State capacity and military conflict

In 1500, Europe was composed of hundreds of statelets and principalities, with weak central authority,no monopoly over the legitimate use of violence, and overlapping jurisdictions. By 1800, only ahandful of powerful, centralized nation states remained. We build a model that explains both the emergenceof capable states and growing divergence between European powers. We argue that the impactof war was crucial for state building, and depended on: i) the financial cost of war, and ii) a country sinitial level of domestic political fragmentation. We emphasize the role of the "Military Revolution",which raised the cost of war. Initially, this caused more cohesive states to invest in state capacity, whilemore divided states rationally dropped out of the competition, causing divergence between Europeanstates. As the cost of war escalated further, all states engaged in a "race to the top" towards greater statebuilding.

Development and evaluation of antibody-MHC/peptide conjugates as a new form of cancer immunotherapy

Summary One of the major goals of cancer immunotherapy is the induction of a specific and effective antitumor cytotoxic T lymphocyte (CTL) response. However, the downregulation of Class I Major Histocompatibility Complexes (MHC) expression and the low level of tumor peptide presentation on tumor cell surface, ás well as the low immunogenicity of tumor specific antigens, limit the effectiveness of anti-tumor CTL responses. On the other hand, monoclonal antibodies, which bind with high affinity to tumor cell surface markers, are powerful tumor targeting tools. However, their capacity to .kill cancer cells is limited and mAb cancer treatments usually require the addition of different form of chemotherapy. The new cancer immunotherapy strategy described herein combines the advantage of the high tumor targeting capacity of monoclonal antibodies (mAb) with the powerful cytotoxicity of CD8 T lymphocytes directed against highly antigenic peptide-MHC complexes. Monoclonal antibody Fab fragments directed against a cell surface tumor associated antigen (TAA) are chemically coupled to soluble MHC class I complexes carrying a highly antigenic peptide. Antibody guided targeting and oligomerization of numerous antigenic class IMHC/peptide complexes on tumor cell surfaces can redirect the cytotoxicity of peptide-specific CD8 T cells towards target cancer cells. After the description of the production of murine anti-tumor xMHC/peptide conjugates in the first part of this thesis, the therapeutic potential of such conjugates were sequentially investigated in different syngeneic tumor mouse models. As a first proof of principle, transgenic OT-1 mice and later CEA transgenic C57BL/6 (B6) mice, adoptively transferred with OT-1 spleen cells and immunized with ovalbumin, were used as a model of high frequency of ova peptide specific T cells. In these mice, growth inhibition and regression of palpable colon carcinoma expressing CEA, were obtained by systemic injection of anti-CEA Fab/H-2Kb/ova peptide conjugates. Next, LCMV virus and influenza virus infection of B6 mice were used as viral models to redirect natural antiviral CTL responses to tumors via conjugates loaded with viral peptides. We showed that in mice infected with the LCMV virus, subcutaneous CEA-expressing tumor cells were inhibited by the H2Db/GP33 restricted anti-viral CTL response when preincubated before grafting with anti-CEA Fab-H-2Db/GP33 peptide conjugates. In mice infected with the influenza virus, lung metastases expressing the HER2 antigen were inhibited by the H-2Db/NP366 restricted CTLs response when preincubated before injection with anti-Her2 Fab-H-2Db/NP366 peptide conjugates. In the last chapter, the stability of the peptide in the anti-CEA Fab-H-2Db/GP33 conjugates was improved by the covalent photocross-link of the GP33 peptide in the H-2Db MHC groove. Thus, LCMV immune mice could reject CEA expressing tumors when treated with systemic injections of anti-CEA