Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations

​Leucine-rich repeat kinase 2 (​LRRK2) mutations are the most common genetic cause of Parkinson’s disease. ​LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson’s disease, but whether ​LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that ​LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase ​αTAT1 prevents association of mutant ​LRRK2 with microtubules, and the deacetylase inhibitor ​trichostatin A (​TSA) restores axonal transport. In vivo knockdown of the deacetylases ​HDAC6 and ​Sirt2, or administration of ​TSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson’s disease

El uso de broncodilatadores en la bronquiolitis

Introducción: La bronquiolitis es una patología frecuente en la práctica clínica pediátrica. Constituye una de las principales entidades clínicas dentro de las infecciones respiratorias agudas bajas (IRAB). Se define como el primer episodio de sibilancias con manifestaciones clínicas de infección viral en un niño menor de dos años y afecta principalmente a lactantes menores de 6 meses. El tratamiento es fundamentalmente de soporte con oxigenoterapia e hidratación, quedando el resto de las terapéuticas bajo una profunda controversia acerca de su real efectividad. Metodología: Desde la exposición de un escenario clínico se planteó una pregunta estructurada para luego realizar una búsqueda bibliográfica con el fin de dar respuesta a la pregunta sobre la efectividad en el tratamiento del bronquiolitis con broncodilatadores. Se realizó una búsqueda en PubMed utilizando los Mesh (Medical Subject Headings) "bronchodilators AND bronchiolitis", se aplicaron distintos filtros, tras lo cual se llegó al número final de 23 artículos. Tras una lectura de los títulos y resúmenes de los artículos, se escogió el artículo "Bronchodilators for bronchiolitis". Análisis del artículo: Nos hemos centrado las siguientes variables con el fin de responder a la pregunta clínica: la mejoría en el score clínico, la reducción de la tasa de internación y la saturometría de oxígeno. Realizamos luego un análisis secundario de los datos de las distintas variables con el fin de definir los valores de riesgo relativo (RR), reducción de riesgo absoluto (RRA), reducción del riesgo relativo (RRR) y el número necesario a tratar (NNT) con sus respectivos intervalos de confianza del 95% (IC 95%). También se llevó a cabo un análisis estadístico para evaluar la variable de saturación de oxígeno. Recomendación final: No está recomendado el uso de broncodilatadores en el manejo del bronquiolitis, ya que no mejoran ninguna de las variables analizadas. Los broncodilatadores no sólo no tienen eficacia, sino que suponen un gasto y presentan efectos adversos indeseables

ICOS regulates the generation and function of human CD4+ Treg in a CTLA-4 dependent manner

Inducible co-stimulator (ICOS) is a member of CD28/Cytotoxic T-lymphocyte Antigen-4 (CTLA-4) family and broadly expressed in activated CD4+ T cells and induced regulatory CD4+ T cells (CD4+ iTreg). ICOS-related signal pathway could be activated by the interaction between ICOS and its ligand (ICOSL). In our previous work, we established a cost-effective system to generate a novel human allo-antigen specific CD4hi Treg by co-culturing their naïve precursors with allogeneic CD40-activated B cells in vitro. Here we investigate the role of ICOS in the generation and function of CD4hi Treg by interrupting ICOS-ICOSL interaction with ICOS-Ig. It is found that blockade of ICOS-ICOSL interaction impairs the induction and expansion of CD4hi Treg induced by allogeneic CD40-activated B cells. More importantly, CD4hi Treg induced with the addition of ICOS-Ig exhibits decreased suppressive capacity on alloantigen-specific responses. Dysfunction of CD4hi Treg induced with ICOS-Ig is accompanied with its decreased exocytosis and surface CTLA-4 expression. Through inhibiting endocytosis with E64 and pepstatin A, surface CTLA-4 expression and suppressive functions of induced CD4hi Treg could be partly reversed. Conclusively, our results demonstrate the beneficial role of ICOS-ICOSL signal pathway in the generation and function of CD4hi Treg and uncover a novel relationship between ICOS and CTLA-4. © 2013 zheng et al.published_or_final_versio

