Mycobacterium tuberculosis-specific CD8 T cells are functionally and phenotypically different between latent infection and active disease

Purpose/Objective: Tuberculosis (TB) is the second worldwide leading cause of death from an infectious disease after HIV infection. Protective immunity to Mycobacterium tuberculosis (Mtb) remains poorly understood and the role of Mtb-specific CD8 T-cells is controversial. We performed comprehensive functional and phenotypic characterizations of Mtb-specific CD8 T-cell responses in 273 subjects with either latent Mtb infection (LTBI) or active TB disease (TB) to assess their profile and relevance in TB. Materials and methods: Using multi-parametric flow cytometry, we assessed Mtb-specific CD8 T-cell functional (production of IFNgamma, IL-2 and TNF-alpha; proliferation capacity and cytotoxicity) and phenotypic (T-cell differentiation and exhaustion) profiles in cells isolated from peripheral blood and correlated these profiles with distinct clinical presentations. Results: Mtb-specific CD8 T-cells were detected in most TB patients and few LTBI subjects (65% and 15%, respectively; P < 0.00001) and were of similar magnitude with a comparable cytokines profile (IFNg+TNFa+IL2-) in both groups. Mtb-specific CD8 T-cells were mostly TEMRA (CD45RA+ CCR7-) co-expressing 2B4 and CD160 in LTBI subjects and mostly TEM (CD45RA-CCR7-) lacking PD-1/ CD160/2B4 in TB patients. Furthermore, Mtb-specific CD8 T-cells mostly expressed very little perforin and granulysin but contained granzymes A and B or lacked all these cytotoxic markers in TB and LTBI subjects, respectively. However, in vitro expanded Mtb-specific CD8 T-cells acquired perforin, granulysin and granzymes. Finally, Mtb-specific CD8 T-cell responses were more robust and prone to proliferate in patients with extrapulmonary compared to pulmonary TB. Conclusions: The clinical status and TB presentation are associated to specific profiles of Mtb-specific CD8 T-cell responses, thus indicating distinct dynamics between the mycobacteria, the CD8 T-cell response and the clinical outcome. Our data shed light on the controversial reached by studies performed in human and animal models, thus advancing the current knowledge on the complex dynamic of TB immunity.

The baby and the couple : understanding and treating young families

The Baby and the Couple provides an insider's view on how infant communication develops in the context of the family and how parents either work together as a team or struggle in the process. The authors present vignettes from everyday life as well as case studies from a longitudinal research project of infants and their parents interacting together in the Lausanne Trilogue Play (LTP), an assessment tool for very young families. Divided into three parts, the book focuses not only on the parents, but also on the infant's contribution to the family. Part 1 presents a case study of Lucas and his family, from infancy to age 5. With each chapter we see how, in the context of their families, infants learn to communicate with more than one person at a time. Part 2 explores how infants cope when their parents struggle to work together - excluding, competing or only connecting through their child. The authors follow several case examples from infancy through to early childhood to illustrate various forms of problematic co-parenting, along with the infant's derailed trajectory at different ages and stages. In Part 3, prevention and intervention models based on the LTP are presented. In addition to an overview of these programs, chapters are devoted to the Developmental Systems Consultation, which combines use of the LTP and video feedback, and a new model, Reflective Family Play, which allows whole families to engage in treatment. The Baby and the Couple is a vital resource for professionals working in the fields of infant and preschool mental health including psychiatrists, psychologists, social workers, family therapists and educators, as well as researchers.

