Paediatric ependymomas remain a clinical management challenge, with a relatively poor prognosis when compared to other childhood tumours of the central nervous system. An improved understanding of underlying ependymoma biology may identify new correlates of outcome and potential therapeutic targets. To address this, AffymetrixTM 500K SNP arrays were used to establish the nature and range of genomic imbalances in 63 paediatric ependymomas (42 primary and 21 recurrent). Over 80 % of tumours were analysed against patient-matched constitutional DNA. In addition, the Illumina® GoldenGate® Cancer Panel I array was used to identify differences in methylation profile across 98 paediatric ependymomas (73 primary and 25 recurrent). While collective assessment revealed the most common anomalies, specific aberrations were characteristic of certain ependymoma subgroups, particularly those relating to tumour location, patient age, disease recurrence and patient prognosis. The genomic imbalance of 15 selected candidate genes (NSL1, DNAJC25, NAV1, CDKN2A, CHI3L1, HOXA5, TXN, BNIPL, and PRUNE) were confirmed by quantitative Polymerase Chain Reaction. Genomic gain involving regions of chromosome 1q were associated with an unfavourable patient outcome, such as the focal locus on 1q21.3 encompassing PRUNE. The genomic gain of PRUNE correlated with an increased encoded protein expression, as assessed by immunohistochemistry (IHC).

This adverse prognostic association with 1q was upheld in the subsequent part of this work. Fluorescent in situ hybridisation and IHC were used to evaluate a panel of six putative prognostic markers (1q25 gain, PRUNE, Tenascin-C, Nucleolin, Ki-67 and NAV1 expression) across a paediatric intracranial ependymoma tissue microarray cohort of 107 primary tumours treated within the confines of two aged defined clinical trials (UK CCLG 1992 04 and SIOP 1999 04). Within the younger UK CCLG 1992 04 cohort, copy number gain of chromosome 1q25 and PRUNE overexpression were independently associated with an increased risk of disease progression, while strong PRUNE expression was also an independent marker of worse overall survival. In addition, increased Tenascin-C expression correlated with a reduced overall survival on univariate analysis. For older children in the SIOP 1999 04 cohort, strong PRUNE expression in ependymomas was again identified as an adverse prognostic marker, correlating with increased mortality on univariate assessment.


A study of the ultrastructural peculiarities of the spinal cord neural cells in 14 day old chick embryos at the early stages of cultivation has shown that adaptation processes are completed within the first days of explant cultivation. Further cultivation leads to the differentiation of neurons and to the recovery of their capacity of bioelectrical activity.


The single European market after 1992 presents a major challenge to small and medium-sized companies in the Community. Whether it is developing exports and/or fighting off new imports, Europe's entrepreneurs will have to 'think European'. Moreover, the European Community institutions themselves have developed special policies designed to promote the interests of Europe's smaller companies. This volume explains how the EC's policies towards small and medium-sized enterprises have developed and what they currently entail. It guides the reader through the various EC policy initiatives and the new legislation - including that in the '1992' package - relevant to the smaller business company. It offers summaries of the key EC documents concerned, and presents a full listing of all the other relevant proposals and policies. Like the others in this series, the volume is both comprehensive and up-to-date: it discusses not only what the EC has done which is relevant to small businesses, but also what it is proposing to do in the future.


This work is concerned with the development of an efficient and robust isogeometric Reissner–Mindlin shell formulation. The basic assumption of shell theories is a dimensional reduction of the three-dimensional continuum to a two-dimensional surface embedded in the three-dimensional space. Consequently, the geometry is described by a reference surface in combination with a director vector field, which defines the expansion in the thickness direction. The main objective of isogeometric analysis is to use the same model description for design and analysis. Thin-walled structures are usually defined by a reference surface and an associated thickness in industrial design software. Thus, the usage of isogeometric shell elements can avoid costly conversions to volumetric geometry descriptions. The usage of NURBS surfaces (Non-Uniform Rational B-splines) possibly yields high continuity between elements. This requires a rethinking of all concepts used in conventional shell elements, which base on linear Lagrange basis functions. The shell formulation presented in this work is derived from the continuum theory and uses an orthogonal rotation described by Rodrigues' tensor to compute the current director vector. Large deformations and finite rotations can be described accurately. The discretization requires nodal director vectors which interpolate the normal vector as exact as possible. A new method for the definition of nodal basis systems and nodal director vectors is derived. Basing on this, a criterion for the automatic assignment of the correct number of rotational degrees of freedom for each node is proposed. This allows stable computations of geometries with kinks while requiring neither the usage of drilling rotation stabilization nor manual user interaction. The main part of this work is the derivation of various concepts for the interpolation of the current director vector, which is a function of the rotational state. The respective concepts differ in the quantity which is actually interpolated and in the chosen update formulation for the rotations. The influence of each concept on the global deformation convergence behavior is assessed with the help of numerical examples. The results suggest that proper convergence behavior for all orders of NURBS basis functions can only be attained if interpolated director vectors are rotated. Concepts of this type are more accurate and expensive than concepts which rotate nodal director vectors. But the higher computational effort pays off for geometries with arbitrary curvature and for basis functions of higher order. Geometries with kinks require a multiplicative rotational update formulation for concepts that rotate interpolated director vectors. Three different integration rules are considered within the numerical examples. Besides full and reduced Gauss integration also a new non-uniform Gauss integration concept following Adam et al. (2015) is assessed. A special focus is put on the interaction between the chosen rotational concept and the integration scheme. The reduction of the number of integration points from full to reduced integration slightly alleviates locking effects. The further reduction entailed by non-uniform integration significantly reduces locking effects in some examples. But this only yields higher accuracy if a concept which rotates interpolated director vectors is chosen. The reduction of locking deteriorates the accuracy of deformation results in other cases. The efficiency of the presented shell formulation is compared to standard shell formulations in terms of computational costs to attain a pre-defined error level. The most effective combination of integration scheme and rotational concept is shown to be competitive to standard shell formulations. A further main concern of this work is the derivation of a mortar-type method for the coupling of non-conforming NURBS surface patches. Methods to handle nonconforming patches without mutual refinement are essential for an efficient application of NURBS-based isogeometric analysis. The proposed method bases on a substitution relation, which is derived from the weak fulfillment of the equality of mutual displacements along the interface. A static condensation can be performed with the help of this substitution relation in order to attain a coupled global system of equations. The variational formulation is not altered and the global stiffness matrix remains positive definite. Numerical examples show the applicability of the method. A comparison to reference results and to computations with the Lagrange multiplier method is given. The applicability of the coupling method for the presented Reissner–Mindlin shell formulation is shown with the help of two nonlinear examples.


Nitrogen oxides (NOx) are formed by oxidation of nitrogen during the combustion process, and production rate is highly affected by flame temperature. NOx is regarded as a local pollutant causing smog, acid rain and health complaints, and strictest emission regulations are found in urban areas. Reduction of NOx emissions from gas turbines can be achieved by modifying the combustion process or by exhaust gas clean up. Several technologies are already commercial available, but there are still a great many being developed. Increased focus on the environment also forces manufacturers to improve existing technology. In this report, different NOx abatement technologies are looked into, and an optimal solution for the coming gas turbines on Skarv Idun is presented. Different techniques are compared in terms of thermal efficiency, emissions, maintenance requirements, load acceptance and rejection, engine stability and reliability and availability. Application and suitability of available technologies for reducing NOx from the selected gas turbines is discussed, and user experience for these is collected. It is showed that all technologies influence operation of the gas turbines to some extent, either by increasing/decreasing efficiency or by affecting engine stability. They also differ in their ability to reduce NOx emissions over the entire load range. Due to weight and space restrictions on offshore installations, limited technologies are suitable for platforms and boats. Gas turbines installed offshore are usually aero-derivative engines with high efficiency and relative low emissions of CO2. This year, Norwegian government introduced a NOx tax in order to reduce NOx emissions from the petroleum industry. Operators are forced to use best available technology, and dry low emission control (DLE) is the only one considered qualified as far as NOx is concerned. DLE is also chosen as the optimal solution for the planned gas turbines on Skarv Idun, due to small operational impacts and positive experience from existing fields. It is however recommended to allocate space in case a new and better combustor with lower emission levels is developed. Looking at a longer perspective, Cheng technology including steam injection into the gas turbine combustor seems very promising for NOx abatement.


Improving the system of anti-brucellosis measures is the ultimate goal of all studies devoted to the problem of brucellosis. Cattle brucellosis outbreaks in the brucellosisfree regions in the Russian Federation indicate a premature cessation of immunization procedures and the need for their continuation. Meanwhile, there is an urgent problem of developing anti-brucellosis immunity in the adult cattle: the initial vaccination of cattle with a full dose of the vaccine from strain B. abortus 82 is fraught with post-vaccination abortions. In order to solve this problem, in the production conditions of one of the farms where the current epizootic situation for brucellosis required alternative approaches for containment of a brucellosis outbreak, a small dose of the vaccine was tested on the cattle without specific immunity. This resulted in immunogenicity, loss of abortogenicity and the presence of provocative properties of the vaccine in small doses. This allowed the detection of antibodies in animals with a hidden infection in the early stages after vaccination. Serological methods (AT, RBT and IDR with O-polysaccharide antigen), which are generally accepted in veterinary practice, were used as diagnostic tests. The reimmunization of the cows with a small dose of the vaccine from strain 82 allowed diagnostic tests to be carried out earlier after vaccination than after the use of a full dose of the vaccine, which made it possible to diagnose brucellosis in a short period of time after vaccination. The provocation of immunological reactions in latently sick animals after the vaccination with small doses, and the isolation of those who responded under the condition of supported immunity made it possible to achieve the recovery of farm animals in a short period of time, which was proved by negative indicators of the immunodiffusion reaction with O-polysaccharide antigen.


