3-amino-1,2,4-triazole inhibits macrophage NO synthase.

Murine macrophages activated by interferon-gamma and lipopolysaccharide become leishmanicidal through a process involving L-arginine-derived nitrogen oxidation products. Both nitrite secretion and parasite killing by activated macrophages were inhibited by 3-amino-1,2,4-triazole as well as the related compound, 3-amino-1,2,4-triazine. Moreover, NO synthase activity in cytosolic extracts of activated cells was inhibited by both compounds. 4-amino-1,2,4-triazole, an isomer of 3-amino-1,2,4-triazole, was without effect. Our results suggest that besides its known inhibitory effect on catalases and peroxidases, 3-amino-1,2,4-triazole is an inhibitor of NO synthase. The resemblance between the tautomeric form of 3-amino-1,2,4-triazole and the guanidino group of L-arginine, the natural substrate for NO synthase, might be responsible for the observed inhibition.

Direct visualization of the trimeric structure of the ASIC1a channel, using AFM imaging.

There has been confusion about the subunit stoichiometry of the degenerin family of ion channels. Recently, a crystal structure of acid-sensing ion channel (ASIC) 1a revealed that it assembles as a trimer. Here, we used atomic force microscopy (AFM) to image unprocessed ASIC1a bound to mica. We detected a mixture of subunit monomers, dimers and trimers. In some cases, triple-subunit clusters were clearly visible, confirming the trimeric structure of the channel, and indicating that the trimer sometimes disaggregated after adhesion to the mica surface. This AFM-based technique will now enable us to determine the subunit arrangement within heteromeric ASICs.

The mif gene is transcriptionally regulated by glucose in insulin-secreting cells.

Macrophage migration inhibitory factor (MIF) is an important regulator of glucose homeostasis. In pancreatic beta-cells, MIF expression is regulated by glucose and its secretion potentiates the glucose-induced insulin secretion. The molecular mechanisms by which glucose mediates its effect on MIF expression are not elucidated. Herein, we report that incubating the differentiated insulin-secreting cell line INS-1 in high glucose concentration increases MIF transcriptional activity as well as the reporter gene activity driven by the -1033 to +63 bp fragment of the MIF promoter. A minimal region located between -187 and -98 bp of this promoter sequence contributes both to basal activity and glucose-responsiveness of the gene. Within this promoter region, two cis-binding sequences were identified by mobility shift assays and footprinting experiments. Both cis-elements interact with nuclear proteins expressed specifically in insulin-secreting cells. In conclusion, we identified a minimal region of the MIF promoter which contributes to the glucose stimulation of the mif gene in insulin-secreting cells.

Isolation from mouse fibroblasts of a cDNA encoding a new form of the fibroblast growth factor receptor (flg).

Structural definition of the receptors for neurotropic and angiogenic modulators such as fibroblast growth factors and related polypeptides will yield insight into the mechanisms that control early development, embryogenesis, organogenesis, wound repair and neovessel formation. We isolated 3 murine cDNAs encoding different binding domains of these receptors (flg). Comparison of these ectoplasmic portions showed that two of the forms corresponded to previously described murine molecules whereas the third one had a different ectoplasmic portion generated by specific changes in two regions. Interestingly, expression of this third form seems to be restricted in its tissue distribution. Such modifications could influence the ligand specificity of the different receptors and/or their binding affinity.

Executive Order Number Ten, June 1972

Authorize and direct the transfer of duties as given to the Administration of State Communications and the State Communications Advisory Council to the General Services Department.

Iowa Department of Commerce - Iowa Utilities Board, Agency Performance Plan, 2007

Annual Report, Agency Performance Plan

Réponses de la musaraigne musette Crocidura russula, aux marquages odorants d'individus de son espèce (Insectivota, Soricidae)

In order to evaluate the reaction to conspecifics scent tracks of Crocidura russula, a shrew with poorly developped territorial behaviour, simple choice tests in a Y-shaped systems were used. C. russula prefers a marked path to an unmarked one, the tracks of an unknown individual to its own, the tracks of an individual of the opposite sex to those of an individual of the same sex, and the tracks of its sexual partner to those of another individual of the same sex. The choices between two tracks gave a less obvious result than the choices between a marked path and an unmarked one. Ecological and social implications of these results are discussed.

Sports-related chronic repetitive head trauma as a cause of pituitary dysfunction.

Traumatic brain injury (TBI) is recognized as a cause of hypopituitarism even after mild TBI. Although over the past decade, a growing body of research has detailed neuroendocrine changes induced by TBI, the mechanisms and risk factors responsible for this pituitary dysfunction are still unclear. Around the world, sports-especially combative sports-are very popular. However, sports are not generally considered as a cause of TBI in most epidemiological studies, and the link between sports-related head trauma and hypopituitarism has not been investigated until recently. Thus, there is a paucity of data regarding this important concern. Because of the large number of young sports participants with near-normal life expectancy, the implications of undiagnosed or untreated postconcussion pituitary dysfunction can be dramatic. Understanding the pathophysiological mechanisms and risk factors of hypopituitarism caused by sports injuries is thus an important issue that concerns both medical staff and sponsors of sports. The aim of this paper was to summarize the best evidence for understanding the pathophysiological mechanisms and to discuss the current data and recommendations on sports-related head trauma as a cause of hypopituitarism.

