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Sample records for multiple differentiation potential

  1. Evoked potential studies in the antiphospholipid syndrome: differential diagnosis from multiple sclerosis

    PubMed Central

    Paran, D; Chapman, J; Korczyn, A D; Elkayam, O; Hilkevich, O; Groozman, G B; Levartovsky, D; Litinsky, I; Caspi, D; Segev, Y; Drory, V E

    2006-01-01

    Background The CNS manifestations of the antiphospholipid syndrome (APS) can mimic multiple sclerosis both clinically and radiologically. Objective To compare evoked potential studies in APS patients and patients with multiple sclerosis with similar neurological disability. Methods 30 APS patients with CNS manifestations and 33 patients with definite multiple sclerosis and similar neurological disability underwent studies of visual evoked potentials (VEP), somatosensory evoked potentials (SSEP) in the upper and lower limbs (UL, LL), and sympathetic skin responses (SSR) in the upper and lower limbs. Results The neurological manifestations in the APS patients included stroke (n?=?17), transient ischaemic attacks (n?=?10), and severe headache with multiple white matter lesions on brain MRI (n?=?3). Abnormal SSEP (LL), and SSR (UL; LL) were seen in APS patients (37%, 27%, and 30%, respectively) but VEP and UL SSEP were rarely abnormal (10% and 6%, respectively in APS v 58% and 33% in multiple sclerosis; p?=?0.0005, p?=?0.008). Mean VEP latencies were more prolonged in multiple sclerosis (116?ms v 101?ms, p<0.001). Only one APS patient had abnormal findings in all three evoked potential studies, compared with seven patients in the multiple sclerosis group (p?=?0.04) Conclusions Abnormal VEPs are uncommon in APS in contrast to multiple sclerosis. Coexisting abnormalities in all other evoked potentials were similarly rare in APS. In patients with brain MRI findings compatible either with multiple sclerosis or APS, normal evoked potential tests, and especially a normal VEP, may support the diagnosis of APS. PMID:16107510

  2. Differential Effects of Oxygen and Oxidation Reduction Potential on the Multiplication of Three Species of Anaerobic Intestinal Bacteria

    PubMed Central

    Walden, William C.; Hentges, David J.

    1975-01-01

    The sensitivity of three strains of anaerobic intestinal bacteria, Clostridium perfringens, Bacteroides fragilis, and Peptococcus magnus, to the differential effects of oxygen and adverse oxidation-reduction potential was measured. The multiplication of the three organisms was inhibited in the presence of oxygen whether the medium was at a negative oxidation-reduction potential (Eh of -50 mV), poised by the intermittent addition of dithiothreitol, or at a positive oxidation-reduction potential (Eh of near +500 mV). However, when these organisms were cultured in the absence of oxygen, no inhibition was observed, even when the oxidation-reduction potential was maintained at an average Eh of +325 mV by the addition of potassium ferricyanide. When the cultures were aerated, the growth patterns of the three organisms demonstrated different sensitivities to oxygen. P. magnus was found to be the most sensitive. After 2 h of aerobic incubation, no viable organisms could be detected. B. fragilis was intermediately sensitive to oxygen with no viable organisms detected after 5 h of aerobic incubation. C. perfringens was the least sensitive. Under conditions of aerobic incubation, viable organisms survived for 10 h. During the experiments with Clostridium, no spores were observed by spore staining. PMID:173238

  3. Multiple Intelligences for Differentiated Learning

    ERIC Educational Resources Information Center

    Williams, R. Bruce

    2007-01-01

    There is an intricate literacy to Gardner's multiple intelligences theory that unlocks key entry points for differentiated learning. Using a well-articulated framework, rich with graphic representations, Williams provides a comprehensive discussion of multiple intelligences. He moves the teacher and students from curiosity, to confidence, to

  4. Differentiation potential of rat amnion.

    PubMed Central

    Knezevic, V

    1996-01-01

    The differentiation potential of rat amnion was investigated by explantation to different extrauterine sites and by culturing in vitro. Amnion differentiated into full skin by a process that is morphologically indistinguishable from normal skin development (interactions of the surface embryonic ectoderm and underlying mesenchyme). This process is not dependent on the age of the amnion but is dependent on the culture conditions used. Possible implications of these findings are discussed. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8771391

  5. MULTIPLE DIFFERENTIAL ROTARY MECHANICAL DRIVE

    DOEpatents

    Smits, R.G.

    1964-01-28

    This patent relates to a mechanism suitable for such applications as driving two spaced-apart spools which carry a roll film strip under conditions where the film movement must be rapidly started, stopped, and reversed while maintaining a constant tension on the film. The basic drive is provided by a variable speed, reversible rnotor coupled to both spools through a first differential mechanism and driving both spools in the same direction. A second motor, providing a constant torque, is connected to the two spools through a second differential mechanism and is coupled to impart torque to one spool in a first direction anid to the other spool in the reverse direction thus applying a constant tension to the film passing over the two spools irrespective of the speed or direction of rotation thereof. (AEC)

  6. Ladder operators and differential equations for multiple orthogonal polynomials

    NASA Astrophysics Data System (ADS)

    Filipuk, Galina; Van Assche, Walter; Zhang, Lun

    2013-05-01

    In this paper, we obtain the ladder operators and associated compatibility conditions for types I and II multiple orthogonal polynomials. These ladder equations extend known results for orthogonal polynomials and can be used to derive the differential equations satisfied by multiple orthogonal polynomials. Our approach is based on Riemann-Hilbert problems and the Christoffel-Darboux formula for multiple orthogonal polynomials, and the nearest-neighbor recurrence relations. As an illustration, we give several explicit examples involving multiple Hermite and Laguerre polynomials, and multiple orthogonal polynomials with exponential weights and cubic potentials.

  7. Multiple-Bit Differential Detection of OQPSK

    NASA Technical Reports Server (NTRS)

    Simon, Marvin

    2005-01-01

    A multiple-bit differential-detection method has been proposed for the reception of radio signals modulated with offset quadrature phase-shift keying (offset QPSK or OQPSK). The method is also applicable to other spectrally efficient offset quadrature modulations. This method is based partly on the same principles as those of a multiple-symbol differential-detection method for M-ary QPSK, which includes QPSK (that is, non-offset QPSK) as a special case. That method was introduced more than a decade ago by the author of the present method as a means of improving performance relative to a traditional (two-symbol observation) differential-detection scheme. Instead of symbol-by-symbol detection, both that method and the present one are based on a concept of maximum-likelihood sequence estimation (MLSE). As applied to the modulations in question, MLSE involves consideration of (1) all possible binary data sequences that could have been received during an observation time of some number, N, of symbol periods and (2) selection of the sequence that yields the best match to the noise-corrupted signal received during that time. The performance of the prior method was shown to range from that of traditional differential detection for short observation times (small N) to that of ideal coherent detection (with differential encoding) for long observation times (large N).

  8. Estimating differential expression from multiple indicators

    PubMed Central

    Ilmjrv, Sten; Hundahl, Christian Ansgar; Reimets, Riin; Niitsoo, Margus; Kolde, Raivo; Vilo, Jaak; Vasar, Eero; Luuk, Hendrik

    2014-01-01

    Regardless of the advent of high-throughput sequencing, microarrays remain central in current biomedical research. Conventional microarray analysis pipelines apply data reduction before the estimation of differential expression, which is likely to render the estimates susceptible to noise from signal summarization and reduce statistical power. We present a probe-level framework, which capitalizes on the high number of concurrent measurements to provide more robust differential expression estimates. The framework naturally extends to various experimental designs and target categories (e.g. transcripts, genes, genomic regions) as well as small sample sizes. Benchmarking in relation to popular microarray and RNA-sequencing data-analysis pipelines indicated high and stable performance on the Microarray Quality Control dataset and in a cell-culture model of hypoxia. Experimental-data-exhibiting long-range epigenetic silencing of gene expression was used to demonstrate the efficacy of detecting differential expression of genomic regions, a level of analysis not embraced by conventional workflows. Finally, we designed and conducted an experiment to identify hypothermia-responsive genes in terms of monotonic time-response. As a novel insight, hypothermia-dependent up-regulation of multiple genes of two major antioxidant pathways was identified and verified by quantitative real-time PCR. PMID:24586062

  9. Effect of Multiple Testing Adjustment in Differential Item Functioning Detection

    ERIC Educational Resources Information Center

    Kim, Jihye; Oshima, T. C.

    2013-01-01

    In a typical differential item functioning (DIF) analysis, a significance test is conducted for each item. As a test consists of multiple items, such multiple testing may increase the possibility of making a Type I error at least once. The goal of this study was to investigate how to control a Type I error rate and power using adjustment

  10. Abnormal Tr1 differentiation in multiple sclerosis.

    PubMed

    Astier, Anne L; Hafler, David A

    2007-11-01

    Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). In the recent years, accumulating evidence has supported an immunosuppressive role for regulatory T cells (Tregs). Most studies in the context of autoimmunity have focused on the defects of the CD4+CD25 high Tregs. However, we recently demonstrated an altered function of Tr1 Treg cells in MS, characterized by a lack of IL-10 secretion. Therefore, several major regulatory T cell defects are involved in human autoimmune disease. Hence, the induction of Tregs or the stimulation of Treg activity may be beneficial for the treatment of such diseases. PMID:17936368

  11. Multiple symbol differential detection of uncoded and trellis coded MPSK

    NASA Technical Reports Server (NTRS)

    Divsalar, Dariush; Simon, Marvin K.; Shahshahani, Mehrdad

    1989-01-01

    A differential detection for MPSK, which uses a multiple symbol observation interval, is presented and its performance analyzed and simulated. The technique makes use of maximum-likelihood sequence estimation of the transmitted phases rather than symbol-by-symbol detection as in conventional differential detection. As such the performance of this multiple symbol detection scheme fills the gap between conventional (two-symbol observation) differentially coherent detection of MPSK and ideal coherent of MPSK with differential encoding. The amount of improvement gained over conventional differential detection depends on the number of phases, M, and the number of additional symbol intervals added to the observation. What is particularly interesting is that substantial performance improvement can be obtained for only one or two additional symbol intervals of observation. The analysis and simulation results presented are for uncoded and trellis coded MPSK.

  12. Testing for Nonuniform Differential Item Functioning with Multiple Indicator Multiple Cause Models

    ERIC Educational Resources Information Center

    Woods, Carol M.; Grimm, Kevin J.

    2011-01-01

    In extant literature, multiple indicator multiple cause (MIMIC) models have been presented for identifying items that display uniform differential item functioning (DIF) only, not nonuniform DIF. This article addresses, for apparently the first time, the use of MIMIC models for testing both uniform and nonuniform DIF with categorical indicators. A

  13. Differential Item Functioning Detection Using the Multiple Indicators, Multiple Causes Method with a Pure Short Anchor

    ERIC Educational Resources Information Center

    Shih, Ching-Lin; Wang, Wen-Chung

    2009-01-01

    The multiple indicators, multiple causes (MIMIC) method with a pure short anchor was proposed to detect differential item functioning (DIF). A simulation study showed that the MIMIC method with an anchor of 1, 2, 4, or 10 DIF-free items yielded a well-controlled Type I error rate even when such tests contained as many as 40% DIF items. In general,

  14. Detection of Differential Item Functioning in Multiple Groups.

    ERIC Educational Resources Information Center

    Kim, Seock-Ho; And Others

    1995-01-01

    A method is presented for detection of differential item functioning in multiple groups. This method is closely related to F. M. Lord's chi square for comparing vectors of item parameters estimated in two groups. An example is provided using data from 600 college students taking a mathematics test with and without calculators. (SLD)

  15. Differentiation and transdifferentiation potentials of cancer stem cells

    PubMed Central

    Liu, Allan Yi; Ouyang, Gaoliang

    2015-01-01

    Tumor cells actively contribute to constructing their own microenvironment during tumorigenesis and tumor progression. The tumor microenvironment contains multiple types of stromal cells that work together with the extracellular matrix and local and systemic factors to coordinately contribute to tumor initiation and progression. Tumor cells and their stromal compartments acquire many genetic and/or epigenetic alternations to facilitate tumor growth and metastasis. The cancer stem cell (CSC) concept has been widely applied to interpreting tumor initiation, growth, metastasis, dormancy and relapse. CSCs have differentiation abilities to generate the original lineage cells that are similar to their normal stem cell counterparts. Interestingly, recent evidence demonstrates that CSCs also have the potential to transdifferentiate into vascular endothelial cells and pericytes, indicating that CSCs can transdifferentiate into other lineage cells for promoting tumor growth and metastasis in some tissue contexts instead of only recruiting stromal cells from local or distant tissues. Although the transdifferentiation of CSCs into tumor stromal cells provides a new dimension that explains tumor heterogeneity, many aspects of CSC transdifferentiation remain elusive. In this review, we summarize the multi-lineage differentiation and transdifferentiation potentials of CSCs as well as discuss their potential contributions to tumor heterogeneity and tumor microenvironment in tumor progression. PMID:26474460

  16. Differential diagnosis of Mendelian and mitochondrial disorders in patients with suspected multiple sclerosis

    PubMed Central

    Katz Sand, Ilana B.; Honce, Justin M.; Lublin, Fred D.

    2015-01-01

    Several single gene disorders share clinical and radiologic characteristics with multiple sclerosis and have the potential to be overlooked in the differential diagnostic evaluation of both adult and paediatric patients with multiple sclerosis. This group includes lysosomal storage disorders, various mitochondrial diseases, other neurometabolic disorders, and several other miscellaneous disorders. Recognition of a single-gene disorder as causal for a patient’s ‘multiple sclerosis-like’ phenotype is critically important for accurate direction of patient management, and evokes broader genetic counselling implications for affected families. Here we review single gene disorders that have the potential to mimic multiple sclerosis, provide an overview of clinical and investigational characteristics of each disorder, and present guidelines for when clinicians should suspect an underlying heritable disorder that requires diagnostic confirmation in a patient with a definite or probable diagnosis of multiple sclerosis. PMID:25636970

  17. A multiple mapping conditioning model for differential diffusion

    NASA Astrophysics Data System (ADS)

    Dialameh, L.; Cleary, M. J.; Klimenko, A. Y.

    2014-02-01

    This work introduces modeling of differential diffusion within the multiple mapping conditioning (MMC) turbulent mixing and combustion framework. The effect of differential diffusion on scalar variance decay is analyzed and, following a number of publications, is found to scale as Re-1/2. The ability to model the differential decay rates is the most important aim of practical differential diffusion models, and here this is achieved in MMC by introducing what is called the side-stepping method. The approach is practical and, as it does not involve an increase in the number of MMC reference variables, economical. In addition we also investigate the modeling of a more refined and difficult to reproduce differential diffusion effect - the loss of correlation between the different scalars. For this we develop an alternative MMC model with two reference variables but which also makes use of the side-stepping method. The new models are successfully validated against DNS results available in literature for homogenous, isotropic two scalar mixing.

  18. Multiple valued floating potentials of Langmuir probes

    NASA Technical Reports Server (NTRS)

    Nam, Cheol-Hee; Hershkowitz, N.; Cho, M. H.; Intrator, T.; Diebold, D.

    1988-01-01

    It is shown that Langmuir probes can have three different floating potentials in plasmas produced by a hot filament discharge in a multi-dipole device when the primary and secondary electron currents are comparable. The measured floating potential depends on the probe's initial condition - the most negative and the least negative potentials are found to be stable and the in-between value is found to be unstable. Results are compared to a simple theoretical model.

  19. Multiple Differential-Amplifier MMICs Embedded in Waveguides

    NASA Technical Reports Server (NTRS)

    Kangaslahti, Pekka; Schlecht, Erich

    2010-01-01

    Compact amplifier assemblies of a type now being developed for operation at frequencies of hundreds of gigahertz comprise multiple amplifier units in parallel arrangements to increase power and/or cascade arrangements to increase gains. Each amplifier unit is a monolithic microwave integrated circuit (MMIC) implementation of a pair of amplifiers in differential (in contradistinction to single-ended) configuration. Heretofore, in cascading amplifiers to increase gain, it has been common practice to interconnect the amplifiers by use of wires and/or thin films on substrates. This practice has not yielded satisfactory results at frequencies greater than 200 Hz, in each case, for either or both of two reasons: Wire bonds introduce large discontinuities. Because the interconnections are typically tens of wavelengths long, any impedance mismatches give rise to ripples in the gain-vs.-frequency response, which degrade the performance of the cascade.

  20. An Enhanced Differential Evolution Algorithm Based on Multiple Mutation Strategies

    PubMed Central

    Xiang, Wan-li; Meng, Xue-lei; An, Mei-qing; Li, Yin-zhen; Gao, Ming-xia

    2015-01-01

    Differential evolution algorithm is a simple yet efficient metaheuristic for global optimization over continuous spaces. However, there is a shortcoming of premature convergence in standard DE, especially in DE/best/1/bin. In order to take advantage of direction guidance information of the best individual of DE/best/1/bin and avoid getting into local trap, based on multiple mutation strategies, an enhanced differential evolution algorithm, named EDE, is proposed in this paper. In the EDE algorithm, an initialization technique, opposition-based learning initialization for improving the initial solution quality, and a new combined mutation strategy composed of DE/current/1/bin together with DE/pbest/bin/1 for the sake of accelerating standard DE and preventing DE from clustering around the global best individual, as well as a perturbation scheme for further avoiding premature convergence, are integrated. In addition, we also introduce two linear time-varying functions, which are used to decide which solution search equation is chosen at the phases of mutation and perturbation, respectively. Experimental results tested on twenty-five benchmark functions show that EDE is far better than the standard DE. In further comparisons, EDE is compared with other five state-of-the-art approaches and related results show that EDE is still superior to or at least equal to these methods on most of benchmark functions. PMID:26609304

  1. Monocyte/macrophage differentiation in early multiple sclerosis lesions.

    PubMed

    Brück, W; Porada, P; Poser, S; Rieckmann, P; Hanefeld, F; Kretzschmar, H A; Lassmann, H

    1995-11-01

    Monocyte/macrophage differentiation was studied in biopsy samples of multiple sclerosis (MS) lesions obtained in the early course of the disease. Macrophages were identified by immunocytochemistry using a panel of antibodies recognizing different macrophage-activation antigens. The number of cells stained with each antibody was related to the demyelinating activity of the lesions as detected by the presence of myelin degradation products. The pan-macrophage marker Ki-M1P revealed the highest numbers of macrophages in early and late active lesions. Lower numbers were encountered in inactive, demyelinated, or remyelinated lesions. The acute stage inflammatory macrophage markers MRP14 and 27E10 were expressed in either only early active (MRP14) or early and late active (27E10) lesions, thus allowing the identification of actively demyelinating lesions. The chronic stage inflammatory macrophage marker 25F9, in contrast, showed increasing expression with decreasing lesional activity. These findings indicate a differentiated pattern of macrophage activation in MS lesions and allow the staging of demyelinating lesions in routinely fixed and paraffin-embedded tissue. PMID:7486871

  2. Multiple scattering of proton via stochastic differential equations

    NASA Astrophysics Data System (ADS)

    Kia, M. R.; Noshad, Houshyar

    2015-08-01

    Multiple scattering of protons through a target is explained by a set of coupled stochastic differential equations. The motion of protons in matter is calculated by analytical random sampling from Moliere and Landau probability density functions (PDF). To satisfy the Vavilov theory, the moments for energy distribution of a 49.1 MeV proton beam in aluminum target are obtained. The skewness for the PDF of energy demonstrates that the energy distribution of protons in thin thickness becomes a Landau function, whereas, by increasing the thickness of the target it does not follow a Gaussian function completely. Afterwards, the depth-dose distributions are calculated for a 60 MeV proton beam traversing soft tissue and for a 160 MeV proton beam travelling through water. The results prove that when elastic scattering is taken into account, the Bragg-peak position is decreased, while the dose deposited in the Bragg region is increased. The results obtained in this article are benchmarked by comparison of our results with the experimental data reported in the literature.

  3. In vitro Differentiation Potential of Mesenchymal Stem Cells

    PubMed Central

    Gimble, Jeffrey M.; Guilak, Farshid; Nuttall, Mark E.; Sathishkumar, Solomon; Vidal, Martin; Bunnell, Bruce A.

    2008-01-01

    Summary Mesenchymal stem cells (MSCs) represent a class of multipotent progenitor cells that have been isolated from multiple tissue sites. Of these, adipose tissue and bone marrow offer advantages in terms of access, abundance, and the extent of their documentation in the literature. This review focuses on the in vitro differentiation capability of cells derived from adult human tissue. Multiple, independent studies have demonstrated that MSCs can commit to mesodermal (adipocyte, chondrocyte, hematopoietic support, myocyte, osteoblast, tenocyte), ectodermal (epithelial, glial, neural), and endodermal (hepatocyte, islet cell) lineages. The limitations and promises of these studies in the context of tissue engineering are discussed. PMID:21547120

  4. A multiple exp-function method for nonlinear differential equations and its application

    NASA Astrophysics Data System (ADS)

    Ma, Wen-Xiu; Huang, Tingwen; Zhang, Yi

    2010-12-01

    A multiple exp-function method for exact multiple wave solutions of nonlinear partial differential equations is proposed. The method is oriented towards the ease of use and capability of computer algebra systems and provides a direct and systematic solution procedure that generalizes Hirota's perturbation scheme. With the help of Maple, applying the approach to the (3+1)-dimensional potential-Yu-Toda-Sasa-Fukuyama equation yields exact explicit one-wave, two-wave and three-wave solutions, which include one-soliton, two-soliton and three-soliton type solutions. Two cases with specific values of the involved parameters are plotted for each of the two-wave and three-wave solutions.

  5. The clinical potential of blood-proteomics in multiple sclerosis

    PubMed Central

    2013-01-01

    Background The aetiology of multiple sclerosis (MS) remains unknown. This hampers molecular diagnosis and the discovery of bio-molecular markers. Consequently, MS diagnostic procedures are complex and criteria for assessing therapeutic efficacy are controversial, suggesting that a pathophysiological rather than an aetiological approach to the disease would be more appropriate. In this regard, blood-proteomics represents a still-unexplored tool. We investigated the potential of proteomics as applied to peripheral blood mononuclear cells (PBMCs) for differentiating treatment-naive RR-MS patients from healthy controls and from IFN-treated RR-MS patients. Methods A comparative analysis of PBMC proteins isolated from 13 unselected IFN-treated RR-MS patients, 6 IFN-untreated RR-MS patients and 14 matched healthy controls was performed using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry. We considered the volume of each spot, expressed as a percentage of the total volume of all spots in the gel. Heuristic clustering was applied to a composite population made up of a random sequence of gels from the different groups in comparison. For the differentially expressed proteins, we applied the Student's t-test to identify only those down- or up-regulated at least 2.5-fold [Ratio(R) ≥ 2.5] with respect to the homologous spots of the compared groups. Results Rho-GDI2, Rab2 and Cofilin1 were found to be associated with down-regulated and naïve group phenotypes; Cortactin and Fibrinogen beta-Chain Precursor were found to be associated with down-regulated and group-related IFN-treated RR-MS phenotypes. Thus, by means of similarity analysis, the proteomes were homogeneously segregated into three distinct groups corresponding to naive, IFN-treated and healthy control subjects. Interestingly, no separation was found between IFN-treated and healthy controls. Moreover, the molecular phenotypes were consistent with disease pathogenesis. Conclusions We demonstrated for the first time, albeit only with preliminary data, the aprioristic possibility of distinguishing naive and IFN-treated MS groups from controls, and naive from IFN-treated MS patients using a blood sample-based methodology (i.e. proteomics) alone. The functional profile of the identified molecules provides new pathophysiological insight into MS. Future development of these techniques could open up novel applications in terms of molecular diagnosis and therapy monitoring in MS patients. PMID:23692923

  6. Local random potentials of high differentiability to model the Landscape

    NASA Astrophysics Data System (ADS)

    Battefeld, T.; Modi, C.

    2015-03-01

    We generate random functions locally via a novel generalization of Dyson Brownian motion, such that the functions are in a desired differentiability class Ck, while ensuring that the Hessian is a member of the Gaussian orthogonal ensemble (other ensembles might be chosen if desired). Potentials in such higher differentiability classes (k>= 2) are required/desirable to model string theoretical landscapes, for instance to compute cosmological perturbations (e.g., k=2 for the power-spectrum) or to search for minima (e.g., suitable de Sitter vacua for our universe). Since potentials are created locally, numerical studies become feasible even if the dimension of field space is large (0D~ 10). In addition to the theoretical prescription, we provide some numerical examples to highlight properties of such potentials; concrete cosmological applications will be discussed in companion publications.

  7. Local random potentials of high differentiability to model the Landscape

    SciTech Connect

    Battefeld, T.; Modi, C.

    2015-03-09

    We generate random functions locally via a novel generalization of Dyson Brownian motion, such that the functions are in a desired differentiability class C{sup k}, while ensuring that the Hessian is a member of the Gaussian orthogonal ensemble (other ensembles might be chosen if desired). Potentials in such higher differentiability classes (k≥2) are required/desirable to model string theoretical landscapes, for instance to compute cosmological perturbations (e.g., k=2 for the power-spectrum) or to search for minima (e.g., suitable de Sitter vacua for our universe). Since potentials are created locally, numerical studies become feasible even if the dimension of field space is large (D∼100). In addition to the theoretical prescription, we provide some numerical examples to highlight properties of such potentials; concrete cosmological applications will be discussed in companion publications.

  8. Multiple Differentiation Capacity of STRO-1+/CD146+ PDL Mesenchymal Progenitor Cells

    PubMed Central

    Xu, Jinping; Wang, Wei; Kapila, Yvonne; Lotz, Jeffrey

    2009-01-01

    Although mesenchymal progenitor cells can be isolated from periodontal ligament (PDL) tissues using stem cell markers STRO-1 and CD146, the proportion of these cells that have the capacity to differentiate into multiple cell lineages remains to be determined. This study was designed to quantify the proportions of primary human PDL cells that can undergo multilineage differentiation and to compare the magnitude of these capabilities relative to bone marrow-derived mesenchymal stem cells (MSCs) and parental PDL (PPDL) cells. PDL mesenchymal progenitor (PMP) cells were isolated from PPDL cells using the markers STRO-1 and CD146. The colony-forming efficiency and multilineage differentiation potential of PMP, PPDL, and MSCs under chondrogenic, osteogenic, and adipogenic conditions were determined. Flow cytometry revealed that on average 2.6% of PPDL cells were STRO-1+/CD146+, whereas more than 63% were STRO-1?/CD146?. Colony-forming efficiency of STRO-1+/CD146+ PMP cells (19.3%) and MSCs (16.7%) was significantly higher than that of PPDL cells (6.8%). Cartilage-specific genes, early markers of osteoblastic differentiation, and adipogenic markers were significantly upregulated under appropriate conditions in PMP cells and MSCs compared to either their noninduced counterparts or induced PPDL cells. Consistent with these findings, immunohistochemistry revealed substantial accumulation of cartilaginous macromolecules, mineralized calcium nodules, and lipid vacuoles under chondrogenic, osteogenic, or adipogenic conditions in PMP and MSC cultures, respectively, compared to noninduced controls or induced PPDL cells. Thus STRO-1+/CD146+ PMP cells demonstrate multilineage differentiation capacity comparable in magnitude to MSCs and could potentially be utilized for regeneration of the periodontium and other tissues. PMID:18593336

  9. Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis.

    PubMed

    Wang, Yong; Sun, Peng; Wang, Qing; Trinkaus, Kathryn; Schmidt, Robert E; Naismith, Robert T; Cross, Anne H; Song, Sheng-Kwei

    2015-05-01

    Axon injury/loss, demyelination and inflammation are the primary pathologies in multiple sclerosis lesions. Despite the prevailing notion that axon/neuron loss is the substrate of clinical progression of multiple sclerosis, the roles that these individual pathological processes play in multiple sclerosis progression remain to be defined. An imaging modality capable to effectively detect, differentiate and individually quantify axon injury/loss, demyelination and inflammation, would not only facilitate the understanding of the pathophysiology underlying multiple sclerosis progression, but also the assessment of treatments at the clinical trial and individual patient levels. In this report, the newly developed diffusion basis spectrum imaging was used to discriminate and quantify the underlying pathological components in multiple sclerosis white matter. Through the multiple-tensor modelling of diffusion weighted magnetic resonance imaging signals, diffusion basis spectrum imaging resolves inflammation-associated cellularity and vasogenic oedema in addition to accounting for partial volume effects resulting from cerebrospinal fluid contamination, and crossing fibres. Quantitative histological analysis of autopsied multiple sclerosis spinal cord specimens supported that diffusion basis spectrum imaging-determined cellularity, axon and myelin injury metrics closely correlated with those pathologies identified and quantified by conventional histological staining. We demonstrated in healthy control subjects that diffusion basis spectrum imaging rectified inaccurate assessments of diffusion properties of white matter tracts by diffusion tensor imaging in the presence of cerebrospinal fluid contamination and/or crossing fibres. In multiple sclerosis patients, we report that diffusion basis spectrum imaging quantitatively characterized the distinct pathologies underlying gadolinium-enhanced lesions, persistent black holes, non-enhanced lesions and non-black hole lesions, a task yet to be demonstrated by other neuroimaging approaches. Diffusion basis spectrum imaging-derived radial diffusivity (myelin integrity marker) and non-restricted isotropic diffusion fraction (oedema marker) correlated with magnetization transfer ratio, supporting previous reports that magnetization transfer ratio is sensitive not only to myelin integrity, but also to inflammation-associated oedema. Our results suggested that diffusion basis spectrum imaging-derived quantitative biomarkers are highly consistent with histology findings and hold promise to accurately characterize the heterogeneous white matter pathology in multiple sclerosis patients. Thus, diffusion basis spectrum imaging can potentially serve as a non-invasive outcome measure to assess treatment effects on the specific components of underlying pathology targeted by new multiple sclerosis therapies. PMID:25724201

  10. Bladder Smooth Muscle Cells Differentiation from Dental Pulp Stem Cells: Future Potential for Bladder Tissue Engineering.

    PubMed

    Song, Bing; Jiang, Wenkai; Alraies, Amr; Liu, Qian; Gudla, Vijay; Oni, Julia; Wei, Xiaoqing; Sloan, Alastair; Ni, Longxing; Agarwal, Meena

    2016-01-01

    Dental pulp stem cells (DPSCs) are multipotent cells capable of differentiating into multiple cell lines, thus providing an alternative source of cell for tissue engineering. Smooth muscle cell (SMC) regeneration is a crucial step in tissue engineering of the urinary bladder. It is known that DPSCs have the potential to differentiate into a smooth muscle phenotype in vitro with differentiation agents. However, most of these studies are focused on the vascular SMCs. The optimal approaches to induce human DPSCs to differentiate into bladder SMCs are still under investigation. We demonstrate in this study the ability of human DPSCs to differentiate into bladder SMCs in a growth environment containing bladder SMCs-conditioned medium with the addition of the transforming growth factor beta 1 (TGF-?1). After 14 days of exposure to this medium, the gene and protein expression of SMC-specific marker (?-SMA, desmin, and calponin) increased over time. In particular, myosin was present in differentiated cells after 11 days of induction, which indicated that the cells differentiated into the mature SMCs. These data suggested that human DPSCs could be used as an alternative and less invasive source of stem cells for smooth muscle regeneration, a technology that has applications for bladder tissue engineering. PMID:26880982

  11. Bladder Smooth Muscle Cells Differentiation from Dental Pulp Stem Cells: Future Potential for Bladder Tissue Engineering

    PubMed Central

    Song, Bing; Jiang, Wenkai; Alraies, Amr; Liu, Qian; Gudla, Vijay; Oni, Julia; Wei, Xiaoqing; Sloan, Alastair; Ni, Longxing; Agarwal, Meena

    2016-01-01

    Dental pulp stem cells (DPSCs) are multipotent cells capable of differentiating into multiple cell lines, thus providing an alternative source of cell for tissue engineering. Smooth muscle cell (SMC) regeneration is a crucial step in tissue engineering of the urinary bladder. It is known that DPSCs have the potential to differentiate into a smooth muscle phenotype in vitro with differentiation agents. However, most of these studies are focused on the vascular SMCs. The optimal approaches to induce human DPSCs to differentiate into bladder SMCs are still under investigation. We demonstrate in this study the ability of human DPSCs to differentiate into bladder SMCs in a growth environment containing bladder SMCs-conditioned medium with the addition of the transforming growth factor beta 1 (TGF-β1). After 14 days of exposure to this medium, the gene and protein expression of SMC-specific marker (α-SMA, desmin, and calponin) increased over time. In particular, myosin was present in differentiated cells after 11 days of induction, which indicated that the cells differentiated into the mature SMCs. These data suggested that human DPSCs could be used as an alternative and less invasive source of stem cells for smooth muscle regeneration, a technology that has applications for bladder tissue engineering. PMID:26880982

  12. Multiple Hypnotizabilities: Differentiating the Building Blocks of Hypnotic Response

    ERIC Educational Resources Information Center

    Woody, Erik Z.; Barnier, Amanda J.; McConkey, Kevin M.

    2005-01-01

    Although hypnotizability can be conceptualized as involving component subskills, standard measures do not differentiate them from a more general unitary trait, partly because the measures include limited sets of dichotomous items. To overcome this, the authors applied full-information factor analysis, a sophisticated analytic approach for

  13. Multiple Hypnotizabilities: Differentiating the Building Blocks of Hypnotic Response

    ERIC Educational Resources Information Center

    Woody, Erik Z.; Barnier, Amanda J.; McConkey, Kevin M.

    2005-01-01

    Although hypnotizability can be conceptualized as involving component subskills, standard measures do not differentiate them from a more general unitary trait, partly because the measures include limited sets of dichotomous items. To overcome this, the authors applied full-information factor analysis, a sophisticated analytic approach for…

  14. Communication: Separable potential energy surfaces from multiplicative artificial neural networks

    SciTech Connect

    Koch, Werner Zhang, Dong H.

    2014-07-14

    We present a potential energy surface fitting scheme based on multiplicative artificial neural networks. It has the sum of products form required for efficient computation of the dynamics of multidimensional quantum systems with the multi configuration time dependent Hartree method. Moreover, it results in analytic potential energy matrix elements when combined with quantum dynamics methods using Gaussian basis functions, eliminating the need for a local harmonic approximation. Scaling behavior with respect to the complexity of the potential as well as the requested accuracy is discussed.

  15. miR-206 integrates multiple components of differentiation pathways to control the transition from growth to differentiation in rhabdomyosarcoma cells

    PubMed Central

    2012-01-01

    Background Similar to replicating myoblasts, many rhabdomyosarcoma cells express the myogenic determination gene MyoD. In contrast to myoblasts, rhabdomyosarcoma cells do not make the transition from a regulative growth phase to terminal differentiation. Previously we demonstrated that the forced expression of MyoD with its E-protein dimerization partner was sufficient to induce differentiation and suppress multiple growth-promoting genes, suggesting that the dimer was targeting a switch that regulated the transition from growth to differentiation. Our data also suggested that a balance between various inhibitory transcription factors and MyoD activity kept rhabdomyosarcomas trapped in a proliferative state. Methods Potential myogenic co-factors were tested for their ability to drive differentiation in rhabdomyosarcoma cell culture models, and their relation to MyoD activity determined through molecular biological experiments. Results Modulation of the transcription factors RUNX1 and ZNF238 can induce differentiation in rhabdomyosarcoma cells and their activity is integrated, at least in part, through the activation of miR-206, which acts as a genetic switch to transition the cell from a proliferative growth phase to differentiation. The inhibitory transcription factor MSC also plays a role in controlling miR-206, appearing to function by occluding a binding site for MyoD in the miR-206 promoter. Conclusions These findings support a network model composed of coupled regulatory circuits with miR-206 functioning as a switch regulating the transition from one stable state (growth) to another (differentiation). PMID:22541669

  16. Multiple-Symbol combined differential detection for satellite-based AIS Signals

    NASA Astrophysics Data System (ADS)

    Hao, Jingsong; Ma, Shexiang; Wang, Junfeng; Meng, Xin

    2015-12-01

    In this paper, a multiple-symbol combined differential Viterbi decoding algorithm which is insensitive to frequency offset is proposed. According to the theories of multiple-symbol differential detection and maximum-likelihood detection, we combine the multiple-order differential information with the Viterbi algorithm. The phase shift caused by the frequency offset is estimated and compensated from the above information in the process of decoding. The simulation results show that the bit error rate (BER) of 2 bits combined differential Viterbi algorithm is below 10-3 when the normalized signal-to-noise ratio (NSNR) is 11 dB, and the decoding performances approach those of the coherent detection as the length of the combined differential symbols increases. The proposed method is simple and its performance remains stable under different frequency offsets.

  17. Bioenergetics and mitochondrial transmembrane potential during differentiation of cultured osteoblasts

    NASA Technical Reports Server (NTRS)

    Komarova, S. V.; Ataullakhanov, F. I.; Globus, R. K.

