Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload

Iron overload is the hallmark of hereditary hemochromatosis and a complication of iron-loading anemias such as β-thalassemia. Treatment can be burdensome and have significant side effects, and new therapeutic options are needed. Iron overload in hereditary hemochromatosis and β-thalassemia intermedia is caused by hepcidin deficiency. Although transgenic hepcidin replacement in mouse models of these diseases prevents iron overload or decreases its potential toxicity, natural hepcidin is prohibitively expensive for human application and has unfavorable pharmacologic properties. Here, we report the rational design of hepcidin agonists based on the mutagenesis of hepcidin and the hepcidin-binding region of ferroportin and computer modeling of their docking. We identified specific hydrophobic/aromatic residues required for hepcidin-ferroportin binding and obtained evidence in vitro that a thiol-disulfide interaction between ferroportin C326 and the hepcidin disulfide cage may stabilize binding. Guided by this model, we showed that 7–9 N-terminal amino acids of hepcidin, including a single thiol cysteine, comprised the minimal structure that retained hepcidin activity, as shown by the induction of ferroportin degradation in reporter cells. Further modifications to increase resistance to proteolysis and oral bioavailability yielded minihepcidins that, after parenteral or oral administration to mice, lowered serum iron levels comparably to those after parenteral native hepcidin. Moreover, liver iron concentrations were lower in mice chronically treated with minihepcidins than those in mice treated with solvent alone. Minihepcidins may be useful for the treatment of iron overload disorders

Post-acute assessment programme for patients with traumatic brain injury: measuring the gap between patients' expectations on entering and end of programme recommendations

Objective: To compare the expectations of patients with brain injury (TBI) entering a post-acute programme to the recommendations made at the end. Design: Retrospective study (1997 and 2009). Intervention: This 12-week post-acute programme included ecological multidisciplinary assessment of physical and cognitive disabilities, independence in activities of daily living and work abilities. Recommendations made at the conclusion of the programme included advice regarding the ability to work in an unsheltered or a sheltered environment and possible social activities. Results: Two hundred and forty patients participated. The main objective of 95.8% was return-to-work: 93.7% expected a normal work environment, 2.1% considered a sheltered environment and 4% entered the programme with the aim of improving social abilities and integration in the community. The recommendations included return-to-work in 68.3% of cases, in an unsheltered environment in 44.2% and in a sheltered environment in 24.1% and advice for contact with social services in order to achieve better social integration in 31.7%. There was a discrepancy between expectations and recommendations in half of the cases. Conclusion: The discrepancy between patients’ expectations and recommendations is in part due to the cognitive disorders; long-term rehabilitation programmes should focus on this issue

Métodos y progreso de la conservación de los recursos genéticos de los olmos en Europa

The progress made in the conservation of European elm genetic resources since the 1st International Elm Conference is reviewed, and the complementarity of in situ and ex situ methods is discussed. The financial support of the European Union to RESGEN project CT96-78 has permitted to co-ordinate and rationalize the ex situ conservation of elms. The project, which involved 17 partner institutes in nine west European countries, aimed at a better evaluation, conservation and utilisation of the existing collections of native elm clones. Main achievements are: establishing a common database of about 2,000 clones; characterizing over 500 clones through RAPDs and chloroplast DNA PCR-RFLPs molecular markers; completing and rationalizing the existing collections; establishing a long-term core collection of 850 clones; cryo-preserving a subset of 444 clones; and identifying clones of interest for breeding and prudent use in the reconstruction of countryside hedges. The «Noble Hardwoods» network of the pan-European programme EUFORGEN groups members representative of 31 countries, and promotes the dynamic conservation of the genetic resources of several genera of broadleaf forest trees, including Ulmus spp. Strategies for the conservation of the adaptive potential of elm resources were defined and will be disseminated among foresters and conservationists through «Guidelines» leaflets. Some countries have already started implementing conservation measures for U. laevis, associating in situ preservation and the establishment of seed orchards. Others are undertaking inventories, or acquiring genetic knowledge on target populations.Se discute el progreso realizado en la conservación de los olmos europeos desde la primera conferencia Internacional del Olmo y los métodos complementarios de conservación in situ y ex situ. El apoyo financiero de la Unión Europea al proyecto RESGEN CT96-78 ha permitido coordinar y racionalizar la conservación ex situ de los olmos. El proyecto, en el cual están involucrados 17 instituciones participantes en nueve países de Europa Occidental, tiene por objetivo una mejor evaluación, conservación y utilización de las colecciones actualmente existentes de clones nativos de olmo. Los principales logros son: el establecimiento de una base de datos común de aproximadamente 2.000 clones; la caracterización de más de 500 clones usando RAPD y marcadores moleculares PCR-RFLP de ADN cloroplástico; la finalización y racionalización de las colecciones existentes; el establecimiento a largo plazo de una colección central con 850 clones; la criopreservación de un conjunto de 444 clones; y la identificación de clones de interés para la mejora y para su uso en la restauración de setos en campo. La red «Noble Hardwoods» del programa pan-europeo EUFORGEN agrupa a miembros representantes de 31 países, y promueve la conservación dinámica de los recursos genéticos de varios géneros de árboles planifolios, incluido Ulmus spp.. Las estrategias para la conservación del potencial adaptativo de los recursos de los olmos se definieron y se dieron a conocer entre forestales y conservacionistas a través de folletos guía. Algunos países han comenzado ya a implementar medidas de conservación para U. laevis mediante el uso de la preservación in situ y el establecimiento de huertos semilleros. Otros están elaborando inventarios, o adquiriendo información genética de poblaciones de interés