Del prestatge a la web: la transformació de la formació de les col·leccions a les biblioteques universitàries

L’existència d’una xarxa mundial de comunicacions ubiqua i barata que cada vegada més permet obtenir documents de manera fàcil i gratuïta requerirà una transformació de les pràctiques de la formació de col·leccions a les biblioteques universitàries. Això estarà impulsat per una sèrie d’avenços específics, que inclouen la digitalització de continguts; el desenvolupament de repositoris d’impresos; el desenvolupament de lectors de llibres electrònics i de l’edició mitjançant la impressió sota demanda; el creixement de l’accés obert; els reptes per establir estructures d’edició acadèmica; i el creixement de noves formes d’activitats acadèmiques basades en l’obertura i la productivitat social. Si les biblioteques universitàries volen tenir èxit, hauran de desmuntar les col·leccions impreses patrimonials; passar de la selecció de llibres ítem a ítem a la compra sota demanda i a les subscripcions; gestionar la transició cap a revistes d’accés obert; centrar-se en conservar ítems únics; i desenvolupar nous mecanismes per finançar una infraestructura nacional.

The inhibition of MAPK potentiates the anti-angiogenic efficacy of mTOR inhibitors.

The mammalian target of rapamycin (mTOR) which is part of two functionally distinct complexes, mTORC1 and mTORC2, plays an important role in vascular endothelial cells. Indeed, the inhibition of mTOR with an allosteric inhibitor such as rapamycin reduces the growth of endothelial cell in vitro and inhibits angiogenesis in vivo. Recent studies have shown that blocking mTOR results in the activation of other prosurvival signals such as Akt or MAPK which counteract the growth inhibitory properties of mTOR inhibitors. However, little is known about the interactions between mTOR and MAPK in endothelial cells and their relevance to angiogenesis. Here we found that blocking mTOR with ATP-competitive inhibitors of mTOR or with rapamycin induced the activation of the mitogen-activated protein kinase (MAPK) in endothelial cells. Downregulation of mTORC1 but not mTORC2 had similar effects showing that the inhibition of mTORC1 is responsible for the activation of MAPK. Treatment of endothelial cells with mTOR inhibitors in combination with MAPK inhibitors reduced endothelial cell survival, proliferation, migration and tube formation more significantly than either inhibition alone. Similarly, in a tumor xenograft model, the anti-angiogenic efficacy of mTOR inhibitors was enhanced by the pharmacological blockade of MAPK. Taken together these results show that blocking mTORC1 in endothelial cells activates MAPK and that a combined inhibition of MAPK and mTOR has additive anti-angiogenic effects. They also provide a rationale to target both mTOR and MAPK simultaneously in anti-angiogenic treatment.

Mechanisms of spindle positioning during "Caenorhabditis elgans" asymmetric cell division

Résumé : Le positionnement correct du fuseau mitotique est crucial pour les divisions cellulaires asymétriques, car il gouverne le contrôle spatial de la division cellulaire et assure la ségrégation adéquate des déterminants cellulaires. Malgré leur importance, les mécanismes contrôlant le positionnement du fuseau mitotique sont encore mal compris. Chez l'embryon au stade une-cellule du nématode Caenorhabditis elegans, le fuseau mitotique est positionné de manière asymétrique durant l'anaphase grâce à l'action de générateurs de force situés au cortex cellulaire, et dont la nature était jusqu'alors indéterminée. Ces générateurs de force corticaux exercent une traction sur les microtubules astraux et sont dépendants de deux protéines Gα et de leurs protéines associées. Cette thèse traite de la nature de la machinerie responsable pour la génération des forces de tractions, ainsi que de son lien avec les protéines Gα et associées. Nous avons combiné des expériences de coupure par faisceau laser du fuseau mitotique avec le contrôle temporel de l'inactivation de gènes ou de l'exposition à des produits pharmacologiques. De cette manière, nous avons établi que la dynéine, un moteur se déplaçant vers l'extrémité négative des microtubules, ainsi que la dynamique des microtubules, sont toutes deux requises pour la génération efficace des forces de tractions. Nous avons démontré que les protéines Gα et leurs protéines associées GPR-1/2 et LIN-5 interagissent in vivo avec LIS-1, un composant du complexe de la dynéine. De plus, nous avons découvert que les protéines Gα, GPR-1/2 et LIN-5 promeuvent la présence du complexe de la dynéine au cortex cellulaire. Nos résultats suggèrent un mécanisme par lequel les protéines Gα permettent le recrutement cortical de GPR-1/2 et LIN-5, assurant ainsi la présence de la dynéine au cortex. Conjointement avec la dynamique des microtubules, ce mécanisme permet la génération des forces de tractions afin d'obtenir une division cellulaire correcte. Comme les mécanismes contrôlant le positionnement du fuseau mitotique et les divisions cellulaires asymétriques sont conservés au cours de l'évolution, nous espérons que les mécanismes élucidés par ce travail sont d'importance générale pour la génération de la diversité cellulaire durant le développement. De plus, ces mécanismes pourraient être applicables à d'autres divisions asymétriques, comme celle des cellules souches, dont le disfonctionnement peut entraîner la génération de cellules cancéreuses. Abstract : Proper spindle positioning is crucial for asymmetric cell division, because it controls spatial aspects of cell division and the correct inheritance of cell-fate determinants. However, the mechanisms governing spindle positioning remain incompletely understood. In the Caenorhabditis elegans one-cell stage embryo, the spindle becomes asymmetrically positioned during anaphase through the action of as-yet unidentified cortical force generators that pull on astral microtubules and that depend on two Gα proteins and associated proteins. This thesis addresses the nature of the force generation machinery and the link with the Gα and associated proteins. By performing spindle-severing experiments following temporally restricted gene inactivation and drug exposure, we established that microtubule dynamics and the minus-end directed motor dynein are both required for generating efficient pulling forces. We discovered that the Gα proteins and their associated proteins GPR-1/2 and LIN-5 interact in vivo with LIS-1, a component of the dynein complex. Moreover, we uncovered that LIN-5, GPR-1/2 and the Gα proteins promote the presence of the dynein complex at the cell cortex. Our findings suggest a mechanism by which the Gα proteins enable GPR-1/2 and LIN-5 recruitment to the cortex, thus ensuring the presence of cortical dynein. Together with microtubule dynamics, this allows pulling forces to be exerted and proper cell division to be achieved. Because the mechanisms of spindle positioning and asymmetric cell division are conserved across evolution, we expect the underlying mechanism uncovered here to be of broad significance for the generation of cell diversity during development. Moreover, this mechanism could be relevant for other asymmetric cell divisions, such as stem cell divisions, whose dysfunction may lead to the generation of cancer cells.

