Decision criteria for optimizing postemergence johnsongrass control in soybean crops in Argentina

Field studies were established in Zavalla and Oliveros, Argentina, during four years in order to optimize Johnsongrass (Sorghum halepense (L.) Pers.) chemical control by means of the thermal calendar model in comparison with other criteria (weed height or days after sowing). The effect of three application dates of postemergence herbicides was determined by visual control, density of tillers originated from rhizome bud regrowth, and from crown and shoot bud regrowth, and soybean yield. Following the thermal calendar model criterion, applications during the second date afforded the best control. Weed height for the first date showed little variability between experiments but was highly variable in the second and third application dates, achieving in some cases values greater than 120 cm. For all years, no significant differences were detected for crop yield between the first and second application dates, and yields were always lower for the third date. The greatest rhizome bud regrowth was observed for the earliest application date and the highest crown and shoot bud regrowth was determined for the last application date. Parameters associated with control efficiency showed the best behaviour for the second date. However, plant height at this moment may interfere with herbicide application and the variability exhibited by this parameter highlights the risk of determining control timing using only one decision criterion.

Short and longterm ocular vascular effects after intravitreal injection of ranibizumab for neovascular age-related macular degeneration

Purpose: To investigate the effect of the first and repeated intravitreal injections of ranibizumab (1.25mg; 0.05ml) on retrobulbar blood flow velocities in patients with wet age-related macular degeneration (AMD). Methods: This prospective non randomized study included twenty consecutive AMD patients. Time- averaged mean blood flow velocities (BFVs) in the central retinal, temporal posterior ciliary and ophthalmic arteries (CRA, TPCA and OA) were measured by ultrasound imaging before, 2 days and 3 weeks after the first injection of ranibizumab, then 6 months after supplemental monthly injections if required. At each visit, complete ophthalmological examination was performed, including best corrected visual acuity measurement according to ETDRS protocol and OCT. Results: In the treated eyes, ranibizumab injection was followed by a significant improvement in visual acuity (from 44.4 ± 21.7, to 50.9±25.9 (p<0.01) at month 6, and a decrease in mean central macular thickness from 377±115 to 267 ± 74 µm (p<0.001) at month 6. At day 2 mean BFVs decreased by 16% in the CRA and by 20% in TPCA (p<0.001, both), then remained stable. Mean BFVs did not change in OA at the day 2 but decreased at week 3 by 18% (p<0.001). Supplemental injections did not lead to additional effects at month 6. No effect was tabulated in the fellow eye. Conclusions: We report an early decrease in mean BFV in CRA and TPRA following intravitreal injections of ranibizumab corresponding to vasoconstrictive effect of this drug. Decrease in mean BFV in all retrobulbar arteries from the week 3 suggests that ranibizumab proceeds to a local and regional vasoconstrictive and antiangiogenic effects after local diffusion. Thus, ranibizumab could induce an actual hypoperfusion of the treated eye which could correspond to a vascular side effect.

Free and total plasma levels of lopinavir during pregnancy, at delivery and postpartum: implications for dosage adjustments in pregnant women.

BACKGROUND: Physiological changes associated with pregnancy may alter antiretroviral plasma concentrations and might jeopardize prevention of mother-to-child HIV transmission. Lopinavir is one of the protease inhibitors more frequently prescribed during pregnancy in Europe. We described the free and total pharmacokinetics of lopinavir in HIV-infected pregnant and non-pregnant women, and evaluated whether significant alterations in its disposition and protein binding warrant systematic dosage adjustment. METHODS: Plasma samples were collected at first, second and third trimester of pregnancy, at delivery, in umbilical cord and postpartum. Lopinavir free and total plasma concentrations were measured by HPLC-MS/MS. Bayesian calculations were used to extrapolate total concentrations to trough (Cmin). RESULTS: A total of 42 HIV-positive pregnant women and 37 non-pregnant women on lopinavir/ritonavir were included in the study. Compared to postpartum and control values, total lopinavir Cmin was decreased moderately (31-39%) during pregnancy, and free Cmin minimally, showing significant alteration only at delivery (-35%). However, total and free Cmin remained in all patients above the target concentrations for wild-type virus of 1,000 ng/ml, and above the unbound IC50(WT) of 0.64-0.77 ng/ml of lopinavir, respectively. Lopinavir free fractions remained higher during pregnancy compared to postpartum and controls, and were influenced by α-1-acid-glycoprotein and albumin decrease. Free cord-to-mother ratio (0.43) was 2.7-fold higher than total cord-to-mother ratio (0.16), suggesting higher fetal exposure. CONCLUSIONS: The moderate decrease of total lopinavir concentrations during pregnancy is not associated with proportional decrease in free concentrations. Both reach a nadir at delivery, albeit not to an extent that would put treatment-naive women at risk of insufficient exposure to the free, pharmacologically active concentrations of lopinavir. No dosage adjustment is therefore needed during pregnancy as it is unlikely to further enhance treatment efficacy but could potentially increase the risk of maternal and fetal toxicity. Nonetheless, in case of viral resistance in treatment-experienced pregnant women, loss of virological control or questionable adherence, it is justified to consider lopinavir dosage adjustment based on total plasma concentration measurement.