Bilingualism and adult differences in inhibitory mechanisms: Evidence from a bilingual stroop task

The present investigation examined the functioning of inhibitory mechanisms in younger and older bilinguals using a bilingual version of the Stroop test. The study predicted different patterns of age related decline in inhibitory mechanisms (inter- and intralingual interference) in bilinguals depending on their level of proficiency. Consistent with expectations, older bilinguals were slower when they responded in their non-dominant language. Furthermore, older unbalanced bilinguals showed greater interlingual interference when they responded with their second language to visual stimuli written in their dominant language. Balanced bilinguals showed equivalent interference effects between all conditions. These findings suggest that manipulating two languages may enhance the efficiency of inhibitory mechanisms

Electrospinning polypropylene with an amino acid as a strategy to bind the antimicrobial peptide Cys-LC-LL-37

Hospital isolation gowns are increasingly competitive, with brands and manufacturers contesting consumer preferences. The textile materials in contact with the skin can acquire secretions and multiresistant microorganisms, causing discomfort and health risks, respectively. A new nanofibrous substrate---polypropylene grafted with l-Cys---was developed with an increased crystallinity, providing its surface with --SH hooks necessary to efficiently cross-link the antimicrobial peptide Cys-LC-LL-37 in order to protect against nosocomial pathogens and their spread to community. Furthermore, this application does not require environmental control of humidity, and it is not susceptible to enzyme and microorganism degradation.The authors acknowledge the Fundação para a Ciência e Tecnologia (FCT) for the PhD Grant SFRH/ BD/91444/2012 and Programa Operacional Capital Humano (POCH) and European Union for co-funding the work.info:eu-repo/semantics/publishedVersio

Novel lines of Pax6-/- embryonic stem cells exhibit reduced neurogenic capacity without loss of viability

<p>Abstract</p> <p>Background</p> <p>Embryonic stem (ES) cells can differentiate into all cell types and have been used extensively to study factors affecting neuronal differentiation. ES cells containing mutations in known genes have the potential to provide useful in vitro models for the study of gene function during neuronal differentiation. Recently, mouse ES cell lines lacking the neurogenic transcription factor Pax6 were reported; neurons derived from these <it>Pax6</it>^-/-ES cells died rapidly after neuronal differentiation in vitro.</p> <p>Results</p> <p>Here we report the derivation of new lines of <it>Pax6</it>^-/-ES cells and the assessment of their ability to survive and differentiate both in vitro and in vivo. Neurons derived from our new <it>Pax6</it>^-/-lines were viable and continued to elaborate processes in culture under conditions that resulted in the death of neurons derived from previously reported <it>Pax6</it>^-/-ES cell lines. The new lines of <it>Pax6</it>^-/-ES cells showed reduced neurogenic potential, mimicking the effects of loss of Pax6 in vivo. We used our new lines to generate <it>Pax6</it>^-/-↔ <it>Pax6</it>^+/+chimeras in which the mutant cells survived and displayed the same phenotypes as <it>Pax6</it>^-/-cells in <it>Pax6</it>^-/-↔ <it>Pax6</it>^+/+chimeras made by embryo aggregation.</p> <p>Conclusions</p> <p>We suggest that loss of Pax6 from ES cells reduces their neurogenic capacity but does not necessarily result in the death of derived neurons. We offer these new lines as additional tools for those interested in the generation of chimeras and the analysis of in vitro ES cell models of Pax6 function during neuronal differentiation, embryonic and postnatal development.</p

Combined loss of the BH3-only proteins Bim and Bmf restores B-cell development and function in TACI-Ig transgenic mice.

Terminal differentiation of B cells depends on two interconnected survival pathways, elicited by the B-cell receptor (BCR) and the BAFF receptor (BAFF-R), respectively. Loss of either signaling pathway arrests B-cell development. Although BCR-dependent survival depends mainly on the activation of the v-AKT murine thymoma viral oncogene homolog 1 (AKT)/PI3-kinase network, BAFF/BAFF-R-mediated survival engages non-canonical NF-κB signaling as well as MAPK/extracellular-signal regulated kinase and AKT/PI3-kinase modules to allow proper B-cell development. Plasma cell survival, however, is independent of BAFF-R and regulated by APRIL that signals NF-κB activation via alternative receptors, that is, transmembrane activator and CAML interactor (TACI) or B-cell maturation (BCMA). All these complex signaling events are believed to secure survival by increased expression of anti-apoptotic B-cell lymphoma 2 (Bcl2) family proteins in developing and mature B cells. Curiously, how lack of BAFF- or APRIL-mediated signaling triggers B-cell apoptosis remains largely unexplored. Here, we show that two pro-apoptotic members of the 'Bcl2 homology domain 3-only' subgroup of the Bcl2 family, Bcl2 interacting mediator of cell death (Bim) and Bcl2 modifying factor (Bmf), mediate apoptosis in the context of TACI-Ig overexpression that effectively neutralizes BAFF as well as APRIL. Surprisingly, although Bcl2 overexpression triggers B-cell hyperplasia exceeding the one observed in Bim(-/-)Bmf(-/-) mice, Bcl2 transgenic B cells remain susceptible to the effects of TACI-Ig expression in vivo, leading to ameliorated pathology in Vav-Bcl2 transgenic mice. Together, our findings shed new light on the molecular machinery restricting B-cell survival during development, normal homeostasis and under pathological conditions. Our data further suggest that Bcl2 antagonists might improve the potency of BAFF/APRIL-depletion strategies in B-cell-driven pathologies