Low TCR avidity and lack of tumor cell recognition in CD8(+) T cells primed with the CEA-analogue CAP1-6D peptide.

The use of "altered peptide ligands" (APL), epitopes designed for exerting increased immunogenicity as compared with native determinants, represents nowadays one of the most utilized strategies for overcoming immune tolerance to self-antigens and boosting anti-tumor T cell-mediated immune responses. However, the actual ability of APL-primed T cells to cross-recognize natural epitopes expressed by tumor cells remains a crucial concern. In the present study, we show that CAP1-6D, a superagonist analogue of a carcinoembriyonic antigen (CEA)-derived HLA-A*0201-restricted epitope widely used in clinical setting, reproducibly promotes the generation of low-affinity CD8(+) T cells lacking the ability to recognized CEA-expressing colorectal carcinoma (CRC) cells. Short-term T cell cultures, obtained by priming peripheral blood mononuclear cells from HLA-A*0201(+) healthy donors or CRC patients with CAP1-6D, were indeed found to heterogeneously cross-react with saturating concentrations of the native peptide CAP1, but to fail constantly lysing or recognizing through IFN- gamma release CEA(+)CRC cells. Characterization of anti-CAP1-6D T cell avidity, gained through peptide titration, CD8-dependency assay, and staining with mutated tetramers (D227K/T228A), revealed that anti-CAP1-6D T cells exerted a differential interaction with the two CEA epitopes, i.e., displaying high affinity/CD8-independency toward the APL and low affinity/CD8-dependency toward the native CAP1 peptide. Our data demonstrate that the efficient detection of self-antigen expressed by tumors could be a feature of high avidity CD8-independent T cells, and underline the need for extensive analysis of tumor cross-recognition prior to any clinical usage of APL as anti-cancer vaccines.

Permian-polysulphide-siderite-barite-haematite deposit Rude in Samoborska Gora Mts., Zagorje-Mid-Transdanubian zone of the Inner Dinarides

Samoborska Gora Mts. is situated within the westernmost part of the Zagorje-Mid-Transdanubian zone of the Internal Dinarides. The Samoborska Gora Mts. predominantly consists of Permian unmetamorphosed siliciclastic sediments and evaporites, overlain by Lower Triassic sediments. Rude mineralisation is hosted by Permian siliciclastic sediments, below gypsum and anhydrite strata. The central part of the deposit consists of a 1.5 km long stratabound mineralisation, grading laterally into ferruginous sandstone and protruding vertically into a gypsum-anhydrite layer. Siderite-polysulphide-barite-quartz veins are located below the stratabound mineralisation. The stratiform part of the deposit is situated above the stratabound and consists of haematite layer with barite concretions and veinlets. Late stage galena-barite veins overprint earlier types of mineralisation. The Rude ore deposit was generated by predominantly NaCl +/- CaCl(2)-H(2)O solutions. Detrital quartz from stratiform mineralisation contains fluid inclusions with salinities between 7 and 11 wt. % NaCl equ., homogenizing between 150 degrees C to 230 degrees C. Stratabound/siderite-polysulphide-barite-quartz vein type mineralisation was derived from solutions with salinities between 5 and 19 wt. % NaCl equ., homogenizing between 60 degrees C and 160 degrees C, while late stage galenabarite veins were precipitated from solutions with salinities between 11 and 16 wt. % NaCl equ., homogenizing between 100 degrees C to 140 degrees C. Fluid inclusion bulk leachate chemistry recorded Na(+)> Mg(2+)>K(+)>Ca(2+)>Li(+) and Cl-> SO(4)(2-) ions. Sulphur isotope composition of barites and overlying gypsum stems from Permian seawater sulphate, supported by increased Br(-) content, which follows successively the seawater evaporation line. The sulphur isotopic composition of sulphides varies between -0.2 and + 12.5 parts per thousand , as a result of thermal reduction of Permian marine sulphate. Ore-forming fluids were produced by hydrothermal convective cells (reflux brine model), and were derived primarily from Permian seawater, modified by evaporation and interaction with Permian sedimentary rocks. Rude deposits in Samoborska Gora Mts. may be declared as a prototype of the Permian siderite-polysulphide-barite deposits (products of rifting along the passive Gondwana margin), in the Inner Dinarides, and their equivalents extending northeastward into the Zagorje-Mid-Transdanubian Zone and the Gemerides, and southeastward to the Hellenide-Albanides.