    2000-01-01

    To evaluate the relationship between osteoblast differentiation and bioenergetics, cultured primary osteoblasts from fetal rat calvaria were grown in medium supplemented with ascorbate to induce differentiation. Before ascorbate treatment, the rate of glucose consumption was 320 nmol. h(-1). 10(6) cells(-1), respiration was 40 nmol. h(-1). 10(6) cells(-1), and the ratio of lactate production to glucose consumption was approximately 2, indicating that glycolysis was the main energy source for immature osteoblasts. Ascorbate treatment for 14 days led to a fourfold increase in respiration, a threefold increase in ATP production, and a fivefold increase in ATP content compared with that shown in immature cells. Confocal imaging of mitochondria stained with a transmembrane potential-sensitive vital dye showed that mature cells possessed abundant amounts of high-transmembrane-potential mitochondria, which were concentrated near the culture medium-facing surface. Acute treatment of mature osteoblasts with metabolic inhibitors showed that the rate of glycolysis rose to maintain the cellular energy supply constant. Thus progressive differentiation coincided with changes in cellular metabolism and mitochondrial activity, which are likely to play key roles in osteoblast function.

  18. System for measuring multiphase flow using multiple pressure differentials

    DOEpatents

    Fincke, James R. (Idaho Falls, ID)

    2003-01-01

    An improved method and system for measuring a multi-phase flow in a pressure flow meter. An extended throat venturi is used and pressure of the multi-phase flow is measured at three or more positions in the venturi, which define two or more pressure differentials in the flow conduit. The differential pressures are then used to calculate the mass flow of the gas phase, the total mass flow, and the liquid phase. The system for determining the mass flow of the high void fraction fluid flow and the gas flow includes taking into account a pressure drop experienced by the gas phase due to work performed by the gas phase in accelerating the liquid phase.

  19. Developing Teacher Leadership in Singapore: Multiple Pathways for Differentiated Journeys

    ERIC Educational Resources Information Center

    Goodwin, A. Lin; Low, Ee Ling; Ng, Pak Tee

    2015-01-01

    In this article, we examine quality teachers through teacher leadership development. Using Singapore as an illustrative case, we describe the redefinition of the teaching profession to include deliberate structures and multiple pathways designed to nurture teacher leaders, and the role of teacher leaders in supporting education reform. We go on to

  20. Differential cryptanalysis of a medical image cryptosystem with multiple rounds.

    PubMed

    Chen, Lei; Wang, Shihong

    2015-10-01

    Recently, Fu et al. proposed a chaos-based medical image encryption scheme that has permutation-substitution architecture. The authors believe that the scheme with bit-level cat map shuffling can be achieved at high level of security even if it is only applied with a few encryption rounds. However, we find that the scheme cannot resist differential cryptanalysis. The differential cryptanalysis shows that the security of the original scheme depends only on permutation key instead of on all of the keys. Moreover, 17 chosen plain-images can reveal equivalent permutation key for 1-round and 2-round encryption. We propose a novel analysis method called double differential cryptanalysis comparison (DDCC) that is valid to break multi-round encryption with 16N(2)+1 chosen plain-images, where N(2) is the size of the image. We also point out several weaknesses of the cryptosystem. The theoretical analysis and simulation results indicate that the encryption scheme is insecure. PMID:26298487

  1. Disulfiram attenuates osteoclast differentiation in vitro: a potential antiresorptive agent.

    PubMed

    Ying, Hua; Qin, An; Cheng, Tak S; Pavlos, Nathan J; Rea, Sarah; Dai, Kerong; Zheng, Ming H

    2015-01-01

    Disulfiram (DSF), a cysteine modifying compound, has long been clinically employed for the treatment of alcohol addiction. Mechanistically, DSF acts as a modulator of MAPK and NF-?B pathways signaling pathways. While these pathways are crucial for osteoclast (OC) differentiation, the potential influence of DSF on OC formation and function has not been directly assessed. Here, we explore the pharmacological effects of DSF on OC differentiation, activity and the modulation of osteoclastogenic signaling cascades. We first analyzed cytotoxicity of DSF on bone marrow monocytes isolated from C57BL/6J mice. Upon the establishment of optimal dosage, we conducted osteoclastogenesis and bone resorption assays in the presence or absence of DSF treatment. Luciferase assays in RAW264.7 cells were used to examine the effects of DSF on major transcription factors activation. Western blot, reverse transcription polymerase chain reaction, intracellular acidification and proton influx assays were employed to further dissect the underlying mechanism. DSF treatment dose-dependently inhibited both mouse and human osteoclastogenesis, especially at early stages of differentiation. This inhibition correlated with a decrease in the expression of key osteoclastic marker genes including CtsK, TRAP, DC-STAMP and Atp6v0d2 as well as a reduction in bone resorption in vitro. Suppression of OC differentiation was found to be due, at least in part, to the blockade of several key receptor activators of nuclear factor kappa-B ligand (RANKL)-signaling pathways including ERK, NF-?B and NFATc1. On the other hand, DSF failed to suppress intracellular acidification and proton influx in mouse and human osteoclasts using acridine orange quenching and microsome-based proton transport assays. Our findings indicate that DSF attenuates OC differentiation via the collective suppression of several key RANKL-mediated signaling cascades, thus making it an attractive agent for the treatment of OC-mediated disorders. PMID:25928135

  2. Disulfiram Attenuates Osteoclast Differentiation In Vitro: A Potential Antiresorptive Agent

    PubMed Central

    Cheng, Tak S.; Pavlos, Nathan J.; Rea, Sarah; Dai, Kerong; Zheng, Ming H.

    2015-01-01

    Disulfiram (DSF), a cysteine modifying compound, has long been clinically employed for the treatment of alcohol addiction. Mechanistically, DSF acts as a modulator of MAPK and NF-?B pathways signaling pathways. While these pathways are crucial for osteoclast (OC) differentiation, the potential influence of DSF on OC formation and function has not been directly assessed. Here, we explore the pharmacological effects of DSF on OC differentiation, activity and the modulation of osteoclastogenic signaling cascades. We first analyzed cytotoxicity of DSF on bone marrow monocytes isolated from C57BL/6J mice. Upon the establishment of optimal dosage, we conducted osteoclastogenesis and bone resorption assays in the presence or absence of DSF treatment. Luciferase assays in RAW264.7 cells were used to examine the effects of DSF on major transcription factors activation. Western blot, reverse transcription polymerase chain reaction, intracellular acidification and proton influx assays were employed to further dissect the underlying mechanism. DSF treatment dose-dependently inhibited both mouse and human osteoclastogenesis, especially at early stages of differentiation. This inhibition correlated with a decrease in the expression of key osteoclastic marker genes including CtsK, TRAP, DC-STAMP and Atp6v0d2 as well as a reduction in bone resorption in vitro. Suppression of OC differentiation was found to be due, at least in part, to the blockade of several key receptor activators of nuclear factor kappa-B ligand (RANKL)-signaling pathways including ERK, NF-?B and NFATc1. On the other hand, DSF failed to suppress intracellular acidification and proton influx in mouse and human osteoclasts using acridine orange quenching and microsome-based proton transport assays. Our findings indicate that DSF attenuates OC differentiation via the collective suppression of several key RANKL-mediated signaling cascades, thus making it an attractive agent for the treatment of OC-mediated disorders. PMID:25928135

  3. A Study of Impulsive Multiterm Fractional Differential Equations with Single and Multiple Base Points and Applications

    PubMed Central

    Liu, Yuji; Ahmad, Bashir

    2014-01-01

    We discuss the existence and uniqueness of solutions for initial value problems of nonlinear singular multiterm impulsive Caputo type fractional differential equations on the half line. Our study includes the cases for a single base point fractional differential equation as well as multiple base points fractional differential equation. The asymptotic behavior of solutions for the problems is also investigated. We demonstrate the utility of our work by applying the main results to fractional-order logistic models. PMID:24578623

  4. Induced Pluripotent Stem Cells Can Effectively Differentiate into Multiple Functional Lymphocyte Lineages In Vivo with Negligible Bias.

    PubMed

    Lan, Tianshu; Wang, Libin; Xu, Lin; Jin, Ning; Yan, Guoliang; Xia, Junjie; Wang, Hailong; Zhuang, Guohong; Gao, Chang; Meng, Luxi; Du, Feifei; Zhou, Qi; Qi, Zhongquan

    2016-03-15

    Lymphohematopoietic stem cells (L-HSCs) generated from self-somatic cell-derived induced pluripotent stem cells (iPSCs) are a potential source of cells for the treatment of hematological disorders. However, the generation of truly functional L-HSCs from iPSCs has yet to be achieved. Thus, whether iPSCs have the inherent potential to generate a normal differentiated phenotype and functional population of multiple lineages of terminally differentiated lymphocytes needs to be assessed. Here, we used tetraploid embryo complementation to provide a normal environment for the differentiation of hematopoietic cells from iPSCs and embryonic stem cells (ESCs). We then evaluated the characteristics, populations, and functions of lymphocytes derived from iPSCs, ESCs, and naïve isogenic C57BL/6 mice. The results showed that iPSC-derived lymphocytes (iPSLs) expressed normal levels of major histocompatibility complex-I (MHC-I) and exhibited a fully pluripotent capacity to differentiate into CD4(+) T, CD8(+) T, regulatory T, B, and natural killer cells. Following in vitro stimulation with either concanavalin A or an alloantigen, iPSLs exhibited the same capacities for proliferation and cytokine secretion as ESC-derived or isogenic lymphocytes. Furthermore, iPSC-derived bone marrow cells could differentiate into multiple lymphocyte lineages that reconstituted the lymphocyte population in syngeneic lethally irradiated recipient animals. Our results demonstrated that iPSCs have the inherent potential to differentiate into multiple lineages of functional lymphocytes without bias, and further support the practical application of iPSC-based treatments to hematological disorders. PMID:26715393

  5. Path integral approach to nonequilibrium potentials in multiplicative Langevin dynamics

    NASA Astrophysics Data System (ADS)

    Barci, Daniel G.; Gonzlez Arenas, Zochil; Moreno, Miguel Vera

    2016-01-01

    We present a path integral formalism to compute potentials for nonequilibrium steady states, reached by a multiplicative stochastic dynamics. We develop a weak-noise expansion, which allows the explicit evaluation of the potential in arbitrary dimensions and for any stochastic prescription. We apply this general formalism to study noise-induced phase transitions. We focus on a class of multiplicative stochastic lattice models and compute the steady-state phase diagram in terms of the noise intensity and the lattice coupling. We obtain, under appropriate conditions, an ordered phase induced by noise. By computing entropy production, we show that microscopic irreversibility is a necessary condition to develop noise-induced phase transitions. This property of the nonequilibrium stationary state has no relation with the initial stages of the dynamical evolution, in contrast with previous interpretations, based on the short-time evolution of the order parameter.

  6. Phonological Fluency Strategy of Switching Differentiates Relapsing-Remitting and Secondary Progressive Multiple Sclerosis Patients

    PubMed Central

    Messinis, L.; Kosmidis, M. H.; Vlahou, C.; Malegiannaki, A. C.; Gatzounis, G.; Dimisianos, N.; Karra, A.; Kiosseoglou, G.; Gourzis, P.; Papathanasopoulos, P.

    2013-01-01

    The strategies used to perform a verbal fluency task appear to be reflective of cognitive abilities necessary for successful daily functioning. In the present study, we explored potential differences in verbal fluency strategies (switching and clustering) used to maximize word production by patients with relapsing-remitting multiple sclerosis (RRMS) versus patients with secondary progressive multiple sclerosis (SPMS). We further assessed impairment rates and potential differences in the sensitivity and specificity of phonological versus semantic verbal fluency tasks in discriminating between those with a diagnosis of MS and healthy adults. We found that the overall rate of impaired verbal fluency in our MS sample was consistent with that in other studies. However, we found no differences between types of MS (SPMS, RRMS), on semantic or phonological fluency word production, or the strategies used to maximize semantic fluency. In contrast, we found that the number of switches differed significantly in the phonological fluency task between the SPMS and RRMS subtypes. The clinical utility of semantic versus phonological fluency in discriminating MS patients from healthy controls did not indicate any significant differences. Further, the strategies used to maximize performance did not differentiate MS subgroups or MS patients from healthy controls. PMID:23401793

  7. Differential downregulation of telomerase activity by bortezomib in multiple myeloma cells-multiple regulatory pathways in vitro and ex vivo

    PubMed Central

    Weiss, C; Uziel, O; Wolach, O; Nordenberg, J; Beery, E; Bulvick, S; Kanfer, G; Cohen, O; Ram, R; Bakhanashvili, M; Magen-Nativ, H; Shilo, N; Lahav, M

    2012-01-01

    Background: The importance of telomerase in multiple myeloma (MM) is well established; however, its response to bortezomib has not been addressed. Methods: The effect of bortezomib on telomerase activity and cell proliferation was evaluated in four MM cell lines and in myeloma cells obtained from eight patients. The mechanism of telomerase regulation on epigenetic, transcriptional, and post-translational levels was further assessed in two selected cell lines: ARP-1 and CAG. Clinical data were correlated with the laboratory findings. Results: Bortezomib downregulated telomerase activity and decreased proliferation in all cell lines and cells obtained from patients, albeit in two different patterns of kinetics. ARP-1 cells demonstrated higher and earlier sensitivity than CAG cells due to differential phosphorylation of hTERT by PKC?. Methylation of hTERT promoter was not affected. Transcription of hTERT was similarly inhibited in both lines by decreased binding of SP-1 and not of C-Myc and NF?B. The ex vivo results confirmed the in vitro findings and suggested existence of clinical relevance. Conclusion: Bortezomib downregulates telomerase activity in MM cells both transcriptionally and post-translationally. MM cells, both in vitro and in patients, exhibit different sensitivity to the drug due to different post-translational response. The effect of bortezomib on telomerase activity may correlate with resistance to bortezomib in patients, suggesting its potential utility as a pre-treatment assessment. PMID:23169337

  8. Reduction of myoblast differentiation following multiple population doublings in mouse C2 C12 cells: a model to investigate ageing?

    PubMed

    Sharples, Adam P; Al-Shanti, Nasser; Lewis, Mark P; Stewart, Claire E

    2011-12-01

    Ageing skeletal muscle displays declines in size, strength, and functional capacity. Given the acknowledged role that the systemic environment plays in reduced regeneration (Conboy et al. [2005] Nature 433: 760-764), the role of resident satellite cells (termed myoblasts upon activation) is relatively dismissed, where, multiple cellular divisions in-vivo throughout the lifespan could also impact on muscular deterioration. Using a model of multiple population doublings (MPD) in-vitro thus provided a system in which to investigate the direct impact of extensive cell duplications on muscle cell behavior. C(2) C(12) mouse skeletal myoblasts (CON) were used fresh or following 58 population doublings (MPD). As a result of multiple divisions, reduced morphological and biochemical (creatine kinase, CK) differentiation were observed. Furthermore, MPD cells had significantly increased cells in the S and decreased cells in the G1 phases of the cell cycle versus CON, following serum withdrawal. These results suggest continued cycling rather than G1 exit and thus reduced differentiation (myotube atrophy) occurs in MPD muscle cells. These changes were underpinned by significant reductions in transcript expression of: IGF-I and myogenic regulatory factors (myoD and myogenin) together with elevated IGFBP5. Signaling studies showed that decreased differentiation in MPD was associated with decreased phosphorylation of Akt, and with later increased phosphorylation of JNK1/2. Chemical inhibition of JNK1/2 (SP600125) in MPD cells increased IGF-I expression (non-significantly), however, did not enhance differentiation. This study provides a potential model and molecular mechanisms for deterioration in differentiation capacity in skeletal muscle cells as a consequence of multiple population doublings that would potentially contribute to the ageing process. PMID:21826704

  9. Multiple Stressor Differential Tolerances: Possible Implications at the Population Level

    PubMed Central

    Venâncio, Cátia; Ribeiro, Rui; Soares, Amadeu; Lopes, Isabel

    2016-01-01

    The probability of the most sensitive genotypes being eliminated from a population due to a contaminant pulse–genetic erosion–is negatively associated to the within-genotype variation. A sensitive genotype with a small phenotypic variation would be more prone to be lost–a critically sensitive genotype. Furthermore, natural populations inhabiting contaminated sites are usually exposed to several pollutants. Such co- or sequential exposure can have severe effects if at least some tolerant clonal lineages surviving one contaminant are sensitive to the others. Such an inverse relationship coupled with a low within-genotype variation potentially enhances genetic erosion. Accordingly, this study evaluated co-tolerance and the occurrence of clonal lineages critically sensitive to 48-hours lethal exposures of copper, zinc, cobalt, and chromium among eight clonal lineages of the cladocerans Daphnia longispina. Median lethal concentrations (LC50) of each metal were found to have the potential to provoke genetic erosion. Pairwise comparisons of LC50, from the eight clonal lineages, revealed neither negative nor positive correlations (r ≤ |0.56|; p ≥ 0.18), but inversely sensitive clonal lineages were found for all pairs of metals. Therefore, besides having the potential to eliminate critically sensitive clonal lineages in a first intermediately lethal pulse, all tested metals may provoke further losses of clonal lineages in an already genetically eroded population. PMID:26990542

  10. Multiple-try differential evolution adaptive Metropolis for efficient solution of highly parameterized models

    NASA Astrophysics Data System (ADS)

    Eric, L.; Vrugt, J. A.

    2010-12-01

    Spatially distributed hydrologic models potentially contain hundreds of parameters that need to be derived by calibration against a historical record of input-output data. The quality of this calibration strongly determines the predictive capability of the model and thus its usefulness for science-based decision making and forecasting. Unfortunately, high-dimensional optimization problems are typically difficult to solve. Here we present our recent developments to the Differential Evolution Adaptive Metropolis (DREAM) algorithm (Vrugt et al., 2009) to warrant efficient solution of high-dimensional parameter estimation problems. The algorithm samples from an archive of past states (Ter Braak and Vrugt, 2008), and uses multiple-try Metropolis sampling (Liu et al., 2000) to decrease the required burn-in time for each individual chain and increase efficiency of posterior sampling. This approach is hereafter referred to as MT-DREAM. We present results for 2 synthetic mathematical case studies, and 2 real-world examples involving from 10 to 240 parameters. Results for those cases show that our multiple-try sampler, MT-DREAM, can consistently find better solutions than other Bayesian MCMC methods. Moreover, MT-DREAM is admirably suited to be implemented and ran on a parallel machine and is therefore a powerful method for posterior inference.

  11. Multiple-Group Noncompensatory Differential Item Functioning in Raju's Differential Functioning of Items and Tests

    ERIC Educational Resources Information Center

    Oshima, T. C.; Wright, Keith; White, Nick

    2015-01-01

    Raju, van der Linden, and Fleer (1995) introduced a framework for differential functioning of items and tests (DFIT) for unidimensional dichotomous models. Since then, DFIT has been shown to be a quite versatile framework as it can handle polytomous as well as multidimensional models both at the item and test levels. However, DFIT is still limited

  12. Medaka tert produces multiple variants with differential expression during differentiation in vitro and in vivo

    PubMed Central

    Rao, Feng; Wang, Tiansu; Li, Mingyou; Li, Zhendong; Hong, Ni; Zhao, Haobin; Yan, Yan; Lu, Wenqing; Chen, Tiansheng; Wang, Weijia; Lim, Menghuat; Yuan, Yongming; Liu, Ling; Zeng, Lingbing; Wei, Qiwei; Guan, Guijun; Li, Changming; Hong, Yunhan

    2011-01-01

    Embryonic stem (ES) cells have immortality for self-renewal and pluripotency. Differentiated human cells undergo replicative senescence. In human, the telomerase reverse transcriptase (Tert), namely the catalytic subunit of telomerase, exhibits differential expression to regulate telomerase activity governing cellular immortality or senescence, and telomerase activity or tert expression is a routine marker of pluripotent ES cells. Here we have identified the medaka tert gene and determined its expression and telomerase activity in vivo and in vitro. We found that the medaka tert locus produces five variants called terta to terte encoding isoforms TertA to TertE. The longest TertA consists of 1090 amino acid residues and displays a maximum of 34% identity to the human TERT and all the signature motifs of the Tert family. TertB to TertE are novel isoforms and have considerable truncation due to alternative splicing. The terta RNA is ubiquitous in embryos, adult tissues and cell lines, and accompanies ubiquitous telomerase activity in vivo and in vitro as revealed by TRAP assays. The tertb RNA was restricted to the testis, absent in embryos before gastrulation and barely detectable in various cell lines The tertc transcript was absent in undifferentiated ES cells but became evident upon ES cell differentiation, in vivo it was barely detectable in early embryos and became evident when embryogenesis proceeds. Therefore, ubiquitous terta expression correlates with ubiquitous telomerase activity in medaka, and expression of other tert variants appears to delineate cell differentiation in vitro and in vivo. PMID:21547060

  13. Multiple-Group Noncompensatory Differential Item Functioning in Raju's Differential Functioning of Items and Tests

    ERIC Educational Resources Information Center

    Oshima, T. C.; Wright, Keith; White, Nick

    2015-01-01

    Raju, van der Linden, and Fleer (1995) introduced a framework for differential functioning of items and tests (DFIT) for unidimensional dichotomous models. Since then, DFIT has been shown to be a quite versatile framework as it can handle polytomous as well as multidimensional models both at the item and test levels. However, DFIT is still limited…

  14. Development of a Multiple-Stage Differential Mobility Analyzer (MDMA)

    SciTech Connect

    Chen, Da-Ren; Cheng, Mengdawn

    2007-01-01

    A new DMA column has been designed with the capability of simultaneously extracting monodisperse particles of different sizes in multiple stages. We call this design a multistage DMA, or MDMA. A prototype MDMA has been constructed and experimentally evaluated in this study. The new column enables the fast measurement of particles in a wide size range, while preserving the powerful particle classification function of a DMA. The prototype MDMA has three sampling stages, capable of classifying monodisperse particles of three different sizes simultaneously. The scanning voltage operation of a DMA can be applied to this new column. Each stage of MDMA column covers a fraction of the entire particle size range to be measured. The covered size fractions of two adjacent stages of the MDMA are designed somewhat overlapped. The arrangement leads to the reduction of scanning voltage range and thus the cycling time of the measurement. The modular sampling stage design of the MDMA allows the flexible configuration of desired particle classification lengths and variable number of stages in the MDMA. The design of our MDMA also permits operation at high sheath flow, enabling high-resolution particle size measurement and/or reduction of the lower sizing limit. Using the tandem DMA technique, the performance of the MDMA, i.e., sizing accuracy, resolution, and transmission efficiency, was evaluated at different ratios of aerosol and sheath flowrates. Two aerosol sampling schemes were investigated. One was to extract aerosol flows at an evenly partitioned flowrate at each stage, and the other was to extract aerosol at a rate the same as the polydisperse aerosol flowrate at each stage. We detail the prototype design of the MDMA and the evaluation result on the transfer functions of the MDMA at different particle sizes and operational conditions.

  15. A novel differential diagnostic model for multiple primary lung cancer: Differentially-expressed gene analysis of multiple primary lung cancer and intrapulmonary metastasis

    PubMed Central

    CHEN, DALI; MEI, LONGYONG; ZHOU, YUBIN; SHEN, CHENG; XU, HUAN; NIU, ZHONGXI; CHE, GUOWEI

    2015-01-01

    The incidence of synchronous multiple primary lung cancer (MPLC) is increasing. However, present diagnostic methods are unable to satisfy the individualized treatment requirements of patients with MPLC. The present study aimed to establish a quantitative mathematical model and analyze its diagnostic value for distinguishing between MPLC and cases of the histologically similar disease, intrapulmonary metastasis (IPM). The sum value of the differential expression ratios of four proteins, namely p53, p16, p27 and c-erbB2, was evaluated by immunohistochemically-staining specimens of primary cancers, second separate cancers, metastatic lymph nodes and metastatic cancers. The sum value of the differential expression ratio of the four proteins from the primary tumor and the lymph-node metastasis or metastatic cancer was <90 in the 11 patients with a single metastatic cancer and in the 30 patients with lymph-node metastasis, but was >90 in the 14 patients with different histological types of MPLC. Therefore, a quantitative differentially-expressed gene mathematical model was established as follows: Sum of the differential expression ratios = p16T1 ? T + p27T1 ? T2 + C-erbB2T1 ? T2 + p53T1 ? T2, where T1 is the primary cancer and T2 is the lymph node metastasis, metastatic cancer or the second separate cancer. The quantitative differentially-expressed gene mathematical model is considered to be a useful tool for distinguishing between MPLC and IPM. PMID:25663860

  16. The VPI&SU multiple polarization plane ZDR radar - The OCTOPOD radar. [ZDR differential reflectivity measurements

    NASA Technical Reports Server (NTRS)

    Andrews, J. H.; Pratt, T.; Porter, R. E.; Imrich, D. M.

    1983-01-01

    The 'OCTOPOD' radar extends the concept of differential reflectivity (ZDR) to multiple polarization planes, so that ZDR measurements can be made in any pair of orthogonal linear polarizations. This allows the mean canting angle of oblate raindrops or ice particles to be determined. Attention is given to the radar hardware employed, the rotating feed system that generates the multiple polarization planes, and the computer controlled data acquisition system which extracts both reflectivity and ZDR data.

  17. dCaP: detecting differential binding events in multiple conditions and proteins

    PubMed Central

    2014-01-01

    Background Current ChIP-seq studies are interested in comparing multiple epigenetic profiles across several cell types and tissues simultaneously for studying constitutive and differential regulation. Simultaneous analysis of multiple epigenetic features in many samples can gain substantial power and specificity than analyzing individual features and/or samples separately. Yet there are currently few tools can perform joint inference of constitutive and differential regulation in multi-feature-multi-condition contexts with statistical testing. Existing tools either test regulatory variation for one factor in multiple samples at a time, or for multiple factors in one or two samples. Many of them only identify binary rather than quantitative variation, which are sensitive to threshold choices. Results We propose a novel and powerful method called dCaP for simultaneously detecting constitutive and differential regulation of multiple epigenetic factors in multiple samples. Using simulation, we demonstrate the superior power of dCaP compared to existing methods. We then apply dCaP to two datasets from human and mouse ENCODE projects to demonstrate its utility. We show in the human dataset that the cell-type specific regulatory loci detected by dCaP are significantly enriched near genes with cell-type specific functions and disease relevance. We further show in the mouse dataset that dCaP captures genomic regions showing significant signal variations for TAL1 occupancy between two mouse erythroid cell lines. The novel TAL1 occupancy loci detected only by dCaP are highly enriched with GATA1 occupancy and differential gene expression, while those detected only by other methods are not. Conclusions Here, we developed a novel approach to utilize the cooperative property of proteins to detect differential binding given multivariate ChIP-seq samples to provide better power, aiming for complementing existing approaches and providing new insights in the method development in this field. PMID:25522020

  18. The neuroprotective potential of flavonoids: a multiplicity of effects

    PubMed Central

    Vauzour, David; Vafeiadou, Katerina; Rodriguez-Mateos, Ana; Rendeiro, Catarina

    2008-01-01

    Flavonoids exert a multiplicity of neuroprotective actions within the brain, including a potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation, and the potential to promote memory, learning and cognitive function. These effects appear to be underpinned by two common processes. Firstly, they interact with critical protein and lipid kinase signalling cascades in the brain leading to an inhibition of apoptosis triggered by neurotoxic species and to a promotion of neuronal survival and synaptic plasticity. Secondly, they induce beneficial effects on the vascular system leading to changes in cerebrovascular blood flow capable of causing angiogenesis, neurogenesis and changes in neuronal morphology. Through these mechanisms, the consumption of flavonoid-rich foods throughout life holds the potential to limit neurodegeneration and to prevent or reverse age-dependent loses in cognitive performance. The intense interest in the development of drugs capable of enhancing brain function means that flavonoids may represent important precursor molecules in the quest to develop of a new generation of brain enhancing drugs. PMID:18937002

  19. Multiple Component Event-Related Potential (mcERP) Estimation

    NASA Technical Reports Server (NTRS)

    Knuth, K. H.; Clanton, S. T.; Shah, A. S.; Truccolo, W. A.; Ding, M.; Bressler, S. L.; Trejo, L. J.; Schroeder, C. E.; Clancy, Daniel (Technical Monitor)

    2002-01-01

    We show how model-based estimation of the neural sources responsible for transient neuroelectric signals can be improved by the analysis of single trial data. Previously, we showed that a multiple component event-related potential (mcERP) algorithm can extract the responses of individual sources from recordings of a mixture of multiple, possibly interacting, neural ensembles. McERP also estimated single-trial amplitudes and onset latencies, thus allowing more accurate estimation of ongoing neural activity during an experimental trial. The mcERP algorithm is related to informax independent component analysis (ICA); however, the underlying signal model is more physiologically realistic in that a component is modeled as a stereotypic waveshape varying both in amplitude and onset latency from trial to trial. The result is a model that reflects quantities of interest to the neuroscientist. Here we demonstrate that the mcERP algorithm provides more accurate results than more traditional methods such as factor analysis and the more recent ICA. Whereas factor analysis assumes the sources are orthogonal and ICA assumes the sources are statistically independent, the mcERP algorithm makes no such assumptions thus allowing investigators to examine interactions among components by estimating the properties of single-trial responses.

  20. Differential rates of phenotypic introgression are associated with male behavioral responses to multiple signals.

    PubMed

    Greig, Emma I; Baldassarre, Daniel T; Webster, Michael S

    2015-10-01

    Sexual selection on multiple signals may lead to differential rates of signal introgression across hybrid zones if some signals contribute to reproductive isolation but others facilitate gene flow. Competition among males is one powerful form of sexual selection, but male behavioral responses to multiple traits have not been considered in a system where traits have introgressed differentially. Using playbacks, mounts, and a reciprocal experimental design, we tested the hypothesis that male responses to song and plumage in two subspecies of red-backed fairy-wren (Malurus melanocephalus) explain patterns of differential signal introgression (song has not introgressed, whereas plumage color has introgressed asymmetrically). We found that males of both subspecies discriminated symmetrically between subspecies' songs at a long range, but at a close range, we found that aggression was equal for both subspecies' plumage and songs. Taken together, our results suggest that male behavioral responses hinder the introgression of song, but allow for the observed asymmetrical introgression of plumage. Our results highlight how behavioral responses are a key component of signal evolution when recently divergent taxa come together, and how differential responses to multiple signals may lead to differential signal introgression and novel trait combinations. PMID:26292844

  1. Identification of Differential Item Functioning in Multiple-Group Settings: A Multivariate Outlier Detection Approach

    ERIC Educational Resources Information Center

    Magis, David; De Boeck, Paul

    2011-01-01

    We focus on the identification of differential item functioning (DIF) when more than two groups of examinees are considered. We propose to consider items as elements of a multivariate space, where DIF items are outlying elements. Following this approach, the situation of multiple groups is a quite natural case. A robust statistics technique is

  2. Identification of Differential Item Functioning in Multiple-Group Settings: A Multivariate Outlier Detection Approach

    ERIC Educational Resources Information Center

    Magis, David; De Boeck, Paul

    2011-01-01

    We focus on the identification of differential item functioning (DIF) when more than two groups of examinees are considered. We propose to consider items as elements of a multivariate space, where DIF items are outlying elements. Following this approach, the situation of multiple groups is a quite natural case. A robust statistics technique is…

  3. Studying Differential Item Functioning via Latent Variable Modeling: A Note on a Multiple-Testing Procedure

    ERIC Educational Resources Information Center

    Raykov, Tenko; Marcoulides, George A.; Lee, Chun-Lung; Chang, Chi

    2013-01-01

    This note is concerned with a latent variable modeling approach for the study of differential item functioning in a multigroup setting. A multiple-testing procedure that can be used to evaluate group differences in response probabilities on individual items is discussed. The method is readily employed when the aim is also to locate possible

  4. Sigma-2 Receptor as Potential Indicator of Stem Cell Differentiation

    PubMed Central

    Haller, Jodi L.; Panyutin, Irina; Chaudhry, Aneeka; Zeng, Chenbo; Mach, Robert H.; Frank, Joseph A.

    2011-01-01

    Purpose The sigma-2 (σ2) receptor is a potential biomarker of proliferative status of solid tumors. Specific synthetic probes using N-substituted-9-azabicyclo[3.3.1]nonan-3α-yl carbamate analogs have been designed and implemented for experimental cancer diagnosis and therapy. Procedures We employed the fluorescently-labeled σ2 receptor probe, SW120, to evaluate σ2 receptor expression in human stem cells (SC), including: bone marrow stromal (BMSC), neural progenitor (NPC), amniotic fluid (AFSC), hematopoetic (HSC) and embryonic stem cells (ESC). We concurrently evaluated the intensity of SW120 and 5-ethynyl-2′-deoxyuridine (EdU) relative to passage number and multipotency. Results We substantiated significantly higher σ2 receptor density among proliferating SC relative to lineage-restricted cell types. Additionally, cellular internalization of the σ2 receptor in SC was consistent with receptor-mediated endocytosis and confocal microscopy indicated SW120 specific co-localization with a fluorescent marker of lysosomes in all SC imaged. Conclusion These results suggest that σ2 receptors may serve to monitor stem cell differentiation in future experimental studies. PMID:21614680

  5. New immunosuppressants with potential implication in multiple sclerosis.

    PubMed

    Gonsette, R E

    2004-08-15

    New immunosuppressants are consistently developed to treat autoimmune diseases and some of them might have implications in multiple sclerosis (MS). A new antiproliferative agent, pixantrone, an analogue of mitoxantrone (MX), has a much lower cardiotoxicity and exerts the same potent immunosuppressive effects in experimental allergic encephalomyelitis (EAE). A phase I trial in MS patients is planned in the next future. New monoclonal antibodies (mAb) and other biological constructs containing foreign proteins are developed but their potential immunogenicity is a considerable drawback to their long-term administration. In addition, their beneficial effects in MS are not evident so far. Small molecules targeting the voltage-gated Kv1.3K+ channel regulating CA2+ signaling in T lymphocytes, specifically target activated, pathogenic T cells. Already found effective in EAE, those agents would be easier to handle than T-cell vaccination. Two new immunosuppressants with a unique mechanism of action (FTY720 and Epomycine M) selectively impair autoreactive T-cell homing, without affecting the other components of the immune response. The potent protective effect of TRY720 has been demonstrated in EAE and a phase I trial in MS appears warranted. Finally, a new concept about immunosuppressive treatments in organ transplantation, "tolerogenic immunosuppression", may have potential in MS. PMID:15261567

  6. Ectopic expression of interferon regulatory factor-1 potentiates granulocytic differentiation.

    PubMed Central

    Coccia, E M; Stellacci, E; Valtieri, M; Masella, B; Feccia, T; Marziali, G; Hiscott, J; Testa, U; Peschle, C; Battistini, A

    2001-01-01

    Numerous transcription factors allow haematopoietic cells to respond to lineage- and stage-specific cytokines and to act as their effectors. It is increasingly evident that the interferon regulatory factor-1 (IRF-1) transcription factor can selectively regulate different sets of genes depending on the cell type and/or the nature of cellular stimuli, evoking distinct responses in each. In the present study, we investigated mechanisms underlying the differentiation-inducing properties of granulocytic colony-stimulating factor (G-CSF) and whether IRF transcription factors are functionally relevant in myeloid differentiation. Both normal human progenitors and murine 32Dcl3 myeloblasts induced to differentiate along the granulocytic pathway showed an up-regulation of IRF-1 expression. Ectopic expression of IRF-1 did not abrogate the growth factor requirement of 32Dcl3 cells, although a small percentage of cells that survived cytokine deprivation differentiated fully to neutrophils. Moreover, in the presence of G-CSF, granulocytic differentiation of IRF-1-expressing cells was accelerated, as assessed by morphology and expression of specific differentiation markers. Down-modulation of c-Myb protein and direct stimulation of lysozyme promoter activity by IRF-1 were also observed. Conversely, constitutive expression of IRF-2, a repressor of IRF-1 transcriptional activity, completely abrogated the G-CSF-induced neutrophilic maturation. We conclude that IRF-1 exerts a pivotal role in granulocytic differentiation and that its induction by G-CSF represents a limiting step in the early events of differentiation. PMID:11716756

  7. Identification of potential glucocorticoid receptor therapeutic targets in multiple myeloma

    PubMed Central

    Thomas, Alexandra L.; Coarfa, Cristian; Qian, Jun; Wilkerson, Joseph J.; Rajapakshe, Kimal; Krett, Nancy L.; Gunaratne, Preethi H.; Rosen, Steven T.

