Length Change of P. C. Concrete Due to Moisture Content, MLR-85-09, 1987

Portland cement concrete is an outstanding structural material but stresses and cracks often occur in large structures due to drying shrinkage. The objective of this research was to determine the change in length due to loss of moisture from placement through complete drying of portland cement concrete. The drying shrinkage was determined for four different combinations of Iowa DOT structural concrete mix proportions and materials. The two mix proportions used were an Iowa DOT D57 (bridge deck mix proportions) and a water reduced modified C4 mix. Three 4"x 4"x 18" beams were made for each mix. After moist curing for three days, all beams were maintained in laboratory dry air and the length and weight were measured at 73°F ± 3°F. The temperature was cycled on alternate days from 73°F to 90°F through four months. From four months through six months, the temperature was cycled one day at 73°F and six days at 130°F. It took approximately six months for the concrete to reach a dry condition with these temperatures. The total drying shrinkage for the four mixes varied from .0106 in. to .0133 in. with an average of .0120 in. The rate of shrinkage was approximately .014% shrinkage per 1% moisture loss for all four mixes. The rate and total shrinkage for all four mixes was very similar and did not seem to depend on the type of coarse aggregate or the use of a retarder.

Demonstration Project using Railroad Flatcars for Low-Volume Road Bridges, TR-444, 2003

The use of Railroad Flatcars (RRFCs) as the superstructure on low-volume county bridges has been investigated in a research project conducted by the Bridge Engineering Center at Iowa State University. These bridges enable county engineers to replace old, inadequate county bridge superstructures for less than half the cost and in a shorter construction time than required for a conventional bridge. To illustrate their constructability, adequacy, and economy, two RRFC demonstration bridges were designed, constructed, and tested: one in Buchanan County and the other in Winnebago County. The Buchanan County Bridge was constructed as a single span with 56-ft-long flatcars supported at their ends by new, concrete abutments. The use of concrete in the substructure allowed for an integral abutment at one end of the bridge with an expansion joint at the other end. Reinforced concrete beams (serving as longitudinal connections between the three adjacent flatcars) were installed to distribute live loads among the RRFCs. Guardrails and an asphalt milling driving surface completed the bridge. The Winnebago County Bridge was constructed using 89-ft-long flatcars. Preliminary calculations determined that they were not adequate to span 89 ft as a simple span. Therefore, the flatcars were supported by new, steel-capped piers and abutments at the RRFCs' bolsters and ends, resulting in a 66-ft main span and two 10-ft end spans. Due to the RRFC geometry, the longitudinal connections between adjacent RRFCs were inadequate to support significant loads; therefore, transverse, recycled timber planks were utilized to effectively distribute live loads to all three RRFCs. A gravel driving surface was placed on top of the timber planks, and a guardrail system was installed to complete the bridge. Bridge behavior predicted by grillage models for each bridge was validated by strain and deflection data from field tests; it was found that the engineered RRFC bridges have live load stresses significantly below the AASHTO Bridge Design Specification limits. To assist in future RRFC bridge projects, RRFC selection criteria were established for visual inspection and selection of structurally adequate RRFCs. In addition, design recommendations have been developed to simplify live load distribution calculations for the design of the bridges. Based on the results of this research, it has been determined that through proper RRFC selection, construction, and engineering, RRFC bridges are a viable, economic replacement system for low-volume road bridges.