The variability of peridotite composition across a mantle shear zone (Lanzo massif, Italy): interplay of melt focusing and deformation

In this paper we present new data on the spatial variability of peridotite composition across a kilometer-scale mantle shear zone within the Lanzo massif (Western Alps, Italy). The shear zone separates the central from the northern part of the massif. Plagioclase peridotite shows gradually increasing deformation towards the shear zone, from porphyroclastic to mylonitic textures in the central body, while the northern body is composed of porphyroclastic rocks. The peridotite displays a large range of compositions, from fertile peridotite to refractory harzburgite and dunite. Deformed peridotites (proto-mylonite and mylonites) tend to be compositionally more homogeneous and fertile than weakly deformed peridotites. The composition of most plagioclase peridotites show rather high and constant (Ce/Yb) (N) ratios, and Yb (N) that cannot be explained by any simple melting model. Instead, refertilization modeling, consisting of melt increments from spinel peridotite sources, particularly with E-MORB melt, reasonably reproduces the plagioclase peridotite whole rock composition. Combined with constraints from Ce-Nb and Ce-Th systematics, we speculate that peridotites such as those from Lanzo record pervasive refertilization processes in the thermal boundary layer. In this scenario, mantle shear zones might act as important areas of melt focusing in the upper mantle that separates the thermal boundary layer from the conductively cooled mantle.

Geodynamic reconstructions of the Australides-1: Palaeozoic

A full global geodynamical reconstruction model has been developed at the University of Lausanne over the past 20 years, and is used herein to re-appraise the evolution of the Australides from 600 to 200 Ma. Geological information of geodynamical interest associated with constraints on tectonic plate driving forces allow us to propose a consistent scenario for the evolution of Australia-Antarctica-proto-Pacific system. According to our model, most geodynamic units (GDUs) of the Australides are exotic in origin, and many tectonic events of the Delamerian Cycle, Lachlan SuperCycle, and New England SuperCycle are regarded as occurring off-shore Gondwana.

The ability model of emotional intelligence: Searching for valid measures

Current measures of ability emotional intelligence (EI)--including the well-known Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT)--suffer from several limitations, including low discriminant validity and questionable construct and incremental validity. We show that the MSCEIT is largely predicted by personality dimensions, general intelligence, and demographics having multiple R's with the MSCEIT branches up to .66; for the general EI factor this relation was even stronger (Multiple R = .76). As concerns the factor structure of the MSCEIT, we found support for four first-order factors, which had differential relations with personality, but no support for a higher-order global EI factor. We discuss implications for employing the MSCEIT, including (a) using the single branches scores rather than the total score, (b) always controlling for personality and general intelligence to ensure unbiased parameter estimates in the EI factors, and (c) correcting for measurement error. Failure to account for these methodological aspects may severely compromise predictive validity testing. We also discuss avenues for the improvement of ability-based tests.

Origin of CO2 and carbonate veins in mantle-derived xenoliths in the Pannonian Basin

