Structure-Based, Rational Design of T Cell Receptors.

Adoptive cell transfer using engineered T cells is emerging as a promising treatment for metastatic melanoma. Such an approach allows one to introduce T cell receptor (TCR) modifications that, while maintaining the specificity for the targeted antigen, can enhance the binding and kinetic parameters for the interaction with peptides (p) bound to major histocompatibility complexes (MHC). Using the well-characterized 2C TCR/SIYR/H-2K(b) structure as a model system, we demonstrated that a binding free energy decomposition based on the MM-GBSA approach provides a detailed and reliable description of the TCR/pMHC interactions at the structural and thermodynamic levels. Starting from this result, we developed a new structure-based approach, to rationally design new TCR sequences, and applied it to the BC1 TCR targeting the HLA-A2 restricted NY-ESO-1157-165 cancer-testis epitope. Fifty-four percent of the designed sequence replacements exhibited improved pMHC binding as compared to the native TCR, with up to 150-fold increase in affinity, while preserving specificity. Genetically engineered CD8(+) T cells expressing these modified TCRs showed an improved functional activity compared to those expressing BC1 TCR. We measured maximum levels of activities for TCRs within the upper limit of natural affinity, K D = ∼1 - 5 μM. Beyond the affinity threshold at K D < 1 μM we observed an attenuation in cellular function, in line with the "half-life" model of T cell activation. Our computer-aided protein-engineering approach requires the 3D-structure of the TCR-pMHC complex of interest, which can be obtained from X-ray crystallography. We have also developed a homology modeling-based approach, TCRep 3D, to obtain accurate structural models of any TCR-pMHC complexes when experimental data is not available. Since the accuracy of the models depends on the prediction of the TCR orientation over pMHC, we have complemented the approach with a simplified rigid method to predict this orientation and successfully assessed it using all non-redundant TCR-pMHC crystal structures available. These methods potentially extend the use of our TCR engineering method to entire TCR repertoires for which no X-ray structure is available. We have also performed a steered molecular dynamics study of the unbinding of the TCR-pMHC complex to get a better understanding of how TCRs interact with pMHCs. This entire rational TCR design pipeline is now being used to produce rationally optimized TCRs for adoptive cell therapies of stage IV melanoma.

Modelling body mass index and endometrial cancer risk in a pooled-analysis of three case-control studies.

OBJECTIVE: To quantify the relation between body mass index (BMI) and endometrial cancer risk, and to describe the shape of such a relation. DESIGN: Pooled analysis of three hospital-based case-control studies. SETTING: Italy and Switzerland. POPULATION: A total of 1449 women with endometrial cancer and 3811 controls. METHODS: Multivariate odds ratios (OR) and 95% confidence intervals (95% CI) were obtained from logistic regression models. The shape of the relation was determined using a class of flexible regression models. MAIN OUTCOME MEASURE: The relation of BMI with endometrial cancer. RESULTS: Compared with women with BMI 18.5 to <25 kg/m(2) , the odds ratio was 5.73 (95% CI 4.28-7.68) for women with a BMI ≥35 kg/m(2) . The odds ratios were 1.10 (95% CI 1.09-1.12) and 1.63 (95% CI 1.52-1.75) respectively for an increment of BMI of 1 and 5 units. The relation was stronger in never-users of oral contraceptives (OR 3.35, 95% CI 2.78-4.03, for BMI ≥30 versus <25 kg/m(2) ) than in users (OR 1.22, 95% CI 0.56-2.67), and in women with diabetes (OR 8.10, 95% CI 4.10-16.01, for BMI ≥30 versus <25 kg/m(2) ) than in those without diabetes (OR 2.95, 95% CI 2.44-3.56). The relation was best fitted by a cubic model, although after the exclusion of the 5% upper and lower tails, it was best fitted by a linear model. CONCLUSIONS: The results of this study confirm a role of elevated BMI in the aetiology of endometrial cancer and suggest that the risk in obese women increases in a cubic nonlinear fashion. The relation was stronger in never-users of oral contraceptives and in women with diabetes. TWEETABLE ABSTRACT: Risk of endometrial cancer increases with elevated body weight in a cubic nonlinear fashion.

Statistical Optimum Design of Heat Exchangers

The optimal design of a heat exchanger system is based on given model parameters together with given standard ranges for machine design variables. The goals set for minimizing the Life Cycle Cost (LCC) function which represents the price of the saved energy, for maximizing the momentary heat recovery output with given constraints satisfied and taking into account the uncertainty in the models were successfully done. Nondominated Sorting Genetic Algorithm II (NSGA-II) for the design optimization of a system is presented and implemented inMatlab environment. Markov ChainMonte Carlo (MCMC) methods are also used to take into account the uncertainty in themodels. Results show that the price of saved energy can be optimized. A wet heat exchanger is found to be more efficient and beneficial than a dry heat exchanger even though its construction is expensive (160 EUR/m2) compared to the construction of a dry heat exchanger (50 EUR/m2). It has been found that the longer lifetime weights higher CAPEX and lower OPEX and vice versa, and the effect of the uncertainty in the models has been identified in a simplified case of minimizing the area of a dry heat exchanger.