This thesis is concerned with the influence of campaign finance on the interplay between political power and electoral competition in the United States and the United Kingdom. The thesis considers both the donation and expenditure sides of campaign finance: In the context of U.S. state and federal legislative elections (1980-2014), I study how political power affects the allocation of campaign contributions, and in the context of U.K. House of Commons elections (1885-2010), I examine how campaign spending restrictions affect political power via electoral behavior. The three papers which make up the construct of the thesis answer the following questions:
(i) What is the financial value of incumbency status, and who generates it?
(ii) Who values legislative agenda setters, and why do they do so?
(iii) What are the electoral consequences of statutory limits on campaign expenditure?
I argue that campaign donors make their contributions to powerful politicians in exchange for access to the policy-making process, and that the power of these politicians is sustained, at least in part, due to these contributions.
In the first paper, I document that U.S. incumbent legislators enjoy sizeable financial advantages compared to challengers, and I demonstrate that this advantage is the result of donations from access-seeking industries. In the second paper, I show that U.S. legislators who are institutionally endowed with agenda-setting powers are given special treatment by campaign donors. I document that donors with vested economic interests in regulatory policy place great value on agenda-setting legislators – in particular when institutions provide these legislators with the authority to block new legislation. In the final paper, I study the consequences of campaign spending limits in the context of U.K. House of Commons elections. I show that unrestrained spending reduces electoral competition, promotes professionalized campaigns, and benefits incumbents and centerright
parties.


This research seeks to evaluate the economic benefits to be gained by installing a small-scale wind turbine for a customer with a three-phase electrical supply requirement. The evidence for the claims made in this paper is obtained by using actual data obtained from the installed equipment over a three year period. The objective is to accurately appraise the financial investment using real data. There appears to be limited studies conducted into this type of research, possibly because the renewable energy sector is in the infancy stage in the host country, Ireland. There are some wind energy installations with financial appraisal techniques based on modeled data, which may, or may not, be accurate. The study concludes by claiming that the financial benefits of the wind energy turbine installation had disappointing results when compared to predicted benefits based on modeled data.


ISSN: 2319-7706 Volume 8 Number 05 (2019) Journal homepage: http://www.ijcmas.com Increased productivity of dry chilli with appreciable fruit quality is the present need in major growing areas to promote export from our country. The present investigation was undertaken to identify important selection indices, and to analyze the genetic divergence of collected germplasm for identification of diverse parents for spice chilli hybridization program. Different components of genetic variability for 15 growth and yield component traits were determined employing 45 genotypes evaluated in autumn-winter season of 2015-16 in Randomized Block Design with three replications. High GCV and PCV values were recorded for all the characters except days to 50% flowering, days to ripe fruit maturity from anthesis and 1000 seed weight. The proportion of genetic contribution to the overall phenotypic expression of most of the traits was very high. Both heritability and genetic advance was high for all the characters under study except days to ripe fruit maturity from anthesis, revealing additive genetic control of characters. Selection would be most useful for the improvement of these traits. Dry fruit yield/plant was found positively and significantly correlated with all the traits except days to 50% flowering and days to ripe fruit maturity from anthesis. Path coefficient analysis indicated that the maximum direct effect on dry fruit yield/plant was through ripe fruit yield/plant followed by dry fruit weight. From the combing study of correlation and path coefficient, the characters, namely ripe fruit yield/plant and dry fruit weight were the most important selection criteria, emphasis should be given on such traits while imposing selection for amenability in dry fruit yield of chilli. Based on the determination of divergence all the genotypes were grouped into 7 clusters. However, random grouping pattern of genotypes was observed indicating that geographical diversity and genetic divergence were unrelated. The intraand inter-cluster distance among the genotypes depicted that crossing between the genotypes belonging in Cluster I and VII or Cluster III and VII will be expected to give high heterotic response in F1 generation. The character fruit length contributed the maximum towards genetic divergence followed by fruit diameter, fruits/plant and plant spread (N-S). Based on D Statistics, PCA and mean performance, six genitors Beldanga, BCCH Sel-4, G-4, BCC-30, BCC-25, and Srinagar possessed the optimum combination of all variables and were identified as most promising donor parents in dry chilli hybridization programme with a view to develop promising hybrids/improved lines. K e y w o r d s Chilli, Correlation, Genetic variability, Multivariate analysis, Path analysis, Dry fruit


Oxford Archaeology East carried out an archaeological evaluation between 15th and 23rd February 2018 at Land north of Greenpark Avenue, King's Lynn, Norfolk. This work was commissioned by NPS Property Consultants Ltd. The site comprised 3.8ha of undeveloped land, within the urban reach of King's Lynn, proposed for redevelopment as a primary school and associated grounds.
These works lie in a significant area of industrial archaeological remains relating to salt-making, during the later Saxon and medieval periods. This industrial landscape is currently being investigated by OA as part of a wider scope of works for the adjacent Lynnsport residential development by Lovell Partnerships Ltd.
Topographical survey of the site along with NHER data indicated that the remains of six saltern mounds, resulting from salt-making activities (including NHER 27907 and 27909), partially or wholly lie within the bounds of the proposed development. The evaluation confirmed the presence of the salterns.
Two of these (Salterns 1 and 4) extended beyond the southern boundary of the site where they were previously excavated by OA in 2017 as part of the Lynnsport 4 and 5 developments. The remains of a further saltern (Saltern 7) were located wholly within the development. However, the remaining salterns (Salterns 5, 6 and 8) lay on the periphery of the site, where they extended beyond the proposed development area into neighbouring plots of land. As well as revealing waste deposits from the salt-making process constituting the
mounds, the evaluation also revealed the remains of broken-up brine boiling hearths and in-situ remains of clay-lined tanks. These remains are typical of the known later Saxon and medieval salt-making evidence previously excavated in
the area by OA East.
The evaluation also revealed a network of ditches across the lower lying areas of the site, probably representing drainage channels of either later medieval or post-medieval origin when the site would have comprised part of a landscape predominantly utilised for pasture. The later date for these drainage features was reinforced with the recovery from the fills of artefacts spanning both these
periods. However, the possibility remains the larger extant (unexcavated) channel observed to extend broadly north to south across the site (skirting Salterns 5 and 7) may delineate the path of a historical creek. In addition to these remains, there was evidence for recent truncation of the deposits comprising Saltern 1 in the southern part of the site, with associated dumps of saltern mound material found to overly the topsoil intermittently across the southern part of the site.


Nanosized TiO2-Ag-SiO2 sols were prepared with modified sol-gel method using reduction agent. The physical properties of the prepared particles were investigated by TEM, XRD and FT-IR. The titanium tetraisopropoxide (TTIP, 98% Aldrich), teraethylorthosilicate (TEOS, 98% Aldrich) and silver nitrate were used as precursors of titania, silica and silver, respectively. Sodium citrate tribasic dihydrate (C6H5Na3.2H2O, Aldrich) was used as a reduction agent. This paper presents the effect of nanosized TiO2-Ag-SiO2 sols on the formation of methane hydrate in a semi-batch vessel. The micrographs of TEM showed that the TiO2-Ag-SiO2 particles possessed a spherical morphology with a narrow size distribution. The crystallite size of particles decreased with an increasing the SiO2 content. In addition, the water solution with 1.0 wt% of TiO2-Ag-SiO2 particles acted as promoter for methane hydrate formation.


Debate about the benefits and problems with competency-based training (CBT) has not paid sufficient attention to the fact that the model satisfies a unique, contemporary demand for cross-occupational curriculum. The adoption of CBT in the UK and Australia, along with at least some of its problems, can be understood in terms of this demand. We argue that a key problem with CBT is that as a cross-occupational curriculum model it impacts too strongly on the way particular occupations are known and represented. Following this line of argument, we propose that more effective models will be those that are 'epistemically neutral' and thus responsive to the inherent knowledge and practice structures of occupations. We explore the 'threshold concepts' approach as an alternative that can claim to be sensitive to occupational structures. We indicate ways it contrasts with CBT but also note some difficulties with the approach for vocational education.


Abstract Today's National Chiropractic Mutual Insurance Company (NCMIC) evolved from the legal protective services offered initially by the Universal Chiropractors' Association, and subsequently, by the National Chiropractic Association (NCA). At first these services focused on the criminal defence of chiropractors charged with unlicensed practice. However, as an increasing number of jurisdictions enacted chiropractic statutes, the NCA's legal program became ever more involved in civil litigation: suits for malpractice and negligence. Steering the NCA throughout its tumultuous voyage was its longtime secretary-treasurer, Loran M. Rogers, D.C. When the NCA spun off its legal services division in 1946, forming the National Chiropractic Insurance Company (predecessor of the NCMIC), Rogers continued his work as executive secretary-treasurer of the malpractice insurer.


Objective: To discover the role of hypertonic sodium lactate (HSL) as the energy source, which in turn will act as a neuroprotector, by measuring adenosine triphosphate (ATP) level, monocarboxylate transporter 1 (MCT-1) and the extent of the necrotic areas. Design: This was an experimental study that used randomized post-test only control group design. Setting: Experimental Animal Care Unit Universitas Gadjah Mada. Patient and participant: 32 white mice of Rattus norvegicus. Intervention: After the protocol of this study was approved by the research ethic committee, _ 32 rats were randomly divided into two groups: HSL group (n=16) and NaCl 3% group (n=16) as the control group. Both groups were anesthetized using conversion-dose pentothal. Results: ATP level in HSL group was higher compared to the control group (p=0.031). MCT1 in HSL group was also higher than the control group (p=0.010). Necrotic areas were less extensive in the HSL group than the control group (p=0.000). Lactate levels at minute 30 (T30) and minute 360 (T360) increased in the HSL group, while increasing in the control group up to T30, then decreased gradually until T360. Conclusion: Exogenous lactate in solution has effect as a neuroprotective of brain in the intracerebral hemorrhage (ICH).


