The design and characterization of receptor-selective APRIL variants.

A proliferation-inducing ligand (APRIL), a member of the TNF ligand superfamily with an important role in humoral immunity, is also implicated in several cancers as a prosurvival factor. APRIL binds two different TNF receptors, B cell maturation antigen (BCMA) and transmembrane activator and cylclophilin ligand interactor (TACI), and also interacts independently with heparan sulfate proteoglycans. Because APRIL shares binding of the TNF receptors with B cell activation factor, separating the precise signaling pathways activated by either ligand in a given context has proven quite difficult. In this study, we have used the protein design algorithm FoldX to successfully generate a BCMA-specific variant of APRIL, APRIL-R206E, and two TACI-selective variants, D132F and D132Y. These APRIL variants show selective activity toward their receptors in several in vitro assays. Moreover, we have used these ligands to show that BCMA and TACI have a distinct role in APRIL-induced B cell stimulation. We conclude that these ligands are useful tools for studying APRIL biology in the context of individual receptor activation.

Forecasting the Earth"s radiation belts and modeling solar energetic particle events: Recent results from SPACECAST

High-energy charged particles in the van Allen radiation belts and in solar energetic particle events can damage satellites on orbit leading to malfunctions and loss of satellite service. Here we describe some recent results from the SPACECAST project on modelling and forecasting the radiation belts, and modelling solar energetic particle events. We describe the SPACECAST forecasting system that uses physical models that include wave-particle interactions to forecast the electron radiation belts up to 3 h ahead. We show that the forecasts were able to reproduce the >2 MeV electron flux at GOES 13 during the moderate storm of 7-8 October 2012, and the period following a fast solar wind stream on 25-26 October 2012 to within a factor of 5 or so. At lower energies of 10- a few 100 keV we show that the electron flux at geostationary orbit depends sensitively on the high-energy tail of the source distribution near 10 RE on the nightside of the Earth, and that the source is best represented by a kappa distribution. We present a new model of whistler mode chorus determined from multiple satellite measurements which shows that the effects of wave-particle interactions beyond geostationary orbit are likely to be very significant. We also present radial diffusion coefficients calculated from satellite data at geostationary orbit which vary with Kp by over four orders of magnitude. We describe a new automated method to determine the position at the shock that is magnetically connected to the Earth for modelling solar energetic particle events and which takes into account entropy, and predict the form of the mean free path in the foreshock, and particle injection efficiency at the shock from analytical theory which can be tested in simulations.

Forecasting the Earth"s radiation belts and modeling solar energetic particle events: Recent results from SPACECAST

High-energy charged particles in the van Allen radiation belts and in solar energetic particle events can damage satellites on orbit leading to malfunctions and loss of satellite service. Here we describe some recent results from the SPACECAST project on modelling and forecasting the radiation belts, and modelling solar energetic particle events. We describe the SPACECAST forecasting system that uses physical models that include wave-particle interactions to forecast the electron radiation belts up to 3 h ahead. We show that the forecasts were able to reproduce the >2 MeV electron flux at GOES 13 during the moderate storm of 7-8 October 2012, and the period following a fast solar wind stream on 25-26 October 2012 to within a factor of 5 or so. At lower energies of 10- a few 100 keV we show that the electron flux at geostationary orbit depends sensitively on the high-energy tail of the source distribution near 10 RE on the nightside of the Earth, and that the source is best represented by a kappa distribution. We present a new model of whistler mode chorus determined from multiple satellite measurements which shows that the effects of wave-particle interactions beyond geostationary orbit are likely to be very significant. We also present radial diffusion coefficients calculated from satellite data at geostationary orbit which vary with Kp by over four orders of magnitude. We describe a new automated method to determine the position at the shock that is magnetically connected to the Earth for modelling solar energetic particle events and which takes into account entropy, and predict the form of the mean free path in the foreshock, and particle injection efficiency at the shock from analytical theory which can be tested in simulations.

Environmental data mining and modeling based on machine learning algorithms and geostatistics

The paper presents some contemporary approaches to spatial environmental data analysis. The main topics are concentrated on the decision-oriented problems of environmental spatial data mining and modeling: valorization and representativity of data with the help of exploratory data analysis, spatial predictions, probabilistic and risk mapping, development and application of conditional stochastic simulation models. The innovative part of the paper presents integrated/hybrid model-machine learning (ML) residuals sequential simulations-MLRSS. The models are based on multilayer perceptron and support vector regression ML algorithms used for modeling long-range spatial trends and sequential simulations of the residuals. NIL algorithms deliver non-linear solution for the spatial non-stationary problems, which are difficult for geostatistical approach. Geostatistical tools (variography) are used to characterize performance of ML algorithms, by analyzing quality and quantity of the spatially structured information extracted from data with ML algorithms. Sequential simulations provide efficient assessment of uncertainty and spatial variability. Case study from the Chernobyl fallouts illustrates the performance of the proposed model. It is shown that probability mapping, provided by the combination of ML data driven and geostatistical model based approaches, can be efficiently used in decision-making process. (C) 2003 Elsevier Ltd. All rights reserved.