FabH-2Db/GP33 cross-linked conjugates. These results are encouraging for the potential application of this strategy in clinic. Such conjugates could be used alone in patients boosted by the relevant virus, or used in combination with existing T cell based ìmmunotherapy. Résumé Une des principales approches utilisées dans l'immunothérapie contre le cancer consiste en l'induction d'une réponse T cytotoxique (CTL) spécifiquement dirigée contre la tumeur. Cependant, le faible niveau d'expression des complexes majeurs d'histocompatibilité de classe I (CMH I) et de présentation des peptides tumoraux à la surface des cellules cancéreuses ainsi que la faible immunogenicité des antigens tumoraux, limitent l'efficacité de la réponse CTL. D'autre part,. l'injection d'anticorps monoclonaux (mAb), se liant avec une haute affinité aux marqueurs de surface des cellules tumorales, a fourni des résultats cliniques encourageant. Cependant l'efficacité de ces mAbs contre des tumeur solides reste limitée et necessite souvent l'addition de chimiotherapie. La nouvelle stratégie thérapeutique décrite dans ce travail associe le fort pouvoir de localisation des anticorps monoclonaux et le fort pouvoir cytotoxique des lymphocytes T CD8+. Des fragments Fab d'anticorps monoclonaux, dirigés contre des antigènes surexprimés à la surface de cellules tumorales, ont été chimiquement couplés à des CMH I solubles, portant un peptide fortement antigénique. Le ciblage et l'oligomérisation à la surface des cellules tumorales de nombreux CMH I présentant un peptide antigénique, va réorienter la cytotoxicité des cellules T CD8+ spécifiques du peptide présenté, vers les cellules tumorales cibles. Après une description de la production de conjugé anti-tumeur x CMH Upeptide dans la première partie de cette thèse, le potentiel thérapeutique de tels conjugés a été successivement étudiés in vivo dans différents modèles de tumeur syngénéiques. Tout d'abord, des souris OT-1 transgéniques, puis des souris C57BL/6 (B6) transférées avec des cellules de rate OT-1 puis immunisées avec l'ovalbumine, ont été employées comme modèle de haute fréquence de cellules T CD8+ spécifiques du peptide ova. Chez ces souris, l'inhibition de la croissance et la régression de nodules palpables de carcinomes exprimant l'antigène caccino embryonaire (ACE), ont été obtenues par l'injection systémique de conjugés anti-ACE Fab/H-2Kb/ova. Par la suite, l'infection de souris B6 par le virus LCMV et par le virus de la grippe, ont été utilisés comme modèles viraux pour redirigées des réponses anti-virales naturelles vers les tumeurs, en utilisant des conjugés chargés avec des peptides viraux. Nous avons montré que .chez les souris infectées par le LCMV, la croissance de carcinome sous-cutané est empêchée par la réponse anti-virale, spécifique du complexe H2Db/GP33, lorsque les cellules tumorales greffées sont pré-incubées avec des conjugés anti-CEA Fab-H-2Db/GP33. Dans le cas de souris infectées par le virus de la grippe, la métastatisation de mélanomes pulmonaires exprimant l'antigène HER-2 est inhibée par la réponse anti-virale spécifique du complexe H-2Db/NP366, après pré-incubation des cellules tumorales avec des conjugés anti-Her2 FabxH-2Db/NP366. Dans le dernier chapitre, la liaison covalente du peptide GP33 dans le complexe H-2Db a amélioré la stabilité des conjugés correspondants et a permis le traitement systémique de souris greffées avec des tumeurs exprimant l'ACE et infectées par le LCMV. L'ensemble de ces résultats sont encourageant pour l'application de cette strategie en clinique. De tels conjugués pourraient être employés seuls ou en combinaison avec des protocols d'immunisation peptidique anti-tumoral. Résumé pour un large public Dans les pays industrialisés, le cancer se situe au deuxième rang des causes de mortalité après les maladies cardiovasculaires. Les principaux traitement de nombreux cancers sont la chirurgie, en association avec la radiothérapie et la chimiothérapie. L'immunothérapie est l'une des nouvelles approches