Conformity, upstream reciprocity and social diversity: secondary mechanisms for the evolution of cooperation

Cooperation is ubiquitous in nature: genes cooperate in genomes, cells in muti- cellular organims, and individuals in societies. In humans, division of labor and trade are key elements of most known societies, where social life is regulated by- moral systems specifying rights and duties often enforced by third party punish¬ment. Over the last decades, several primary mechanisms, such as kin selection, direct and indirect reciprocity, have been advanced to explain the evolution of cooperation from a naturalistic approach. In this thesis, I focus on the study of three secondary mechanisms which, although insufficient to allow for the evo¬lution of cooperation, have been hypothesized to further promote it when they are linked to proper primary mechanisms: conformity (the tendency to imitate common behaviors), upstream reciprocity (the tendency to help somebody once help has been received from somebody else) and social diversity (heterogeneous social contexts). I make use of mathematical and computational models in the formal framework of evolutionary game theory in order to investigate the theoret¬ical conditions under which conformity, upstream reciprocity and social diversity are able to raise the levels of cooperation attained in evolving populations. - La coopération est ubiquitaire dans la nature: les gènes coopèrent dans les génomes, les cellules dans les organismes muticellulaires, et les organismes dans les sociétés. Chez les humains, la division du travail et le commerce sont des éléments centraux de la plupart des sociétés connues, où la vie sociale est régie par des systèmes moraux établissant des droits et des devoirs, souvent renforcés par la punition. Au cours des dernières décennies, plusieurs mécanismes pri¬maires, tels que la sélection de parentèle et les réciprocités directe et indirecte, ont été avancés pour expliquer l'évolution de la coopération d'un point de vue nat¬uraliste. Dans cette thèse, nous nous concentrons sur l'étude de trois mécanismes secondaires qui, bien qu'insuffisants pour permettre l'évolution de la coopération, sont capables de la promouvoir davantage s'ils sont liés aux mécanismes primaires appropriés: la conformité (tendance à imiter des comportements en commun), la 'réciprocité en amont' (tendance à aider quelqu'un après avoir reçu l'aide de quelqu'un d'autre) et la diversité sociale (contextes sociaux hétérogènes). Nous faisons usage de modèles mathématiques et informatiques dans le cadre formel de la théorie des jeux évolutionnaires afin d'examiner les conditions théoriques dans lesquelles la conformité, la 'réciprocité en amont' et la diversité sociale sont capables d'élever le niveau de coopération des populations en évolution.

Simulation and Analysis of Arterial Traffic Operations Along the U.S. 61 Corridor in Burlington, Iowa, 1998

The Center for Transportation Research and Education (CTRE) used the traffic simulation model CORSIM to access proposed capacity and safety improvement strategies for the U.S. 61 corridor through Burlington, Iowa. The comparison between the base and alternative models allow for evaluation of the traffic flow performance under the existing conditions as well as other design scenarios. The models also provide visualization of performance for interpretation by technical staff, public policy makers, and the public. The objectives of this project are to evaluate the use of traffic simulation models for future use by the Iowa Department of Transportation (DOT) and to develop procedures for employing simulation modeling to conduct the analysis of alternative designs. This report presents both the findings of the U.S. 61 evaluation and an overview of model development procedures. The first part of the report includes the simulation modeling development procedures. The simulation analysis is illustrated through the Burlington U.S. 61 corridor case study application. Part I is not intended to be a user manual but simply introductory guidelines for traffic simulation modeling. Part II of the report evaluates the proposed improvement concepts in a side by side comparison of the base and alternative models.

Mechanical properties of viral capsids

Viruses are known to tolerate wide ranges of pH and salt conditions and to withstand internal pressures as high as 100 atmospheres. In this paper we investigate the mechanical properties of viral capsids, calling explicit attention to the inhomogeneity of the shells that is inherent to their discrete and polyhedral nature. We calculate the distribution of stress in these capsids and analyze their response to isotropic internal pressure (arising, for instance, from genome confinement and/or osmotic activity). We compare our results with appropriate generalizations of classical (i.e., continuum) elasticity theory. We also examine competing mechanisms for viral shell failure, e.g., in-plane crack formation vs radial bursting. The biological consequences of the special stabilities and stress distributions of viral capsids are also discussed.

