Intracellular trafficking of interleukin-1 receptor I requires Tollip.

Interleukin-1 receptor (IL-1RI) is a master regulator of inflammation and innate immunity. When triggered by IL-1beta, IL-1RI aggregates with IL-1R-associated protein (IL-1RAcP) and forms a membrane proximal signalosome that potently activates downstream signaling cascades. IL-1beta also rapidly triggers endocytosis of IL-1RI. Although internalization of IL-1RI significantly impacts signaling, very little is known about trafficking of IL-1RI and therefore about precisely how endocytosis modulates the overall cellular response to IL-1beta. Upon internalization, activated receptors are often sorted through endosomes and delivered to lysosomes for degradation. This is a highly regulated process that requires ubiquitination of cargo proteins as well as protein-sorting complexes that specifically recognize ubiquitinated cargo. Here, we show that IL-1beta induces ubiquitination of IL-1RI and that via these attached ubiquitin groups, IL-1RI interacts with the ubiquitin-binding protein Tollip. By using an assay to follow trafficking of IL-1RI from the cell surface to late endosomes and lysosomes, we demonstrate that Tollip is required for sorting of IL-1RI at late endosomes. In Tollip-deficient cells and cells expressing only mutated Tollip (incapable of binding IL-1RI and ubiquitin), IL-1RI accumulates on late endosomes and is not efficiently degraded. Furthermore, we show that IL-1RI interacts with Tom1, an ubiquitin-, clathrin-, and Tollip-binding protein, and that Tom1 knockdown also results in the accumulation of IL-1RI at late endosomes. Our findings suggest that Tollip functions as an endosomal adaptor linking IL-1RI, via Tom1, to the endosomal degradation machinery.

Screening for wound-induced oxylipins in Arabidopsis thaliana by differential HPLC-APCI/MS profiling of crude leaf extracts and subsequent characterisation by capillary-scale NMR

A simple non-targeted differential HPLC-APCI/MS approach has been developed in order to survey metabolome modifications that occur in the leaves of Arabidopsis thaliana following wound-induced stress. The wound-induced accumulation of metabolites, particularly oxylipins, was evaluated by HPLC-MS analysis of crude leaf extracts. A generic, rapid and reproducible pressure liquid extraction procedure was developed for the analysis of restricted leaf samples without the need for specific sample preparation. The presence of various oxylipins was determined by head-to-head comparison of the HPLC-MS data, filtered with a component detection algorithm, and automatically compared with the aid of software searching for small differences in similar HPLC-MS profiles. Repeatability was verified in several specimens belonging to different series. Wound-inducible jasmonates were efficiently highlighted by this non-targeted approach without the need for complex sample preparation as is the case for the 'oxylipin signature' procedure based on GC-MS. Furthermore this HPLC-MS screening technique allowed the isolation of induced compounds for further characterisation by capillary-scale NMR (CapNMR) after HPLC scale-up. In this paper, the screening method is described and applied to illustrate its potential for monitoring polar and non-polar stress-induced constituents as well as its use in combination with CapNMR for the structural assignment of wound-induced compounds of interest

A case of acute retinal pigment epithelitis: spectral domain optical coherence tomography time course and physiopathologic hypothesis.

PURPOSE: To report the time course of retinal morphologic changes in a patient with acute retinal pigment epithelitis (ARPE) using spectral domain optical coherence tomography (SD-OCT). METHODS: A 30-year old man was referred for blurred vision of his right eye after five days that appeared suddenly 15 days after recovery from a flu-like syndrome. SD-OCT was performed immediately, followed by fluorescein and infracyanine angiography at eight days and then at three weeks. RESULTS: At presentation, a bubble of sub-macular deposit was observed on the right macula with central golden micronodules in a honeycomb pattern. SD-OCT showed an "anterior dislocation" of all the retinal layers up to the inner/outer segment (IS/OS) line and irregular deposits at the OS level together with thickening of the retinal pigment epithelial (RPE) layer. As visual acuity increased, eight days later, the OCT showed reduction of the sub-retinal deposits and an abnormal hyperflectivity of the sub-retinal and RPE layers was observed. The patient showed a positive serology for picornavirus. DISCUSSION: The acute SD-OCT sections of this patient with ARPE were compared with histological sections of a 35 day old Royal College of Surgeons rat. Similar findings could be observed, with preservation of the IS/OS line and accumulation of debris at the OS level, suggesting that ARPE symptoms could result from a transient phagocytic dysfunction of the RPE at the fovea, inducing reversible accumulation of undigested OS. Picornaviruses comprising enterovirus and coxsachievirus described as being associated with acute chorioretinitis. In this case, it was responsible for ARPE. CONCLUSION: We hypothesize that ARPE syndrome results from a transient dysfunction of RPE, which can occur as a post viral reaction.

