Malaria vaccine candidate: design of a multivalent subunit α-helical coiled coil poly-epitope.

A new strategy for the rapid identification of new malaria antigens based on protein structural motifs was previously described. We identified and evaluated the malaria vaccine potential of fragments of several malaria antigens containing α-helical coiled coil protein motifs. By taking advantage of the relatively short size of these structural fragments, we constructed different poly-epitopes in which 3 or 4 of these segments were joined together via a non-immunogenic linker. Only peptides that are targets of human antibodies with anti-parasite in vitro biological activities were incorporated. One of the constructs, P181, was well recognized by sera and peripheral blood mononuclear cells (PBMC) of adults living in malaria-endemic areas. Affinity purified antigen-specific human antibodies and sera from P181-immunized mice recognised native proteins on malaria-infected erythrocytes in both immunofluorescence and western blot assays. In addition, specific antibodies inhibited parasite development in an antibody dependent cellular inhibition (ADCI) assay. Naturally induced antigen-specific human antibodies were at high titers and associated with clinical protection from malaria in longitudinal follow-up studies in Senegal.

Redox dysregulation, neurodevelopment, and schizophrenia.

In schizophrenia, a developmental redox dysregulation constitutes one 'hub' on which converge genetic impairments of glutathione synthesis and environmental vulnerability factors generating oxidative stress. Their timing at critical periods of neurodevelopment could play a decisive role in inducing impairment of neural connectivity and synchronization as observed in schizophrenia. In experimental models, such redox dysregulation induces anomalies strikingly similar to those observed in patients. This is mediated by hypoactive NMDA receptors, impairment of fast-spiking parvalbumin GABA interneurons and deficit in myelination. A treatment restoring the redox balance without side effects yields improvements of negative symptoms in chronic patients. Novel interventions based on these mechanisms if applied in early phases of the disease hold great therapeutic promise.

Distributed all-atom simulations of intrinsically unstructured proteins

The Computational Biophysics Group at the Universitat Pompeu Fabra (GRIB-UPF) hosts two unique computational resources dedicated to the execution of large scale molecular dynamics (MD) simulations: (a) the ACMD molecular-dynamics software, used on standard personal computers with graphical processing units (GPUs); and (b) the GPUGRID. net computing network, supported by users distributed worldwide that volunteer GPUs for biomedical research. We leveraged these resources and developed studies, protocols and open-source software to elucidate energetics and pathways of a number of biomolecular systems, with a special focus on flexible proteins with many degrees of freedom. First, we characterized ion permeation through the bactericidal model protein Gramicidin A conducting one of the largest studies to date with the steered MD biasing methodology. Next, we addressed an open problem in structural biology, the determination of drug-protein association kinetics; we reconstructed the binding free energy, association, and dissaciociation rates of a drug like model system through a spatial decomposition and a Makov-chain analysis. The work was published in the Proceedings of the National Academy of Sciences and become one of the few landmark papers elucidating a ligand-binding pathway. Furthermore, we investigated the unstructured Kinase Inducible Domain (KID), a 28-peptide central to signalling and transcriptional response; the kinetics of this challenging system was modelled with a Markovian approach in collaboration with Frank Noe’s group at the Freie University of Berlin. The impact of the funding includes three peer-reviewed publication on high-impact journals; three more papers under review; four MD analysis components, released as open-source software; MD protocols; didactic material, and code for the hosting group.