The new voluntarism.The article is based on an evaluation of the first two years of the Swedish volunteer centre Viljan. The aim is to arrive at a deeper understanding of the phenomenon of voluntary work based on the experience of one volunteer centre. The stydy comprised 39 users and 62 volunteers. Viljan's users consists of two main groups frail, elderly women and single mothers. The group of single mothers needed baby-sitters but also wanted an adult contact for themselves. It is difficult for Viljan to meet this need. The direction taken by Viljan has been a relatively traditional role of befriending the old and the sick, initially with strong control from the social services. All the interviewees were satisfied with the help they had recieved, but it was clear that they want more assistance and contact, which they do not dare to ask for out of fear if becoming a burden. Volunteers and the users appear to have the same needs for social contact which is why they turned to Viljan. There is a serious risk, however, that the volunteer centre may emphasize assistance to people to the expence of meetings between people and that the volunteers may be proffesionalized. The volunteers live all over the Stockholm area, few of them living close to the people they help. The volunteer centre can be seen as a modern welfare phenomenon, which make visible civic needs which the family, the public sphere and the private sphere have not been able to satisfy. Viljan appears to be able to fill this vacuum partially.


This research addresses two important issues for the future expansion of organic consumption in France. The first one is related to knowing whether the organic choice is a permanent feature of consumer's attitude or not: Do organic buyers occasionally pick one organic product or do they choose organic for "several" categories? The second issue concerns the impact of prices on buying organics which is revisited, distinguishing between capturing new consumers and increasing the demand coming from people already involved in organic markets. These questions are examined using the market basket approach; the price issue requires further estimations of demand models. The study relies on two staple food products, eggs and milk. The findings are : (i) choosing organic for one of the two items reinforces the probability of purchasing also the organic version of the second item; (ii) marginal reductions of the organic price have no impact on the decision of buying organic rather than conventional products; (iii) on the contrary, when people already purchase organic products, price elasticities are rather high; (iv) organic buyers' demographic profile is not related to income neither to age nor to family size, but to the educational level.


The mystique of the Wild West perpetuated by Buffalo Bill, Zane Grey and Louis L'Amour, John Wayne, and the Marlboro Man has hindered the serious study of the real region west of the ninety-eighth meridian. Michael P. Malone and Richard W. Etulain move beyond myth and beyond the influential frontier thesis advanced by Frederick Jackson Turner to write about the American West as it has actually developed in the twentieth century. In vivid detail they describe a region too richly varied and dynamic to be contained by the imagination. Extending into the 1980s, The American West: A Twentieth-Century History is the first comprehensive survey of the modern West to appear in many years. Malone and Etulain discuss economic, political, social, and cultural developments in the West from the turn of the century to the onset of the Great Depression, when the region was still in a colonial relationship to the urban, industrial Northeast and upper Midwest; from 1930 to the end of World War II, when the West was transformed by New Deal programs and by even greater federal spending in military installations; and from 1945 to the present, when the West experienced rapid changes in demographics and a series of trendsetting lifestyles. Unique to this history are chapters about the rich cultural heritage of the modern West and about the lives of men, women, and children of various ethnic groups. Detailed bibliographical essays are included.


In Crete, as in the rest of the Ottoman Empire, patients who suffered from hernias and other diseases that required surgery made statements to the court of law that absolved the surgeons of liability in case of death as a result of the operation. These statements also included information about the medical condition concerned, the surgeon, the medical procedure and the fee to be paid. In this article, we discuss such statements of the period 1670–1760 from the town of Kandiye (mod. Heraklion). On one hand, we demonstrate that a critical analysis of the statements reveals a dynamic society, which actively overcomes its ideology of submission to God and religious prejudices when it comes to dealing with health issues. On the other hand, we argue that, as the statements were made before the official court of law, they constitute a facet of the Ottomanisation of Cretan society and its practices.


To meet the national regulation on building energy needs while preserving the architectural heritage, the renovation of protected historic buildings implies to insulate internally their facades. However, it is a technically risky solution. This work is part of the European project RIBuild that develops guidelines to ensure moisture-safe solutions. For that purpose, historical buildings were monitored to confront the current state-of-the-art of hygrothermal simulations with in-situ measurements. To enforce these calculations, stones used in Swiss traditional construction were characterised, and materials' modelling were investigated. The results of the study will be integrated into a probabilistic web-tool.


Local binary pattern (LBP) is a simple, yet efficient coding model for extracting texture features. To improve texture classification, this paper designs a median sampling regulation, defines a group of gradient LBP (gLBP) descriptors, proposes a training-based feature model mapping method, and then develops a texture classification frame using the multiresolution feature fusion of four gLBP descriptors. Cooperated by median sampling, four descriptors encode a pixel respectively by central gradient, radial gradient, magnitude gradient and tangent gradient to generate initial gLBP patterns. The feature mapping models of gLBP descriptors are constructed by the maximal relative-variation rate (mr2) of rotation-invariant patterns, and then prestored as mapping lookup files. By mapping, initial patterns can be transformed into low-dimensional ones. And then it generates multiresolution texture features via the joint and concatenation of gLBP descriptors on different sampling parameters. A trained nearest neighbor classifier with chi-square distance is applied to classify textures by feature histograms. The experimental results of simulation on five public texture databases show that the proposed method is reliable and efficient in texture classification. In comparison with nine other similar approaches, including two state-of-the-art ones, the proposed method runs faster than most of them and also outperforms all of them in terms of classification accuracy and noise robustness. It achieves higher accuracy and has also better robustness to the Salt&Pepper and Gaussian noise added artificially into texture images.


Background: Oral anticoagulation is the mainstay of stroke prevention in atrial fibrillation (AF), but must be balanced against the associated bleeding risk. Several risk scores have been proposed for prediction of bleeding events in patients with AF. Objectives: To compare the performance of contemporary clinical bleeding risk scores in 18,113 patients with AF randomized to dabigatran 110 mg, 150 mg or warfarin in the RE-LY trial. Methods: HAS-BLED, ORBIT, ATRIA and HEMORR 2 HAGES bleeding risk scores were calculated based on clinical information at baseline. All major bleeding events were centrally adjudicated. Results: There were 1,182 (6.5%) major bleeding events during a median follow-up of 2.0 years. For all the four schemes, high-risk subgroups had higher risk of major bleeding (all p<0.001). The ORBIT score showed the best discrimination with c-indices of 0.66, 0.66 and 0.62, respectively, for major, life-threatening and intracranial bleeding, which were significantly better than for the HAS-BLED score (difference in c-indices: 0.050, 0.053 and 0.048, respectively, all p<0.05). The ORBIT score also showed the best calibration compared with previous data. Significant treatment interactions between the bleeding scores and the risk of major bleeding with dabigatran 150 mg BD versus warfarin were found for the ORBIT (p=0.0019), ATRIA (p<0.001), and HEMORR 2 HAGES (p<0.001) scores. HAS-BLED score showed a non-significant trend for interaction (p=0.0607). Conclusions: Among the current clinical bleeding risk scores, the ORBIT score demonstrated the best discrimination and calibration. All the scores demonstrated, to a variable extent, an interaction with bleeding risk associated with dabigatran or warfarin.


The world's grasslands, both natural and managed, provide food and many non-provisioning ecosystem services. Although most grasslands today are used for livestock grazing or fodder production, little is known about the spatial patterns of grassland management intensity, especially at broad geographic scales. Using the European Union as a case study, we mapped mowing frequency as a key indicator of grassland management intensity. We used MODIS NDVI time series from 2000–2012 to map mowing frequency using a spline-fitting algorithm that detects up to five mowing events within a single growing season. We combined mowing frequency maps with existing maps of livestock distribution and grassland management frequency to identify clusters of similar grassland management intensity across Europe. Our results highlight generally high mowing frequency in areas of high grassland productivity, especially in Ireland, northern and central France, and the Netherlands. Our analyses also show distinct clusters of similar grassland management, representing different grassland-management intensity regimes. High intensity clusters occurred particularly in western and southern Europe, especially in Ireland, in the northern and central parts of France and Spain, and the Netherlands but also in northern and southern Germany and eastern Poland. Low intensity clusters were found mainly in central and eastern Europe and in mountainous regions but also in Extremadura in Spain, Wales and western England (UK). Generally, our analyses emphasize the usefulness of jointly using satellite time series and agricultural statistics to monitor grassland intensity across broad geographic extents. Our maps allow for a new, spatially-detailed view of management intensity in grassland systems and may help to improve regionally targeted land-use and conservation policies.


