Human Physiology of Genetic Defects Causing Beta-cell Dysfunction

The last decade has revealed hundreds of genetic variants associated with type 2 diabetes, many especially with insulin secretion. However, the evidence for their single or combined effect on beta-cell function relies mostly on genetic association of the variants or genetic risk scores with simple traits, and few have been functionally fully characterized even in cell or animal models. Translating the measured traits into human physiology is not straightforward: none of the various indices for beta-cell function or insulin sensitivity recapitulates the dynamic interplay between glucose sensing, endogenous glucose production, insulin production and secretion, insulin clearance, insulin resistance-to name just a few factors. Because insulin sensitivity is a major determinant of physiological need of insulin, insulin secretion should be evaluated in parallel with insulin sensitivity. On the other hand, multiple physiological or pathogenic processes can either mask or unmask subtle defects in beta-cell function. Even in monogenic diabetes, a clearly pathogenic genetic variant can result in different phenotypic characteristics-or no phenotype at all. In this review, we evaluate the methods available for studying beta-cell function in humans, critically examine the evidence linking some identified variants to a specific beta-cell phenotype, and highlight areas requiring further study. (C) 2020 The Authors. Published by Elsevier Ltd.Peer reviewe

Industrial Agile Transformations Lacking Business Emphasis: Results from a Nordic Survey Study

Peer reviewe

Role of disorder in the size-scaling of material strength

We study the sample size dependence of the strength of disordered materials with a flaw, by numerical simulations of lattice models for fracture. We find a crossover between a regime controlled by the fluctuations due to disorder and another controlled by stress-concentrations, ruled by continuum fracture mechanics. The results are formulated in terms of a scaling law involving a statistical fracture process zone. Its existence and scaling properties are only revealed by sampling over many configurations of the disorder. The scaling law is in good agreement with experimental results obtained from notched paper samples.Comment: 4 pages 5 figure

Geospatial images in the acquisition of spatial knowledge for wayfinding

Geospatial images such as maps and aerial photographs are important sources of spatial knowledge that people use for wayfinding. The rapid development of geodata acquisition and digital graphics has recently led to rather complete geographic coverage of both traditional and novel types of geospatial images. Divergent types of geospatial images vary in their support of human acquisition of spatial knowledge. However evaluative studies about the acquisition of spatial knowledge from the diversity of geospatial images have been rare. In this article we review a variety of literature about the acquisition of spatial knowledge while paying particular attention to the role of geospatial images. Based on the literature we present a framework of image parameters that characterize the acquisition of spatial knowledge from geospatial images: vantage point number of visible vertical features and visual realism. With the help of the framework we evaluate commonly used geospatial images. In concordance with the previous experiments our evaluation shows that the different types of geospatial images have large differences in the types of spatial knowledge they support and to what extent. However further experimentation is needed in order to better understand the human cognitive needs for geospatial images and to develop more useful geospatial images for wayfinding

Valence electronic structure and photofragmentation of 1,1,1,2-tetrafluoroethane (CF3-CH2F)

The electronic structure and fragmentation of the hydrofluorocarbon compound 1,1,1,2-tetrafluoroethane (CF3-CH2F) were studied using spectroscopical methods and quantum chemical calculations. Valence photoelectron spectra and the ionic fragmentation products were recorded with synchrotron radiation in the vacuum ultraviolet (VUV) region. The geometric and electronic structures of the CF3-CH2F molecule were calculated using the complete active space perturbation theory of second order. The calculated vertical ionization energies were used to interpret the experimental photoelectron spectrum. VUV photodissociation of the sample molecule was studied with photoelectron-photoion coincidence spectroscopy. Coincident ion yields are shown for several cations as a function of electron binding energy. The experimental data are discussed in comparison with theory and previous work

Biliary Anomalies in Patients With HNF1B Diabetes

Context: The clinical spectrum of organogenetic anomalies associated with HNF1B mutations is heterogeneous. Besides cystic kidney disease, diabetes, and various other manifestations, odd cases of mainly neonatal and posttransplantation cholestasis have been described. The biliary phenotype is incompletely defined. Objective: To systematically characterize HNF1B-related anomalies in the bile ducts by imaging with magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography (MRCP). Setting and Patients: Fourteen patients with HNF1B mutations in the catchment area of the Helsinki University Hospital were evaluated with upper abdominal MRI and MRCP. Blood samples and clinical history provided supplemental data on the individual phenotype. Main Outcome Measure(s): Structural anomalies in the biliary system, medical history of cholestasis, other findings in abdominal organs, diabetes and antihyperglycemic treatment, hypomagnesemia, and hyperuricemia. Results: Structural anomalies of the bile ducts were found in seven of 14 patients (50%). Six patients had choledochal cysts, which are generally considered premalignant. Conclusions: Structural anomalies of the biliary system were common in HNF1B mutation carriers. The malignant potential of HNF1B-associated choledochal cysts warrants further studies.Peer reviewe

