Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: insights from animal models.

Abstract Significance: Schizophrenia (SZ) and bipolar disorder (BD) are classified as two distinct diseases. However, accumulating evidence shows that both disorders share genetic, pathological, and epidemiological characteristics. Based on genetic and functional findings, redox dysregulation due to an imbalance between pro-oxidants and antioxidant defense mechanisms has been proposed as a risk factor contributing to their pathophysiology. Recent Advances: Altered antioxidant systems and signs of increased oxidative stress are observed in peripheral tissues and brains of SZ and BD patients, including abnormal prefrontal levels of glutathione (GSH), the major cellular redox regulator and antioxidant. Here we review experimental data from rodent models demonstrating that permanent as well as transient GSH deficit results in behavioral, morphological, electrophysiological, and neurochemical alterations analogous to pathologies observed in patients. Mice with GSH deficit display increased stress reactivity, altered social behavior, impaired prepulse inhibition, and exaggerated locomotor responses to psychostimulant injection. These behavioral changes are accompanied by N-methyl-D-aspartate receptor hypofunction, elevated glutamate levels, impairment of parvalbumin GABA interneurons, abnormal neuronal synchronization, altered dopamine neurotransmission, and deficient myelination. Critical Issues: Treatment with the GSH precursor and antioxidant N-acetylcysteine normalizes some of those deficits in mice, but also improves SZ and BD symptoms when given as adjunct to antipsychotic medication. Future Directions: These data demonstrate the usefulness of GSH-deficient rodent models to identify the mechanisms by which a redox imbalance could contribute to the development of SZ and BD pathophysiologies, and to develop novel therapeutic approaches based on antioxidant and redox regulator compounds. Antioxid. Redox Signal. 18, 1428-1443.

RECHERCHE TRANSLATIONNELLE EN NEUROSCIENCES PSYCHIATRIQUES: DE L'ANIMAL MODELE DE SCHIZOPHRENIE A LA DETECTION D'UNE DESORIENTATION SPATIALE, PRATIQUE OU SYMBOLIQUE CHEZ DES PATIENTS

La modélisation, chez l'animal, de maladies psychiatriques telles que la schizophrénie repose sur différentes démarches visant à induire des perturbations cérébrales similaires à celles observées dans la maladie. Nous avons cherché à étudier chez le rat les effets d'une diminution (50%) transitoire en glutathion (GSH) durant le développement (PND 5 à PND 16) à partir de l'implication, chez des adultes, des conséquences de cette perturbation dans des mécanismes fondamentaux de traitement de l'information sensorielle. Cette thèse évalue et documente les déficits de compétences de navigation spatiale dans ce modèle. Nous avons mis en évidence des effets comportementaux à partir de l'identification de différences particulières dans des tâches d'orientation: des difficultés, chez les rats ayant subi un déficit en GSH, à élaborer une représentation globale de l'environnement dans lequel ils se déplacent, difficultés compensées par une attention particulière aux détails visuels le composant. Cette stratégie réactive compensatoire est efficace lorsque les conditions permettent un ajustement continu aux repères visuels environnementaux. Elle ne permet cependant pas des prédictions et des attentes sur ce qui devrait être rencontré et perçu dans une certaine direction, dès qu'une partie des informations visuelles familières disparaît. Il faudrait pour cela une capacité fondée sur une représentation abstraite, à distance des modalités sensorielles qui en ont permis son élaboration. Notre thèse soutient que les déficits, supposés participer à l'émergence de certains symptômes de la maladie, auraient également des conséquences sur l'élaboration de la représentation spatiale nécessaire à des capacités d'orientation effectives et symboliques. - The study of a psychiatric disease such as schizophrenia in an animal model relies on different approaches attempting to replicate brain perturbations similar to those observed in the illness. In the present work, behavioural consequences of a functional deficit in brain connectivity and coordination were assessed in rats with a transitory glutathione (GSH) deficit induced during the postnatal development (PND 5-PND 16) with daily injections of BSO (1- buthionine-(S,R)- sulfoximine). We searched for a theoretical syndrome associating ecologically relevant behavioural adaptive deficits and resulting from the weakening of sensory integration processes. Our results revealed significant and specific deficit of BSO treated rats in spatial orientation tasks designed to test for cognitive mapping abilities. Treated rats behaved as if impaired in the proactive strategies supported by an abstract representation such as a cognitive map. In contrast their performances were preserved whenever the environmental conditions allowed for adaptative reactive strategies, an equivalent of the visual affordances described by Gibson (1958). This supports our thesis that BSO treated rats expressed difficulties in elaborating a global representation of the environment. This deficit was completely - or - partially compensated by the development of an increased attention to the environment's visual details. This compensatory reactive strategy requires a rich environment allowing for continuous adjustment to visual cues. However, such adjustment doesn't allow to predictions and expectancies about what should be met and perceived in a certain direction, when familiar visual spatial cues are missing. Such competencies require orientation based on the use of an abstract spatial representation, independent from the specific sensory modalities that have participated to its elaboration. The impairment of BSO rats such spatial representation could result from a deficit in the integration and organization of perceptual information. Our model leads to the hypothesis that these fundamental deficits might account for certain symptoms of schizophrenia. They would also interfere with in the capacity to elaborate spatial representation necessary for optimal orientation in natural, artificial or symbolic environment.

