493 research outputs found

    HER2 expression and efficacy of T-DM1

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    Molecular diversity and distribution of eastern Atlantic and Mediterranean dogfishes Squalus highlight taxonomic issues in the genus

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    This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.The alpha taxonomy of the globally distributed shark genus Squalus has been under intense investigation recently, and many new species have been described over the last decade. However, taxonomic uncertainty remains about several taxa. Without consistent nomenclature and the ability to reliably distinguish between the different Squalus species, basic data collection, downstream conservation and management efforts are seriously compromised. To aid in clarifying the taxonomic status of Squalus species in the eastern Atlantic and Mediterranean, we assessed species diversity at the molecular level and evaluated the consistency in species identification in the region. Samples from all nominal Squalus species recognized in the above regions were collected in an international effort and sequenced for regions of the mitochondrial COI and ND2 genes. These data were further analysed alongside publicly available sequences, including 19 of the 26 Squalus species globally recognized, to compare the regional genus-level diversity with that found elsewhere. Our results confirm inconsistent species identification in the eastern Atlantic and Mediterranean Squalus, particularly concerning S. blainville and S. megalops, and reinforce the need to revise the status of S. megalops and S. mitsukurii as they may include several distinct species distributed around the world. The status of S. blainville is also discussed in the light of the current findings and its problematic taxonomic history.Systematic Research Fund. Fundação para a Ciência e Tecnologia. Grant Number: SFRH/BPD/77487/2007. Social European Fund. Portuguese funds. New Zealand National Institute of Water and Atmospheric Research Lt

    On lattice profile of the elliptic curve linear congruential generators

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    Lattice tests are quality measures for assessing the intrinsic structure of pseudorandom number generators. Recently a new lattice test has been introduced by Niederreiter and Winterhof. In this paper, we present a general inequality that is satisfied by any periodic sequence. Then, we analyze the behavior of the linear congruential generators on elliptic curves (EC-LCG) under this new lattice test and prove that the EC-LCG passes it up to very high dimensions. We also use a result of Brandstätter and Winterhof on the linear complexity profile related to the correlation measure of order k to present lower bounds on the linear complexity profile of some binary sequences derived from the EC-LCG

    Scalable High-Affinity Stabilization of Magnetic Iron Oxide Nanostructures by a Biocompatible Antifouling Homopolymer

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    Iron oxide nanostructures have been widely developed for biomedical applications because of their magnetic properties and biocompatibility. In clinical applications, stabilization of these nanostructures against aggregation and nonspecific interactions is typically achieved using weakly anchored polysaccharides, with better-defined and more strongly anchored synthetic polymers not commercially adopted because of their complexity of synthesis and use. Here, we show for the first time stabilization and biocompatibilization of iron oxide nanoparticles by a synthetic homopolymer with strong surface anchoring and a history of clinical use in other applications, poly(2-methacryloyloxyethyl phosphorylcholine) [poly(MPC)]. For the commercially important case of spherical particles, binding of poly(MPC) to iron oxide surfaces and highly effective individualization of magnetite nanoparticles (20 nm) are demonstrated. Next-generation high-aspect-ratio nanowires (both magnetite/maghemite and core–shell iron/iron oxide) are, furthermore, stabilized by poly(MPC) coating, with the nanowire cytotoxicity at large concentrations significantly reduced. The synthesis approach exploited to incorporate functionality into the poly(MPC) chain is demonstrated by random copolymerization with an alkyne-containing monomer for click chemistry. Taking these results together, poly(MPC) homopolymers and random copolymers offer a significant improvement over current iron oxide nanoformulations, combining straightforward synthesis, strong surface anchoring, and well-defined molecular weight

    Scalable High-Affinity Stabilization of Magnetic Iron Oxide Nanostructures by a Biocompatible Antifouling Homopolymer

    Get PDF
    Iron oxide nanostructures have been widely developed for biomedical applications because of their magnetic properties and biocompatibility. In clinical applications, stabilization of these nanostructures against aggregation and nonspecific interactions is typically achieved using weakly anchored polysaccharides, with better-defined and more strongly anchored synthetic polymers not commercially adopted because of their complexity of synthesis and use. Here, we show for the first time stabilization and biocompatibilization of iron oxide nanoparticles by a synthetic homopolymer with strong surface anchoring and a history of clinical use in other applications, poly(2-methacryloyloxyethyl phosphorylcholine) [poly(MPC)]. For the commercially important case of spherical particles, binding of poly(MPC) to iron oxide surfaces and highly effective individualization of magnetite nanoparticles (20 nm) are demonstrated. Next-generation high-aspect-ratio nanowires (both magnetite/maghemite and core–shell iron/iron oxide) are, furthermore, stabilized by poly(MPC) coating, with the nanowire cytotoxicity at large concentrations significantly reduced. The synthesis approach exploited to incorporate functionality into the poly(MPC) chain is demonstrated by random copolymerization with an alkyne-containing monomer for click chemistry. Taking these results together, poly(MPC) homopolymers and random copolymers offer a significant improvement over current iron oxide nanoformulations, combining straightforward synthesis, strong surface anchoring, and well-defined molecular weight

    Copy Number Variation in Intron 1 of SOX5 Causes the Pea-comb Phenotype in Chickens

