The co-evolution of social institutions, demography, and large-scale human cooperation.

Human cooperation is typically coordinated by institutions, which determine the outcome structure of the social interactions individuals engage in. Explaining the Neolithic transition from small- to large-scale societies involves understanding how these institutions co-evolve with demography. We study this using a demographically explicit model of institution formation in a patch-structured population. Each patch supports both social and asocial niches. Social individuals create an institution, at a cost to themselves, by negotiating how much of the costly public good provided by cooperators is invested into sanctioning defectors. The remainder of their public good is invested in technology that increases carrying capacity, such as irrigation systems. We show that social individuals can invade a population of asocials, and form institutions that support high levels of cooperation. We then demonstrate conditions where the co-evolution of cooperation, institutions, and demographic carrying capacity creates a transition from small- to large-scale social groups.

Extrafollicular plasmablast B cells play a key role in carrying retroviral infection to peripheral organs.

B cells can either differentiate in germinal centers or in extrafollicular compartments of secondary lymphoid organs. Here we show the migration properties of B cells after differentiation in murine peripheral lymph node infected with mouse mammary tumor virus. Naive B cells become activated, infected, and carry integrated retroviral DNA sequences. After production of a retroviral superantigen, the infected B cells receive cognate T cell help and differentiate along the two main differentiation pathways analogous to classical Ag responses. The extrafollicular differentiation peaks on day 6 of mouse mammary tumor virus infection, and the follicular one becomes detectable after day 10. B cells participating in this immune response carry a retroviral DNA marker that can be detected by using semiquantitative PCR. We determined the migration patterns of B cells having taken part in the T cell-B cell interaction from the draining lymph node to different tissues. Waves of immigration and retention of infected cells in secondary lymphoid organs, mammary gland, salivary gland, skin, lung, and liver were observed correlating with the two peaks of B cell differentiation in the draining lymph node. Other organs revealed immigration of infected cells at later time points. The migration properties were correlated with a strong up-regulation of alpha(4)beta(1) integrin expression. These results show the migration properties of B cells during an immune response and demonstrate that a large proportion of extrafolliculary differentiating plasmablasts can escape local cell death and carry the retroviral infection to peripheral organs.

Violent adolescents and their educational environment: a multilevel analysis.

OBJECTIVE: This study examined the respective roles of personal and environmental factors in youth violence in a nationally representative sample of 7548 postmandatory school students and apprentices ages 16-20 years in Switzerland. METHODS: Youth violence was defined as having committed at least one of the following in the previous 12 months: attacking an adult, snatching something, carrying a weapon, or using a weapon in a fight. Different ecological levels were tested, resulting in a three-level model only in males (individual, classroom, and school) as the low prevalence of female violence did not allow for a multilevel analysis. Dependent variables were attributed to each level. For males, the classroom level (10%) and the school level (24%) accounted for more than one third in interindividual variance. RESULTS: Factors associated with violence perpetration in females were being a victim of physical violence and sensation seeking at the individual level. In males, practicing unsafe sex, sensation seeking, being a victim of physical violence, having a poor relationship with parents, being depressed, and living in a single-parent household at the individual level; violence and antisocial acts at the classroom level; and being in a vocational school at the school level showed a correlation with violence perpetration. CONCLUSION: Interventions at the classroom level as well as an explicit school policy on violence and other risk behaviors should be considered a priority when dealing with the problem of youth violence. Furthermore, prevention should take into account gender differences.

Diet and gene interactions influence the skeletal response to polyunsaturated fatty acids.