Les Marques blanques, anàlisi en temps de crisi

La situació econòmica actual porta a moltes i diverses conseqüències en diferents àmbits, un d’ells és el consum. Les marques blanques s’han fet un lloc important en la nostra cistella de consum, sobretot en aquest últim any, i és aquest impacte de la crisi a les marques blanques el que intentem analitzar en el nostre treball.El tema central del treball es basa en endinsar-nos en el món de les marques blanques prestant especial interès al seu context actual, una situació de crisi econòmica i un conflicte vigent entre marques blanques i marques de renom.En primer lloc, hem analitzat la situació actual del sector. Per això, hem obtingut diversa informació procedent tant dels mitjans de comunicació com d’estudis realitzats per diferents consultores.Una vegada analitzada l’actualitat, hem cregut convenient centrar-nos en dos casos concrets per tal d’acotar l’anàlisi i obtenir resultats més fiables. En aquest apartat, introduïm al lector a la realitat de les empreses Grup Bonpreu i Mercadona i lesanalitzem principalment des de la seva política respecte la marca blanca.Seguidament, una part fonamental del treball es basa en l’anàlisi de les enquestes realitzades a varis establiments de les cadenes escollides. A partir del resultat d’aquestes enquestes, hem pogut realitzar comparacions entre les dues empreses pel que fa a les seves estratègies, els preus i els hàbits de consum dels seus clients.També hem vist que existeixen diferents perfils de consumidor pel que fa a les dues empreses escollides, ja que són presents grans diferències en les estratègies d’ambdues cadenes.Amb tot això, hem comprovat que, efectivament, el consum de marques blanques ha augmentat en aquest període de crisi i que, aquest fet és degut, en gran part, al canvi de comportament de compra dels consumidors en aquest últim any.

Appropriate management of special situations in Crohn's disease (upper gastro-intestinal; extra-intestinal manifestations; drug safety during pregnancy and breastfeeding): results of a multidisciplinary international expert panel-EPACT II

Introduction: High-grade evidence is lacking for most therapeutic decisions in Crohn's disease. Appropriateness criteria were developed for upper gastro-intestinal, extra-intestinal manifestations and drug safety during conception, pregnancy and breastfeeding in patients with Crohn's disease, to assist the physician in clinical decision making. Methods: The European Panel on the Appropriateness of Crohn's Disease Therapy (EPACT II), a multidisciplinary international European expert panel, rated clinical scenarios based on evidence from the published literature and panelists' own clinical expertise. Median ratings (on a 9-point scale) were stratified into three categories: appropriate (7-9), uncertain (4-6 with or without disagreement) and inappropriate (1-3). Experts were also asked to rank appropriate medications by priority. Results: Proton pump inhibitors, steroids, azathioprine/6-mercaptopurine and infliximab are appropriate for upper gastro-duodenal Crohn's disease; for stenosis, endoscopic balloon dilation is the first-tine therapy, although surgery is also appropriate. Ursodeoxycholic acid is the only appropriate treatment for primary sclerosing cholangitis. Infliximab is appropriate for Pyoderma gangrenosum, ankylosing spondylitis and uveitis, steroids for Pyoderma gangrenosum and ankylosing spondylitis, adalimumab for Pyoderma gangrenosum and ankylosing spondylitis, cyclosporine-A/tacrolimus for Pyoderma gangrenosum. Mesalamine, sulfasalazine, prednisone, azathioprine/6-mercaptopurine, ciprofloxacin, and probiotics, may be administered safety during pregnancy or for patients wishing to conceive, with the exception that mate patients considering conception should avoid sulfasalazine. Metronidazol is considered safe in the 2nd and 3rd trimesters whereas infliximab is rated safe in the 1st trimester but uncertain in the 2nd and 3rd trimesters. Methotrexate is always contraindicated at conception, during pregnancy or during breastfeeding, due to its known teratogenicity. Mesalamine, prednisone, probiotics and infliximab are considered safe during breastfeeding. Conclusion: EPACT II recommendations are freely available online (www.epact.ch). The validity of these criteria should now be tested by prospective evaluation. (C) 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

A developmental in vivo 1H NMR study in mice with genetic redox dysregulation: an animal model with relevance to schizophrenia

