Traveling Granular Segregation Patterns in a Long Drum Mixer

Mixtures of granular media often exhibit size segregation along the axis of a partially-filled, horizontal, rotating cylinder. Previous experiments have observed axial bands of segregation that grow from concentration fluctuations and merge in a manner analogous to spinodal decomposition. We have observed that a new dynamical state precedes this effect in certain mixtures: bi-directional traveling waves. By preparing initial conditions, we found that the wave speed decreased with wavelength. Such waves appear to be inconsistent with simple PDE models which are first order in time.Comment: 11 page

Dexmedetomidine is neuroprotective in an in vitro model for traumatic brain injury

<p>Abstract</p> <p>Background</p> <p>The α₂-adrenoreceptor agonist dexmedetomidine is known to provide neuroprotection under ischemic conditions. In this study we investigated whether dexmedetomidine has a protective effect in an <it>in vitro </it>model for traumatic brain injury.</p> <p>Methods</p> <p>Organotypic hippocampal slice cultures were subjected to a focal mechanical trauma and then exposed to varying concentrations of dexmedetomidine. After 72 h cell injury was assessed using propidium iodide. In addition, the effects of delayed dexmedetomidine application, of hypothermia and canonical signalling pathway inhibitors were examined.</p> <p>Results</p> <p>Dexmedetomidine showed a protective effect on traumatically injured hippocampal cells with a maximum effect at a dosage of 1 μM. This effect was partially reversed by the simultaneous administration of the ERK inhibitor PD98059.</p> <p>Conclusion</p> <p>In this TBI model dexmedetomidine had a significant neuroprotective effect. Our results indicate that activation of ERK might be involved in mediating this effect.</p

Reduction of Mitoferrin Results in Abnormal Development and Extended Lifespan in Caenorhabditis elegans

Iron is essential for organisms. It is mainly utilized in mitochondria for biosynthesis of iron-sulfur clusters, hemes and other cofactors. Mitoferrin 1 and mitoferrin 2, two homologues proteins belonging to the mitochondrial solute carrier family, are required for iron delivery into mitochondria. Mitoferrin 1 is highly expressed in developing erythrocytes which consume a large amount of iron during hemoglobinization. Mitoferrin 2 is ubiquitously expressed, whose functions are less known. Zebrafish with mitoferrin 1 mutation show profound hypochromic anaemia and erythroid maturation arrests, and yeast with defects in MRS3/4, the counterparts of mitoferrin 1/2, has low mitochondrial iron levels and grows poorly by iron depletion. Mitoferrin 1 expression is up-regulated in yeast and mouse models of Fiedreich's ataxia disease and in human cell culture models of Parkinson disease, suggesting its involvement in the pathogenesis of diseases with mitochondrial iron accumulation. In this study we found that reduced mitoferrin levels in C. elegans by RNAi treatment causes pleiotropic phenotypes such as small body size, reduced fecundity, slow movement and increased sensitivity to paraquat. Despite these abnormities, lifespan was increased by 50% to 80% in N2 wild type strain, and in further studies using the RNAi sensitive strain eri-1, more than doubled lifespan was observed. The pathways or mechanisms responsible for the lifespan extension and other phenotypes of mitoferrin RNAi worms are worth further study, which may contribute to our understanding of aging mechanisms and the pathogenesis of iron disorder related diseases

Ectopic Pregnancy as a Model to Identify Endometrial Genes and Signaling Pathways Important in Decidualization and Regulated by Local Trophoblast