The origin and evolution of CO2 inclusions and calcite veins in peridotite xenoliths of the Pannonian Basin, Hungary, were investigated by means of petrographic investigation and stable isotope analyses. The fluid inclusions recovered in paragenetic olivine and clinopyroxene belong to distinct populations: type A (texturally early) inclusions with regular shapes (often with negative crystal forms) forming intragranular trails, type B (texturally late) inclusions defining randomly oriented trails that reach grain boundaries Type B inclusions are often associated with silicate melt (type C) inclusions Stable carbon isotope compositions in inclusion-hosted CO2 were obtained by vacuum crushing followed by conventional dual inlet as well as continuous flow mass spectrometry in order to eliminate possible lab artifacts. Olivines, clino- and orthopyroxenes of the host peridotite have oxygen isotope compositions from 5.3 to 6.0 parts per thousand (relative to V-SMOW). without any relationship with xenolith texture. Some of the xenoliths contained calcite in various forms veins and infillings in silicate globules in veins, secondary carbonate veins filling cracks and metasomatic veins with diffuse margins The former two carbonate types have delta C-13 values around -13 parts per thousand (relative to V-PDB) and low Sr contents (<05 wt %), whereas the third type,veins with high-temperature metasomatic features have a delta C-13 value of -5 0 parts per thousand and high Sr contents up to 34 wt.% In spite of the mantle-like delta C-13 value and the unusually high Sr content typical for mantle-derived carbonate, trace element compositions have proven a crustal origin. This observation supports the conclusions of earlier studies that the carbonate melt droplets found on peridotite xenoliths in the alkaline basalts represent mobilized sedimentary carbonate. The large delta C-13 range and the C-12-enrichment in the carbonates can be attributed to devolanlization of the migrating carbonate or infiltration of surficial fluids containing C-12-rich dissolved carbon Carbon isotope compositions of inclusion-hosted CO2 range from -17 8 to -4.8 parts per thousand (relative to V-PDB) with no relation to the amount of CO2 released by vacuum crushing. Low-delta C-13 values measured by stepwise heating under vacuum suggest that the carbon component is pristine and not related to surficial contamination, and that primary mantle fluids with delta C-13 values around -5 parts per thousand were at least partly preserved in the xenoliths Tectonic reworking and heating by the basaltic magma resulted in partial CO2 release and local C-13-depletion. (C) 2010 Elsevier B V All rights reserved

An 8-Item Short Form of the Inventory of Dimensions of Emerging Adulthood (IDEA) Among Young Swiss Men.

Emerging adulthood is a period of life transition, in which youths are no longer adolescents but have not yet reached full adulthood. Measuring emerging adulthood is crucial because of its association with psychopathology and risky behaviors such as substance use. Unfortunately, the only validated scale for such measurement has a long format (Inventory of Dimensions of Emerging Adulthood [IDEA]-31 items). This study aimed to test whether a shorter form yields satisfactory results without substantial loss of information among a sample of young Swiss men. Data from the longitudinal Cohort Study on Substance Use Risk Factors were used (N = 5,049). IDEA, adulthood markers (e.g., parenthood or financial independence), and risk factors (i.e., substance use and mental health issues) were assessed. The results showed that an 8-item, short-form scale (IDEA-8) with four factors (experimentation, negativity, identity exploration, and feeling in between) returned satisfactory results, including good psychometric properties, high convergence with the initial scale, and strong empirical validity. This study was a step toward downsizing a measure of emerging adulthood. Indeed, this 8-item short form is a good alternative to the 31-item long form and could be more convenient for surveys with constraints on questionnaire length. Moreover, it should help health care practitioners in identifying at-risk populations to prevent and treat risky behaviors.

Trafficking of Estrella lausannensis in human macrophages.

Estrella lausannensis is a new member of the Chlamydiales order. Like other Chlamydia-related bacteria, it is able to replicate in amoebae and in fish cell lines. A preliminary study investigating the pathogenic potential of Chlamydia-related bacteria found a correlation between antibody response to E. lausannensis and pneumonia in children. To further investigate the pathogenic potential of E. lausannensis, we determined its ability to grow in human macrophages and its intracellular trafficking. The replication in macrophages resulted in viable E. lausannensis; however, it caused a significant cytopathic effect. The intracellular trafficking of E. lausannensis was analyzed by determining the interaction of the Estrella-containing inclusions with various endocytic markers as well as host organelles. The E. lausannensis inclusion escaped the endocytic pathway rapidly avoiding maturation into phagolysosomes by preventing both EEA-1 and LAMP-1 accumulation. Compared to Waddlia chondrophila, another Chlamydia-related bacteria, the recruitment of mitochondria and endoplasmic reticulum was minimal for E. lausannensis inclusions. Estrella lausannensis appears to use a distinct source of nutrients and energy compared to other members of the Chlamydiales order. In conclusion, we hypothesize that E. lausannensis has a restricted growth in human macrophages, due to its reduced capacity to control programmed cell death.