The Paleozoic magmatic history of the Maggia and Sambuco nappes, Lower Penninic, Central Lepontine Alps

Résumé : Les corps magmatiques sont des indicateurs essentiels dans toute reconstitution paléogéographique et/ou géodynamique d'un cycle orogénique, en particulier en contexte polycyclique, où la plupart des autres indices ont été oblitérés. Ils sont aisément datables et leurs caractéristiques géochimiques permettent de contraindre leur contexte tectonique de mise en place. Cette approche a été appliquée aux socles pré-mésozoïques des nappes penniques inférieures de Sambuco et de la Maggia, dans les Alpes centrales lepontines. Plusieurs événements magmatiques ont été identifiés dans le socle de Sambuco et datés par la méthode U-Pb sur zircon couplée à la technique LA-ICPMS. La suite calco-alcaline mafique rubanée de Scheggia est datée du Cambrien inférieur à 540-530 Ma ; le métagranite alumineux oeillé de Sasso Nero a un âge de 480-470 Ma, tout comme bien d'autres «older orthogneisses» des socles alpins. Il contient des zircons hérités d'âge panafricain à 630-610 Ma, indicateur d'une affiliation gondwanienne de ces terrains. Le pluton calco-alcalin du Matorello est daté à environ 300-310 Ma, et les filons lamprophyriques qu'il abrite à 300 Ma. La granodiorite de Cocco et le leucogranite de Ruscada, tous deux intrudés dans le socle de la nappe adjacente de la Maggia, ont des âges similaires à celui du Matorello. Ceci ajouté aux similitudes magmatiques observées entre Cocco et Matorello suggère une proximité paléogéographique des deux nappes au Permien-Carbonifère. Or ces dernières sont actuellement considérées appartenir à deux domaines paléogéographiques mésozoïques distincts : helvétique pour Sambuco et briançonnais pour Maggia, séparés par un bassin océanique. Si tel fut le cas, aucun mouvement décrochant ne doit avoir décalé les marges continentales de l'océan, retrouvées en parfaite coïncidence lors de sa fermeture. Le Matorello est un pluton recristallisé en faciès amphibolite et plissé par cinq phases successives de déformation non-coaxiales, qui ont conduit à son renversement complet, attesté par des indicateurs de paléogravité. Il préserve de spectaculaires phénomènes de coexistence liquide de magmas (essaims d'enclaves et Bills composites). Ce pluton était originellement tabulaire, construit par l'accumulation de multiples injections de magma en feuillets d'épaisseur métrique à décamétrique. Suivant le rythme de mise en place, les injections successives ont rapidement cristallisé avec des contours nets et bien définis (Bills composites) ou se sont mélangées avec les précédentes pour former une couche non consolidée de plusieurs dizaines de mètres d'épaisseur (granodiorite principale). Les injections individuelles sont délimitées par de subtils contrastes en granulométrie, proportions modales ou ségrégation de minéraux (schlieren), ou par des phénomènes d'érosion le long des surfaces de contact. Deux couches métriques à contour sinueux consistent en une accumulation compacte d'enclaves mafiques arrondies dans une matrice granodioritique fine. Le granoclassement des enclaves, la présence de figures de charge et de phénomènes érosifs en base de couche, ainsi que des schlieren de biotite entrecroisés évoquent l'injection de coulées de magma chargé d'enclaves et de faible viscosité en régime hydrodynamique turbulent dans un encaissant granodioritique encore largement liquide. La nature hybride des roches implique une chambre magmatique sous-jacente, en cours de différenciation et périodiquement réalimentée. Les magmas sont des liquides mafiques dérivés du manteau et des liquides anatectiques d'origine crustale, comme l'indique la gamme mesurée des rapports isotopiques initiaux du Sr (0.704 à 0.709) et des valeurs epsilon Nd (-2.1 à -4.7). Ces données montrent également que la contribution crustale est dominante, en accord avec les isotopes du plomb. Les phénomènes d'hybridation ont vraisemblablement eu lieu en base de croûte et dans la chambre magmatique sous-jacente au laccolite du Matorello. Les indicateurs de paléogravité du Matorello contribuent accessoirement à la compréhension de l'architecture actuelle de la nappe de Sambuco. Des plis isoclinaux à surface axiale verticale peuvent être mis en évidence par le contact entre les faciès dioritique et granodioritique. L'antiforme dont le Matorello forme le coeur est un synclinal, ce qui le positionne dans le Flanc inverse du grand pli couché que forme la nappe de Sambuco. Par ailleurs, des blocs de gneiss retrouvés dans le wildflysch sommital de la couverture de la nappe d'Antigorio ont été