The endometrium in early pregnancy undergoes decidualization and functional changes induced by local trophoblast, which are not fully understood. We hypothesized that endometrium from tubal ectopic pregnancy (EP) could be interrogated to identify novel genes and pathways involved in these processes. Gestation-matched endometrium was collected from women with EP (n = 11) and intrauterine pregnancies (IUP) (n = 13). RNA was extracted from the tissue. In addition, tissues were prepared for histological analysis for degree of decidualization. We compared a) the samples from EP that were decidualized (n = 6) with non-decidualized samples (n = 5), and b) the decidualized EP (n = 6) with decidualization-matched IUP (n = 6) samples using an Affymetrix gene array platform, with Ingenuity Pathway Analysis, combined with quantitative RT-PCR. Expression of PRL and IGFBP1 was used to confirm the degree of decidualization in each group. There were no differences in PRL or IGFBP1 expression in the decidualization-matched samples but a marked reduction (P<0.001) in the non-decidualized samples. Decidualization was associated with increased expression of 428 genes including SCARA5 (181-fold), DKK1 (71-fold) and PROK1 (32-fold), and decreased expression of 230 genes including MMP-7 (35-fold) and SFRP4 (21-fold). The top canonical pathways associated with these differentially expressed genes were Natural Killer Cell and Wnt/b-Catenin signaling. Local trophoblast was associated with much less alteration of endometrial gene expression with an increase in 56 genes, including CSH1 (8-fold), and a reduction in 29 genes including CRISP3 (8-fold). The top associated canonical pathway was Antigen Presentation. The study of endometrium from tubal EP may promote novel insights into genes involved in decidualization and those influenced by factors from neighboring trophoblast. This has afforded unique information not highlighted by previous studies and adds to our understanding of the endometrium in early pregnancy

Role of P2 purinergic receptors in synaptic transmission under normoxic and ischaemic conditions in the CA1 region of rat hippocampal slices

The role of ATP and its stable analogue ATPγS [adenosine-5′-o-(3-thio)triphosphate] was studied in rat hippocampal neurotransmission under normoxic conditions and during oxygen and glucose deprivation (OGD). Field excitatory postsynaptic potentials (fEPSPs) from the dendritic layer or population spikes (PSs) from the soma were extracellularly recorded in the CA1 area of the rat hippocampus. Exogenous application of ATP or ATPγS reduced fEPSP and PS amplitudes. In both cases the inhibitory effect was blocked by the selective A1 adenosine receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine) and was potentiated by different ecto-ATPase inhibitors: ARL 67156 (6-N,N-diethyl-D-β,γ-dibromomethylene), BGO 136 (1-hydroxynaphthalene-3,6-disulfonate) and PV4 [hexapotassium dihydrogen monotitanoundecatungstocobaltate(II) tridecahydrate, K6H2[TiW11CoO40]·13H2O]. ATPγS-mediated inhibition was reduced by the P2 antagonist suramin [8-(3-benzamido-4-methylbenzamido)naphthalene-1,3,5-trisulfonate] at the somatic level and by other P2 blockers, PPADS (pyridoxalphosphate-6-azophenyl-2′,4′-disulfonate) and MRS 2179 (2′-deoxy-N6-methyladenosine 3′,5′-bisphosphate), at the dendritic level. After removal of both P2 agonists, a persistent increase in evoked synaptic responses was recorded both at the dendritic and somatic levels. This effect was prevented in the presence of different P2 antagonists. A 7-min OGD induced tissue anoxic depolarization and was invariably followed by irreversible loss of fEPSP. PPADS, suramin, MRS2179 or BBG (brilliant blue G) significantly prevented the irreversible failure of neurotransmission induced by 7-min OGD. Furthermore, in the presence of these P2 antagonists, the development of anoxic depolarization was blocked or significantly delayed. Our results indicate that P2 receptors modulate CA1 synaptic transmission under normoxic conditions by eliciting both inhibitory and excitatory effects. In the same brain region, P2 receptor stimulation plays a deleterious role during a severe OGD insult

Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia

Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR–ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals. Downregulation of miR-126 levels in CML LSCs was due to phosphorylation of Sprouty-related EVH1-domain-containing 1 (SPRED1) by BCR–ABL, which led to inhibition of the RAN–exportin-5–RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using mouse models of CML in which Mir126a (encoding miR-126) was conditionally knocked out in ECs and/or LSCs. Inhibition of BCR–ABL by TKI treatment caused an undesired increase in endogenous miR-126 levels, which enhanced LSC quiescence and persistence. Mir126a knockout in LSCs and/or ECs, or treatment with a miR-126 inhibitor that targets miR-126 expression in both LSCs and ECs, enhanced the in vivo anti-leukemic effects of TKI treatment and strongly diminished LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in individuals with CML

The dopamine β-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project

Contains fulltext : 88930.pdf (publisher's version ) (Open Access)BACKGROUND: The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine beta-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the pro-inflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls. METHODS: We genotyped eight single nucleotide polymorphisms (SNPs) in the three genes, DBH, IL1A and IL6. We used logistic regression models and synergy factor analysis to examine potential interactions and associations with AD. RESULTS: We found that the presence of the -1021T allele was associated with AD: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). This association was nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004). We also found an interaction between the presence of DBH -1021T and the -889TT genotype (rs1800587) of IL1A: synergy factor = 1.9 (1.2-3.1, 0.005). All these results were consistent between North Europe and North Spain. CONCLUSIONS: Extensive, previous evidence (reviewed here) indicates an important role for noradrenaline in the control of inflammation in the brain. Thus, the -1021T allele with presumed low activity may be associated with misregulation of inflammation, which could contribute to the onset of AD. We suggest that such misregulation is the predominant mechanism of the association we report here

First TILLING Platform in Cucurbita pepo: A New Mutant Resource for Gene Function and Crop Improvement