Genetic factors of obesity and eating disorders: Copy number variations (CNV) involving SH2B1

Context : It is now clearly shown that genetic factors in association with environment play a key role in obesity and eating disorders. This project studies the clinical symptoms and molecular abnormalities in patients carrying a strong hereditary predisposition to obesity and eating behavior disorders. We have previously published the association between the 16:29.5-30.1 deletion and a very penetrant form of morbid obesity and macrocephaly. We have also demonstrated the association between the reciprocal 16:29.5-30.1 duplication and underweight and small head circumference. These 2 studies demonstrate that gene dosage of one or several genes in this region regulates BMI as well as brain growth. At present, there are no data pointing towards particular candidate genes. We are currently investigating a second non-overlapping recurrent CNV encompassing SH2B1, upstream of the aforementioned rearrangement. SNPs in this gene have been associated with BMI in GWAS studies and mice models confirmed this association. Bokuchova et al have reported an association between deletions encompassing this gene and severe early onset obesity, as well as insulin resistance. We are currently collecting and analyzing data to fully characterize the phenotype and the transcriptional patterns associated with this rearrangement. Aims : 1. Identify carriers of any CNVs in the greater 16p11.2 region (between 16:28MB and 32MB) in the EGG consortium. 2. Perform association studies between SNPs in the greater 16p11.2 region (16:28-32MB) and anthropometric measures with adjusted "locus-wide significance", to identify or prioritize candidate genes potentially driving the association observed in patients with the CNVs (and thus worthy of further validation and sequencing). 3. Explore associations between GSV genome-wide and brain volume. 4. Explore relationship between brain volumes (whole brain and regional for those who underwent brain MRI), head circumference and BMI. 5. Extrapolate this procedure to other regions covered by the Metabochip. Methods : - Examine and collect clinical informations, as well as molecular informations in these patients. - Analysis of MRI data in children and adults with BMI > 2SD. Compare changes to MRI data obtained in patients with monogenic forms of obesity (data from Lausanne study) and to underweight (BMI<-2SD) individuals from EGG. - Test whether opposite extremes of the phenotypic distribution may be highly informative Expected results : This is a highly focused study, pertaining to approximately 1 0/00 of the human genome. Yet it is clear that if successful, the lessons learned from this study could be extrapolated to other segments of the genome and would need validation and replication by additional studies. Altogether they will contribute to further explore the missing heritability and point to etiologic genes and pathways underlying these important health burdens.

Quantification of Myocardial Perfusion Using 13N-ammonia PET: a Cross-Comparison Study on Analysis Software Packages - Carimas, PMOD and FlowQuant

Aim. Several software packages (SWP) and models have been released for quantification of myocardial perfusion (MP). Although they all are validated against something, the question remains how well their values agree. The present analysis focused on cross-comparison of three SWP for MP quantification of 13N-ammonia PET studies. Materials & Methods. 48 rest and stress MP 13N-ammonia PET studies of hypertrophic cardiomyopathy (HCM) patients (Sciagrà et al., 2009) were analysed with three SW packages - Carimas, PMOD, and FlowQuant - by three observers blinded to the results of each other. All SWP implement the one-tissue-compartment model (1TCM, DeGrado et al. 1996), and first two - the two-tissue-compartment model (2TCM, Hutchins et al. 1990) as well. Linear mixed model for the repeated measures was fitted to the data. Where appropriate we used Bland-Altman plots as well. The reproducibility was assessed on global, regional and segmental levels. Intraclass correlation coefficients (ICC), differences between the SWPs and between models were obtained. ICC≥0.75 indicated excellent reproducibility, 0.4≤ICC<0.75 indicated fair to good reproducibility, ICC<0.4 - poor reproducibility (Rosner, 2010). Results. When 1TCM MP values were compared, the SW agreement on global and regional levels was excellent, except for Carimas vs. PMOD at RCA: ICC=0.715 and for PMOD vs. FlowQuant at LCX:ICC=0.745 which were good. In segmental analysis in five segments: 7,12,13, 16, and 17 the agreement between all SWP was excellent; in the remaining 12 segments the agreement varied between the compared SWP. Carimas showed excellent agreement with FlowQuant in 13 segments and good in four - 1, 5, 6, 11: 0.687≤ICCs≤0.73; Carimas had excellent agreement with PMOD in 11 segments, good in five_4, 9, 10, 14, 15: 0.682≤ICCs≤0.737, and poor in segment 3: ICC=0.341. PMOD had excellent agreement with FlowQuant in eight segments and substantial-to-good in nine_1, 2, 3, 5, 6,8-11: 0.585≤ICCs≤0.738. Agreement between Carimas and PMOD for 2TCM was good at a global level: ICC=0.745, excellent at LCX (0.780) and RCA (0.774), good at LAD (0.662); agreement was excellent for ten segments, fair-to-substantial for segments 2, 3, 8, 14, 15 (0.431≤ICCs≤0.681), poor for segments 4 (0.384) and 17 (0.278). Conclusions. The three SWP used by different operators to analyse 13N-ammonia PET MP studies provide results that agree well at a global level, regional levels, and mostly well even at a segmental level. Agreement is better for 1TCM. Poor agreement at segments 4 and 17 for 2TCM needs further clarification.