Glutathione (GSH), a major redox regulator and anti-oxidant, is decreased in cerebrospinal fluid and prefrontal cortex of schizophrenia patients. The gene of the key GSH-synthesizing enzyme, glutamate-cysteine ligase, modifier (GCLM) subunit, is associated with schizophrenia, suggesting that the deficit in the GSH system is of genetic origin. Using the GCLM knock-out (KO) mouse model with 60% decreased brain GSH levels, we have shown that redox dysregulation results in abnormal brain morphology and function. Current theory holds that schizophrenia is a developmental disease involving progressive anatomical and functional brain pathology. Here, we used GCLM KO mice to investigate the impact of a genetically dysregulated redox system on the neurochemical profile of the developing brain. The anterior and posterior cortical neurochemical profile of male and female GCLM KO, heterozygous and wildtype mice was determined by localised in vivo 1H NMR spectroscopy at 14.1 T (Varian/Magnex spectrometer) on post-natal days 10, 20, 30, 60 and 90. We show, for the first time, (1) that high quality 1H NMR spectra can be acquired from early developing mouse brains and (2) that recurrent anaesthesia by itself when administered at the same developmental days has no adverse effects on brain metabolites nor on adult behaviour. (3) Most importantly, our results reveal genotype and age specific changes for a number of metabolites revealing insight into normal brain development and about the impact of genetic GSH dysregulation.

Development of appropriateness criteria for the surgical treatment of symptomatic lumbar degenerative spondylolisthesis (LDS).

PURPOSE: Spine surgery rates are increasing worldwide. Treatment failures are often attributed to poor patient selection and inappropriate treatment, but for many spinal disorders there is little consensus on the precise indications for surgery. With an aging population, more patients with lumbar degenerative spondylolisthesis (LDS) will present for surgery. The aim of this study was to develop criteria for the appropriateness of surgery in symptomatic LDS. METHODS: A systematic review was carried out to summarize the current level of evidence for the treatment of LDS. Clinical scenarios were generated comprising combinations of signs and symptoms in LDS and other relevant variables. Based on the systematic review and their own clinical experience, twelve multidisciplinary international experts rated each scenario on a 9-point scale (1 highly inappropriate, 9 highly appropriate) with respect to performing decompression only, fusion, and instrumented fusion. Surgery for each theoretical scenario was classified as appropriate, inappropriate, or uncertain based on the median ratings and disagreement in the ratings. RESULTS: 744 hypothetical scenarios were generated; overall, surgery (of some type) was rated appropriate in 27 %, uncertain in 41 % and inappropriate in 31 %. Frank panel disagreement was low (7 % scenarios). Face validity was shown by the logical relationship between each variable's subcategories and the appropriateness ratings, e.g., no/mild disability had a mean appropriateness rating of 2.3 ± 1.5, whereas the rating for moderate disability was 5.0 ± 1.6 and for severe disability, 6.6 ± 1.6. Similarly, the average rating for no/minimal neurological abnormality was 2.3 ± 1.5, increasing to 4.3 ± 2.4 for moderate and 5.9 ± 1.7 for severe abnormality. The three variables most likely (p < 0.0001) to be components of scenarios rated "appropriate" were: severe disability, no yellow flags, and severe neurological deficit. CONCLUSION: This is the first study to report criteria for determining candidacy for surgery in LDS developed by a multidisciplinary international panel using a validated method (RAM). The panel ratings followed logical clinical rationale, indicating good face validity. The work refines clinical classification and the phenotype of degenerative spondylolisthesis. The predictive validity of the criteria should be evaluated prospectively to examine whether patients treated "appropriately" have better clinical outcomes.

Unemployment in an estimated new Keynesian model

We reformulate the Smets-Wouters (2007) framework by embedding the theory of unemployment proposed in Galí (2011a,b). Weestimate the resulting model using postwar U.S. data, while treatingthe unemployment rate as an additional observable variable. Our approach overcomes the lack of identification of wage markup and laborsupply shocks highlighted by Chari, Kehoe and McGrattan (2008) intheir criticism of New Keynesian models, and allows us to estimate a"correct" measure of the output gap. In addition, the estimated modelcan be used to analyze the sources of unemployment fluctuations.