mises en oeuvre pour la lutte contre le cancer. Elle peut être humorale, et s'appuyer alors sur la perfusion d'anticorps monoclonaux dirigés contre des antigènes tumoraux, par exemple les anticorps dirigés contre les protéines oncogéniques Her-2/neu dans le cancer du sein. Ces anticorps ont le grand avantage de spécifiquement se localiser à la tumeur et d'induire la lyse ou d'inhiber la proliferation des cellules tumorales exprimant l'antigène. Certains sont utilisés en clinique pour le traitement de lymphomes, de carcinomes de l'ovaire et du sein ou encore de carcinomes metastatiques du côlon. Cependant l'efficacité de ces anticorps contre des tumeurs solides reste limitée et les traitements exigent souvent d'être combiner avec de la chimiothérapie. L'immunothérapie spécifique peut également être cellulaire et reposer sur une démarche de type vaccinal, consistant à générer des lymphocytes T cytotoxiques (cytotoxic T lymphocytes :CTL) capables de détruire spécifiquement les cellules malignes. Pour obtenir une réponse lymphocytaire T cytotoxique antitumorale, la cellule T doit reconnaître un antigène associé à la tumeur, présenté sous forme de peptide dans un complexe majeur d'histocompatibilité de classe I. Or les cellules tumorales ne presentent pas efficacement les peptides antigèniques, car elles se caractérisent par une diminution ou une absence d'expression des antigènes d'histocompatibilité de classe I, des molécules d'adhésion et des cytokines costimulatrices, et par une faible expression des antigènes associés aux tumeurs. C'est en partie pourquoi, malgré l'induction de fortes réponses CTL specifiquement dirigés contre des antigens tumoraux, les régressions tumorales obtenus grace à ces vaccinations sont relativement rares. Alors que chez les personnes atteintes du cancer on observe l'instauration d'une tolérance immunitaire vis-à-vis de la tumeur, à l'inverse, notre systeme immunitaire reste parfaitement capable de combattre des infection virales classiques, tels que la grippe, qui font aussi appel à une réponse T cytotoxique. Notre groupe de recherche a donc eu l'idee de développer une nouvelle approche thérapeutique où une réponse immunitaire anti-virale très efficace serait redirigée vers les tumeurs par des anticorps monoclonaux. Concrètement, nous avons chimiquement couplés des fragments d'anticorps monoclonaux dirigés contre des antigènes surexprimés à la surface de cellules tumorales, à des CMH I portant un peptide viral antigénique. Les cellules tumorales, ciblées par le fragment anticorps et couvertes d' antigènes viraux présentés par des molécules de CMH I, peuvent ainsi tromper les lymphocytes cytotoxiques anti-viraux qui vont détruire les cellules tumorales comme si elles étaient infectées par le virus. Suite à des résultats prometteurs obtenus in vitro avec différents conjugués anticorps-CMH humain de type HLA.A2/peptide Flu, le but du projet était de tester in vivo des conjugués anticorps-CMH I murins sur des modèles expérimentaux de souris. Tout d'abord, des souris transgéniques pour un recepteur T specifique du peptide ova, puis des transferts adoptifs de ces cellules T specifiques dans des souris immunocompétentes, ont été choisi comme modèle de haute fréquence des cellules T spécifiques, et ont permi de valider le principe de la strategie in vivo. Puis, deux modèles viraux ont été elaboré avec le virus LCMV et le virus Influenza, pour réorienter des réponses antivirales naturelles vers les tumeurs grâce à des conjugés chargés avec des peptides viraux. Nous avons montré la grande capacité de nos conjugués à rediriger des réponses cytotoxiques vers les tumeurs et inhiber la croissance de tumeurs syngénéiques sous cutanés et pulmonaires. Ces résultats d'inhibition tumorales obtenus dans des souris immunocompétentes, grâce à l'injection de conjugués anticorps xCMH/peptide et réorientant deux réponses antivirales différentes vers deux modèles tumoraux syngeneiques, sont encourageant pour l'application de cette nouvelle stratégie en clinique.