Effects of sample size on the performance of species distribution models

A wide range of modelling algorithms is used by ecologists, conservation practitioners, and others to predict species ranges from point locality data. Unfortunately, the amount of data available is limited for many taxa and regions, making it essential to quantify the sensitivity of these algorithms to sample size. This is the first study to address this need by rigorously evaluating a broad suite of algorithms with independent presence-absence data from multiple species and regions. We evaluated predictions from 12 algorithms for 46 species (from six different regions of the world) at three sample sizes (100, 30, and 10 records). We used data from natural history collections to run the models, and evaluated the quality of model predictions with area under the receiver operating characteristic curve (AUC). With decreasing sample size, model accuracy decreased and variability increased across species and between models. Novel modelling methods that incorporate both interactions between predictor variables and complex response shapes (i.e. GBM, MARS-INT, BRUTO) performed better than most methods at large sample sizes but not at the smallest sample sizes. Other algorithms were much less sensitive to sample size, including an algorithm based on maximum entropy (MAXENT) that had among the best predictive power across all sample sizes. Relative to other algorithms, a distance metric algorithm (DOMAIN) and a genetic algorithm (OM-GARP) had intermediate performance at the largest sample size and among the best performance at the lowest sample size. No algorithm predicted consistently well with small sample size (n < 30) and this should encourage highly conservative use of predictions based on small sample size and restrict their use to exploratory modelling.

Prediction of soil shear strength in agricultural and natural environments of the Brazilian Cerrado

The objective of this work was to develop uni- and multivariate models to predict maximum soil shear strength (τmax) under different normal stresses (σn), water contents (U), and soil managements. The study was carried out in a Rhodic Haplustox under Cerrado (control area) and under no-tillage and conventional tillage systems. Undisturbed soil samples were taken in the 0.00-0.05 m layer and subjected to increasing U and σn, in shear strength tests. The uni- and multivariate models - respectively τmax=10(a+bU) and τmax=10(a+bU+cσn) - were significant in all three soil management systems evaluated and they satisfactorily explain the relationship between U, σn, and τmax. The soil under Cerrado has the highest shear strength (τ) estimated with the univariate model, regardless of the soil water content, whereas the soil under conventional tillage shows the highest values with the multivariate model, which were associated to the lowest water contents at the soil consistency limits in this management system.

Priorities and hierarchical accounts of translation

This paper is a study of the concept of priority and its use together with the notion of hierarchy in academic writing and theoretical models of translation. Hierarchies and priorities can be implicit or explicit, prescribed, suggested or described. The paper starts, chronologically, wtih Nida and Levý’s hierarchical accounts of translation and follows their legacy in scholars as different as Newmark and Gutt. The concept of priorities is hinted at also in didactic models (Nord) as well as in norm-theoretical and accounts of translation (Toury and Chesterman) within Descriptive Translation Studies. All of these authors are analyzed and commented. The paper calls for a more systematic and straightforward account of translational priorities, and proposes a few conceptual tools that stem from this research model, including the concepts of ambition and richness of a translation. Finally, the paper concludes with an adaptation of Lakoff and Johnson’s view of prototypicality and its potential usefulness in research into and the understanding of translation.