    2015-01-01

    Glucocorticoids (GC) are a cornerstone of combination therapies for multiple myeloma. However, patients ultimately develop resistance to GCs frequently based on decreased glucocorticoid receptor (GR) expression. An understanding of the direct targets of GC actions, which induce cell death, is expected to culminate in potential therapeutic strategies for inducing cell death by regulating downstream targets in the absence of a functional GR. The specific goal of our research is to identify primary GR targets that contribute to GC-induced cell death, with the ultimate goal of developing novel therapeutics around these targets that can be used to overcome resistance to GCs in the absence of GR. Using the MM.1S glucocorticoid-sensitive human myeloma cell line, we began with the broad platform of gene expression profiling to identify glucocorticoid-regulated genes further refined by combination treatment with phosphatidylinositol-3’-kinase inhibition (PI3Ki). To further refine the search to distinguish direct and indirect targets of GR that respond to the combination GC and PI3Ki treatment of MM.1S cells, we integrated 1) gene expression profiles of combination GC treatment with PI3Ki, which induces synergistic cell death; 2) negative correlation between genes inhibited by combination treatment in MM.1S cells and genes over-expressed in myeloma patients to establish clinical relevance and 3) GR chromatin immunoprecipitation with massively parallel sequencing (ChIP-Seq) in myeloma cells to identify global chromatin binding for the glucocorticoid receptor (GR). Using established bioinformatics platforms, we have integrated these data sets to identify a subset of candidate genes that may form the basis for a comprehensive picture of glucocorticoid actions in multiple myeloma. As a proof of principle, we have verified two targets, namely RRM2 and BCL2L1, as primary functional targets of GR involved in GC-induced cell death. PMID:26715915

  8. Small Buccal Fat Pad Cells Have High Osteogenic Differentiation Potential.

    PubMed

    Tsurumachi, Niina; Akita, Daisuke; Kano, Koichiro; Matsumoto, Taro; Toriumi, Taku; Kazama, Tomohiko; Oki, Yoshinao; Tamura, Yoko; Tonogi, Morio; Isokawa, Keitaro; Shimizu, Noriyoshi; Honda, Masaki

    2016-03-01

    Dedifferentiated fat (DFAT) cells derived from mature adipocytes have mesenchymal stem cells' (MSCs) characteristics. Generally, mature adipocytes are 60-110 μm in diameter; however, association between adipocyte size and dedifferentiation efficiency is still unknown. This study, therefore, investigated the dedifferentiation efficiency of adipocytes based on cell diameter. Buccal fat pad was harvested from five human donors and dissociated by collagenase digestion. After exclusion of unwanted stromal cells by centrifugation, floating adipocytes were collected and their size distribution was analyzed. The floating adipocytes were then separated into two groups depending on cell size using 40- and 100-μm nylon mesh filters: cell diameters less than 40 μm (small adipocytes: S-adipocytes) and cell diameters of 40-100 μm (large adipocytes: L-adipocytes). Finally, we evaluated the efficiency of adipocyte dedifferentiation and then characterized the resultant DFAT cells. The S-adipocytes showed a higher capacity to dedifferentiate into DFAT cells (S-DFAT cells) compared to the L-adipocytes (L-DFAT cells). The S-DFAT cells also showed a relatively higher proportion of CD146-positive cells than L-DFAT cells, and exhibited more osteogenic differentiation ability based on the alkaline phosphatase activity and amount of calcium deposition. These results suggested that the S- and L-DFAT cells had distinct characteristics, and that the higher dedifferentiation potential of S-adipocytes compared to L-adipocytes gives the former group an advantage in yielding DFAT cells. PMID:26651216

  9. SELECTIVE OESTROGEN RECEPTOR MODULATORS DIFFERENTIALLY POTENTIATE BRAIN MITOCHONDRIAL FUNCTION

    PubMed Central

    Irwin, Ronald W.; Yao, Jia; To, Jimmy; Hamilton, Ryan T.; Cadenas, Enrique; Brinton, Roberta Diaz

    2011-01-01

    The mitochondrial energy-transducing capacity of the brain is important for long-term neurological health and is influenced by endocrine hormone responsiveness. This study aimed to determine the role of oestrogen receptor (ER) subtypes in regulating mitochondrial function using selective agonists for ER? (PPT) and ER? (DPN). Ovariectomised female rats were treated with 17?-oestradiol (E2), PPT, DPN or vehicle control. Both ER selective agonists significantly increased the mitochondrial respiratory control ratio and cytochrome oxidase (COX) activity relative to vehicle. Western blots of purified whole brain mitochondria detected ER? and to a greater extent, ER? localization. Pre-treatment with DPN, an ER? agonist, significantly increased ER? association with mitochondria. In hippocampus, DPN activated mitochondrial DNA-encoded COXI expression whereas PPT was ineffective indicating that mechanistically ER?, not ER?, activated mitochondrial transcriptional machinery. Both selective ER agonists increased protein expression of nuclear DNA-encoded COXIV suggesting that activation of ER? or ER? is sufficient. Selective ER agonists up-regulated a panel of bioenergetic enzymes and antioxidant defense proteins. Up-regulated proteins included pyruvate dehydrogenase, ATP synthase, manganese superoxide dismutase, and peroxiredoxin V. In vitro, whole cell metabolism was assessed in live primary cultured hippocampal neurons and mixed glia. Results of in vitro analyses were consistent with in vivo data. Further, lipid peroxides, accumulated as a result of hormone deprivation, were significantly reduced by E2, PPT, and DPN. These findings suggest that activation of both ER? and ER? are differentially required to potentiate mitochondrial function in brain. As active components in hormone therapy, synthetically designed oestrogens as well as natural phyto-oestrogen cocktails can be tailored to improve brain mitochondrial endpoints. PMID:22070562

  10. Basal Expression of Pluripotency-Associated Genes Can Contribute to Stemness Property and Differentiation Potential

    PubMed Central

    Dadheech, Nidheesh; Srivastava, Abhay; Belani, Muskaan; Gupta, Sharad; Pal, Rajarshi; Bhonde, Ramesh R.; Srivastava, Anand S.

    2013-01-01

    Pluripotency and stemness is believed to be associated with high Oct-3/4, Nanog, and Sox-2 (ONS) expression. Similar to embryonic stem cells (ESCs), high ONS expression eventually became the measure of pluripotency in any cell. The threshold expression of ONS genes that underscores pluripotency, stemness, and differentiation potential is still unclear. Therefore, we raised a question as to whether pluripotency and stemness is a function of basal ONS gene expression. To prove this, we carried out a comparative study between basal ONS expressing NIH3T3 cells with pluripotent mouse bone marrow mesenchymal stem cells (mBMSC) and mouse ESC. Our studies on cellular, molecular, and immunological biomarkers between NIH3T3 and mBMSC demonstrated stemness property of undifferentiated NIH3T3 cells that was similar to mBMSC and somewhat close to ESC as well. In vivo teratoma formation with all three germ layer derivatives strengthen the fact that these cells in spite of basal ONS gene expression can differentiate into cells of multiple lineages without any genetic modification. Conclusively, our novel findings suggested that the phenomenon of pluripotency which imparts ability for multilineage cell differentiation is not necessarily a function of high ONS gene expression. PMID:23343006

  11. Revealing Pathway Dynamics in Heart Diseases by Analyzing Multiple Differential Networks

    PubMed Central

    Ma, Xiaoke; Gao, Long; Karamanlidis, Georgios; Gao, Peng; Lee, Chi Fung; Garcia-Menendez, Lorena; Tian, Rong; Tan, Kai

    2015-01-01

    Development of heart diseases is driven by dynamic changes in both the activity and connectivity of gene pathways. Understanding these dynamic events is critical for understanding pathogenic mechanisms and development of effective treatment. Currently, there is a lack of computational methods that enable analysis of multiple gene networks, each of which exhibits differential activity compared to the network of the baseline/healthy condition. We describe the iMDM algorithm to identify both unique and shared gene modules across multiple differential co-expression networks, termed M-DMs (multiple differential modules). We applied iMDM to a time-course RNA-Seq dataset generated using a murine heart failure model generated on two genotypes. We showed that iMDM achieves higher accuracy in inferring gene modules compared to using single or multiple co-expression networks. We found that condition-specific M-DMs exhibit differential activities, mediate different biological processes, and are enriched for genes with known cardiovascular phenotypes. By analyzing M-DMs that are present in multiple conditions, we revealed dynamic changes in pathway activity and connectivity across heart failure conditions. We further showed that module dynamics were correlated with the dynamics of disease phenotypes during the development of heart failure. Thus, pathway dynamics is a powerful measure for understanding pathogenesis. iMDM provides a principled way to dissect the dynamics of gene pathways and its relationship to the dynamics of disease phenotype. With the exponential growth of omics data, our method can aid in generating systems-level insights into disease progression. PMID:26083688

  12. Harmonizing multiple methods for reconstructing historical potential and reference evapotranspiration

    USGS Publications Warehouse

    Belaineh, Getachew; Sumner, David; Carter, Edward; Clapp, David

    2013-01-01

    Potential evapotranspiration (PET) and reference evapotranspiration (RET) data are usually critical components of hydrologic analysis. Many different equations are available to estimate PET and RET. Most of these equations, such as the Priestley-Taylor and Penman- Monteith methods, rely on detailed meteorological data collected at ground-based weather stations. Few weather stations collect enough data to estimate PET or RET using one of the more complex evapotranspiration equations. Currently, satellite data integrated with ground meteorological data are used with one of these evapotranspiration equations to accurately estimate PET and RET. However, earlier than the last few decades, historical reconstructions of PET and RET needed for many hydrologic analyses are limited by the paucity of satellite data and of some types of ground data. Air temperature stands out as the most generally available meteorological ground data type over the last century. Temperature-based approaches used with readily available historical temperature data offer the potential for long period-of-record PET and RET historical reconstructions. A challenge is the inconsistency between the more accurate, but more data intensive, methods appropriate for more recent periods and the less accurate, but less data intensive, methods appropriate to the more distant past. In this study, multiple methods are harmonized in a seamless reconstruction of historical PET and RET by quantifying and eliminating the biases of the simple Hargreaves-Samani method relative to the more complex and accurate Priestley-Taylor and Penman-Monteith methods. This harmonization process is used to generate long-term, internally consistent, spatiotemporal databases of PET and RET.

  13. [Intrathecal immunoglobulin production in the diagnosis and differential diagnosis of multiple sclerosis].

    PubMed

    Totolian, N A; Gotovchikov, A A; Lapin, S V; Maksimov, I V; Kodzaeva, A Iu; Prakhova, L N; Il'ves, A G; Skoromets, A P; Totolian, A A; Skoromets, A A

    2012-01-01

    The evaluation of diagnostic significance of different immunological tests for intrathecal immunoglobulin production is summarized on the historical basis of investigation of patients with inflammatory, demyelinating and other neurological disorders. The assessment of cerebrospinal fluid lost its previous significance in the 2010 revision of diagnostic criteria for multiple sclerosis. Nowadays, it is used only for the diagnosis of primary progressive multiple sclerosis. Nevertheless, the requirements of the analysis of the cerebrospinal fluid are increasing due to subtle, subclinical and atypical cases of multiple sclerosis as well as undetermined demyelinating disorders. Intrathecal humoral immune response may be pathogenic in multiple sclerosis as suggest immunological data and effectiveness of anti-B cells treatment. Based on these tests, it is useful, to differentiate subgroups of patients and to evaluate different effects of treatment in perspective. PMID:23235427

  14. Local field potentials reflect multiple spatial scales in V4

    PubMed Central

    Mineault, Patrick J.; Zanos, Theodoros P.; Pack, Christopher C.

    2013-01-01

    Local field potentials (LFP) reflect the properties of neuronal circuits or columns recorded in a volume around a microelectrode (Buzsáki et al., 2012). The extent of this integration volume has been a subject of some debate, with estimates ranging from a few hundred microns (Katzner et al., 2009; Xing et al., 2009) to several millimeters (Kreiman et al., 2006). We estimated receptive fields (RFs) of multi-unit activity (MUA) and LFPs at an intermediate level of visual processing, in area V4 of two macaques. The spatial structure of LFP receptive fields varied greatly as a function of time lag following stimulus onset, with the retinotopy of LFPs matching that of MUAs at a restricted set of time lags. A model-based analysis of the LFPs allowed us to recover two distinct stimulus-triggered components: an MUA-like retinotopic component that originated in a small volume around the microelectrodes (~350 μm), and a second component that was shared across the entire V4 region; this second component had tuning properties unrelated to those of the MUAs. Our results suggest that the LFP reflects neural activity across multiple spatial scales, which both complicates its interpretation and offers new opportunities for investigating the large-scale structure of network processing. PMID:23533106

  15. Animal models of multiple sclerosis--potentials and limitations.

    PubMed

    Mix, Eilhard; Meyer-Rienecker, Hans; Hartung, Hans-Peter; Zettl, Uwe K

    2010-11-01

    Experimental autoimmune encephalomyelitis (EAE) is still the most widely accepted animal model of multiple sclerosis (MS). Different types of EAE have been developed in order to investigate pathogenetic, clinical and therapeutic aspects of the heterogenic human disease. Generally, investigations in EAE are more suitable for the analysis of immunogenetic elements (major histocompatibility complex restriction and candidate risk genes) and for the study of histopathological features (inflammation, demyelination and degeneration) of the disease than for screening of new treatments. Recent studies in new EAE models, especially in transgenic ones, have in connection with new analytical techniques such as microarray assays provided a deeper insight into the pathogenic cellular and molecular mechanisms of EAE and potentially of MS. For example, it was possible to better delineate the role of soluble pro-inflammatory (tumor necrosis factor-?, interferon-? and interleukins 1, 12 and 23), anti-inflammatory (transforming growth factor-? and interleukins 4, 10, 27 and 35) and neurotrophic factors (ciliary neurotrophic factor and brain-derived neurotrophic factor). Also, the regulatory and effector functions of distinct immune cell subpopulations such as CD4+ Th1, Th2, Th3 and Th17 cells, CD4+FoxP3+ Treg cells, CD8+ Tc1 and Tc2, B cells and ??+ T cells have been disclosed in more detail. The new insights may help to identify novel targets for the treatment of MS. However, translation of the experimental results into the clinical practice requires prudence and great caution. PMID:20558237

  16. Multiple organ failure. Pathophysiology and potential future therapy.

    PubMed Central

    Deitch, E A

    1992-01-01

    Multiple organ failure (MOF) has reached epidemic proportions in most intensive care units and is fast becoming the most common cause of death in the surgical intensive care unit. Furthermore, in spite of the development of successive generations of new and more powerful antibiotics and increasing sophisticated techniques of organ support, our ability to salvage patients once MOF has become established has not appreciably improved over the last two decades. Clearly, new therapeutic strategies aimed at preventing or limiting the development of the physiologic abnormalities that induce organ failure are needed to improve survival in these critically ill patients. Based on our rapidly increasing knowledge of the mechanisms of MOF and the fruits of molecular biology, a number of new therapeutic approaches are in various stages of development. To effectively use these new therapeutic options as they become available, it is necessary to have a clear understanding of the pathophysiology of MOF. Thus, the goals of this review are to integrate the vast amount of new information on the basic biology of MOF and to focus special attention on the potential therapeutic consequences of these recent advances in our understanding of this complex and perplexing syndrome. PMID:1503516

  17. Differentially Variable Component Analysis (dVCA): Identifying Multiple Evoked Components using Trial-to-Trial Variability

    NASA Technical Reports Server (NTRS)

    Knuth, Kevin H.; Shah, Ankoor S.; Truccolo, Wilson; Ding, Ming-Zhou; Bressler, Steven L.; Schroeder, Charles E.

    2003-01-01

    Electric potentials and magnetic fields generated by ensembles of synchronously active neurons in response to external stimuli provide information essential to understanding the processes underlying cognitive and sensorimotor activity. Interpreting recordings of these potentials and fields is difficult as each detector records signals simultaneously generated by various regions throughout the brain. We introduce the differentially Variable Component Analysis (dVCA) algorithm, which relies on trial-to-trial variability in response amplitude and latency to identify multiple components. Using simulations we evaluate the importance of response variability to component identification, the robustness of dVCA to noise, and its ability to characterize single-trial data. Finally, we evaluate the technique using visually evoked field potentials recorded at incremental depths across the layers of cortical area VI, in an awake, behaving macaque monkey.

  18. Differential uptake of silver, copper and zinc suggests complementary species-specific phytoextraction potential.

    PubMed

    Desjardins, D; Pitre, F E; Nissim, W Guidi; Labrecque, M

    2016-06-01

    The aim of our study, conducted as a pot experiment, was to assess the potential of willow (Salix miyabeana), alfalfa (Medicago sativa), tall fescue (Festuca arundinacea), and Indian mustard (Brassica juncea) to remediate two brownfield soils differentially contaminated with Ag, Cu and Zn (up to 113.60, 47.50, and 117.00 mg kg(-1) respectively). While aboveground Ag accumulation was highest in B. juncea (4.60 ± 2.58 mg kg(-1)), lower levels were also measured in M. sativa and F. arundinacea. Cu accumulation was observed in all species, but only in underground parts, and was highest in F. arundinacea (269.20 ± 74.75 mg kg(-1)), with a bioconcentration factor of 13.85. Salix miyabeana was found to have the highest Zn aerial tissue concentration (119.96 ± 20.04 mg kg(-1)). Because of its high Ag uptake, the remediation potential of B. juncea should be evaluated more extensively on the site from which we excavated the soil for this study. Given the multiple forms of contamination on the site and the differential specie-related uptake evident in our findings, we hypothesize that an optimal plantation allowing expression of complementary remediation functions would include B. juncea for extraction of Ag, in combination with F. arundinacea for stabilization of Cu and S. miyabeana for extraction of Zn. PMID:26361089

  19. "Brain sex differentiation" in teleosts: Emerging concepts with potential biomarkers.

    PubMed

    Senthilkumaran, Balasubramanian; Sudhakumari, Cheni-Chery; Mamta, Sajwan-Khatri; Raghuveer, Kavarthapu; Swapna, Immani; Murugananthkumar, Raju

    2015-09-01

    "Brain sex differentiation" in teleosts is a contentious topic of research as most of the earlier reports tend to suggest that gonadal sex differentiation drives brain sex differentiation. However, identification of sex-specific marker genes in the developing brain of teleosts signifies brain-gonadal interaction during early sexual development in lower vertebrates. In this context, the influence of gonadotropin-releasing hormone (GnRH)-gonadotropin (GTH) axis on gonadal sex differentiation, if any requires in depth analysis. Presence of seabream (sb) GnRH immunoreactivity (ir-) in the brain of XY Nile tilapia was found as early as 5days post hatch (dph) followed by qualitative reduction in the preoptic area-hypothalamus region. In contrast, in the XX female brain a steady ir- of sbGnRH was evident from 15dph. Earlier studies using sea bass already implied the importance of hypothalamic gonadotropic axis completion during sex differentiation period. Such biphasic pattern of localization was also seen in pituitary GTHs using heterologous antisera in tilapia. However, more recent analysis in the same species could not detect any sexually dimorphic pattern using homologous antisera for pituitary GTHs. Detailed studies on the development of hypothalamo-hypophyseal-gonadal axis in teleosts focusing on hypothalamic monoamines (MA) and MA-related enzymes demonstrated sex-specific differential expression of tryptophan hydroxylase (Tph) in the early stages of developing male and female brains of tilapia and catfish. The changes in Tph expression was in agreement with the levels of serotonin (5-HT) and 5-hydroxytryptophan in the preoptic area-hypothalamus. Considering the stimulatory influence of 5-HT on GnRH and GTH release, it is possible to propose a network association between these correlates during early development, which may bring about brain sex dimorphism in males. A recent study from our laboratory during female brain sex development demonstrated high expression of tyrosine hydroxylase in correlation with catecholamine levels, brain aromatase and its related transcription factors such as fushi tarazu factor 1, Ftz-f1 and fork head box protein L2, foxl2. Taken together, gender differences in the levels of various transcripts provide new perspectives on brain sex differentiation in lower vertebrates. Sexually dimorphic or differentially expressing genes may play an essential role at the level of brain in response to gonadal differentiation, which might consequentially or causatively respond to gonadal sex. PMID:26116093

  20. Automatic differentiation for design sensitivity analysis of structural systems using multiple processors

    NASA Technical Reports Server (NTRS)

    Nguyen, Duc T.; Storaasli, Olaf O.; Qin, Jiangning; Qamar, Ramzi

    1994-01-01

    An automatic differentiation tool (ADIFOR) is incorporated into a finite element based structural analysis program for shape and non-shape design sensitivity analysis of structural systems. The entire analysis and sensitivity procedures are parallelized and vectorized for high performance computation. Small scale examples to verify the accuracy of the proposed program and a medium scale example to demonstrate the parallel vector performance on multiple CRAY C90 processors are included.

  1. Single- and Multiple-Objective Optimization with Differential Evolution and Neural Networks

    NASA Technical Reports Server (NTRS)

    Rai, Man Mohan

    2006-01-01

    Genetic and evolutionary algorithms have been applied to solve numerous problems in engineering design where they have been used primarily as optimization procedures. These methods have an advantage over conventional gradient-based search procedures became they are capable of finding global optima of multi-modal functions and searching design spaces with disjoint feasible regions. They are also robust in the presence of noisy data. Another desirable feature of these methods is that they can efficiently use distributed and parallel computing resources since multiple function evaluations (flow simulations in aerodynamics design) can be performed simultaneously and independently on ultiple processors. For these reasons genetic and evolutionary algorithms are being used more frequently in design optimization. Examples include airfoil and wing design and compressor and turbine airfoil design. They are also finding increasing use in multiple-objective and multidisciplinary optimization. This lecture will focus on an evolutionary method that is a relatively new member to the general class of evolutionary methods called differential evolution (DE). This method is easy to use and program and it requires relatively few user-specified constants. These constants are easily determined for a wide class of problems. Fine-tuning the constants will off course yield the solution to the optimization problem at hand more rapidly. DE can be efficiently implemented on parallel computers and can be used for continuous, discrete and mixed discrete/continuous optimization problems. It does not require the objective function to be continuous and is noise tolerant. DE and applications to single and multiple-objective optimization will be included in the presentation and lecture notes. A method for aerodynamic design optimization that is based on neural networks will also be included as a part of this lecture. The method offers advantages over traditional optimization methods. It is more flexible than other methods in dealing with design in the context of both steady and unsteady flows, partial and complete data sets, combined experimental and numerical data, inclusion of various constraints and rules of thumb, and other issues that characterize the aerodynamic design process. Neural networks provide a natural framework within which a succession of numerical solutions of increasing fidelity, incorporating more realistic flow physics, can be represented and utilized for optimization. Neural networks also offer an excellent framework for multiple-objective and multi-disciplinary design optimization. Simulation tools from various disciplines can be integrated within this framework and rapid trade-off studies involving one or many disciplines can be performed. The prospect of combining neural network based optimization methods and evolutionary algorithms to obtain a hybrid method with the best properties of both methods will be included in this presentation. Achieving solution diversity and accurate convergence to the exact Pareto front in multiple objective optimization usually requires a significant computational effort with evolutionary algorithms. In this lecture we will also explore the possibility of using neural networks to obtain estimates of the Pareto optimal front using non-dominated solutions generated by DE as training data. Neural network estimators have the potential advantage of reducing the number of function evaluations required to obtain solution accuracy and diversity, thus reducing cost to design.

  2. Equivalent system for a multiple-rational-order fractional differential system.

    PubMed

    Li, Changpin; Zhang, Fengrong; Kurths, Jrgen; Zeng, Fanhai

    2013-05-13

    The equivalent system for a multiple-rational-order (MRO) fractional differential system is studied, where the fractional derivative is in the sense of Caputo or Riemann-Liouville. With the relationship between the Caputo derivative and the generalized fractional derivative, we can change the MRO fractional differential system with a Caputo derivative into a higher-dimensional system with the same Caputo derivative order lying in (0,1). The stability of the zero solution to the original system is studied through the analysis of its equivalent system. For the Riemann-Liouville case, we transform the MRO fractional differential system into a new one with the same order lying in (0,1), where the properties of the Riemann-Liouville derivative operator and the fractional integral operator are used. The corresponding stability is also studied. Finally, several numerical examples are provided to illustrate the derived results. PMID:23547233

  3. Control of matric water potential by temperature differential

    NASA Technical Reports Server (NTRS)

    Palmer, R. J. Jr; Nienow, J. A.; Friedmann, E. I.

    1987-01-01

    A method for controlling relative humidity based on temperature differentials, rather than on salt solutions, is described. This method has the following advantages: (1) it does not exhibit the anomalous CO2 solution effects that we have found to occur with salt solutions; (2) humidity is continuously adjustable without sample removal; (3) circulation of the atmosphere results in short equilibration times.

  4. Differentiation of multiple giant cell lesions, Noonan-like syndrome, and (occult) hyperparathyroidism. Case report and review of the literature.

    PubMed

    van Damme, P A; Mooren, R E

    1994-02-01

    The history is reported of a boy known to have von Recklinghausen neurofibromatosis and multiple recurrent central giant cell granulomata of the mandible and maxilla. This paper discusses the problem of differentiating multiple central giant cell granulomata, Noonan-like/multiple giant cell lesion syndrome, and brown tumor resulting from (occult) hyperparathyroidism. PMID:8163857

  5. Improved detection of differentially expressed genes in microarray experiments through multiple scanning and image integration

    PubMed Central

    Romualdi, Chiara; Trevisan, Silvia; Celegato, Barbara; Costa, Germano; Lanfranchi, Gerolamo

    2003-01-01

    The variability of results in microarray technology is in part due to the fact that independent scans of a single hybridised microarray give spot images that are not quite the same. To solve this problem and turn it to our advantage, we introduced the approach of multiple scanning and of image integration of microarrays. To this end, we have developed specific software that creates a virtual image that statistically summarises a series of consecutive scans of a microarray. We provide evidence that the use of multiple imaging (i) enhances the detection of differentially expressed genes; (ii) increases the image homogeneity; and (iii) reveals false-positive results such as differentially expressed genes that are detected by a single scan but not confirmed by successive scanning replicates. The increase in the final number of differentially expressed genes detected in a microarray experiment with this approach is remarkable; 50% more for microarrays hybridised with targets labelled by reverse transcriptase, and 200% more for microarrays developed with the tyramide signal amplification (TSA) technique. The results have been confirmed by semi-quantitative RT–PCR tests. PMID:14627839

  6. Multicolor Quantum Dot-Based Chemical Nose for Rapid and Array-Free Differentiation of Multiple Proteins.

    PubMed

    Xu, Qinfeng; Zhang, Yihong; Tang, Bo; Zhang, Chun-Yang

    2016-02-16

    Nanomaterial-based differential sensors (e.g., chemical nose) have shown great potential for identification of multiple proteins because of their modulatable recognition and transduction capability but with the limitation of array separation, single-channel read-out, and long incubation time. Here, we develop a multicolor quantum dot (QD)-based multichannel sensing platform for rapid identification of multiple proteins in an array-free format within 1 min. A protein-binding dye of bromophenol blue (BPB) is explored as an efficient reversible quencher of QDs, and the mixture of BPB with multicolor QDs may generate the quenched QD-BPB complexes. The addition of proteins will disrupt the QD-BPB complexes as a result of the competitive protein-BPB binding, inducing the separation of BPB from the QDs and the generation of distinct fluorescence patterns. The multicolor patterns may be collected at a single-wavelength excitation and differentiated by a linear discriminant analysis (LDA). This multichannel sensing platform allows for the discrimination of ten proteins and seven cell lines with the fastest response rate reported to date, holding great promise for rapid and high-throughput medical diagnostics. PMID:26759896

  7. Differentiation potential of SHEDs using biomimetic periosteum containing dexamethasone.

    PubMed

    Su, Wen-Ta; Chiou, Wei-Ling; Yu, Ho-Hsu; Huang, Te-Yang

    2016-01-01

    Mimicking the architecture of the natural environment in vivo is an effective strategy for tissue engineering. The periosteum has an important function in bone regeneration. However, the harvesting of autogenous periosteum has the disadvantages of donor site morbidity and limited donor sources. This study uses an innovative artificial periosteum that forms dexamethasone (DEX)-containing polyvinyl alcohol (PVA) nanofiber obtained from skin fibrous scaffold. The aim was to evaluate the effect on bone healing of osteogenic differentiation in stems originating from human exfoliated deciduous teeth (SHEDs) in vitro. The microstructure of fabricated periosteum was observed through SEM, and results showed the apparent homogenous distribution of porous structures. DEX was also found to be continuously released into the culture medium from the periosteum for 28 days. MTT results further revealed that fabricated periosteum was cytocompatible and non-toxic to SHEDs. After 21 days of induced culture, the expression of alkaline phosphatase activity and calcium mineralization notably increased. Osteogenic results showed high early and late osteoblast gene expression by RT-PCR analysis, such as collagen type I, Runx2, OPN, and OCN. The osteoblastic protein expression of BMP-2 and OCN was clearly observed as well under fluorescence microscopy. The results, which could be applied to bone regeneration, demonstrated that skin fibrous scaffold provided an osteoinductive environment for stem cells to differentiate and that PVA nanofiber was a suitable reservoir for osteogenic factors with controlled release profile. PMID:26478401

  8. Virtual Reality and Multiple Intelligences: Potentials for Higher Education.

    ERIC Educational Resources Information Center

    McLellan, Hilary

    1994-01-01

    Discussion of the use of virtual reality in higher education looks at how this emerging computer-based technology can promote learning that engages all seven forms of intelligence proposed in H. Gardner's theory of multiple intelligences. Technical and conceptual issues in implementation of virtual reality in education are also examined.

  9. Phosphoproteomic analysis of kinase-deficient mice reveals multiple TAK1 targets in osteoclast differentiation.

    PubMed

    Sumiya, Eriko; Negishi-Koga, Takako; Nagai, Yusuke; Suematsu, Ayako; Suda, Tomomi; Shinohara, Masahiro; Sato, Kojiro; Sanjo, Hideki; Akira, Shizuo; Takayanagi, Hiroshi

    2015-08-01

    TAK1 (encoded by Map3k7) is a mitogen-activated protein kinase kinase kinase (MAP3K), which activates the transcription factors AP-1 and NF-?B in response to receptor activator of NF-?B ligand (RANKL) stimulation, thus constituting a key regulator of osteoclast differentiation. Here we report the functional relevance of the kinase activity of TAK1 in the late stage of osteoclast differentiation invivo using Ctsk-Cre mice and TAK1 mutant mice in which the TAK1 kinase domain was flanked by loxP. The Map3k7(flox/kd)Ctsk(Cre/+) mice displayed a severe osteopetrotic phenotype due to a marked decrease in osteoclast number. RANKL-induced activation of MAPK and NF-?B was impaired in the late stage of osteoclast differentiation. The absence of suppressive effect of an administered NF-?B inhibitor on the late stage of osteoclastogenesis led us to investigate unknown TAK1 targets in osteoclast differentiation. We performed a phosphoproteomic analysis of RANKL-stimulated osteoclast precursor cells from Map3k7(flox/kd)Ctsk(Cre/+) mice, revealing multiple targets regulated by TAK1 during osteoclastogenesis. Thus, TAK1 functions as a critical regulator of the phosophorylation status of various cellular proteins that govern osteoclastogenesis. PMID:26102028

  10. Involvement of multiple myeloma cell-derived exosomes in osteoclast differentiation

    PubMed Central

    Raimondi, Lavinia; De Luca, Angela; Amodio, Nicola; Manno, Mauro; Raccosta, Samuele; Taverna, Simona; Bellavia, Daniele; Naselli, Flores; Fontana, Simona; Schillaci, Odessa; Giardino, Roberto; Fini, Milena; Tassone, Pierfrancesco; Santoro, Alessandra; De Leo, Giacomo; Giavaresi, Gianluca; Alessandro, Riccardo

    2015-01-01

    Bone disease is the most frequent complication in multiple myeloma (MM) resulting in osteolytic lesions, bone pain, hypercalcemia and renal failure. In MM bone disease the perfect balance between bone-resorbing osteoclasts (OCs) and bone-forming osteoblasts (OBs) activity is lost in favour of OCs, thus resulting in skeletal disorders. Since exosomes have been described for their functional role in cancer progression, we here investigate whether MM cell-derived exosomes may be involved in OCs differentiation. We show that MM cells produce exosomes which are actively internalized by Raw264.7 cell line, a cellular model of osteoclast formation. MM cell-derived exosomes positively modulate pre-osteoclast migration, through the increasing of CXCR4 expression and trigger a survival pathway. MM cell-derived exosomes play a significant pro-differentiative role in murine Raw264.7 cells and human primary osteoclasts, inducing the expression of osteoclast markers such as Cathepsin K (CTSK), Matrix Metalloproteinases 9 (MMP9) and Tartrate-resistant Acid Phosphatase (TRAP). Pre-osteoclast treated with MM cell-derived exosomes differentiate in multinuclear OCs able to excavate authentic resorption lacunae. Similar results were obtained with exosomes derived from MM patient's sera. Our data indicate that MM-exosomes modulate OCs function and differentiation. Further studies are needed to identify the OCs activating factors transported by MM cell-derived exosomes. PMID:25944696

  11. Multiple Active Contours Guided by Differential Evolution for Medical Image Segmentation

    PubMed Central

    Cruz-Aceves, I.; Avina-Cervantes, J. G.; Lopez-Hernandez, J. M.; Rostro-Gonzalez, H.; Garcia-Capulin, C. H.; Torres-Cisneros, M.; Guzman-Cabrera, R.

    2013-01-01

    This paper presents a new image segmentation method based on multiple active contours guided by differential evolution, called MACDE. The segmentation method uses differential evolution over a polar coordinate system to increase the exploration and exploitation capabilities regarding the classical active contour model. To evaluate the performance of the proposed method, a set of synthetic images with complex objects, Gaussian noise, and deep concavities is introduced. Subsequently, MACDE is applied on datasets of sequential computed tomography and magnetic resonance images which contain the human heart and the human left ventricle, respectively. Finally, to obtain a quantitative and qualitative evaluation of the medical image segmentations compared to regions outlined by experts, a set of distance and similarity metrics has been adopted. According to the experimental results, MACDE outperforms the classical active contour model and the interactive Tseng method in terms of efficiency and robustness for obtaining the optimal control points and attains a high accuracy segmentation. PMID:23983809

  12. Multiple spacecraft rendezvous maneuvers by differential drag and low thrust engines

    NASA Astrophysics Data System (ADS)

    Bevilacqua, Riccardo; Hall, Jason S.; Romano, Marcello

    2010-01-01

    A novel two-phase hybrid controller is proposed to optimize propellant consumption during multiple spacecraft rendezvous maneuvers in Low Earth Orbit. This controller exploits generated differentials in aerodynamic drag on each involved chaser spacecraft to effect a propellant-free trajectory near to the target spacecraft during the first phase of the maneuver, and then uses a fuel optimal control strategy via continuous low-thrust engines to effect a precision dock during the second phase. In particular, by varying the imparted aerodynamic drag force on each of the chaser spacecraft, relative differential accelerations are generated between each chaser and the target spacecraft along two of the three translational degrees of freedom. In order to generate this required differential, each chaser spacecraft is assumed to include a system of rotating flat panels. Additionally, each chaser spacecraft is assumed to have continuous low-thrust capability along the three translational degrees of freedom and full-axis attitude control. Sample simulations are presented to support the validity and robustness of the proposed hybrid controller to variations in the atmospheric density along with different spacecraft masses and ballistic coefficients. Furthermore, the proposed hybrid controller is validated against a complete nonlinear orbital model to include relative navigation errors typical of carrier-phase differential GPS (CDGPS). Limitations of the proposed controller appear relative to the target spacecraft's orbit eccentricity and a general characterization of the atmospheric density. Bounds on these variables are included to provide a framework within which the proposed hybrid controller can effect an extremely low propellant rendezvous of multiple chaser spacecraft to a desired target spacecraft.

  13. Immune responses in multiple myeloma: role of the natural immune surveillance and potential of immunotherapies.

    PubMed

    Guillerey, Camille; Nakamura, Kyohei; Vuckovic, Slavica; Hill, Geoffrey R; Smyth, Mark J

    2016-04-01

    Multiple myeloma (MM) is a tumor of terminally differentiated B cells that arises in the bone marrow. Immune interactions appear as key determinants of MM progression. While myeloid cells foster myeloma-promoting inflammation, Natural Killer cells and T lymphocytes mediate protective anti-myeloma responses. The profound immune deregulation occurring in MM patients may be involved in the transition from a premalignant to a malignant stage of the disease. In the last decades, the advent of stem cell transplantation and new therapeutic agents including proteasome inhibitors and immunoregulatory drugs has dramatically improved patient outcomes, suggesting potentially key roles for innate and adaptive immunity in disease control. Nevertheless, MM remains largely incurable for the vast majority of patients. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential of very long term disease control. Here, we review the immunological microenvironment in myeloma. We discuss the role of naturally arising anti-myeloma immune responses and their potential corruption in MM patients. Finally, we detail the numerous promising immune-targeting strategies approved or in clinical trials for the treatment of MM. PMID:26801219

  14. Multiple wall-reflection effect in adaptive-array differential-phase reflectometry on QUEST

    NASA Astrophysics Data System (ADS)

    Idei, H.; Mishra, K.; Yamamoto, M. K.; Fujisawa, A.; Nagashima, Y.; Hamasaki, M.; Hayashi, Y.; Onchi, T.; Hanada, K.; Zushi, H.; QUEST team

    2016-01-01

    A phased array antenna and Software-Defined Radio (SDR) heterodyne-detection systems have been developed for adaptive array approaches in reflectometry on the QUEST. In the QUEST device considered as a large oversized cavity, standing wave (multiple wall-reflection) effect was significantly observed with distorted amplitude and phase evolution even if the adaptive array analyses were applied. The distorted fields were analyzed by Fast Fourier Transform (FFT) in wavenumber domain to treat separately the components with and without wall reflections. The differential phase evolution was properly obtained from the distorted field evolution by the FFT procedures. A frequency derivative method has been proposed to overcome the multiple-wall reflection effect, and SDR super-heterodyned components with small frequency difference for the derivative method were correctly obtained using the FFT analysis.