Improving Transition Outcomes: Capacity Building Forum: Dissemination of Promising Transition Practices

Information on the Promising Transition Practices shared at the September 28, 2007 Capacity Building Forum sponsored by Improving Transition Outcomes with Iowa Vocational Rehabilitation Services.

On equilibria in duopolies with finite strategy spaces

We will call a game a reachable (pure strategy) equilibria game if startingfrom any strategy by any player, by a sequence of best-response moves weare able to reach a (pure strategy) equilibrium. We give a characterizationof all finite strategy space duopolies with reachable equilibria. Wedescribe some applications of the sufficient conditions of the characterization.

Disability, capacity for work and the business cycle: An international perspective

An important policy issue in recent years concerns the number of people claimingdisability benefits for reasons of incapacity for work. We distinguish between workdisability , which may have its roots in economic and social circumstances, and healthdisability which arises from clear diagnosed medical conditions. Although there is a linkbetween work and health disability, economic conditions, and in particular the businesscycle and variations in the risk of unemployment over time and across localities, mayplay an important part in explaining both the stock of disability benefit claimants andinflows to and outflow from that stock. We employ a variety of cross?country andcountry?specific household panel data sets, as well as administrative data, to testwhether disability benefit claims rise when unemployment is higher, and also toinvestigate the impact of unemployment rates on flows on and off the benefit rolls. Wefind strong evidence that local variations in unemployment have an importantexplanatory role for disability benefit receipt, with higher total enrolments, loweroutflows from rolls and, often, higher inflows into disability rolls in regions and periodsof above?average unemployment. Although general subjective measures of selfreporteddisability and longstanding illness are also positively associated withunemployment rates, inclusion of self?reported health measures does not eliminate thestatistical relationship between unemployment rates and disability benefit receipt;indeed including general measures of health often strengthens that underlyingrelationship. Intriguingly, we also find some evidence from the United Kingdom and theUnited States that the prevalence of self?reported objective specific indicators ofdisability are often pro?cyclical that is, the incidence of specific forms of disability arepro?cyclical whereas claims for disability benefits given specific health conditions arecounter?cyclical. Overall, the analysis suggests that, for a range of countries and datasets, levels of claims for disability benefits are not simply related to changes in theincidence of health disability in the population and are strongly influenced by prevailingeconomic conditions. We discuss the policy implications of these various findings.

Drivers and sources of supply flexibility: An exploratory study

Purpose - There has been much research on manufacturing flexibility, but supply chain flexibility is still an under-investigated area. This paper focuses on supply flexibility, the aspects of flexibility related to the upstream supply chain. Our purpose is to investigate why and how firms increase supply flexibility.Methodology/Approach An exploratory multiple case study was conducted. We analyzed seven Spanish manufacturers from different sectors (automotive, apparel, electronics and electrical equipment).Findings - The results show that there are some major reasons why firms need supply flexibility (manufacturing schedule fluctuations, JIT purchasing, manufacturing slack capacity, low level of parts commonality, demand volatility, demand seasonality and forecast accuracy), and that companies increase this type of flexibility by implementing two main strategies: to increase suppliers responsiveness capability and flexible sourcing . The results also suggest that the supply flexibility strategy selected depends on two factors: the supplier searching and switching costs and the type of uncertainty (mix, volume or delivery).Research limitations - This paper has some limitations common to all case studies, such as the subjectivity of the analysis, and the questionable generalizability of results (since the sample of firms is not statistically significant).Implications - Our study contributes to the existing literature by empirically investigating which are the main reasons for companies needing to increase supply flexibility, how they increase this flexibility, and suggesting some factors that could influence the selection of a particular supply flexibility strategy.

Strategy communication and measurement systems

Organizations often face the challenge of communicating their strategiesto local decision makers. The difficulty presents itself in finding away to measure performance wich meaningfully conveys how to implement theorganization's strategy at local levels. I show that organizations solvethis communication problem by combining performance measures in such away that performance gains come closest to mimicking value-added asdefined by the organization's strategy. I further show how organizationsrebalance performance measures in response to changes in their strategies.Applications to the design of performance metrics, gaming, and divisionalperformance evaluation are considered. The paper also suggests severalempirical ways to evaluate the practical importance of the communicationrole of measurement systems.