Spatio-temporal differentiation and sociality in spiders.

Species that differ in their social system, and thus in traits such as group size and dispersal timing, may differ in their use of resources along spatial, temporal, or dietary dimensions. The role of sociality in creating differences in habitat use is best explored by studying closely related species or socially polymorphic species that differ in their social system, but share a common environment. Here we investigate whether five sympatric Anelosimus spider species that range from nearly solitary to highly social differ in their use of space and in their phenology as a function of their social system. By studying these species in Serra do Japi, Brazil, we find that the more social species, which form larger, longer-lived colonies, tend to live inside the forest, where sturdier, longer lasting vegetation is likely to offer better support for their nests. The less social species, which form single-family groups, in contrast, tend to occur on the forest edge where the vegetation is less robust. Within these two microhabitats, species with longer-lived colonies tend to occupy the potentially more stable positions closer to the core of the plants, while those with smaller and shorter-lived colonies build their nests towards the branch tips. The species further separate in their use of common habitat due to differences in the timing of their reproductive season. These patterns of habitat use suggest that the degree of sociality can enable otherwise similar species to differ from one another in ways that may facilitate their co-occurrence in a shared environment, a possibility that deserves further consideration.

Animal Industry News, February 2004, Vol. 5, No. 1

Newsletter produced by Iowa Department of Agriculture and Land Stewardship.

Establishment of animal models to analyze the kinetics and distribution of human tumor antigen-specific CD8⁺ T cells.

Many patients develop tumor antigen-specific T cell responses detectable in peripheral blood mononuclear cells (PBMCs) following cancer vaccine. However, measurable tumor regression is observed in a limited number of patients receiving cancer vaccines. There is a need to re-evaluate systemically the immune responses induced by cancer vaccines. Here, we established animal models targeting two human cancer/testis antigens, NY-ESO-1 and MAGE-A4. Cytotoxic T lymphocyte (CTL) epitopes of these antigens were investigated by immunizing BALB/c mice with plasmids encoding the entire sequences of NY-ESO-1 or MAGE-A4. CD8(+) T cells specific for NY-ESO-1 or MAGE-A4 were able to be detected by ELISPOT assays using antigen presenting cells pulsed with overlapping peptides covering the whole protein, indicating the high immunogenicity of these antigens in mice. Truncation of these peptides revealed that NY-ESO-1-specific CD8(+) T cells recognized D(d)-restricted 8mer peptides, NY-ESO-181-88. MAGE-A4-specific CD8(+) T cells recognized D(d)-restricted 9mer peptides, MAGE-A4265-273. MHC/peptide tetramers allowed us to analyze the kinetics and distribution of the antigen-specific immune responses, and we found that stronger antigen-specific CD8(+) T cell responses were required for more effective anti-tumor activity. Taken together, these animal models are valuable for evaluation of immune responses and optimization of the efficacy of cancer vaccines.