El uso de broncodilatadores en la bronquiolitis

Introducción: La bronquiolitis es una patología frecuente en la práctica clínica pediátrica. Constituye una de las principales entidades clínicas dentro de las infecciones respiratorias agudas bajas (IRAB). Se define como el primer episodio de sibilancias con manifestaciones clínicas de infección viral en un niño menor de dos años y afecta principalmente a lactantes menores de 6 meses. El tratamiento es fundamentalmente de soporte con oxigenoterapia e hidratación, quedando el resto de las terapéuticas bajo una profunda controversia acerca de su real efectividad. Metodología: Desde la exposición de un escenario clínico se planteó una pregunta estructurada para luego realizar una búsqueda bibliográfica con el fin de dar respuesta a la pregunta sobre la efectividad en el tratamiento del bronquiolitis con broncodilatadores. Se realizó una búsqueda en PubMed utilizando los Mesh (Medical Subject Headings) "bronchodilators AND bronchiolitis", se aplicaron distintos filtros, tras lo cual se llegó al número final de 23 artículos. Tras una lectura de los títulos y resúmenes de los artículos, se escogió el artículo "Bronchodilators for bronchiolitis". Análisis del artículo: Nos hemos centrado las siguientes variables con el fin de responder a la pregunta clínica: la mejoría en el score clínico, la reducción de la tasa de internación y la saturometría de oxígeno. Realizamos luego un análisis secundario de los datos de las distintas variables con el fin de definir los valores de riesgo relativo (RR), reducción de riesgo absoluto (RRA), reducción del riesgo relativo (RRR) y el número necesario a tratar (NNT) con sus respectivos intervalos de confianza del 95% (IC 95%). También se llevó a cabo un análisis estadístico para evaluar la variable de saturación de oxígeno. Recomendación final: No está recomendado el uso de broncodilatadores en el manejo del bronquiolitis, ya que no mejoran ninguna de las variables analizadas. Los broncodilatadores no sólo no tienen eficacia, sino que suponen un gasto y presentan efectos adversos indeseables

Avian Pathogenic Escherichia coli (APEC) Infection Alters Bone Marrow Transcriptome in Chickens

Avian pathogenic Escherichia coli (APEC) is a major cause of disease impacting animal health. The bone marrow is the reservoir of immature immune cells; however, it has not been examined to date for gene expression related to developmental changes (cell differentiation, maturation, programming) after APEC infection. Here, we study gene expression in the bone marrow between infected and non-infected animals, and between infected animals with mild (resistant) versus severe (susceptible) pathology, at two times post-infection. We sequenced 24 bone marrow RNA libraries generated from the six different treatment groups with four replicates each, and obtained an average of 22 million single-end, 100-bp reads per library. Genes were detected as differentially expressed (DE) between APEC treatments (mild pathology, severe pathology, and mock-challenged) at a given time point, or DE between 1 and 5 days post-infection (dpi) within the same treatment group. Results demonstrate that many immune cells, genes and related pathways are key contributors to the different responses to APEC infection between susceptible and resistant birds and between susceptible and non-challenged birds, at both times post-infection. In susceptible birds, lymphocyte differentiation, proliferation, and maturation were greatly impaired, while the innate and adaptive immune responses, including dendritic cells, monocytes and killer cell activity, TLR- and NOD-like receptor signaling, as well as T helper cells and many cytokine activities, were markedly enhanced. The resistant birds’ immune system, however, was similar to that of non-challenged birds. The DE genes in the immune cells and identified signaling models are representative of activation and resolution of infection in susceptible birds at both post-infection days. These novel results characterizing transcriptomic response to APEC infection reveal that there is combinatorial activity of multiple genes controlling myeloid cells, and B and T cell lymphopoiesis, as well as immune responses occurring in the bone marrow in these early stages of response to infection

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Mechanisms of T cell organotropism

F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation

Deficiency of GDP-l-galactose phosphorylase, an enzyme required for ascorbic acid synthesis, reduces tomato fruit yield

