Education of Murine NK Cells Requires Both cis and trans Recognition of MHC Class I Molecules.

Although NK cells use invariant receptors to identify diseased cells, they nevertheless adapt to their environment, including the presence of certain MHC class I (MHC-I) molecules. This NK cell education, which is mediated by inhibitory receptors specific for MHC-I molecules, changes the responsiveness of activating NK cell receptors (licensing) and modifies the repertoire of MHC-I receptors used by NK cells. The fact that certain MHC-I receptors have the unusual capacity to recognize MHC-I molecules expressed by other cells (trans) and by the NK cell itself (cis) has raised the question regarding possible contributions of the two types of interactions to NK cell education. Although the analysis of an MHC-I receptor variant suggested a role for cis interaction for NK cell licensing, adoptive NK cell transfer experiments supported a key role for trans recognition. To reconcile some of these findings, we have analyzed the impact of cell type-specific deletion of an MHC-I molecule and of a novel MHC-I receptor variant on the education of murine NK cells when these mature under steady-state conditions in vivo. We find that MHC-I expression by NK cells (cis) and by T cells (trans), and MHC-I recognition in cis and in trans, are both needed for NK cell licensing. Unexpectedly, modifications of the MHC-I receptor repertoire are chiefly dependent on cis binding, which provides additional support for an essential role for this unconventional type of interaction for NK cell education. These data suggest that two separate functions of MHC-I receptors are needed to adapt NK cells to self-MHC-I.

Shape complexity based on mutual information

Shape complexity has recently received attention from different fields, such as computer vision and psychology. In this paper, integral geometry and information theory tools are applied to quantify the shape complexity from two different perspectives: from the inside of the object, we evaluate its degree of structure or correlation between its surfaces (inner complexity), and from the outside, we compute its degree of interaction with the circumscribing sphere (outer complexity). Our shape complexity measures are based on the following two facts: uniformly distributed global lines crossing an object define a continuous information channel and the continuous mutual information of this channel is independent of the object discretisation and invariant to translations, rotations, and changes of scale. The measures introduced in this paper can be potentially used as shape descriptors for object recognition, image retrieval, object localisation, tumour analysis, and protein docking, among others

Rates and pattern of evolution among Cretaceous radiolarians: relations with global paleoceanographic events

We present a new approach for analyzing the turnover rates of Cretaceous radiolarians recorded in pelagic sequences of western Tethys, The analysis of major extinction-radiation events and the fluctuation of diversity are compared with major paleoceanographic events and variation of diversity in dinoflagellates, calcareous nannoplankton and ammonites. There is an extraordinary correlation between biotic changes and sea level changes, temperatures, O, C and Sr isotopes, phosphorus accumulation rates and anoxic episodes. This reveals a predominantly abiotic control on the evolution of radiolarians. The rate of turnover and the diversity through time of two major orders of radiolarians (nassellarians and spumellarians) exhibits (1) the quasi-parallelism of their diversity curves, excluding a direct competition between them, (2) greater resistance of spumellarians to extinction during the early stage of extinction intervals and (3) a stronger post-extinction recovery of nassellarians. Evolutionary rates of radiolarians can be a good means of monitoring global environmental changes and allowing us to understand more clearly the relationship between plankton evolution, climate and pale oceanographic processes.

Globally aligned photomosaic of the Lucky Strike hydrothermal vent field (Mid-Atlantic Ridge, 37°18.5’N): Release of georeferenced data, mosaic construction, and viewing software

We present a georeferenced photomosaic of the Lucky Strike hydrothermal vent field (Mid-Atlantic Ridge, 37°18’N). The photomosaic was generated from digital photographs acquired using the ARGO II seafloor imaging system during the 1996 LUSTRE cruise, which surveyed a ~1 km2 zone and provided a coverage of ~20% of the seafloor. The photomosaic has a pixel resolution of 15 mm and encloses the areas with known active hydrothermal venting. The final mosaic is generated after an optimization that includes the automatic detection of the same benthic features across different images (feature-matching), followed by a global alignment of images based on the vehicle navigation. We also provide software to construct mosaics from large sets of images for which georeferencing information exists (location, attitude, and altitude per image), to visualize them, and to extract data. Georeferencing information can be provided by the raw navigation data (collected during the survey) or result from the optimization obtained from imatge matching. Mosaics based solely on navigation can be readily generated by any user but the optimization and global alignment of the mosaic requires a case-by-case approach for which no universally software is available. The Lucky Strike photomosaics (optimized and navigated-only) are publicly available through the Marine Geoscience Data System (MGDS, http://www.marine-geo.org). The mosaic-generating and viewing software is available through the Computer Vision and Robotics Group Web page at the University of Girona (http://eia.udg.es/_rafa/mosaicviewer.html)

Mechanisms of synchronization and pattern formation in a lattice of pulse-coupled oscillators

We analyze the physical mechanisms leading either to synchronization or to the formation of spatiotemporal patterns in a lattice model of pulse-coupled oscillators. In order to make the system tractable from a mathematical point of view we study a one-dimensional ring with unidirectional coupling. In such a situation, exact results concerning the stability of the fixed of the dynamic evolution of the lattice can be obtained. Furthermore, we show that this stability is the responsible for the different behaviors.