The maximum voltage drop in an on-chip power distribution network: analysis of square, triangular and hexagonal power pad arrangements

A mathematical model of the voltage drop which arises in on-chip power distribution networks is used to compare the maximum voltage drop in the case of different geometric arrangements of the pads supplying power to the chip. These include the square or Manhattan power pad arrangement, which currently predominates, as well as equilateral triangular and hexagonal arrangements. In agreement with the findings in the literature and with physical and SPICE models, the equilateral triangular power pad arrangement is found to minimize the maximum voltage drop. This headline finding is a consequence of relatively simple formulas for the voltage drop, with explicit error bounds, which are established using complex analysis techniques, and elliptic functions in particular.

Value added logistics in supply and demand chains. Smile. Part 1. eBusiness between global company and itslocal sme supplier network

VALOSADE (Value Added Logistics in Supply and Demand Chains) is the research project of Anita Lukka's VALORE (Value Added Logistics Research) research team inLappeenranta University of Technology. VALOSADE is included in ELO (Ebusiness logistics) technology program of Tekes (Finnish Technology Agency). SMILE (SME-sector, Internet applications and Logistical Efficiency) is one of four subprojects of VALOSADE. SMILE research focuses on case network that is composed of small and medium sized mechanical maintenance service providers and global wood processing customers. Basic principle of SMILE study is communication and ebusiness insupply and demand network. This first phase of research concentrates on creating backgrounds for SMILE study and for ebusiness solutions of maintenance case network. The focus is on general trends of ebusiness in supply chains and networksof different industries; total ebusiness system architecture of company networks; ebusiness strategy of company network; information value chain; different factors, which influence on ebusiness solution of company network; and the correlation between ebusiness and competitive advantage. Literature, interviews and benchmarking were used as research methods in this qualitative case study. Networks and end-to-end supply chains are the organizational structures, which can add value for end customer. Information is one of the key factors in these decentralized structures. Because of decentralization of business, information is produced and used in different companies and in different information systems. Information refinement services are needed to manage information flows in company networksbetween different systems. Furthermore, some new solutions like network information systems are utilised in optimising network performance and in standardizingnetwork common processes. Some cases have however indicated, that utilization of ebusiness in decentralized business model is not always a necessity, but value-add of ICT must be defined case-specifically. In the theory part of report, different ebusiness and architecture models are introduced. These models are compared to empirical case data in research results. The biggest difference between theory and empirical data is that models are mainly developed for large-scale companies - not for SMEs. This is due to that implemented network ebusiness solutions are mainly large company centered. Genuine SME network centred ebusiness models are quite rare, and the study in that area has been few in number. Business relationships between customer and their SME suppliers are nowadays concentrated more on collaborative tactical and strategic initiatives besides transaction based operational initiatives. However, ebusiness systems are further mainly based on exchange of operational transactional data. Collaborative ebusiness solutions are in planning or pilot phase in most case companies. Furthermore, many ebusiness solutions are nowadays between two participants, but network and end-to-end supply chain transparency and information systems are quite rare. Transaction volumes, data formats, the types of exchanged information, information criticality,type and duration of business relationship, internal information systems of partners, processes and operation models (e.g. different ordering models) differ among network companies, and furthermore companies are at different stages on networking and ebusiness readiness. Because of former factors, different customer-supplier combinations in network must utilise totally different ebusiness architectures, technologies, systems and standards.

Washing and Dewatering of Different Starches in Pressure Filters

The main objective of this thesis was togenerate better filtration technologies for effective production of pure starchproducts, and thereby the optimisation of filtration sequences using created models, as well as the synthesis of the theories of different filtration stages, which were suitable for starches. At first, the structure and the characteristics of the different starch grades are introduced and each starch grade is shown to have special characteristics. These are taken as the basis of the understanding of the differences in the behaviour of the different native starch grades and their modifications in pressure filtration. Next, the pressure filtration process is divided into stages, which are filtration, cake washing, compression dewatering and displacement dewatering. Each stage is considered individually in their own chapters. The order of the different suitable combinations of the process stages are studied, as well as the proper durations and pressures of the stages. The principles of the theory of each stageare reviewed, the methods for monitoring the progress of each stage are presented, and finally, the modelling of them is introduced. The experimental results obtained from the different stages of starch filtration tests are given and the suitability of the theories and models to the starch filtration are shown. Finally, the theories and the models are gathered together and shown, that the analysis of the whole starch pressure filtration process can be performed with the software developed.