Diets rich in omega-3s have been thought to prevent both obesity and osteoporosis. However, conflicting findings are reported, probably as a result of gene by nutritional interactions. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear receptor that improves insulin sensitivity but causes weight gain and bone loss. Fish oil is a natural agonist for PPARγ and thus may exert its actions through the PPARγ pathway. We examined the role of PPARγ in body composition changes induced by a fish or safflower oil diet using two strains of C57BL/6J (B6); i.e. B6.C3H-6T (6T) congenic mice created by backcrossing a small locus on Chr 6 from C3H carrying 'gain of function' polymorphisms in the Pparγ gene onto a B6 background, and C57BL/6J mice. After 9months of feeding both diets to female mice, body weight, percent fat and leptin levels were less in mice fed the fish oil vs those fed safflower oil, independent of genotype. At the skeletal level, fish oil preserved vertebral bone mineral density (BMD) and microstructure in B6 but not in 6T mice. Moreover, fish oil consumption was associated with an increase in bone marrow adiposity and a decrease in BMD, cortical thickness, ultimate force and plastic energy in femur of the 6T but not the B6 mice. These effects paralleled an increase in adipogenic inflammatory and resorption markers in 6T but not B6. Thus, compared to safflower oil, fish oil (high ratio omega-3/-6) prevents weight gain, bone loss, and changes in trabecular microarchitecture in the spine with age. These beneficial effects are absent in mice with polymorphisms in the Pparγ gene (6T), supporting the tenet that the actions of n-3 fatty acids on bone microstructure are likely to be genotype dependent. Thus caution must be used in interpreting dietary intervention trials with skeletal endpoints in mice and in humans.

Crohn's disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy.

BACKGROUND: The single nucleotide polymorphism (SNP) rs2542151 within the gene locus region encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) has been associated with Crohn's disease (CD), ulcerative colitis (UC), type-I diabetes, and rheumatoid arthritis. We have previously shown that PTPN2 regulates mitogen-activated protein kinase (MAPK) signaling and cytokine secretion in human THP-1 monocytes and intestinal epithelial cells (IEC). Here, we studied whether intronic PTPN2 SNP rs1893217 regulates immune responses to the nucleotide-oligomerization domain 2 (NOD2) ligand, muramyl-dipeptide (MDP). MATERIALS AND METHODS: Genomic DNA samples from 343 CD and 663 non-IBD control patients (male and female) from a combined German, Swiss, and Polish cohort were genotyped for the presence of the PTPN2 SNPs, rs2542151, and rs1893217. PTPN2-variant rs1893217 was introduced into T(84) IEC or THP-1 cells using a lentiviral vector. RESULTS: We identified a novel association between the genetic variant, rs1893217, located in intron 7 of the PTPN2 gene and CD. Human THP-1 monocytes carrying this variant revealed increased MAPK activation as well as elevated mRNA expression of T-bet transcription factor and secretion of interferon-γ in response to the bacterial wall component, MDP. In contrast, secretion of interleukin-8 and tumor necrosis factor were reduced. In both, T(84) IEC and THP-1 monocytes, autophagosome formation was impaired. CONCLUSIONS: We identified a novel CD-associated PTPN2 variant that modulates innate immune responses to bacterial antigens. These findings not only provide key insights into the effects of a functional mutation on a clinically relevant gene, but also reveal how such a mutation could contribute to the onset of disease.

Diagnostic et traitement des tumeurs intra-oculaires chez l'enfant [Diagnosis and treatment of intraocular tumors in the child]

PURPOSE: To remind of the absolute necessity for early diagnosis in the presence of ocular signs in children giving rise to possible intraocular tumours. METHOD: Based on our own experience of intraocular tumours in children, together with findings from the literature, diagnostic criteria and methods of treatment are presented. RESULTS: Retinoblastoma is the predominant cause of intraocular tumours in children, representing over 80% of cases under the age of 15 years. Other diseases may give rise to the same initial signs, usually leukocoria, sometimes strabismus, more rarely other atypical signs. Elements taken into account for diagnosis include age, sex, laterality, heredity, size of the globe, clinical aspect of the tumours, presence of calcifications and vitreous seeding. Full fundus examination under general anaesthetic is usually necessary. Biological examination, ultrasonography, computerized tomography and MRI enable an accurate diagnosis to be made in the majority of doubtful cases. The management of retinoblastoma is adapted for each individual case from the wide range of treatments available. Enucleation, radioactive applicators (...), brachytherapy (...), cryo- and photocoagulation represent classical measures. Primary chemotherapy, combined with other treatments such as thermotherapy, has become the treatment of choice in those cases where external beam radiotherapy has been used up to now, or in some instances before enucleation. Enucleation is usually carried out for medullo-epitheliomas, but brachytherapy may offer an alternative. CONCLUSION: Any unexplained ocular sign in children should be considered as a possible retinoblastoma, making an accurate and certain diagnosis imperative. Early treatment may save not only the life but also the vision of patients carrying this highly malignant lesion.