EDITOR,-Albert Figueras and colleagues' recommendation that gangliosides should be withdrawn, which is based on their experience of 17 patients diagnosed as having the Guillain-Barre syndrome and other acute motor neuropathy, is inappropriate.' Firstly, they give no details from which the validity of the diagnosis can be judged. Retrospectively collected data are notoriously incomplete, and even if the diagnoses were "confirmed by a neurologist" it is not clear that acceptable diagnostic criteria were uniformly applied.2 Moreover, in nine of their cases the use of gangliosides for prodromal symptoms of the disease allegedly caused by the ganglioside could not be excluded. In addition, in at least three cases an antecedent illness that often precedes the onset of polyneuropathy was known to have been present. Thus in 12 of the 17 cases the clinical basis for implicating gangliosides as a cause is uncertain at best. If even five cases of acute motor polyneuropathy were caused by gangliosides the risk should be calculated. To do this requires knowledge of the size of the population exposed to ganglioside. Figueras and colleagues do not give this information, stating only that the 17 reports were among 18000 reports in their database. In a recent epidemiological study in Spain no association between use of gangliosides and polyneuropathy was found.3 An epidemiological study in Italy reported that if a risk of polyneuropathy exists at all it is less than 1 in 10000 exposed.4 Finally, evidence is accumulating, based on well controlled clinical trials, that GM1 ganglioside may be beneficial in several types of injury to the central nervous system.85Colleagues and I recently completed a randomised double blind, multicentre clinical trial of 287 patients with acute stroke treated with 100 mg Gm1 ganglioside intramuscularly or placebo daily for 28 days.9 No cases of acute polyneuropathy occurred, nor was there any significant difference in deaths or adverse effects between the two groups of patients. We found consistent benefits favouring the group treated with Gm, when we measured the change from baseline values in the motor component of the Toronto stroke scale at day 28 (p=002) and day 84 (p=0 06). The Fugl Meyer scale, all 10 components of the Barthel index, and four of five tests in a neuropsychological battery also favoured the patients treated with G1.I To withdraw ganglioside treatment on the basis of the evidence presentedbyFigueras and colleagues would be a disservice to patients who suffer from conditions for which no other effective treatment exists.


Peripheral neuropathy and optic neuritis occurring in alcoholics are sometimes due to the toxic effects of disulfiram rather than to alcohol. Unless this is considered in the management of such patients it is likely that administration of the drug will be continued. In the past there have been reports of 16 cases of peripheral neuropathy and six cases of optic neuritis, possibly caused in this way; these reports are reviewed and a further six cases are described. The effects of disulfiram on the nervous system are briefly discussed.


Here we report multisatellite observations of ionospheric disturbances in relation to the occurrence of the M8.7 northern Sumatra earthquake of 28 March 2005. The DEMETER (Detection of Electro‐Magnetic Emissions Transmitted from Earthquake Regions) and CHAMP (Challenging Minisatellite Payload) satellite data were investigated to find possible precursory and postevent phenomena. It was found that EIA (equatorial ionization anomaly) strength expressed in the apex height, derived from the CHAMP plasma density profile, was intensified along the orbits whose longitudes were close to the epicenter within about a week before and after occurrence of the earthquake. Increases in electron and O+ density along the orbits close to the epicenter were also observed in the DEMETER measurements. The normalized equatorial plasma density derived from the DEMETER measurements showed intensification about a week before and after the earthquake reaching maximum the day after the shock and afterward disappearing. In addition, similar behavior of the EIA enhancements related to the M8.0 Pisco earthquake of 15 August 2007 was observed. Surveys of space weather and geomagnetic activities excluded the possibility that these fluctuations were caused by changes in space weather or by a geomagnetic storm. Statistical analyses of the longitudinal variation revealed that the EIA was enhanced in the west of the epicenter and reduced in the east of the epicenter, and this fits the "increased conductivity" model. Based on these observations, we proposed a revised view of seismo‐ionospheric coupling in the region of the geomagnetic equator, to explain the EIA features observed in this study.


Abstract A microwave path survey is critical before any wireless communication infrastructure can be put into place. It is on the basis of this that the line of sight possibility between any pair of stations is established. This survey can also be used to determine whether there is sufficient space available on existing telecommunication towers, where additional telecommunication facilities can be hosted. This study has demonstrated that differential GPS techniques can successfully be used in microwave path surveys within the framework of telegeoinformatics. The adopted methodology simulated a levelling circuit for the defined observation network. This resulted in an acceptable misclosure of 0.039m which was distributed among the various stations in proportion to the relative length of each link. Natural and man-made obstacles (critical points) along the various telecommunication links were also determined.


e-commerce
adoption has caused the marketplace to undergo transformation from
intermediation as in the case of traditional retailers who help selling goods
for bricks-and-mortar companies, to the disintermediation stage that has
resulted from companies selling their products directly over the internet, to
the current stage of reintermediation realizing the importance of Internet
Intermediaries that have caused disruption to the traditional supply chain and
gave rise to new business models. It is evident how Internet Intermediaries –known
as cybermediaries - are playing an important role in the internet marketplace
and how they generate revenues from their activities and revolutionize the way suppliers
manage their supply chain. Past research noted that despite the emergence of
new e-commerce business models, little has been done to investigate these
business models. In the context of this research (Middle East), it becomes
increasingly important to investigate the existing cybermediaries business
models which is useful to new entrants to ecommerce fields. Based on a
framework adopted from Barnesa and Hinton (2007), business models of selected
Middle East cybermediaries and their characteristics will be revealed,
evaluated, and documented. Having a clear idea about business models is
beneficial for online startup companies as well as existing businesses (Chaffey, 2015).


POMDP algorithms have made significant progress in recent years by allowing practitioners to find good solutions to increasingly large problems. Most approaches (including point-based and policy iteration techniques) operate by refining a lower bound of the optimal value function. Several approaches (e.g., HSVI2, SARSOP, grid-based approaches and online forward search) also refine an upper bound. However, approximating the optimal value function by an upper bound is computationally expensive and therefore tightness is often sacrificed to improve efficiency (e.g., sawtooth approximation). In this paper, we describe a new approach to efficiently compute tighter bounds by i) conducting a prioritized breadth first search over the reachable beliefs, ii) propagating upper bound improvements with an augmented POMDP and iii) using exact linear programming (instead of the sawtooth approximation) for upper bound interpolation. As a result, we can represent the bounds more compactly and significantly reduce the gap between upper and lower bounds on several benchmark problems.


This paper discusses a transformerless hybrid active filter integrated into the 6.6-kV, 1-MW adjustable-speed motor drive having a three-phase diode rectifier at the front end. The hybrid filter consists of an active filter using a three-level diode-clamped PWM converter rated at 60 kVA, and a 250-kVA passive filter tuned to the 7th-harmonic frequency. They are directly connected in series without transformer. This circuit configuration enables to use 1.2-kV IGBTs because the dc voltage of the three-level converter is 1.32 kV (20% of 6.6 kV). Voltage-balancing control characterized by superimposing a 6th-harmonic zero-sequence voltage on the active-filter voltage reference in each phase is introduced to the three-level converter with triangle-carrier modulation. Experimental waveforms obtained from a 400-V 15-kW down-scaled system verify the viability and effectiveness of the proposed hybrid filter, keeping the two dc-capacitor voltages balanced well.


When an influenza virus tries to enter a cell, it has to fuse its viral membrane with the cell membrane. This fusion is mediated by a protein called hemagglutinin. hemagglutinin(HA) facilitates the fusion by bending into a hairpin configuration. In this study the bending region, called the hinge region, was simulated to elucidate the molecular dynamics(MD) and structures of this hinge region. To enhance the MD simulations, Hamiltonian replica exchange was used. Two implementations of Hamiltonian replica exchange where tested, a implementation using the free energy perturbation of GROMACS and a implementation using the plugin PLUMED. The methods where tested on an alanine dipeptide and a 3K(I) molecule. The PLUMED method was easiest to implement and had the fastest simulations, thus was used for the HA simulation. The hinge region was simulated from an initial straight, helical configuration. The histidine residue of the peptide was not protonated. After about 700 ns of simulation the peptide was in a folded configuration, in contrast to simulations done by Kalani et al.. The configuration switched between a helical folded structure and a non helical folded structure. In the folded configuration, the location of the histidine residue was on the outside of the folded structure, the location of the non polar residues was on the inside and the acid, polar and non polar residues on the outside of the structure. I propose that the bending of the hinge region is probably mediated by hydrophobic interactions and not by the protonation of the histidine residue.


The due diligence in merger and acquisition, which has been normal in the United Kingdom and the United States for decades, is now spreading to the globe. Due diligence is becoming a widely accepted practice in merger and acquisition deals in China. Before indulging into this flaming market, due diligence is requisite to foreign investors, concerning the special social and economical situation.


Biometric heart-rate information is increasingly proliferating through simple wearable technology. However, this technology presents a need for contextual information to guide interpreting physiological responses in lower and higher levels of cognitive abilities. In this paper, the author introduces HeartBit, a sensor-based intervention used for non-obtrusive heart-rate observation of elementary age children within the creative and critical thinking contexts. The author describes the Sandbox as single-session workshop with individual children, the development of HeartBit, and results from Sandboxes with 35 K-1 students (ages 6 and 7). Findings reveal how children's in-situ levels of creativity and critical thinking were observed through an interplay of system design, heart-rate monitoring, and Bloom's Taxonomy educational learning objectives, and how this differed between the individual children.


A sample of 171 college students was selected, with each participant randomly assigned to one of three treatments. Groups of 3 to 5 students were formed. Each group, using group support system (GSS) software, creativity support system (CSS) software, or no computer software (NCS) support, was asked to propose an innovative information system idea. Participants then rated the method used for idea generation on four measures: usefulness, difficulty, enjoyment, and overall satisfaction. The results indicated that using GSS software is viewed by users as being more useful, less difficult, more enjoyable, and more satisfying overall for idea generation than not using computers at all. Moreover, GSS software resulted in better ratings than CSS software on three of the above measures — usefulness, difficulty, and overall satisfaction, and the two methods were statistically equivalent with regard to enjoyment. The practical managerial implication of this study is that GSS is the support tool of choice for idea generation.