Design concepts for the Cherenkov Telescope Array CTA: an advanced facility for ground-based high-energy gamma-ray astronomy

Ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes. Ground-based gamma-ray astronomy has a huge potential in astrophysics, particle physics and cosmology. CTA is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100 GeV and above 100 TeV. CTA will consist of two arrays (one in the north, one in the south) for full sky coverage and will be operated as open observatory. The design of CTA is based on currently available technology. This document reports on the status and presents the major design concepts of CTA.

Design concepts for the Cherenkov Telescope Array CTA: an advanced facility for ground-based high-energy gamma-ray astronomy

Ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes. Ground-based gamma-ray astronomy has a huge potential in astrophysics, particle physics and cosmology. CTA is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100 GeV and above 100 TeV. CTA will consist of two arrays (one in the north, one in the south) for full sky coverage and will be operated as open observatory. The design of CTA is based on currently available technology. This document reports on the status and presents the major design concepts of CTA.

Design concepts for the Cherenkov Telescope Array CTA: an advanced facility for ground-based high-energy gamma-ray astronomy

Ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes. Ground-based gamma-ray astronomy has a huge potential in astrophysics, particle physics and cosmology. CTA is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100 GeV and above 100 TeV. CTA will consist of two arrays (one in the north, one in the south) for full sky coverage and will be operated as open observatory. The design of CTA is based on currently available technology. This document reports on the status and presents the major design concepts of CTA.

Assessment of facilitators' design thinking

Meeting design is one of the most critical prerequisites of the success of facilitated meetings but how to achieve the success is not yet fully understood. This study presents a descriptive model of the design of technology supported meetings based on literature findings about the key factors contributing to the success of collaborative meetings, and linking these factors to the meeting design steps by exploring how facilitators consider the factors in practice in their design process. The empirical part includes a multiple-case study conducted among 12 facilitators. The case concentrates on the GSS laboratory at LUT, which has been working on facilitation and GSS for the last fifteen years. The study also includes ‘control’ cases from two comparable institutions. The results of this study highlight both the variances and commonalities among facilitators in how they design collaboration processes. The design thinking of facilitators of all levels of experience is found to be largely consistent wherefore the key design factors as well as their role across the design process can be outlined. Session goals, group composition, supporting technology, motivational aspects, physical constraints, and correct design practices were found to outline the key factors in design thinking. These factors are further categorized into three factor types of controllable, constraining, and guiding design factors, because the study findings indicate the factor type to have an effect on the factor’s importance in design. Furthermore, the order of considering these factors in the design process is outlined.

Design Process of Packaging Laboratory at Lappeenranta University of Technology

The layout design process of the packaging laboratory at Lappeenranta University of Technology is documented in this thesis. Layout planning methods are discussed in general. The systematic layout planning procedure is presented in more detail as it is utilised in the case of layout planning of the packaging laboratory. General demands for research laboratory are discussed both from the machine and product perspectives. The possibilities for commercial food processing in the laboratory are discussed from the point of view of foodstuff processing regulations and hygiene demands. The layout planning process is documented and different layout possibilities are presented. Different layout drafts are evaluated and one layout draft is developed to be the final layout of the packaging laboratory. Guideline for technical planning and implementation based on the final layout is given

Assessing functional relations in single-case designs: Quantitative proposals in the context of the evidence-based movement

In the context of the evidence-based practices movement, the emphasis on computing effect sizes and combining them via meta-analysis does not preclude the demonstration of functional relations. For the latter aim, we propose to augment the visual analysis to add consistency to the decisions made on the existence of a functional relation without losing sight of the need for a methodological evaluation of what stimuli and reinforcement or punishment are used to control the behavior. Four options for quantification are reviewed, illustrated, and tested with simulated data. These quantifications include comparing the projected baseline with the actual treatment measurements, on the basis of either parametric or nonparametric statistics. The simulated data used to test the quantifications include nine data patterns in terms of the presence and type of effect and comprising ABAB and multiple baseline designs. Although none of the techniques is completely flawless in terms of detecting a functional relation only when it is present but not when it is absent, an option based on projecting split-middle trend and considering data variability as in exploratory data analysis proves to be the best performer for most data patterns. We suggest that the information on whether a functional relation has been demonstrated should be included in meta-analyses. It is also possible to use as a weight the inverse of the data variability measure used in the quantification for assessing the functional relation. We offer an easy to use code for open-source software for implementing some of the quantifications.