Myelin basic protein content of aggregating rat brain cell cultures treated with cytokines and/or demyelinating antibody: effects of macrophage enrichment.

The demyelinative potential of the cytokines interleukin-1 alpha (IL-1 alpha), interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) has been investigated in myelinating aggregate brain cell cultures. Treatment of myelinated cultures with these cytokines resulted in a reduction in myelin basic protein (MBP) content. This effect was additively increased by anti-myelin/oligodendrocyte glycoprotein (alpha-MOG) in the presence of complement. Qualitative immunocytochemistry demonstrated that peritoneal macrophages, added to the fetal telencephalon cell suspensions at the start of the culture period, successfully integrated into aggregate cultures. Supplementing the macrophage component of the cultures in this fashion resulted in increased accumulation of MBP. The effect of IFN-gamma on MBP content of cultures was not affected by the presence of macrophages in increased numbers.

Tropical terrestrial model ecosystems for evaluation of soil fauna and leaf litter quality effects on litter consumption, soil microbial biomass and plant growth

The aim of this work was to evaluate whether terrestrial model ecosystems (TMEs) are a useful tool for the study of the effects of litter quality, soil invertebrates and mineral fertilizer on litter decomposition and plant growth under controlled conditions in the tropics. Forty-eight intact soil cores (17.5-cm diameter, 30-cm length) were taken out from an abandoned rubber plantation on Ferralsol soil (Latossolo Amarelo) in Central Amazonia, Brazil, and kept at 28ºC in the laboratory during four months. Leaf litter of either Hevea pauciflora (rubber tree), Flemingia macrophylla (a shrubby legume) or Brachiaria decumbens (a pasture grass) was put on top of each TME. Five specimens of either Pontoscolex corethrurus or Eisenia fetida (earthworms), Porcellionides pruinosus or Circoniscus ornatus (woodlice), and Trigoniulus corallinus (millipedes) were then added to the TMEs. Leaf litter type significantly affected litter consumption, soil microbial biomass and nitrate concentration in the leachate of all TMEs, but had no measurable effect on the shoot biomass of rice seedlings planted in top soil taken from the TMEs. Feeding rates measured with bait lamina were significantly higher in TMEs with the earthworm P. corethrurus and the woodlouse C. ornatus. TMEs are an appropriate tool to assess trophic interactions in tropical soil ecossistems under controlled laboratory conditions.

Genetic improvement and population structure of the Nelore breed in Northern Brazil

The objective of this work was to evaluate the population structure and the genetic and phenotypic progress of Nelore cattle in Northern Brazil. Pedigree information concerning animals born between 1942 and 2006 were analyzed. Population structure was performed using the Endog program. Out of the 140,628 animals studied, 67.7, 14.52 and 3.18% had complete pedigree record of the first, second and third parental generation, respectively. Inbreeding and average relatedness coefficients were low: 0.2 and 0.13%, respectively. However, these parameters may have been underestimated, since information on pedigree was incomplete. The effective number of founders was 370 and the genetic contribution of 10, 50 and 448 most influent ancestors explained 13.2, 28 and 50% of the genetic variability in the population, respectively. The genetic variability for growth traits and population structure demonstrates high probability of increasing productivity through selective breeding. Moreover, management strategies to reduce the currently observed age at first calving and generation intervals are important for Nelore cattle genetic improvement.

Male mutation bias and possible long-term effects of human activities.

The ability of a population to adapt to changing environments depends critically on the amount and kind of genetic variability it possesses. Mutations are an important source of new genetic variability and may lead to new adaptations, especially if the population size is large. Mutation rates are extremely variable between and within species, and males usually have higher mutation rates as a result of elevated rates of male germ cell division. This male bias affects the overall mutation rate. We examined the factors that influence male mutation bias, and focused on the effects of classical life-history parameters, such as the average age at reproduction and elevated rates of sperm production in response to sexual selection and sperm competition. We argue that human-induced changes in age at reproduction or in sexual selection will affect male mutation biases and hence overall mutation rates. Depending on the effective population size, these changes are likely to influence the long-term persistence of a population.