affiliés dans cette étude au pluton du Matorello. Ceci implique que le front de la nappe de Sambuco chevauchait déjà la partie est du bassin d'Antigorio au moment de sa fermeture. Par conséquent, ce n'est qu'en position externe que la nappe du Lebendun chevauche directement la nappe d'Antigorio. Abstract Magmatic bodies are important markers in paleo-geographic or geodynamic reconstructions of orogenic cycles, even more so in the case of polycyclic events where many of the other markers have been overwritten or destroyed. Plutons are relatively easy to date and their geochemical properties help constrain the tectonic context in which they were emplaced. This study focuses on the pre-mesozoic basement in the Sambuco and Maggia lower Penninic nappes located in the central Lepontine domain of the Alps. A number of magmatic events have been identified in the Sambuco basement. These events were dated using LA-ICPMS U/Pb on zircon grains. The mafic calc-alkaline banded Scheggia suite is dated as lower Cambrian, 540-530 Ma. The Al-rich Sasso-Nero lenticular gneiss is 480-470 Ma old (similarly to many older orfhogneisses of the Alpine basement) and contains 630-610 Ma old pan-African inherited zircons that illustrate the Gondwanian origin of these terranes.The calc-alkaline Matorello pluton is dated as 310-300 Ma whereas the lamprophyric bodies it contains are of 300 Ma. The Cocco granodiorite and the Ruscada leucogranite both intrude the basement of the adjacent Maggia nappe and are of similar ages to the Matorello. The ages as well as the geochemical similarities between the Cocco, Rucada and Matorello plutons suggest their paleo-geographic proximity at the Permian-Carboniferous boundary. However, these nappes are currently considered as belonging to two different Mesozoic paleo-geographic domains. Indeed, the Sambuco is considered as Helvetic whereas the Maggia is said to be Briançonnais, both separated by an oceanic basin. If this is the case, then it is essential that nostrike-slip movement has misaligned both continental margins since these coincide perfectly now that the oceanic domain closed. The Matorello pluton was originally a tabular intrusion, built up by the accumulation of multiple, several meter-thick, subhorizontal sheet-like injections of magma. Depending on their emplacement rate, the successive magma injections either solidified rapidly with sharp and rather well-defined boundaries (like the composite sills) or mingled with previous injections generating a thick molten layer up to several tens to hundred meters thick, like in the main granodioritic facies. These coalesced injections are hardly distinguishable, however subtle contrasts in granulometry, mineral modal proportions or mineral sorting (cross-bedded biotite-rich schlieren), as well as erosional features and/or crystal entrapment along contact surfaces allow to distinguish between the different injections. Two exceptional meter-thick layers display sinuous boundaries with the host granodiorite and consist of a densely packed accumulation of mafic enclaves in a granodioritic matrix. Gravitational sorting of the enclaves with load cast features at the base of the layers and sinuous biotite schlieren point to injection of low viscosity turbulent composite magma flows in the still largely molten granodiorite host. The hybrid nature of these rocks implies the existence of á periodically replenished and differentiated underlying magma chamber. Magmas are mafic liquids derived from the mantle and anatectic liquids of crustal origin, as shown by the (87Sr/86Sr), and epsilon Nd values (0.704-0.709 and -2.1 to -4.7 respectively. These data show that the crustal contribution is important, as confirmed by the Pb isotopes. The hybridisation processes seem to have occurred in the lower crust in magma chambers underlying the Matorello laccolith. The paleo-gravity markers in the Matorello help understand the architecture of the Sambuco nappe. Isoclinal folds with a vertical axial plane can be seen at the contact between dioritic and granodioritic facies. The antiform structure of which the Matorello is the heart is in fact a syncline. This places it in the inverse flanc of the large recumbent fold that constitutes the Sambuco nappe. The gneiss blocs found in the summital wildflysh cover of the Antigorio nappe have been linked to the Matorello pluton. This means that the front of the Sambuco nappe already overlapped the Antigorio basin when it closed. This implies that the Lebendun nappe can only overlap the Antigorio nappe in it's external position. Résumé grand public La chaîne alpine est la