Differential effect of long versus short wavelength light exposure on pupillary re-dilation in patients with outer retinal disease.

BACKGROUND: In patients with outer retinal degeneration, a differential pupil response to long wavelength (red) versus short wavelength (blue) light stimulation has been previously observed. The goal of this study was to quantify differences in the pupillary re-dilation following exposure to red versus blue light in patients with outer retinal disease and compare them with patients with optic neuropathy and with healthy subjects. DESIGN: Prospective comparative cohort study. PARTICIPANTS: Twenty-three patients with outer retinal disease, 13 patients with optic neuropathy and 14 normal subjects. METHODS: Subjects were tested using continuous red and blue light stimulation at three intensities (1, 10 and 100 cd/m2) for 13 s per intensity. Pupillary re-dilation dynamics following the brightest intensity was analysed and compared between the three groups. MAIN OUTCOME MEASURES: The parameters of pupil re-dilation used in this study were: time to recover 90% of baseline size; mean pupil size at early and late phases of re-dilation; and differential re-dilation time for blue versus red light. RESULTS: Patients with outer retinal disease showed a pupil that tended to stay smaller after light termination and thus had a longer time to recovery. The differential re-dilation time was significantly greater in patients with outer retinal disease (median = 28.0 s, P < 0.0001) compared with controls and patients with optic neuropathy. CONCLUSIONS: A differential response of pupil re-dilation following red versus blue light stimulation is present in patients with outer retinal disease but is not found in normal eyes or among patients with visual loss from optic neuropathy.

Differential association of drinking motives with alcohol use on weekdays and weekends.

Drinking motives (DM) reflect the reasons why individuals drink alcohol. Weekdays are mainly dedicated to work, whereas weekends are generally associated with spending time with friends during special events or leisure activities; using alcohol on weekdays and weekends may also be related to different DM. This study examined whether DM were differentially associated with drinking volume (DV) on weekdays and weekends. A representative sample of 5,391 young Swiss men completed a questionnaire assessing weekday and weekend DV, as well as their DM, namely, enhancement, social, coping, and conformity motives. Associations of DM with weekday and weekend DV were examined using structural equation models. Each DM was tested individually in a separate model; all associations were positive and generally stronger (except conformity) for weekend rather than for weekday DV. Further specific patterns of association were found when DM were entered into a single model simultaneously. Associations with weekday and with weekend DV were positive for enhancement and coping motives. However, associations were stronger with weekend rather than with weekday DV for enhancement, and stronger with weekday than with weekend DV for coping motives. Associations of social motives were not significant with weekend DV and negative with weekday DV. Conformity motives were negatively associated with weekend DV and positively related to weekday DV. These results suggest that interventions targeting enhancement motives should be particularly effective at decreasing weekend drinking, whereas interventions targeted at coping motives would be particularly effective at reducing alcohol use on weekdays. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Increased α2- and β1-adrenoceptor densities in postmortem brain of subjects with depression: differential effect of antidepressant treatment.