Trials using a crossover design and ambulatory blood pressure recordings to determine the efficacy of antihypertensive agents in individual patients.

The antihypertensive effects of the beta-blocking agent betaxolol and the calcium entry blocker verapamil were compared in a crossover single-blind trial. Seventeen patients with uncomplicated essential hypertension took either betaxolol or a slow-release formulation of verapamil for two consecutive 6-week periods. The sequence of treatment phases was randomly allocated and a 2-week washout period preceded each treatment. The antihypertensive effect of the test drugs was assessed both at the physician's office and during everyday activities using a portable blood pressure recorder. The crossover design of the trial made it possible to evaluate the antihypertensive efficacy of betaxolol and verapamil both in the group as a whole and in the individual patient. The individual patient response to one of these agents was not a reliable indicator of the same patient's response to the alternative agent. Betaxolol brought both office and ambulatory recorded blood pressures under control in a larger fraction of patients than verapamil, although the magnitude of the blood pressure fall in the responders was equal for each drug. These observations stress the need for an individualized approach to the evaluation of antihypertensive therapy. The present results also demonstrate that optimal antihypertensive therapy is still a matter of trial and error. The precise methodology that ought to characterize crossover trials may make it possible to improve the therapeutic approach to hypertensive patients.

Study and modeling of the desintegration kinetics of coated paper

The disintegration of recovered paper is the first operation in the preparation of recycled pulp. It is known that the defibering process follows a first order kinetics from which it is possible to obtain the disintegration kinetic constant (KD) by means of different ways. The disintegration constant can be obtained from the Somerville index results (%lsv and from the dissipated energy per volume unit (Ss). The %slv is related to the quantity of non-defibrated paper, as a measure of the non-disintegrated fiber residual (percentage of flakes), which is expressed in disintegration time units. In this work, disintegration kinetics from recycled coated paper has been evaluated, working at 20 revise rotor speed and for different fiber consistency (6, 8, 10, 12 and 14%). The results showed that the values of experimental disintegration kinetic constant, Ko, through the analysis of Somerville index, as function of time. Increased, the disintegration time was drastically reduced. The calculation of the disintegration kinetic constant (modelled Ko), extracted from the Rayleigh’s dissipation function, showed a good correlation with the experimental values using the evolution of the Somerville index or with the dissipated energy

Design and methodology of the Swiss Transplant Cohort Study (STCS): a comprehensive prospective nationwide long-term follow-up cohort.

In Switzerland, organ procurement is well organized at the national-level but transplant outcomes have not been systematically monitored so far. Therefore, a novel project, the Swiss Transplant Cohort Study (STCS), was established. The STCS is a prospective multicentre study, designed as a dynamic cohort, which enrolls all solid organ recipients at the national level. The features of the STCS are a flexible patient-case system that allows capturing all transplant scenarios and collection of patient-specific and allograft-specific data. Beyond comprehensive clinical data, specific focus is directed at psychosocial and behavioral factors, infectious disease development, and bio-banking. Between May 2008 and end of 2011, the six Swiss transplant centers recruited 1,677 patients involving 1,721 transplantations, and a total of 1,800 organs implanted in 15 different transplantation scenarios. 10 % of all patients underwent re-transplantation and 3% had a second transplantation, either in the past or during follow-up. 34% of all kidney allografts originated from living donation. Until the end of 2011 we observed 4,385 infection episodes in our patient population. The STCS showed operative capabilities to collect high-quality data and to adequately reflect the complexity of the post-transplantation process. The STCS represents a promising novel project for comparative effectiveness research in transplantation medicine.