conséquence de la collision tertiaire entre deux masses continentales, l'Europe au nord et la péninsule apulienne africaine au sud, originellement séparées par l'océan mésozoïque téthysien. Cette collision a fermé un espace large de plusieurs centaines de km avec pour résultat l'écaillage de la croûte terrestre en unités tectoniques de dimensions variables, qui se sont empilées, imbriquées, éventuellement replissées en nappes de géométrie complexe. Cet amoncellement de 40 km d'épaisseur a vu sa température et sa pression lithostatique internes augmenter jusqu'à des valeurs de l'ordre de 680 °C et 6000 bars, induisant une recristallisation métamorphique des roches. L'un des objectifs de la géologie alpine est de reconstituer la géographie de la région aux temps mésozoïques de l'océan téthysien, en d'autres termes, de replacer chacune des unités tectoniques identifiées au sein de l'empilement alpin dans sa position originelle. Le défi est de taille et peut être comparé à celui de la reconstitution d'un vaste puzzle, dont certaines pièces seraient endommagées au niveau de leur contour ou leurs couleurs (métamorphisme), dissimulées par d'autres (enfouissement), voire tombées de la table de jeu (subduction, échappement latéral). Plusieurs approches ont été mises en oeuvre au cours du siècle écoulé. On citera en particulier la stratigraphie, la tectonique et le paléomagnétisme. Dans ce travail, nous avons essentiellement utilisé des techniques de datation isotopique absolue des roches (U/Pb sur zircon) qui, sur la base des connaissances acquises par l'ensemble des autres disciplines géologiques, nous ont permis de mieux contraindre ta paléogéographie mésozoïque du domaine «pennique inférieur » des Alpes centrales lépontines. Et au-delà? Nous savons tous que la disposition des continents à la surface de la Terre évolue constamment. Il est donc tentant d'essayer de remonter plus loin encore dans le temps et de reconstituer la physionomie de la marge sud européenne, tout au moins certains éléments de son histoire, au cours de l'ère paléozoïque. Les traces de ces événements très anciens sont naturellement ténues et dans ce contexte, les techniques de datation mentionnées ci-dessus deviennent les outils les plus performants. Ainsi, des datations u/Pb sur zircon nous ont permis de recenser plusieurs intrusions magmatiques, attribuées à quatre événements orogéniques anté-alpins. Des âges néoprotérozoïques (630-610 millions d'années ou Ma), cambrien inférieur (540-530 Ma), ordovicien inférieur (480-470 Ma) et carbonifère supérieur-permien inférieur (310-285 Ma) ont été obtenus dans le socle de la nappe de Sambuco. Des âges similaires à 300 Ma ont été obtenus dans la nappe voisine de la Maggia, qui permettent de relier ces deux unités. Aujourd'hui côte à côte, ces deux nappes devaient également se trouver proches l'une de l'autre il y a 300 Ma, lors de l'extension post-varisque. Les structures magmatiques spectaculaires préservées dans le pluton du Matorello (300 Ma) contraignent la géométrie actuelle de la nappe de Sambuco dans laquelle l'intrusion s'est mise en place. La forme originelle du pluton, aujourd'hui retourné et replissé plusieurs fois, s'avère être tabulaire, faite d'intrusions de faible épaisseur (1-300 m) s'étalant en forme de disque (30m à 2 km de diamètre). Les injections successives de magma se sont accumulées sous un toit dioritique précoce; elles sont issues, par le refais de fractures, d'une chambre magmatique plus profonde, périodiquement réalimentée par des magmas calco-alcalins d'origine mantellique contaminés parla croûte continentale profonde (εNd = -2.1 à -4.7). Des accumulations d'enclaves magmatiques arrondies et granoclassées dans des paléo-chenaux à fond érosif témoignent de conditions de mise en place hydrodynamiques à haute énergie. Ces enclaves sont emmenées de la chambre magmatique sous-jacente à la faveur d'épisodes de fracturation hydraulique liés à l'injection de magmas matelliques chauds dans des liquides différenciés riches en eau. Cette hypothèse est étayée par l'existence de filons composites. Une paléohorizontale a pu être déduite au sein du pluton, indiquant que cette partie de la nappe de Sambuco est verticalisée et isoclinalement replissée par la déformation alpine. Finalement, des blocs érodés du socle Sambuco ont été retrouvés dans le wildflysch sommital de la couverture sédimentaire mésozoïque de la nappe d'Antigorio sous-jacente. Ceci suggère que les blocs ont été fournis parle front de la nappe de Sambuco en train de chevaucher sur la nappe d'Antigorio au moment de la fermeture du bassin sédimentaire de cette dernière.