A comparison of Bayesian and frequentist approaches to incorporating external information for the prediction of prostate cancer risk.

We present the most comprehensive comparison to date of the predictive benefit of genetics in addition to currently used clinical variables, using genotype data for 33 single-nucleotide polymorphisms (SNPs) in 1,547 Caucasian men from the placebo arm of the REduction by DUtasteride of prostate Cancer Events (REDUCE®) trial. Moreover, we conducted a detailed comparison of three techniques for incorporating genetics into clinical risk prediction. The first method was a standard logistic regression model, which included separate terms for the clinical covariates and for each of the genetic markers. This approach ignores a substantial amount of external information concerning effect sizes for these Genome Wide Association Study (GWAS)-replicated SNPs. The second and third methods investigated two possible approaches to incorporating meta-analysed external SNP effect estimates - one via a weighted PCa 'risk' score based solely on the meta analysis estimates, and the other incorporating both the current and prior data via informative priors in a Bayesian logistic regression model. All methods demonstrated a slight improvement in predictive performance upon incorporation of genetics. The two methods that incorporated external information showed the greatest receiver-operating-characteristic AUCs increase from 0.61 to 0.64. The value of our methods comparison is likely to lie in observations of performance similarities, rather than difference, between three approaches of very different resource requirements. The two methods that included external information performed best, but only marginally despite substantial differences in complexity.

2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on first line/second and further lines of treatment in advanced disease.

Investigating ferromagnetism and charge order in Bi1-xSrxMnO3(x<0.3)ceramic oxides.

The possible coexistence of ferromagnetism and charge/orbital order in Bi3/4Sr1/4MnO3 has been investigated. The manganite Bi0.75Sr0.25MnO3, with commensurate charge balance, undergoes an electronic transition at TCO~600 K that produces a longrange modulation with double periodicity along a and c axis, and unusual anisotropic evolution of the lattice parameters. The previously proposed ferromagnetic properties of this new ordered phase were studied by magnetometry and diffraction techniques. In zero field the magnetic structure is globally antiferromagnetic, ruling out the apparition of spontaneous ferromagnetism. However, the application of magnetic fields produces a continuous progressive canting of the moments, inducing a ferromagnetic phase even for relatively small fields (H<<1 T). Application of pulsed high fields produces a remarkable and reversible spin polarization (under 30 T, the ferromagnetic moment is ~3 ¿B/Mn, without any sign of charge order melting). The coexistence of ferromagnetism and charge order at low and very-high fields is a remarkable property of this system.

Present standards and future perspectives in the treatment of metastatic non-small cell lung cancer.

The development of novel effective immunotherapeutic agents and early clinical data hinting at significant activity in non-small cell lung cancer (NSCLC) has introduced yet another player in the field of management of advanced disease. At present, first-line cytotoxic chemotherapy is generally withheld pending results of molecular testing for any actionable genetic alteration that could lead to targeted treatment, and in their absence chemotherapy is prescribed as a default therapy. Phase III trials comparing head-to-head immune checkpoint inhibitors with standard platinum-based doublet chemotherapy are underway. Second-line chemotherapy is likewise being challenged in phase III trials, one of which having recently reported positive results in advanced squamous cell carcinoma. In tumors harboring actionable transforming genetic alterations such as EGFR mutations and ALK rearrangements, second- and third-generation inhibitors allow for multiple lines of targeted treatment beyond initial resistance, postponing the use of cytotoxic chemotherapy to very late lines of therapy. Chemotherapy as a longstanding but still present standard of care capable of prolonging survival, improving quality of life, and relieving symptoms sees its role increasingly restricted to clinical, immunological, and molecular subsets of patients where its activity and efficacy have never been tested prospectively.