Field and Laboratory Evaluation of Precast Concrete Bridges, TR-440, 2001

Recent data compiled by the National Bridge Inventory revealed 29% of Iowa's approximate 24,600 bridges were either structurally deficient or functionally obsolete. This large number of deficient bridges and the high cost of needed repairs create unique problems for Iowa and many other states. The research objective of this project was to determine the load capacity of a particular type of deteriorating bridge – the precast concrete deck bridge – which is commonly found on Iowa's secondary roads. The number of these precast concrete structures requiring load postings and/or replacement can be significantly reduced if the deteriorated structures are found to have adequate load capacity or can be reliably evaluated. Approximately 600 precast concrete deck bridges (PCDBs) exist in Iowa. A typical PCDB span is 19 to 36 ft long and consists of eight to ten simply supported precast panels. Bolts and either a pipe shear key or a grouted shear key are used to join adjacent panels. The panels resemble a steel channel in cross-section; the web is orientated horizontally and forms the roadway deck and the legs act as shallow beams. The primary longitudinal reinforcing steel bundled in each of the legs frequently corrodes and causes longitudinal cracks in the concrete and spalling. The research team performed service load tests on four deteriorated PCDBs; two with shear keys in place and two without. Conventional strain gages were used to measure strains in both the steel and concrete, and transducers were used to measure vertical deflections. Based on the field results, it was determined that these bridges have sufficient lateral load distribution and adequate strength when shear keys are properly installed between adjacent panels. The measured lateral load distribution factors are larger than AASHTO values when shear keys were not installed. Since some of the reinforcement had hooks, deterioration of the reinforcement has a minimal affect on the service level performance of the bridges when there is minimal loss of cross-sectional area. Laboratory tests were performed on the PCDB panels obtained from three bridge replacement projects. Twelve deteriorated panels were loaded to failure in a four point bending arrangement. Although the panels had significant deflections prior to failure, the experimental capacity of eleven panels exceeded the theoretical capacity. Experimental capacity of the twelfth panel, an extremely distressed panel, was only slightly below the theoretical capacity. Service tests and an ultimate strength test were performed on a laboratory bridge model consisting of four joined panels to determine the effect of various shear connection configurations. These data were used to validate a PCDB finite element model that can provide more accurate live load distribution factors for use in rating calculations. Finally, a strengthening system was developed and tested for use in situations where one or more panels of an existing PCDB need strengthening.

Effectiveness of Electrochemical Chloride Extraction for the Iowa Avenue Pedestrian Bridge, TR-499, 2005

The main objective of this study is to determine the effectiveness of the Electrochemical Chloride Extraction (ECE) technique on a bridge deck with very high concentrations of chloride. This ECE technique was used during the summer of 2003 to reverse the effects of corrosion, which had occurred in the reinforcing steel embedded in the pedestrian bridge deck over Highway 6, along Iowa Avenue, in Iowa City, Iowa, USA. First, the half cell potential was measured to determine the existing corrosion level in the field. The half-cell potential values were in the indecisive range of corrosion (between -200 mV and -350 mV). The ECE technique was then applied to remove the chloride from the bridge deck. The chloride content in the deck was significantly reduced from 25 lb/cy to 4.96 lb/cy in 8 weeks. Concrete cores obtained from the deck were measured for their compressive strengths and there was no reduction in strength due to the ECE technique. Laboratory tests were also performed to demonstrate the effectiveness of the ECE process. In order to simulate the corrosion in the bridge deck, two reinforced slabs and 12 reinforced beams were prepared. First, the half-cell potentials were measured from the test specimens and they all ranged below -200 mV. Upon introduction of 3% salt solution, the potential reached up to -500 mV. This potential was maintained while a salt solution was being added for six months. The ECE technique was then applied to the test specimens in order to remove the chloride from them. Half-cell potential was measured to determine if the ECE technique can effectively reduce the level of corrosion.

Laboratory Investigation of Concrete Beam-End Treatments, RB08-013, 2015

The ends of prestressed concrete beams under expansion joints are often exposed to moisture and chlorides. Left unprotected, the moisture and chlorides come in contact with the ends of the prestressing strands and/or the mild reinforcing, resulting in corrosion. Once deterioration begins, it progresses unless some process is employed to address it. Deterioration can lead to loss of bearing area and therefore a reduction in bridge capacity. Previous research has looked into the use of concrete coatings (silanes, epoxies, fiber-reinforced polymers, etc.) for protecting prestressed concrete beam ends but found that little to no laboratory research has been done related to the performance of these coatings in this specific type of application. The Iowa Department of Transportation (DOT) currently specifies coating the ends of exposed prestressed concrete beams with Sikagard 62 (a high-build, protective, solvent-free, epoxy coating) at the precast plant prior to installation on the bridge. However, no physical testing of Sikagard 62 in this application has been completed. In addition, the Iowa DOT continues to see deterioration in the prestressed concrete beam ends, even those treated with Sikagard 62. The goals of this project were to evaluate the performance of the Iowa DOT-specified beam-end coating as well as other concrete coating alternatives based on the American Association of State Highway and Transportation Officials (AASHTO) T259-80 chloride ion penetration test and to test their performance on in-service bridges throughout the duration of the project. In addition, alternative beam-end forming details were developed and evaluated for their potential to mitigate and/or eliminate the deterioration caused by corrosion of the prestressing strands on prestressed concrete beam ends used in bridges with expansion joints. The alternative beam-end details consisted of individual strand blockouts, an individual blockout for a cluster of strands, dual blockouts for two clusters of strands, and drilling out the strands after they are flush cut. The goal of all of the forming alternatives was to offset the ends of the prestressing strands from the end face of the beam and then cover them with a grout/concrete layer, thereby limiting or eliminating their exposure to moisture and chlorides.

Differential effects of immunosuppressive drugs on effector and regulatory T cells.

Purpose: Current experimental data suggest that CD4+CD25+Foxp3+regulatory T cells (Tregs) based immunotherapy would be of greatinterest to promote donor-specific immune tolerance in transplantation(Tx). Whether and how adoptive transfer of Tregs could be bestcombined with current immunosuppressive regimens in clinicalsettings remains to be defined. Using an experimental Tx model,we had previously shown that the transfer of antigen-specific Tregspromoted long-term skin allograft acceptance in lymphopenic mice,in the absence of any immunosuppressive drug. However, allograftsurvival was only slightly prolonged when Tregs were transferredalone into non-lymphopenic mice, suggesting that in more stringentconditions such as in clinical settings adjuvant therapies may beneeded to effectively control alloreactive T cells (Teff).Methods and Materials: Here we have investigated the effects ofvarious immunosuppressive drugs on the survival, proliferation andeffector function of Teff and Tregs in response to alloantigens in in vitroassays and in our in vivo Tx model.Results: Teff proliferation was inhibited in a dose-dependant mannerby rapamycin and cyclosporine A, while anti-CD154 only marginallyaffected Teff proliferation and survival in vitro. Rapamycin promotedapoptosis of Teff as compared to Tregs that were more resistant underthe same culture conditions. In vivo, the transfer of donor-specificTregs could be advantageously combined with rapamycin andanti-CD154 to significantly prolong MHC-mismatched skin allograftsurvival in non-lymphopenic recipients.Conclusion: Taken together, our data indicate thatimmunosuppressive drugs differentially target T-cell subsets and couldpromote Tregs expansion and/or function while controlling the Teff pool.

Optimized back-focal-plane interferometry directly measures forces of optically trapped particles

Back-focal-plane interferometry is used to measure displacements of optically trapped samples with very high spatial and temporal resolution. However, the technique is closely related to a method that measures the rate of change in light momentum. It has long been known that displacements of the interference pattern at the back focal plane may be used to track the optical force directly, provided that a considerable fraction of the light is effectively monitored. Nonetheless, the practical application of this idea has been limited to counter-propagating, low-aperture beams where the accurate momentum measurements are possible. Here, we experimentally show that the connection can be extended to single-beam optical traps. In particular, we show that, in a gradient trap, the calibration product κ·β (where κ is the trap stiffness and 1/β is the position sensitivity) corresponds to the factor that converts detector signals into momentum changes; this factor is uniquely determined by three construction features of the detection instrument and does not depend, therefore, on the specific conditions of the experiment. Then, we find that force measurements obtained from back-focal-plane displacements are in practice not restricted to a linear relationship with position and hence they can be extended outside that regime. Finally, and more importantly, we show that these properties are still recognizable even when the system is not fully optimized for light collection. These results should enable a more general use of back-focal-plane interferometry whenever the ultimate goal is the measurement of the forces exerted by an optical trap.

Optimized back-focal-plane interferometry directly measures forces of optically trapped particles

Back-focal-plane interferometry is used to measure displacements of optically trapped samples with very high spatial and temporal resolution. However, the technique is closely related to a method that measures the rate of change in light momentum. It has long been known that displacements of the interference pattern at the back focal plane may be used to track the optical force directly, provided that a considerable fraction of the light is effectively monitored. Nonetheless, the practical application of this idea has been limited to counter-propagating, low-aperture beams where the accurate momentum measurements are possible. Here, we experimentally show that the connection can be extended to single-beam optical traps. In particular, we show that, in a gradient trap, the calibration product κ·β (where κ is the trap stiffness and 1/β is the position sensitivity) corresponds to the factor that converts detector signals into momentum changes; this factor is uniquely determined by three construction features of the detection instrument and does not depend, therefore, on the specific conditions of the experiment. Then, we find that force measurements obtained from back-focal-plane displacements are in practice not restricted to a linear relationship with position and hence they can be extended outside that regime. Finally, and more importantly, we show that these properties are still recognizable even when the system is not fully optimized for light collection. These results should enable a more general use of back-focal-plane interferometry whenever the ultimate goal is the measurement of the forces exerted by an optical trap.

Characterising the role of T-cell subsets in experimental allograft rejection and transplantation tolerance

SUMMARY : The recognition by recipient T cells of the allograft major histocompatibility complex (MHC)mismatched antigens is the primary event that ultimately leads to rejection. In the transplantation setting, circulating alloreactive CD4+ T cells play a central role in the initiation and the coordination of the immune response and can initiate the rejection of an allograft via three distinct pathways: the direct, indirect and the recently described semi-direct pathway. However, the exact role of individual CD4+ T-cell subsets in the development of allograft rejection is not clearly defined. Furthermore, besides pathogenic effector T cells, a new subset of T cells with regulatory properties, the CD4+CD25+Foxp3+ (Treg) cells, has come under increased scrutiny over the last decade. The experiments presented in this thesis were designed to better define the phenotype and functional characteristics of CD4+ T-cell subsets and Treg cells in vitro and in vivo in a marine adoptive transfer and skin transplantation model. As Treg cells play a key role in the induction and maintenance of peripheral transplantation tolerance, we have explored whether donor-antigen specific Treg cells could be expanded in vitro. Here we describe a robust protocol for the ex-vivo generation and expansion of antigen-specific Treg cells, without loss of their characteristic phenotype and suppressive function. In our in vivo transplantation model, antigen-specific Treg cells induced donor-specific tolerance to skin allografts in lymphopenic recipients and significantly delayed skin graft rejection in wild-type mice in the absence of any other immunosuppression. Naïve and memory CD4+ T cells have distinct phenotypes, effector functions and in vivo homeostatsis, and thus may play different roles in anti-donor immunity after transplantation. We have analyzed in vitro and in vivo primary alloresponses of naïve and cross-reactive memory CD4+ T cells. We found that the CD4+CD45RBlo memory T-cell pool was heterogeneous and contained cells with regulatory potentials, both in the CD4+CD25+ and CD4+CD25- populations. CD4+ T cells capable of inducing strong primary alloreactive responses in vitro and rejection of a first allograft in vivo were mainly contained within the CD45RBhi naïve CD4+ T-cell compartment. Taken together, the work described in this thesis provides new insights into the mechanisms that drive allograft rejection or donor-specific transplantation tolerance. These results will help to optimise current clinical immunosuppressive regimens used after solid organ transplantation and design new immunotherapeutic strategies to prevent transplant rejection. RÉSUMÉ : ROLE DES SOUS-POPULATIONS DE CELLULES T DANS LE REJET DE GREFFE ET L'INDUCTION DE TOLERANCE EN TRANSPLANTATION La reconnaissance par les cellules T du receveur des alloantigènes du complexe majeur d'histocompatibilité (CMIT) présentés par une greffe allogénique, est le premier événement qui aboutira au rejet de l'organe greffé. Dans le contexte d'une transplantation, les cellules alloréactives T CD4+ circulantes jouent un rôle central dans l'initiation et la coordination de 1a réponse immune, et peuvent initier le rejet par 3 voies distinctes : la voie directe, indirecte et la voie servi-directe, plus récemment décrite. Toutefois, le rôle exact des sous-populations de cellules T CD4+ dans les différentes étapes menant au rejet d'une allogreffe n'est pas clairement établi. Par ailleurs, hormis les cellules T effectrices pathogéniques, une sous-population de cellules T ayant des propriétés régulatrices, les cellules T CD4+CD25+Foxp3+ (Treg), a été nouvellement décrite et est intensément étudiée depuis environ dix ans. Les expériences présentées dans cette thèse ont été planifiées afin de mieux définir le phénotype et les caractéristiques fonctionnels des sous-populations de cellules T CD4+ et des Treg in vitro et in vivo dans un modèle marin de transfert adoptif de cellules et de transplantation de peau. Comme les cellules Treg jouent un rôle clé dans l'induction et le maintien de la tolérance périphérique en transplantation, nous avons investigué la possibilité de multiplier in vitro des cellules Treg avec spécificité antigénique pour le donneur. Nous décrivons ici un protocole reproductible pour la génération et l'expansion ex-vivo de cellules Treg avec spécificité antigénique, sans perte de leur phénotype caractéristique et de leur fonction suppressive. Dans notre modèle in vivo de transplantation de peau, ces cellules Treg pouvaient induire une tolérance spécifique vis-à-vis du donneur chez des souris lymphopéniques, et, chez des souris normales non-lymphopéniques ces Treg ont permis de retarder significativement le rejet en l'absence de tout traitement immunosuppresseur. Les cellules T CD4+ naïves et mémoires se distinguent par leur phénotype, fonction effectrice et leur homéostasie in vivo, et peuvent donc moduler différemment la réponse immune contre le donneur après transplantation. Nous avons analysé in vitro et in vivo les réponses allogéniques primaires de cellules T CD4+ naïves et mémoires non-spécifiques (cross-réactives). Nos résultats ont montré que le pool de cellules T CD4+CD45RB'° mémoires était hétérogène et contenait des cellules avec un potentiel régulateur, aussi bien parmi la sous-population de cellules CD4+CD25+ que CD4+CD25+. Les cellules T CD4+ capables d'induire une alloréponse primaire intense in vitro et le rejet d'une première allogreffe in vivo étaient essentiellement contenues dans le pool de cellules T CD4+CD45RBhi naïves. En conclusion, le travail décrit dans cette thèse amène un nouvel éclairage sur les mécanismes responsables du rejet d'une allogreffe ou de l'induction de tolérance en transplantation. Ces résultats permettront d'optimaliser les traitements immunosuppresseurs utilisés en transplantation clinique et de concevoir des nouvelles stratégies irnmuno-thérapeutiques pour prévenir le rejet de greffe allogénique.

VP22 light controlled delivery of oligonucleotides to ocular cells in vitro and in vivo.

PURPOSE: To study VP22 light controlled delivery of antisense oligonucleotide (ODN) to ocular cells in vitro and in vivo. METHODS: The C-terminal half of VP22 was expressed in Escherichia coli, purified and mixed with 20 mer phosphorothioate oligonucleotides (ODNs) to form light sensitive complex particles (vectosomes). Uptake of vectosomes and light induced redistribution of ODNs in human choroid melanoma cells (OCM-1) and in human retinal pigment epithelial cells (ARPE-19) were studied by confocal and electron microscopy. The effect of vectosomes formed with an antisense ODN corresponding to the 3'-untranslated region of the human c-raf kinase gene on the viability and the proliferation of OCM-1 cells was assessed before and after illumination. Cells incubated with vectosomes formed with a mismatched ODN, a free antisense ODN or a free mismatched ODN served as controls. White light transscleral illumination was carried out 24 h after the intravitreal injection of vectosomes in rat eyes. The distribution of fluorescent vectosomes and free fluorescent ODN was evaluated on cryosections by fluorescence microscopy before, and 1 h after illumination. RESULTS: Overnight incubation of human OCM-1 and ARPE-19 cells with vectosomes lead to intracellular internalization of the vectosomes. When not illuminated, internalized vectosomes remained stable within the cell cytoplasm. Disruption of vectosomes and release of the complexed ODN was induced by illumination of the cultures with a cold white light or a laser beam. In vitro, up to 60% inhibition of OCM-1 cell proliferation was observed in illuminated cultures incubated with vectosomes formed with antisense c-raf ODN. No inhibitory effect on the OCM-1 cell proliferation was observed in the absence of illumination or when the cells are incubated with a free antisense c-raf ODN and illuminated. In vivo, 24 h after intravitreal injection, vectosomes were observed within the various retinal layers accumulating in the cytoplasm of RPE cells. Transscleral illumination of the injected eyes with a cold white light induced disruption of the vectosomes and a preferential localization of the "released" ODNs within the cell nuclei of the ganglion cell layer, the inner nuclear layer and the RPE cells. CONCLUSIONS: In vitro, VP22 light controlled delivery of ODNs to ocular cells nuclei was feasible using white light or laser illumination. In vivo, a single intravitreal injection of vectosomes, followed by transscleral illumination allowed for the delivery of free ODNs to retinal and RPE cells.

Paperin pinnan karakterisoinnin ja painettavuuden tutkimusmenetelmät

Työn tarkoituksena on ollut tutkia paperin pinnan karakterisoinnin menetelmiä ja tehdä katsauspaperin painettavuuden ennustamisen tutkimuksiin. Kaikkien kehitettyjen menetelmien tarkoituksena on tavalla tai toisella mitata paperin visuaalista vaikutelmaa loppukäyttäjän kannalta sekä ennustaa paperin painettavuutta. Menetelmiä on kehitetty aina 1940-luvulta lähtien ja tekniikan kehittyessä markkinoille tulee uusia menetelmiä, jotka ovat nopeampia ja tarkempia kuin edeltäjänsä. Työssä tarkasteltavat menetelmät on jaoteltu mekaanisiin, optisiin ja elektronisäteilyn läpäisyyn perustuviin menetelmiin. Lopuksi on tarkasteltu tutkimuksia, joiden pääasiallinen tarkoitus on ollut kehittää mittalaitteita ennustamaan paperin painotulosta todellisissa painatusolosuhteissa. Laboratoriolaitteita ja on-line-mittareita ei ole jaoteltu erikseen, koska menetelmän perusteella on helppo havaita, voiko laite mitata jotakin paperin ominaisuutta jopa yli 40 metriä sekunnissa liikkuvalla paperirainalla.

Vaiheohjatut antenniryhmät GSM-tukiasemissa

Diplomityön aiheena oli selvittää onko Suomessa GSM-tukiasemissa käytössä vaiheohjattuja antenniryhmiäja olisiko tällaisten antennien käyttöön kiinnostusta tai mitään es-teitä. Lähtökohtana tälle työlle oli ajatus GSM-tukiasema-antennista, jota voitaisiin kääntää tarpeen mukaan haluttuun suuntaan. Vaiheohjatut antenniryhmät mahdollistavat juuri tällaisen antennin keilan kääntämisen ja muokkaamisen elektronisesti, ilman kuluvia osia. Keilan muitakin ominaisuuksia voidaan säätää, kuten muotoa ja keilojen määrää. Nämä ominaisuudet mahdollistaisivat esimerkiksi ruuhkaisilla alueilla keilojen lisäämisen, jolloin alueen puhelujen välityskapasiteetti kasvaisi.Tarvittaessa voitaisiin myös keilan muotoa muuttaa. Esimerkiksi hätätilanteessasaadaan haluttu keila suunnattua tarkasti tietylle alueelle tai toiselle tukiasemalle ja näin varmistettua kuuluvuus. Myös huoltotoimenpiteet joissakin tapauksissa helpottuisivat. Etenkin vaikeakulkuisissa paikoissa sijaitsevien tukiasemien ensiapu, esimerkiksi antennin fyysisesti kääntyessä, voitaisiin hoitaa etänä kääntämällä pelkkää keilaa ja tässä tapauksessa kääntää antenni tukiaseman normaalin huollon yhteydessä. Suurimpia ongelmakohtia kyseisen tekniikan käyttöönotossa on ollut hinta, mutta muun muassa uusien valmistustekniikoiden avulla vaiheohjattujen antenniryhmien hintoja ollaan saatu pudotettua.

Developmental critical period in genetic redox dysregulation: animal and human studies in schizophrenia

Converging evidence favors an abnormal susceptibility to oxidative stress in schizophrenia. Decreased levels of glutathione (GSH), the major cellular antioxidant and redox regulator, was observed in cerebrospinal-fluid and prefrontal cortex of patients. Importantly, abnormal GSH synthesis of genetic origin was observed: Two case-control studies showed an association with a GAG trinucleotide repeat (TNR) polymorphism in the GSH key synthesizing enzyme glutamate-cysteine-ligase (GCL) catalytic subunit (GCLC) gene. The most common TNR genotype 7/7 was more frequent in controls, whereas the rarest TNR genotype 8/8 was three times more frequent in patients. The disease associated genotypes (35% of patients) correlated with decreased GCLC protein, GCL activity and GSH content. Similar GSH system anomalies were observed in early psychosis patients. Such redox dysregulation combined with environmental stressors at specific developmental stages could underlie structural and functional connectivity anomalies. In pharmacological and knock-out (KO) models, GSH deficit induces anomalies analogous to those reported in patients. (a) morphology: spine density and GABA-parvalbumine immunoreactivity (PV-I) were decreased in anterior cingulate cortex. KO mice showed delayed cortical PV-I at PD10. This effect is exacerbated in mice with increased DA from PD5-10. KO mice exhibit cortical impairment in myelin and perineuronal net known to modulate PV connectivity. (b) physiology: In cultured neurons, NMDA response are depressed by D2 activation. In hippocampus, NMDA-dependent synaptic plasticity is impaired and kainate induced g-oscillations are reduced in parallel to PV-I. (c) cognition: low GSH models show increased sensitivity to stress, hyperactivity, abnormal object recognition, olfactory integration and social behavior. In a clinical study, GSH precursor N-acetyl cysteine (NAC) as add on therapy, improves the negative symptoms and decreases the side effects of antipsychotics. In an auditory oddball paradigm, NAC improves the mismatched negativity, an evoked potential related to pre-attention and to NMDA receptors function. In summary, clinical and experimental evidence converge to demonstrate that a genetically induced dysregulation of GSH synthesis combined with environmental insults in early development represent a major risk factor contributing to the development of schizophrenia

Développement et validation d'une méthode de calcul indépendant des unités moniteur basée sur les simulations Monte Carlo pour la vérification des traitements IMRT

Résumé : La radiothérapie par modulation d'intensité (IMRT) est une technique de traitement qui utilise des faisceaux dont la fluence de rayonnement est modulée. L'IMRT, largement utilisée dans les pays industrialisés, permet d'atteindre une meilleure homogénéité de la dose à l'intérieur du volume cible et de réduire la dose aux organes à risque. Une méthode usuelle pour réaliser pratiquement la modulation des faisceaux est de sommer de petits faisceaux (segments) qui ont la même incidence. Cette technique est appelée IMRT step-and-shoot. Dans le contexte clinique, il est nécessaire de vérifier les plans de traitement des patients avant la première irradiation. Cette question n'est toujours pas résolue de manière satisfaisante. En effet, un calcul indépendant des unités moniteur (représentatif de la pondération des chaque segment) ne peut pas être réalisé pour les traitements IMRT step-and-shoot, car les poids des segments ne sont pas connus à priori, mais calculés au moment de la planification inverse. Par ailleurs, la vérification des plans de traitement par comparaison avec des mesures prend du temps et ne restitue pas la géométrie exacte du traitement. Dans ce travail, une méthode indépendante de calcul des plans de traitement IMRT step-and-shoot est décrite. Cette méthode est basée sur le code Monte Carlo EGSnrc/BEAMnrc, dont la modélisation de la tête de l'accélérateur linéaire a été validée dans une large gamme de situations. Les segments d'un plan de traitement IMRT sont simulés individuellement dans la géométrie exacte du traitement. Ensuite, les distributions de dose sont converties en dose absorbée dans l'eau par unité moniteur. La dose totale du traitement dans chaque élément de volume du patient (voxel) peut être exprimée comme une équation matricielle linéaire des unités moniteur et de la dose par unité moniteur de chacun des faisceaux. La résolution de cette équation est effectuée par l'inversion d'une matrice à l'aide de l'algorithme dit Non-Negative Least Square fit (NNLS). L'ensemble des voxels contenus dans le volume patient ne pouvant être utilisés dans le calcul pour des raisons de limitations informatiques, plusieurs possibilités de sélection ont été testées. Le meilleur choix consiste à utiliser les voxels contenus dans le Volume Cible de Planification (PTV). La méthode proposée dans ce travail a été testée avec huit cas cliniques représentatifs des traitements habituels de radiothérapie. Les unités moniteur obtenues conduisent à des distributions de dose globale cliniquement équivalentes à celles issues du logiciel de planification des traitements. Ainsi, cette méthode indépendante de calcul des unités moniteur pour l'IMRT step-andshootest validée pour une utilisation clinique. Par analogie, il serait possible d'envisager d'appliquer une méthode similaire pour d'autres modalités de traitement comme par exemple la tomothérapie. Abstract : Intensity Modulated RadioTherapy (IMRT) is a treatment technique that uses modulated beam fluence. IMRT is now widespread in more advanced countries, due to its improvement of dose conformation around target volume, and its ability to lower doses to organs at risk in complex clinical cases. One way to carry out beam modulation is to sum smaller beams (beamlets) with the same incidence. This technique is called step-and-shoot IMRT. In a clinical context, it is necessary to verify treatment plans before the first irradiation. IMRT Plan verification is still an issue for this technique. Independent monitor unit calculation (representative of the weight of each beamlet) can indeed not be performed for IMRT step-and-shoot, because beamlet weights are not known a priori, but calculated by inverse planning. Besides, treatment plan verification by comparison with measured data is time consuming and performed in a simple geometry, usually in a cubic water phantom with all machine angles set to zero. In this work, an independent method for monitor unit calculation for step-and-shoot IMRT is described. This method is based on the Monte Carlo code EGSnrc/BEAMnrc. The Monte Carlo model of the head of the linear accelerator is validated by comparison of simulated and measured dose distributions in a large range of situations. The beamlets of an IMRT treatment plan are calculated individually by Monte Carlo, in the exact geometry of the treatment. Then, the dose distributions of the beamlets are converted in absorbed dose to water per monitor unit. The dose of the whole treatment in each volume element (voxel) can be expressed through a linear matrix equation of the monitor units and dose per monitor unit of every beamlets. This equation is solved by a Non-Negative Least Sqvare fif algorithm (NNLS). However, not every voxels inside the patient volume can be used in order to solve this equation, because of computer limitations. Several ways of voxel selection have been tested and the best choice consists in using voxels inside the Planning Target Volume (PTV). The method presented in this work was tested with eight clinical cases, which were representative of usual radiotherapy treatments. The monitor units obtained lead to clinically equivalent global dose distributions. Thus, this independent monitor unit calculation method for step-and-shoot IMRT is validated and can therefore be used in a clinical routine. It would be possible to consider applying a similar method for other treatment modalities, such as for instance tomotherapy or volumetric modulated arc therapy.

Are we wasting our talent? Overqualification and overskilling among PhD graduates

Drawing on a very rich data set from a recent cohort of PhD graduates, we examine the correlates and consequences of qualification and skills mismatch. We show that job characteristics such as the economic sector and the main activity at work play a fundamental direct role in explaining the probability of being well matched. However, the effect of academic attributes seems to be mainly indirect, since it disappears once we control for the full set of work characteristics. We detected a significant earnings penalty for those who are both overqualified and overskilled and also showed that being mismatched reduces job satisfaction, especially for those whose skills are underutilized. Overall, the problem of mismatch among PhD graduates is closely related to demand-side constraints of the labor market. Increasing the supply of adequate jobs and broadening the skills PhD students acquire during training should be explored as possible responses.