Wet Oxidation of Concentrated Wastewaters: Process Combination and Reaction Kinetic Modeling

The accumulation of aqueous pollutants is becoming a global problem. The search for suitable methods and/or combinations of water treatment processes is a task that can slow down and stop the process of water pollution. In this work, the method of wet oxidation was considered as an appropriate technique for the elimination of the impurities present in paper mill process waters. It has been shown that, when combined with traditional wastewater treatment processes, wet oxidation offers many advantages. The combination of coagulation and wet oxidation offers a new opportunity for the improvement of the quality of wastewater designated for discharge or recycling. First of all, the utilization of coagulated sludge via wet oxidation provides a conditioning process for the sludge, i.e. dewatering, which is rather difficult to carry out with untreated waste. Secondly, Fe2(SO4)3, which is employed earlier as a coagulant, transforms the conventional wet oxidation process into a catalytic one. The use of coagulation as the post-treatment for wet oxidation can offer the possibility of the brown hue that usually accompanies the partial oxidation to be reduced. As a result, the supernatant is less colored and also contains a rather low amount of Fe ions to beconsidered for recycling inside mills. The thickened part that consists of metal ions is then recycled back to the wet oxidation system. It was also observed that wet oxidation is favorable for the degradation of pitch substances (LWEs) and lignin that are present in the process waters of paper mills. Rather low operating temperatures are needed for wet oxidation in order to destruct LWEs. The oxidation in the alkaline media provides not only the faster elimination of pitch and lignin but also significantly improves the biodegradable characteristics of wastewater that contains lignin and pitch substances. During the course of the kinetic studies, a model, which can predict the enhancements of the biodegradability of wastewater, was elaborated. The model includes lumped concentrations suchas the chemical oxygen demand and biochemical oxygen demand and reflects a generalized reaction network of oxidative transformations. Later developments incorporated a new lump, the immediately available biochemical oxygen demand, which increased the fidelity of the predictions made by the model. Since changes in biodegradability occur simultaneously with the destruction of LWEs, an attempt was made to combine these two facts for modeling purposes.

An update of the mechanisms of resistance to EGFR-tyrosine kinase inhibitors in breast cancer: gefitinib (Iressatrade mark)-induced changes in the expression and nucleo-cytoplasmic trafficking of HER-ligands (Review)

Intrinsic resistance to the epidermal growth factor receptor (EGFR; HER1) tyrosine kinase inhibitor (TKI) gefitinib, and more generally to EGFR TKIs, is a common phenomenon in breast cancer. The availability of molecular criteria for predicting sensitivity to EGFR-TKIs is, therefore, the most relevant issue for their correct use and for planning future research. Though it appears that in non-small-cell lung cancer (NSCLC) response to gefitinib is directly related to the occurrence of specific mutations in the EGFR TK domain, breast cancer patients cannot be selected for treatment with gefitinib on the same basis as such EGFR mutations have beenreported neither in primary breast carcinomas nor in several breast cancer cell lines. Alternatively, there is a generalagreement on the hypothesis that the occurrence of molecular alterations that activate transduction pathways downstreamof EGFR (i.e., MEK1/MEK2 - ERK1/2 MAPK and PI-3'K - AKT growth/survival signaling cascades) significantly affect the response to EGFR TKIs in breast carcinomas. However,there are no studies so far addressing a role of EGF-related ligands as intrinsic breast cancer cell modulators of EGFR TKIefficacy. We recently monitored gene expression profiles andsub-cellular localization of HER-1/-2/-3/-4 related ligands (i.e., EGF, amphiregulin, transforming growth factor-α, ß-cellulin,epiregulin and neuregulins) prior to and after gefitinib treatment in a panel of human breast cancer cell lines. First, gefitinibinduced changes in the endogenous levels of EGF-related ligands correlated with the natural degree of breast cancer cellsensitivity to gefitinib. While breast cancer cells intrinsically resistant to gefitinib (IC50 ≥15 μM) markedly up-regulated(up to 600 times) the expression of genes codifying for HERspecific ligands, a significant down-regulation (up to 106 times)of HER ligand gene transcription was found in breast cancer cells intrinsically sensitive to gefitinib (IC50 ≤1 μM). Second,loss of HER1 function differentially regulated the nuclear trafficking of HER-related ligands. While gefitinib treatment induced an active import and nuclear accumulation of the HER ligand NRG in intrinsically gefitinib-resistant breastcancer cells, an active export and nuclear loss of NRG was observed in intrinsically gefitinib-sensitive breast cancer cells.In summary, through in vitro and pharmacodynamic studies we have learned that, besides mutations in the HER1 gene,oncogenic changes downstream of HER1 are the key players regulating gefitinib efficacy in breast cancer cells. It now appears that pharmacological inhibition of HER1 functionalso leads to striking changes in both the gene expression and the nucleo-cytoplasmic trafficking of HER-specific ligands,and that this response correlates with the intrinsic degree of breast cancer sensitivity to the EGFR TKI gefitinib. Therelevance of this previously unrecognized intracrine feedback to gefitinib warrants further studies as cancer cells could bypassthe antiproliferative effects of HER1-targeted therapeutics without a need for the overexpression and/or activation of other HER family members and/or the activation of HER-driven downstream signaling cascades