Direct torque control of permanent magnet synchronous machines - analysis and implementation

Thedirect torque control (DTC) has become an accepted vector control method besidethe current vector control. The DTC was first applied to asynchronous machines,and has later been applied also to synchronous machines. This thesis analyses the application of the DTC to permanent magnet synchronous machines (PMSM). In order to take the full advantage of the DTC, the PMSM has to be properly dimensioned. Therefore the effect of the motor parameters is analysed taking the control principle into account. Based on the analysis, a parameter selection procedure is presented. The analysis and the selection procedure utilize nonlinear optimization methods. The key element of a direct torque controlled drive is the estimation of the stator flux linkage. Different estimation methods - a combination of current and voltage models and improved integration methods - are analysed. The effect of an incorrect measured rotor angle in the current model is analysed andan error detection and compensation method is presented. The dynamic performance of an earlier presented sensorless flux estimation method is made better by improving the dynamic performance of the low-pass filter used and by adapting the correction of the flux linkage to torque changes. A method for the estimation ofthe initial angle of the rotor is presented. The method is based on measuring the inductance of the machine in several directions and fitting the measurements into a model. The model is nonlinear with respect to the rotor angle and therefore a nonlinear least squares optimization method is needed in the procedure. A commonly used current vector control scheme is the minimum current control. In the DTC the stator flux linkage reference is usually kept constant. Achieving the minimum current requires the control of the reference. An on-line method to perform the minimization of the current by controlling the stator flux linkage reference is presented. Also, the control of the reference above the base speed is considered. A new estimation flux linkage is introduced for the estimation of the parameters of the machine model. In order to utilize the flux linkage estimates in off-line parameter estimation, the integration methods are improved. An adaptive correction is used in the same way as in the estimation of the controller stator flux linkage. The presented parameter estimation methods are then used in aself-commissioning scheme. The proposed methods are tested with a laboratory drive, which consists of a commercial inverter hardware with a modified software and several prototype PMSMs.

Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis.

Poly (ADP-ribose) polymerase 1 (PARP-1) is a constitutive enzyme, the major isoform of the PARP family, which is involved in the regulation of DNA repair, cell death, metabolism, and inflammatory responses. Pharmacological inhibitors of PARP provide significant therapeutic benefits in various preclinical disease models associated with tissue injury and inflammation. However, our understanding the role of PARP activation in the pathophysiology of liver inflammation and fibrosis is limited. In this study we investigated the role of PARP-1 in liver inflammation and fibrosis using acute and chronic models of carbon tetrachloride (CCl4 )-induced liver injury and fibrosis, a model of bile duct ligation (BDL)-induced hepatic fibrosis in vivo, and isolated liver-derived cells ex vivo. Pharmacological inhibition of PARP with structurally distinct inhibitors or genetic deletion of PARP-1 markedly attenuated CCl4 -induced hepatocyte death, inflammation, and fibrosis. Interestingly, the chronic CCl4 -induced liver injury was also characterized by mitochondrial dysfunction and dysregulation of numerous genes involved in metabolism. Most of these pathological changes were attenuated by PARP inhibitors. PARP inhibition not only prevented CCl4 -induced chronic liver inflammation and fibrosis, but was also able to reverse these pathological processes. PARP inhibitors also attenuated the development of BDL-induced hepatic fibrosis in mice. In liver biopsies of subjects with alcoholic or hepatitis B-induced cirrhosis, increased nitrative stress and PARP activation was noted. CONCLUSION: The reactive oxygen/nitrogen species-PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism, and fibrosis. PARP inhibitors are currently in clinical trials for oncological indications, and the current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential.