Type I interferon inhibits interleukin-1 production and inflammasome activation.

Type I interferon (IFN) is a common therapy for autoimmune and inflammatory disorders, yet the mechanisms of action are largely unknown. Here we showed that type I IFN inhibited interleukin-1 (IL-1) production through two distinct mechanisms. Type I IFN signaling, via the STAT1 transcription factor, repressed the activity of the NLRP1 and NLRP3 inflammasomes, thereby suppressing caspase-1-dependent IL-1β maturation. In addition, type I IFN induced IL-10 in a STAT1-dependent manner; autocrine IL-10 then signaled via STAT3 to reduce the abundance of pro-IL-1α and pro-IL-1β. In vivo, poly(I:C)-induced type I IFN diminished IL-1β production in response to alum and Candida albicans, thus increasing susceptibility to this fungal pathogen. Importantly, monocytes from multiple sclerosis patients undergoing IFN-β treatment produced substantially less IL-1β than monocytes derived from healthy donors. Our findings may thus explain the effectiveness of type I IFN in the treatment of inflammatory diseases but also the observed "weakening" of the immune system after viral infection.

R&D Expenditures and Firm Performance: Empirical Evidence on Finnish Data

Tutkielman tavoitteena on tutkia yrityksen tutkimus- ja tuotekehitystoiminnan (T&K) vaikutuksia yrityksen suorituskykyyn. Tutkielmassa tarkastellaan myös lyhyesti T&K- toimintaa osana yrityksen toimintoja ja ympäristöä. Tutkielman empiirisessä osassa tutkitaan poikkileikkausmenetelmää käyttäen T&K- menojen vaikutusta yrityksen kasvuun, kannattavuuteen ja osakkeen hintaan (tuottoon). Tutkielman empiirinen osa toteutettiin keräämällä tilinpäätös- ja osaketiedot 65 yritykselle vuosilta 1999-2005. T&K- menojen vaikutusta yrityksen kasvuun, kannattavuuteen ja osakkeen tuottoon tutkittiin eri aikavälejä käyttäen, jotta mahdolliset syy-seuraussuhteet voitaisiin luotettavasti osoittaa. Tutkimustulokset osoittavat, että yrityksen T&K- menoilla on positiivinen vaikutus yrityksen kasvuun ja kannattavuuteen ja,siten tulokset tukevat kahta tutkimuksen päähypoteesia. Yrityksen T&K- menoilla ja osakkeen tuoton välillä ei kuitenkaan käytetyllä aineistolla empiiristä yhteyttä löytynyt, joten kolmas päähypoteesi hylättiin.

Crisis de las solidaridades tradicionales y nuevas formas de asociación y resistencia campesina en la Cataluña occidental (1750-1920)

El objeto de este estudio es el análisis de las solidaridades campesinas y de su crisis en la etapa final del Antiguo Régimen. A través de la Cofradía de Labradores - que, en el siglo XVIII, representaba de hecho a la mayor parte del campesinado de Lleida -, se analiza la defensa de los comunales y la lucha contra el diezmo. Estos conflictos en el fondo traducen las dificultades del pequeño campesinado de Lleida para obtener los ingresos necesarios para reproducir la unidad familiar. Se estudian las dos vías - la campesina y la de los hacendados - de desarrollo social y económico en relación con la propiedad de la tierra en la etapa de reforma liberal. Ante el fracaso de la "vía campesina", se estudia el origen del asociacionismo tanto el impulsado por el pequeño campesinado -a través de sociedades de socorros mutuos en un primer momento- como aquél que tiene como objetivo la introducción de mejoras técnico-productivas. Como en el resto de Cataluña, en la parte occidental llana se desarrollarán estas experiencias de manera más intensa en el marco de la crisis finisecular y etapa posterior.

Las experiencias escolares de la inmigración

Las experiencias escolares son múltiples y diversas, y su análisis nos puede ayudar a comprender las actitudes de los inmigrantes respecto a la escolarización de sus hijos y las expectativas de futuro que el sistema educativo representa para las nuevas generaciones. Las oportunidades educativas, las dinámicas de los centros escolares (positivas o negativas), el enfoque pedagógico, los roles docentes, etc. , presentes y pasados, van conformando la manera que tiene una comunidad de entender la educación y la importancia que le otorgan tanto los alumnos como sus familias. El estudio que presentamos, basado en una metodología cualitativa (mediante la realización de entrevistas en profundidad), es una primera aproximación a las experiencias escolares vividas en España por parte de las familias inmigradas y sus hijos y, también, a las experiencias profesionales de los docentes en relación con las citadas familias y alumnado.

Occurrence of Arthroderma benhamiae Genotype in Japan.