Survival in soil and detection of co-transformed Trichoderma harzianum by nested PCR

The objective of this work was to evaluate the survival of two Trichoderma harzianum co-transformants, TE 10 and TE 41, carrying genes for green fluorescent protein (egfp) and for resistance to benomyl, during four weeks in a contained soil microcosm. Selective culture media were used to detect viable fungal material, whose identity was confirmed by the observation of the fluorescent phenotype by direct epifluorence microscopy. PCR using two nested primer pairs specific to the egfp gene was also used to detect the transformed fungi. Although it was not possible to reliably detect the egfp gene directly from soil extracts, an enrichment step involving selective culture of soil samples in liquid medium prior to DNA extraction enabled the consistent detection of the T. harzianum co-transformants by nested PCR for the duration of the incubation period.

Evaluation of clinician-operated sonography and fine-needle aspiration in the assessment of salivary gland tumours.

OBJECTIVES: To evaluate the combination of ultrasound (US) + fine-needle aspiration (FNA) in the assessment of salivary gland tumours in the hands of the otolaryngologist. DESIGN: A retrospective review of case notes was performed. SETTING: Two university teaching hospitals in Switzerland. PARTICIPANTS: One hundred and three patients with a total of 106 focal masses of the salivary glands were included. Clinician-operated US + FNA were the first line of investigation for these lesions. All patients underwent surgical excision of the lesion, which allowed for confirmation of diagnosis by histopathology in 104 lesions and by laboratory testing in two lesions. MAIN OUTCOME MEASURES: Primary--diagnostic accuracy in identifying true salivary gland neoplasms and detecting malignancy. Secondary--predicting an approximate and specific diagnosis in these tumours. RESULTS: The combination of US + FNA achieved a diagnostic accuracy of 99% in identifying and differentiating true salivary gland neoplasms from tumour-like lesions. In detecting malignancy, this combination permitted an accuracy of 98%. An approximate diagnosis was possible in 89%, and a specific diagnosis in 69% of our patients. CONCLUSIONS: Due to economic factors and a high diagnostic accuracy, the combination of US + FNA represents the investigation method of choice for most salivary gland tumours. We suggest that the otolaryngologist be employed in carrying out these procedures, as is already the rule in other medical specialties, while computed tomography and magnetic resonance imaging should be reserved to those few lesions, which cannot be delineated completely by sonography.

Case Study of Seasonal Variation in the Subgrade and Subbase Layers of Highway US 20, TR-516, 2008

Seasonal variations in ground temperature and moisture content influence the load carrying capacity of pavement subgrade layers. To improve pavement performance, pavement design guidelines require knowledge of environmental factors and subgrade stiffness relationships. As part of this study, in-ground instrumentation was installed in the pavement foundation layers of a newly constructed section along US Highway 20 near Fort Dodge, Iowa, to monitor the seasonal variations in temperature, frost depth, groundwater levels, and moisture regime. Dynamic cone penetrometer (DCP), nuclear gauge, and Clegg hammer tests were performed at 64 test points in a 6-ft x 6-ft grid pattern to characterize the subgrade stiffness properties (i.e., resilient modulus) prior to paving. The purpose of this paper is to present the field instrumentation results and the observed changes in soil properties due to seasonal environmental effects.

Investigation of Steel-Stringer Bridges: Superstructures and Substructures, Volume I, TR-522, 2007

There are hundreds of structurally deficient or functionally obsolete bridges in the state of Iowa. With the majority of these bridges located on rural county roads where there is limited funding available to replace the bridges, diagnostic load testing can be utilized to determine the actual load carrying capacity of the bridge. One particular family or fleet of bridges that has been determined to be desirable for load testing consists of single-span bridges with non-composite, cast-in-place concrete decks, steel stringers, and timber substructures. Six bridges with poor performing superstructure and substructure from the aforementioned family of bridges were selected to be load tested. The six bridges were located on rural roads in five different counties in Iowa: Boone, Carroll, Humboldt, Mahaska, and Marshall. Volume I of this report focuses on evaluating the superstructure for this family of bridges. This volume discusses the behavior characteristics that influence the load carrying capacity of this fleet of bridges. In particular, the live load distribution, partial composite action, and bearing restraint were investigated as potential factors that could influence the bridge ratings. Implementing fleet management practices, the bridges were analyzed to determine if the load test results could be predicted to better analyze previously untested bridges. For this family of bridges it was found that the ratings increased as a result of the load testing demonstrating a greater capacity than determined analytically. Volume II of this report focuses on evaluating the timber substructure for this family of bridges. In this volume, procedures for detecting pile internal decay using nondestructive ultrasonic stress wave techniques, correlating nondestructive ultrasonic stress wave techniques to axial compression tests to estimate deteriorated pile residual strength, and evaluating load distribution through poor performing timber substructure elements by instrumenting and load testing the abutments of the six selected bridges are discussed. Also, in this volume pile repair methods for restoring axial and bending capacities of pile are developed and evaluated.

Investigation of Steel-Stringer Bridges: Superstructures and Substructures, Volume II, TR-522, 2007

Problems with unknown bridge foundations in Iowa are often associated with timber substructures. Timber piles are subject to biological and physical deterioration, which makes quantifying in-service pile capacity difficult. Currently there are no reliable means to estimate the residual carrying capacity of an in-service deteriorated pile; and thus, the overall safety of the bridge cannot be determined. The lack of reliable evaluation methods can lead to conservative and costly maintenance practices. This research study was undertaken to investigate procedures for assessing bridge substructures, and evaluating procedures for rehabilitating/strengthening/replacing inadequate substructure components. The report includes an extensive literature review, a field reconnaissance study of 49 bridges, a survey of substructure problems from the perspective of County Engineers, a laboratory study aiming to correlate nondestructive tests to residual pile strength and stiffness values, nondestructive and destructive load tests for 6 bridges with poor substructures, and finally a laboratory study evaluating selected repair methods.

Youths carrying a weapon or using a weapon in a fight: what makes the difference?

The objective of this study was to characterize weapon-carrying adolescents and to assess whether weapon carriers differ from weapon users. Data were drawn from a cross-sectional school-based survey of 7548 adolescents aged 16-20 years in Switzerland. Youths carrying a weapon were compared with those who do not. Subsequently, weapon carriers were divided into those who had used it in a fight and those who had not. Individual, family, school and social factors were analyzed using bivariate and stepwise multivariate analysis. For both genders, delinquent behavior and being victim of physical violence were associated with weapon carrying. For males, quarreling while intoxicated, being an apprentice, being sensation seekers, having a tattoo, having a poor relationship with parents and practicing unsafe sex were also related to weapon carrying. Compared with weapon carriers, female weapon users were more likely to be regular smokers. Male weapon users were foreign born, urban and apprentices; had poor school connectedness; practiced unsafe sex and quarreled while intoxicated. Carrying a weapon is a relatively frequent behavior among youths in Switzerland and a sizeable proportion of weapon carriers have used it in a fight. Weapon carrying should be part of the clinical assessment and preventive counseling of adolescents. Preventive programs specific for at-risk youth groups need to be developed.