Expression of cysteine proteinase type I and II of Leishmania infantum and their recognition by sera during canine and human visceral leishmaniasis.

In this study, the mature domains of type I (CPB) and type II (CPA) cysteine proteinases (CPs) of Leishmania infantum were expressed and their immunogenic properties defined using sera from active and recovered cases of human visceral leishmaniasis and sera from infected dogs. Immunoblotting and ELISA analysis indicated that a freeze/thaw extract of parasite antigens showed similar and intensive recognition in both active cases of human and dog sera but lower recognition in recovered human individuals. The total IgG of actively infected human sera was higher than in recovered cases when rCPs were used as antigen. In contrast to dog sera, both active and recovered human cases have higher recognition toward rCPB than rCPA. Furthermore, the asymptomatic dogs in contrast to the symptomatic cases exhibited specific lymphocyte proliferation to both crude antigens and rCPs.

Assessing the epidemiology and pattern of care of colorectal cancer in Valais, Switzerland

Background: The Valais's cancer registry (RVsT) of the Observatoire valaisan de le santé (OVS) and the department of oncology of Valais's Hospital conducted a study on the epidemiology and pattern of care of colorectal cancer in Valais. Colorectal cancer is the third cause of death by cancer in Switzerland with about 1600 deaths per year. It is the third most frequent cancer for males and the second most frequent for females in Valais. The number of new colorectal cancer cases (average per year) increased between 1989 and 2009 for males as well as for females in Valais. The number of colorectal cancer death cases (average per year) slightly increased between 1989 and 2009 for males as well as for females in Valais. Age-standardized rates of incidence were stable for males and females in Valais and in Switzerland between 1989 and 2009, while age-standardized rates of mortality decreased for males and females in Valais and Switzerland. Results: 774 cases were recorded (59% males). Median age at diagnosis was 70 years old. Most of cancers were invasive (79%) and the main localization was the colon (71%). The most frequent mode of detection was a consultation for non emergency symptoms (75%), but almost 10% of patients consulted in emergency. 82% of patients were treated within 30 days from diagnosis. 90% of the patients were treated by surgery alone or with combined treatment. The first treatment was surgery, including endoscopic resection in 86% of the cases. The treatment was different according to the localization and the stage of the cancer. Survival rate was 95% at 30 days and 79% at one year. The survival was dependent on the stage and the age at diagnosis. Cox model shows an association between mortality and age (better survival for young people) and between mortality and stage (better survival for the lower stages). Methods: RVsT collects information on all cancer cases since 1989 for people registered in the communes of Valais. RVsT has an authorization to collect non anonymized data. All new incident cancers are coded according to the International Classification of Diseases for Oncology (ICD-O-3) and the stages are coded according to the TNM classification. We studied all cases of in situ and invasive colorectal cancers diagnosed between 2006 and 2009 and registered routinely at the RVsT. We checked for data completeness and if necessary sent questionnaires to avoid missing data. A distance of 15 cm has been chosen to delimitate the colon (sigmoid) and the rectal cancers. We made an active follow-up for vital status to have a valid survival analysis. We analyzed the characteristics of the tumors according to age, sex, localization and stage with stata 9 software. Kaplan-Meier curves were generated and Cox model were fitted to analyze survival. Conclusion: The characteristics of patients and tumors and the one year survival were similar to those observed in Switzerland and some European countries. Patterns of care were close to those recommended in guidelines. Routine data recorded in a cancer registry can be used, not only to provide general statistics, but also to help clinicians assess local practices.

Effects of epitope modification on T cell receptor-ligand binding and antigen recognition by seven H-2Kd-restricted cytotoxic T lymphocyte clones specific for a photoreactive peptide derivative.

We tested for antigen recognition and T cell receptor (TCR)-ligand binding 12 peptide derivative variants on seven H-2Kd-restricted cytotoxic T lymphocytes (CTL) clones specific for a bifunctional photoreactive derivative of the Plasmodium berghei circumsporozoite peptide 252-260 (SYIPSAEKI). The derivative contained iodo-4-azidosalicylic acid in place of PbCS S-252 and 4-azidobenzoic acid on PbCS K-259. Selective photoactivation of the N-terminal photoreactive group allowed crosslinking to Kd molecules and photoactivation of the orthogonal group to TCR. TCR photoaffinity labeling with covalent Kd-peptide derivative complexes allowed direct assessment of TCR-ligand binding on living CTL. In most cases (over 80%) cytotoxicity (chromium release) and TCR-ligand binding differed by less than fivefold. The exceptions included (a) partial TCR agonists (8 cases), for which antigen recognition was five-tenfold less efficient than TCR-ligand binding, (b) TCR antagonists (2 cases), which were not recognized and capable of inhibiting recognition of the wild-type conjugate, (c) heteroclitic agonists (2 cases), for which antigen recognition was more efficient than TCR-ligand binding, and (d) one partial TCR agonist, which activated only Fas (C1)95), but not perforin/granzyme-mediated cytotoxicity. There was no correlation between these divergences and the avidity of TCR-ligand binding, indicating that other factors than binding avidity determine the nature of the CTL response. An unexpected and novel finding was that CD8-dependent clones clearly incline more to TCR antagonism than CD8-independent ones. As there was no correlation between CD8 dependence and the avidity of TCR-ligand binding, the possibility is suggested that CD8 plays a critical role in aberrant CTL function.

