Autoreactive T cells bypass negative selection and respond to self-antigen stimulation during infection.

Central and peripheral tolerance prevent autoimmunity by deleting the most aggressive CD8(+) T cells but they spare cells that react weakly to tissue-restricted antigen (TRA). To reveal the functional characteristics of these spared cells, we generated a transgenic mouse expressing the TCR of a TRA-specific T cell that had escaped negative selection. Interestingly, the isolated TCR matches the affinity/avidity threshold for negatively selecting T cells, and when developing transgenic cells are exposed to their TRA in the thymus, only a fraction of them are eliminated but significant numbers enter the periphery. In contrast to high avidity cells, low avidity T cells persist in the antigen-positive periphery with no signs of anergy, unresponsiveness, or prior activation. Upon activation during an infection they cause autoimmunity and form memory cells. Unexpectedly, peptide ligands that are weaker in stimulating the transgenic T cells than the thymic threshold ligand also induce profound activation in the periphery. Thus, the peripheral T cell activation threshold during an infection is below that of negative selection for TRA. These results demonstrate the existence of a level of self-reactivity to TRA to which the thymus confers no protection and illustrate that organ damage can occur without genetic predisposition to autoimmunity.

Elder Abuse Task Force Report Pursuant to HF 2387: An Act Relating to Improvements to and Implementation of Laws Concerning Elder Abuse

During its 2012 session, Iowa’s 84th General Assembly passed House File 2387. The bill was signed into law by Governor Branstad and mandated a review of occurrences of and laws relating to abuse, neglect, or exploitation of individuals who are sixty years of age or older. After conducting the review, the twenty-three member Elder Abuse Task Force presents the following recommendations. These recommendations build upon current Iowa law and practice for the purpose of protecting older Iowans from abuse, neglect, and exploitation.

RTS,S/AS02A malaria vaccine does not induce parasite CSP T cell epitope selection and reduces multiplicity of infection

Objective: The candidate malaria vaccine RTS,S/AS02A is a recombinant protein containing part of the circumsporozoite protein (CSP) sequence of Plasmodium falciparum, linked to the hepatitis B surface antigen and formulated in the proprietary adjuvant system AS02A. In a recent trial conducted in children younger than age five in southern Mozambique, the vaccinedemonstrated significant and sustained efficacy against both infection and clinical disease. In a follow-up study to the main trial, breakthrough infections identified in the trial were examined to determine whether the distribution of csp sequences was affected by the vaccine and to measure the multiplicity of infecting parasite genotypes. Design: P. falciparum DNA from isolates collected during the trial was used for genotype studies. Setting: The main trial was carried out in the Manhiça district, Maputo province, Mozambique, between April 2003 and May 2004. Participants: Children from the two cohorts of the main trial provided parasite isolates as follows: children from Cohort 1 who were admitted to hospital with clinical malaria; children from Cohort 1 who were parasite-positive in a cross-sectional survey at study month 8.5; children from Cohort 2 identified as parasite-positive during follow-up by active detection of infection. Outcome: Divergence of DNA sequence encoding the CSP T cell-epitope region sequence from that of the vaccine sequence was measured in 521 isolates. The number of distinct P. falciparum genotypes was also determined. Results: We found no evidence that parasite genotypes from children in the RTS,S/AS02A arm were more divergent than those receiving control vaccines. For Cohort 1 (survey at studymonth 8.5) and Cohort 2, infections in the vaccine group contained significantly fewer genotypes than those in the control group, (p 1/4 0.035, p 1/4 0.006), respectively, for the two cohorts. This was not the case for children in Cohort 1 who were admitted to hospital (p 1/4 0.478). Conclusions: RTS,S/AS02A did not select for genotypes encoding divergent T cell epitopes in the C-terminal region of CSP in this trial. In both cohorts, there was a modest reduction in the mean number of parasite genotypes harboured by vaccinated children compared with controls, but only among those with asymptomatic infections.