CARDIAC AND MUSCLE CHANNELOPATHIES: ROLES AND REGULATION OF VOLTAGE-GATED SODIUM CHANNELS

Abstract :The contraction of the heart or skeletal muscles is mainly due to the propagation, through excitable cells, of an electrical influx called action potential (AP). The AP results from the sequential opening of ion channels that generate inward or outward currents through the cell membrane. Among all the channels involved, the voltage-gated sodium channel is responsible for the rising phase of the action potential. Ten genes encode the different isoforms of these channels (from Nav1.1 to Nav1.9 and an atypical channel named NavX). Nav1.4 and Nav1.5 are the main skeletal muscle and cardiac sodium channels respectively. Their importance for muscle and heart function has been highlighted by the description of mutations in their encoding genes SCN4A and SCNSA. They lead respectively to neuromuscular disorders such as myotonia or paralysis (for Nav1.4), and to cardiac arrhythmias that can deteriorate into sudden cardiac death (for Nav1.5).The general aim of my PhD work has been to study diseases linked with channels dysfunction, also called channelopathies. In that purpose, I investigated the function and the regulation of the muscle and cardiac voltage-gated sodium channels. During the two first studies, I characterized the effects of two mutations affecting Nav1.4 and Nav1.5 function. I used the HEK293 model cells to express wild-type or mutant channels and then studied their biophysical properties with the patch-clamp technique, in whole cell configuration. We found that the SCN4A mutation produced complex alterations of the muscle sodium channel function, that could explain the myotonic phenotype described in patients carrying the mutation. In the second study, the index case was an heterozygous carrier of a SCNSA mutation that leads to a "loss of function" of the channel. The decreased sodium current measured with mutated Nay 1.5 channels, at physiological temperature, was a one of the factors that could explain the observed Brugada syndrome. The last project aimed at identifying a new potential protein interacting with the cardiac sodium channel. We found that the protein SAP97 binds the three last amino-acids of the C-terminus of Na,, 1.5. Our results also indicated that silencing the expression of SAP97 in HEK293 cells decreased the sodium current. Sodium channels lacking their three last residues also produced a reduced INa. These preliminary results suggest that SAP97 is implicated in the regulation of sodium channel. Whether this effect is direct or imply the action of an adaptor protein remains to be investigated. Moreover, our group has previously shown that Nav1.5 channels are localized to lateral membranes of cardiomyocytes by the dystrophin multiprotein complex (DMC). This suggests that sodium channels are distributed in, at least, two different pools: one targeted at lateral membranes by DMC and the other at intercalated discs by another protein such as SAP97.These studies reveal that cardiac and muscle diseases may result from ion channel mutations but also from regulatory proteins affecting their regulation.Résumé :La contraction des muscles et du coeur est principalement due à la propagation, à travers les cellules excitables, d'un stimulus électrique appelé potentiel d'action (PA). C'est l'ouverture séquentielle de plusieurs canaux ioniques transmembranaires, permettant l'entrée ou la sortie d'ions dans la cellule, qui est à l'origine de ce PA. Parmi tous les canaux ioniques impliqués dans ce processus, les canaux sodiques dépendant du voltage sont responsables de la première phase du potentiel d'action. Les différentes isoformes de ces canaux (de Nav1.1 à Nav1.9 et NavX) sont codées par dix gènes distincts. Nav1.4 et Nav1.5 sont les principaux variants exprimés respectivement dans le muscle et le coeur. Plusieurs mutations ont été décrites dans les gènes qui codent pour ces deux canaux: SCN4A (pour Nav1.4) et SCNSA (pour Nav1.5). Elles sont impliquées dans des pathologies neuromusculaires telles que des paralysies ou myotonies (SCN4A) ou des arythmies cardiaques pouvant conduire à la mort subite cardiaque (SCNSA).Mon travail de thèse a consisté à étudier les maladies liées aux dysfonctionnements de ces canaux, aussi appelées canalopathies. J'ai ainsi analysé la fonction et la régulation des canaux sodiques dépendant du voltage dans le muscle squelettique et le coeur. A travers les deux premières études, j'ai ainsi pu examiner les conséquences de deux mutations affectant respectivement les canaux Nav1.4 et Nav1.5. Les canaux sauvages ou mutants ont été exprimés dans des cellules HEK293 afin de caractériser leurs propriétés biophysiques par la technique du patch clamp en configuration cellule entière. Nous avons pu déterminer que la mutation trouvée dans le gène SCN4A engendrait des modifications importantes de la fonction du canal musculaire. Ces altérations fournissent des indications nous permettant d'expliquer certains aspects de la myotonie observée chez les membres de la famille étudiée. Le patient présenté dans la deuxième étude était hétérozygote pour la mutation identifiée dans le gène SCNSA. La perte de fonction des canaux Nav1.5 ainsi engendrée, a été observée lors d'analyses à températures physiologiques. Elle représente l'un des éléments pouvant potentiellement expliquer le syndrome de Brugada du patient. La dernière étude a consisté à identifier une nouvelle protéine impliquée dans la régulation du canal sodique cardiaque. Nos expériences ont démontré que les trois derniers acides aminés de la partie C-terminale de Nav1.5 pouvaient interagir avec la protéine SAP97. Lorsque que l'expression de la SAP97 est réduite dans les cellules HEK293, cela induit une baisse importante du courant sodique. De même, les canaux tronqués de leurs trois derniers acides aminés génèrent un flux ionique réduit. Ces résultats préliminaires suggèrent que SAP97 est peut-être impliquée dans la régulation du canal Na,,1.5. Des expériences complémentaires permettront de déterminer si ces deux protéines interagissent directement ou si une protéine adaptatrice est nécessaire. De plus, nous avons préalablement montré que les canaux Nav1.5 étaient localisés au niveau de la membrane latérale des cardiomyocytes par le complexe multiprotéique de la dystrophine (DMC). Ceci suggère que les canaux sodiques peuvent être distribués dans un minimum de deux pools, l'un ciblé aux membranes latérales pax le DMC et l'autre dirigé vers les disques intercalaires par des protéines telles que SAP97.L'ensemble de ces études met en évidence que certaines maladies musculaires et cardiaques peuvent être la conséquence directe de mutations de canaux ioniques, mais que l'action de protéines auxiliaires peut aussi affecter leur fonction.