In this study, we epidemiologically investigated on clinical isolates of Arthroderma benhamiae from humans and animals in Japan by internal transcribed spacer (ITS) region sequence analysis and mating type (MAT)-specific PCR. Seven of 8 A. benhamiae isolates from a human, rabbits and guinea pigs were identified as group I (white phenotype) by morphological characters and ITS region sequence analysis. One strain isolated from a degus (Octodon degus) produced colonies with few irregular folds and yellow velvety mycelium without macro- and microconidia. This strain resembled to group II (yellow phenotype) strain. ITS sequence analysis was also 100 % identical to that of group II. MAT-specific PCR indicated that 6 of these 7 isolates of group I contained an alpha-box gene and that one strain contained high-mobility-group (HMG) gene. One strain of group II was revealed to have an alpha-box gene and no HMG gene. To our knowledge, it is the first A. benhamiae isolate of group II found in Japan. The A. benhamiae may be more widespread in worldwide than our surpassing what is common or usual or expected.

Prospective motion correction of 3D echo-planar imaging data for functional MRI using optical tracking.

We evaluated the performance of an optical camera based prospective motion correction (PMC) system in improving the quality of 3D echo-planar imaging functional MRI data. An optical camera and external marker were used to dynamically track the head movement of subjects during fMRI scanning. PMC was performed by using the motion information to dynamically update the sequence's RF excitation and gradient waveforms such that the field-of-view was realigned to match the subject's head movement. Task-free fMRI experiments on five healthy volunteers followed a 2×2×3 factorial design with the following factors: PMC on or off; 3.0mm or 1.5mm isotropic resolution; and no, slow, or fast head movements. Visual and motor fMRI experiments were additionally performed on one of the volunteers at 1.5mm resolution comparing PMC on vs PMC off for no and slow head movements. Metrics were developed to quantify the amount of motion as it occurred relative to k-space data acquisition. The motion quantification metric collapsed the very rich camera tracking data into one scalar value for each image volume that was strongly predictive of motion-induced artifacts. The PMC system did not introduce extraneous artifacts for the no motion conditions and improved the time series temporal signal-to-noise by 30% to 40% for all combinations of low/high resolution and slow/fast head movement relative to the standard acquisition with no prospective correction. The numbers of activated voxels (p<0.001, uncorrected) in both task-based experiments were comparable for the no motion cases and increased by 78% and 330%, respectively, for PMC on versus PMC off in the slow motion cases. The PMC system is a robust solution to decrease the motion sensitivity of multi-shot 3D EPI sequences and thereby overcome one of the main roadblocks to their widespread use in fMRI studies.

Quest for Orthologs Entails Quest for Tree of Life: In Search of the Gene Stream.

Quest for Orthologs (QfO) is a community effort with the goal to improve and benchmark orthology predictions. As quality assessment assumes prior knowledge on species phylogenies, we investigated the congruency between existing species trees by comparing the relationships of 147 QfO reference organisms from six Tree of Life (ToL)/species tree projects: The National Center for Biotechnology Information (NCBI) taxonomy, Opentree of Life, the sequenced species/species ToL, the 16S ribosomal RNA (rRNA) database, and trees published by Ciccarelli et al. (Ciccarelli FD, et al. 2006. Toward automatic reconstruction of a highly resolved tree of life. Science 311:1283-1287) and by Huerta-Cepas et al. (Huerta-Cepas J, Marcet-Houben M, Gabaldon T. 2014. A nested phylogenetic reconstruction approach provides scalable resolution in the eukaryotic Tree Of Life. PeerJ PrePrints 2:223) Our study reveals that each species tree suggests a different phylogeny: 87 of the 146 (60%) possible splits of a dichotomous and rooted tree are congruent, while all other splits are incongruent in at least one of the species trees. Topological differences are observed not only at deep speciation events, but also within younger clades, such as Hominidae, Rodentia, Laurasiatheria, or rosids. The evolutionary relationships of 27 archaea and bacteria are highly inconsistent. By assessing 458,108 gene trees from 65 genomes, we show that consistent species topologies are more often supported by gene phylogenies than contradicting ones. The largest concordant species tree includes 77 of the QfO reference organisms at the most. Results are summarized in the form of a consensus ToL (http://swisstree.vital-it.ch/species_tree) that can serve different benchmarking purposes.

Neuropathogenesis in glutaric aciduria type I and methylmalonic aciduria

Glutaric aciduria type-I (GA-I) and methylmalonic aciduria (MMA-uria) are two neurometabolic diseases manifesting in neonatal period and early childhood. They belong to the group of organic acidurias and are caused by defects in the catabolism of amino acids, leading to massive accumulation of toxic metabolites in the body and severe brain injury. Therapeutic strategies are mainly based on reversing catabolic state during metabolic crisis and dietary protein restriction that both aim to prevent extra production of toxic metabolites. Specific and neuroprotective treatments are missing because the mechanisms of brain damage in these diseases are only poorly understood. The principal objective of my work was to develop in vitro models for both diseases aiming at elucidation of toxic effects of the main metabolites accumulating in GA-I (glutaric acid (GA) and 3-hydroxy glutaric acid (3-OHGA)) and MMA-uria (methylmalonic acid (MMA), propionic acid (PA) and 2-methylcitric acid (2-MCA)) on developing brain cells, and to study the cellular pathways targeted by these deleterious effects in order to find new therapeutic potentials. We used re-aggregated embryonic rat brain cells in organotypic 3D cultures, which were exposed to toxic metabolites at different developing stages of the cultures. In parallel, we studied the cellular localization of the defected enzyme in GA-I, glutaryl-CoA dehydrogenase (GCDH), in the brain and peripheral tissues of rats in adulthood and during embryonic development. GCDH expression: GCDH showed a strong neuronal expression in embryonic central and peripheral nervous system. In the adult brain, GCDH expression was exclusively neuronal with the strongest signal in cerebral cortex and Purkinje cells. GCDH expression was homogenous in embryonic peripheral organs with high levels in intestinal mucosa at late stages. Strong GCDH expression was also observed in liver and intestinal mucosa and with lower intensity in muscles, convoluted renal tubules and renal collecting tubes in adult peripheral organs. GA-I and MMA-uria in vitro models: 3-OHGA (for GA-I) and 2-MCA (for MMA-uria) showed the most deleterious effects at early stages of the cultures with morphological and biochemical alterations and induction of cell death. 3-OHGA and 2-MCA caused astrocytic cell suffering reflected by astrocytic fiber loss and swelling and retardation in oligodendrocytic maturation and/or differentiation. High ammonium increase concomitant with glutamine decrease was observed in these cultures. Neurons were not substantially affected. Our studies revealed that brain-cell generated ammonia may play a role in the neuropathogenesis of these diseases. Thus, developing neuroprotective strategies that target ammonium toxicity in the brain of GA-I and MMA-uria patients might be important according to our findings. -- L'acidurie glutarique de type I (GA-I) et l'acidurie méthylmalonique (MMA-urie) sont deux maladies neurométaboliques se manifestant durant la période néonatale ou la petite enfance, et qui appartiennent aux aciduries organiques. Elles sont causées par des défauts dans le catabolisme des acides aminés, conduisant à une accumulation des métabolites toxiques dans le corps et aussi des lésions cérébrales sévères. Le traitement est limité à une prise en charge d'urgence pendant la crise métabolique et à une diète restreinte en protéines naturelles. Des traitements spécifiques, neuroprotecteurs manquent principalement parce que les mécanismes conduisant aux lésions cérébrales dans ces maladies sont peu connus. L'objectif principal de mon travail était d'élucider les effets toxiques des métabolites accumulés dans GA-I (l'acide glutarique (GA) et l'acide 3-hydroxyglutarique (3-OHGA)) et MMA-uria (l'acide méthylmalonique (MMA), l'acide propionique (PA) et l'acide 2-méthylcitrique(2-MCA) sur les cellules du cerveau ainsi que les voies cellulaires impliquées, dans le but de trouver de potentielles nouvelles stratégies thérapeutiques. Nous avons utilisé un modèle in vitro de cultures 3D de cellules de cerveau d'embryons de rat (en développement) en les exposant aux métabolites toxiques à différents stades de développement des cultures. En parallèle, nous avons étudié la localisation cellulaire de l'enzyme déficiente dans GA-I, la CoA-glutarly déshydrogénase (GCDH), dans le cerveau et les organes périphériques des rats adultes et pendant le développement embryonnaire. L'expression de GCDH: GCDH a montré une expression neuronale forte dans le système nerveux chez l'embryon et le cerveau adulte. L'expression était homogène dans les organes périphériques avec une forte expression dans l'intestin. Les modèles in vitro de GA-I et MMA-uria : 3-OHGA en modèle GA-I et 2-MCA en modèle MMA-uria ont montré les effets délétères les plus importants avec des altérations morphologiques des cellules et biochimiques dans le milieu de culture et l'induction de mort cellulaire non-apoptotique (3-OHGA) ou apoptotique (2-MCA). 3-OHGA et 2-MCA ont provoqué une souffrance astrocytaire avec perte des fibres et gonflement et un retard de maturation et/ou de différentiation des oligodendrocytes. Une augmentation importante d'ammonium avec une diminution concomitante de glutamine a été observée dans les cultures. Les neurones n'étaient pas vraiment affectés. Nos études ont révélé que l'ammonium généré par les cellules cérébrales pourrait jouer un rôle dans la neuropathogenèse de ces deux maladies. Par conséquent, développer des stratégies neuroprotectrices ciblant la toxicité de l'ammonium dans le cerveau des patients atteints de GA-I ou MMA-urie pourrait être très important selon nos résultats.