3,4-Methylenedioxy-methamphetamine induces in vivo regional up-regulation of central nicotinic receptors in rats and potentiates the regulatory effects of nicotine on these receptors

Nicotine (NIC), the main psychostimulant compound of smoked tobacco, exerts its effects through activation of central nicotinic acetylcholine receptors (nAChR), which become up-regulated after chronic administration. Recent work has demonstrated that the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) has affinity for nAChR and also induces up-regulation of nAChR in PC 12 cells. Tobacco and MDMA are often consumed together. In the present work we studied the in vivo effect of a classic chronic dosing schedule of MDMA in rats, alone or combined with a chronic schedule of NIC, on the density of nAChR and on serotonin reuptake transporters. MDMA induced significant decreases in [3H]paroxetine binding in the cortex and hippocampus measured 24 h after the last dose and these decreases were not modified by the association with NIC. In the prefrontal cortex, NIC and MDMA each induced significant increases in [3H]epibatidine binding (29.5 and 34.6%, respectively) with respect to saline-treated rats, and these increases were significantly potentiated (up to 72.1%) when the two drugs were associated. Also in this area, [3H]methyllycaconitine binding was increased a 42.1% with NIC + MDMA but not when they were given alone. In the hippocampus, MDMA potentiated the a7 regulatory effects of NIC (raising a 25.5% increase to 52.5%) but alone was devoid of effect. MDMA had no effect on heteromeric nAChR in striatum and a coronal section of the midbrain containing superior colliculi, geniculate nuclei, substantia nigra and ventral tegmental area. Specific immunoprecipitation of solubilised receptors suggests that the up-regulated heteromeric nAChRs contain a4 and b2 subunits. Western blots with specific a4 and a7 antibodies showed no significant differences between the groups, indicating that, as reported for nicotine, up-regulation caused by MDMA is due to post-translational events rather than increased receptor synthesis.

Functional impact of genetic variation on gene expression

Numerous links between genetic variants and phenotypes are known and genome-wide association studies dramatically increased the number of genetic variants associated with traits during the last decade. However, how changes in the DNA perturb the molecular mechanisms and impact on the phenotype of an organism remains elusive. Studies suggest that many traitassociated variants are in the non-coding region of the genome and probably act through regulation of gene expression. During my thesis I investigated how genetic variants affect gene expression through gene regulatory mechanisms. The first chapter was a collaborative project with a pharmaceutical company, where we investigated genome-wide copy number variation (CNVs) among Cynomolgus monkeys (Macaca fascicularis) used in pharmaceutical studies, and associated them to changes in gene expression. We found substantial copy number variation and identified CNVs linked to tissue-specific expression changes of proximal genes. The second and third chapters focus on genetic variation in humans and its effects on gene regulatory mechanisms and gene expression. The second chapter studies two human trios, where the allelic effects of genetic variation on genome-wide gene expression, protein-DNA binding and chromatin modifications were investigated. We found abundant allele specific activity across all measured molecular phenotypes and show extended coordinated behavior among them. In the third chapter, we investigated the impact of genetic variation on these phenotypes in 47 unrelated individuals. We found that chromatin phenotypes are organized into local variable modules, often linked to genetic variation and gene expression. Our results suggest that chromatin variation emerges as a result of perturbations of cis-regulatory elements by genetic variants, leading to gene expression changes. The work of this thesis provides novel insights into how genetic variation impacts gene expression by perturbing regulatory mechanisms. -- De nombreux liens entre variations génétiques et phénotypes sont connus. Les études d'association pangénomique ont considérablement permis d'augmenter le nombre de variations génétiques associées à des phénotypes au cours de la dernière décennie. Cependant, comprendre comment ces changements perturbent les mécanismes moléculaires et affectent le phénotype d'un organisme nous échappe encore. Des études suggèrent que de nombreuses variations, associées à des phénotypes, sont situées dans les régions non codantes du génome et sont susceptibles d'agir en modifiant la régulation d'expression des gènes. Au cours de ma thèse, j'ai étudié comment les variations génétiques affectent les niveaux d'expression des gènes en perturbant les mécanismes de régulation de leur expression. Le travail présenté dans le premier chapitre est un projet en collaboration avec une société pharmaceutique. Nous avons étudié les variations en nombre de copies (CNV) présentes chez le macaque crabier (Macaca fascicularis) qui est utilisé dans les études pharmaceutiques, et nous les avons associées avec des changements d'expression des gènes. Nous avons découvert qu'il existe une variabilité substantielle du nombre de copies et nous avons identifié des CNVs liées aux changements d'expression des gènes situés dans leur voisinage. Ces associations sont présentes ou absentes de manière spécifique dans certains tissus. Les deuxième et troisième chapitres se concentrent sur les variations génétiques dans les populations humaines et leurs effets sur les mécanismes de régulation des gènes et leur expression. Le premier se penche sur deux trios humains, père, mère, enfant, au sein duquel nous avons étudié les effets alléliques des variations génétiques sur l'expression des gènes, les liaisons protéine-ADN et les modifications de la chromatine. Nous avons découvert que l'activité spécifique des allèles est abondante abonde dans tous ces phénotypes moléculaires et nous avons démontré que ces derniers ont un comportement coordonné entre eux. Dans le second, nous avons examiné l'impact des variations génétiques de ces phénotypes moléculaires chez 47 individus, sans lien de parenté. Nous avons observé que les phénotypes de la chromatine sont organisés en modules locaux, qui sont liés aux variations génétiques et à l'expression des gènes. Nos résultats suggèrent que la variabilité de la chromatine est due à des variations génétiques qui perturbent des éléments cis-régulateurs, et peut conduire à des changements dans l'expression des gènes. Le travail présenté dans cette thèse fournit de nouvelles pistes pour comprendre l'impact des différentes variations génétiques sur l'expression des gènes à travers les mécanismes de régulation.