Although the availability of genetic and genomic resources for Cucurbita pepo has increased significantly, functional genomic resources are still limited for this crop. In this direction, we have developed a high throughput reverse genetic tool: the first TILLING (Targeting Induced Local Lesions IN Genomes) resource for this species. Additionally, we have used this resource to demonstrate that the previous EMS mutant population we developed has the highest mutation density compared with other cucurbits mutant populations. The overall mutation density in this first C. pepo TILLING platform was estimated to be 1/133 Kb by screening five additional genes. In total, 58 mutations confirmed by sequencing were identified in the five targeted genes, thirteen of which were predicted to have an impact on the function of the protein. The genotype/phenotype correlation was studied in a peroxidase gene, revealing that the phenotype of seedling homozygous for one of the isolated mutant alleles was albino. These results indicate that the TILLING approach in this species was successful at providing new mutations and can address the major challenge of linking sequence information to biological function and also the identification of novel variation for crop breeding.Financial support was provided by the Spanish Project INIA (Instituto Nacional de Investigacion y Tecnologia Agraria y Almentaria) RTA2011-00044C02-01, the ANR MELODY (ANR-11-BSV7-0024), the European Research Council (ERCSEXYPARTH), FEDER, and FSE funds. NVD has been awarded a grant by the Andalusian Institute of Agronomy Research IFAPA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Vicente-Dolera, N.; Troadec, C.; Moya, M.; Río-Celestino, MD.; Pomares-Viciana, T.; Bendahmane, A.; Picó Sirvent, MB.... (2014). First TILLING Platform in Cucurbita pepo: A New Mutant Resource for Gene Function and Crop Improvement. PLoS ONE. 9(11):112743-112743. https://doi.org/10.1371/journal.pone.0112743S112743112743911Paris, H. S., Yonash, N., Portnoy, V., Mozes-Daube, N., Tzuri, G., & Katzir, N. (2002). Assessment of genetic relationships in Cucurbita pepo (Cucurbitaceae) using DNA markers. Theoretical and Applied Genetics, 106(6), 971-978. doi:10.1007/s00122-002-1157-0Parry, M. A. J., Madgwick, P. J., Bayon, C., Tearall, K., Hernandez-Lopez, A., Baudo, M., … Phillips, A. L. (2009). Mutation discovery for crop improvement. Journal of Experimental Botany, 60(10), 2817-2825. doi:10.1093/jxb/erp189Gilchrist, E., & Haughn, G. (2010). Reverse genetics techniques: engineering loss and gain of gene function in plants. Briefings in Functional Genomics, 9(2), 103-110. doi:10.1093/bfgp/elp059McCallum, C. M., Comai, L., Greene, E. A., & Henikoff, S. (2000). Targeting Induced LocalLesions IN Genomes (TILLING) for Plant Functional Genomics. Plant Physiology, 123(2), 439-442. doi:10.1104/pp.123.2.439Colbert, T., Till, B. J., Tompa, R., Reynolds, S., Steine, M. N., Yeung, A. T., … Henikoff, S. (2001). High-Throughput Screening for Induced Point Mutations. Plant Physiology, 126(2), 480-484. doi:10.1104/pp.126.2.480Wang, T. L., Uauy, C., Robson, F., & Till, B. (2012). TILLINGin extremis. Plant Biotechnology Journal, 10(7), 761-772. doi:10.1111/j.1467-7652.2012.00708.xDong, C., Dalton-Morgan, J., Vincent, K., & Sharp, P. (2009). A Modified TILLING Method for Wheat Breeding. The Plant Genome Journal, 2(1), 39. doi:10.3835/plantgenome2008.10.0012Uauy, C., Paraiso, F., Colasuonno, P., Tran, R. K., Tsai, H., Berardi, S., … Dubcovsky, J. (2009). A modified TILLING approach to detect induced mutations in tetraploid and hexaploid wheat. BMC Plant Biology, 9(1), 115. doi:10.1186/1471-2229-9-115Kumar, A. P., Boualem, A., Bhattacharya, A., Parikh, S., Desai, N., Zambelli, A., … Bendahmane, A. (2013). SMART -- Sunflower Mutant population And Reverse genetic Tool for crop improvement. BMC Plant Biology, 13(1), 38. doi:10.1186/1471-2229-13-38Kurowska, M., Daszkowska-Golec, A., Gruszka, D., Marzec, M., Szurman, M., Szarejko, I., & Maluszynski, M. (2011). TILLING - a shortcut in functional genomics. Journal of Applied Genetics, 52(4), 371-390. doi:10.1007/s13353-011-0061-1Rigola, D., van Oeveren, J., Janssen, A., Bonné, A., Schneiders, H., van der Poel, H. J. A., … van Eijk, M. J. T. (2009). High-Throughput Detection of Induced Mutations and Natural Variation Using KeyPoint™ Technology. PLoS ONE, 4(3), e4761. doi:10.1371/journal.pone.0004761González, M., Xu, M., Esteras, C., Roig, C., Monforte, A. J., Troadec, C., … Picó, B. (2011). Towards a TILLING platform for functional genomics in Piel de Sapo melons. BMC Research Notes, 4(1). doi:10.1186/1756-0500-4-289Elias, R., Till, B. J., Mba, C., & Al-Safadi, B. (2009). Optimizing TILLING and Ecotilling techniques for potato (Solanum tuberosum L). BMC Research Notes, 2(1), 141. doi:10.1186/1756-0500-2-141Dahmani-Mardas, F., Troadec, C., Boualem, A., Lévêque, S., Alsadon, A. A., Aldoss, A. A., … Bendahmane, A. (2010). Engineering Melon Plants with Improved Fruit Shelf Life Using the TILLING Approach. PLoS ONE, 5(12), e15776. doi:10.1371/journal.pone.0015776Boualem, A., Fleurier, S., Troadec, C., Audigier, P., Kumar, A. P. K., Chatterjee, M., … Bendahmane, A. (2014). Development of a Cucumis sativus TILLinG Platform for Forward and Reverse Genetics. PLoS ONE, 9(5), e97963. doi:10.1371/journal.pone.0097963Blanca, J., Cañizares, J., Roig, C., Ziarsolo, P., Nuez, F., & Picó, B. (2011). Transcriptome characterization and high throughput SSRs and SNPs discovery in Cucurbita pepo (Cucurbitaceae). BMC Genomics, 12(1). doi:10.1186/1471-2164-12-104Esteras, C., Gomez, P., Monforte, A. J., Blanca, J., Vicente-Dolera, N., Roig, C., … Pico, B. (2012). High-throughput SNP genotyping in Cucurbita pepo for map construction and quantitative trait loci mapping. BMC Genomics, 13(1), 80. doi:10.1186/1471-2164-13-80Vicente-Dólera, N., Pinillos, V., Moya, M., Del Río-Celestino, M., Pomares-Viciana, T., Román, B., & Gómez, P. (2014). An improved method to obtain novel mutants in Cucurbita pepo by pollen viability. Scientia Horticulturae, 169, 14-19. doi:10.1016/j.scienta.2014.01.045Martín, B., Ramiro, M., Martínez-Zapater, J. M., & Alonso-Blanco, C. (2009). A high-density collection of EMS-induced mutations for TILLING in Landsberg erecta genetic background of Arabidopsis. BMC Plant Biology, 9(1), 147. doi:10.1186/1471-2229-9-147Wienholds, E. (2003). Efficient Target-Selected Mutagenesis in Zebrafish. Genome Research, 13(12), 2700-2707. doi:10.1101/gr.1725103Dalmais, M., Schmidt, J., Le Signor, C., Moussy, F., Burstin, J., Savois, V., … Bendahmane, A. (2008). UTILLdb, a Pisum sativum in silico forward and reverse genetics tool. Genome Biology, 9(2), R43. doi:10.1186/gb-2008-9-2-r43Triques, K., Sturbois, B., Gallais, S., Dalmais, M., Chauvin, S., Clepet, C., … Bendahmane, A. (2007). Characterization of Arabidopsis thaliana mismatch specific endonucleases: application to mutation discovery by TILLING in pea. The Plant Journal, 51(6), 1116-1125. doi:10.1111/j.1365-313x.2007.03201.xTaylor, N. E. (2003). PARSESNP: a tool for the analysis of nucleotide polymorphisms. Nucleic Acids Research, 31(13), 3808-3811. doi:10.1093/nar/gkg574Ng, P. C. 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Une anémie ferriprive génétique rare : le syndrome IRIDA