Finding the Fit Between Engineering Design and Cost Information

This paper analyzes the possibilities of integrating cost information and engineering design. Special emphasis is put on finding the potential of using the activity-based costing (ABC) method. Today, the problem of cost estimation in engineering design is that there are two separate extremes of knowledge. On the one extreme, the engineers model the technical parametres behindcosts in great detail but do not get appropriate cost information to their elegant models. On the other extreme, the accounting professionals are stuck with traditional cost accounting methods driven by the procedures and cycles of financial accounting. Therefore, in many cases, the cost information needs of various decision making groups, for example design engineers, are not served satisfactorily. This paper studies if the activity-based costing (ABC) method could offer a compromise between the two extremes. Recognizing activities and activity chains as well as activity and cost drivers could be specially beneficial for design engineers. Also, recognizing the accurate and reliable product costs of existing products helps when doing variant design. However, ABC is not at its best if the cost system becomes too complicated. This is why a comprehensive ABC-cost information system with detailed cost information for the use of design engineers should be examined critically. ABC is at its best when considering such issues as which activities drive costs, the cost of product complexity, allocating indirect costs on the products, the relationships between processes and costs, and the cost of excess capacity.

Design and implementation of FPGA-based LQ control of active magnetic bearings

The need for high performance, high precision, and energy saving in rotating machinery demands an alternative solution to traditional bearings. Because of the contactless operation principle, the rotating machines employing active magnetic bearings (AMBs) provide many advantages over the traditional ones. The advantages such as contamination-free operation, low maintenance costs, high rotational speeds, low parasitic losses, programmable stiffness and damping, and vibration insulation come at expense of high cost, and complex technical solution. All these properties make the use of AMBs appropriate primarily for specific and highly demanding applications. High performance and high precision control requires model-based control methods and accurate models of the flexible rotor. In turn, complex models lead to high-order controllers and feature considerable computational burden. Fortunately, in the last few years the advancements in signal processing devices provide new perspective on the real-time control of AMBs. The design and the real-time digital implementation of the high-order LQ controllers, which focus on fast execution times, are the subjects of this work. In particular, the control design and implementation in the field programmable gate array (FPGA) circuits are investigated. The optimal design is guided by the physical constraints of the system for selecting the optimal weighting matrices. The plant model is complemented by augmenting appropriate disturbance models. The compensation of the force-field nonlinearities is proposed for decreasing the uncertainty of the actuator. A disturbance-observer-based unbalance compensation for canceling the magnetic force vibrations or vibrations in the measured positions is presented. The theoretical studies are verified by the practical experiments utilizing a custom-built laboratory test rig. The test rig uses a prototyping control platform developed in the scope of this work. To sum up, the work makes a step in the direction of an embedded single-chip FPGA-based controller of AMBs.

Design and optimization of selfnanoemulsifying drug delivery systems for enhanced dissolution of gemfibrozil

Self-nanoemulsifying drug delivery systems of gemfibrozil were developed under Quality by Design approach for improvement of dissolution and oral absorption. Preliminary screening was performed to select proper components combination. BoxBehnken experimental design was employed as statistical tool to optimize the formulation variables, X1 (Cremophor® EL), X2 (Capmul® MCM-C8), and X3 (lemon essential oil). Systems were assessed for visual characteristics (emulsification efficacy), turbidity, droplet size, polydispersity index and drug release. Different pH media were also assayed for optimization. Following optimization, the values of formulation components (X1, X2, and X3) were 32.43%, 29.73% and 21.62%, respectively (16.22% of gemfibrozil). Transmission electron microscopy demonstrated spherical droplet morphology. SNEEDS release study was compared to commercial tablets. Optimized SNEDDS formulation of gemfibrozil showed a significant increase in dissolution rate compared to conventional tablets. Both formulations followed Weibull mathematical model release with a significant difference in td parameter in favor of the SNEDDS. Equally amodelistic parameters were calculated being the dissolution efficiency significantly higher for SNEDDS, confirming that the developed SNEDDS formulation was superior to commercial formulation with respect to in vitro dissolution profile. This paper provides an overview of the SNEDDS of the gemfibrozil as a promising alternative to improve oral absorption.

The design and implementation of a standards-based mobile messaging platform - case WAP Push Proxy Gateway

Tässä diplomityössä perehdytään WAP:in Push -viitekehykseen. WAP-standardit määrittelevät kuinka Internet-tyyppisiä palveluita, joita voidaan käyttää erilaisia mobiileja päätelaiteitteita käyttäen, toteutetaan tehokkaalla ja verkkoteknologiasta riippumattomalla tavalla. WAP pohjautuu Internet:iin, mutta huomioi pienten päätelaitteiden ja mobiiliverkkojen rajoitukset ja erikoisominaisuudet. WAP Push viitekehys määrittelee verkon aloittaman palvelusisällön toimittamisen. Työn teoriaosassa käydään läpi yleinen WAP-arkkitehtuuri ja WAP-protokollapino käyttäen vertailukohtina lanka-Internetin arkkitehtuuria ja protokollapinoa. Edellistä perustana käyttäen tutustaan WAP Push -viitekehykseen. Käytännönosassa kuvataan WAP Push -välityspalvelimen suunnittelu ja kehitystyö. WAP Push -välityspalvelin on keskeinen verkkoelementti WAP Push -viitekehyksessä. WAP Push -välityspalvelin yhdistää Internetin ja mobiiliverkon tavalla, joka piilottaa teknologiaeroavaisuudet Internetissä olevalta palveluntuottajalta.