  15. Understanding multiple ecological responses to anthropogenic disturbance: rivers and potential flow regime change.

    PubMed

    Leigh, Catherine; Stewart-Koster, Ben; Sheldon, Fran; Burford, Michele A

    2012-01-01

    Human-induced alteration of the natural flow regime is a major threat to freshwater ecosystems and biodiversity. The effects of hydrological alteration on the structural and functional attributes of riverine communities are expected to be multiple and complex, and they may not be described easily by a single model. Based on existing knowledge of key hydrological and ecological attributes, we explored potential effects of a flow-regulation scenario on macroinvertebrate assemblage composition and diversity in two river systems in Australia's relatively undeveloped wet-dry tropics. We used a single Bayesian belief network (BBN) to model potential changes in multiple assemblage attributes within each river type during dry and wet seasons given two flow scenarios: the current, near-natural flow condition, and flow regulation. We then used multidimensional scaling (MDS) ordination to visually summarize and compare the most probable attributes of assemblages and their environment under the different scenarios. The flow-regulation scenario provided less certainty in the ecological responses of one river type during the dry season, which reduced the ability to make predictions from the BBN outputs directly. However, visualizing the BBN results in an ordination highlighted similarities and differences between the scenarios that may have been otherwise difficult to ascertain. In particular, the MDS showed that flow regulation would reduce the seasonal differentiation in hydrology and assemblage characteristics that is expected under the current low level of development. Our approach may have wider application in understanding ecosystem responses to different river management practices and should be transferred easily to other ecosystems or biotic assemblages to provide researchers, managers, and decision makers an enhanced understanding of ecological responses to potential anthropogenic disturbance. PMID:22471088

  16. Potential role of daratumumab in the treatment of multiple myeloma.

    PubMed

    Khagi, Yulian; Mark, Tomer M

    2014-01-01

    Multiple myeloma is the second most common hematologic malignancy in the US. Treatments utilizing alkylating agents, corticosteroids, proteasome inhibitors, and immunomodulatory drugs have resulted in significant survival benefits, however, despite the advances, relapse is inevitable. Decreased depth and duration of response obtained with each successive relapse of disease is typical of the disease course, thereby highlighting a continuing need for new treatment options. With the introduction of monoclonal antibodies for multiple myeloma, new options for treatment in the relapsed setting are on the horizon. Among the new immunologic agents is daratumumab (DARA), a humanized antibody to CD38 with potent multifaceted antitumor activity. Phase I and II clinical trials have demonstrated significant reduction in serum M-protein and bone marrow plasma cell percentage in refractory patients, with an acceptable toxicity profile. Moreover, ex vivo studies have shown that DARA may be particularly useful in combination with currently used anti-myeloma agents. With a recent breakthrough drug designation by the US Food and Drug Administration, DARA shows promise as mono- and combination therapy for the treatment of relapsed/refractory multiple myeloma. PMID:24971019

  17. Phosphorylated α-synuclein in skin nerve fibres differentiates Parkinson's disease from multiple system atrophy.

    PubMed

    Zange, Leonora; Noack, Cornelia; Hahn, Katrin; Stenzel, Werner; Lipp, Axel

    2015-08-01

    Deposition of phosphorylated SNCA (also known as α-synuclein) in cutaneous nerve fibres has been shown pre- and post-mortem in Parkinson's disease. Thus far, no pre-mortem studies investigating the presence of phosphorylated SNCA in skin sympathetic nerve fibres of multiple system atrophy, another synucleinopathy, have been conducted. In this in vivo study, skin from the ventral forearm of 10 patients with multiple system atrophy and 10 with Parkinson's disease, together with six control subjects with essential tremor, were examined by immunohistochemistry. Phosphorylated SNCA deposits in skin sympathetic nerve fibres and dermal nerve fibre density were assessed. All patients with Parkinson's disease expressed phosphorylated SNCA in sympathetic skin nerve fibres, correlating with an age-independent denervation of autonomic skin elements. In contrast, no phosphorylated SNCA was found in autonomic skin nerve fibres of patients with multiple system atrophy and essential tremor control subjects. These findings support that phosphorylated SNCA deposition is causative for nerve fibre degeneration in Parkinson's disease. Moreover, pre-mortem investigation of phosphorylated SNCA in cutaneous nerve fibres may prove a relevant and easily conductible diagnostic procedure to differentiate Parkinson's disease from multiple system atrophy. PMID:26017579

  18. Serum-free spheroid suspension culture maintains mesenchymal stem cell proliferation and differentiation potential.

    PubMed

    Alimperti, Stella; Lei, Pedro; Wen, Yuan; Tian, Jun; Campbell, Andrew M; Andreadis, Stelios T

    2014-01-01

    There have been many clinical trials recently using ex vivo-expanded human mesenchymal stem cells (MSCs) to treat several disease states such as graft-versus-host disease, acute myocardial infarction, Crohn's disease, and multiple sclerosis. The use of MSCs for therapy is expected to become more prevalent as clinical progress is demonstrated. However, the conventional 2-dimensional (2D) culture of MSCs is laborious and limited in scale potential. The large dosage requirement for many of the MSC-based indications further exacerbates this manufacturing challenge. In contrast, expanding MSCs as spheroids does not require a cell attachment surface and is amenable to large-scale suspension cell culture techniques, such as stirred-tank bioreactors. In the present study, we developed and optimized serum-free media for culturing MSC spheroids. We used Design of Experiment (DoE)-based strategies to systematically evaluate media mixtures and a panel of different components for effects on cell proliferation. The optimization yielded two prototype serum-free media that enabled MSCs to form aggregates and proliferate in both static and dynamic cultures. MSCs from spheroid cultures exhibited the expected immunophenotype (CD73, CD90, and CD105) and demonstrated similar or enhanced differentiation potential toward all three lineages (osteogenic, chondrogenic, adipogenic) as compared with serum-containing adherent MSC cultures. Our results suggest that serum-free media for MSC spheroids may pave the way for scale-up production of MSCs in clinically relevant manufacturing platforms such as stirred tank bioreactors. PMID:24616445

  19. Spotlight on ixazomib: potential in the treatment of multiple myeloma

    PubMed Central

    Muz, Barbara; Ghazarian, Rachel Nicole; Ou, Monica; Luderer, Micah John; Kusdono, Hubert Daniel; Azab, Abdel Kareem

    2016-01-01

    Despite the significant therapeutic advances achieved with proteasome inhibitors (PIs) such as bortezomib and carfilzomib in prolonging the survival of patients with multiple myeloma, the development of drug resistance, peripheral neuropathy, and pharmacokinetic limitations continue to pose major challenges when using these compounds. Ixazomib is a second-generation PI with improved activity over other PIs. Unlike bortezomib and carfilzomib, which are administered by injection, ixazomib is the first oral PI approved by US Food and Drug Administration. This review discusses the biochemical properties, mechanisms of action, preclinical efficacy, and clinical trial results leading to the US Food and Drug Administration approval of ixazomib. PMID:26811670

  20. Therapeutic Potential of Differentiated Mesenchymal Stem Cells for Treatment of Osteoarthritis

    PubMed Central

    Ham, Onju; Lee, Chang Youn; Kim, Ran; Lee, Jihyun; Oh, Sekyung; Lee, Min Young; Kim, Jongmin; Hwang, Ki-Chul; Maeng, Lee-So; Chang, Woochul

    2015-01-01

    Osteoarthritis (OA) is a chronic, progressive, and irreversible degenerative joint disease. Conventional OA treatments often result in complications such as pain and limited activity. However, transplantation of mesenchymal stem cells (MSCs) has several beneficial effects such as paracrine effects, anti-inflammatory activity, and immunomodulatory capacity. In addition, MSCs can be differentiated into several cell types, including chondrocytes, osteocytes, endothelia, and adipocytes. Thus, transplantation of MSCs is a suggested therapeutic tool for treatment of OA. However, transplanted naïve MSCs can cause problems such as heterogeneous populations including differentiated MSCs and undifferentiated cells. To overcome this problem, new strategies for inducing differentiation of MSCs are needed. One possibility is the application of microRNA (miRNA) and small molecules, which regulate multiple molecular pathways and cellular processes such as differentiation. Here, we provide insight into possible strategies for cartilage regeneration by transplantation of differentiated MSCs to treat OA patients. PMID:26147426

  1. Derivation and characterization of canine embryonic stem cell lines with in vitro and in vivo differentiation potential.

    PubMed

    Vaags, Andrea K; Rosic-Kablar, Suzana; Gartley, Cathy J; Zheng, Yan Zhen; Chesney, Alden; Villagmez, Daniel A F; Kruth, Stephen A; Hough, Margaret R

    2009-02-01

    Embryonic stem cells (ESCs) represent permanent cell lines that can be maintained in an undifferentiated state. In an environment that induces differentiation, they form derivatives of the three embryonic germ layers: mesoderm, ectoderm, and endoderm. These characteristics give ESCs great potential for both basic research and clinical applications in the areas of regenerative medicine and tissue engineering. The establishment of ESCs from large animals that model human diseases is of significant importance. We describe the derivation of permanent canine cell lines from preimplantation-stage embryos. Similar to human ESCs, canine ESCs expressed OCT3/4, NANOG, SOX2, SSEA-3, SSEA-4, TRA-1-60, TRA-1-81, and alkaline phosphatase, whereas they expressed very low levels of SSEA-1. They maintained a normal karyotype and morphology typical of undifferentiated ESCs after multiple in vitro passages and rounds of cryopreservation. Plating cells in the absence of a feeder layer, either in attachment or suspension culture, resulted in the formation of embryoid bodies and their differentiation to multiple cell types. In vivo, canine ESCs gave rise to teratomas comprising cell types of all three embryonic germ layers. These cells represent the first pluripotent canine ESC lines with both in vitro and in vivo differentiation potential and offer the exciting possibility of testing the efficacy and safety of ESC-based therapies in large animal models of human disease. PMID:19038794

  2. Habitat differentiation within the large-carnivore community of Norway's multiple-use landscapes.

    PubMed

    May, Roel; van Dijk, Jiska; Wabakken, Petter; Swenson, Jon E; Linnell, John Dc; Zimmermann, Barbara; Odden, John; Pedersen, Hans C; Andersen, Reidar; Landa, Arild

    2008-10-01

    The re-establishment of large carnivores in Norway has led to increased conflicts and the adoption of regional zoning for these predators. When planning the future distribution of large carnivores, it is important to consider details of their potential habitat tolerances and strength of inter-specific differentiation. We studied differentiation in habitat and kill sites within the large-carnivore community of south-eastern Norway.We compared habitat selection of the brown bear Ursus arctos L., Eurasian lynx Lynx lynx L., wolf Canis lupus L. and wolverine Gulo gulo L., based on radio-tracking data. Differences in kill site locations were explored using locations of documented predator-killed sheep Ovis aries L. We modelled each species' selection for, and differentiation in, habitat and kill sites on a landscape scale using resource selection functions and multinomial logistic regression. Based on projected probability of occurrence maps, we estimated continuous patches of habitat within the study area.Although bears, lynx, wolves and wolverines had overlapping distributions, we found a clear differentiation for all four species in both habitat and kill sites. The presence of bears, wolves and lynx was generally associated with rugged, forested areas at lower elevations, whereas wolverines selected rugged terrain at higher elevations. Some degree of sympatry was possible in over 40% of the study area, although only 1.5% could hold all four large carnivores together.Synthesis and applications. A geographically differentiated management policy has been adopted in Norway, aimed at conserving viable populations of large carnivores while minimizing the potential for conflicts. Sympatry of all four carnivores will be most successful if regional zones are established of adequate size spanning an elevational gradient. High prey densities, low carnivore densities, low dietary overlap and scavenging opportunities have most probably led to reduced competitive exclusion. Although regional sympatry enhances the conservation of an intact guild of large carnivores, it may well increase conflict levels and resistance to carnivore conservation locally. PMID:19330031

  3. Habitat differentiation within the large-carnivore community of Norway's multiple-use landscapes

    PubMed Central

    May, Roel; van Dijk, Jiska; Wabakken, Petter; Swenson, Jon E; Linnell, John DC; Zimmermann, Barbara; Odden, John; Pedersen, Hans C; Andersen, Reidar; Landa, Arild

    2008-01-01

    The re-establishment of large carnivores in Norway has led to increased conflicts and the adoption of regional zoning for these predators. When planning the future distribution of large carnivores, it is important to consider details of their potential habitat tolerances and strength of inter-specific differentiation. We studied differentiation in habitat and kill sites within the large-carnivore community of south-eastern Norway. We compared habitat selection of the brown bear Ursus arctos L., Eurasian lynx Lynx lynx L., wolf Canis lupus L. and wolverine Gulo gulo L., based on radio-tracking data. Differences in kill site locations were explored using locations of documented predator-killed sheep Ovis aries L. We modelled each species’ selection for, and differentiation in, habitat and kill sites on a landscape scale using resource selection functions and multinomial logistic regression. Based on projected probability of occurrence maps, we estimated continuous patches of habitat within the study area. Although bears, lynx, wolves and wolverines had overlapping distributions, we found a clear differentiation for all four species in both habitat and kill sites. The presence of bears, wolves and lynx was generally associated with rugged, forested areas at lower elevations, whereas wolverines selected rugged terrain at higher elevations. Some degree of sympatry was possible in over 40% of the study area, although only 1·5% could hold all four large carnivores together. Synthesis and applications. A geographically differentiated management policy has been adopted in Norway, aimed at conserving viable populations of large carnivores while minimizing the potential for conflicts. Sympatry of all four carnivores will be most successful if regional zones are established of adequate size spanning an elevational gradient. High prey densities, low carnivore densities, low dietary overlap and scavenging opportunities have most probably led to reduced competitive exclusion. Although regional sympatry enhances the conservation of an intact guild of large carnivores, it may well increase conflict levels and resistance to carnivore conservation locally. PMID:19330031

  4. Differential meta-analysis of RNA-seq data from multiple studies

    PubMed Central

    2014-01-01

    Background High-throughput sequencing is now regularly used for studies of the transcriptome (RNA-seq), particularly for comparisons among experimental conditions. For the time being, a limited number of biological replicates are typically considered in such experiments, leading to low detection power for differential expression. As their cost continues to decrease, it is likely that additional follow-up studies will be conducted to re-address the same biological question. Results We demonstrate how p-value combination techniques previously used for microarray meta-analyses can be used for the differential analysis of RNA-seq data from multiple related studies. These techniques are compared to a negative binomial generalized linear model (GLM) including a fixed study effect on simulated data and real data on human melanoma cell lines. The GLM with fixed study effect performed well for low inter-study variation and small numbers of studies, but was outperformed by the meta-analysis methods for moderate to large inter-study variability and larger numbers of studies. Conclusions The p-value combination techniques illustrated here are a valuable tool to perform differential meta-analyses of RNA-seq data by appropriately accounting for biological and technical variability within studies as well as additional study-specific effects. An R package metaRNASeq is available on the CRAN (http://cran.r-project.org/web/packages/metaRNASeq). PMID:24678608

  5. Multiple Antenatal Dexamethasone Treatment Alters Brain Vessel Differentiation in Newborn Mouse Pups

    PubMed Central

    Neuhaus, Winfried; Schlundt, Marian; Fehrholz, Markus; Ehrke, Alexander; Kunzmann, Steffen; Liebner, Stefan; Speer, Christian P.; Förster, Carola Y.

    2015-01-01

    Antenatal steroid treatment decreases morbidity and mortality in premature infants through the maturation of lung tissue, which enables sufficient breathing performance. However, clinical and animal studies have shown that repeated doses of glucocorticoids such as dexamethasone and betamethasone lead to long-term adverse effects on brain development. Therefore, we established a mouse model for antenatal dexamethasone treatment to investigate the effects of dexamethasone on brain vessel differentiation towards the blood-brain barrier (BBB) phenotype, focusing on molecular marker analysis. The major findings were that in total brains on postnatal day (PN) 4 triple antenatal dexamethasone treatment significantly downregulated the tight junction protein claudin-5, the endothelial marker Pecam-1/CD31, the glucocorticoid receptor, the NR1 subunit of the N-methyl-D-aspartate receptor, and Abc transporters (Abcb1a, Abcg2 Abcc4). Less pronounced effects were found after single antenatal dexamethasone treatment and in PN10 samples. Comparisons of total brain samples with isolated brain endothelial cells together with the stainings for Pecam-1/CD31 and claudin-5 led to the assumption that the morphology of brain vessels is affected by antenatal dexamethasone treatment at PN4. On the mRNA level markers for angiogenesis, the sonic hedgehog and the Wnt pathway were downregulated in PN4 samples, suggesting fundamental changes in brain vascularization and/or differentiation. In conclusion, we provided a first comprehensive molecular basis for the adverse effects of multiple antenatal dexamethasone treatment on brain vessel differentiation. PMID:26274818

  6. Therapeutic potential of carbon monoxide in multiple sclerosis

    PubMed Central

    Fagone, P; Mangano, K; Coco, M; Perciavalle, V; Garotta, G; Romao, C C; Nicoletti, F

    2012-01-01

    Summary Carbon monoxide (CO) is produced during the catabolism of free haem, catalyzed by haem oxygenase (HO) enzymes, and its physiological roles include vasodilation, neurotransmission, inhibition of platelet aggregation and anti-proliferative effects on smooth muscle. In vivo preclinical studies have shown that exogenously administered quantities of CO may represent an effective treatment for conditions characterized by a dysregulated immune response. The carbon monoxide-releasing molecules (CORMs) represent a group of compounds capable of carrying and liberating controlled quantities of CO in the cellular systems. This review covers the physiological and anti-inflammatory properties of the HO/CO pathway in the central nervous system. It also discusses the effects of CORMs in preclinical models of inflammation. The accumulating data discussed herein support the possibility that CORMs may represent a novel class of drugs with disease-modifying properties in multiple sclerosis. PMID:22235993

  7. Integrated model of multiple kernel learning and differential evolution for EUR/USD trading.

    PubMed

    Deng, Shangkun; Sakurai, Akito

    2014-01-01

    Currency trading is an important area for individual investors, government policy decisions, and organization investments. In this study, we propose a hybrid approach referred to as MKL-DE, which combines multiple kernel learning (MKL) with differential evolution (DE) for trading a currency pair. MKL is used to learn a model that predicts changes in the target currency pair, whereas DE is used to generate the buy and sell signals for the target currency pair based on the relative strength index (RSI), while it is also combined with MKL as a trading signal. The new hybrid implementation is applied to EUR/USD trading, which is the most traded foreign exchange (FX) currency pair. MKL is essential for utilizing information from multiple information sources and DE is essential for formulating a trading rule based on a mixture of discrete structures and continuous parameters. Initially, the prediction model optimized by MKL predicts the returns based on a technical indicator called the moving average convergence and divergence. Next, a combined trading signal is optimized by DE using the inputs from the prediction model and technical indicator RSI obtained from multiple timeframes. The experimental results showed that trading using the prediction learned by MKL yielded consistent profits. PMID:25097891

  8. Integrated Model of Multiple Kernel Learning and Differential Evolution for EUR/USD Trading

    PubMed Central

    Deng, Shangkun; Sakurai, Akito

    2014-01-01

    Currency trading is an important area for individual investors, government policy decisions, and organization investments. In this study, we propose a hybrid approach referred to as MKL-DE, which combines multiple kernel learning (MKL) with differential evolution (DE) for trading a currency pair. MKL is used to learn a model that predicts changes in the target currency pair, whereas DE is used to generate the buy and sell signals for the target currency pair based on the relative strength index (RSI), while it is also combined with MKL as a trading signal. The new hybrid implementation is applied to EUR/USD trading, which is the most traded foreign exchange (FX) currency pair. MKL is essential for utilizing information from multiple information sources and DE is essential for formulating a trading rule based on a mixture of discrete structures and continuous parameters. Initially, the prediction model optimized by MKL predicts the returns based on a technical indicator called the moving average convergence and divergence. Next, a combined trading signal is optimized by DE using the inputs from the prediction model and technical indicator RSI obtained from multiple timeframes. The experimental results showed that trading using the prediction learned by MKL yielded consistent profits. PMID:25097891

  9. Restricted differentiation potential of progenitor cell populations obtained from the equine superficial digital flexor tendon (SDFT)

    PubMed Central

    Williamson, Kate Ann; Lee, Katie Joanna; Humphreys, William James Edward; Comerford, Eithne Josephine Veronica; Clegg, Peter David; Canty-Laird, Elizabeth Gail

    2015-01-01

    The aim of this study was to characterize stem and progenitor cell populations from the equine superficial digital flexor tendon, an energy-storing tendon with similarities to the human Achilles tendon, which is frequently injured. Using published methods for the isolation of tendon-derived stem/progenitor cells by low-density plating we found that isolated cells possessed clonogenicity but were unable to fully differentiate towards mesenchymal lineages using trilineage differentiation assays. In particular, adipogenic differentiation appeared to be restricted, as assessed by Oil Red O staining of stem/progenitor cells cultured in adipogenic medium. We then assessed whether differential adhesion to fibronectin substrates could be used to isolate a population of cells with broader differentiation potential. However we found little difference in the stem and tenogenic gene expression profile of these cells as compared to tenocytes, although the expression of thrombospondin-4 was significantly reduced in hypoxic conditions. Tendon-derived stem/progenitor cells isolated by differential adhesion to fibronectin had a similar differentiation potential to cells isolated by low density plating, and when grown in either normoxic or hypoxic conditions. In summary, we have found a restricted differentiation potential of cells isolated from the equine superficial digital flexor tendon despite evidence for stem/progenitor-like characteristics. 2015 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 33:849858, 2015. PMID:25877997

  10. Restricted differentiation potential of progenitor cell populations obtained from the equine superficial digital flexor tendon (SDFT).

    PubMed

    Williamson, Kate Ann; Lee, Katie Joanna; Humphreys, William James Edward; Comerford, Eithne Josephine Veronica; Clegg, Peter David; Canty-Laird, Elizabeth Gail

    2015-06-01

    The aim of this study was to characterize stem and progenitor cell populations from the equine superficial digital flexor tendon, an energy-storing tendon with similarities to the human Achilles tendon, which is frequently injured. Using published methods for the isolation of tendon-derived stem/progenitor cells by low-density plating we found that isolated cells possessed clonogenicity but were unable to fully differentiate towards mesenchymal lineages using trilineage differentiation assays. In particular, adipogenic differentiation appeared to be restricted, as assessed by Oil Red O staining of stem/progenitor cells cultured in adipogenic medium. We then assessed whether differential adhesion to fibronectin substrates could be used to isolate a population of cells with broader differentiation potential. However we found little difference in the stem and tenogenic gene expression profile of these cells as compared to tenocytes, although the expression of thrombospondin-4 was significantly reduced in hypoxic conditions. Tendon-derived stem/progenitor cells isolated by differential adhesion to fibronectin had a similar differentiation potential to cells isolated by low density plating, and when grown in either normoxic or hypoxic conditions. In summary, we have found a restricted differentiation potential of cells isolated from the equine superficial digital flexor tendon despite evidence for stem/progenitor-like characteristics. PMID:25877997

  11. Alternative to the Kohn-Sham equations: The Pauli potential differential equation

    NASA Astrophysics Data System (ADS)

    Levämäki, H.; Nagy, Á.; Kokko, K.; Vitos, L.

    2015-12-01

    A recently developed theoretical framework of performing self-consistent orbital-free (OF) density functional theory (DFT) calculations at Kohn-Sham DFT level accuracy is tested in practice. The framework is valid for spherically symmetric systems. Numerical results for the Beryllium atom are presented and compared to accurate Kohn-Sham data. These calculations make use of a differential equation that we have developed for the so called Pauli potential, a key quantity in OF-DFT. The Pauli potential differential equation and the OF Euler equation form a system of two coupled differential equations, which have to be solved simultaneously within the DFT self-consistent loop.

  12. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment.

    PubMed

    Krumbholz, Markus; Theil, Diethilde; Cepok, Sabine; Hemmer, Bernhard; Kivisäkk, Pia; Ransohoff, Richard M; Hofbauer, Monika; Farina, Cinthia; Derfuss, Tobias; Hartle, Caroline; Newcombe, Jia; Hohlfeld, Reinhard; Meinl, Edgar

    2006-01-01

    Understanding the mechanisms of immune cell migration to multiple sclerosis lesions offers significant therapeutic potential. This study focused on the chemokines CXCL12 (SDF-1) and CXCL13 (BCA-1), both of which regulate B cell migration in lymphoid tissues. We report that immunohistologically CXCL12 was constitutively expressed in CNS parenchyma on blood vessel walls. In both active and chronic inactive multiple sclerosis lesions CXCL12 protein was elevated and detected on astrocytes and blood vessels. Quantitative PCR demonstrated that CXCL13 was produced in actively demyelinating multiple sclerosis lesions, but not in chronic inactive lesions or in the CNS of subjects who had no neurological disease. CXCL13 protein was localized in perivascular infiltrates and scattered infiltrating cells in lesion parenchyma. In the CSF of relapsing-remitting multiple sclerosis patients, both CXCL12 and CXCL13 were elevated. CXCL13, but not CXCL12, levels correlated strongly with intrathecal immunoglobulin production as well as the presence of B cells, plasma blasts and T cells. About 20% of CSF CD4+ cells and almost all B cells expressed the CXCL13 receptor CXCR5. In vitro, CXCL13 was produced by monocytes and at much higher levels by macrophages. CXCL13 mRNA and protein expression was induced by TNFalpha and IL-1beta but inhibited by IL-4 and IFNgamma. Together, CXCL12 and CXCL13 are elevated in active multiple sclerosis lesions and CXCL12 also in inactive lesions. The consequences of CXCL12 up-regulation could be manifold. CXCL12 localization on blood vessels indicates a possible role in leucocyte extravasation, and CXCL12 may contribute to plasma cell persistence since its receptor CXCR4 is retained during plasma cell differentiation. CXCL12 may contribute to axonal damage as it can become a neurotoxic mediator of cleavage by metalloproteases, which are present in multiple sclerosis lesions. The strong linkage of CXCL13 to immune cells and immunoglobulin levels in CSF suggests that this is one of the factors that attract and maintain B and T cells in inflamed CNS lesions. Therefore, both CXCL13 and CXCR5 may be promising therapeutic targets in multiple sclerosis. PMID:16280350

  13. RBC micromotors carrying multiple cargos towards potential theranostic applications

    NASA Astrophysics Data System (ADS)

    Wu, Zhiguang; Esteban-Fernández de Ávila, Berta; Martín, Aída; Christianson, Caleb; Gao, Weiwei; Thamphiwatana, Soracha Kun; Escarpa, Alberto; He, Qiang; Zhang, Liangfang; Wang, Joseph

    2015-08-01

    Red blood cell (RBC)-based micromotors containing both therapeutic and diagnostic modalities are described as a means for potential theranostic applications. In this natural RBC-based multicargo-loaded micromotor system, quantum dots (QDs), anti-cancer drug doxorubicin (DOX), and magnetic nanoparticles (MNPs), were co-encapsulated into RBC micromotors. The fluorescent emission of both QDs and DOX provides direct visualization of their loading inside the RBC motors at two distinct wavelengths. The presence of MNPs within the RBCs allows for efficient magnetic guidance under ultrasound propulsion along with providing the potential for magnetic resonance imaging. The simultaneous encapsulation of the imaging nanoparticles and therapeutic payloads within the same RBC micromotor has a minimal effect upon its propulsion behavior. The ability of the RBC micromotors to transport imaging and therapeutic agents at high speed and spatial precision through a complex microchannel network is also demonstrated. Such ability to load and transport diagnostic imaging agents and therapeutic drugs within a single cell-based motor, in addition to a lower toxicity observed once the drug is encapsulated within the multicargo RBC motor, opens the door to the development of theranostic micromotors that may simultaneously treat and monitor diseases.Red blood cell (RBC)-based micromotors containing both therapeutic and diagnostic modalities are described as a means for potential theranostic applications. In this natural RBC-based multicargo-loaded micromotor system, quantum dots (QDs), anti-cancer drug doxorubicin (DOX), and magnetic nanoparticles (MNPs), were co-encapsulated into RBC micromotors. The fluorescent emission of both QDs and DOX provides direct visualization of their loading inside the RBC motors at two distinct wavelengths. The presence of MNPs within the RBCs allows for efficient magnetic guidance under ultrasound propulsion along with providing the potential for magnetic resonance imaging. The simultaneous encapsulation of the imaging nanoparticles and therapeutic payloads within the same RBC micromotor has a minimal effect upon its propulsion behavior. The ability of the RBC micromotors to transport imaging and therapeutic agents at high speed and spatial precision through a complex microchannel network is also demonstrated. Such ability to load and transport diagnostic imaging agents and therapeutic drugs within a single cell-based motor, in addition to a lower toxicity observed once the drug is encapsulated within the multicargo RBC motor, opens the door to the development of theranostic micromotors that may simultaneously treat and monitor diseases. Electronic supplementary information (ESI) available: Videos of the propulsion of the multicargo-loaded, RBC-based micromotors and more data are available in the ESI. See DOI: 10.1039/c5nr03730a

  14. Differentiation potential of individual olfactory c-Kit+ progenitors determined via multicolor lineage tracing.

    PubMed

    Goss, Garrett M; Chaudhari, Nirupa; Hare, Joshua M; Nwojo, Raphael; Seidler, Barbara; Saur, Dieter; Goldstein, Bradley J

    2016-03-01

    Olfactory tissue undergoes lifelong renewal, due to the presence of basal neural stem cells. Multiple categories of globose basal stem cells have been identified, expressing markers such as Lgr5, Ascl1, GBC-2, and c-Kit. The differentiation potential of individual globose cells has remained unclear. Here, we utilized Cre/loxP lineage tracing with a multicolor reporter system to define c-Kit+ cell contributions at clonal resolution. We determined that reporter expression permitted identification of c-Kit derived progeny with fine cellular detail, and that clones were found to be comprised by neurons only, microvillar cells only, microvillar cells and neurons, or gland/duct cells. Quantification of reporter-labeled cells indicated that c-Kit+ cells behave as transit amplifying or immediate precursors, although we also found evidence for longer-term c-Kit+ cell contributions. Our results from the application of multicolor fate mapping delineate the clonal contributions of c-Kit+ cells to olfactory epithelial renewal, and provide novel insight into tissue maintenance of an adult neuroepithelium. 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 241-251, 2016. PMID:26016700

  15. Regenerative medicine in multiple sclerosis: identifying pharmacological targets of adult neural stem cell differentiation.

    PubMed

    Huang, Jeffrey K; Franklin, Robin J M

    2011-09-01

    Progressive axonal loss from chronic demyelination in multiple sclerosis (MS) is the key contributor to clinical decline. Failure to regenerate myelin by adult oligodendrocyte precursor cells (OPCs), a widely distributed neural stem cell population in the adult brain, is one of the major causes of axonal degeneration. In order to develop successful therapies to protect the integrity of axons in MS, it is important to identify and understand the key molecular pathways involved in myelin regeneration (remyelination) by adult OPCs. This review highlights recent findings on the critical signaling pathways associated with OPC differentiation following CNS demyelination. We discuss the role of LINGO-1, Notch, Wnt, and retinoid X receptor (RXR) signaling, and how they might be useful pharmacological targets to overcoming remyelination failure in MS. PMID:21300122

  16. Multiple antimelanoma potential of dry olive leaf extract.

    PubMed

    Mijatovic, Sanja A; Timotijevic, Gordana S; Miljkovic, Djordje M; Radovic, Julijana M; Maksimovic-Ivanic, Danijela D; Dekanski, Dragana P; Stosic-Grujicic, Stanislava D

    2011-04-15

    Various constituents of the olive tree (Olea europaea) have been traditionally used in the treatment of infection, inflammation, prevention of chronic diseases, cardiovascular disorders and cancer. The anticancer potential of dry olive leaf extract (DOLE) represents the net effect of multilevel interactions between different biologically active compounds from the extract, cancer cells and conventional therapy. In this context, it was of primary interest to evaluate the influence of DOLE on progression of the highly malignant, immuno- and chemoresistant type of skin cancer-melanoma. DOLE significantly inhibited proliferation and subsequently restricted clonogenicity of the B16 mouse melanoma cell line in vitro. Moreover, late phase tumor treatment with DOLE significantly reduced tumor volume in a syngeneic strain of mice. DOLE-treated B16 cells were blocked in the G(0) /G(1) phase of the cell cycle, underwent early apoptosis and died by late necrosis. At the molecular level, the dying process started as caspase dependent, but finalized as caspase independent. In concordance, overexpression of antiapoptotic members of the Bcl-2 family, Bcl-2 and Bcl-XL, and diminished expression of their natural antagonists, Bim and p53, were observed. Despite molecular suppression of the proapoptotic process, DOLE successfully promoted cell death mainly through disruption of cell membrane integrity and late caspase-independent fragmentation of genetic material. Taken together, the results of this study indicate that DOLE possesses strong antimelanoma potential. When DOLE was applied in combination with different chemotherapeutics, various outcomes, including synergy and antagonism, were observed. This requires caution in the use of the extract as a supplementary antitumor therapeutic. PMID:20568104

  17. Application of differential analysis of VLF signals for seismic-ionospheric precursor detection from multiple receivers

    NASA Astrophysics Data System (ADS)

    Skeberis, Christos; Zaharis, Zaharias; Xenos, Thomas; Contadakis, Michael; Stratakis, Dimitrios; Tommaso, Maggipinto; Biagi, Pier Francesco

    2015-04-01

    This study investigates the application of differential analysis on VLF signals emitted from a single transmitter and received by multiple stations in order to filter and detect disturbances that can be attributed to seismic-ionospheric precursor phenomena. The cross-correlation analysis applied on multiple VLF signals provides a way of discerning the nature of a given disturbance and accounts for more widespread geomagnetic interferences compared to local precursor phenomena. For the purpose of this paper, data acquired in Thessaloniki (40.59N, 22,78E) and in Heraklion (35.31N, 25.10E) from the VLF station in Tavolara, Italy (ICV station Lat. 40.923, Lon. 9.731) for a period of four months (September 2014 - December 2014) are used. The receivers have been developed by Elettronika Srl and are part of the International Network for Frontier Research on Earthquake Precursors (INFREP). A normalization process and an improved variant of the Hilbert-Huang transform are initially applied to the received VLF signals. The signals derived from the first two Intrinsic Mode Functions (IMF1 and IMF2) undergo a cross-correlation analysis and, in this way, time series from the two receivers can be compared. The efficacy of the processing method and the results produced by the proposed process are then discussed. Finally, results are presented along with an evaluation of the discrimination and detection capabilities of the method on disturbances of the received signals. Based upon the results, the merits of such a processing method are discussed to further improve the current method by using differential analysis to better classify between different disturbances but, more importantly, discriminate between points of interest in the provided spectra. This could provide an improved method of detecting disturbances attributed to seismic-ionospheric precursor phenomena and also contribute to a real-time method for correlating seismic activity with the observed disturbances.

  18. Multimodal evoked potentials in multiple system and late onset cerebellar atrophies.

    PubMed

    Arpa, J; Lpez-Pajares, R; Cruz-Martnez, A; Palomo, F; Ferrer, T; Caminero, A B; Rodrguez-Albario, A; Alonso, M; Lacasa, T; Nos, J

    1995-01-01

    Forty subjects were clinically examined using scales for cerebellar, pyramidal, parkinsonian, and mental status and by quantitative evaluation of neuroimages. The patients were classified into two groups: cerebellar-plus and "pure" cerebellar syndromes. Patients with "pure" cerebellar syndrome were diagnosed as autosomal dominant cerebellar ataxia III (ADCA III) or "pure idiopathic" late-onset cerebellar ataxia (ILOCA) in this series. Patients with cerebellar-plus syndrome were diagnosed as multiple system atrophy (MSA), subclassified as either ILOCA-plus, ADCA I, ADCA II or autosomal recessive LOCA. We have used visual (VEP), brainstem auditory (BAEP) and somatosensory (SEP) evoked potentials in order to establish their diagnostic validity. Cerebellar-plus syndrome and "pure" cerebellar syndrome showed overlapping VEP, BAEP and SEP abnormalities. VEP P100 latency, however, shows a certain ability to differentiate between the two groups (p = 0.08) and appears useful in distinguishing between sporadic cerebellar-plus syndromes (MSA or ILOCA-plus) and "pure" cerebellar syndromes (p < 0.02). The incidence of prolonged N9-N13 latency was significantly higher in the latter subgroup (p < 0.04) as well. Within cerebellar-plus syndromes, VEP, BAEP and SEP abnormalities were more frequent in inherited cases (ADCA I and II, along with autosomal recessive LOCA) than in sporadic ones. The most apparent differences were a higher incidence of abnormal BAEPs at brainstem level (p < 0.002), and of both peripheral and possible central SEP impairment in hereditary cerebellar-plus syndrome than in sporadic cerebellar-plus syndrome (p < 0.03). EP investigation is useful to a certain extent in differentiating between some variants of LOCA. PMID:7576727

  19. Multisensor readout circuit using a multiple differential-input operation amplifier with pulse output

    NASA Astrophysics Data System (ADS)

    Wang, Ruey-Lue; Fu, Chien-Cheng; Yu, Chi; Wu, Wei-De; Chuang, Yan-Tse; Lin, Chen-Fu; Liao, Hsin-Hao; Tsai, Hann-Huei; Juang, Ying-Zong

    2014-01-01

    In this paper, a CMOS multisensor readout circuit is presented. A multiple differential-input operational amplifier (MDI-OPA) with three distinct positive inputs and one common negative input is designed to make one of the three inputs to act as a general differential-input OPA through a built-in multiplexer. A voltage-to-current converter and a current-controlled oscillator are integrated with the MDI-OPA so that the selected analog input voltage can be used to generate a pulse output whose frequency is linearly proportional to the selected input voltage. The linearity of the transfer characteristic is at least 99.99% for input voltages below 1.44 V. An added current-offset structure is used to modify the transfer characteristic that usually varies owing to process variation. The measured output transfer characteristics of three input channels show nearly the same sensitivity of 90 Hz/mV or so with a linearity of at least 99.99% with the assistance of the current-offset mechanism.