Genome Biology and Evolution of the Animal Kingdom

Estudi realitzat a partir d’una estada a la Institut J.W. Jenkinson Laboratory for Evolution and Development of the University of Oxford, Regne Unit, entre 2010 i 2012. He estat membre del laboratori del Professor Peter W.H. Holland com a becari post-doctoral Beatriu de Pinós des de setembre de 2010 al setembre de 2012. El nostre projecte de recerca se centra en l'anàlisi genòmic comparatiu del Regne Animal, tot explorant el contingut dels genomes a través de totes les branques de l'arbre dels animals. Totes les referències a les meves publicacions durant aquest post-doc es poden trobar a http://about.me/jordi_paps. Crec que el nombre i la qualitat dels resultats del meu post-doc, un total de 8 publicacions incloent dos articles a la prestigiosa revista Nature, són prova de l'èxit d'aquest post-doc. Prof Peter W. H. Holland (Departament de Zoologia de la Universitat d'Oxford) i jo som coautors de tres articles de genòmica comparativa, resultats directes d'aquest projecte: 1) comparació de families gèniques entre vertebrats invertebrats (Briefings in Functional Genomics), 2) el genoma de l'ostra (publicat a la revista Nature), i 3) els genomes de 6 platihelmints paràsits (acceptat també a Nature). A més, tenim altres 2 treballs en preparació. Un d'ells analitza l'evolució, expressió i funció dels gens Hox al a la tènia Hymenolepis. El perfil fi d'aquests gens clau del desenvolupament esclareix els canvis d'estil de vida dels organismes. A més, durant aquest últim post-doc he participat en diverses col•laboracions, incloent anàlisi de gens d'envelliment a cucs plans, un estudi sobre la filogènia del grup Gastrotricha, una revisió de l'evolució phylum Platyhelminthes, així com un capítol d'un llibre sobre l'evolució dels animals bilaterals. Finalment, gràcies a la beca Beatriu de Pinós, el Prof. Peter W.H. Holland m'ha convidat a formar part del seu equip com un investigador post-doctoral en el seu projecte ERC Advance actual sobre duplicacions genòmiques.

On-farm animal welfare assessment in dairy cattle: improved lameness detection

Estudi realitzat a partir d’una estada a la University of British Columbia, Canada, entre 2010 i 2012. Primerament es va desenvolupar una escala per mesurar coixeses (amb valors de l’1 al 5). Aquesta escala es va utilitzar per estudiar l’associació entre factors de risc a nivell de granja (disseny de le instal.lacions i maneig) i la prevalencia de coixeses a Nord America. Les dades es van recollir en un total de 40 granges al Nord Est dels E.E.U.U (NE) i 39 a California (CA) . Totes les vaques del group mes productiu es van categoritzar segons la severitat de les coixeses: sanes, coixes i severament coixes. La prevalencia de coixeses en general fou del 55 % a NE i del 31% a CA. La prevalencia de coixeses severes fou del 8% a NE i del 4% a Ca. A NE, les coixeses en general increntaren amb la presencia de serradura als llits i disminuiren en granjes grans, amb major quantitat de llit i acces a pastura. Les coixeses mes severes incrementaren amb la falta d’higiene als llit i amb la presencia de serradura als llits, i disminuiren amb la quantitat de llit proveit, l’us de sorra als llits i amb la mida de la granja. A CA, les coixeses en general incrementaren amb la falta d’higiene al llit, i disminuiren amb la mida de la granja, la presencia de terres de goma, l’increment d’espai als cubicles , l’espai a l’abeuredor i la desinfeccio de les peulles. Les coixeses severes incrementaren amb la falta d’higiene al llit i disminuixen amb la frequencia de neteja del corral. En conclusio, canvis en el maneig i el disseny de les instal.lacions poden ajudar a disminuir la prevalencia de coixeses, tot i que les estrategies a seguir variaran segons la regio.