Trichogramma acacioi (Hymenoptera, Trichogrammatidae) parasitism capacity at different temperatures and factitious hosts

It was studied the parasitism capacity of Trichogramma acacioi on Anagasta kuehniella and Sitotroga cerealella eggs at different temperatures (15, 20, 25, 30 and 35 ± 1°C). The parasitism of T. acacioi varied with temperature and host. The highest parasitism (³80%) were observed during the first days after emergence in both hosts, at all tested temperatures. The accumulated parasitism varied with both host and temperature, being higher on A. kuehniella at 20°C, what shows good parasitoid species adaptation to this temperature. Thus, we conclude that the best host and best temperature to be used at mass-rearing of T. acacioi is A. kuehniella and 20ºC, respectively. Moreover, this Trichogramma species has great potential to be used in field releases at regions where average temperature is around 20ºC.

Monitoring of NY-ESO-1 specific CD4+ T cells using molecularly defined MHC class II/His-tag-peptide tetramers.

MHC-peptide tetramers have become essential tools for T-cell analysis, but few MHC class II tetramers incorporating peptides from human tumor and self-antigens have been developed. Among limiting factors are the high polymorphism of class II molecules and the low binding capacity of the peptides. Here, we report the generation of molecularly defined tetramers using His-tagged peptides and isolation of folded MHC/peptide monomers by affinity purification. Using this strategy we generated tetramers of DR52b (DRB3*0202), an allele expressed by approximately half of Caucasians, incorporating an epitope from the tumor antigen NY-ESO-1. Molecularly defined tetramers avidly and stably bound to specific CD4(+) T cells with negligible background on nonspecific cells. Using molecularly defined DR52b/NY-ESO-1 tetramers, we could demonstrate that in DR52b(+) cancer patients immunized with a recombinant NY-ESO-1 vaccine, vaccine-induced tetramer-positive cells represent ex vivo in average 1:5,000 circulating CD4(+) T cells, include central and transitional memory polyfunctional populations, and do not include CD4(+)CD25(+)CD127(-) regulatory T cells. This approach may significantly accelerate the development of reliable MHC class II tetramers to monitor immune responses to tumor and self-antigens.

Iowa’s Drug Control Strategy, November 1, 2007

The attached annual report is submitted in satisfaction of Chapter 80E.1 of the Code of Iowa which directs the Drug Policy Coordinator to monitor and coordinate all drug prevention, enforcement and treatment activities in the state. Further, it requires the Coordinator to submit an annual report to the Governor and Legislature concerning the activities and programs of the Coordinator, the Governor’s Office of Drug Control Policy and all other state departments with drug enforcement, substance abuse treatment, and prevention programs. Chapter 80E.2 establishes the Drug Policy Advisory Council (DPAC), chaired by the Coordinator, and consisting of a prosecuting attorney, substance abuse treatment specialists, law enforcement officers, a prevention specialist, a judge and representatives from the departments of corrections, education, public health, human services, public safety and human rights. This report and strategy were in developed in consultation with the DPAC.

Biological characteristics and parasitism capacity of Trichogramma pretiosum Riley (Hymenoptera, Trichogrammatidae) on eggs of Spodoptera frugiperda (J. E. Smith) (Lepidoptera, Noctuidae)