Spatial visualisation ability is a subset of spatial ability - one of the factors of human
intelligence structure. Spatial visualisation ability has been defined as, " the ability to
mentally manipulate, rotate, twist, or invert pictorially presented stimulus objects." (McGee,
1979, p. 893). This multi-faceted ability helps engineers including civil engineers to
conceptualise links between reality and the abstract model of that reality. For example, in the
analysis of a loaded beam structure, the deflected shape of the beam is the reality and the
mathematical equation chosen (often unseen in a computer design package) to represent this
deflected shape is the abstract model of that reality. A civil engineer needs first to have an
intuitive understanding of the interactive relationships among structural components before he
could begin to predict the deflected shape, which leads to the identification of the abstract
model. This intuitive understanding is also essential to civil engineers in another way. It helps
them in visualising, predicting, designing and checking for the worst possible combination of
loads on a given structure. In the design of a reinforced concrete design for example, the
ability to visualise aids the engineer in the prediction of critical loading conditions, which is
necessary in reaching an adequate reinforcement design.
Spatial visualisation ability has also been found to be essential to a student's success in some
engineering related subjects such as calculus (Winkle, 1997), mathematics, (Battista,Wheatley and Talsma, 1989), engineering drawing (Sorby and Baartmans, 1996a) and
computer-aided design (Sorby, 1999). Early indication for a positive relationship between this
ability and structural design has also been found. Alias (2000) carried out a learning task
analysis on the design of a reinforced concrete column - an area that demands a wide variety
of structural design skills - and discovered that spatial skills are pre-requisite to the learning of
column design suggesting that spatial visualisation ability may be essential to the success of
structural design.
Overall, spatial visualisation ability may be critical to learning and problem solving in civil
engineering especially to the learning of subject matter that demands spatial strategies such as
structural design, engineering mathematics and soil mechanics. There has also been some
suggestions that spatial ability is relevant to problem solving that is not dependent on spatial
strategies proposed by Roberts, Gilmore and Wood (1997). Roberts, et al. proposed that in
cases where non-spatial strategies are required, spatial ability influences the degree to which a
problem solver is able to develop and evaluate these strategies.
In summary, spatial visualisation ability appears to be necessary to problem solving in
engineering related areas that requires spatial as well as non-spatial strategies. Therefore, a
better understanding of this ability should be potentially beneficial to the engineering
education and profession.


BACKGROUND
We examined associations between parental separation during childhood and offspring alcohol involvement, adjusting for genetic and environmental risks specific to parental alcohol (AD) and cannabis/other illicit drug dependence (DD).

METHODS
The sample consisted of 1,828 offspring of male twins from the Vietnam Era Twin (VET) Registry, who completed a telephone diagnostic interview. Cox proportional hazards regression analyses were conducted predicting onset of first use, transition from first use to first AD symptom, and transition from first use to AD diagnosis from paternal and avuncular AD and DD history, parental separation, and offspring and family background characteristics. Paternal/avuncular DD/AD was based on the DSM-III-R; offspring and maternal AD were based on DSM-IV criteria.

RESULTS
Paternal DD/AD predicted increased offspring risk for all transitions, with genetic effects suggested on rate of transitioning to AD diagnosis. Parental separation was predictive of increased risk for early alcohol use, but a reduced rate of transition to both AD symptom onset and onset of AD. No interactions between separation and familial risk (indexed by paternal or avuncular DD/AD) were found.

CONCLUSIONS
Findings highlight the contribution of both parental separation and paternal substance dependence in predicting timing of offspring alcohol initiation and problems across adolescence into early adulthood.


In both Qur'anic and public schools in Maroua, Cameroon, the development of competence in a second language is fundamental, and rote learning is the primary mode of teaching and learning in both types of schooling. Through the lens of language socialization theory, I have examined rote learning as it is practiced in Maroua schools and reframed it as a tradition of learning and teaching I call 'guided repeti- tion'. In this article I discuss similarities and differences in how and why guided repetition is done, linking interactional patterns with the second-language competencies and the ways of being that children are expected or hoped to develop through Qur'anic and public schooling. While the use of guided repetition in both types of schooling is rooted in very similar goals for and ideologies of second-language acquisition, it is accomplished in culturally distinct ways to socialize novices into 'traditional' and 'modern' subjectivities.


We present a new model-independent method to determine spatial curvature and to mitigate the circularity problem affecting the use of quasars as distance indicators. Cosmic-chronometer measurements are used to construct the curvature-dependent luminosity distance using a polynomial fit. Based on the reconstructed and the known ultraviolet versus X-ray luminosity correlation of quasars, we simultaneously place limits on the curvature parameter ΩK and the parameters characterizing the luminosity correlation function. This model-independent analysis suggests that a mildly closed universe ( ) is preferred at the 2.1σ level. With the calibrated luminosity correlation, we build a new data set consisting of 1598 quasar distance moduli, and use these calibrated measurements to test and compare the standard ΛCDM model and the Rh = ct universe. Both models account for the data very well, though the optimized flat ΛCDM model has one more free parameter than Rh = ct, and is penalized more heavily by the Bayes Information Criterion. We find that Rh = ct is slightly favored over ΛCDM with a likelihood of ∼57.7% versus 42.3%.


The paper aims to empirically analyze the relationship between Public Infrastructure Investment and economic growth for India using yearly data for its twenty-eight states (excluding Telangana) over the time-period of 1999-00 to 2014-15. We have aimed to assess this eye catching issue after the recent focus of Indian government to devote a majority of public funds to finance Infrastructure. For all the states, we have taken Public Investment data for six major sub sectors falling under overall Infrastructure sector: Transport, Education, Sports, Art and Culture, Medical and Public Health, Water supply and sanitation, Irrigation, Energy/Power. The Per Capita Gross State Domestic Product is taken as an indicator to represent economic growth. For empirical analysis, we apply panel unit root and cointegration tests, and estimate a panel error correction model. The Per Capita Gross State Domestic Product along with Public Investment in analyzed sectors have a unit root at their levels suggesting that there is presence of long-term relationships among the variables for the whole sample. Finally, Granger causality tests are applied to check for the presence of causal relationships between Per Capita Gross State Domestic Product and Public Investment in different sub sectors of Infrastructure. The research study proposes that the state governments across India should focus upon private as well as foreign direct investment options which would ultimately help in improving the landscape of India's Infrastructure sector.


This research applied muted group theory to investigate female and male athletes' experiences with not reporting concussions sustained during athletic competition. Using snowball-sampling techniques, a total of 365 women and 247 men completed an online open-ended questionnaire about their reasons for not reporting a concussion. Results indicated that male athletes were more likely to continue to play through and not report a concussion than female athletes. Participants also indicated that they did not report concussions due to (a) perceived lack of resources, (b) perceived lack of severity, (c) conformance to sport cultural norms, which was comprised of two subthemes: adherence to the pain principle and team allegiance. The results suggest that efforts to address concussion management in sport need to focus on the communicative and structural elements that privilege hegemonic masculinity and playing through pain, as they contribute to muting athletes in advocating for their health.


Kawasaki disease (KD) is an acute febrile illness that can result in life threatening coronary artery aneurysms in up to 25% of untreated patients. These aneurysms put patients at risk for thrombus formation, myocardial infarction and sudden death. Currently, clinical decisions are made based on anatomy alone, with aneurysm diameter > 8mm as the arbitrary cutoff for anticoagulation therapy, despite a lack of evidence for this choice. We postulate that patient specific hemodynamics may be a better predictor for the risk of thrombosis than maximum diameter alone. To quantify hemodynamics, we performed computational fluid dynamics (CFD) simulations using patient specific models with custom coronary boundary conditions.Copyright © 2013 by ASME


A theoretical study of the nature and the mechanism of the bonding of an alkali metal (Cs) on a transition-metal surface [W(001)] in the high-coverage limit is presented in order to understand and explain the lowering of the work function and to elucidate the role of W surface states and surface resonance states in the adsorption process. The analysis is based on all-electron local-density-functional results obtained with our self-consistent full-potential linearized augmented-plane-wave method for thin films for (1) a five-layer slab of W, (2) an unsupported Cs monolayer, and (3) Cs in a $c(2\ifmmode\times\else\texttimes\fi{}2)$ structure on both sides of the five-layer W slab for three different Cs-W separations. We find that Cs forms a polarized-metallic rather than ionic overlayer: The Cs valence electrons originating from the atomic $6s$ states are polarized toward the W surface leading to an increase of electronic charge in the Cs/W interface region and a depletion of electronic charge on the vacuum side of the overlayer. In addition, the semicore Cs $5p$ electrons are markedly counterpolarized. The net result of these multiple surface dipoles is a lowering of the work function upon cesiation from 4.77 eV (clean five-layer W slab) to 2.77, 2.55, and 2.28 eV, corresponding to heights of the Cs atoms above the W surface of 2.60, 2.75, and 2.90 \AA{}, respectively. The Cs-induced changes in the charge density are essentially localized outside the surface W atoms. The W $d$ surface states and surface resonance states which are so characteristic of the W(001) surface are found to persist on the cesiated W(001) surface. The main effect of the Cs overlayer on these states is their energetic stabilization; this effect is most pronounced for the contamination-sensitive ${\overline{\ensuremath{\Gamma}}}_{1}$ surface state just below the Fermi energy, which is lowered in energy by 1 eV due to hybridization with Cs $s$ states.