Intravascular ultrasound underestimates vessel dimensions.

The information gathered with intravascular ultrasound (IVUS) are of great value in endovascular techniques. The aim of this study was to evaluate the reliability of IVUS when measuring vessel dimensions by comparison with an established reference method. The left carotid artery was exposed in 4 pigs (45-55 kg) and two piezoelectric crystals were sutured on the adventitia in the same cross-sectional plane. The distance between them was measured either by IVUS and by sonomicrometers. The mean distance between the two crystals calculated by the sonomicrometer was 4.7+/-0.4 mm (mean systolic distance was 4.9+/-0.2 mm, mean diastolic distance was 4.6+/-0.1 mm). The mean distance between the two targets calculated by IVUS was 4. 5+/-0.2 mm (mean systolic distance was 4.6+/-0.2 mm and mean diastolic 4.4+/-0.2 mm). Regression analysis of the two series of data shows a R(2)=0.9984. IVUS measurements are an average 5% smaller than sonomicrometer measurements (3.6% up to 8.3%) and the difference is statistically significant ( p <0.05). The underestimation of IVUS measurements will affect the accuracy, and probably the long-term outcome, of endovascular procedures.

Nematode selenoproteome: the use of the selenocysteine insertion system to decode one codon in an animal genome?

Selenocysteine (Sec) is co-translationally inserted into selenoproteins in response to codon UGA with the help of the selenocysteine insertion sequence (SECIS) element. The number of selenoproteins in animals varies, with humans having 25 and mice having 24 selenoproteins. To date, however, only one selenoprotein, thioredoxin reductase, has been detected in Caenorhabditis elegans, and this enzyme contains only one Sec. Here, we characterize the selenoproteomes of C.elegans and Caenorhabditis briggsae with three independent algorithms, one searching for pairs of homologous nematode SECIS elements, another searching for Cys- or Sec-containing homologs of potential nematode selenoprotein genes and the third identifying Sec-containing homologs of annotated nematode proteins. These methods suggest that thioredoxin reductase is the only Sec-containing protein in the C.elegans and C.briggsae genomes. In contrast, we identified additional selenoproteins in other nematodes. Assuming that Sec insertion mechanisms are conserved between nematodes and other eukaryotes, the data suggest that nematode selenoproteomes were reduced during evolution, and that in an extreme reduction case Sec insertion systems probably decode only a single UGA codon in C.elegans and C.briggsae genomes. In addition, all detected genes had a rare form of SECIS element containing a guanosine in place of a conserved adenosine present in most other SECIS structures, suggesting that in organisms with small selenoproteomes SECIS elements may change rapidly.

Prenatal exposure to traffic-related air pollution and ultrasound measures of fetal growth in the INMA Sabadell cohort

Background: Few studies have used longitudinal ultrasound measurements to assess the effect of traffic-related air pollution on fetal growth.Objective: We examined the relationship between exposure to nitrogen dioxide (NO2) and aromatic hydrocarbons [benzene, toluene, ethylbenzene, m/p-xylene, and o-xylene (BTEX)] on fetal growth assessed by 1,692 ultrasound measurements among 562 pregnant women from the Sabadell cohort of the Spanish INMA (Environment and Childhood) study.Methods: We used temporally adjusted land-use regression models to estimate exposures to NO2 and BTEX. We fitted mixed-effects models to estimate longitudinal growth curves for femur length (FL), head circumference (HC), abdominal circumference (AC), biparietal diameter (BPD), and estimated fetal weight (EFW). Unconditional and conditional SD scores were calculated at 12, 20, and 32 weeks of gestation. Sensitivity analyses were performed considering time–activity patterns during pregnancy.Results: Exposure to BTEX from early pregnancy was negatively associated with growth in BPD during weeks 20–32. None of the other fetal growth parameters were associated with exposure to air pollution during pregnancy. When considering only women who spent 2 hr/day in nonresidential outdoor locations, effect estimates were stronger and statistically significant for the association between NO2 and growth in HC during weeks 12–20 and growth in AC, BPD, and EFW during weeks 20–32.Conclusions: Our results lend some support to an effect of exposure to traffic-related air pollutants from early pregnancy on fetal growth during mid-pregnancy.