  20. Proresolution Lipid Mediators in Multiple Sclerosis Differential, Disease Severity-Dependent Synthesis A Clinical Pilot Trial

    PubMed Central

    Brommer, Benedikt; Wengert, Oliver; Gronert, Karsten; Schwab, Jan M.

    2013-01-01

    Background The severity and longevity of inflammation is controlled by endogenous counter-regulatory signals. Among them are long-chain polyunsaturated fatty acid (PUFA)-derived lipid mediators, which promote the resolution of inflammation, an active process for returning to tissue homeostasis. Objective To determine whether endogenous production of lipid-derived resolution agonists is regulated differentially in patients with highly active and less active multiple sclerosis (MS). Design Matched-pairs study in University hospital Neurology department. Patients Based on clinical (relapse frequency) and paraclinical (MRI lesions, contrast enhancement) criteria, 10 pairs of age- and sex-matched patients with relapsing-remitting MS were assigned either to a group with highly active or less active MS. Lipid mediators were quantified in serum and cerebrospinal fluid using LC-MS/MS-based lipidomics. Results Levels of the key arachidonic (?-6) and docosahexaenoic acid (?-6)-derived mediators prostaglandins (PG), leukotrienes, hydroxyeicosatetraenoic acids (HETE) and resolution agonists lipoxin A4 (LXA4), resolvin D1 (RvD1) and neuroprotectin D1 (NPD1) were quantified. In the patient group with highly active MS, 15-HETE and PGE2 were increased, which are products of the 15-lipoxygenase and cyclooxygenase pathways. The proresolution mediator RvD1 was significantly upregulated and NPD1 was detected in the highly active group only. LXA4 levels were not increased in patients with highly active MS. Conclusions Lipid mediator pathways are regulated differentially in the cerebrospinal fluid of MS patients, depending on disease severity. Non-exhaustive or possibly delayed resolution pathways may suggest a defective resolution program in patients with highly active MS. Longitudinal analyses are required to hetero-typify this differential resolution capacity, which may be associated with disease progression, longevity and eventual termination. PMID:23409068

  1. Potential of Multiple Dendroclimatic Proxies for the Prairies?

    NASA Astrophysics Data System (ADS)

    Vanstone, J. R.; Sauchyn, D. J.

    2009-05-01

    Concern to establish the nature and rate of climatic changes, should serve to reinforce our determination to understand similar details of the 'natural' (i.e. non-anthropogenic) variability of climate. Dendrochronology offers great potential for studying climatic and environmental variability at local and regional levels, because of the wide geographical distribution of suitable sites, high temporal resolution (annual or even seasonal), continuous and relatively long, absolutely-dated, well replicated and environmentally sensitive (i.e. accurate) characteristics of tree rings. Patterns within the annual rings of Quercus (oak) species, suggest that environmental factors influence the size and density of vessels within the ring, either by acting as a limiting factor for growth or through fine tuning of the wood structure to environmental factors. The purpose of this study is to investigate growth responses (annual, early- and late-wood widths) of Q. macrocarpa to regional climatic variability affecting the Canadian Prairies. Results indicate that annual ring widths, as well as early- and late- wood chronologies from southeastern Saskatchewan capture regional signals related to moisture and drought conditions. Correlations suggest that late-wood measurements are more strongly representative of annual ring-widths, than are early-wood widths, and can therefore be applied for investigating seasonal fluctuations in climatic data. Correlations with precipitation and PDSI values indicate that annual, early- and latewood chronologies are useful proxies for investigating large scale climatic fluctuations, and present the opportunity for further investigation of the effects of indices that represent major modes of climate variability, such as the effects of El Nio/Southern Oscillation (ENSO) and Pacific Decadal Oscillation (PDO) patterns that are thought to influence climate within the Prairie region. This study is novel in terms of sub-annual analysis of tree-rings in a region that previously lacked dendrochronological research.

  2. Differentiation between multiple liver hemangiomas and liver metastases of gastrinomas: Value of enhanced MRI

    SciTech Connect

    Berger, J.F.; Laissy, J.P.; Limot, O.; Cadiot, G.

    1996-05-01

    Hepatic metastases of neuroendocrine tumors are known to mimic hemangiomas on nonenhanced SE MR sequences. The usefulness of MR examination with gadolinium injection to identify lesions was prospectively evaluated. Nine patients with multiple liver metastases of gastrinomas were compared with six patients showing multiple liver hemangiomas. Patients underwent unenhanced T2-weighted SE, T1-weighted SE, and FLASH sequences, followed by enhanced sequential FLASH sequences and a 5 min delayed T1-weighted SE sequence. On T2-weighted SE sequence, all hemangiomas displayed the same typical morphology as a sharply defined, homogeneous, high signal intensity lesion, but this pattern was also observed for some or all of the lesions in seven of nine patients with gastrinoma metastases. Dynamic FLASH sequences were accurate for lesions larger than 2 cm, hemangiomas displaying a nodular peripheral enhancement with centripetal filling in, and metastases displaying either an initial homogeneous or a regular peripheral enhancement. Precise assessment of lesions smaller than 2 cm remained equivocal. Delayed T1-weighted SE sequence (performed at least 5 min after Gd-chelate injection) was the most accurate technique to identify metastases by showing hypo-or isointensity signal, whereas all hemangiomas were hyperintense. Postcontrast delayed T1-weighted sequence is the primary technique to differentiate equivocal cases of hemangiomas from metastases of gastrinoma. 25 refs., 3 figs., 2 tabs.

  3. Advances in T Helper 17 Cell Biology: Pathogenic Role and Potential Therapy in Multiple Sclerosis

    PubMed Central

    Volpe, Elisabetta; Battistini, Luca; Borsellino, Giovanna

    2015-01-01

    The discovery of the T helper (Th) 17 lineage, involved in the protection against fungal and extracellular bacterial infections, has profoundly revolutionized our current understanding of T cell-mediated responses in autoimmune diseases, including multiple sclerosis (MS). Indeed, recent data demonstrate the pathogenic role of Th17 cells in autoimmune disorders. In particular, studies in MS and in its animal model (EAE, experimental autoimmune encephalomyelitis) have revealed a crucial role of Th17 cells in the pathogenesis of autoimmune demyelinating diseases in both mice and humans. Over the past years, several important aspects concerning Th17 cells have been elucidated, such as the factors which promote or inhibit their differentiation and the effector cytokines which mediate their responses. The identification of the features endowing Th17 cells with high pathogenicity in MS is of particular interest, and discoveries in Th17 cell biology and function could lead to the design of new strategies aimed at modulating the immune response in MS. Here, we will discuss recent advances in this field, with particular focus on the mechanisms conferring pathogenicity in MS and their potential modulation. PMID:26770017

  4. HERV-W polymorphism in chromosome X is associated with multiple sclerosis risk and with differential expression of MSRV

    PubMed Central

    2014-01-01

    Background Multiple Sclerosis (MS) is an autoimmune demyelinating disease that occurs more frequently in women than in men. Multiple Sclerosis Associated Retrovirus (MSRV) is a member of HERV-W, a multicopy human endogenous retroviral family repeatedly implicated in MS pathogenesis. MSRV envelope protein is elevated in the serum of MS patients and induces inflammation and demyelination but, in spite of this pathogenic potential, its exact genomic origin and mechanism of generation are unknown. A possible link between the HERV-W copy on chromosome Xq22.3, that contains an almost complete open reading frame, and the gender differential prevalence in MS has been suggested. Results MSRV transcription levels were higher in MS patients than in controls (U-MannWhitney; p?=?0.004). Also, they were associated with the clinical forms (Spearman; p?=?0.0003) and with the Multiple Sclerosis Severity Score (MSSS) (Spearman; p?=?0.016). By mapping a 3kb region in Xq22.3, including the HERV-W locus, we identified three polymorphisms: rs6622139 (T/C), rs6622140 (G/A) and rs1290413 (G/A). After genotyping 3127 individuals (1669 patients and 1458 controls) from two different Spanish cohorts, we found that in women rs6622139 T/C was associated with MS susceptibility: [?2; p?=?0.004; OR (95% CI)?=?0.50 (0.31-0.81)] and severity, since CC women presented lower MSSS scores than CT (U-MannWhitney; p?=?0.039) or TT patients (U-MannWhitney; p?=?0.031). Concordantly with the susceptibility conferred in women, rs6622139*T was associated with higher MSRV expression (U-MannWhitney; p?=?0.003). Conclusions Our present work supports the hypothesis of a direct involvement of HERV-W/MSRV in MS pathogenesis, identifying a genetic marker on chromosome X that could be one of the causes underlying the gender differences in MS. PMID:24405691

  5. Neuronal differentiation potential of human adipose-derived mesenchymal stem cells.

    PubMed

    Anghileri, Elena; Marconi, Silvia; Pignatelli, Angela; Cifelli, Pierangelo; Gali, Mirco; Sbarbati, Andrea; Krampera, Mauro; Belluzzi, Ottorino; Bonetti, Bruno

    2008-10-01

    Adult mesenchymal stem cells derived from adipose tissue (A-MSC) have the capacity to differentiate in vitro into mesenchymal as well as endodermal and ectodermal cell lineages. We investigated the neuronal differentiation potential of human A-MSC with a protocol which included sphere formation and sequential culture in brain-derived neurotrophic factor (BDNF) and retinoic acid (RA). After 30 days, about 57% A-MSC showed morphological, immunocytochemical and electrophysiological evidence of initial neuronal differentiation. In fact, A-MSC displayed elongated shape with protrusion of two or three cellular processes, selectively expressed nestin and neuronal molecules (including GABA receptor and tyroxine hydroxilase) in the absence of glial phenotypic markers. Differentiated cells showed negative membrane potential (-60 mV), delayed rectifier potassium currents and TTX-sensitive sodium currents. Such changes were stable for at least 7 days after removal of differentiation medium. In view of these results and the easy availability of adipose tissue, A-MSC may be a ready source of adult MSC with neuronal differentiation potential, an useful tool to treat neurodegenerative diseases. PMID:18564036

  6. Effects of Severe Hypoxia on Bone Marrow Mesenchymal Stem Cells Differentiation Potential

    PubMed Central

    Cicione, Claudia; Muios-Lpez, Emma; Hermida-Gmez, Tamara; Fuentes-Boquete, Isaac; Daz-Prado, Silvia; Blanco, Francisco J.

    2013-01-01

    Background. The interests in mesenchymal stem cells (MSCs) and their application in cell therapy have resulted in a better understanding of the basic biology of these cells. Recently hypoxia has been indicated as crucial for complete chondrogenesis. We aimed at analyzing bone marrow MSCs (BM-MSCs) differentiation capacity under normoxic and severe hypoxic culture conditions. Methods. MSCs were characterized by flow cytometry and differentiated towards adipocytes, osteoblasts, and chondrocytes under normoxic or severe hypoxic conditions. The differentiations were confirmed comparing each treated point with a control point made of cells grown in DMEM and fetal bovine serum (FBS). Results. BM-MSCs from the donors displayed only few phenotypical differences in surface antigens expressions. Analyzing marker genes expression levels of the treated cells compared to their control point for each lineage showed a good differentiation in normoxic conditions and the absence of this differentiation capacity in severe hypoxic cultures. Conclusions. In our experimental conditions, severe hypoxia affects the in vitro differentiation potential of BM-MSCs. Adipogenic, osteogenic, and chondrogenic differentiations are absent in severe hypoxic conditions. Our work underlines that severe hypoxia slows cell differentiation by means of molecular mechanisms since a decrease in the expression of adipocyte-, osteoblast-, and chondrocyte-specific genes was observed. PMID:24082888

  7. Brain magnetic resonance imaging and multimodal evoked potentials in benign and secondary progressive multiple sclerosis.

    PubMed Central

    Filippi, M; Campi, A; Mammi, S; Martinelli, V; Locatelli, T; Scotti, G; Amadio, S; Canal, N; Comi, G

    1995-01-01

    Brain MRI and multimodal evoked potentials (EPs) were obtained for 13 patients with benign multiple sclerosis and 13 patients with secondary progressive multiple sclerosis, matched for age and duration of the disease, to investigate the nature of the disability in multiple sclerosis. Patients with secondary progressive multiple sclerosis had significantly greater lesion loads for five of seven periventricular regions and for three of nine regions separate from the ventricles. Patients with secondary progressive multiple sclerosis also had more severe infratentorial atrophy scores (p = 0.04), whereas there were no differences between the two groups in number and extent of enhancing lesions. The frequencies were significantly higher and severities greater for multimodal EP abnormalities of all the modalities in patients with secondary progressive multiple sclerosis. At least one EP component was absent in 12 (92%) patients with secondary progressive multiple sclerosis but in only one patient (8%) with benign multiple sclerosis (p < 0.001). There was neurophysiological evidence for cervical cord involvement in eight (61%) patients with secondary progressive multiple sclerosis and in one with benign multiple sclerosis (p < 0.01). These data indicate that the total amount of lesions, the distribution, and the nature of the pathological process might all account for the development of disability in multiple sclerosis. PMID:7823064

  8. Voxel based comparison of glucose metabolism in the differential diagnosis of the multiple system atrophy

    NASA Astrophysics Data System (ADS)

    Juh, Rahyeong; Suh, Taesuk; Chung, Yongan; Yang, Dongwon

    2005-04-01

    Multiple system atrophy (MSA) including striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA) is a group of heterogeneous degenerative neurological disorders, which differ from the idiopathic Parkinson"s disease (IPD) in certain clinical features. The differential diagnosis between IPD and MSA is difficult because of the common of signs and symptoms common. The purpose of this study was comparison of cerebral glucose metabolic differences of SND, OPCA and IPD. The 18F-FDG PET images of SND, OPCA and IPD patients were assessed by statistical pattern analysis using statistical parametric mapping (SPM) and image registration in order to determine the useful metabolic patterns. A total of 11 patients with MSA (5 SND: mean age 61.6+/-8.3 y, M/F 1/4; 6 OPCA: mean age 55.3+/-8.4 y, M/F 3/3), 8 patients (mean age 67.9 10.7y; M/F: 3/5) with IPD were enrolled in this study. All subjects and 22 age matched normal controls underwent 18F-FDG PET. Each of the SND, OPCA and IPD patients were individually compared with the normal control group using a two-sided t-test for SPM (P<0.05). The OPCA group showed significant hypometabolism in the cerebellum and pons compared to the control group, whereas in the patients with SND showed significant hypometabolism in the putamen. SPM also revealed pons, putamen hypometabolism in OPCA and SND patients compared with IPD patients. An assessment of the 18F-FDG PET images using the image registration and statistical analysis might be a useful adjunct to a clinical examination when making a differential diagnosis of Parkinsonism.

  9. DIFFERENTIAL EMISSION MEASURE ANALYSIS OF MULTIPLE STRUCTURAL COMPONENTS OF CORONAL MASS EJECTIONS IN THE INNER CORONA

    SciTech Connect

    Cheng, X.; Ding, M. D.; Zhang, J.; Saar, S. H. E-mail: jzhang7@gmu.edu

    2012-12-10

    In this paper, we study the temperature and density properties of multiple structural components of coronal mass ejections (CMEs) using differential emission measure (DEM) analysis. The DEM analysis is based on the six-passband EUV observations of solar corona from the Atmospheric Imaging Assembly on board the Solar Dynamic Observatory. The structural components studied include the hot channel in the core region (presumably the magnetic flux rope of the CME), the bright loop-like leading front (LF), and coronal dimming in the wake of the CME. We find that the presumed flux rope has the highest average temperature (>8 MK) and density ({approx}1.0 Multiplication-Sign 10{sup 9} cm{sup -3}), resulting in an enhanced emission measure over a broad temperature range (3 {<=} T(MK) {<=} 20). On the other hand, the CME LF has a relatively cool temperature ({approx}2 MK) and a narrow temperature distribution similar to the pre-eruption coronal temperature (1 {<=} T(MK) {<=} 3). The density in the LF, however, is increased by 2%-32% compared with that of the pre-eruption corona, depending on the event and location. In coronal dimmings, the temperature is more broadly distributed (1 {<=} T(MK) {<=} 4), but the density decreases by {approx}35%-{approx}40%. These observational results show that: (1) CME core regions are significantly heated, presumably through magnetic reconnection; (2) CME LFs are a consequence of compression of ambient plasma caused by the expansion of the CME core region; and (3) the dimmings are largely caused by the plasma rarefaction associated with the eruption.

  10. Global map of physical interactions among differentially expressed genes in multiple sclerosis relapses and remissions.

    PubMed

    Tuller, Tamir; Atar, Shimshi; Ruppin, Eytan; Gurevich, Michael; Achiron, Anat

    2011-09-15

    Multiple sclerosis (MS) is a central nervous system autoimmune inflammatory T-cell-mediated disease with a relapsing-remitting course in the majority of patients. In this study, we performed a high-resolution systems biology analysis of gene expression and physical interactions in MS relapse and remission. To this end, we integrated 164 large-scale measurements of gene expression in peripheral blood mononuclear cells of MS patients in relapse or remission and healthy subjects, with large-scale information about the physical interactions between these genes obtained from public databases. These data were analyzed with a variety of computational methods. We find that there is a clear and significant global network-level signal that is related to the changes in gene expression of MS patients in comparison to healthy subjects. However, despite the clear differences in the clinical symptoms of MS patients in relapse versus remission, the network level signal is weaker when comparing patients in these two stages of the disease. This result suggests that most of the genes have relatively similar expression levels in the two stages of the disease. In accordance with previous studies, we found that the pathways related to regulation of cell death, chemotaxis and inflammatory response are differentially expressed in the disease in comparison to healthy subjects, while pathways related to cell adhesion, cell migration and cell-cell signaling are activated in relapse in comparison to remission. However, the current study includes a detailed report of the exact set of genes involved in these pathways and the interactions between them. For example, we found that the genes TP53 and IL1 are 'network-hub' that interacts with many of the differentially expressed genes in MS patients versus healthy subjects, and the epidermal growth factor receptor is a 'network-hub' in the case of MS patients with relapse versus remission. The statistical approaches employed in this study enabled us to report new sets of genes that according to their gene expression and physical interactions are predicted to be differentially expressed in MS versus healthy subjects, and in MS patients in relapse versus remission. Some of these genes may be useful biomarkers for diagnosing MS and predicting relapses in MS patients. PMID:21676896

  11. Transcriptome analysis of differentiating trypanosomes reveals the existence of multiple post-transcriptional regulons

    PubMed Central

    Queiroz, Rafael; Benz, Corinna; Fellenberg, Kurt; Hoheisel, Jrg D; Clayton, Christine

    2009-01-01

    Background Trypanosome gene expression is regulated almost exclusively at the post-transcriptional level, with mRNA degradation playing a decisive role. When trypanosomes are transferred from the blood of a mammal to the midgut of a Tsetse fly, they transform to procyclic forms: gene expression is reprogrammed, changing the cell surface and switching the mode of energy metabolism. Within the blood, trypanosomes can pre-adapt for Tsetse transmission, becoming growth-arrested stumpy forms. We describe here the transitions in gene expression that occur during differentiation of in-vitro cultured bloodstream forms to procyclic forms. Results Some mRNAs showed changes within 30 min of cis-aconitate addition, whereas others responded 12-24 hours later. For the first 12 h after addition of cis-aconitate, cells accumulated at the G1 phase of the cell cycle, and showed decreases in mRNAs required for proliferation, mimicking the changes seen in stumpy forms: many mRNAs needed for ribosomal and flagellar biogenesis showed striking co-regulation. Other mRNAs encoding components of signal transduction pathways and potential regulators were specifically induced only during differentiation. Messenger RNAs encoding proteins required for individual metabolic pathways were often co-regulated. Conclusion Trypanosome genes form post-transcriptional regulons in which mRNAs with functions in particular pathways, or encoding components of protein complexes, show almost identical patterns of regulation. PMID:19857263

  12. Rocaglamide-A Potentiates Osteoblast Differentiation by Inhibiting NF-κB Signaling

    PubMed Central

    Li, Aiguo; Yang, Libin; Geng, Xiaolin; Peng, Xingmei; Lu, Tan; Deng, Yanjun; Dong, Yuzheng

    2015-01-01

    Rheumatoid arthritis is a chronic inflammatory disease that leads to bone and cartilage erosion. The inhibition of osteoblast differentiation by the inflammatory factor TNF-α is critical for the pathogenesis of rheumatoid arthritis. To modulate TNF-α mediated inhibition of osteoblast differentiation is required to improve therapeutic efficacy of rheumatoid arthritis. Here, we explored the potential role of rocaglamide-A, a component of Aglaia plant, in osteoblast differentiation. Rocaglamide-A prevented TNF-α mediated inhibition of osteoblast differentiation, and promoted osteoblast differentiation directly, in both C2C12 and primary mesenchymal stromal cells. Mechanistically, Rocaglamide-A inhibited the phosphorylation of NF-κB component p65 protein and the accumulation of p65 in nucleus, which resulted in the diminished NF-κB responsible transcriptional activity. Oppositely, overexpression of p65 reversed rocaglamide-A’s protective effects on osteoblast differentiation. Collectively, rocaglamide-A protected and stimulated osteoblast differentiation via blocking NF-κB pathway. It suggests that rocaglamide-A may be a good candidate to develop as therapeutic drug for rheumatoid arthritis associated bone loss diseases. PMID:26549505

  13. Gliotoxin potentiates osteoblast differentiation by inhibiting nuclear factor-?B signaling.

    PubMed

    Wang, Guangye; Zhang, Xiaohai; Yu, Baoqing; Ren, Ke

    2015-07-01

    The differentiation of pluripotent mesenchymal stem cells to mature osteoblasts is crucial for the maintenance of the adult skeleton. In rheumatic arthritis, osteoblast differentiation is impaired by the overproduction of cytokine tumor necrosis factor (TNF)??. It has been demonstrated that TNF-? is able to inhibit osteoblast differentiation through the activation of nuclear factor (NF)-?B signaling. As a result of the critical role of TNF-? and NF-?B in the pathogenesis of bone-loss associated diseases, these factors are regarded as key targets for the development of therapeutic agents. In the current study, the role of the NF-?B inhibitor gliotoxin (GTX) in the regulation of osteoblast differentiation was evaluated. The non-toxic GTX doses were determined to be ? 3 g/ml. It was revealed that GTX was able to block TNF-?-induced inhibition of osteoblast differentiation, as indicated by alkaline phosphatase (ALP) activity and ALP staining assays, as well as the expression levels of osteoblast-associated genes Col I, Ocn, Bsp, Runx2, Osx and ATF4. Additionally, it was identified that gliotoxin directly promoted bone morphogenetic protein-2-induced osteoblast differentiation. GTX was found to inhibit the accumulation of NF-?B protein p65 in the nucleus and reduce NF-?B transcriptional activity, suggesting that GTX potentiated osteoblast differentiation via the suppression of NF-?B signaling. PMID:25816130

  14. Characterization of the effects and potential mechanisms leading to increased megakaryocytic differentiation under mild hyperthermia.

    PubMed

    Pineault, Nicolas; Boucher, Jean-Franois; Cayer, Marie-Pierre; Palmqvist, Lars; Boyer, Lucie; Lemieux, Ral; Proulx, Chantal

    2008-06-01

    The physical culture parameters have important influences on the proliferation and differentiation fate of hematopoietic stem cells. Recently, we have demonstrated that CD34+ cord blood (CB) cells undergo accelerated and increased megakaryocyte (Mk) differentiation when incubated under mild hyperthermic conditions (i.e., 39 degrees C). In this study, we investigated in detail the impacts of mild hyperthermia on Mk differentiation and maturation, and explored potential mechanisms responsible for these phenomena. Our results demonstrate that the qualitative and quantitative effects on Mk differentiation at 39 degrees C appear rapidly within 7 days, and that early transient culture at 39 degrees C led to even greater Mk yields (p<0.03). Surprisingly, cell viability was only found to be significantly reduced in the early stages of culture, suggesting that CB cells are able with time to acclimatize themselves to 39 degrees C. Although mild hyperthermia accelerated differentiation and maturation of CB-derived Mks, it failed to promote their polyploidization further but rather led to a small reduction in the proportion of polyploid Mks (p=0.01). Conversely, gene arrays analysis demonstrated that Mks derived at 39 degrees C have a normal gene expression program consistent with an advanced maturation state. Finally, two independent mechanisms that could account for the accelerated Mk differentiation were investigated. Our results suggest that the accelerated and increased Mk differentiation induced by mild hyperthermia is not mediated by cell-secreted factors but could perhaps be mediated by the increased expression of Mk transcription factors. PMID:18522497

  15. The G alpha i homologue gna-1 controls multiple differentiation pathways in Neurospora crassa.

    PubMed Central

    Ivey, F D; Hodge, P N; Turner, G E; Borkovich, K A

    1996-01-01

    Heterotrimeric G proteins are components of principal signaling pathways in eukaryotes. In higher organisms, alpha subunits of G proteins have been divided into four families, Gi, Gs, Gq, and G12. We previously identified a G alpha i homologue gna-1 in the filamentous fungus Neurospora crassa. Now we report that deletion of gna-1 leads to multiple phenotypes during the vegetative and sexual cycles in N. crassa. On solid medium, delta gna-1 strains have a slower rate of hyphal apical extension than wild type, a rate that is more pronounced under hyperosmotic conditions or in the presence of a cellophane overlay. delta gna-1 mutants accumulate less mass than wild-type strains, and their mass accumulation is not affected in the same way by exposure to light. delta gna-1 strains are defective in macroconidiation, possessing aerial hyphae that are shorter, contain abnormal swellings, and differentiate adherent macroconidia. During the sexual cycle, delta gna-1 strains are fertile as males. However, the mutants are female-sterile, producing small, aberrant female reproductive structures. After fertilization, delta gna-1 female structures do not enlarge and develop normally, and no sexual spores are produced. Thus, mutation of gna-1 results in sex-specific loss of fertility. Images PMID:8856670

  16. Investigating osteogenic differentiation in multiple myeloma using a novel 3D bone marrow niche model

    PubMed Central

    Reagan, Michaela R.; Mishima, Yuji; Glavey, Siobhan V.; Zhang, Yong; Manier, Salomon; Lu, Zhi Ning; Memarzadeh, Masoumeh; Zhang, Yu; Sacco, Antonio; Aljawai, Yosra; Shi, Jiantao; Tai, Yu-Tzu; Ready, John E.; Kaplan, David L.; Roccaro, Aldo M.

    2014-01-01

    Clonal proliferation of plasma cells within the bone marrow (BM) affects local cells, such as mesenchymal stromal cells (MSCs), leading to osteolysis and fatality in multiple myeloma (MM). Consequently, there is an urgent need to find better mechanisms of inhibiting myeloma growth and osteolytic lesion development. To meet this need and accelerate clinical translation, better models of myeloma within the BM are required. Herein we have developed a clinically relevant, three-dimensional (3D) myeloma BM coculture model that mimics bone cell/cancer cell interactions within the bone microenvironment. The coculture model and clinical samples were used to investigate myeloma growth, osteogenesis inhibition, and myeloma-induced abnormalities in MM-MSCs. This platform demonstrated myeloma support of capillarylike assembly of endothelial cells and cell adhesionmediated drug resistance (CAM-DR). Also, distinct normal donor (ND)- and MM-MSC miRNA (miR) signatures were identified and used to uncover osteogenic miRs of interest for osteoblast differentiation. More broadly, our 3D platform provides a simple, clinically relevant tool to model cancer growth within the boneuseful for investigating skeletal cancer biology, screening compounds, and exploring osteogenesis. Our identification and efficacy validation of novel bone anabolic miRs in MM opens more opportunities for novel approaches to cancer therapy via stromal miR modulation. PMID:25205118

  17. CD24: from a Hematopoietic Differentiation Antigen to a Genetic Risk Factor for Multiple Autoimmune Diseases.

    PubMed

    Tan, Yixin; Zhao, Ming; Xiang, Bo; Chang, Christopher; Lu, Qianjin

    2016-02-01

    The autoantibody is an essential characteristic of inflammatory disorders, including autoimmune diseases. Although the exact pathogenic mechanisms of these diseases remain elusive, accumulated evidence has implicated that genetic factors play important roles in autoimmune inflammation. Among these factors, CD24 was first identified as a heat-stable antigen in 1978 and first successfully cloned in 1990. Thereafter, its functional roles have been intensively investigated in various human diseases, especially autoimmune diseases and cancers. It is currently known that CD24 serves as a costimulatory factor of T cells that regulate their homeostasis and proliferation, while in B cells, CD24 is functionally involved in cell activation and differentiation. CD24 can enhance autoimmune diseases in terms of its protective role in the clonal deletion of autoreactive thymocytes. Furthermore, CD24 deficiency has been linked to mouse experimental autoimmune encephalomyelitis. Finally, CD24 genetic variants, including single-nucleotide polymorphisms and deletions, are etiologically relevant to autoimmune diseases, such as multiple sclerosis and systemic lupus erythematosus. Therefore, CD24 is a promising biomarker and novel therapeutic target for autoimmune diseases. PMID:25666875

  18. Differential multiple-quantum relaxation arising from cross-correlated time-modulation of isotropic chemical shifts.

    PubMed

    Kloiber, K; Konrat, R

    2000-09-01

    In this paper it is demonstrated that cross-correlated time modulation of isotropic chemical shifts ('conformational exchange') leads to differential relaxation of double- and zero-quantum coherences, respectively. Quantitative information can be obtained from the time dependence of the interconversion between the two two-spin coherences 2IxSx and 2IySy, induced by the differential relaxation. The effect is illustrated with an application to 13C,15N-labeled quail CRP2(LIM2), by studying 15N-1H(N) multiple-quantum relaxation. Significant cross-correlated fluctuations of isotropic chemical shifts were observed for residues which are part of a disordered loop region connecting two beta-strands in CRP2(LIM2). Differential 1H(N) and 15N exchange contributions to multiple-quantum relaxation observed at these sites illustrate the complex interplay between hydrogen bonding events and conformational reorientations in proteins. PMID:11061226

  19. The Housekeeping Gene Hypoxanthine Guanine Phosphoribosyltransferase (HPRT) Regulates Multiple Developmental and Metabolic Pathways of Murine Embryonic Stem Cell Neuronal Differentiation

    PubMed Central

    Bader, Joel S.; Friedmann, Theodore

    2013-01-01

    The mechanisms by which mutations of the purinergic housekeeping gene hypoxanthine guanine phosphoribosyltransferase (HPRT) cause the severe neurodevelopmental Lesch Nyhan Disease (LND) are poorly understood. The best recognized neural consequences of HPRT deficiency are defective basal ganglia expression of the neurotransmitter dopamine (DA) and aberrant DA neuronal function. We have reported that HPRT deficiency leads to dysregulated expression of multiple DA-related developmental functions and cellular signaling defects in a variety of HPRT-deficient cells, including human induced pluripotent stem (iPS) cells. We now describe results of gene expression studies during neuronal differentiation of HPRT-deficient murine ESD3 embryonic stem cells and report that HPRT knockdown causes a marked switch from neuronal to glial gene expression and dysregulates expression of Sox2 and its regulator, genes vital for stem cell pluripotency and for the neuronal/glial cell fate decision. In addition, HPRT deficiency dysregulates many cellular functions controlling cell cycle and proliferation mechanisms, RNA metabolism, DNA replication and repair, replication stress, lysosome function, membrane trafficking, signaling pathway for platelet activation (SPPA) multiple neurotransmission systems and sphingolipid, sulfur and glycan metabolism. We propose that the neural aberrations of HPRT deficiency result from combinatorial effects of these multi-system metabolic errors. Since some of these aberrations are also found in forms of Alzheimer's and Huntington's disease, we predict that some of these systems defects play similar neuropathogenic roles in diverse neurodevelopmental and neurodegenerative diseases in common and may therefore provide new experimental opportunities for clarifying pathogenesis and for devising new potential therapeutic targets in developmental and genetic disease. PMID:24130677

  20. The housekeeping gene hypoxanthine guanine phosphoribosyltransferase (HPRT) regulates multiple developmental and metabolic pathways of murine embryonic stem cell neuronal differentiation.

    PubMed

    Kang, Tae Hyuk; Park, Yongjin; Bader, Joel S; Friedmann, Theodore

    2013-01-01

    The mechanisms by which mutations of the purinergic housekeeping gene hypoxanthine guanine phosphoribosyltransferase (HPRT) cause the severe neurodevelopmental Lesch Nyhan Disease (LND) are poorly understood. The best recognized neural consequences of HPRT deficiency are defective basal ganglia expression of the neurotransmitter dopamine (DA) and aberrant DA neuronal function. We have reported that HPRT deficiency leads to dysregulated expression of multiple DA-related developmental functions and cellular signaling defects in a variety of HPRT-deficient cells, including human induced pluripotent stem (iPS) cells. We now describe results of gene expression studies during neuronal differentiation of HPRT-deficient murine ESD3 embryonic stem cells and report that HPRT knockdown causes a marked switch from neuronal to glial gene expression and dysregulates expression of Sox2 and its regulator, genes vital for stem cell pluripotency and for the neuronal/glial cell fate decision. In addition, HPRT deficiency dysregulates many cellular functions controlling cell cycle and proliferation mechanisms, RNA metabolism, DNA replication and repair, replication stress, lysosome function, membrane trafficking, signaling pathway for platelet activation (SPPA) multiple neurotransmission systems and sphingolipid, sulfur and glycan metabolism. We propose that the neural aberrations of HPRT deficiency result from combinatorial effects of these multi-system metabolic errors. Since some of these aberrations are also found in forms of Alzheimer's and Huntington's disease, we predict that some of these systems defects play similar neuropathogenic roles in diverse neurodevelopmental and neurodegenerative diseases in common and may therefore provide new experimental opportunities for clarifying pathogenesis and for devising new potential therapeutic targets in developmental and genetic disease. PMID:24130677

  1. Withania somnifera Water Extract as a Potential Candidate for Differentiation Based Therapy of Human Neuroblastomas

    PubMed Central

    Kataria, Hardeep; Wadhwa, Renu; Kaul, Sunil C.; Kaur, Gurcharan

    2013-01-01

    Neuroblastoma is an aggressive childhood disease of the sympathetic nervous system. Treatments are often ineffective and have serious side effects. Conventional therapy of neuroblastoma includes the differentiation agents. Unlike chemo-radiotherapy, differentiation therapy shows minimal side effects on normal cells, because normal non-malignant cells are already differentiated. Keeping in view the limited toxicity of Withania somnifera (Ashwagandha), the current study was aimed to investigate the efficacy of Ashwagandha water extract (ASH-WEX) for anti-proliferative potential in neuroblastoma and its underlying signalling mechanisms. ASH-WEX significantly reduced cell proliferation and induced cell differentiation as indicated by morphological changes and NF200 expression in human IMR-32 neuroblastoma cells. The induction of differentiation was accompanied by HSP70 and mortalin induction as well as pancytoplasmic translocation of the mortalin in ASH-WEX treated cells. Furthermore, the ASH-WEX treatment lead to induction of neural cell adhesion molecule (NCAM) expression and reduction in its polysialylation, thus elucidating its anti-migratory potential, which was also supported by downregulation of MMP 2 and 9 activity. ASH-WEX treatment led to cell cycle arrest at G0/G1 phase and increase in early apoptotic population. Modulation of cell cycle marker Cyclin D1, anti-apoptotic marker bcl-xl and Akt-P provide evidence that ASH-WEX may prove to be a promising phytotherapeutic intervention in neuroblatoma related malignancies. PMID:23383150

  2. An Efficient Protocol for Deriving Liver Stem Cells from Neonatal Mice: Validating Its Differentiation Potential

    PubMed Central

    Dhanasekaran, Sugapriya; Sithambaram, Devilakshmi; Govarthanan, Kavitha; Biswal, Bijesh Kumar; Verma, Rama S.

    2015-01-01

    The success of liver regeneration depends on the availability of suitable cell types and their potential to differentiate into functional hepatocytes. To identify the stem cells which have the ability to differentiate into hepatocytes, we used neonatal liver as source. However, the current protocol for isolating stem cells from liver involves enzymes like collagenase, hyaluronidase exposed for longer duration which limits the success. This results in the keen interest to develop an easy single step enzyme digestion protocol for isolating stem cells from liver for tissue engineering approaches. Thus, the unlimited availability of cell type favors setting up the functional recovery of the damaged liver, ensuring ahead success towards treating liver diseases. We attempted to isolate liver stem derived cells (LDSCs) from mouse neonatal liver using single step minimal exposure to enzyme followed by in vitro culturing. The cells isolated were characterized for stem cell markers and subjected to lineage differentiation. Further, LDSCs were induced to hepatocyte differentiation and validated with hepatocyte markers. Finally, we developed a reproducible, efficient protocol for isolation of LDSCs with functional hepatocytes differentiation potential, which further can be used as in vitro model system for assessing drug toxicity assays in various preclinical trials. PMID:26557474

  3. UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells

    PubMed Central

    Zhang, Jin; Khvorostov, Ivan; Hong, Jason S; Oktay, Yavuz; Vergnes, Laurent; Nuebel, Esther; Wahjudi, Paulin N; Setoguchi, Kiyoko; Wang, Geng; Do, Anna; Jung, Hea-Jin; McCaffery, J Michael; Kurland, Irwin J; Reue, Karen; Lee, Wai-Nang P; Koehler, Carla M; Teitell, Michael A

    2011-01-01

    It has been assumed, based largely on morphologic evidence, that human pluripotent stem cells (hPSCs) contain underdeveloped, bioenergetically inactive mitochondria. In contrast, differentiated cells harbour a branched mitochondrial network with oxidative phosphorylation as the main energy source. A role for mitochondria in hPSC bioenergetics and in cell differentiation therefore remains uncertain. Here, we show that hPSCs have functional respiratory complexes that are able to consume O2 at maximal capacity. Despite this, ATP generation in hPSCs is mainly by glycolysis and ATP is consumed by the F1F0 ATP synthase to partially maintain hPSC mitochondrial membrane potential and cell viability. Uncoupling protein 2 (UCP2) plays a regulating role in hPSC energy metabolism by preventing mitochondrial glucose oxidation and facilitating glycolysis via a substrate shunting mechanism. With early differentiation, hPSC proliferation slows, energy metabolism decreases, and UCP2 is repressed, resulting in decreased glycolysis and maintained or increased mitochondrial glucose oxidation. Ectopic UCP2 expression perturbs this metabolic transition and impairs hPSC differentiation. Overall, hPSCs contain active mitochondria and require UCP2 repression for full differentiation potential. PMID:22085932

  4. Compression of the multiple ion-acoustic soliton at the bottom of the space potential

    SciTech Connect

    Nagasawa, T.; Nishida, Y.