Background Multiple sclerosis (MS) is a chronic, neurodegenerative disease that causes a range of motor, sensory, and cognitive symptoms. Due to these symptoms, people with MS are at a high risk for falls, fall-related injuries, and reductions in quality of life. There is no cure for MS, and managing symptoms and disease progression is important to maintain a high quality of life. Mobile health (mHealth) apps are commonly used by people with MS to help manage their health. However, there are limited health apps for people with MS designed to evaluate fall risk. A fall risk app can increase access to fall risk assessments and improve self-management. When designing mHealth apps, a user-centered approach is critical for improving use and adoption. Objective The purpose of this study is to undergo a user-centered approach to test and refine the usability of the app through an iterative design process. Methods The fall risk app Steady-MS is an extension of Steady, a fall risk app for older adults. Steady-MS consists of 2 components: a 25-item questionnaire about demographics and MS symptoms and 5 standing balance tasks. Data from the questionnaire and balance tasks were inputted into an algorithm to compute a fall risk score. Two iterations of semistructured interviews (n=5 participants per iteration) were performed to evaluate usability. People with MS used Steady-MS on a smartphone, thinking out loud. Interviews were recorded, transcribed, and developed into codes and themes. People with MS also completed the System Usability Scale. Results A total of 3 themes were identified: intuitive navigation, efficiency of use, and perceived value. Overall, the participants found Steady-MS efficient to use and useful to learn their fall risk score. There were challenges related to cognitive overload during the balance tasks. Modifications were made, and after the second iteration, people with MS reported that the app was intuitive and efficient. Average System Usability Scale scores were 95.5 in both iterations, representing excellent usability. Conclusions Steady-MS is the first mHealth app for people with MS to assess their overall risk of falling and is usable by a subset of people with MS. People with MS found Steady-MS to be usable and useful for understanding their risk of falling. When developing future mHealth apps for people with MS, it is important to prevent cognitive overload through simple and clear instructions and present scores that are understood and interpreted correctly through visuals and text. These findings underscore the importance of user-centered design and provide a foundation for the future development of tools to assess and prevent scalable falls for people with MS. Future steps include understanding the validity of the fall risk algorithm and evaluating the clinical utility of the app.


Key Points UBASH3A interacts with the TCR–CD3 complex and regulates its turnover. UBASH3A facilitates the downmodulation of cell-surface TCR–CD3 upon TCR engagement. UBASH3A binds to CBL-B, another T1D-associated protein that inhibits T cell function. The TCR–CD3 complex is a multicomponent membrane receptor, the expression of which is tightly regulated in thymocytes, as well as in mature T cells both at steady state and upon stimulation. In this study, we report novel roles for UBASH3A in TCR–CD3 synthesis and turnover. UBASH3A is a negative regulator of T cell function and plays a broad role in autoimmunity. We show that modulation of UBASH3A levels in unstimulated Jurkat cells leads to altered amounts of total cellular CD3 chains and of cell-surface TCR–CD3 complexes; in contrast, UBASH3A does not affect the level of cell-surface CD28, an important T cell costimulatory receptor. Upon TCR engagement, UBASH3A enhances the downmodulation of cell-surface TCR–CD3. Mass spectrometry and protein–protein interaction studies uncover novel associations between UBASH3A and components of several cellular pathways involved in the regulation of TCR–CD3 turnover and dynamics, including endoplasmic reticulum–associated protein degradation, cell motility, endocytosis, and endocytic recycling of membrane receptors. Finally, we demonstrate that the SH3 domain of UBASH3A mediates its binding to CBL-B, an E3 ubiquitin ligase that negatively regulates CD28-mediated signaling and, hence, T cell activation. In summary, this study provides new mechanistic insights into how UBASH3A regulates T cell activation and contributes to autoimmunity. The interaction between UBASH3A and CBL-B may synergistically inhibit T cell function and affect risk for type 1 diabetes, as both genes have been shown to be associated with this autoimmune disease.


: The mainstream economic theory generally assumes that the characteristics of the products are obvious for the consumer who can choose between any given product on the basis of prices and preferences. This simplistic presentation of product qualities is discussed by many researchers in socio-economics through the theme of measurement: How are qualities evaluated? What role do physical characteristics and price play in such an evaluation? These questions are particularly striking when the compared products are presented like identical in composition, as it is the case for the generic drugs in France. The French authorities legally defined the generic drug as identical in essence to the original drug but a myriad of small differences remain in its presentation. The consumers are assured that it is the same thing while it doesn't look like the same thing. Who must they trust to measure the differences between generic and original drugs: the composition written on the box ? the doctor or the pharmacist ? their own body ? This question is all the more important as in the field of health self-realizing prophecies are numerous. In this paper, we would like to analyze the way in which the actors on the health field (especially pharmacists and patients) discuss the best way of measuring economic and physical differences between generic drugs and original drugs.


Purpose: To compare the University of California Davis experience using the Boston keratoprosthesis with the Boston Keratoprosthesis Study Group's initial report. Design: Retrospective chart review. Participants: We analyzed 30 eyes of 28 patients who previously underwent Boston type 1 keratoprosthesis surgery at our institution between 2004 and 2008. Methods: Preoperative, intraoperative, and postoperative parameters were collected and analyzed. Main Outcome Measures: Visual acuity and keratoprosthesis stability. Results: Preoperative diagnoses were failed graft (26 eyes, 87%), chemical injury (3 eyes, 10%), and Stevens-Johnson syndrome (1 eye, 3%). Twenty eyes (66%) had preoperative glaucoma. Preoperative best-corrected visual acuity ranged from 20/150 to light perception and was <20/200 in 83% of eyes. At an average follow-up of 19 months (range, 1-48; SD, 13.8; and median, 13), postoperative vision improved to ≥20/200 in 77% of eyes. Among eyes at least 1 year after the operation (16 eyes), vision was ≥20/200 in 75% of eyes and ≥20/40 in 25% of eyes. At an average follow-up of 19 months, retention of the initial keratoprosthesis was 83.3%. Conclusions: The Boston type 1 keratoprosthesis is a viable option after multiple keratoplasty failures or in conditions with a poor prognosis for primary keratoplasty. Patients with autoimmune disease are at higher risk for complications. The University of California Davis experience seems equivalent to the initial report of the Boston Keratoprosthesis Study Group. With longer follow-up, additional surgical procedures may be required but good anatomic and functional outcomes can be maintained.


Penal mediation is an alternative settlement of criminal cases emphasizing restorative justice approach, which is carried out between the victims and the offenders or his/her families with the purpose of restoring the balance in the society. The major problem in this research is, firstly, how is the penal mediation in criminal law enforcement implemented today? Secondly, how are the weaknesses of the implementation of the penal mediation in criminal law enforcement today? Thirdly, how is the penal mediation in criminal law enforcement based on Pancasila values of justice constructed today? In order to answer the problems mentioned above is obtained by using social legal research method, conducted with case studies that have already been through the legal processes by law enforcement officials until the court makes the decision, this kind of legal processes is deemed to have injured sense of justice in the community by the society. Penal mediation provides the best way to resolve problems or conflicts between the perpetrator and the victims by engaging between them directly in order to solve the problems with peaceful means in accordance with Pancasila values of justice. The conclusion in this study is the current formulation of the regulations has not accommodated penal mediation as a form of settling disputes outside the criminal justice processes. Penal mediation arrangements in the future must be included in the substantive criminal law, the formal criminal law and the implementation of criminal law.


All material supplied via JYX is protected by copyright and other intellectual property rights, and duplication or sale of all or part of any of the repository collections is not permitted, except that material may be duplicated by you for your research use or educational purposes in electronic or print form. You must obtain permission for any other use. Electronic or print copies may not be offered, whether for sale or otherwise to anyone who is not an authorised user. Industrial branding in the digital age Lipiäinen, Heini; Karjaluoto, Heikki


Past research suggests that the emotional content of words has greater impact when presented in a bilingual's first language (L1) compared to their second language (L2). This is predicted to be a consequence of automatic processing of emotional words in L1 compared to slower, semantic processing in L2. In the current study 58 Chinese-English bilinguals from Hong Kong rated the valence and arousal of positive, neutral, and negative words presented in Chinese (L1) and English (L2). In contrast to predictions, perceived emotionality of the words was higher in L2, with positive words rated more positively and negative words rated more negatively when presented in English compared to Chinese. The findings suggest that words presented in L2 did not have lower emotional impact than L1, the results indicate that emotional processing of words may be influenced by language proficiency and language complexity.


The scattering angle, the Haze ratio, and the field polarization factor of the frequency-doubled Nd:YAG laser nonlinearly scattered from the semiconductor nanorod surface are investigated. Both the scattering angle and the reflected Haze ratio of the laser beam reflected from Si nanorod surface present a nonlinearly increasing trend with nanorod length. As the nanorod lengthens from 190 to 2760 nm, the scattering angle broadens from 2.5° to 25° and from 2.5° to 24°. Concurrently, the reflected Haze ratio increases from 5% to 22% and 3% to 21% under TE and TM-mode incidences, respectively. A significant polarization scrambling transfers the linearly polarization into an elliptical polarization, and the field polarization factor increases from 0.54 to 0.86 and from 0.42 to 0.84 under TE- and TM-mode incidences with an enlarging nanorod length from 190 to 2760 nm. The reflected Haze ratio is linearly proportional with the broadened scattering angle. However, the field polarization factor shows a gradually saturating effect at larger scattering angle. The theoretical calculation is used to quantitatively analyze the polarization scrambling effect, which demonstrates that the scattered wave nonlinearly depends on the surface corrugation and can be expressed by the second-order function of the surface corrugation strength. The strong correlations of the TE-mode scattering with the nanorod length and the TM-mode scattering with the laser incident angle are observed. The polarization of the reflected laser beam eventually transfers from a linear to an elliptical one with a nanorod length exceeding over 1 μm.


The potent bryostatin antitumor agents are currently in phase II clinical trials for the treatment of a variety of forms of cancer. Aldol reactions and directed reductions are among the essential steps for the formation of fragments A-C in the total synthesis of the title compound. Coupling of these fragments by sulfone-based olefination and alkylation reactions was followed by macrocyclization and introduction of the enoate moieties on rings B and C.