Erosió hídrica en vinya per a producció de vi d'alta qualitat en zona mediterrània (Anoia-Penedès): quantificació de les pèrdues de nutrients per erosió del sòl i implicacions

La vinya, malgrat que no és una planta exigent pel que fa als sòls, es veu afectada per la pèrdua de sed per causa de l'erosió hídrica. En aquest treball es presenten uns primers resultats de mesures de pèrdues de sed en condicions reals de camp. Les parcel les control són de grans dimensions, conreades segons els costums de la zona. Com a referencia es prenen les pèrdues de sòl mitjanes, calculades a partir de l'USLE, per al conreu de vinya. Es determinen, a més de les pèrdues globals de sòlids, les de nutrients que això comporta. Tenint en compte que la metodologia emprada en el camp i en el laboratori condueix a resultats per defecte, les pèrdues mesurades del període de l'any de màximes pluges (tardor) són, de mitjana, de 13 Mg ha-1 en un sistema de cultiu tradicional i fins a 100 Mg ha-1 en un sistema de cultiu emparrat. La importància del problema a curt termini encareix els factors de producció i fa perillar la sostenibilitat de la vinya a llarg termini.

Plant-derived phenolics inhibit the accrual of structurally characterised protein and lipid oxidative modifications

Epidemiological data suggest that plant-derived phenolics beneficial effects include an inhibition of LDL oxidation. After applying a screening method based on 2,4-dinitrophenyl hydrazine- protein carbonyl reaction to 21 different plant-derived phenolic acids, we selected the most antioxidant ones. Their effect was assessed in 5 different oxidation systems, as well as in other model proteins. Mass-spectrometry was then used, evidencing a heterogeneous effect on the accumulation of the structurally characterized protein carbonyl glutamic and aminoadipic semialdehydes as well as for malondialdehyde-lysine in LDL apoprotein. After TOF based lipidomics, we identified the most abundant differential lipids in Cu++-incubated LDL as 1-palmitoyllysophosphatidylcholine and 1-stearoyl-sn-glycero-3-phosphocholine. Most of selected phenolic compounds prevented the accumulation of those phospholipids and the cellular impairment induced by oxidized LDL. Finally, to validate these effects in vivo, we evaluated the effect of the intake of a phenolic-enriched extract in plasma protein and lipid modifications in a well-established model of atherosclerosis (diet-induced hypercholesterolemia in hamsters). This showed that a dietary supplement with a phenolic-enriched extract diminished plasma protein oxidative and lipid damage. Globally, these data show structural basis of antioxidant properties of plant-derived phenolic acids in protein oxidation that may be relevant for the health-promoting effects of its dietary intake. that a dietary supplement with a phenolic-enriched extract diminished plasma protein oxidative and lipid damage. Globally, these data show structural basis of antioxidant properties of plant-derived phenolic acids in protein oxidation that may be relevant for the health-promoting effects of its dietary intake.

Memory Revisited in Julian Barnes's The Sense of an Ending

An accumulation of years brings with it an accumulation of experiences. The revision of such experiences usually becomes more recurrent after retirement, a transition time from one period of life to another and, as such, a time in which we, human beings, have a tendency to take stock of our lives. This is actually one of the main issues present in Julian Barnes's last novel The Sense of an Ending (2011). When the main protagonist, a retired man quite comfortable and contented with his present life, receives an unexpected inheritance from the mother of a girlfriend from his university years, he is forced to track down a part of his life that he had left at the back of his mind a long time ago. As he explains his story, the protagonist and narrator of the novel raises a number of questions related to the quality and function of memory as one gets into old age. He experiments the unreliability of memory and questions to what extent memory is constructed through the remembered emotions that invaded him over that episode of his life rather than through the events as they actually took place. On the other hand, the act of revisiting and revising that specific episode, brings with it feelings of guilt and remorse as the protagonist realises that his past acts were not as noble as he remembered them to be. However, these acts are part of the past and they cannot be changed; thus, another question that the novel raises is how to account for those actions of which one does not feel proud and, more importantly, how to manage those bad memories as one gets older.