Network Device Driver Design and Implementation for Symbian Operating System

Tämä diplomityö esittää Symbianin käyttöjärjestelmän verkkoarkkitehtuuriin perustuvan paikallisverkkokortin (LAN) käyttöönottoa. Pääajatus oli keskitetty langattoman LAN— kortin (WLAN) ajureiden käyttöönottoon. Jokainen Symbianin käyttöjärjestelmän verkkoarkkitehtuurin komponentti oli huolellisesti tutkittu, painottaen mahdollista langattoman yhteyden uudelleenkäyttöä. Myös olemassaolevan Ethernetkortin ajureiden uudelleenkäyttö oli huolellisesti otettu huomioon. Diplomityöprojektin aikana esimerkki WLAN-kortin ajurin lähdekoodista oli esitetty. Tämä ajuri on kirjoitettu NOKIA DTN-20 WLAN-korttia varten. Havaittiin myös, että suurin osa Symbianin käyttöjärjestelmän verkkoarkkitehtuurista voidaan käyttää myös WLAN-pohjaisessa yhteydessä ilman muutoksia.. Esitetty ajuri käyttää myös tiettyjä olemassaolevan Ethernetkortin ajureita, esim. Logical Device Driver (LDD):tä.

The Design and Implementation of Loudspeaker Control Network Protocols

The networking and digitalization of audio equipment has created a need for control protocols. These protocols offer new services to customers and ensure that the equipment operates correctly. The control protocols used in the computer networks are not directly applicable since embedded systems have resource and cost limitations. In this master's thesis the design and implementation of new loudspeaker control network protocols are presented. The protocol stack was required to be reliable, have short response times, configure the network automatically and support the dynamic addition and removal of loudspeakers. The implemented protocol stack was also required to be as efficient and lightweight as possible because the network nodes are fairly simple and lack processing power. The protocol stack was thoroughly tested, validated and verified. The protocols were formally described using LOTOS (Language of Temporal Ordering Specifications) and verified using reachability analysis. A prototype of the loudspeaker network was built and used for testing the operation and the performance of the control protocols. The implemented control protocol stack met the design specifications and proved to be highly reliable and efficient.

Interfacing Health Care Information Systems Design and Implementation

Terveydenhuollossa käytetään nykyisin informaatioteknologian (IT) mahdollisuuksia parantamaan hoidon laatua, vähentämään hoitoon liittyviä kuluja sekä yksinkertaistamaan ja selkeyttämään laakareiden työnkulkua. Tietojärjestelmät, jotka edustavat jokaisen IT-ratkaisun ydintä, täytyy kehittää täyttämään lukuisia vaatimuksia, ja yksi niistä on kyky integroitua saumattomasti toisten tietojärjestelmien kanssa. Järjestelmäintegraatio on kuitenkin yhä haastava tehtävä, vaikka sita varten on kehitetty useita standardeja. Tässä työssä kuvataan vastakehitetyn lääketieteellisen tietojärjestelmän liittymäratkaisu. Työssä pohditaan vaatimuksia, jotka tällaiselle sovellukselle asetetaan, ja myös tapa, jolla vaatimukset toteutuvat on esitetty. Liittymaratkaisu on jaettu kahteen osaan, tietojärjestelmaliittymään ja "liittymakoneeseen" (interfacing engine). Edellinen on käsittää perustoiminnallisuuden, jota tarvitaan vastaanottamaan ja lähettämään tietoa toisiin järjestelmiin, kun taas jälkimmäinen tarjoaa tuen tuotantoympäristössa käytettäville standardeille. Molempien osien suunnitelu on esitelty perusteellisesti tässä työssä. Ongelma ratkaistiin modulaarisen ja geneerisen suunnittelun avulla. Tämä lähestymistapa osoitetaan työssä kestäväksi ja joustavaksi ratkaisuksi, jota voidaan käyttää tarkastelemaan laajaa valikoimaa liittymäratkaisulle asetettuja vaatimuksia. Lisaksi osoitetaan kuinka tehty ratkaisu voidaan joustavuutensa ansiosta helposti mukauttaa vaatimuksiin, joita ei ole etukäteen tunnistettu, ja siten saavutetaan perusta myös tulevaisuuden tarpeille