The papers collected in this volume were written for a conference held at the Hong Kong Monetary Authority in November 2005. It was organised jointly by the BIS Representative Office for Asia and the Pacific in Hong Kong SAR and the Hong Kong Institute for Monetary Research. The objective of the conference was to take stock of the current practice of monetary policy in a broad cross section of Asian economies. Papers on China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, the Philippines, Singapore, Thailand and Vietnam were presented and discussed at the conference and subsequently revised by the authors. In addition, the experience of a "mature" inflation targeter, the Reserve Bank of Australia, was presented. The result is an up-to-date account and assessment of the strategies followed by the respective central banks and monetary authorities.


Project complexity has commonly been cited as a major cause of poor project performance (Al-ahmad et al, 2019). Although literature has identified various methods to measure and define project complexity, research insights did not find an explanation of how to reduce project complexity or its effect on project performance. Expertise has been identified as a potential solution; however, little is known about the extent of impact that expertise may have on project complexity. Using a multimethod approach inclusive of literature, survey and interview research we investigate the "effect' of expertise on project complexity. We analyzed the effect of expertise on 22 unique project complexity factors. Data consists of 97 survey respondents and 15 interview participants. The research led to the following results which should be incorporated into future models: (1) expertise reduces project complexity, (2) experts do not perceive ICT projects as complex while nonexperts perceive ICT projects as complex, and (3) experts' challenges that relate to project complexity factors correspond to project stakeholders as they ultimately fall outside the control of the expert.


Nowadays as a result of the increasing environmental friendly consciousness and the decreasing oil reserves, natural origin based materials are developed. These materials are not only based on renewable, natural resources, but capable of biodegradation in compost. These biodegradable polymers (biopolymers) can be inserted into the nature's recycling process. One of the most important biopolymers is starch. Starch can be processed like a thermoplastic material by adding plasticizers, creating the so called thermoplastic starch. However the price of starch is rather low, it has certain drawbacks retarding its wide industrial usage. It is sensitive to moisture, disrupts in pure water, has low mechanical properties, and in time it ages. This ageing or time-dependent behavior was analyzed with injection molded tensile specimens. The shrinkage and mechanical properties of the specimens were determined as a function of ageing time. The fracture surface was analyzed by scanning electron microscope. The results of the measurements were compared with previous examinations.


Achieving the EU policy goals of a secure, affordable, and sustainable electricity system available to all household customers requires the deployment of smart electricity systems (SES). In SES, all actors (eg consumer, producers, system operators) in the system are enabled to interact with each other by means of information and communication technology (ICT). From an infrastructural perspective SES can therefore also be described as electricity systems that are enhanced with communication systems. Both the electricity- and communication systems are subject to specific access conditions for household customers imposed by EU legislation. Whereas household customers have a clear right to access the electricity system, their right to access communication systems is limited. This article hypothesises that without the legal guarantees to ensure access for household customers to SES communication systems, the level playing field for household customers to participate in SES might be distorted. Therefore, this article addresses the following research question: what are the legal conditions for household customers to access SES communication services and what are their guarantees for accessing SES communication services? The article identifies four different options for household customers to access communication systems for SES under current EU legislation. Furthermore, it concludes that ensuring a level playing field for household customers to participate in SES requires EU and national policy makers to guarantee comparable conditions for household customers to access SES communication services.


We present analyses of the 2D seismic structure beneath Source Physics Experiments (SPE) geophone lines that extended radially at 100 m spacing from 100 to 2000 m from the source borehole. With seismic sources at only one end of the geophone lines, standard refraction profiling methods cannot resolve seismic velocity structures unambiguously. In previous work, we demonstrated overall agreement between body‐wave refraction modeling and Rg dispersion curves for the least complex of the five lines. A more detailed inspection supports a 2D reinterpretation of the structure. We obtained Rg phase velocity measurements in both the time and frequency domains, then used iterative adjustment of the initial 1D body‐wave model to predict Rg dispersion curves to fit the observed values. Our method applied to the most topographically severe of the geophone lines is supplemented with a 2D ray‐tracing approach, whose application to P ‐wave arrivals supports the Rg analysis. In addition, midline sources will allow us to refine our characterization in future work.


The field of near-eye see-through devices has recently received significant media attention and financial investments. However, devices demonstrated to date suffer from significant practical limitations resulting from the conventional optics on which they are based. Potential manufacturers seek to surpass these limitations using novel optical schemes. In this paper, we propose such a potentially disruptive optical technology that may be used for this application. Conceptually, our optical scheme is situated at the interface of geometric incoherent refractive imaging and radiative coherent diffractive imaging. The generation of an image occurs as a result of data transmission through a two-dimensional network of optical waveguides that addresses a distribution of switchable holographic elements. The device acts as a wavefront generator, and the eye is the only optical system in which the image is formed. In the following we describe the device concept and characteristics, as well as the results of initial simulations.


We conduct statistical analysis of a phenomenon recently identified by Foley (2013), the rise in the number of votes counted after Election Day ("overtime votes") and the growing tendency of these votes to disproportionately favor Democrats in presidential elections (the "blue shift.") We provide a historical description of these two time series, from 1948 to 2012, and establish that the timing of the persistent growth in the blue-shifted overtime vote began with the 2004 election. While some of the interstate variability in these time series is accounted for by regional factors (e.g., a lag in news travelling to New York), changes in the time series are broadly consistent with changes in electoral practices, especially in recent years. We perform statistical analysis to understand better interstate variability in the overtime vote and the blue shift in the 2012 presidential election. We discover that variation in the size of the overtime vote is associated with the number of provisional ballots, but not the number of absentee/mail ballots; variation in the relative size of the blue shift is positively associated with the number of provisional ballots and with the Democratic partisanship of the states. We also perform an analysis of the overtime vote in seven statewide contests in Virginia, using that state's change log as evidence. We find a tendency of provisional ballots to persistently favor Democrats in these races, whereas other sources of votes accounted for after Election Day do not persistently favor Democrats in that state. We conclude the paper by suggesting how the analysis offered here might be expanded in future work.


Plastics is a group of materials commonly encountered on a daily basis by many people. They have enabled rapid, low-cost manufacturing of products with complicated geometries and have contributed to the weight reduction of heavy components, especially when produced into a foamed structure. Despite the many advantages of plastics, some drawbacks such as the often fossil-based raw-material and the extensive littering of the material in nature, where it is not degraded for a very long time, needs to be dealt with. One way to address at least one of the issues could be to use polymers from nature instead of fossil-based ones. Here, a β-glucan concentrate originating from barley was investigated. The concentrate was processed into a foam by hot-melt extrusion, and the processing window was established. The effect of different blowing agents was also investigated. Water or a combination of water and sodium bicarbonate were used as blowing agents, the latter apparently giving a more uniform pore structure. The porous structure of the foamed materials was characterized mainly by using a combination of confocal laser scanning microscope and image analysis. The density of the samples was estimated and found to be in a similar range as some polyurethane foams. A set of 3D parameters were also quantified on two selected samples using X-ray microtomography in combination with image analysis, where it was indicated that the porous structure had a pre-determined direction, which followed the direction of the extrusion process.


We consider the homogeneous and isotropic cosmological fluid dynamics which is compatible with a homothetic, timelike motion, equivalent to an equation of state ρ + 3P = 0. By splitting the total pressure P into the sum of an equilibrium part p and a non-equilibrium part Π, we find that on thermodynamical grounds this split is necessarily given by p = ρ and Π = − 4 3 ρ, corresponding to a dissipative stiff (Zel'dovich) fluid.


The basic theory of Jacquin's fractal block coding is to approximate a na tural image by its partial subdivided parts, given that the parts resemble the whole at either the same scale or different scales. The fact that self-similarity most commonly exists within an entire natural image leads to the development of the proposed method that uses arc as the fractal descriptor, in which an arc commonly exists within the entire natural image, named as Arc-Descriptor Fractal Coding (ADFC) method. In the ADFC, each range block is approximated by using the selected arc-descriptor from an optimal pool. This paper experimentally demonstrates the ADFC method on Java and the ADFC system is verified with 5 medical images. The experim ental results indicate the ADFC method can encode and decode the experimental images effectively. The PSNR of the images after encoding can reach 30 dB at limited cost while the CR is less than 17%. The ADFC outperforms Jacquin's method under the comparison of the number of search in matching process. We conclude that the ADFC successfully encodes and decodes image in an efficient s earch during encoding phase without noticeable loss of image quality.


Declining achievement in various core subjects has led to a debate on strat egies to enhance student achievement. Identifying factors in the school environment that affect student performance in science, are therefore, of vital importance. The aim of this study is to identify school-level factors that are associated with eighth-grade students' achievement in science based on results from TIMSS (Trends in International Mathematics and Science Study) 2003 and 2007. Because the TIMSS data includes schoollevel factors at two different time points, we expected to find factors that influence science performance by Swedish and Norwegian students. Multilevel analysis was used, and this framework allowed us to account for the influence of the students' home backgrounds. After controlling for student background, our results show that there are only a few school-level factors that are associated with student achievement in science, and the influence of these factors differ between Sweden and Norway.


UISCE (Union for Improved Services Communication and Education) provide an independent representative voice for people who use drugs and work towards protecting their civil liberties and human rights. UISCE is aware of the need to constantly renew and regenerate our priorities to be responsive to the needs of people who use drugs. The use of drugs and the people who use them are an ever changing landscape. The influence of new psychoactive substances is evolving and with the recent amendments to the Misuse of Drugs act, the number people who identify as people who use drugs is growing. UISCE undertakes outreach to engage with the community to identify trends and issues from a broad range of people who use drugs. We share this information where decisions are made that impact the lives of people who use drugs to ensure their voice is included in the development of policy and programs. UISCE is aligned with the National Drug strategy and makes sure that the centrality of engagement in the strategy is made actual through our involvement. In a survey among people who inject drugs in public places undertaken by UISCE from December 2016 to January 2017 undertaken by UISCE, 86.7% identified heroin as the primary drug used. A report from the Health Service Executive (2017) Health service performance report August/September 2016 says â?oAs of 31st August 2016, there were 9,652 patients receiving treatment for opiate use (excluding prisons).â? For this reason, UISCEâ?Ts focus is on the group of people who have the least opportunity to have their voice heard. This means, we actively seek out people who are currently injecting on the streets, many of whom identify as homeless. UISCE acknowledge many people in this group identify as poly drug users and will continue to support any person seeking representation. UISCE aims in all communication and activities to be mindful of the stigma associated with the use of drugs and works to reduce the impact of stigma on the community of people who use drugs.