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this recordReduced GDP-L-galactose phosphorylase expression and deficiency of ascorbic acid content lead to decreased fruit set and yield in tomato plants. GDP-L-galactose phosphorylase (GGP) catalyzes the first step committed to ascorbic acid synthesis. The participation of GDP-L-galactose phosphorylase and ascorbate in tomato fruit production and quality was studied in this work using two SlGGP1 deficient EMS Micro-Tom mutants. The SlGGP1 mutants display decreased concentrations of ascorbate in roots, leaves, flowers, and fruit. The initiation of anthesis is delayed in ggp1 plants but the number of flowers is similar to wild type. The number of fruits is reduced in ggp1 mutants with an increased individual weight. However, the whole fruit biomass accumulation is reduced in both mutant lines. Fruits of the ggp1 plants produce more ethylene and show higher firmness and soluble solids content than the wild type after the breaker stage. Leaf CO2 uptake decreases about 50% in both ggp1 mutants at saturating light conditions; however, O2 production in an enriched CO2 atmosphere is only 19% higher in wild type leaves. Leaf conductance that is largely reduced in both mutants may be the main limitation for photosynthesis. Sink-source assays and hormone concentration were measured to determine restrictions to fruit yield. Manipulation of leaf area/fruit number relationship demonstrates that the number of fruits and not the provision of photoassimilates from the source restricts biomass accumulation in the ggp1 lines. The lower gibberellins concentration measured in the flowers would contribute to the lower fruit set, thus impacting in tomato yield. Taken as a whole these results demonstrate that ascorbate biosynthetic pathway critically participates in tomato development and fruit production.ANPCyTUniversidad Nacional de La Plata, Argentin

Foxp3 and IL-10 Expression Correlates with Parasite Burden in Lesional Tissues of Post Kala Azar Dermal Leishmaniasis (PKDL) Patients

Post kala azar dermal leishamniasis (PKDL), an unusual dermatosis develops in 5–15% of apparently cured visceral leishmaniasis cases in India and in about 60% of cases in Sudan. PKDL cases assume importance since they constitute a major human reservoir for the parasite. Inadequate treatment of VL, genetics, nutrition and immunological mechanisms that allow renewed multiplication of latent parasites or reinfection predispose to PKDL. Immunopathogenesis of PKDL is poorly understood. IL-10 is widely accepted as an immuno-suppressive cytokine and produced by diverse cell populations including, B cells, macrophages and CD4+ T cells. Natural T regulatory (nTreg) cells are subpopulation of CD4+ T cells that inhibit the response of other T cells. In this study we reported the accumulation of nTreg cells in lesion tissues of PKDL patients. Further correlation of Treg markers and IL-10 with parasite load in lesion tissues suggested a role of IL-10 and Treg in parasite establishment or persistence. Further studies are warranted to explore antigen specific IL-10 source in lesion tissues and unravel the concerted induction or accumulation of Treg in PKDL

Three allele combinations associated with Multiple Sclerosis

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease of polygenic etiology. Dissection of its genetic background is a complex problem, because of the combinatorial possibilities of gene-gene interactions. As genotyping methods improve throughput, approaches that can explore multigene interactions appropriately should lead to improved understanding of MS. METHODS: 286 unrelated patients with definite MS and 362 unrelated healthy controls of Russian descent were genotyped at polymorphic loci (including SNPs, repeat polymorphisms, and an insertion/deletion) of the DRB1, TNF, LT, TGFβ1, CCR5 and CTLA4 genes and TNFa and TNFb microsatellites. Each allele carriership in patients and controls was compared by Fisher's exact test, and disease-associated combinations of alleles in the data set were sought using a Bayesian Markov chain Monte Carlo-based method recently developed by our group. RESULTS: We identified two previously unknown MS-associated tri-allelic combinations: -509TGFβ1*C, DRB1*18(3), CTLA4*G and -238TNF*B1,-308TNF*A2, CTLA4*G, which perfectly separate MS cases from controls, at least in the present sample. The previously described DRB1*15(2) allele, the microsatellite TNFa9 allele and the biallelic combination CCR5Δ32, DRB1*04 were also reidentified as MS-associated. CONCLUSION: These results represent an independent validation of MS association with DRB1*15(2) and TNFa9 in Russians and are the first to find the interplay of three loci in conferring susceptibility to MS. They demonstrate the efficacy of our approach for the identification of complex-disease-associated combinations of alleles