BACKGROUND: Brain α2- and β-adrenoceptor alterations have been suggested in suicide and major depressive disorder. METHODS: The densities of α2-, β1- and β2-adrenoceptors in postmortem prefrontal cortex of 26 subjects with depression were compared with those of age-, gender- and postmortem delay-matched controls. The effect of antidepressant treatment on α2- and β-adrenoceptor densities was also evaluated. α2- and β-adrenoceptor densities were measured by saturation experiments with respective radioligands [(3)H]UK14304 and [(3)H]CGP12177. β1- and β2-adrenoceptor subtype densities were dissected by means of β1-adrenoceptor selective antagonist CGP20712A. RESULTS: Both, α2- and β1-adrenoceptors densities were higher in antidepressant-free depressed subjects (n=14) than those in matched controls (Δ~24%, p=0.013 and Δ~20%, p=0.044, respectively). In antidepressant-treated subjects (n=12), α2-adrenoceptor density remained increased over that in controls (Δ~20%), suggesting a resistance of α2-adrenoceptors to the down-regulatory effect of antidepressants. By contrast, β1-adrenoceptor density in antidepressant-treated depressed subjects was not different from controls, suggesting a possible down-regulation by antidepressants. The down-regulation of β1-adrenoceptor density in antidepressant-treated depressed subjects differs from the unaltered β1-adrenoceptor density observed in citalopram-treated rats and in a group of non-depressed subjects also treated with antidepressants (n=6). β2-adrenoceptor density was not altered in depressed subjects independently of treatment. LIMITATIONS: Antidepressant-treated subjects had been treated with a heterogeneous variety of antidepressant drugs. The results should be understood in the context of suicide victims with depression. CONCLUSIONS: These results show the up-regulation of brain α2- and β1-adrenoceptors in depression and suggest that the regulation induced by chronic antidepressant treatment would be altered in these subjects.

Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1.

Through their capacity to sense danger signals and to generate active interleukin-1β (IL-1β), inflammasomes occupy a central role in the inflammatory response. In contrast to IL-1β, little is known about how IL-1α is regulated. We found that all inflammasome activators also induced the secretion of IL-1α, leading to the cosecretion of both IL-1 cytokines. Depending on the type of inflammasome activator, release of IL-1α was inflammasome dependent or independent. Calcium influx induced by the opening of cation channels was sufficient for the inflammasome-independent IL-1α secretion. In both cases, IL-1α was released primarily in a processed form, resulting from intracellular cleavage by calpain-like proteases. Inflammasome-caspase-1-dependent release of IL-1α and IL-1β was independent of caspase-1 catalytic activity, defining a mode of action for caspase-1. Because inflammasomes contribute to the pathology of numerous chronic inflammatory diseases such as gout and diabetes, IL-1α antagonists may be beneficial in the treatment of these disorders.

Differential damage in the frontal cortex with aging, sporadic and familial Alzheimer's disease.

In order to understand relationships between executive and structural deficits in the frontal cortex of patients within normal aging or Alzheimer's disease, we studied frontal pathological changes in young and old controls compared to cases with sporadic (AD) or familial Alzheimer's disease (FAD). We performed a semi-automatic computer assisted analysis of the distribution of beta-amyloid (Abeta) deposits revealed by Abeta immunostaining as well as of neurofibrillary tangles (NFT) revealed by Gallyas silver staining in Brodman areas 10 (frontal polar), 12 (ventro-infero-median) and 24 (anterior cingular), using tissue samples from 5 FAD, 6 sporadic AD and 10 control brains. We also performed densitometric measurements of glial fibrillary acidic protein, principal compound of intermediate filaments of astrocytes, and of phosphorylated neurofilament H and M epitopes in areas 10 and 24. All regions studied seem almost completely spared in normal old controls, with only the oldest ones exhibiting a weak percentage of beta-amyloid deposit and hardly any NFT. On the contrary, all AD and FAD cases were severely damaged as shown by statistically significant increased percentages of beta-amyloid deposit, as well as by a high number of NFT. FAD cases (all from the same family) had statistically more beta-amyloid and GFAP than sporadic AD cases in both areas 10 and 24 and statistically more NFT only in area 24. The correlation between the percentage of beta-amyloid and the number of NFT was significant only for area 24. Altogether, these data suggest that the frontal cortex can be spared by AD type lesions in normal aging, but is severely damaged in sporadic and still more in familial Alzheimer's disease. The frontal regions appear to be differentially vulnerable, with area 12 having the less amyloid burden, area 24 the less NFT and area 10 having both more amyloid and more NFT. This pattern of damage in frontal regions may represent a strong neuroanatomical support for the deterioration of attention and cognitive capacities as well as for the presence of emotional and behavioral troubles in AD patients.