    1997-10-01

    Detailed experimental investigations on compressive phenomena are performed using a double-plasma-type device. When the incident multiple ion-acoustic soliton propagates to the ion-sheath edge, which is produced by the biased reflector to deep negative potential, this multiple soliton is compressed by the accelerated velocities of the second and third pulses and becomes a single soliton at the reflection point. It then resumes the form of a multiple soliton, as if via a recurrence phenomenon, and each pulse of this multiple soliton propagates toward the reflector. These phenomena are caused by an uneven space potential, which in turn is produced by deep negative voltage on the reflector and ion wakefield. Also, the reflection soliton is produced at this reflection point. {copyright} {ital 1997} {ital The American Physical Society}

  5. Gene Expression Profiling Reveals New Potential Players of Gonad Differentiation in the Chicken Embryo

    PubMed Central

    Carr, Gwenn-Al; Couty, Isabelle; Hennequet-Antier, Christelle; Govoroun, Marina S.

    2011-01-01

    Background In birds as in mammals, a genetic switch determines whether the undifferentiated gonad develops into an ovary or a testis. However, understanding of the molecular pathway(s) involved in gonad differentiation is still incomplete. Methodology/Principal Findings With the aim of improving characterization of the molecular pathway(s) involved in gonad differentiation in the chicken embryo, we developed a large scale real time reverse transcription polymerase chain reaction approach on 110 selected genes for evaluation of their expression profiles during chicken gonad differentiation between days 5.5 and 19 of incubation. Hierarchical clustering analysis of the resulting datasets discriminated gene clusters expressed preferentially in the ovary or the testis, and/or at early or later periods of embryonic gonad development. Fitting a linear model and testing the comparisons of interest allowed the identification of new potential actors of gonad differentiation, such as Z-linked ADAMTS12, LOC427192 (corresponding to NIM1 protein) and CFC1, that are upregulated in the developing testis, and BMP3 and Z-linked ADAMTSL1, that are preferentially expressed in the developing ovary. Interestingly, the expression patterns of several members of the transforming growth factor ? family were sexually dimorphic, with inhibin subunits upregulated in the testis, and bone morphogenetic protein subfamily members including BMP2, BMP3, BMP4 and BMP7, upregulated in the ovary. This study also highlighted several genes displaying asymmetric expression profiles such as GREM1 and BMP3 that are potentially involved in different aspects of gonad left-right asymmetry. Conclusion/Significance This study supports the overall conservation of vertebrate sex differentiation pathways but also reveals some particular feature of gene expression patterns during gonad development in the chicken. In particular, our study revealed new candidate genes which may be potential actors of chicken gonad differentiation and provides evidence of the preferential expression of BMPs in the developing ovary and Inhibin/Activin subunits in the developing testis. PMID:21931629

  6. The Therapeutic Potential of the Ketogenic Diet in Treating Progressive Multiple Sclerosis

    PubMed Central

    Storoni, Mithu; Plant, Gordon T.

    2015-01-01

    Until recently, multiple sclerosis has been viewed as an entirely inflammatory disease without acknowledgment of the significant neurodegenerative component responsible for disease progression and disability. This perspective is being challenged by observations of a dissociation between inflammation and neurodegeneration where the neurodegenerative component may play a more significant role in disease progression. In this review, we explore the relationship between mitochondrial dysfunction and neurodegeneration in multiple sclerosis. We review evidence that the ketogenic diet can improve mitochondrial function and discuss the potential of the ketogenic diet in treating progressive multiple sclerosis for which no treatment currently exists. PMID:26839705

  7. Depletion of MEIS2 inhibits osteogenic differentiation potential of human dental stem cells

    PubMed Central

    Wu, Zhifang; Wang, Jinsong; Dong, Rui; Wang, Liping; Fan, Zhipeng; Liu, Dayong; Wang, Songlin

    2015-01-01

    Dental mesenchymal stem cells (MSCs) are a reliable and promising cell source for the regeneration of tooth,bone and other tissues . However, the molecular mechanisms underlying their differentiation are still largely unknown, which restricts their further wide application. Here, we investigate regulatory function of homeobox gene MEIS2 in the osteogenic differentiation potential of MSCs using stem cells from apical papilla (SCAPs) and dental pulp stem cells (DPSCs) by loss-of-function experiments. Our findings demonstrated that knockdown of MEIS2 in SCAPs and DPSCs decreased alkaline phosphatase (ALP) activity and mineralization, and inhibited the mRNA expression of ALP, bone sialoprotein (BSP), and osteocalcin (OCN). Besides, depletion of MEIS2 resulted in reduced expression of the key osteogenesis-related transcription factor, osterix (OSX) but not in the expression of runt-related transcription factor 2 (RUNX2). Furthermore, MEIS2 expression significantly increased during osteogenic induction and was strongly upregulated by BMP4 stimulation. Taken together, these results indicated that MEIS2 played an essential role in maintaining osteogenic differentiation potential of dental tissue- derived MSCs. These findings will provide new insights into the mechanisms underlying directed differentiation of MSCs, and identify a potential target gene in dental tissues derived MSCs for promoting the tissue regeneration. PMID:26221261

  8. Differential cross sections for p?+H and d?+D scattering using the Morse potential

    NASA Astrophysics Data System (ADS)

    Gronowski, Jakub; Adamczak, Andrzej

    2010-06-01

    Quantum-mechanical calculations of the differential cross sections for p?+H and d?+D scattering have been performed using the Morse potential for the interaction of nuclei in the hydrogenic molecules. The rotational-vibrational transitions and dissociation of these molecules are taken into account. The spin-flip processes of the muonic atoms are also considered. The differential cross sections, calculated for centre-of-mass collision energies ??30 eV, are needed for a correct description of many experiments in low-energy muon physics.

  9. Determination of the Na-Xe interaction potential from differential scattering cross-section measurements

    NASA Astrophysics Data System (ADS)

    van Deventer, J. M. M.; van der Valk, F.

    1982-04-01

    High-resolution differential cross sections for the scattering of Na from Xe atoms have been measured. They were used to check the parameters of potential models previously proposed for the interaction of these particles. Special attention was given to the question of whether the use of different potential models leads to significant differences in the main potential parameters ε and rm. It is concluded that the use of well-chosen models for the Na-Xe interaction gives a uncertainty of no more than about 1% in the values of ε and rm.

  10. Differentiation of ocular fundus fluorophores by fluorescence lifetime imaging using multiple excitation and emission wavelengths

    NASA Astrophysics Data System (ADS)

    Hammer, M.; Schweitzer, D.; Schenke, S.; Becker, W.; Bergmann, A.

    2006-10-01

    Ocular fundus autofluorescence imaging has been introduced into clinical diagnostics recently. It is in use for the observation of the age pigment lipofuscin, a precursor of age - related macular degeneration (AMD). But other fluorophores may be of interest too: The redox pair FAD - FADH II provides information on the retinal energy metabolism, advanced glycation end products (AGE) indicate protein glycation associated with pathologic processes in diabetes as well as AMD, and alterations in the fluorescence of collagen and elastin in connective tissue give us the opportunity to observe fibrosis by fluorescence imaging. This, however, needs techniques able to differentiate particular fluorophores despite limited permissible ocular exposure as well as excitation wavelength (limited by the transmission of the human ocular lens to >400 nm). We present an ophthalmic laser scanning system (SLO), equipped with picosecond laser diodes (FWHM 100 ps, 446 nm or 468 nm respectively) and time correlated single photon counting (TCSPC) in two emission bands (500 - 560 nm and 560 - 700 nm). The decays were fitted by a bi-exponential model. Fluorescence spectra were measured by a fluorescence spectrometer fluorolog. Upon excitation at 446 nm, the fluorescence of AGE, FAD, and lipofuscin were found to peak at 503 nm, 525 nm, and 600 nm respectively. Accordingly, the statistical distribution of the fluorescence decay times was found to depend on the different excitation wavelengths and emission bands used. The use of multiple excitation and emission wavelengths in conjunction with fluorescence lifetime imaging allows us to discriminate between intrinsic fluorophores of the ocular fundus. Taken together with our knowledge on the anatomical structure of the fundus, these findings suggest an association of the short, middle and long fluorescence decay time to the retinal pigment epithelium, the retina, and connective tissue respectively.

  11. Profile of Differential Promoter Activity by Nucleotide Substitution at GWAS Signals For Multiple Sclerosis

    PubMed Central

    Ryu, Jihye; Woo, Jeyoung; Shin, Jimin; Ryoo, Hyunju; Kim, Younyoung; Lee, Chaeyoung

    2014-01-01

    Abstract This experimental study was conducted with completely randomized design. Genome-wide association studies (GWAS) have revealed a large number of genetic associations of nucleotide sequence variants with susceptibility to multiple sclerosis (MS). Nevertheless, studies to identify the functional relevance of these variants lag far behind identification of the GWAS signals. Expression quantitative trait loci (eQTLs) analysis and promoter activity analysis with the variants filtered by GWAS were conducted to identify their functional alleles and haplotypes. The promoter activity was assayed with reporter constructs containing variants at 8 MS GWAS signals resulted from 18 GWAS. The promoter activity differed by alternative sequence variants at upstream regions of the CYP24A1, CYP27B1, SYK, RAD21L1, PVR, ODF3B, and RGS14 genes (P < 0.05). The transcriptional regulations of sequence variants were also found by identifications of eQTLs for their corresponding genes with lymphoblastoid cells in the current study (SYK, ODF3B, RGS14, and PVR, P < 8.33 × 10−3) and with dendritic cells in a previous study (CYP27B1, P = 1.84 × 10−6). This study identified regulatory nucleotide sequences in the promoters of the CYP24A1, CYP27B1, SYK, RAD21L1, PVR, ODF3B, and RGS14 genes, and their variants differentially affected gene expression. This might result in their associations with MS susceptibility in previous GWAS. Further functional studies are required to understand the process of transcriptional regulation of the variants identified in the current study and the mechanisms underlying susceptibility to MS. PMID:25526461

  12. A cost-effective differential mobility analyzer (cDMA) for multiple DMA column applications

    SciTech Connect

    Mei, F.; Fu, H.; Chen, D.-R.

    2011-05-04

    In aerosol research and applications, a differential mobility analyzer (DMA) is now considered the standard tool for sizing and classifying monodisperse particles in the sub-micrometer and nanometer size ranges. However, DMA application at the pilot or industrial production scale remains infeasible because of the low mass throughput. A simple way to scale up DMA operation is to use multiple DMA columns. The manufacture and maintenance costs of existing DMAs, however, limit such a scale-up. A cost-effective DMA column (named cDMA) has thus been developed in this work to address the above issue. To reduce its manufacturing cost, the prototype was constructed using parts requiring little machining. The cDMA column was also designed for easy maintenance and easy variation of the classification length for any application-specified size range. In this study, prototypes with two particle classification lengths, 1.75 and 4.50 cm, were constructed and their performance was experimentally evaluated at sheath-to-aerosol flowrate ratios of 5:1, 10:1, and 15:1 via the tandem DMA (TDMA) technique. It was concluded that both prototype cDMAs, operated at a sheath/aerosol flowrate ratio less than 15:1 and with a polydisperse aerosol flowrate of 1.0 lpm, achieved sizing resolution comparable to that offered by Nano-DMA. The longer cDMA had comparable transmission efficiency to that of Nano-DMA, and the shorter cDMA exceeded the performance of Nano-DMA. Hence, the cDMA with the shorter (1.75 cm) classification length is better suited for the characterization of macromolecular samples.

  13. Limbal Stromal Tissue Specific Stem Cells and Their Differentiation Potential to Corneal Epithelial Cells.

    PubMed

    Katikireddy, Kishore Reddy; Jurkunas, Ula V

    2016-01-01

    From the derivation of the first human embryonic stem (hES) cell line to the development of induced pluripotent stem (iPS) cells; it has become evident that tissue specific stem cells are able to differentiate into a specific somatic cell types. The understanding of key processes such as the signaling pathways and the role of the microenvironment in epidermal/epithelial development has provided important clues for the derivation of specific epithelial cell types.Various differentiation protocols/methods were used to attain specific epithelial cell types. Here, we describe in detail the procedure to follow for isolation of tissue specific stem cells, mimicking their microenvironment to attain stem cell characteristics, and their potential differentiation to corneal epithelial cells. PMID:25762299

  14. Cell differentiation along multiple pathways accompanied by changes in histone acetylation status.

    PubMed

    Legartov, So?a; Kozubek, Stanislav; Franek, Michal; Zdrhal, Zbyn?k; Lochmanov, Gabriela; Martinet, Nadine; Brtov, Eva

    2014-04-01

    Post-translational modification of histones is fundamental to the regulation of basic nuclear processes and subsequent cellular events, including differentiation. In this study, we analyzed acetylated forms of histones H2A, H2B, and H4 during induced differentiation in mouse (mESCs) and human (hESCs) embryonic stem cells and during induced enterocytic differentiation of colon cancer cells in vitro. Endoderm-like differentiation of mESCs induced by retinoic acid and enterocytic differentiation induced by histone deacetylase inhibitor sodium butyrate were accompanied by increased mono-, di-, and tri-acetylation of histone H2B and a pronounced increase in di- and tri-acetylation of histone H4. In enterocytes, mono-acetylation of histone H2A also increased and tetra-acetylation of histone H4 appeared only after induction of this differentiation pathway. During differentiation of hESCs, we observed increased mono-acetylation and decreased tri-acetylation of H2B. Mono-, di-, and tri-acetylation of H4 were reduced, manifested by a significant increase in nonacetylated H4 histones. Levels of acetylated histones increased during induced differentiation in mESCs and during histone deacetylase (HDAC) inhibitor-induced enterocytic differentiation, whereas differentiation of human ESCs was associated with reduced acetylation of histones H2B and H4. PMID:24697692

  15. Dynamic regulation of human endogenous retroviruses mediates factor-induced reprogramming and differentiation potential

    PubMed Central

    Ohnuki, Mari; Tanabe, Koji; Sutou, Kenta; Teramoto, Ito; Sawamura, Yuka; Narita, Megumi; Nakamura, Michiko; Tokunaga, Yumie; Nakamura, Masahiro; Watanabe, Akira; Yamanaka, Shinya; Takahashi, Kazutoshi

    2014-01-01

    Pluripotency can be induced in somatic cells by overexpressing transcription factors, including POU class 5 homeobox 1 (OCT3/4), sex determining region Y-box 2 (SOX2), Krppel-like factor 4 (KLF4), and myelocytomatosis oncogene (c-MYC). However, some induced pluripotent stem cells (iPSCs) exhibit defective differentiation and inappropriate maintenance of pluripotency features. Here we show that dynamic regulation of human endogenous retroviruses (HERVs) is important in the reprogramming process toward iPSCs, and in re-establishment of differentiation potential. During reprogramming, OCT3/4, SOX2, and KLF4 transiently hyperactivated LTR7sthe long-terminal repeats of HERV type-H (HERV-H)to levels much higher than in embryonic stem cells by direct occupation of LTR7 sites genome-wide. Knocking down LTR7s or long intergenic non-protein coding RNA, regulator of reprogramming (lincRNA-RoR), a HERV-Hdriven long noncoding RNA, early in reprogramming markedly reduced the efficiency of iPSC generation. KLF4 and LTR7 expression decreased to levels comparable with embryonic stem cells once reprogramming was complete, but failure to resuppress KLF4 and LTR7s resulted in defective differentiation. We also observed defective differentiation and LTR7 activation when iPSCs had forced expression of KLF4. However, when aberrantly expressed KLF4 or LTR7s were suppressed in defective iPSCs, normal differentiation was restored. Thus, a major mechanism by which OCT3/4, SOX2, and KLF4 promote human iPSC generation and reestablish potential for differentiation is by dynamically regulating HERV-H LTR7s. PMID:25097266

  16. Shifted excitation Raman difference spectroscopy at multiple wavelengths for in-situ meat species differentiation

    NASA Astrophysics Data System (ADS)

    Sowoidnich, Kay; Kronfeldt, Heinz-Detlef

    2012-09-01

    Two miniaturized Raman measurement heads containing microsystem diode lasers emitting at 783 and 671 nm suitable for shifted excitation Raman difference spectroscopy (SERDS) were applied for the non-invasive in situ differentiation of selected meat species. This allows using the fingerprint characteristics of Raman spectra without a disturbing fluorescence background. At 783 nm, two emission lines with a spectral shift of 0.5 nm (7 cm-1) and optical powers of up to 110 mW were realized. For 671 nm excitation, the spectral shift amounts to 0.6 nm (12 cm-1) and optical powers of up to 40 mW were obtained. In both cases, meat Raman spectra could be recorded with integration times of 10 s. The investigations were carried out using selected cuts from the most commonly consumed meat species in the US and Europe, i.e. beef, pork, chicken, and turkey. A principal components analysis of the SERDS spectra revealed a clear separation of the meat species into four distinct groups for both excitation wavelengths. This classification is based on the myoglobin content and gradual differences of protein Raman band intensities and positions. The results demonstrate the potential of SERDS as rapid and non-destructive screening method for the discrimination of selected meat species.

  17. Yolk Sac Mesenchymal Progenitor Cells from New World Mice (Necromys lasiurus) with Multipotent Differential Potential

    PubMed Central

    Favaron, Phelipe Oliveira; Mess, Andrea; Will, Snia Elisabete; Maiorka, Paulo Csar; de Oliveira, Moacir Franco; Miglino, Maria Angelica

    2014-01-01

    Fetal membranes are abundant, ethically acceptable and readily accessible sources of stem cells. In particular, the yolk sac is a source of cell lineages that do not express MHCs and are mainly free from immunological incompatibles when transferred to a recipient. Although data are available especially for hematopoietic stem cells in mice and human, whereas other cell types and species are dramatically underrepresented. Here we studied the nature and differentiation potential of yolk sac derived mesenchymal stem cells from a New World mouse, Necromys lasiurus. Explants from mid-gestation were cultured in DMEM-High glucose medium with 10% defined fetal bovine serum. The cells were characterized by standard methods including immunophenotyping by fluorescence and flow cytometry, growth and differentiation potential and tumorigenicity assays. The first adherent cells were observed after 7 days of cell culture and included small, elongated fibroblast-like cells (92.13%) and large, round epithelial-like cells with centrally located nuclei (6.5%). Only the fibroblast-like cells survived the first passages. They were positive to markers for mesenchymal stem cells (Stro-1, CD90, CD105, CD73) and pluripotency (Oct3/4, Nanog) as well as precursors of hematopoietic stem cells (CD117). In differentiation assays, they were classified as a multipotent lineage, because they differentiated into osteogenic, adipogenic, and chondrogenic lineages and, finally, they did not develop tumors. In conclusion, mesenchymal progenitor cells with multipotent differentiation potential and sufficient growth and proliferation abilities were able to be obtained from Necromys yolk sacs, therefore, we inferred that these cells may be promising for a wide range of applications in regenerative medicine. PMID:24918429

  18. A matter of identity - Phenotype and differentiation potential of human somatic stem cells.

    PubMed

    New, S E P; Alvarez-Gonzalez, C; Vagaska, B; Gomez, S G; Bulstrode, N W; Madrigal, A; Ferretti, P

    2015-07-01

    Human somatic stem cells with neural differentiation potential can be valuable for developing cell-based therapies, including treatment of birth-related defects, while avoiding issues associated with cell reprogramming. Precisely defining the "identity" and differentiation potential of somatic stem cells from different sources, has proven difficult, given differences in sets of specific markers, protocols used and lack of side-by-side characterization of these cells in different studies. Therefore, we set to compare expression of mesenchymal and neural markers in human umbilical cord-derived mesenchymal stem cells (UC-MSCs), pediatric adipose-derived stem cells (p-ADSCs) in parallel with human neural stem cells (NSCs). We show that UC-MSCs at a basal level express mesenchymal and so-called "neural" markers, similar to that we previously reported for the p-ADSCs. All somatic stem cell populations studied, independently from tissue and patient of origin, displayed a remarkably similar expression of surface markers, with the main difference being the restricted expression of CD133 and CD34 to NSCs. Expression of certain surface and neural markers was affected by the expansion medium used. As predicted, UC-MSCs and p-ADSCs demonstrated tri-mesenchymal lineage differentiation potential, though p-ADSCs display superior chondrogenic differentiation capability. UC-MSCs and p-ADSCs responded also to neurogenic induction by up-regulating neuronal markers, but crucially they appeared morphologically immature when compared with differentiated NSCs. This highlights the need for further investigation into the use of these cells for neural therapies. Crucially, this study demonstrates the lack of simple means to distinguish between different cell types and the effect of culture conditions on their phenotype, and indicates that a more extensive set of markers should be used for somatic stem cell characterization, especially when developing therapeutic approaches. PMID:25957945

  19. Water Vapor, Differential Rates of Warming, Available Potential Energy, and the Hadley Circulation

    NASA Astrophysics Data System (ADS)

    Funk, C. C.; Dettinger, M. D.

    2012-12-01

    In 1686 Halley advanced the idea that trade winds and monsoon circulations were tied to differential patterns in solar heating. Hadley (1735) soon added the important concept of conservation of angular momentum. Lorenz (1955) described how temperature gradients produced the potential energy, maintaining the general circulation. The differential heating patterns that drive the Hadley circulation arise through variations in insolation and water vapor-related warming. Water vapor is a very effective greenhouse gas, and the tropical-to-extra tropical water vapor gradient increases the longwave radiation absorbed at the surface, increasing the meridional temperature gradient. Increases in water vapor are accepted as one robust feature of anthropogenic climate change. While it is generally accepted that that the 'rich will get richer' (in the sense that moist regions will see a disproportionate increase in water vapor), there has been relatively little discussion of how these differential changes in moisture will translate into differential changes in water vapor related increases in longwave radiation. These increases in longwave radiation may result in a tendency for the 'warm to get warmer' and the Hadley circulation to intensify. In this presentation we examine this issue using i) a single column plane-parallel radiative transfer model, ii) reanalysis climate fields, iii) sea surface temperature observations, and iv) historical climate change simulations drawn from the phase 5 coupled model intercomparison project (CMIP5) archive. We conclude with an examination of potential impacts on arid and semi-arid zones.

  20. Determination of Kohn-Sham effective potentials from electron densities using the differential virial theorem.

    PubMed

    Ryabinkin, Ilya G; Staroverov, Viktor N

    2012-10-28

    We present an accurate method for constructing the Kohn-Sham effective potential corresponding to a given electron density in one-dimensional and spherically symmetric systems. The method is based on the differential virial theorem--an exact relation between the effective potential, the electron density, and the kinetic energy density. A distinctive feature of the proposed technique is that it employs a size-consistent bosonic reference potential to ensure the correct asymptotic behavior of the resulting Kohn-Sham potential. We describe a practical implementation of our method and use it to obtain high-quality exchange-correlation and correlation potentials of the neon and argon atoms from ab initio densities generated in large Slater- and Gaussian-type basis sets. PMID:23126701

  1. Cryopreservation characteristics of adipose-derived stem cells: maintenance of differentiation potential and viability.

    PubMed

    Goh, Brian C; Thirumala, Sreedhar; Kilroy, Gail; Devireddy, Ram V; Gimble, Jeffrey M

    2007-01-01

    With the emergence of regenerative medicine, many researchers have turned to fat tissue as a source of adipose-derived stem cells (ASCs). Because freshly collected adipose tissue is not always readily available, there will be a need for improved cryopreservation methods to reproducibly maintain ASC viablility and multipotentiality in long-term storage. This study examines the efficiency of conventional dimethyl sulphoxide cryopreservation methods by measuring the maintenance of differentiation potential after one freeze cycle. Additionally, we analysed the viability of ASCs as a function of varying cell concentrations in cryopreservation media. We evaluated four distinct colony-forming unit assays (fibroblast, alkaline phosphatase, adipocyte and osteoblast) to monitor quantitatively the differentiation potential in ASCs after one freeze cycle. We found that the post-thaw viability was a function of storage concentration and that an optimal viability was observed for a concentration of 0.5 x 10(6) cells/ml cryopreservation medium. PMID:18038424

  2. Towards quantitative, atomic-resolution reconstruction of the electrostatic potential via differential phase contrast using electrons.

    PubMed

    Close, R; Chen, Z; Shibata, N; Findlay, S D

    2015-12-01

    Differential phase contrast images in scanning transmission electron microscopy can be directly and quantitatively related to the gradient of the projected specimen potential provided that (a) the specimen can be treated as a phase object and (b) full 2D diffraction patterns as a function of probe position can be obtained. Both are challenging to achieve in atomic resolution imaging. The former is fundamentally limited by probe spreading and dynamical electron scattering, and we explore its validity domain in the context of atomic resolution differential phase contrast imaging. The latter, for which proof-of-principle experimental data sets exist, is not yet routine. We explore the extent to which more established segmented detector geometries can instead be used to reconstruct a quantitatively good approximation to the projected specimen potential. PMID:26381331

  3. On orthogonality constrained multiple core-hole states and optimized effective potential method.

    PubMed

    Glushkov, V N; Assfeld, X

    2012-10-01

    An attempt to construct a multiple core-hole state within the optimized effective potential (OEP) methodology is presented. In contrast to the conventional ?-self-consistent field method for hole states, the effects of removing an electron is achieved using some orthogonality constraints imposed on the orbitals so that a Slater determinant describing a hole state is constrained to be orthogonal to that of a neutral system. It is shown that single, double, and multiple core-hole states can be treated within a unified framework and can be easily implemented for atoms and molecules. For this purpose, a constrained OEP method proposed earlier for excited states (Glushkov and Levy, J. Chem. Phys. 2007, 126, 174106) is further developed to calculate single and double core ionization energies using a local effective potential expressed as a direct mapping of the external potential. The corresponding equations, determining core-hole orbitals from a one-particle Schrdinger equation with a local potential as well as correlation corrections derived from the second-order many-body perturbation theory are given. One of the advantages of the present direct mapping formulation is that the effective potential, which plays the role of the Kohn-Sham potential, has the symmetry of the external potential. Single and double core ionization potentials computed with the presented scheme were found to be in agreement with data available from experiment and other calculations. We also discuss core-hole state local potentials for the systems studied. PMID:22696265

  4. Effect of raising body temperature on visual and somatosensory evoked potentials in patients with multiple sclerosis.

    PubMed Central

    Matthews, W B; Read, D J; Pountney, E

    1979-01-01

    The effects of raising body temperature on the visual (VEP) and somatosensory (SEP) evoked potentials were observed in normal subjects and in patients with multiple sclerosis. The amplitude of the VEP was significantly reduced to the same degree after heating in normal subjects and in patients with multiple sclerosis but there was no effect on the latency of the potential. Changes in amplitude could not be related to reduction in acuity. In contrast, the cervical SEP was greatly disorganised after heating in many patients with multiple sclerosis while the only effect in normal subjects was to reduce the latency by increasing peripheral conduction velocity. These results suggest that heat caused conduction block in demyelinated axons in the sensory pathways of the cervical spinal cord. PMID:438834

  5. Appearance potential spectroscopy with a photon counting detector and multiple scattering spectral interpretation

    SciTech Connect

    Amidani, L.; Pasquini, L.; Boscherini, F.

    2012-08-15

    We describe a soft x-ray appearance potential spectroscopy apparatus, which uses a windowless hyperpure Ge detector operated in the photon counting mode. Direct comparisons of recorded spectra with the self-convolution of x-ray absorption spectra and with ab initio simulations in the multiple scattering framework are reported and discussed.

  6. Periodontitis promotes the proliferation and suppresses the differentiation potential of human periodontal ligament stem cells

    PubMed Central

    ZHENG, WEI; WANG, SHI; WANG, JIANGUO; JIN, FANG

    2015-01-01

    The aim of the present study was to investigate the periodontitis-associated changes in the number, proliferation and differentiation potential of human periodontal ligament stem cells (PDLSCs). Cultures of human periodontal ligament cells (PDLCs) were established from healthy donors and donors with periodontitis. The numbers of stem cell were characterized using flow cytometry. PDLSCs were isolated from the PDLCs by immunomagnetic bead selection. Colony-forming abilities, osteogenic and adipogenic potential, gene expression of cementoblast phenotype, alkaline phosphatase activity and in vivo differentiation capacities were then evaluated. Periodontitis caused an increase in the proliferation of PDLSCs and a decrease in the commitment to the osteoblast lineage. This is reflected by changes in the expression of osteoblast markers. When transplanted into immunocompromised mice, PDLSCs from the healthy donors exhibited the capacity to produce cementum PDL-like structures, whereas, the inflammatory PDLSCs transplants predominantly formed connective tissues. In conclusion, the data from the present study suggest that periodontitis affects the proliferation and differentiation potential of human PDLSCs in vitro and in vivo. PMID:26310866

  7. Multiple actions of stem cell factor in neural crest cell differentiation in vitro.

    PubMed

    Langtimm-Sedlak, C J; Schroeder, B; Saskowski, J L; Carnahan, J F; Sieber-Blum, M

    1996-03-15

    The neural crest is a transient tissue of the vertebrate embryo that gives rise to most primary sensory neurons and pigment cells in the adult organism, among other cell types and tissues. Many neural crest cells are pluripotent in the sense that their progeny can generate more than one phenotype. The presence of pluripotent neural crest cell-derived cells at sites of terminal differentiation suggests that location-specific cues from the embryonic environment, such as growth factors, are involved in directing their survival, proliferation, and cell type specification. We have therefore examined the influences of one pertinent growth factor, stem cell factor (SCF), on neural crest cell development by in vitro colony assay in a serum-free culture medium. SCF showed three major effects. (1) SCF is trophic for early neural crest cells, that is, either pluripotent cells and/or their more mature progeny. This effect occurs only if SCF is present throughout the culture period, and it is not observed when a neurotrophin is present in addition to SCF. (2) More colonies contain sensory neuron precursors in the presence of SCF. This effect is neutralized by NGF and neurotrophin-3 (NT-3), but not by brain-derived neurotrophic factor (BDNF). (3) The combination of SCF and any neurotrophin tested (NGF, BDNF, NT-3) is trophic for melanogenic cells, whereas SCF alone does not detectably affect melanogenesis. This suggests either that both types of factor are required for melanotrophic action or that melanogenic cells become dependent on neurotrophins after exposure to SCF. Our observation that SCF is required during the first half of the culture period only, and NGF during the second half only, indicates the latter possibility. Whereas coat color changes in the mouse mutants W (c-kit defect) and Steel (SCF defect) and several in vivo and in vitro studies by other investigators have shown previously that SCF is melanotrophic, they also indicated the requirement of an additional factor, or factors, in melanogenesis. Our data suggest that SCF affects neural crest cell development at multiple levels and that survival of melanogenic cells is mediated by a combination of SCF and a neurotropin, rather than by SCF alone. PMID:8631506

  8. Identification of cord blood-derived mesenchymal stem/stromal cell populations with distinct growth kinetics, differentiation potentials, and gene expression profiles.

    PubMed

    Markov, Vladimir; Kusumi, Kenro; Tadesse, Mahlet G; William, Dilusha A; Hall, Dorian M; Lounev, Vitali; Carlton, Arlene; Leonard, Jay; Cohen, Rick I; Rappaport, Eric F; Saitta, Biagio

    2007-02-01

    Phenotypic heterogeneity has been observed among mesenchymal stem/stromal cell (MSC) populations, but specific genes associated with this variability have not been defined. To study this question, we analyzed two distinct isogenic MSC populations isolated from umbilical cord blood (UCB1 and UCB2). The use of isogenic populations eliminated differences contributed by genetic background. We characterized these UCB MSCs for cell morphology, growth kinetics, immunophenotype, and potential for differentiation. UCB1 displayed faster growth kinetics, higher population doublings, and increased adipogenic lineage differentiation compared to UCB2. However, osteogenic differentiation was stronger for the UCB2 population. To identify MSC-specific genes and developmental genes associated with observed phenotypic differences, we performed expression analysis using Affymetrix microarrays and compared them to bone marrow (BM) MSCs. We compared UCB1, UCB2, and BM and identified distinct gene expression patterns. Selected clusters were analyzed demonstrating that genes of multiple developmental pathways, such as transforming growth factor-beta (TGF-beta) and wnt genes, and markers of early embryonic stages and mesodermal differentiation displayed significant differences among the MSC populations. In undifferentiated UCB1 cells, multiple genes were significantly up-regulated (p < 0.0001): peroxisome proliferation activated receptor gamma (PPARG), which correlated with adipogenic differentiation capacities, hepatocyte growth factor (HGF), and stromal-derived factor 1 (SDF1/CXCL12), which could both potentially contribute to the higher growth kinetics observed in UCB1 cells. Overall, the results confirmed the presence of two distinct isogenic UCB-derived cell populations, identified gene profiles useful to distinguish MSC types with different lineage differentiation potentials, and helped clarify the heterogeneity observed in these cells. PMID:17348805

  9. The Wnt11 Signaling Pathway in Potential Cellular EMT and Osteochondral Differentiation Progression in Nephrolithiasis Formation

    PubMed Central

    He, Deng; Lu, Yuchao; Hu, Henglong; Zhang, Jiaqiao; Qin, Baolong; Wang, Yufeng; Xing, Shuai; Xi, Qilin; Wang, Shaogang

    2015-01-01

    The molecular events leading to nephrolithiasis are extremely complex. Previous studies demonstrated that calcium and transforming growth factor-?1 (TGF-?1) may participate in the pathogenesis of stone formation, but the explicit mechanism has not been defined. Using a self-created genetic hypercalciuric stone-forming (GHS) rat model, we observed that the increased level of serous/uric TGF-?1 and elevated intracellular calcium in primary renal tubular epithelial cells (PRECs) was associated with nephrolithiasis progression in vivo. In the setting of high calcium plus high TGF-?1 in vitro, PRECs showed great potential epithelial to mesenchymal transition (EMT) progression and osteochondral differentiation properties, representing the multifarious increased mesenchymal and osteochondral phenotypes (Zeb1, Snail1, Col2A1, OPN, Sox9, Runx2) and decreased epithelial phenotypes (E-cadherin, CK19) bythe detection of mRNAs and corresponding proteins. Moreover, TGF-?-dependent Wnt11 knockdown and L-type Ca2+ channel blocker could greatly reverse EMT progression and osteochondral differentiation in PRECs. TGF-?1 alone could effectively promote EMT, but it had no effect on osteochondral differentiation in NRK cells (Rat kidney epithelial cell line). Stimulation with Ca2+ alone did not accelerate differentiation of NRK. Co-incubation of extracellular Ca2+ and TGF-?1 synergistically promotes EMT and osteochondral differentiation in NRK control cells. Our data supplied a novel view that the pathogenesis of calcium stone development may be associated with synergic effects of TGF-?1 and Ca2+, which promote EMT and osteochondral differentiation via Wnt11 and the L-type calcium channel. PMID:26193266

  10. Effects of artemether on the proliferation, apoptosis, and differentiation of keratinocytes: potential application for psoriasis treatment

    PubMed Central

    Wu, Jie; Li, Hong; Li, Ming

    2015-01-01

    Artemether exhibits diverse pharmacological effects and has multiple applications. This study aimed to investigate its antiproliferative and apoptogenic effects on HaCaT cells and keratinocyte differentiation-inducing activity in vivo. WST-8 analysis demonstrated that Artemether can inhibit the proliferation of cultured HaCaT cells in a time- and dose-dependent manner. Annexin V/PI dual staining and JC-1 staining further revealed that Artemether can dose-dependently augment HaCaT apoptosis. To investigate the keratinocyte differentiation-inducing activity of Artemether, it was prepared as topical creams at concentrations of 1%, 3%, and 5%. During the 4 weeks of topical treatment, no evidence of irritation was observed in the mouse tail test. Artemether cream dose-dependently increased the degree of orthokeratosis and the relative epidermal thickness of mouse tail skin, indicative of the keratinocyte differentiation-inducing activity. Taking the in vitro and in vivo findings together, the present study suggests that Artemether may be a promising antipsoriatic agent worthy of further investigation. PMID:26221244

  11. Bioinformatics analyses of differentially expressed genes associated with bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma

    PubMed Central

    Sun, Jingnan; Wen, Xue; Jin, Fengyan; Li, Yuying; Hu, Jifan; Sun, Yunpeng

    2015-01-01

    Purpose This study aimed to explore the molecular mechanisms associated with bisphosphonate (BP)-related osteonecrosis of the jaw (ONJ) in patients with multiple myeloma (MM). Methods The gene expression profile GSE7116 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) from eleven patients with ONJ resulting from MM treated with BPs (ONJBPs) and ten MM patients without ONJ treated with BPs (MMBPs) were analyzed. Gene ontology (GO) and pathway enrichment analyses of DEGs were performed, followed by functional annotation and proteinprotein interaction network construction. Finally, sub-network modules were constructed and analyzed. Results A total of 166 up- and 473 down-regulated DEGs were identified. The up-regulated DEGs were enriched in pathways related to cancer, and the down-regulated DEGs were enriched in pathways related to the immune system. Moreover, the GO terms enriched by the up-regulated DEGs were associated with misfolded proteins, and the down-regulated DEGs were associated with immune responses. After functional annotation, 16 transcription factors were identified, including X-box binding protein 1 (XBP1). In proteinprotein interaction network analysis, tumor necrosis factor (TNF) and interleukin 1, beta (IL1B) had higher connectivity degrees. Among the constructed sub-network modules, module 1 was the best one, and DEAD (Asp-Glu-Ala-Asp) box helicase 5 (DDX5) was a hub gene. The DEGs in module 1 were mainly enriched in GO terms related to RNA splicing. Conclusion DEGs of ONJ were mainly enriched in pathways related to the immune system and RNA splicing. DEGs such as TNF, ILB1, DDX5, and XBP1 may be the potential targets of ONJ treatment. PMID:26445550

  12. Detection of Olfactory Dysfunction Using Olfactory Event Related Potentials in Young Patients with Multiple Sclerosis

    PubMed Central

    Caminiti, Fabrizia; De Salvo, Simona; De Cola, Maria Cristina; Russo, Margherita; Bramanti, Placido; Marino, Silvia; Ciurleo, Rosella

    2014-01-01

    Background Several studies reported olfactory dysfunction in patients with multiple sclerosis. The estimate of the incidence of olfactory deficits in multiple sclerosis is uncertain; this may arise from different testing methods that may be influenced by patients' response bias and clinical, demographic and cognitive features. Aims To evaluate objectively the olfactory function using Olfactory Event Related Potentials. Materials and Methods We tested the olfactory function of 30 patients with relapsing remitting multiple sclerosis (mean age of 36.036.96 years) and of 30 age, sex and smokinghabit matched healthy controls by using olfactory potentials. A selective and controlled stimulation of the olfactory system to elicit the olfactory event related potentials was achieved by a computer-controlled olfactometer linked directly with electroencephalograph. Relationships between olfactory potential results and patients' clinical characteristics, such as gender, disability status score, disease-modifying therapy, and disease duration, were evaluated. Results Seven of 30 patients did not show olfactory event related potentials. Sixteen of remaining 23 patients had a mean value of amplitude significantly lower than control group (p<0.01). The presence/absence of olfactory event related potentials was associated with dichotomous expanded disability status scale (p?=?0.0433), as well as inversely correlated with the disease duration (r?=??0.3641, p?=?0.0479). Conclusion Unbiased olfactory dysfunction of different severity found in multiple sclerosis patients suggests an organic impairment which could be related to neuroinflammatory and/or neurodegenerative processes of olfactory networks, supporting the recent findings on neurophysiopathology of disease. PMID:25047369

  13. Fibronectin promotes differentiation of neural crest progenitors endowed with smooth muscle cell potential

    SciTech Connect

    Costa-Silva, Bruno; Coelho da Costa, Meline; Melo, Fernanda Rosene; Neves, Cynara Mendes; Alvarez-Silva, Marcio; Calloni, Giordano Wosgrau; Trentin, Andrea Goncalves

    2009-04-01

    The neural crest (NC) is a model system used to investigate multipotency during vertebrate development. Environmental factors control NC cell fate decisions. Despite the well-known influence of extracellular matrix molecules in NC cell migration, the issue of whether they also influence NC cell differentiation has not been addressed at the single cell level. By analyzing mass and clonal cultures of mouse cephalic and quail trunk NC cells, we show for the first time that fibronectin (FN) promotes differentiation into the smooth muscle cell phenotype without affecting differentiation into glia, neurons, and melanocytes. Time course analysis indicated that the FN-induced effect was not related to massive cell death or proliferation of smooth muscle cells. Finally, by comparing clonal cultures of quail trunk NC cells grown on FN and collagen type IV (CLIV), we found that FN strongly increased both NC cell survival and the proportion of unipotent and oligopotent NC progenitors endowed with smooth muscle potential. In contrast, melanocytic progenitors were prominent in clonogenic NC cells grown on CLIV. Taken together, these results show that FN promotes NC cell differentiation along the smooth muscle lineage, and therefore plays an important role in fate decisions of NC progenitor cells.