National audienceDevant une anémie chronique ferriprive non inflammatoire, typiquement caractérisée par une diminution combinée du taux d’hémoglobine plasmatique, du volume globulaire moyen, de la concentration du fer plasmatique (avec baisse de la saturation de la transferrine) avec un taux de ferritine plasmatique le plus souvent bas, l’orientation première est celle d’un saignement, en premier lieu d’origine digestive ou gynécologique. En cas de négativité de ces recherches, il convient d’évoquer un défaut d’apport de fer d’origine digestive, qu’il s’agisse d’une carence alimentaire en fer ou d’un défaut d’absorption du fer. Ce défaut d’absorption peut être consécutif à une inhibition de l’absorption du fer par prise excessive de thé ou de médicaments, ou à une malabsorption comme dans la maladie coeliaque. En l’absence de détection d’une cause acquise, et notamment chez un sujet jeune chez qui l’effondrement de la sidérémie contraste avec l’absence d’hypoferritinémie, et qui ne répond pas, ou seulement partiellement, à la supplémentation orale en fer, il faut penser à la possibilité d’une origine génétique telle que le syndrome IRIDA (« Iron-Refractory Iron Deficiency Anemia »). Ce syndrome s’explique par une hyperhepcidinémie constitutionnelle due à des mutations du gène TMPRSS6 de la matriptase 2. La présente observation d’une enfant de trois ans, outre qu’elle montre un profil génétique original, illustre, dans la vraie vie, les difficultés rencontrées pour évoquer ce syndrome dont la pénétrance et l’expression sont hétérogènes, ainsi que les conséquences favorables, pour l’enfant et sa famille, qui découlent de l’affirmation du diagnostic