Preferential infection of immature dendritic cells and B cells by mouse mammary tumor virus.

Until now it was thought that the retrovirus mouse mammary tumor virus preferentially infects B cells, which thereafter proliferate and differentiate due to superantigen-mediated T cell help. We describe in this study that dendritic cells are infectable at levels comparable to B cells in the first days after virus injection. Moreover, IgM knockout mice have chronically deleted superantigen-reactive T cells after MMTV injection, indicating that superantigen presentation by dendritic cells is sufficient for T cell deletion. In both subsets initially only few cells were infected, but there was an exponential increase in numbers of infected B cells due to superantigen-mediated T cell help, explaining that at the peak of the response infection is almost exclusively found in B cells. The level of infection in vivo was below 1 in 1000 dendritic cells or B cells. Infection levels in freshly isolated dendritic cells from spleen, Langerhans cells from skin, or bone marrow-derived dendritic cells were compared in an in vitro infection assay. Immature dendritic cells such as Langerhans cells or bone marrow-derived dendritic cells were infected 10- to 30-fold more efficiently than mature splenic dendritic cells. Bone marrow-derived dendritic cells carrying an endogenous mouse mammary tumor virus superantigen were highly efficient at inducing a superantigen response in vivo. These results highlight the importance of professional APC and efficient T cell priming for the establishment of a persistent infection by mouse mammary tumor virus.

Susceptibility and adaptation to human TRIM5α alleles at positive selected sites in HIV-1 capsid.

Numerous in vitro studies attribute to human TRIM5α some modest anti-HIV-1 activity and human population studies suggest some differential effect of TRIM5α polymorphisms on disease progression. If the activity of TRIM5α were relevant in vivo, it could result in positive selection on the viral capsid. To address this issue, we identified 10 positively selected sites in HIV-1 capsid from multiple viral strains and generated 17 clade B viruses carrying a minor (i.e. low frequency) residue or an alanine at those positions. All recombinant viruses were susceptible to the modest effect of common human TRIM5α and allelic variants R136Q, and H419Y; H43Y and G249D TRIM5α were generally inactive. Increased sensitivity to TRIM5α was observed for some capsid variants, suggesting that minor residues are selected against in human populations. On the other hand, the modest potency of human TRIM5α does not translate in escape mutations in the viral capsid.