This study aimed at evaluating the biological characteristics and the capacity of parasitism of a Trichogramma pretiosum Riley, 1869 (Hymenoptera, Trichogrammatidae) strain (T. pretiosum RV) collected in Rio Verde County, State of Goiás, Brazil. The study was carried out on eggs of Spodoptera frugiperda (J. E. Smith, 1797) (Lepidoptera, Noctuidae) and conducted under controlled environmental conditions at different constant temperatures. The biological parameters determined were: developmental time (egg-adult; days); emergence (%); sex ratio; number of progeny/egg; number of generation/year; thermal constant (K); temperature threshold (Tb); daily number of parasitized eggs; cumulative parasitism (%); total number of eggs parasitized by T. pretiosum; and female longevity. To study the T. pretiosum parasitism capacity, 20 S. frugiperda eggs (< 24 h old) were placed into 8.0 cm x 2.0 cm glass vials containing one female (< 24 h old) each. Trials were carried out in a completely randomized experimental design, with 20 replications at each temperature. The environmental chambers (BOD type) were set at 18ºC, 20ºC, 22ºC, 25ºC, 28ºC and 32ºC ± 1ºC, 70 ±10% relative humidity, and 14/10 h (L:D) photoperiod. The eggs of S. frugiperda were replaced daily until parasitoid death. Results have shown an inverse correlation between developmental time and temperature, with statistically significant differences among means, except at 25ºC and 28ºC (10 days). Parasitoid emergence (%) was also influenced by temperature. The lowest percent emergence was observed at 32ºC, and the highest ones at 18ºC and 20ºC temperatures. The temperature did not affect T. pretiosum sex ratio and number of parasitoids per egg, thus allowing changes in the temperature to control insect mass production in the laboratory to meet the needs for field releases.

Soil and Water Conservation Strategies in Cape Verde (Cabo Verde in Portuguese) and Their Impacts on Livelihoods - An Overview from the Ribeira Seca Watershed

Severe land degradation has strongly affected both people’s livelihood and the environment in Cape Verde (Cabo Verde in Portuguese), a natural resource poor country. Despite the enormous investment in soil and water conservation measures (SWC or SLM), which are visible throughout the landscape, and the recognition of their benefits, their biophysical and socioeconomic impacts have been poorly assessed and scientifically documented. This paper contributes to filling this gap, by bringing together insights from literature and policy review, field survey and participatory assessment in the Ribeira Seca Watershed through a concerted approach devised by the DESIRE project (the “Desire approach”). Specifically, we analyze government strategies towards building resilience against the harsh conditions, analyze the state of land degradation and its drivers, survey and map the existing SWC measures, and assess their effectiveness against land degradation, on crop yield and people’s livelihood. We infer that the relative success of Cape Verde in tackling desertification and rural poverty owes to an integrated governance strategy that comprises raising awareness, institutional framework development, financial resource allocation, capacity building, and active participation of rural communities. We recommend that specific, scientific-based monitoring and assessment studies be carried out on the biophysical and socioeconomic impact of SLM and that the “Desire approach” be scaled-up to other watersheds in the country.

Building adaptive capacity and resilience to climate change in the water sector in Cape Verde

Purpose of the evaluation This is a scheduled standard mid-term evaluation (MTR) of a UNDP implemented GEF LDCF co-financed project. It is conducted by a team of an international and a national independent evaluator. The objective of the MTR, as set out in the Terms of Reference (TORs; Annex 1), is to provide an independent analysis of the progress of the project so far. The MTR aims to:  identify potential project design problems,  assess progress towards the achievement of the project objective and outcomes,  identify and document lessons learned (including lessons that might improve design and implementation of other projects, including UNDP-GEF supported projects), and  make recommendations regarding specific actions that should be taken to improve the project. The MTR is intended to assess signs of project success or failure and identify the necessary changes to be made. The project commenced its implementation in the first half of 2010 with the recruitment of project staff. According to the updated project plan, it is due to close in July 201410 with operations scaling down in December 2013 due to funding limits. Because of a slow implementation start, the mid-term evaluation was delayed to July 201311 The intended target audience of the evaluation are:  The project team and decision makers in the INGRH  The GEF and UNFCCC Operational Focal Points  The project partners and beneficiaries  UNDP in Cape Verde as well as the regional and headquarter (HQ) office levels  The GEF Secretariat.