Supporting interdisciplinary case studies: development and implementation of a joint learning environment for students in forensic science and criminal law

Scientific reporting and communication is a challenging topic for which traditional study programs do not offer structured learning activities on a regular basis. This paper reports on the development and implementation of a web application and associated learning activities that intend to raise the awareness of reporting and communication issues among students in forensic science and law. The project covers interdisciplinary case studies based on a library of written reports about forensic examinations. Special features of the web framework, in particular a report annotation tool, support the design of various individual and group learning activities that focus on the development of knowledge and competence in dealing with reporting and communication challenges in the students' future areas of professional activity.

Group selection and kin selection: two concepts but one process.

In a recent paper, Traulsen and Nowak use a multilevel selection model to show that cooperation can be favored by group selection in finite populations [Traulsen A, Nowak M (2006) Proc Natl Acad Sci USA 103:10952-10955]. The authors challenge the view that kin selection may be an appropriate interpretation of their results and state that group selection is a distinctive process "that permeates evolutionary processes from the emergence of the first cells to eusociality and the economics of nations." In this paper, we start by addressing Traulsen and Nowak's challenge and demonstrate that all their results can be obtained by an application of kin selection theory. We then extend Traulsen and Nowak's model to life history conditions that have been previously studied. This allows us to highlight the differences and similarities between Traulsen and Nowak's model and typical kin selection models and also to broaden the scope of their results. Our retrospective analyses of Traulsen and Nowak's model illustrate that it is possible to convert group selection models to kin selection models without disturbing the mathematics describing the net effect of selection on cooperation.

Development and Implementation of an Expert System for Forecasting Fog on US Highway 30 in Cedar Rapids, Iowa, HR-357, 1996

Several accidents, some involving fatalities, have occurred on U.S. Highway 30 near the Archer Daniels Midland Company (ADM) Corn Sweeteners plant in Cedar Rapids, Iowa. A contributing factor to many of these accidents has been the large amounts of water (vapor and liquid) emitted from multiple sources at ADM's facility located along the south side of the highway. Weather and road closure data acquired from IDOT have been used to develop a database of meteorological conditions preceding and accompanying closure of Highway 30 in Cedar Rapids. An expert system and a FORTRAN program were developed as aids in decision making with regard to closure of Highway 30 near the plant. The computer programs were used for testing, evaluation, and final deployment. Reports indicate the decision tools have been successfully implemented and were judged to be helpful in forecasting road closures and in reducing costs and personnel time in monitoring the roadway.

Opportunity for sexual selection and effective population size in the lek-breeding European treefrog (Hyla arborea).

Sexual selection in lek-breeding species might drastically lower male effective population size, with potentially important consequences for evolutionary and conservation biology. Using field-monitoring and parental-assignment methods, we analyzed sex-specific variances in breeding success in a population of European treefrogs, to (1) help understanding the dynamics of genetic variance at sex-specific loci, and (2) better quantify the risk posed by genetic drift in this species locally endangered by habitat fragmentation. The variance in male mating success turned out to be markedly lower than values obtained from other amphibian species with polygamous mating systems. The ratio of effective breeding size to census breeding size was only slightly lower in males (0.44) than in females (0.57), in line with the patterns of genetic diversity previously reported from H. arborea sex chromosomes. Combining our results with data on age at maturity and adult survival, we show that the negative effect of the mating system is furthermore compensated by the effect of delayed maturity, so that the estimated instantaneous effective size broadly corresponded to census breeding size. We conclude that the lek-breeding system of treefrogs impacts only weakly the patterns of genetic diversity on sex-linked genes and the ability of natural populations to resist genetic drift.