Using the CAVE virtual-reality environment as an aid to 3-D electromagnetic field computation

One of the major problems in three-dimensional (3-D) field computation is visualizing the resulting 3-D field distributions. A virtual-reality environment, such as the CAVE, (CAVE Automatic Virtual Environment) is helping to overcome this problem, thus making the results of computation more usable for designers and users of magnets and other electromagnetic devices. As a demonstration of the capabilities of the CAVE, the elliptical multipole wiggler (EMW), an insertion device being designed for the Advanced Photon Source (APS) now being commissioned at Argonne National Laboratory (ANL), wa made visible, along with its fields and beam orbits. Other uses of the CAVE in preprocessing and postprocessing computation for electromagnetic applications are also discussed

"Pay Now, Argue Later" Rule – Before and After the Tax Administration Act

The South African Revenue Service (SARS) is entrusted with the duty of collecting tax on behalf of the South African government. In order to ensure effective and prompt collection of taxes, the payment of tax is not suspended pending an objection or an appeal, unless directed otherwise. This is also known as the "pay now, argue later" rule, and, for value-added tax purposes, is provided for in terms of section 36 of the Value-Added Tax Act 89 of 1991. The "pay now, argue later" rule in terms of section 36 of the Value-Added Tax Act prima facie infringes on a taxpayer's right of access to the courts as envisaged in section 34 of the Constitution. This is due to the fact that a taxpayer is obliged to pay tax before being afforded the opportunity to challenge the assessment in a court. In Metcash Trading Ltd v Commissioner for the South African Revenue Service, the Constitutional Court held the "pay now, argue later" rule in terms of section 36 to be constitutional. Olivier, however, does not agree with the court on several matters. Amongst the problems she indicates are that the taxpayer does not have access to the courts at the time the rule is invoked, and that the court did not consider the fact that there might be less invasive means available which would ensure that SARS's duty is balanced with the taxpayer's right of access to the courts. Guidelines were also issued which provide legal certainty regarding the factors SARS may consider in determining whether the payment of tax should be suspended or not. These guidelines also evoked some points of criticism. Since 1 October 2012, the "pay now, argue later" rule has been applied in terms of section 164 of the Tax Administration Act 28 of 2011. The question arises whether this provision addresses the problems identified in respect of section 36 of the Value-Added Tax Act and the guidelines. In comparing these sections, only slight differences emerged. The most significant difference is that section 164(6) of the Tax Administration Act stipulates that the enforcement of tax be suspended for a period when SARS is considering a request for suspension. Section 164(6) does not provide a solution to the problems identified regarding section 36 of the Value-Added Tax Act. It is even possible that this section could give rise to further problems. Therefore, the legislature has failed to address the imbalance between the duties of SARS and the right of a taxpayer to access the courts.   

Benefits Analysis of Wind-Optimal Operations For Trans-Atlantic Flights

North Atlantic Tracks are trans-Atlantic routes across the busiest oceanic airspace in the world. This study analyzes and compares current flight-plan routes to wind-optimal routes for trans-Atlantic flights in terms of aircraft fuel burn, emissions and the associated climate impact. The historical flight track data recorded by EUROCONTROL's Central Flow Management Unit is merged with data from FAA's Enhanced Traffic Management System to provide an accurate flight movement database containing the highest available flight path resolution in both systems. The combined database is adopted for airspace simulation integrated with aircraft fuel burn and emissions models, contrail models, simplified climate response models, and a common climate metric to assess the climate impact of flight routes within the Organized Track System (OTS). The fuel burn and emissions for the tracks in the OTS are compared with the corresponding quantities for the wind-optimized routes to evaluate the potential environmental benefits of flying wind-optimal routes in North Atlantic Airspace. The potential fuel savings and reduction in emissions depend on existing inefficiencies in current flight plans, atmospheric conditions and location of the city-pairs. The potential benefits are scaled by comparing them with actual flight tests that have been conducted since 2010 between a few city-pairs in the transatlantic and trans-pacific region to improve fuel consumption and reduce the environmental impact of aviation