Profile, cost and pattern of prescriptions for polymedicated patients in Catalonia (Spain).

OBJECTIVES: Polypharmacy is one of the main management issues in public health policies because of its financial impact and the increasing number of people involved. The polymedicated population according to their demographic and therapeutic profile and the cost for the public healthcare system were characterised. DESIGN: Cross-sectional study. SETTING: Primary healthcare in Barcelona Health Region, Catalonia, Spain (5 105 551 inhabitants registered). PARTICIPANTS: All insured polymedicated patients. Polymedicated patients were those with a consumption of ≥16 drugs/month. MAIN OUTCOMES MEASURES: The study variables were related to age, gender and medication intake obtained from the 2008 census and records of prescriptions dispensed in pharmacies and charged to the public health system. RESULTS: There were 36 880 polymedicated patients (women: 64.2%; average age: 74.5±10.9 years). The total number of prescriptions billed in 2008 was 2 266 830 (2 272 920 total package units). The most polymedicated group (up to 40% of the total prescriptions) was patients between 75 and 84 years old. The average number of prescriptions billed monthly per patient was 32±2, with an average cost of 452.7±27.5. The total cost of those prescriptions corresponded to 2% of the drug expenditure in Catalonia. The groups N, C, A, R and M represented 71.4% of the total number of drug package units dispensed to polymedicated patients. Great variability was found between the medication profiles of men and women, and between age groups; greater discrepancies were found in paediatric patients (5-14 years) and the elderly (≥65 years). CONCLUSIONS: This study provides essential information to take steps towards rational drug use and a structured approach in the polymedicated population in primary healthcare.

Nuclear translocation and DNA recognition signals colocalized within the bZIP domain of cyclic adenosine 3',5'-monophosphate response element-binding protein CREB.

CREB is a cAMP-responsive nuclear DNA-binding protein that binds to cAMP response elements and stimulates gene transcription upon activation of the cAMP signalling pathway. The protein consists of an amino-terminal transcriptional transactivation domain and a carboxyl-terminal DNA-binding domain (bZIP domain) comprised of a basic region and a leucine zipper involved in DNA recognition and dimerization, respectively. Recently, we discovered a testis-specific transcript of CREB that contains an alternatively spliced exon encoding multiple stop codons. CREB encoded by this transcript is a truncated protein lacking the bZIP domain. We postulated that the antigen detected by CREB antiserum in the cytoplasm of germinal cells is the truncated CREB that must also lack its nuclear translocation signal (NTS). To test this hypothesis we prepared multiple expression plasmids encoding carboxyl-terminal deletions of CREB and transiently expressed them in COS-1 cells. By Western immunoblot analysis as well as immunocytochemistry of transfected cells, we show that CREB proteins truncated to amino acid 286 or shorter are sequestered in the cytoplasm, whereas a CREB of 295 amino acids is translocated into the nucleus. Chimeric CREBs containing a heterologous NTS fused to the first 248 or 261 amino acids of CREB are able to drive the translocation of the protein into the nucleus. Thus, the nine amino acids in the basic region involved in DNA recognition between positions 287 and 295 (RRKKKEYVK) of CREB contain the NTS. Further, mutation of the lysine at position 290 in CREB to an asparagine diminishes nuclear translocation of the protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Membrane insertion and antibody recognition of a glycosylphosphatidylinositol-anchored protein: an optical study.

The kinetics of binding of a glycolipid-anchored protein (the promastigote surface protease, PSP) to planar lecithin bilayers is studied by an integrated optics technique, in which the bilayer membrane is supported on an optical wave guide and the phase velocities of guided light modes in the wave guide are measured. From these velocities, the optical parameters of the membrane and PSP layers deposited on the waveguide are determined, yielding in particular the mass of PSP bound to the membrane, which is followed in real time. From a comparison of the binding rates of PSP and PSP from which the lipid moiety has been removed, it is shown that the lipid moiety plays a key role in anchoring the protein to the membrane. Specific and nonspecific binding of antibodies to membrane-anchored PSP is also investigated. As little as a fifth of a monolayer of PSP is sufficient to suppress the appreciable nonspecific binding of antibodies to the membrane.