Heterogeneity, selection and labor market disparities

We study the incentives to acquire skill in a model where heterogeneous firmsand workers interact in a labor market characterized by matching frictions and costlyscreening. When effort in acquiring skill raises both the mean and the variance of theresulting ability distribution, multiple equilibria may arise. In the high-effort equilibrium, heterogeneity in ability is sufficiently large to induce firms to select the bestworkers, thereby confirming the belief that effort is important for finding good jobs.In the low-effort equilibrium, ability is not sufficiently dispersed to justify screening,thereby confirming the belief that effort is not so important. The model has implications for wage inequality, the distribution of firm characteristics, sorting patternsbetween firms and workers, and unemployment rates that can help explaining observedcross-country variation in socio-economic and labor market outcomes.

Growth, selection and appropriate contracts

We study a dynamic model where growth requires both long-term investmentand the selection of talented managers. When ability is not ex-ante observable and contracts are incomplete, managerial selection imposes a cost, as managers facing the risk ofbeing replaced choose a sub-optimally low level of long-term investment. This generates atrade-off between selection and investment that has implications for the choice of contractualrelationships and institutions. Our analysis shows that rigid long-term contracts sacrificingmanagerial selection may prevail at early stages of economic development and when heterogeneity in ability is low. As the economy grows, however, knowledge accumulation increasesthe return to talent and makes it optimal to adopt flexible contractual relationships, wheremanagerial selection is implemented even at the cost of lower investment. Measures of investor protection aimed at limiting the bargaining power of managers improve selection undershort-term contract. Given that knowledge accumulation raises the value of selection, theoptimal level of investor protection increases with development.

Review of Automated Vehicle Technology: Policy and Implementation Implications; Version 1.0; RB28-015, 2016

This report provides recommendations for the state of Iowa over the next five years in regards to automated vehicle policy development. These administrative, planning, legal, and community strategy recommendations for government agencies include: • Encouraging automation by preparing government agencies, infrastructure, leveraging procurement, and advocating for safety mandates • Adjusting long range planning processes by identifying and incorporating a wide range of new automation scenarios • Beginning to analyze and, as necessary, clarify existing law as it apples to automated driving • Auditing existing law • Enforcing existing laws • Ensuring vehicle owners and operators bear the true cost of driving • Embracing flexibility by giving agencies the statutory authority to achieve regulatory goals through different means, allowing them to make small-scale exemptions to statutory regimes and clarifying their enforcement discretion • Thinking locally and preparing publicly • Sharing the steps being taken to promote (as well as to anticipate and regulate) automated driving • Instituting public education about automated vehicle technologies.

Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation

Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints. Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1. These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show lower population differentiation, while genes involved in traits related to the environment should show higher variability. Taken together, this work broadens our knowledge on how events of population differentiation and of positive selection are distributed among different parts of a metabolic pathway.

FOSS License Selection and Code Management

With nearly 2,000 free and open source software (FLOSS) licenses, software license proliferation¿ can be a major headache for software development organizations trying to speed development through software component reuse, as well as companies redistributing software packages as components of their products. Scope is one problem: from the Free Beer license to the GPL family of licenses to platform-specific licenses such as Apache and Eclipse, the number and variety of licenses make it difficult for companies to ¿do the right thing¿ with respect to the software components in their products and applications. In addition to the sheer number of licenses, each license carries within it the author¿s specific definition of how the software can be used and re-used. Permissive licenses like BSD and MIT make it easy; software can be redistributed and developers can modify code without the requirement of making changes publicly available. Reciprocal licenses, on the other hand, place varying restrictions on re-use and redistribution. Woe to the developer who snags a bit of code after a simple web search without understanding the ramifications of license restrictions.

La dépression majeure en hôpital général: adaptation et mise en oeuvre de recommandations pour la pratique clinique [Major depression in the general hospital: adaptation and implementation of guidelines]

Major depression IMD) is highly prevalent in the general hospital and adds a considerable burden to affected patients, but remains under detected and under treated. In an attempt to improve this situation, existing guidelines on MD were retrieved, systematically evaluated with the instrument AGREE (Appraisal of guidelines for research and evaluation), and adapted to the needs of the general hospital. These guidelines were made available on intranet, and actively implemented in two wards, where their impact on clinical practice was evaluated.