  14. Illustrating the Use of Nonparametric Regression To Assess Differential Item and Bundle Functioning among Multiple Groups.

    ERIC Educational Resources Information Center

    Gierl, Mark J.; Bolt, Daniel M.

    2001-01-01

    Presents an overview of nonparametric regression as it allies to differential item functioning analysis and then provides three examples to illustrate how nonparametric regression can be applied to multilingual, multicultural data to study group differences. (SLD)

  15. GPR120: A bi-potential mediator to modulate the osteogenic and adipogenic differentiation of BMMSCs

    PubMed Central

    Gao, Bo; Huang, Qiang; Jie, Qiang; Lu, Wei-Guang; Wang, Long; Li, Xiao-Jie; Sun, Zhen; Hu, Ya-Qian; Chen, Li; Liu, Bao-Hua; Liu, Jian; Yang, Liu; Luo, Zhuo-Jing

    2015-01-01

    Free fatty acids display diverse effects as signalling molecules through GPCRs in addition to their involvement in cellular metabolism. GPR120, a G protein-coupled receptor for long-chain unsaturated fatty acids, has been reported to mediate adipogenesis in lipid metabolism. However, whether GPR120 also mediates osteogenesis and regulates BMMSCs remain unclear. In this study, we showed that GPR120 targeted the bi-potential differentiation of BMMSCs in a ligand dose-dependent manner. High concentrations of TUG-891 (a highly selective agonist of GPR120) promoted osteogenesis via the Ras-ERK1/2 cascade, while low concentrations elevated P38 and increased adipogenesis. The fine molecular regulation of GPR120 was implemented by up-regulating different integrin subunits (?1, ?2 and ?1; ?5 and ?3). The administration of high doses of TUG-891 rescued oestrogen-deficient bone loss in vivo, further supporting an essential role of GPR120 in bone metabolism. Our findings, for the first time, showed that GPR120-mediated cellular signalling determines the bi-potential differentiation of BMMSCs in a dose-dependent manner. Additionally, the induction of different integrin subunits was involved in the cytoplasmic regulation of a seesaw-like balance between ERK and p38 phosphorylation. These findings provide new hope for developing novel remedies to treat osteoporosis by adjusting the GPR120-mediated differentiation balance of BMMSCs. PMID:26365922

  16. Transcriptome analysis reveals the potential contribution of long noncoding RNAs to brown adipocyte differentiation.

    PubMed

    You, Liang Hui; Zhu, Li Jun; Yang, Lei; Shi, Chun Mei; Pang, Ling Xia; Zhang, Jun; Cui, Xian Wei; Ji, Chen Bo; Guo, Xi Rong

    2015-10-01

    Brown adipose tissue (BAT) functions to dissipate energy in response to cold exposure or overfeeding. Counteracting obesity has been extensively considered as a promising target. Long noncoding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. However, the potential biological functions of lncRNAs during mouse brown fat cell differentiation have not been fully understood. Here, we performed lncRNA and mRNA expression profile analysis using microarray technology and identified 1064 lncRNAs with differential expression (fold change| ≥4, p ≤ 0.01) on day 0 and day 8 during differentiation. Furthermore, candidate lncRNAs were characterized by comprehensive examination of their genomic context, gene ontology (GO) enrichment of their associated protein-coding genes and pathway analysis. We identified three lncRNAs (Gm15051, Tmem189 and Cebpd) associated with their flanking coding genes (Hoxa1, C/EBPβ and C/EBPδ), which participated in adipose commitment. Collectively, our findings indicated lncRNAs are involved in mouse BAT development and provide potential targets for obesity therapy. PMID:25773316

  17. The Milky Way in Stereo: Constraints on the Galactic Gravitational Potential from Multiple Stellar Streams

    NASA Astrophysics Data System (ADS)

    Bonaca, Ana; Geha, Marla C.; Hogg, David W.; Kupper, Andreas Hans Wilhelm; Johnston, Kathryn V.; Diemand, Juerg

    2016-01-01

    Stellar streams are powerful constraints of the Galactic gravitational potential, but because the true potential form is unknown, individual streams can produce very biased results. Most potential recovery methods rely on full, observationally expensive, 6D information for the stream member stars. Consequently, current constraints of the Milky Way potential are based on individual streams, with some tension between different streams.These discrepancies can be resolved by simultaneously modeling multiple stellar streams that have been discovered in the Galactic halo. We use two most prominent cold streams in the Milky Way, tidal tails of the Palomar 5 globular cluster and GD-1 stream, to measure the global properties of our dark matter halo. Based on the analysis of synthetic streams on similar orbits in a realistic dark matter-only simulation, we discuss which new data would most improve our understanding of the Galactic gravitational potential.

  18. Differential expression of estrogen receptor α and β isoforms in multiple and solitary leiomyomas.

    PubMed

    Shao, Ruyue; Fang, Liaoqiong; Xing, Ruoxi; Xiong, Yu; Fang, Liaoqiong; Wang, Zhibiao

    Uterine leiomyomas are benign myometrial neoplasms that function as one of the common indications for hysterectomy. Clinical and biological evidences indicate that uterine leiomyomas are estrogen-dependent. Estrogen stimulates cell proliferation through binding to the estrogen receptor (ER), of which both subtypes α and β are present in leiomyomas. Clinically, leiomyomas may be singular or multiple, where the first one is rarely recurring if removed and the latter associated to a relatively young age or genetic predisposition. These markedly different clinical phenotypes indicate that there may different mechanism causing a similar smooth muscle response. To investigate the relative expression of ERα and ERβ in multiple and solitary uterine leiomyomas, we collected samples from 35 Chinese women (multiple leiomyomas n = 20, solitary leiomyoma n = 15) undergoing surgery to remove uterine leiomyomas. ELISA assay was performed to detect estrogen(E2) concentration. Quantitative real-time PCR analysis was performed to detect ERα and ERβ mRNA expression. Western blot and immunohistochemical analysis were performed to detect ERα and ERβ protein expression. We found that ERα mRNA and protein levels of in multiple leiomyomas were significantly lower than those of solitary leiomyomas, whereas ERβ mRNA and protein levels in multiple leiomyomas were significantly higher than those in solitary leiomyomas, irrespectively of the menstrual cycle stage. In both multiple and solitary leiomyomas, ERα expression was higher than that of ERβ. E2 concentration in multiple and solitary leiomyomas correlated with that of ERα expression. ERα was present in nuclus and cytoplasma while estrogen receptor β localized only in nuclei in both multiple and solitary leiomyomas. Our findings suggest that the difference of ERα and ERβ expression between multiple and solitary leiomyomas may be responsible for the course of the disease subtypes. PMID:26529545

  19. Multiple myeloma cell lines and primary tumors proteoma: protein biosynthesis and immune system as potential therapeutic targets.

    PubMed

    Fernando, Rodrigo Carlini; de Carvalho, Fabricio; Mazzotti, Diego Robles; Evangelista, Adriane Feij; Braga, Walter Moiss Tobias; de Lourdes Chauffaille, Maria; Paes Leme, Adriana Franco; Colleoni, Gisele Wally Braga

    2015-11-01

    Despite great advance in multiple myeloma (MM) treatment since 2000s, it is still an incurable disease and novel therapies are welcome. Therefore, the purpose of this study was to explore MM plasma cells' (MM-PC) proteome, in comparison with their normal counterparts (derived from palatine tonsils of normal donors, ND-PC), in order to find potential therapeutic targets expressed on the surface of these cells. We also aimed to evaluate the proteome of MM cell lines with different genetic alterations, to confirm findings obtained with primary tumor cells. Bone marrow (BM) samples from eight new cases of MM and palatine tonsils from seven unmatched controls were submitted to PC separation and, in addition to two MM cell lines (U266, RPMI-8226), were submitted to protein extraction for mass spectrometry analyses. A total of 81 proteins were differentially expressed between MM-PC and ND-PC - 72 upregulated and nine downregulated; U266 vs. RPMI 8226 cell lines presented 61 differentially expressed proteins - 51 upregulated and 10 downregulated. On primary tumors, bioinformatics analyses highlighted upregulation of protein biosynthesis machinery, as well as downregulation of immune response components, such as MHC class I and II, and complement receptors. We also provided comprehensive information about U266 and RPMI-8226 cell lines' proteome and could confirm some patients' findings. PMID:26807199

  20. Multiple myeloma cell lines and primary tumors proteoma: protein biosynthesis and immune system as potential therapeutic targets

    PubMed Central

    Mazzotti, Diego Robles; Evangelista, Adriane Feijó; Braga, Walter Moisés Tobias; de Lourdes Chauffaille, Maria; Leme, Adriana Franco Paes; Colleoni, Gisele Wally Braga

    2015-01-01

    Despite great advance in multiple myeloma (MM) treatment since 2000s, it is still an incurable disease and novel therapies are welcome. Therefore, the purpose of this study was to explore MM plasma cells' (MM-PC) proteome, in comparison with their normal counterparts (derived from palatine tonsils of normal donors, ND-PC), in order to find potential therapeutic targets expressed on the surface of these cells. We also aimed to evaluate the proteome of MM cell lines with different genetic alterations, to confirm findings obtained with primary tumor cells. Bone marrow (BM) samples from eight new cases of MM and palatine tonsils from seven unmatched controls were submitted to PC separation and, in addition to two MM cell lines (U266, RPMI-8226), were submitted to protein extraction for mass spectrometry analyses. A total of 81 proteins were differentially expressed between MM-PC and ND-PC - 72 upregulated and nine downregulated; U266 vs. RPMI 8226 cell lines presented 61 differentially expressed proteins - 51 upregulated and 10 downregulated. On primary tumors, bioinformatics analyses highlighted upregulation of protein biosynthesis machinery, as well as downregulation of immune response components, such as MHC class I and II, and complement receptors. We also provided comprehensive information about U266 and RPMI-8226 cell lines' proteome and could confirm some patients' findings. PMID:26807199

  1. Twin Promotes the Maintenance and Differentiation of Germline Stem Cell Lineage through Modulation of Multiple Pathways.

    PubMed

    Fu, Ziwen; Geng, Cuiyun; Wang, Hui; Yang, Zhihao; Weng, Changjiang; Li, Hua; Deng, Lamei; Liu, Luping; Liu, Nan; Ni, Jianquan; Xie, Ting

    2015-11-17

    The central question in stem cell regulation is how the balance between self-renewal and differentiation is controlled at the molecular level. This study uses germline stem cells (GSCs) in the Drosophila ovary to demonstrate that the Drosophila CCR4 homolog Twin is required intrinsically to promote both GSC self-renewal and progeny differentiation. Twin/CCR4 is one of the two catalytic subunits in the highly conserved CCR4-NOT mRNA deadenylase complex. Twin works within the CCR4-NOT complex to intrinsically maintain GSC self-renewal, at least partly by sustaining E-cadherin-mediated GSC-niche interaction and preventing transposable element-induced DNA damage. It promotes GSC progeny differentiation by forming protein complexes with differentiation factors Bam and Bgcn independently of other CCR4-NOT components. Interestingly, Bam can competitively inhibit the association of Twin with Pop2 in the CCR4-NOT complex. Therefore, this study demonstrates that Twin has important intrinsic roles in promoting GSC self-renewal and progeny differentiation by functioning in different protein complexes. PMID:26549449

  2. The in vitro drug interaction potential of dietary supplements containing multiple herbal components.

    PubMed

    Foti, Robert S; Wahlstrom, Jan L; Wienkers, Larry C

    2007-02-01

    Herbal-based remedies are widely used as alternative treatments for a number of ailments. In addition, the use of products that contain both single and multiple herbal constituents is becoming increasingly common. The work described in this report examined the in vitro drug interaction potential for a commonly used herbal cold remedy reported to contain a mixture of eight herbal components. Experiments conducted in human liver microsomes exhibited significant inhibition (<10% of control activity remaining) of multiple cytochrome P450 (P450) isoforms, including CYP2B6, CYP2C9, and CYP2D6, by the herbal mixture. In an attempt to explain the observed P450 inhibition by the herbal mixture, individual active components were obtained and tested for inhibitory potency. Inhibition of multiple P450 activities by a single constituent, luteolin, was observed. Conversely, inhibition of a single isoform by several herbal components was noted for CYP2B6. Based on the data presented, it is concluded that mixtures of herbal components may exhibit multiple modes of P450 inhibition, indicating the potential for complex herbal-drug interaction scenarios to occur. PMID:17093003

  3. Adsorption of histones on natural polysaccharides: The potential as agent for multiple organ failure in sepsis.

    PubMed

    Isobe, Takashi; Kofuji, Kyoko; Okada, Kenji; Fujimori, Junya; Murata, Mikio; Shigeyama, Masato; Hanioka, Nobumitsu; Murata, Yoshifumi

    2016-03-01

    Histones are intracellular proteins that are structural elements of nuclear chromatin and regulate gene transcription. However, the extracellular histones released in response to bacterial challenges have been identified as mediators contributing to endothelial dysfunction, organ failure, and death during sepsis. In the present study, the adsorption of histones as well as plasma proteins (?1-acid glycoprotein (AGP), albumin, and ?-globulin) on alginic acid, pectin, dextran, and chitosan was examined in order to evaluate the potential of natural polysaccharides as therapeutic agents for multiple organ failure in sepsis. Alginic acid and pectin strongly adsorbed histones, whereas the adsorption abilities of dextran and chitosan toward histones were very low or negligible. Among the natural polysaccharides examined, only alginic acid did not adsorb any of the plasma proteins. These results demonstrated that alginic acid strongly adsorbed histones, but not plasma proteins; therefore, it has potential as a candidate drug for the treatment of multiple organ failure in sepsis. PMID:26627603

  4. EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion

    SciTech Connect

    Huang, Er-Wen; Xue, Sheng-Jiang; Li, Xiao-Yan; Xu, Suo-Wen; Cheng, Jian-Ding; Zheng, Jin-Xiang; Shi, He; Lv, Guo-Li; Li, Zhi-Gang; Li, Yue; Liu, Chang-Hui; Chen, Xiao-Hui; Liu, Hong; Li, Jie; Liu, Chao

    2014-05-02

    Highlights: • Levels of EEN expression paralleled with the rate of cell proliferation. • EEN was involved in the proliferation and survival of multiple myeloma (MM) cells. • EEN regulated the activity of IGF-1-Akt/mTOR pathway. • EEN regulated proliferation and survival of MM cells by enhancing IGF-1 secretion. - Abstract: The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma.

  5. Potential role of immunoglobulin replacement therapy on MRI measures in multiple sclerosis: a systematic review.

    PubMed

    Zare-Shahabadi, Ameneh; Rashidian, Arash; Sahraian, Mohammad Ali; Rezaei, Nima

    2015-12-01

    Multiple sclerosis is a chronic immune-mediated disease of the nervous system. In the early disease course, axonal loss and neurodegeneration occurs that could possibly lead to irreversible neurological impairments. Preventing brain atrophy may have important clinical implications affecting treatment decisions in the future. In recent years, research efforts have directed towards finding agents to modify the disease and reduce brain volume loss. Intravenous immunoglobulin (IVIg) may have some potential roles in this regard. PMID:26488634

  6. Isorotation and differential rotation in a magnetic mirror with imposed E Multiplication-Sign B rotation

    SciTech Connect

    Romero-Talamas, C. A.; Elton, R. C.; Young, W. C.; Reid, R.; Ellis, R. F.

    2012-07-15

    Doppler spectroscopy of helium impurities in the Maryland Centrifugal Experiment reveals the simultaneous existence of isorotating and differentially rotating magnetic surfaces. Differential rotation occurs at the innermost surfaces and is conjectured to cause plasma voltage oscillations of hundreds of kilohertz by periodically changing the current path inductance. High-speed images show the periodic expulsion of plasma near the mirror ends at the same frequencies. In spite of this, the critical ionization velocity limit is exceeded, with respect to the vacuum field definition, for at least 0.5 ms.

  7. Why do multiple traits determine mating success? Differential use in female choice and male competition in a water boatman

    PubMed Central

    Candolin, Ulrika

    2004-01-01

    Mating success is often determined by multiple traits, but why this occurs is largely unknown. Much attention has been paid to female preferences for multiple traits, but surprisingly few researchers have addressed the possibility that multiple traits are important because they serve different functions in female choice and malemale competition. Differential trait function could result from a conflict of interest between the sexes or from constraints forcing the sexes to pay attention to different traits. I show that traits determined at distinct life-history stages differ in their importance in female choice and malemale competition in a water boatman Sigara falleni. Juvenile conditions determined body and foreleg pala size and were the main determinants of mating success under female choice, whereas adult conditions determined body mass and influenced mating success when male competition was included. This differential use of condition-dependent traits under the two selection regimes appeared to arise partly from a conflict between the sexes, since the two selection forces (female choice and male competition) conflict for selection on pala size, and partly from constraints, as females appeared unable to assess adult condition. PMID:15875569

  8. Proliferation and Differentiation Potential of Human Adipose-Derived Stem Cells Grown on Chitosan Hydrogel

    PubMed Central

    Debnath, Tanya; Ghosh, Sutapa; Potlapuvu, Usha Shalini; Kona, Lakshmi; Kamaraju, Suguna Ratnakar; Sarkar, Suprabhat; Gaddam, Sumanlatha; Chelluri, Lakshmi Kiran

    2015-01-01

    Applied tissue engineering in regenerative medicine warrants our enhanced understanding of the biomaterials and its function. The aim of this study was to evaluate the proliferation and differentiation potential of human adipose-derived stem cells (hADSCs) grown on chitosan hydrogel. The stability of this hydrogel is pH-dependent and its swelling property is pivotal in providing a favorable matrix for cell growth. The study utilized an economical method of cross linking the chitosan with 0.5% glutaraldehyde. Following the isolation of hADSCs from omentum tissue, these cells were cultured and characterized on chitosan hydrogel. Subsequent assays that were performed included JC-1 staining for the mitochondrial integrity as a surrogate marker for viability, cell proliferation and growth kinetics by MTT assay, lineage specific differentiation under two-dimensional culture conditions. Confocal imaging, scanning electron microscopy (SEM), and flow cytometry were used to evaluate these assays. The study revealed that chitosan hydrogel promotes cell proliferation coupled with > 90% cell viability. Cytotoxicity assays demonstrated safety profile. Furthermore, glutaraldehyde cross linked chitosan showed < 5% cytotoxicity, thus serving as a scaffold and facilitating the expansion and differentiation of hADSCs across endoderm, ectoderm and mesoderm lineages. Additional functionalities can be added to this hydrogel, particularly those that regulate stem cell fate. PMID:25746846

  9. Hematopoietic Progenitors from Early Murine Fetal Liver Possess Hepatic Differentiation Potential

    PubMed Central

    Khurana, Satish; Mukhopadhyay, Asok

    2008-01-01

    Bipotential hepatoblasts differentiate into hepatocytes and cholangiocytes during liver development. It is believed that hepatoblasts originate from endodermal tissue. Here, we provide evidence for the presence of hepatic progenitor cells in the hematopoietic compartment at an early stage of liver development. Flow cytometric analysis showed that at early stages of liver development, approximately 13% of CD45+ cells express Δ-like protein-1, a marker of hepatoblasts. Furthermore, reverse transcriptase-PCR data suggest that many hepatic genes are expressed in these cells. Cell culture experiments confirmed the hepatic differentiation potential of these cells with the loss of the CD45 marker. We observed that both hematopoietic activity in Δ-like protein-1+ cells and hepatic activity in CD45+ cells were high at embryonic day 10.5 and declined thereafter. Clonal analysis revealed that the hematopoietic fraction of fetal liver cells at embryonic day 10.5 gave rise to both hepatic and hematopoietic colonies. The above results suggest a common source of these two functionally distinct cell lineages. In utero transplantation experiments confirmed these results, as green fluorescent protein-expressing CD45+ cells at the same stage of development yielded functional hepatocytes and hematopoietic reconstitution. Since these cells were unable to differentiate into cytokeratin-19-expressing cholangiocytes, we distinguished them from hepatoblasts. This preliminary study provides hope to correct many liver diseases during prenatal development via transplantation of fetal liver hematopoietic cells. PMID:18988804

  10. Cell differentiation and the multiple drug resistance phenotype in human erythroleukemic cells.

    PubMed

    Carrett-Dias, Michele; Almeida, Leda Karine; Pereira, Juliano Lacava; Almeida, Daniela Volcan; Filgueira, Daza Moraes Vaz Batista; Marins, Luis Fernando; Votto, Ana Paula de Souza; Trindade, Gilma Santos

    2016-03-01

    The gene expression of Oct-4, a transcription factor and hematopoietic stem cell marker, is higher in Lucena lines, which is MDR, and the gene Alox-5 has also been implicated in the differentiation of some cell lines. The aim of this study was to compare the response to PMA-induced differentiation in MDR and non-MDR cells. We observed the differentiation to megakaryocytes in the K562 cell line, which is non-MDR. The expression of Alox-5 and Nanog genes was downregulated and that of Mdr-1 was upregulated in K562 cells. The Lucena cell line contained a higher number of megakaryocytes than the non-MDR, but this number was not altered by PMA, as well as Mdr-1 gene expression. However, Alox-5 expression was downregulated. Alox-5, Mdr-1, Nanog, Oct-4 and Sox-2 basal expression was also evaluated in the K562, Lucena and FEPS (also MDR) cell lines. The transcription factors gene expression was similar in MDR cell lines. The expression of Alox-5 was higher in the non-MDR cell line, while FEPS had the lowest expression of this gene. The opposite pattern was observed for Mdr-1 gene expression. These results suggest that the Alox-5 gene might play a role in the differentiation of these cell lines. PMID:26852002

  11. The concentration-estimation problem for multiple-wavelength differential absorption lidar

    SciTech Connect

    Payne, A.N.

    1994-07-01

    We are seeking to develop a reliable methodology for multi-chemicai detection and discrimination based upon multi-wavelength differential absorption lidar measurements. In this paper, we summarize some preliminary results of our efforts to devise suitable concentration-estimation algorithms for use in detection and discrimination schemes.

  12. A Generalized Logistic Regression Procedure to Detect Differential Item Functioning among Multiple Groups

    ERIC Educational Resources Information Center

    Magis, David; Raiche, Gilles; Beland, Sebastien; Gerard, Paul

    2011-01-01

    We present an extension of the logistic regression procedure to identify dichotomous differential item functioning (DIF) in the presence of more than two groups of respondents. Starting from the usual framework of a single focal group, we propose a general approach to estimate the item response functions in each group and to test for the presence

  13. Activities for Differentiated Instruction Addressing All Levels of Bloom's Taxonomy and Eight Multiple Intelligences.

    ERIC Educational Resources Information Center

    Rule, Audrey C., Ed.; Lord, Linda Hurley, Ed.

    This manuscript contains 13 curriculum units designed to enhance differentiated instruction for learners with special needs from grades 1-12, including gifted students. It integrates Benjamin S. Bloom's levels of cognitive understanding with Howard Gardner's eight domains of intelligence to provide a framework for individualized instruction. Each…

  14. Reduction of Multiple Aberrant Behaviors and Concurrent Development of Self-Care Skills with Differential Reinforcement.

    ERIC Educational Resources Information Center

    Vollmer, Timothy R.; And Others

    1992-01-01

    A modified functional analysis was used to assess the behavioral function of a profoundly retarded man's self-injurious behavior (SIB). Differential reinforcement of alternative behavior effectively reduced SIB and related behavior problems, while compliance of a self-care acquisition task increased markedly. (Author/DB)

  15. Commentary: Differentiated Measures of Temperament and Multiple Pathways to Childhood Disorders

    ERIC Educational Resources Information Center

    Rothbart, Mary K.

    2004-01-01

    Provided is a commentary on articles written for a special section on temperament and childhood disorders. Temperament's contributions to the development of childhood disorders are considered both generally and specifically. Questions are raised about the use of terminology in the field, particularly the term difficult. Differentiation of outcomes

  16. Articular cartilage-derived cells hold a strong osteogenic differentiation potential in comparison to mesenchymal stem cells in vitro

    SciTech Connect

    Salamon, Achim; Jonitz-Heincke, Anika; Adam, Stefanie; Rychly, Joachim; Müller-Hilke, Brigitte; Bader, Rainer; Lochner, Katrin; Peters, Kirsten

    2013-11-01

    Cartilaginous matrix-degenerative diseases like osteoarthritis (OA) are characterized by gradual cartilage erosion, and also by increased presence of cells with mesenchymal stem cell (MSC) character within the affected tissues. Moreover, primary chondrocytes long since are known to de-differentiate in vitro and to be chondrogenically re-differentiable. Since both findings appear to conflict with each other, we quantitatively assessed the mesenchymal differentiation potential of OA patient cartilage-derived cells (CDC) towards the osteogenic and adipogenic lineage in vitro and compared it to that of MSC isolated from adipose tissue (adMSC) of healthy donors. We analyzed expression of MSC markers CD29, CD44, CD105, and CD166, and, following osteogenic and adipogenic induction in vitro, quantified their expression of osteogenic and adipogenic differentiation markers. Furthermore, CDC phenotype and proliferation were monitored. We found that CDC exhibit an MSC CD marker expression pattern similar to adMSC and a similar increase in proliferation rate during osteogenic differentiation. In contrast, the marked reduction of proliferation observed during adipogenic differentiation of adMSC was absent in CDC. Quantification of differentiation markers revealed a strong osteogenic differentiation potential for CDC, however almost no capacity for adipogenic differentiation. Since in the pathogenesis of OA, cartilage degeneration coincides with high bone turnover rates, the high osteogenic differentiation potential of OA patient-derived CDC may affect clinical therapeutic regimens aiming at autologous cartilage regeneration in these patients. - Highlights: • We analyze the mesenchymal differentiation capacity of cartilage-derived cells (CDC). • CDC express mesenchymal stem cell (MSC) markers CD29, CD44, CD105, and CD166. • CDC and MSC proliferation is reduced in adipogenesis and increased in osteogenesis. • Adipogenic differentiation is virtually absent in CDC, but strong in MSC. • Osteogenic differentiation is significantly stronger for CDC than for MSC.

  17. CS1, a Potential New Therapeutic Antibody Target for the Treatment of Multiple Myeloma

    PubMed Central

    Hsi, Eric D.; Steinle, Roxanne; Balasa, Balaji; Szmania, Susann; Draksharapu, Aparna; Shum, Benny P.; Huseni, Mahrukh; Powers, David; Nanisetti, Amulya; Zhang, Yin; Rice, Audie G.; van Abbema, Anne; Wong, Melanie; Liu, Gao; Zhan, Fenghuang; Dillon, Myles; Chen, Shihao; Rhodes, Susan; Fuh, Franklin; Tsurushita, Naoya; Kumar, Shankar; Vexler, Vladimir; Shaughnessy, John D.; Barlogie, Bart; van Rhee, Frits; Hussein, Mohamad; Afar, Daniel E.H.; Williams, Marna B.

    2015-01-01

    Purpose We generated a humanized antibody, HuLuc63, which specifically targets CS1 (CCND3 subset 1, CRACC, and SLAMF7), a cell surface glycoprotein not previously associated with multiple myeloma. To explore the therapeutic potential of HuLuc63 in multiple myeloma, we examined in detail the expression profile of CS1, the binding properties of HuLuc63 to normal and malignant cells, and the antimyeloma activity of HuLuc63 in preclinical models. Experimental Design CS1 was analyzed by gene expression profiling and immunohistochemistry of multiple myeloma samples and numerous normal tissues. HuLuc63-mediated anti-myeloma activity was tested in vitro in antibody-dependent cellular cytotoxicity (ADCC) assays and in vivo using the human OPM2 xenograft model in mice. Results CS1 mRNA was expressed in >90% of 532 multiple myeloma cases, regardless of cytogenetic abnormalities. Anti-CS1 antibody staining of tissues showed strong staining of myeloma cells in all plasmacytomas and bone marrow biopsies. Flow cytometric analysis of patient samples using HuLuc63 showed specific staining of CD138+ myeloma cells, natural killer (NK), NK-like Tcells, and CD8+ Tcells, with no binding detected on hematopoietic CD34+ stem cells. HuLuc63 exhibited significant in vitro ADCC using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. HuLuc63 exerted significant in vivo antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in the mice. Conclusions These results suggest that HuLuc63 eliminates myeloma cells, at least in part, via NK-mediated ADCC and shows the therapeutic potential of targeting CS1 with HuLuc63 for the treatment of multiple myeloma. PMID:18451245

  18. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis.

    PubMed

    Weiner, Howard L

    2008-03-01

    Multiple sclerosis is postulated to be a T cell-mediated autoimmune disease characterised by a relapsing-remitting stage followed by a secondary progressive phase. The relapsing remitting phase may involve waves of proinflammatory Th1 and Th17 cells that infiltrate the nervous system, provoking a clinical attack. The activity of these cells is modulated by other populations of regulatory T cells and the balance between the pro-inflammatory and regulatory T cells is critical for determining disease activity. Promoting the activity of regulatory cells is a potentially beneficial therapeutic strategy, and probably contributes to the action of glatiramer acetate. The progressive phase of multiple sclerosis is believed to be secondary to neurodegenerative changes triggered by inflammation. The status of the innate immune system and its relationship to the stages of multiple sclerosis has been poorly defined until recently. However, recent data suggest that these results demonstrate abnormalities of dendritic cell activation or maturation may underlie the transition to the progressive phase of the disease. Preventing this transition, perhaps by acting at the level of the innate immune system, is an important treatment goal. The identification of biomarkers to predict disease course and treatment response is a major challenge in multiple sclerosis research. Studies using antigen arrays have identified antibody patterns related to CNS antigens and heat-shock proteins that are associated with different disease stages and with response to therapy. In the future, such antibody repertoires could be used as biomarkers for the diagnosis and evaluation of patients with multiple sclerosis, for matching treatments to individual patients and, potentially, to identify healthy individuals at risk for this autoimmune disease. PMID:18317671

  19. Electrospun scaffolds for multiple tissues regeneration in vivo through topography dependent induction of lineage specific differentiation.

    PubMed

    Yin, Zi; Chen, Xiao; Song, Hai-Xin; Hu, Jia-Jie; Tang, Qiao-Mei; Zhu, Ting; Shen, Wei-Liang; Chen, Jia-Lin; Liu, Huanhuan; Heng, Boon Chin; Ouyang, Hong-Wei

    2015-03-01

    Physical topographic cues from various substrata have been shown to exert profound effects on the growth and differentiation of stem cells due to their niche-mimicking features. However, the biological function of different topographic materials utilized as bio-scaffolds in vivo have not been rigorously characterized. This study investigated the divergent differentiation pathways of mesenchymal stem cells (MSCs) and neo-tissue formation trigged by aligned and randomly-oriented fibrous scaffolds, both in vitro and in vivo. The aligned group was observed to form more mature tendon-like tissue in the Achilles tendon injury model, as evidenced by histological scoring and collagen I immunohistochemical staining data. In contrast, the randomly-oriented group exhibited much chondrogenesis and subsequent bone tissue formation through ossification. Additionally, X-ray imaging and osteocalcin immunohistochemical staining also demonstrated that osteogenesis in vivo is driven by randomly oriented topography. Furthermore, MSCs on the aligned substrate exhibited tenocyte-like morphology and enhanced tenogenic differentiation compared to cells grown on randomly-oriented scaffold. qRT-PCR analysis of osteogenic marker genes and alkaline phosphatase (ALP) staining demonstrated that MSCs cultured on randomly-oriented fiber scaffolds displayed enhanced osteogenic differentiation compared with cells cultured on aligned fiber scaffolds. Finally, it was demonstrated that cytoskeletal tension release abrogated the divergent differentiation pathways on different substrate topography. Collectively, these findings illustrate the relationship between topographic cues of the scaffold and their inductive role in tissue regeneration; thus providing an insight into future development of smart functionalized bio-scaffold design and its application in tissue engineering. PMID:25617136

  20. Human amniotic fluid stem cells possess the potential to differentiate into primordial follicle oocytes in vitro.

    PubMed

    Yu, Xiaoli; Wang, Ning; Qiang, Rong; Wan, Qianhui; Qin, Mingming; Chen, Shuai; Wang, Huayan

    2014-04-01

    Previous reports have demonstrated that embryonic stem cells were capable of differentiating into primordial germ cells through the formation of embryoid bodies that subsequently generated oocyte-like cells (OLCs). Such a process could facilitate studies of primordial follicle oocyte development in vitro and regenerative medicine. To investigate the pluripotency of human amniotic fluid stem cells (hAFSCs) and their ability to differentiate into germ cells, we isolated a CD117(+)/CD44(+) hAFSC line that showed fibroblastoid morphology and intrinsically expressed both stem cell markers (OCT4, NANOG, SOX2) and germ cell markers (DAZL, STELLA). To encourage differentiation into OLCs, the hAFSCs were first cultured in a medium supplemented with 5% porcine follicular fluid for 10 days. During the induction period, cell aggregates formed and syntheses of steroid hormones were detected; some OLCs and granulosa cell-like cells could be loosened from the surface of the culture dish. Cell aggregates were collected and replated in oocyte culture medium for an additional 7-10 days. OLCs ranging from 50 to 120 ?m presenting zona pellucida were observed in cumulus-oocyte complexes; some OLCs developed spontaneously into multicell structures similar to preimplantation embryos. Approximately 2% of the hAFSCs differentiated to meiotic germ cells that expressed folliculogenesis- and oogenesis-associated markers. Although the in vitro maturation and fertilization potentials are as yet unproven, short-term (<25 days) and high-efficiency (>2%) derivation of OLCs from hAFSCs might provide a new approach to the study of human germ cell development in vitro. PMID:24571984

  1. Lymphoid lineage differentiation potential of mouse nuclear transfer embryonic stem cells.

    PubMed

    Eslami-Arshaghi, Tarlan; Salehi, Mohammad; Soleimani, Masoud; Gholipourmalekabadi, Mazaher; Mossahebi-Mohammadi, Majid; Ardeshirylajimi, Abdolreza; Rajabi, Hoda

    2015-09-01

    Stem cells therapy is considered as an efficient strategy for the treatment of some diseases. Nevertheless, some obstacles such as probability of rejection by the immune system limit applications of this strategy. Therefore, several efforts have been made to overcome this among which using the induced pluripotent stem cells (iPSCs) and nuclear transfer embryonic stem cell (nt-ESCs) are the most efficient strategies. The objective of this study was to evaluate the differentiation potential of the nt-ESCs to lymphoid lineage in the presence of IL-7, IL-3, FLT3-ligand and TPO growth factors invitro. To this end, the nt-ESCs cells were prepared and treated with aforementioned growth factors for 7 and 14 days. Then, the cells were examined for expression of lymphoid markers (CD3, CD25, CD127 and CD19) by quantitative PCR (q-PCR) and flow cytometry. An increased expression of CD19 and CD25 markers was observed in the treated cells compared with the negative control samples by day 7. After 14 days, the expression level of all the tested CD markers significantly increased in the treated groups in comparison with the control. The current study reveals the potential of the nt-ESCs in differentiation to lymphoid lineage in the presence of defined growth factors. PMID:26239678

  2. Electrospun SF/PLCL nanofibrous membrane: a potential scaffold for retinal progenitor cell proliferation and differentiation.