This study of the anemia produced by P. lophurae in ducks emphasizes the significance of a decrease in the number of red cells in this disease, and furthermore, it suggests that the rapid diminution in the number of parasites following the peak of the parasitemia may be directly related to the character of this anemia since these parasites apparently do not prefer young erythroblasts to mature erythrocytes. The observations made in this study show that erythrocytes in the ducks first appear as spherical bodies in stained smears and when mature they are elliptical in shape. Under abnormal conditions such as may occur with a severe parasitemia, erythroblasts appear in the peripheral blood in large numbers, sometimes almost completely replacing the adult type of red cell. Both microcytes and macrocytes appear in the blood stream. The amount of hemoglobin within some of these young erythrocytes is small as indicated by the hemoglobin determinations and the staining reaction. Small young erythroblasts with little hemoglobin appear in the peripheral blood when the maximum load is placed upon the hematopoietic tissues.


We study the following problem: Given $k$ paths that share the same vertex set, is there a simultaneous geometric embedding of these paths such that each individual drawing is monotone in some direction? We prove that for any dimension $d\geq 2$, there is a set of $d + 1$ paths that does not admit a monotone simultaneous geometric embedding.


The effects of field electrical stimulation on the contractile response of the isolated middle cerebral artery of the goat were evaluated before and after the use of experimental procedures designed to test the adrenergic component involved. Supramaximal stimuli produced frequency-dependent increases in tension. This response was significantly reduced by phentolamine (10(-6) M), tetrodotoxin (3 X 10(-6) M), and bretylium (5 X 10(-5) M), but not by cocaine (10(-6) M). Arterial segments from goats pretreated with reserpine and from goats in which both superior cervical sympathetic ganglia had been removed 12 days prior to the experiment also showed a significant decrease in the contraction elicited by electrical stimulation. The norepinephrine concentration of the arteries of the circle of Willis from control goats was 2.10 microgram per gram of tissue. Reserpine or gangliectomy reduced the catecholamine content to undetectable levels. It is likely that a major part of the contractile response of cerebral arteries to electrical stimulation is due to release of endogenous norepinephrine which in turn activates the alpha-adrenergic receptors.


Whether the plasma proteome can predict the course of heart failure (HF) and has incremental value to established predictors is uncertain.

 Patients meeting Framingham HF criteria with history of reduced ejection fraction (n=1017) were prospectively enrolled in a registry and donated fasting blood samples. Plasma underwent analysis on the SOMAscan proteomic discovery platform, quantifying 4789 proteins using standard assay and quality controls. Patients were randomly divided into derivation (n=681) and validation (n=336) cohorts. We derived a proteomic risk score (PRS) in the derivation cohort using Lasso-penalized Cox regression and then tested it in the validation cohort. Both models were adjusted for an establish HF clinical risk score (MAGGIC) and NTproBNP. We assessed risk stratification improvement in the validation cohort by comparing models with and without PRS using the model C statistic, continuous net reclassification index (NRI), integrated discrimination index (IDI), and the median improvement in risk score (MIRS).

 Overall 47.5% of patients were African American, 35.2% were female, mean ejection fraction was 34.8%, and average age was 67.9 years. After median follow-up of 3.6 years, there were 296 deaths (194 in derivation and 102 in validation). Optimized modeling defined a 32 protein PRS (hazard ratio [HR] 2.33, p<2.00E-16) which was also statistically significant when tested in the validation cohort (PRS HR=1.19, p=4.87E-02) and showed some improvement in risk stratification (Table).
 Methods Variables Estimate 95% CI P Validation Testing MAGGIC 1.06 1.027, 1.092 2.84E-04 NTproBNP 1.84 1.430, 2.359 1.88E-06 PRS 1.19 1.001, 1.408 4.87E-02 Risk Stratification Assessment C-statistic improvement 0.012 −0.076, 0.101 8.30E-01 IDI 0.034 0.007, 0.095 <2.00E-16 Continuous-NRI 0.286 −0.062, 0.475 9.00E-02 Median Improvement in Risk Score 0.015 0.001, 0.078 2.00E-02

 A plasma multi-protein predictive score can improve risk stratification in HF patients on top of a validated clinical score and NTproBNP. Additional investigation is warranted to define mechanisms underlying individual proteins and explore proteomic clinical applications.


In the present study, we assessed whether nootkatone (NKT), a sesquiterpene in edible plants, can provide protection against dyslipidemia, intramyocardial lipid accumulation, and altered lipid metabolism in a rat model of myocardial infarction (MI) induced by subcutaneous injections of isoproterenol (ISO, 85 mg/kg) on days 9 and 10. The rats were pre- and co-treated with NKT (10 mg/kg, p.o.) administered daily for 11 days. A significant reduction in the activities of myocardial creatine kinase and lactate dehydrogenase, as well as non-enzymatic antioxidants, and alterations in lipids and lipoproteins, along with a rise in plasma lipid peroxidation and intramyocardial lipid accumulation, were observed in ISO-treated rats. ISO administration induced alterations in the activities of enzymes/expressions that played a significant role in altering lipid metabolism. However, NKT treatment favorably modulated all biochemical and molecular parameters altered by ISO and showed protective effects against oxidative stress, dyslipidemia, and altered lipid metabolism, attributed to its free-radical-scavenging and antihyperlipidemic activities in rats with ISO-induced MI. Additionally, NKT decreased the accumulation of lipids in the myocardium as evidenced from Oil red O staining. Furthermore, the in vitro observations demonstrate the potent antioxidant property of NKT. The present study findings are suggestive of the protective effects of NKT on dyslipidemia and the underlying mechanisms. Based on our findings, it can be suggested that NKT or plants rich in NKT can be promising for use as a phytopharmaceutical or nutraceutical in protecting the heart and correcting lipid abnormalities and dyslipidemia, which are risk factors for ischemic heart diseases.


This paper is a report into an experimental and theoretical investigation of the effect of oil thermal properties on the performance of a tilting-pad thrust bearing. Three oils, namely poly-α-olefin, ester and mineral base, were chosen for this study. These oils all have same viscosity grade (ISO VG46) but differ in their rates of viscosity variation with temperature and in their heat capacity and thermal conductivity values. Mineral base oil of a higher viscosity grade (ISO VG68) was also analyzed for comparison. Experimental data were obtained from an equalizing tilting-pad thrust bearing with an outer diameter of 228.6 mm operating in a flooded lubrication mode. Simultaneous measurements of pad and collar temperatures, friction torque, pressures and oil film thickness were taken. In the tests, oil supply temperature and flow rate were held constant for all load-speed combinations. The theoretical analysis of oil performance was based on a three-dimensional TEHD model. In the analysis, thermal effects were locally taken into account and heat transfer into the pads was considered. The displacements of the active surface of the pads, due to pressure and temperature fields, were determined. The effect of initial pad crowning on the oil film thickness is discussed. Experimental and theoretical results are compared and analyzed in terms of the inlet and outlet oil film thickness, bearing operating temperature and power loss.


This paper assesses educational attainment of immigrant children, in particular evaluating whether naturalised parents invest more in their children's human capital than nonnaturalised parents. Findings of the literature indicate that citizenship is associated with lower return migration probability. Since the returns to investments in (country-specific) human capital increase with the duration of residence, naturalised parents may have more incentives to invest in the educational success of their children. I exploit a natural experiment that took place in Germany in the year 2000 that reduced the required years of residence for naturalisation from 15 to 8 and therefore exogenously increased naturalisation. Multivariate estimations (based on the German Socio-Economic Panel) show a positive and significant correlation between parents' citizenship status and their children's educational attainment. Results of difference-in-differences and instrumental variable models are also positive but not significant. JEL: classification: J15; J24; I24


Presenilin (PSEN) 1 and 2 are the catalytic components of the Gamma-secretase complex, which cleaves a variety of proteins, including the amyloid precursor protein (APP). Proteolysis of APP leads to the formation of the APP intracellular domain (AICD) and amyloid Beta that is crucially involved in the pathogenesis of Alzheimer's disease. Prolyl-4-hydroxylase-domain (PHD) proteins regulate the hypoxia inducible factors (HIFs), the master regulators of the hypoxic response.Wepreviously identified the FK506 binding protein 38 (FKBP38)as a negative regulator of PHD2. Genetic ablation of PSEN1/2 has been shown to increase FKBP38 protein levels. Therefore, we investigated the role of PSEN1/2 in the oxygen sensing pathway using a variety of genetically modified cell and mouse lines. Increased FKBP38 protein levels and decreased PHD2 protein levels were found in PSEN1/2-deficient mouse embryonic fibroblasts and in the cortex of forebrain-specific PSEN1/2 conditional double knock-out mice. Hypoxic HIF-1alpha protein accumulation and transcriptional activity were decreased, despite reduced PHD2 protein levels. Proteolytic gamma-secretase function ofPSEN1/2wasneeded for proper HIF activation. Intriguingly, PSEN1/2 mutations identified in Alzheimer patients differentially affected the hypoxicresponse, involving the generation of AICD. Together,our results suggest a direct role for PSEN in the regulation of the oxygen sensing pathway via the APP/AICD cleavage cascade.