Slow recoveries: A structural interpretation

An analysis of the performance of GDP, employment and otherlabor market variables following the troughs in postwar U.S. businesscycles points to much slower recoveries in the three most recentepisodes, but does not reveal any significant change over time in therelation between GDP and employment. This leads us to characterizethe last three episodes as slow recoveries, as opposed to jobless recoveries.We use the estimated New Keynesian model in Galí-Smets-Wouters (2011) to provide a structural interpretation for the slowerrecoveries since the early nineties.

Notes and descriptions of Neotropical Macrotomini (Coleoptera, Cerambycidae, Prioninae)

Mallodon vermiculatus sp. nov. (from Panama) and Nothopleurus santacruzensis sp. nov. (from Bolivia) are described and illustrated. Mallodon dasystomus dasystomus (Say, 1824) = M. mandibularis Lackerbeck, 1998 syn. nov.

Crises and growth: A re-evaluation

We address the question of whether growth and welfare can be higher in crisis prone economies. First, we show that there is a robust empirical link between per-capita GDP growth and negative skewness of credit growth across countries with active financial markets. That is, countries that have experienced occasional crises have grown on average faster than countries with smooth credit conditions. We then present a two-sector endogenous growth model in which financial crises can occur, and analyze the relationship between financial fragility and growth. The underlying credit market imperfections generateborrowing constraints, bottlenecks and low growth. We show that under certain conditions endogenous real exchange rate risk arises and firms find it optimal to take on credit risk in the form of currency mismatch. Along such a risky path average growth is higher, but self-fulfilling crises occur occasionally. Furthermore, we establish conditions under which the adoption of credit risk is welfare improving and brings the allocation nearer to the Pareto optimal level. The design of the model is motivated by several features of recent crises: credit risk in the form of foreign currency denominated debt; costly crises that generate firesales and widespread bankruptcies; and asymmetric sectorial responses, wherethe nontradables sector falls more than the tradables sector in the wake of crises.

Measuring strategic uncertainty in coordination games

This paper explores three aspects of strategic uncertainty: its relation to risk, predictability of behavior and subjective beliefs of players. In a laboratory experiment we measure subjects certainty equivalents for three coordination games and one lottery. Behavior in coordination games is related to risk aversion, experience seeking, and age.From the distribution of certainty equivalents we estimate probabilities for successful coordination in a wide range of games. For many games, success of coordination is predictable with a reasonable error rate. The best response to observed behavior is close to the global-game solution. Comparing choices in coordination games with revealed risk aversion, we estimate subjective probabilities for successful coordination. In games with a low coordination requirement, most subjects underestimate the probability of success. In games with a high coordination requirement, most subjects overestimate this probability. Estimating probabilistic decision models, we show that the quality of predictions can be improved when individual characteristics are taken into account. Subjects behavior is consistent with probabilistic beliefs about the aggregate outcome, but inconsistent with probabilistic beliefs about individual behavior.

Vaccine potentials of an intrinsically unstructured fragment derived from the blood stage-associated Plasmodium falciparum protein PFF0165c.

We have identified new malaria vaccine candidates through the combination of bioinformatics prediction of stable protein domains in the Plasmodium falciparum genome, chemical synthesis of polypeptides, in vitro biological functional assays, and association of an antigen-specific antibody response with protection against clinical malaria. Within the predicted open reading frame of P. falciparum hypothetical protein PFF0165c, several segments with low hydrophobic amino acid content, which are likely to be intrinsically unstructured, were identified. The synthetic peptide corresponding to one such segment (P27A) was well recognized by sera and peripheral blood mononuclear cells of adults living in different regions where malaria is endemic. High antibody titers were induced in different strains of mice and in rabbits immunized with the polypeptide formulated with different adjuvants. These antibodies recognized native epitopes in P. falciparum-infected erythrocytes, formed distinct bands in Western blots, and were inhibitory in an in vitro antibody-dependent cellular inhibition parasite-growth assay. The immunological properties of P27A, together with its low polymorphism and association with clinical protection from malaria in humans, warrant its further development as a malaria vaccine candidate.