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    Pea-comb is a dominant mutation in chickens that drastically reduces the size of the comb and wattles. It is an adaptive trait in cold climates as it reduces heat loss and makes the chicken less susceptible to frost lesions. Here we report that Pea-comb is caused by a massive amplification of a duplicated sequence located near evolutionary conserved non-coding sequences in intron 1 of the gene encoding the SOX5 transcription factor. This must be the causative mutation since all other polymorphisms associated with the Pea-comb allele were excluded by genetic analysis. SOX5 controls cell fate and differentiation and is essential for skeletal development, chondrocyte differentiation, and extracellular matrix production. Immunostaining in early embryos demonstrated that Pea-comb is associated with ectopic expression of SOX5 in mesenchymal cells located just beneath the surface ectoderm where the comb and wattles will subsequently develop. The results imply that the duplication expansion interferes with the regulation of SOX5 expression during the differentiation of cells crucial for the development of comb and wattles. The study provides novel insight into the nature of mutations that contribute to phenotypic evolution and is the first description of a spontaneous and fully viable mutation in this developmentally important gene

    Symptom Remission and Brain Cortical Networks at First Clinical Presentation of Psychosis: The OPTiMiSE Study

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    Individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, that may be particularly prominent, already at illness onset, in those more likely to have poorer symptom remission following treatment with the first antipsychotic. The identification of strong neuroanatomical markers of symptom remission could thus facilitate stratification and individualized treatment of patients with schizophrenia. We used magnetic resonance imaging at baseline to examine brain regional and network correlates of subsequent symptomatic remission in 167 medication-naïve or minimally treated patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder entering a three-phase trial, at seven sites. Patients in remission at the end of each phase were randomized to treatment as usual, with or without an adjunctive psycho-social intervention for medication adherence. The final follow-up visit was at 74 weeks. A total of 108 patients (70%) were in remission at Week 4, 85 (55%) at Week 22, and 97 (63%) at Week 74. We found no baseline regional differences in volumes, cortical thickness, surface area, or local gyrification between patients who did or did not achieved remission at any time point. However, patients not in remission at Week 74, at baseline showed reduced structural connectivity across frontal, anterior cingulate, and insular cortices. A similar pattern was evident in patients not in remission at Week 4 and Week 22, although not significantly. Lack of symptom remission in first-episode psychosis is not associated with regional brain alterations at illness onset. Instead, when the illness becomes a stable entity, its association with the altered organization of cortical gyrification becomes more defined

    E-Cadherin Acts as a Regulator of Transcripts Associated with a Wide Range of Cellular Processes in Mouse Embryonic Stem Cells

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    We have recently shown that expression of the cell adhesion molecule E-cadherin is required for LIF-dependent pluripotency of mouse embryonic stem (ES) cells.In this study, we have assessed global transcript expression in E-cadherin null (Ecad-/-) ES cells cultured in either the presence or absence of LIF and compared these to the parental cell line wtD3.We show that LIF has little effect on the transcript profile of Ecad-/- ES cells, with statistically significant transcript alterations observed only for Sp8 and Stat3. Comparison of Ecad-/- and wtD3 ES cells cultured in LIF demonstrated significant alterations in the transcript profile, with effects not only confined to cell adhesion and motility but also affecting, for example, primary metabolic processes, catabolism and genes associated with apoptosis. Ecad-/- ES cells share similar, although not identical, gene expression profiles to epiblast-derived pluripotent stem cells, suggesting that E-cadherin expression may inhibit inner cell mass to epiblast transition. We further show that Ecad-/- ES cells maintain a functional β-catenin pool that is able to induce β-catenin/TCF-mediated transactivation but, contrary to previous findings, do not display endogenous β-catenin/TCF-mediated transactivation. We conclude that loss of E-cadherin in mouse ES cells leads to significant transcript alterations independently of β-catenin/TCF transactivation

    Sub region-specific modulation of synchronous neuronal burst firing after a kainic acid insult in organotypic hippocampal cultures

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    <p>Abstract</p> <p>Background</p> <p>Excitotoxicity occurs in a number of pathogenic states including stroke and epilepsy. The adaptations of neuronal circuits in response to such insults may be expected to play an underlying role in pathogenesis. Synchronous neuronal firing can be induced in isolated hippocampal slices and involves all regions of this structure, thereby providing a measure of circuit activity. The effect of an excitotoxic insult (kainic acid, KA) on Mg<sup>2+</sup>-free-induced synchronized neuronal firing was tested in organotypic hippocampal culture by measuring extracellular field activity in CA1 and CA3.</p> <p>Results</p> <p>Within 24 hrs of the insult regional specific changes in neuronal firing patterns were evident as: (i) a dramatic <it>reduction </it>in the ability of CA3 to generate firing; and (ii) a contrasting <it>increase </it>in the frequency and duration of synchronized neuronal firing events in CA1. Two distinct processes underlie the increased propensity of CA1 to generate synchronized burst firing; a lack of ability of the CA3 region to 'pace' CA1 resulting in an increased frequency of synchronized events; and a change in the 'intrinsic' properties limited to the CA1 region, which is responsible for increased event duration. Neuronal quantification using NeuN immunoflurescent staining and stereological confocal microscopy revealed no significant cell loss in hippocampal sub regions, suggesting that changes in the properties of neurons within this region were responsible for the KA-mediated excitability changes.</p> <p>Conclusion</p> <p>These results provide novel insight into adaptation of hippocampal circuits following excitotoxic injury. KA-mediated disruption of the interplay between CA3 and CA1 clearly increases the propensity to synchronized firing in CA1.</p
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