Business Sphere, Vol. 18, no.1

Information technology is a strong and important sector of the Iowa economy employing 30,000 Iowans at more than 2,000 companies, according to a new analysis from Battelle Institute consultants. The strength of Iowa’s IT industry is based in the service-segment. Internet and data services, communications network services, and software and computer services constitute 81 percent of all IT employment. Slightly ahead of U.S. trends, these service sectors compose the backbone of Iowa’s IT industry,

A joint back calculation model for the imputation of the date of HIV infection in a prevalent cohort.

In studies of the natural history of HIV-1 infection, the time scale of primary interest is the time since infection. Unfortunately, this time is very often unknown for HIV infection and using the follow-up time instead of the time since infection is likely to provide biased results because of onset confounding. Laboratory markers such as the CD4 T-cell count carry important information concerning disease progression and can be used to predict the unknown date of infection. Previous work on this topic has made use of only one CD4 measurement or based the imputation on incident patients only. However, because of considerable intrinsic variability in CD4 levels and because incident cases are different from prevalent cases, back calculation based on only one CD4 determination per person or on characteristics of the incident sub-cohort may provide unreliable results. Therefore, we propose a methodology based on the repeated individual CD4 T-cells marker measurements that use both incident and prevalent cases to impute the unknown date of infection. Our approach uses joint modelling of the time since infection, the CD4 time path and the drop-out process. This methodology has been applied to estimate the CD4 slope and impute the unknown date of infection in HIV patients from the Swiss HIV Cohort Study. A procedure based on the comparison of different slope estimates is proposed to assess the goodness of fit of the imputation. Results of simulation studies indicated that the imputation procedure worked well, despite the intrinsic high volatility of the CD4 marker.

Squared interaction matrix Sherrington-Kirkpatrick model for a spin glass

The mean-field theory of a spin glass with a specific form of nearest- and next-nearest-neighbor interactions is investigated. Depending on the sign of the interaction matrix chosen we find either the continuous replica symmetry breaking seen in the Sherrington-Kirkpartick model or a one-step solution similar to that found in structural glasses. Our results are confirmed by numerical simulations and the link between the type of spin-glass behavior and the density of eigenvalues of the interaction matrix is discussed.

Peroxynitrite cytotoxicity on bovine retinal pigmented epithelial cells in culture.

Peroxynitrite induced in vitro a dose dependent toxicity on retinal pigmented epithelial (RPE) cells. Cell death was partially mediated by apoptosis as demonstrated by nuclear fragmentation and TdT-mediated dUTP nick-end labeling assay. Peroxynitrite-induced tyrosine nitration was revealed by immunocytochemistry, both in the cytoplasm and in the nucleus of the cells. Nitration was not observed in RPE cells, producing nitric oxide (NO) after stimulation by lipopolysacharide and interferon-g (IFN-gamma), suggesting that peroxynitrite was not formed in vitro in such conditions. Peroxynitrite could be responsible for the retinal damages observed in pathological conditions in which NO has been demonstrated to be involved. In this context, EGb761, identified as a free radical scavenger, was showed herein to protect RPE cells against peroxynitrite injury.