COMPARAÇÃO ENTRE AS REGIÕES VITÍCOLAS DE SÃO JOAQUIM – SC, BRASIL E SAN MICHELE ALL’ADIGE – TN, ITÁLIA

A fenologia da videira, a produtividade das plantas e a qualidade da uva apresentam forte relação com os fatores ambientais. O objetivo deste trabalho foi comparar as regiões vitícolas de altitude elevada de Santa Catarina com a região de San Michele All’Adige localizada na Itália. Para os estudos, utilizou-se dos dados da Estação Experimental de São Joaquim - EPAGRI (28°16’30,08”S, 49°56’09,34”O, altitude 1.400 m), localizada em São Joaquim e do Istituto Agrario di San Michele All’Adige – Fondazione Edmund Mach46°11’41,46”N, 11°08’04,41”L, altitude 223 m), localizado na Província de Trento. A variedade avaliada foi a Rebo, para a qual foram determinados osprincipais estádios fenológicos e calculada a exigência térmica através dos graus-dia, temperaturas média, máxima, mínima, amplitude, precipitação, umidade relativa do ar, insolação e radiação solar global. No momento da colheita, foi avaliado o desempenho agronômico da variedade Rebo. Em São Joaquim, o ciclo da variedade Rebo é mais longo, o acúmulo térmico é menor, a precipitação pluviométrica e a radiação solar global acumulada são maiores do que em San Michele All’Adige. As temperaturas mais baixas e a menor insolação durante a floração-mudança de cor das bagas são os principais fatores climáticos relacionados com as menores produtividades das plantas. Em São Joaquim, as baixas temperaturas e as elevadas taxas de radiação solar global na maturação contribuem de maneira positiva na formação dos compostos fenólicos, mas dificultam a degradação dos ácidos da variedade Rebo.

Haciendo visible lo invisible : Peralada, un estudio de caso

Las diferencias entre municipios rurales y urbanos definen escenarios diferentes donde las personas mayores se enfrentan a necesidades también diferentes. En general, la falta de estudios sobre el envejecimiento entendido como un reto y que, además, asuman la variabilidad del proceso, pone al descubierto la necesidad particular de investigaciones que busquen comprender cómo viven los mayores en entornos como el rural. Este artículo describe nuestra experiencia investigadora en un municipio de la Comarca del Alt Empordà, Cataluña, España. El objetivo principal era entender a las personas mayores establecidas en entornos rurales a través de las situaciones de su vida cotidiana, identificar sus necesidades, contribuir a su autonomía funcional y elaborar propuestas de intervención. La muestra la formaron las 223 personas mayores residentes en el municipio de Peralada y Vilanova de la Muga. Los datos se recogieron utilizando los cuestionarios de Barber, Pfeifer y Barthel, y se realizaron entrevistas en profundidad. Los resultados proporcionan cinco claves relevantes al plantear intervenciones en el contexto rural. Básicamente, la intervención profesional en este ámbito debe ir orientada a mantener y fortalecer las redes de apoyo naturales funcionales en el territorio

Use of the Flixene vascular access graft as an early cannulation solution.

OBJECTIVE: The primary end points of this study were safety and efficacy of early cannulation of the Flixene graft (Maquet-Atrium Medical, Hudson, NH). Secondary end points were complications and patency. METHODS: This is a prospective single-center nonrandomized study. Study data included patient characteristics; history of vascular access; operative technique; interval between implantation and initial cannulation; complications; and patency at 1 month, 3 months, and every 6 months. Patency rates were estimated by the Kaplan-Meier method. RESULTS: Between January 2011 and September 2013, a total of 46 Flixene grafts were implanted in 44 patients (27 men) with a mean age of 63 years. The implantation site was the upper arm in 67% of cases, the forearm in 11%, and the thigh in 22%. Seven grafts were never cannulated during the study period. Of the remaining 39 grafts, 32 (82%) were successfully cannulated within the first week after implantation, including 16 (41%) on the first day. The median interval from implantation to initial cannulation was 2 days (interquartile range, 1-3 days). The median follow-up was 223.5 days (interquartile range, 97-600 days). Five hematomas occurred, but only one required surgical revision. Primary assisted and secondary patency rates were 65% and 86%, respectively, at 6 months and 56% and 86%, respectively, at 1 year. CONCLUSIONS: This study suggests that cannulation of the Flixene graft within 1 week after implantation is safe and effective. Early cannulation avoids or shortens the need for a temporary catheter. One-year patency rates appeared to be comparable to those achieved with conventional grafts, but long-term follow-up and randomized controlled studies will be needed to confirm this finding.