Insertion of a malE B-Galactosidase fusion protein into the envelope of Escherichia coli disrupts biogenesis of outer membrane proteins and processing of inner membrane proteins

The synthesis of a membrane-bound MalE ,B-galactosidase hybrid protein, when induced by growth of Escherichia coli on maltose, leads to inhibition of cell division and eventually a reduced rate of mass increase. In addition, the relative rate of synthesis of outer membrane proteins, but not that of inner membrane proteins, was reduced by about 50%o. Kinetic experiments demonstrated that this reduction coincided with the period of maximum synthesis of the hybrid protein (and another maltose-inducible protein, LamB). The accumulation of this abnormal protein in the envelope therefore appeared specifically to inhibit the synthesis, the assembly of outer membrane proteins, or both, indicating that the hybrid protein blocks some export site or causes the sequestration of some limiting factor(s) involved in the export process. Since the MalE protein is normally located in the periplasm, the results also suggest that the synthesis of periplasmic and outer membrane proteins may involve some steps in common. The reduced rate of synthesis of outer membrane proteins was also accompanied by the accumulation in the envelope of at least one outer membrane protein and at least two inner membrane proteins as higher-molecular-weight forms, indicating that processing (removal of the N-terminal signal sequence) was also disrupted by the presence of the hybrid protein. These results may indicate that the assembly of these membrane proteins is blocked at a relatively late step rather than at the level of primary recognition of some site by the signal sequence. In addition, the results suggest that some step common to the biogenesis of quite different kinds of envelope protein is blocked by the presence of the hybrid protein.

Glutaredoxins Grx3 and Grx4 regulate nuclear localisation of Aft1 and the oxidative stress response in Saccharomyces cerevisiae

Grx3 and Grx4, two monothiol glutaredoxins of Saccharomyces cerevisiae, regulate Aft1 nuclear localisation. We provide evidence of a negative regulation of Aft1 activity by Grx3 and Grx4. The Grx domain of both proteins played an important role in Aft1 translocation to the cytoplasm. This function was not, however, dependent on the availability of iron. Here we demonstrate that Grx3, Grx4 and Aft1 interact each other both in vivo and in vitro, which suggests the existence of a functional protein complex. Interestingly, each interaction occurred independently on the third member of the complex. The absence of both Grx3 and Grx4 induced a clear enrichment of G1 cells in asynchronous cultures, a slow growth phenotype, the accumulation of intracellular iron and a constitutive activation of the genes regulated by Aft1. The grx3grx4 double mutant was highly sensitive to the oxidising agents hydrogen peroxide and t-butylhydroperoxide but not to diamide. The phenotypes of the double mutant grx3grx4 characterised in this study were mainly mediated by the Aft1 function, suggesting that grx3grx4 could be a suitable cellular model for studying endogenous oxidative stress induced by deregulation of the iron homeostasis. However, our results also suggest that Grx3 and Grx4 might play additional roles in the oxidative stress response through proteins other than Aft1.

Effects of prolonged ethanol intake and malnutrition on rat pancreas

Nutritional factors, especially the protein and fat content of the diet, may change pancreatic morphology after ethanol induced injury. This study was performed to delineate the combined effects of a low fat diet and longterm ethanol ingestion on the rat pancreas. Male Sprague-Dawley rats were maintained with five different diets for 12 weeks and the pancreas removed on the day they were killed. Rats fed a very low fat diet without ethanol (5% of total calories as lipid) developed malnutrition, pancreatic steatosis, and reduction in zymogen granules content. Animals fed a 35% lipid diet with ethanol also developed pancreatic steatosis but changes in zymogen granules content were not detected. Both malnutrition and longterm ethanol consumption increased pancreatic cholesterol ester content, and their effects were additive. Pancreatic steatosis was accompanied with hypercholesterolaemia. Amylase, lipase, and cholesterol esterase content were reduced in malnourished rats; but longterm ethanol ingestion, regardless of the nutritional state, increased lipase content and decreased amylase. It is suggested that high serum cholesterol concentrations and increased pancreatic lipase activity could cause accumulation of cholesterol esters in acinar cells. Fat accumulation in the pancreas has been reported as the earliest histopathological feature in alcoholic patients and may be responsible for cytotoxic effects on the acinar cells at the level of the cell membrane. Although it is difficult to extrapolate results in this animal study to the human situation, the results presented in this work might explain the higher incidence of pancreatitis is malnourished populations as well as in alcoholic subjects that is reported in dietary surveys.