Feeding and the Equilibrium Feeder Animal Price-Weight Schedule, June 2005

The feeder animal price is a derivative in the sense that its value depends upon the price of animals for the consumption market. It also depends upon the biological growth technology and feed costs. Daily maintenance costs are of particular interest to the husbander because they can be avoided through accelerated feeding. In this paper, the optimal feeding path under equilibrium feeder animal prices is established. This analysis is used to gain a better understanding of feeding decisions, regulation in feedstuff markets, and the consequences of genetic innovations. It is shown that days on feed can increase or decrease with a genetic innovation or other improvement in feed conversion efficiency. The structure of comparative prices for feeder animals at different weights, the early slaughter decision, and equilibrium in feeder animal markets are also developed. Feeder animal prices can increase over a weight interval if biological feed efficiency parameters are low over the interval.

Estimation of the viscoelastic properties of vessel walls using a computational model and Doppler ultrasound

Human arteries affected by atherosclerosis are characterized by altered wall viscoelastic properties. The possibility of noninvasively assessing arterial viscoelasticity in vivo would significantly contribute to the early diagnosis and prevention of this disease. This paper presents a noniterative technique to estimate the viscoelastic parameters of a vascular wall Zener model. The approach requires the simultaneous measurement of flow variations and wall displacements, which can be provided by suitable ultrasound Doppler instruments. Viscoelastic parameters are estimated by fitting the theoretical constitutive equations to the experimental measurements using an ARMA parameter approach. The accuracy and sensitivity of the proposed method are tested using reference data generated by numerical simulations of arterial pulsation in which the physiological conditions and the viscoelastic parameters of the model can be suitably varied. The estimated values quantitatively agree with the reference values, showing that the only parameter affected by changing the physiological conditions is viscosity, whose relative error was about 27% even when a poor signal-to-noise ratio is simulated. Finally, the feasibility of the method is illustrated through three measurements made at different flow regimes on a cylindrical vessel phantom, yielding a parameter mean estimation error of 25%.

ROCK Inhibitor Enhances Adhesion and Wound Healing of Human Corneal Endothelial Cells.

Maintenance of corneal transparency is crucial for vision and depends mainly on the endothelium, a non-proliferative monolayer of cells covering the inner part of the cornea. When endothelial cell density falls below a critical threshold, the barrier and "pump" functions of the endothelium are compromised which results in corneal oedema and loss of visual acuity. The conventional treatment for such severe disorder is corneal graft. Unfortunately, there is a worldwide shortage of donor corneas, necessitating amelioration of tissue survival and storage after harvesting. Recently it was reported that the ROCK inhibitor Y-27632 promotes adhesion, inhibits apoptosis, increases the number of proliferating monkey corneal endothelial cells in vitro and enhance corneal endothelial wound healing both in vitro and in vivo in animal models. Using organ culture human cornea (N = 34), the effect of ROCK inhibitor was evaluated in vitro and ex vivo. Toxicity, corneal endothelial cell density, cell proliferation, apoptosis, cell morphometry, adhesion and wound healing process were evaluated by live/dead assay standard cell counting method, EdU labelling, Ki67, Caspase3, Zo-1 and Actin immunostaining. We demonstrated for the first time in human corneal endothelial cells ex vivo and in vitro, that ROCK inhibitor did not induce any toxicity effect and did not alter cell viability. ROCK inhibitor treatment did not induce human corneal endothelial cells proliferation. However, ROCK inhibitor significantly enhanced adhesion and wound healing. The present study shows that the selective ROCK inhibitor Y-27632 has no effect on human corneal endothelial cells proliferative capacities, but alters cellular behaviours. It induces changes in cell shape, increases cell adhesion and enhances wound healing ex vivo and in vitro. Its absence of toxicity, as demonstrated herein, is relevant for its use in human therapy.