimum overall cycle performance. This paper presents the rationale for the use of radial-inflow turbines for ORC applications and the preliminary design of several radial-inflow turbines based on a selection of promising ORC cycles using five different high-density working fluids: R134a, R143a, R236fa, R245fa and n-Pentane at sub- or trans-critical conditions. Numerous studies published compare a variety of working fluids for various ORC configurations. However, there is little information specifically pertaining to the design and implementation of ORCs using realistic radial turbine designs in terms of pressure ratios, inlet pressure, rotor size and rotational speed. Preliminary 1D analysis leads to the generation of turbine designs for the various cycles with similar efficiencies (77%) but large differences in dimensions (139289 mm rotor diameter). The highest performing cycle (R134a) was found to produce 33% more net power from a 150°C resource flowing at 10 kg/s than the lowest performing cycle (n-Pentane).