Effects of prolonged ethanol intake and malnutrition on rat pancreas

Nutritional factors, especially the protein and fat content of the diet, may change pancreatic morphology after ethanol induced injury. This study was performed to delineate the combined effects of a low fat diet and longterm ethanol ingestion on the rat pancreas. Male Sprague-Dawley rats were maintained with five different diets for 12 weeks and the pancreas removed on the day they were killed. Rats fed a very low fat diet without ethanol (5% of total calories as lipid) developed malnutrition, pancreatic steatosis, and reduction in zymogen granules content. Animals fed a 35% lipid diet with ethanol also developed pancreatic steatosis but changes in zymogen granules content were not detected. Both malnutrition and longterm ethanol consumption increased pancreatic cholesterol ester content, and their effects were additive. Pancreatic steatosis was accompanied with hypercholesterolaemia. Amylase, lipase, and cholesterol esterase content were reduced in malnourished rats; but longterm ethanol ingestion, regardless of the nutritional state, increased lipase content and decreased amylase. It is suggested that high serum cholesterol concentrations and increased pancreatic lipase activity could cause accumulation of cholesterol esters in acinar cells. Fat accumulation in the pancreas has been reported as the earliest histopathological feature in alcoholic patients and may be responsible for cytotoxic effects on the acinar cells at the level of the cell membrane. Although it is difficult to extrapolate results in this animal study to the human situation, the results presented in this work might explain the higher incidence of pancreatitis is malnourished populations as well as in alcoholic subjects that is reported in dietary surveys.

Effects of prolonged ethanol intake and malnutrition on rat pancreas

Nutritional factors, especially the protein and fat content of the diet, may change pancreatic morphology after ethanol induced injury. This study was performed to delineate the combined effects of a low fat diet and longterm ethanol ingestion on the rat pancreas. Male Sprague-Dawley rats were maintained with five different diets for 12 weeks and the pancreas removed on the day they were killed. Rats fed a very low fat diet without ethanol (5% of total calories as lipid) developed malnutrition, pancreatic steatosis, and reduction in zymogen granules content. Animals fed a 35% lipid diet with ethanol also developed pancreatic steatosis but changes in zymogen granules content were not detected. Both malnutrition and longterm ethanol consumption increased pancreatic cholesterol ester content, and their effects were additive. Pancreatic steatosis was accompanied with hypercholesterolaemia. Amylase, lipase, and cholesterol esterase content were reduced in malnourished rats; but longterm ethanol ingestion, regardless of the nutritional state, increased lipase content and decreased amylase. It is suggested that high serum cholesterol concentrations and increased pancreatic lipase activity could cause accumulation of cholesterol esters in acinar cells. Fat accumulation in the pancreas has been reported as the earliest histopathological feature in alcoholic patients and may be responsible for cytotoxic effects on the acinar cells at the level of the cell membrane. Although it is difficult to extrapolate results in this animal study to the human situation, the results presented in this work might explain the higher incidence of pancreatitis is malnourished populations as well as in alcoholic subjects that is reported in dietary surveys.

Effects of prolonged ethanol intake and malnutrition on rat pancreas

Nutritional factors, especially the protein and fat content of the diet, may change pancreatic morphology after ethanol induced injury. This study was performed to delineate the combined effects of a low fat diet and longterm ethanol ingestion on the rat pancreas. Male Sprague-Dawley rats were maintained with five different diets for 12 weeks and the pancreas removed on the day they were killed. Rats fed a very low fat diet without ethanol (5% of total calories as lipid) developed malnutrition, pancreatic steatosis, and reduction in zymogen granules content. Animals fed a 35% lipid diet with ethanol also developed pancreatic steatosis but changes in zymogen granules content were not detected. Both malnutrition and longterm ethanol consumption increased pancreatic cholesterol ester content, and their effects were additive. Pancreatic steatosis was accompanied with hypercholesterolaemia. Amylase, lipase, and cholesterol esterase content were reduced in malnourished rats; but longterm ethanol ingestion, regardless of the nutritional state, increased lipase content and decreased amylase. It is suggested that high serum cholesterol concentrations and increased pancreatic lipase activity could cause accumulation of cholesterol esters in acinar cells. Fat accumulation in the pancreas has been reported as the earliest histopathological feature in alcoholic patients and may be responsible for cytotoxic effects on the acinar cells at the level of the cell membrane. Although it is difficult to extrapolate results in this animal study to the human situation, the results presented in this work might explain the higher incidence of pancreatitis is malnourished populations as well as in alcoholic subjects that is reported in dietary surveys.