Generalization transitions in Hidden-Layer neural networks for third-order feature discrimination

Stochastic learning processes for a specific feature detector are studied. This technique is applied to nonsmooth multilayer neural networks requested to perform a discrimination task of order 3 based on the ssT-block¿ssC-block problem. Our system proves to be capable of achieving perfect generalization, after presenting finite numbers of examples, by undergoing a phase transition. The corresponding annealed theory, which involves the Ising model under external field, shows good agreement with Monte Carlo simulations.

Bien-être et croyance en un monde juste en ex-Yougoslavie: traces laissées par les guerres et la précarité socio-économique

RÉSUMÉ En combinant la perspective du parcours de vie à la théorie du stress et selon une approche psychosociale, cette thèse montre comment les expériences individuelles et collectives de victimisation ont marqué les parcours de vie, les croyances et le bien-être d'une cohorte de jeunes adultes ayant traversé les guerres en ex-Yougoslavie. Le premier article applique des analyses de courbes de croissance à classes latentes et dégage différentes trajectoires d'exclusion entre 1990 et 2006. L'analyse de ces trajectoires met en évidence les intersections entre vies individuelles, contexte et temps socio-historique et démontre que les expériences de guerre et les périodes d'exclusion socio-économique laissent des traces sur le bien-être à long terme. Les deuxième et troisième articles montrent que la croyance en un monde juste est ébranlée suite à des expériences de précarité socio-économique et de victimisation dues à la guerre au niveau individuel et contextuel. Un effet curvilinéaire et des interactions entre les niveaux indiquent que ces relations varient en fonction de l'intensité de la victimisation au niveau contextuel. Des effets de récence sont aussi relevés. Le quatrième article démontre que l'impact négatif de la victimisation sur le bien-être est en partie expliqué par un effritement de la croyance en un monde juste. De plus, si les individus qui croient davantage en un monde juste sont plus satisfaits de leur vie, la force de ce lien varie en fonction du niveau de victimisation dans certains contextes. Cette thèse présente un modèle multiniveaux dynamique dans lequel la croyance en un monde juste n'exerce plus le rôle de ressource personnelle stable mais s'érode face à la victimisation, entraînant ainsi un bien-être moindre. Ce travail souligne l'importance d'articuler les niveaux individuels et contextuels et de considérer la dimension temporelle pour expliquer les liens entre victimisation, croyance en un monde juste et bien-être. ABSTRACT By combining a life course perspective to stress theory and according to a psychosocial approach, this thesis shows how individual and collective victimisation experiences marked the life course, beliefs and well-being of a cohort of young adults who lived through the wars in former Yugoslavia. In the first article, latent class growth analyses were applied to identify different exclusion trajectories between 1990 and 2006. The analysis of these trajectories highlighted the intersections between individual lives, socio-historical context and time and demonstrated that experiences of war and socio-economic exclusion leave traces on well-being in the long term. The second and third articles showed that the belief in a just world was shattered due to socio-economic precariousness and war victimisation at individual and contextual levels. A curvilinear effect and cross-level interactions indicated that these relations varied according to the intensity of victimisation at the contextual level. Time effects were also noted. The fourth article showed that the negative impact of victimisation on well-being was partly explained by an erosion of the belief in a just world. Furthermore, if high believers were more satisfied with their lives, the strength of this relation varied depending on the level of victimisation in particular contexts. This thesis presents a multilevel dynamic model in which the belief in a just world no longer exercises the role of a stable personal resource but erodes in the face of victimisation, leading to a lower well-being. This work stresses the importance of articulating individual and contextual levels as well as considering the temporal dimension to explain the links between victimisation, belief in a just world and well-being.