Introducing online teaching in Humanities: A case study about the acceptance of online activities by the academic staff of classical languages

The purpose of this paper is to show the perceptions of the academic staff of classical languages (ancient Greek and Latin) concerning use of online activities during their courses. The study was carried out in three countries: Greece (three major Universities), Spain (University of Barcelona) and the United States (University of California, Berkeley) with the participation of thirty-three academic instructors. Depending on the level of use and acceptance of the ICT and following G. Moore¿s classification, we separated the participating academics in three groups: the conservatives, the mainstream and the early adopters. The fact that the smallest group is the third clearly shows the necessity for teachers¿ preparation and training before introducing innovative projects in the classroom. Since the starting point for the application of innovation in the classroom is the teacher, policy makers should focus on helping them become conscious of changes in teaching methods and include their opinion during the design of innovative projects.

Introducing online teaching in Humanities: A case study about the acceptance of online activities by the academic staff of classical languages

The purpose of this paper is to show the perceptions of the academic staff of classical languages (ancient Greek and Latin) concerning use of online activities during their courses. The study was carried out in three countries: Greece (three major Universities), Spain (University of Barcelona) and the United States (University of California, Berkeley) with the participation of thirty-three academic instructors. Depending on the level of use and acceptance of the ICT and following G. Moore¿s classification, we separated the participating academics in three groups: the conservatives, the mainstream and the early adopters. The fact that the smallest group is the third clearly shows the necessity for teachers¿ preparation and training before introducing innovative projects in the classroom. Since the starting point for the application of innovation in the classroom is the teacher, policy makers should focus on helping them become conscious of changes in teaching methods and include their opinion during the design of innovative projects.

Design of an Event Based Messaging System

B2B document handling is moving from paper to electronic networks and electronic domain very rapidly. Moving, handling and transforming large electronic business documents requires a lot from the systems handling them. This paper explores new technologies such as SOA, event-driven systems and ESB and a scalable, event-driven enterprise service bus is created to demonstrate these new approaches to message handling. As an end result, we have a small but fully functional messaging system with several different components. This is the first larger Java-project done in-house, so on the side we developed our own set of best practices of Java development, setting up configurations, tools, code repositories and class naming and much more.

Engendering Group Support Based Foresight for Capital Intensive Manufacturing Industries - Case Paper and Steel Industry Scenarios by 2018

In recent times of global turmoil, the need for uncertainty management has become ever momentous. The need for enhanced foresight especially concerns capital-intensive industries, which need to commit their resources and assets with long-term planning horizons. Scenario planning has been acknowledged to have many virtues - and limitations - concerning the mapping of the future and illustrating the alternative development paths. The present study has been initiated to address both the need of improved foresight in two capital-intensive industries, i.e. the paper and steel industries and the imperfections in the current scenario practice. The research problem has been approached by engendering a problem-solving vehicle, which combines, e.g. elements of generic scenario process, face-to-face group support methods, deductive scenario reasoning and causal mapping into a fully integrated scenario process. The process, called the SAGES scenario framework, has been empirically tested by creating alternative futures for two capital-intensive industries, i.e. the paper and steel industries. Three scenarios for each industry have been engendered together with the identification of the key megatrends, the most important foreign investment determinants, key future drivers and leading indicators for the materialisation of the scenarios. The empirical results revealed a two-fold outlook for the paper industry, while the steel industry future was seen as much more positive. The research found support for utilising group support systems in scenario and strategic planning context with some limitations. Key perceived benefits include high time-efficiency, productivity and lower resource-intensiveness. Group support also seems to enhance participant satisfaction, encourage innovative thinking and provide the users with personalised qualitative scenarios.

BIOFILMS BASED ON CANIHUA FLOUR (Chenopodium Pallidicaule): DESIGN AND CHARACTERIZATION

This work aims to (1) produce and characterize the flour obtained from two varieties of canihua, cupi and illpa-inia, and (2) evaluate the ability of these flours to form biofilms. The flours produced contain proteins, starches, lipids, organic substances containing phenol groups, and high percentages of unsaturated fatty acids. Films produced from the illpa variety presented lower water vapor permeability and larger Young’s modulus values than the films formed from the cupi variety. Both films were yellowish and displayed a high light blocking ability (as compared with polyethylene films), which can be attributed to the presence of phenolic compounds. Furthermore, they showed lesser solubility and water permeability than other polysaccharide films, which may be the result of the higher protein (12%–13.8%) and lipid (11%) contents in canihua flours, as well as the formation of a larger number of S–S bonds. On the other hand, these films presented a single vitreous transition temperature at low temperatures (< 0 °C), crystallization of the A and Vh types, and an additional diffraction peak at 2 = 7.5º, ascribed to the presence of essential fatty acids in canihua flour. Canihua flour can form films with adequate properties and shows promise for potential applications in food packaging, because it acts as a good barrier to incident ultraviolet light.