    PubMed

    Zhang, Dandan; Ni, Ni; Chen, Junzhao; Yao, Qinke; Shen, Bingqiao; Zhang, Yi; Zhu, Mengyu; Wang, Zi; Ruan, Jing; Wang, Jing; Mo, Xiumei; Shi, Wodong; Ji, Jing; Fan, Xianqun; Gu, Ping

    2015-01-01

    Biocompatible polymer scaffolds are promising as potential carriers for the delivery of retinal progenitor cells (RPCs) in cell replacement therapy for the repair of damaged or diseased retinas. The primary goal of the present study was to investigate the effects of blended electrospun nanofibrous membranes of silk fibroin (SF) and poly(L-lactic acid-co-?-caprolactone) (PLCL), a novel scaffold, on the biological behaviour of RPCs in vitro. To assess the cell-scaffold interaction, RPCs were cultured on SF/PLCL scaffolds for indicated durations. Our data revealed that all the SF/PLCL scaffolds were thoroughly cytocompatible, and the SF:PLCL (1:1) scaffolds yielded the best RPC growth. The in vitro proliferation assays showed that RPCs proliferated more quickly on the SF:PLCL (1:1) than on the other scaffolds and the control. Quantitative polymerase chain reaction (qPCR) and immunocytochemistry analyses demonstrated that RPCs grown on the SF:PLCL (1:1) scaffolds preferentially differentiated toward retinal neurons, including, most interestingly, photoreceptors. In summary, we demonstrated that the SF:PLCL (1:1) scaffolds can not only markedly promote RPC proliferation with cytocompatibility for RPC growth but also robustly enhance RPCs' differentiation toward specific retinal neurons of interest in vitro, suggesting that SF:PLCL (1:1) scaffolds may have potential applications in retinal cell replacement therapy in the future. PMID:26395224

  3. Electrospun SF/PLCL nanofibrous membrane: a potential scaffold for retinal progenitor cell proliferation and differentiation

    PubMed Central

    Zhang, Dandan; Ni, Ni; Chen, Junzhao; Yao, Qinke; Shen, Bingqiao; Zhang, Yi; Zhu, Mengyu; Wang, Zi; Ruan, Jing; Wang, Jing; Mo, Xiumei; Shi, Wodong; Ji, Jing; Fan, Xianqun; Gu, Ping

    2015-01-01

    Biocompatible polymer scaffolds are promising as potential carriers for the delivery of retinal progenitor cells (RPCs) in cell replacement therapy for the repair of damaged or diseased retinas. The primary goal of the present study was to investigate the effects of blended electrospun nanofibrous membranes of silk fibroin (SF) and poly(L-lactic acid-co-?-caprolactone) (PLCL), a novel scaffold, on the biological behaviour of RPCs in vitro. To assess the cell-scaffold interaction, RPCs were cultured on SF/PLCL scaffolds for indicated durations. Our data revealed that all the SF/PLCL scaffolds were thoroughly cytocompatible, and the SF:PLCL (1:1) scaffolds yielded the best RPC growth. The in vitro proliferation assays showed that RPCs proliferated more quickly on the SF:PLCL (1:1) than on the other scaffolds and the control. Quantitative polymerase chain reaction (qPCR) and immunocytochemistry analyses demonstrated that RPCs grown on the SF:PLCL (1:1) scaffolds preferentially differentiated toward retinal neurons, including, most interestingly, photoreceptors. In summary, we demonstrated that the SF:PLCL (1:1) scaffolds can not only markedly promote RPC proliferation with cytocompatibility for RPC growth but also robustly enhance RPCs differentiation toward specific retinal neurons of interest in vitro, suggesting that SF:PLCL (1:1) scaffolds may have potential applications in retinal cell replacement therapy in the future. PMID:26395224

  4. Precancerous Stem Cells Have the Potential for both Benign and Malignant Differentiation

    PubMed Central

    Chen, Li; Shen, Rulong; Ye, Yin; Pu, Xin-An; Liu, Xingluo; Duan, Wenrui; Wen, Jing; Zimmerer, Jason; Wang, Ying; Liu, Yan; Lasky, Larry C.; Heerema, Nyla A.; Perrotti, Danilo; Ozato, Keiko; Kuramochi-Miyagawa, Satomi; Nakano, Toru; Yates, Allen J.; Carson III, William E.; Lin, Haifan; Barsky, Sanford H.; Gao, Jian-Xin

    2007-01-01

    Cancer stem cells (CSCs) have been identified in hematopoietic and solid tumors. However, their precursorsnamely, precancerous stem cells (pCSCs) have not been characterized. Here we experimentally define the pCSCs that have the potential for both benign and malignant differentiation, depending on environmental cues. While clonal pCSCs can develop into various types of tissue cells in immunocompetent mice without developing into cancer, they often develop, however, into leukemic or solid cancers composed of various types of cancer cells in immunodeficient mice. The progress of the pCSCs to cancers is associated with the up-regulation of c-kit and Sca-1, as well as with lineage markers. Mechanistically, the pCSCs are regulated by the PIWI/AGO family gene called piwil2. Our results provide clear evidence that a single clone of pCSCs has the potential for both benign and malignant differentiation, depending on the environmental cues. We anticipate pCSCs to be a novel target for the early detection, prevention, and therapy of cancers. PMID:17356702

  5. Methodology for Estimating Solar Potential on Multiple Building Rooftops for Photovoltaic Systems

    SciTech Connect

    Kodysh, Jeffrey B; Omitaomu, Olufemi A; Bhaduri, Budhendra L; Neish, Bradley S

    2013-01-01

    In this paper, a methodology for estimating solar potential on multiple building rooftops is presented. The objective of this methodology is to estimate the daily or monthly solar radiation potential on individual buildings in a city/region using Light Detection and Ranging (LiDAR) data and a geographic information system (GIS) approach. Conceptually, the methodology is based on the upward-looking hemispherical viewshed algorithm, but applied using an area-based modeling approach. The methodology considers input parameters, such as surface orientation, shadowing effect, elevation, and atmospheric conditions, that influence solar intensity on the earth s surface. The methodology has been implemented for some 212,000 buildings in Knox County, Tennessee, USA. Based on the results obtained, the methodology seems to be adequate for estimating solar radiation on multiple building rooftops. The use of LiDAR data improves the radiation potential estimates in terms of the model predictive error and the spatial pattern of the model outputs. This methodology could help cities/regions interested in sustainable projects to quickly identify buildings with higher potentials for roof-mounted photovoltaic systems.

  6. Smart SUDS: recognising the multiple-benefit potential of sustainable surface water management systems.

    PubMed

    Jose, Roshni; Wade, Rebecca; Jefferies, Chris

    2015-01-01

    How can we make sustainable urban drainage systems (SUDS) smart? SUDS help us to manage surface water runoff from urban environments but they are capable of delivering much more. This paper looks beyond the water quantity and quality improvement functions of SUDS and investigates the multiple benefits that can be gained by implementing smart SUDS solutions. This work provides a new perspective, using methodologies not normally associated with SUDS research, to determine multiple benefits. The outputs of the work can potentially assist decision-makers, designer and planners in recognising the potential for multiple benefits that can be delivered by SUDS. The ecosystem services (ES) associated with a large redevelopment in Dundee, Scotland, UK, are identified and a public perception study together with public participatory geographical information system (PPGIS) methods was used to confirm the goods and benefits of the SUDS. The paper presents findings on the public perception of SUDS as they provide cultural benefits such as recreation, aesthetics and biodiversity. The results show that greenspace is important when choosing a location, and willingness to pay for greenspace is high in this area. This paper concludes that SUDS provide multi-functional benefits in relation to the ES, thereby justifying the cachet of being termed Smart SUDS. PMID:25633948

  7. Modeling Differential Item Functioning Using a Generalization of the Multiple-Group Bifactor Model

    ERIC Educational Resources Information Center

    Jeon, Minjeong; Rijmen, Frank; Rabe-Hesketh, Sophia

    2013-01-01

    The authors present a generalization of the multiple-group bifactor model that extends the classical bifactor model for categorical outcomes by relaxing the typical assumption of independence of the specific dimensions. In addition to the means and variances of all dimensions, the correlations among the specific dimensions are allowed to differ

  8. Gender and Perceived Illness Severity: Differential Indicators of Employment Concerns for Adults with Multiple Sclerosis?

    ERIC Educational Resources Information Center

    Roessler, Richard T.; Turner, Ronna C.; Robertson, Judith L.; Rumrill,Phillip D.

    2005-01-01

    Although research has indicated a link between gender and perceived illness severity and the employment status of people with multiple sclerosis (MS), it has not addressed questions regarding the relationship between those variables and specific types of employment concerns. In this study, a sample of 1,310 adults with MS replied to a mail survey

  9. Meaning Change, Multiple Routes, and the Role of Differentiation in Conceptual Change: Alternatives to Resubsumption?

    ERIC Educational Resources Information Center

    Ohlsson, Stellan

    2009-01-01

    The three commentaries on the resubsumption theory highlight three key ideas: that the term "conceptual change", as commonly used, is ambiguous between "change in the meaning of a concept" and "change in what someone believes"; that there are multiple routes to successful learning of conceptual subject matters; and that the noticing of a

  10. Mindful Education for ADHD Students: Differentiating Curriculum and Instruction Using Multiple Intelligences

    ERIC Educational Resources Information Center

    Proulx-Schirduan, Victoria; Shearer, C. Branton; Case, Karen I.

    2009-01-01

    This practical guide describes ways of working with learners diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) by using Multiple Intelligences Theory. Written for all educators as well as parents, it examines curricular, instructional, school partnering, and leadership issues that may arise for these students in grades K-8. Supported

  11. SUPT6H controls estrogen receptor activity and cellular differentiation by multiple epigenomic mechanisms.

    PubMed

    Bedi, U; Scheel, A H; Hennion, M; Begus-Nahrmann, Y; Rschoff, J; Johnsen, S A

    2015-01-22

    The estrogen receptor alpha (ER?) is the central transcriptional regulator of ductal mammary epithelial lineage specification and is an important prognostic marker in human breast cancer. Although antiestrogen therapies are initially highly effective at treating ER?-positive tumors, a large number of tumors progress to a refractory, more poorly differentiated phenotype accompanied by reduced survival. A better understanding of the molecular mechanisms involved in the progression from estrogen-dependent to hormone-resistant breast cancer may uncover new targets for treatment and the discovery of new predictive markers. Recent studies have uncovered an important role for transcriptional elongation and chromatin modifications in controlling ER? activity and estrogen responsiveness. The human Suppressor of Ty Homologue-6 (SUPT6H) is a histone chaperone that links transcriptional elongation to changes in chromatin structure. We show that SUPT6H is required for estrogen-regulated transcription and the maintenance of chromatin structure in breast cancer cells, possibly in part through interaction with RNF40 and regulation of histone H2B monoubiquitination (H2Bub1). Moreover, we demonstrate that SUPT6H protein levels decrease with malignancy in breast cancer. Consistently, SUPT6H, similar to H2Bub1, is required for cellular differentiation and suppression of the repressive histone mark H3K27me3 on lineage-specific genes. Together, these data identify SUPT6H as a new epigenetic regulator of ER? activity and cellular differentiation. PMID:24441044

  12. Selected extracellular microRNA as potential biomarkers of multiple sclerosis activity--preliminary study.

    PubMed

    Kacperska, Magdalena Justyna; Jastrzebski, Karol; Tomasik, Bartlomiej; Walenczak, Jakub; Konarska-Krol, Maria; Glabinski, Andrzej

    2015-05-01

    Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). Four distinct disease courses are known, although approximately 90% of patients are diagnosed with the relapsing-remitting form (RRMS). The name "multiple sclerosis" pertains to the underlying pathology: the presence of demyelinating plaques in the CNS, in particular in the periventricular region, corpus callosum, cervical spine, and the cerebellum. There are ongoing efforts to discover biomarkers that would allow for an unequivocal diagnosis, assess the activity of inflammatory and neurodegenerative processes, or warn of disease progression. At present, small noncoding RNA particles-microRNA (miRNA, miR) seem to be particularly noteworthy, as they take part in posttranscriptional regulation of expression of various genes. Changes in composition as well as function of miRNA found in body fluids of MS patients are subjects of research, in the hope they prove accurate markers of MS activity. This preliminary study aims to evaluate the expression of selected extracellular microRNA particles (miRNA-let-7a, miRNA-92a, miRNA-684a) in patients experiencing MS relapse and remission, with healthy volunteers serving as a control group and to evaluate the correlation between miRNA expression and selected clinical parameters of those patients. Thirty-seven patients suffering from MS formed two examined groups: 20 patients undergoing relapse and 17 in remission. Thirty healthy volunteers formed the control group. All patients who were subjects to peripheral blood sampling had been hospitalized in the Department of Neurology and Stroke(1). Four milliliters of venous whole blood had been collected into EDTA tubes. The basis for the selection of the three particular miRNA investigated in this study (miRNA-let-7a, miRNA-92a, miRNA-684a) was a preliminary bioinformatic analysis of data compiled from several medical databases, including Ovid MEDLINE, Embase, Cochrane Database of Systematic Reviews (CDSR), miRWalk, and miRBase. The isolation of extracellular microRNA from plasma was carried out using miRNeasy Mini Kit (Qiagen) reagents. The reverse transcription was carried out with TaqMan MicroRNA Reverse Transcription Kit (Applied Biosystems), as per manufacturers' instructions. Standard microRNA TaqMan tests (Applied Biosystems) were used for miRNA quantification. The qPCR were performed on a 7900 HT Fast Real-Time PCR System (Applied Biosystems) and analyzed using Sequence Detection System 2.3 software. In addition, all patients at the Department of Neurology and Stroke undergo a routine complete blood count with differential. The main objective of this study was to evaluate the expression of selected microRNA (has-miR-let-7a, miR-92a, and miR-648a) in the plasma of patients with MS during a relapse as well as in remission and attempt to correlate the acquired data with clinically relevant parameters of the disease. Finding such correlations may potentially lead to the use of miRNA as a biomarker of MS, which could help diagnose the disease and assess its severity and the efficacy of treatment. The difference in the expression of has-miR-let-7a in the remission group and the control group was statistically significant (p?=?0.002). Similarly, the expression of miRNA-648a in patients in remission was significantly different from the expression in the control group (p?=?0.02). Analysis of the correlation between the expression of miRNA-92a and the severity of the disease as measured by the EDSS scale in patients undergoing relapse showed significant negative linear correlation (r?=?-0.54, p?=?0.01). Higher miR-648a expression correlated with more frequent flare-ups in the joint group of patients in remission and relapse (p?=?0.03). This study is one of the few that demonstrate significantly changed expression of selected extracellular miRNA in plasma of MS patients and correlate those findings with clinical parameters. These observations may suggest that some miRNA subsets may be potential biomarkers for M

  13. Multiple Scattering of Laser Pulses in Snow Over Ice: Modeling the Potential Bias in ICESat Altimetry

    NASA Technical Reports Server (NTRS)

    Davis, A. B.; Varnai, T.; Marshak, A.

    2010-01-01

    The primary goal of NASA's current ICESat and future ICESat2 missions is to map the altitude of the Earth's land ice with high accuracy using laser altimetry technology, and to measure sea ice freeboard. Ice however is a highly transparent optical medium with variable scattering and absorption properties. Moreover, it is often covered by a layer of snow with varying depth and optical properties largely dependent on its age. We describe a modeling framework for estimating the potential altimetry bias caused by multiple scattering in the layered medium. We use both a Monte Carlo technique and an analytical diffusion model valid for optically thick media. Our preliminary numerical results are consistent with estimates of the multiple scattering delay from laboratory measurements using snow harvested in Greenland, namely, a few cm. Planned refinements of the models are described.

  14. [Multiple time scales analysis of spatial differentiation characteristics of non-point source nitrogen loss within watershed].

    PubMed

    Liu, Mei-bing; Chen, Xing-wei; Chen, Ying

    2015-07-01

    Identification of the critical source areas of non-point source pollution is an important means to control the non-point source pollution within the watershed. In order to further reveal the impact of multiple time scales on the spatial differentiation characteristics of non-point source nitrogen loss, a SWAT model of Shanmei Reservoir watershed was developed. Based on the simulation of total nitrogen (TN) loss intensity of all 38 subbasins, spatial distribution characteristics of nitrogen loss and critical source areas were analyzed at three time scales of yearly average, monthly average and rainstorms flood process, respectively. Furthermore, multiple linear correlation analysis was conducted to analyze the contribution of natural environment and anthropogenic disturbance on nitrogen loss. The results showed that there were significant spatial differences of TN loss in Shanmei Reservoir watershed at different time scales, and the spatial differentiation degree of nitrogen loss was in the order of monthly average > yearly average > rainstorms flood process. TN loss load mainly came from upland Taoxi subbasin, which was identified as the critical source area. At different time scales, land use types (such as farmland and forest) were always the dominant factor affecting the spatial distribution of nitrogen loss, while the effect of precipitation and runoff on the nitrogen loss was only taken in no fertilization month and several processes of storm flood at no fertilization date. This was mainly due to the significant spatial variation of land use and fertilization, as well as the low spatial variability of precipitation and runoff. PMID:26710649

  15. Multiple polymerase chain reaction markers for the differentiation of canine cutaneous peripheral nerve sheath tumours versus canine fibrosarcomas.

    PubMed

    Meyer, A; Klopfleisch, R

    2014-01-01

    Currently canine fibrosarcomas and peripheral nerve sheath tumours (PNSTs) are differentiated by their histopathological phenotype. Preliminary global transcriptomic analysis has identified genes with significant differential expression in both tumour types that may act as potential tumour markers. The aim of the present study was to establish reverse transcriptase polymerase chain reaction (RT-PCR) assays for the differentiation of formalin-fixed and paraffin wax-embedded tumours of both types. Fifty histologically well-defined examples of canine fibrosarcomas and PNSTs were characterized immunohistochemically for the expression of S100, laminin and PGP 9.5. RT-PCR assays for the potential fibrosarcoma markers FHL2-Ex4 and FHL2-Ex9 and the PNST markers GLI1 and CLEC3B were established and tested for their specificity and sensitivity to differentiate fibrosarcomas and PNSTs by their mRNA expression. Immunohistochemical analysis challenged the value of S100, laminin and PGP 9.5 for the diagnosis of PNSTs, since both PNSTs and fibrosarcomas showed similar expression of these proteins. In contrast, a combination of the markers GLI1 and CLEC3B differentiated PNSTs from fibrosarcomas with a sensitivity of 89% and a specificity of 87%. The proposed fibrosarcoma markers FHL2-Ex4 and FHL2-Ex9 failed to separate PNSTs and fibrosarcomas (sensitivity 50%, specificity 88%). The failure of these markers to unequivocally separate fibrosarcomas and PNSTs raises questions as to whether histologically uniform PNSTs are less uniform at the molecular level than expected or if both tumour types, despite their different morphology, are more closely related in terms of their histogenesis than previously thought. PMID:24650889

  16. Dkk-1 and IL-7 in plasma of patients with multiple myeloma prevent differentiation of mesenchymal stem cells into osteoblasts.

    PubMed

    Nierste, Brittany A; Glackin, Carlotta A; Kirshner, Julia

    2014-01-01

    Bone disease is the leading cause of morbidity associated with multiple myeloma (MM). Lytic bone lesions have been detected in 90% of patients diagnosed with MM and present a great therapeutic challenge. After the removal of the tumor burden, the bone lesions persist and the bone remodeling homeostasis is not restored even in patients in clinical remission. To determine whether systemic factors generated by malignant MM cells can skew the osteoblast (OB) differentiation program of normal mesenchymal stem cells (MSCs), we generated an immortalized bone marrow MSC line (hTERT-MSC). The hTERT-MSCs were exposed to plasma from healthy donors and patients with MM. Cells grown in media supplemented with plasma from MM patients failed to differentiate into OBs, while the hTERT-MSCs grown in the presence of normal human plasma generated OB clusters that mineralized calcium, expressed Runx2, and were positive for alkaline phosphatase, fibronectin, collagen I, osteocalcin, and osteopontin. Blocking Dickkopf-1 (Dkk-1) and interleukin-7 (IL-7) in MM plasma restored proper OB differentiation of hTERT-MSCs. Finally, we show that hTERT-MSCs cultured in the presence of MM plasma adopt a cancer-associated stroma phenotype. Thus, we show, that systemic factors present in the plasma of patients with MM affect the behavior of non-malignant MSCs and contribute to the sustained bone disease reported in MM. PMID:25755907

  17. SATB1 dictates expression of multiple genes including IL-5 involved in human T helper cell differentiation

    PubMed Central

    Ahlfors, Helena; Limaye, Amita; Elo, Laura L.; Tuomela, Soile; Burute, Mithila; Gottimukkala, Kamal Vishnu P.; Notani, Dimple; Rasool, Omid

    2010-01-01

    Special AT-rich binding protein 1 (SATB1) is a global chromatin organizer and a transcription factor regulated by interleukin-4 (IL-4) during the early T helper 2 (Th2) cell differentiation. Here we show that SATB1 controls multiple IL-4 target genes involved in human Th cell polarization or function. Among the genes regulated by SATB1 is that encoding the cytokine IL-5, which is predominantly produced by Th2 cells and plays a key role in the development of eosinophilia in asthma. We demonstrate that, during the early Th2 cell differentiation, IL-5 expression is repressed through direct binding of SATB1 to the IL-5 promoter. Furthermore, SATB1 knockdown-induced up-regulation of IL-5 is partly counteracted by down-regulating GATA3 expression using RNAi in polarizing Th2 cells. Our results suggest that a competitive mechanism involving SATB1 and GATA3 regulates IL-5 transcription, and provide new mechanistic insights into the stringent regulation of IL-5 expression during human Th2 cell differentiation. PMID:20522714

  18. Graphene oxide selectively targets cancer stem cells, across multiple tumor types: implications for non-toxic cancer treatment, via "differentiation-based nano-therapy".

    PubMed

    Fiorillo, Marco; Verre, Andrea F; Iliut, Maria; Peiris-Pags, Maria; Ozsvari, Bela; Gandara, Ricardo; Cappello, Anna Rita; Sotgia, Federica; Vijayaraghavan, Aravind; Lisanti, Michael P

    2015-02-28

    Tumor-initiating cells (TICs), a.k.a. cancer stem cells (CSCs), are difficult to eradicate with conventional approaches to cancer treatment, such as chemo-therapy and radiation. As a consequence, the survival of residual CSCs is thought to drive the onset of tumor recurrence, distant metastasis, and drug-resistance, which is a significant clinical problem for the effective treatment of cancer. Thus, novel approaches to cancer therapy are needed urgently, to address this clinical need. Towards this end, here we have investigated the therapeutic potential of graphene oxide to target cancer stem cells. Graphene and its derivatives are well-known, relatively inert and potentially non-toxic nano-materials that form stable dispersions in a variety of solvents. Here, we show that graphene oxide (of both big and small flake sizes) can be used to selectively inhibit the proliferative expansion of cancer stem cells, across multiple tumor types. For this purpose, we employed the tumor-sphere assay, which functionally measures the clonal expansion of single cancer stem cells under anchorage-independent conditions. More specifically, we show that graphene oxide effectively inhibits tumor-sphere formation in multiple cell lines, across 6 different cancer types, including breast, ovarian, prostate, lung and pancreatic cancers, as well as glioblastoma (brain). In striking contrast, graphene oxide is non-toxic for "bulk" cancer cells (non-stem) and normal fibroblasts. Mechanistically, we present evidence that GO exerts its striking effects on CSCs by inhibiting several key signal transduction pathways (WNT, Notch and STAT-signaling) and thereby inducing CSC differentiation. Thus, graphene oxide may be an effective non-toxic therapeutic strategy for the eradication of cancer stem cells, via differentiation-based nano-therapy. PMID:25708684

  19. Graphene oxide selectively targets cancer stem cells, across multiple tumor types: Implications for non-toxic cancer treatment, via “differentiation-based nano-therapy”

    PubMed Central

    Fiorillo, Marco; Verre, Andrea F.; Iliut, Maria; Peiris-Pagés, Maria; Ozsvari, Bela; Gandara, Ricardo; Cappello, Anna Rita; Sotgia, Federica; Vijayaraghavan, Aravind; Lisanti, Michael P.

    2015-01-01

    Tumor-initiating cells (TICs), a.k.a. cancer stem cells (CSCs), are difficult to eradicate with conventional approaches to cancer treatment, such as chemo-therapy and radiation. As a consequence, the survival of residual CSCs is thought to drive the onset of tumor recurrence, distant metastasis, and drug-resistance, which is a significant clinical problem for the effective treatment of cancer. Thus, novel approaches to cancer therapy are needed urgently, to address this clinical need. Towards this end, here we have investigated the therapeutic potential of graphene oxide to target cancer stem cells. Graphene and its derivatives are well-known, relatively inert and potentially non-toxic nano-materials that form stable dispersions in a variety of solvents. Here, we show that graphene oxide (of both big and small flake sizes) can be used to selectively inhibit the proliferative expansion of cancer stem cells, across multiple tumor types. For this purpose, we employed the tumor-sphere assay, which functionally measures the clonal expansion of single cancer stem cells under anchorage-independent conditions. More specifically, we show that graphene oxide effectively inhibits tumor-sphere formation in multiple cell lines, across 6 different cancer types, including breast, ovarian, prostate, lung and pancreatic cancers, as well as glioblastoma (brain). In striking contrast, graphene oxide is non-toxic for “bulk” cancer cells (non-stem) and normal fibroblasts. Mechanistically, we present evidence that GO exerts its striking effects on CSCs by inhibiting several key signal transduction pathways (WNT, Notch and STAT-signaling) and thereby inducing CSC differentiation. Thus, graphene oxide may be an effective non-toxic therapeutic strategy for the eradication of cancer stem cells, via differentiation-based nano-therapy. PMID:25708684

  20. Multiple pathways are involved in DNA degradation during keratinocyte terminal differentiation

    PubMed Central

    Yamamoto-Tanaka, M; Makino, T; Motoyama, A; Miyai, M; Tsuboi, R; Hibino, T

    2014-01-01

    Loss of the nucleus is a critical step in keratinocyte terminal differentiation. To elucidate the mechanisms involved, we focused on two characteristic events: nuclear translocation of N-terminal fragment of profilaggrin and caspase-14-dependent degradation of the inhibitor of caspase-activated DNase (ICAD). First, we demonstrated that epidermal mesotrypsin liberated a 55-kDa N-terminal fragment of profilaggrin (FLG-N) and FLG-N was translocated into the nucleus. Interestingly, these cells became TUNEL positive. Mutation in the mesotrypsin-susceptible Arg-rich region between FLG-N and the first filaggrin domain abolished these changes. Furthermore, caspase-14 caused limited proteolysis of ICAD, followed by accumulation of caspase-activated DNase (CAD) in TUNEL-positive nuclei. Knockdown of both proteases resulted in a significant increase of remnant nuclei in a skin equivalent model. Immunohistochemical study revealed that both caspase-14 and mesotrypsin were markedly downregulated in parakeratotic areas of lesional skin from patients with atopic dermatitis and psoriasis. Collectively, our results indicate that at least two pathways are involved in the DNA degradation process during keratinocyte terminal differentiation. PMID:24743736

  1. Osteogenic differentiation of amniotic fluid mesenchymal stromal cells and their bone regeneration potential

    PubMed Central

    Pipino, Caterina; Pandolfi, Assunta

    2015-01-01

    In orthopedics, tissue engineering approach using stem cells is a valid line of treatment for patients with bone defects. In this context, mesenchymal stromal cells of various origins have been extensively studied and continue to be a matter of debate. Although mesenchymal stromal cells from bone marrow are already clinically applied, recent evidence suggests that one may use mesenchymal stromal cells from extra-embryonic tissues, such as amniotic fluid, as an innovative and advantageous resource for bone regeneration. The use of cells from amniotic fluid does not raise ethical problems and provides a sufficient number of cells without invasive procedures. Furthermore, they do not develop into teratomas when transplanted, a consequence observed with pluripotent stem cells. In addition, their multipotent differentiation ability, low immunogenicity, and anti-inflammatory properties make them ideal candidates for bone regenerative medicine. We here present an overview of the features of amniotic fluid mesenchymal stromal cells and their potential in the osteogenic differentiation process. We have examined the papers actually available on this regard, with particular interest in the strategies applied to improve in vitro osteogenesis. Importantly, a detailed understanding of the behavior of amniotic fluid mesenchymal stromal cells and their osteogenic ability is desirable considering a feasible application in bone regenerative medicine. PMID:26029340

  2. Increased expression of transient receptor potential canonical 6 (TRPC6) in differentiating human megakaryocytes.

    PubMed

    Ramanathan, Gajalakshmi; Mannhalter, Christine

    2016-02-01

    Members of the transient receptor potential (TRP) family of cation conducting channels are found in several tissues and cell types where they have different physiological functions. The canonical TRP channel 6 (TRPC6) is present on the platelet membrane and appears to participate in calcium influx during platelet activation. However, limited information is available on the importance of TRPC channels in megakaryocytes (MKs), the precursor cells of platelets. We determined the mRNA and protein expression of TRPC family members and investigated the role of TRPC6 for proliferation and differentiation of human MKs derived from CD34+ progenitor cells. TRPC6 transcripts were highly expressed during the differentiation of MKs and TRPC6 protein was detectable in MK cytoplasm by confocal staining. TRPC6 channel activity was modulated by pharmacological approaches using flufenamic acid (FFA) for activation and SKF96365 for inhibition. Upon FFA stimulation in MKs, an increase in intracellular calcium was observed, which was blocked by SKF96365 at 10?M concentration. Incubation of MKs with SKF96365 resulted in a reduction in thrombopoietin-stimulated cell proliferation. Our results suggest a role of TRPC6 in calcium homeostasis during MK development, particularly for cell proliferation. PMID:26514329

  3. Focused arousal and the cognitive 40-Hz event-related potentials: differential diagnosis of Alzheimer's disease.

    PubMed

    Sheer, D E

    1989-01-01

    Focused arousal is a first-order energetic functional component of information processing, operative between sensory inputs and motor outputs. At the neural level of analysis, it represents a first-order interactive system of neural connectivity, providing a mechanism for the organization of unit specificities--coherent resonance at an optional periodicity in finite cell assemblies. Cognitive 40-Hz event-related potentials (CERP), loosely coupled with antecedent and concurrent stimuli, index the operation of focused arousal in circuitry convergent at parietal-temporal-occipital cortex. Methods are described for recording and computer-analyzing CERP, integrated with an automated behavioral testing procedure. The present report summarizes the results from a series of three studies where CERP was used to differentiate early Alzheimer patients from normal geriatrics, multi-infarct, and retarded depression patients. The three normal geriatric groups showed consistent task-dependent hemispheric lateralization. CERP was significantly higher in the left hemisphere with a verbal task, and in the right hemisphere, with a visual-spatial task. The Alzheimer patients showed no hemispheric lateralization and were markedly lower on CERP under all behavioral conditions, as compared with the normal geriatric, multi-infarct, and depression groups. Predictive efficiency of individual cases, differentiating Alzheimer patients from normal geriatrics, multi-infarct, and retarded depression patients, was 80 to 90 percent. PMID:2690123

  4. Reconstruction of Multiple Gastric Electrical Wave Fronts Using Potential Based Inverse Methods

    PubMed Central

    Kim, J. H. K.; Pullan, A. J.; Cheng, L. K.

    2014-01-01

    The ability to reconstruct gastric electrical activity (termed slow waves) non-invasively from potential field measurements made on the torso surface would be a useful tool to aid in the clinical diagnosis of a number of gastric disorders. This is mathematically akin to the inverse problem of electrocardiography. To investigate this problem, an anatomically realistic torso model and an electrical stomach model were used to simulate potentials on the stomach and skin surfaces arising from normal gastric electrical activity. Gaussian noise was added to the torso potentials to represent experimental signal noise. The stomach potentials, activation profiles and gastric slow wave velocities were inversely reconstructed from the torso potentials, using the Tikhonov-Greensite inverse method with regularisation determined using an L-curve method. The inverse solutions were then compared with the known input solutions. The reconstructed solutions were able to represent the presence of multiple propagating wave fronts, determine average activation times to within 5 s and average velocities to within 1 mm/s. When more virtual body surface electrodes were used in the inverse calculations, the accuracy of the reconstructed activity improved. PMID:22254568

  5. [Multiple functions-targeted algorithms and potential applications of forest simulation optimization system (FSOS)].

    PubMed

    Liu, Li; Liu, Guo-Liang; Chen, Shao-Zhi; Tian, Chu-Ping

    2011-11-01

    Forest Simulation and Optimization System (FSOS) model has been widely used in British Columbia of Canada and in Changbai Mountains of China. This model is based on the viewpoint of harmonized and balanced management of forest resources and the application of simulated annealing optimized algorithms in arranging forest management schemes, aimed to realize the sustainable and harmonized development of forest resources multiple objective management and to transform forests to their desired status. The multiple functions (or the multiple objectives) in the FSOS model include water storage and purification, carbon sequestration, wildlife habitat protection, biodiversity conservation, visual landscape quality, and timber production, and the desired forest status is comprehensively defined by experts, environmental organizations, and government policies. This paper introduced in detail the simulated annealing algorithms in FSOS, including solution representation, evaluations, and transitions, and the potential applications of the algorithms in forest ecosystem planning, aimed to provide helps to the planning and management of forest resources and to the governments to quantify, analyze, and manage the forest resources, effectively monitor forest operations, and achieve the sustainable development of forest ecosystem. PMID:22303689

  6. Growth, immortalization, and differentiation potential of normal adult human proximal tubule cells.

    PubMed

    Orosz, David E; Woost, Philip G; Kolb, Robert J; Finesilver, Margaret B; Jin, Wenwu; Frisa, Phyllis S; Choo, Chee-Keong; Yau, Chung-Fai; Chan, Kwok-Wah; Resnick, Martin I; Douglas, Janice G; Edwards, John C; Jacobberger, James W; Hopfer, Ulrich

    2004-01-01

    Human proximal tubule epithelial cell lines are potentially useful models to elucidate the complex cellular and molecular details of water and electrolyte homeostasis in the kidney. Samples of normal adult human kidney tissue were obtained from surgical specimens, and S1 segments of proximal convoluted tubules were microdissected, placed on collagen-coated culture plate inserts, and cocultured with lethally irradiated 3T3 fibroblasts. Primary cultures of proximal tubule epithelial cells were infected with a replication-defective retroviral construct encoding either wild-type or temperature-sensitive simian virus 40 large T-antigen. Cells forming electrically resistive monolayers were selected and expanded in culture. Three cell lines (HPCT-03-ts, HPCT-05-wt, and HPCT-06-wt) were characterized for proximal tubule phenotype by electron microscopy, electrophysiology, immunofluorescence, Southern hybridization, and reverse transcriptase-polymerase chain reaction. Each of the three formed polarized, resistive epithelial monolayers with apical microvilli, tight junctional complexes, numerous mitochondria, well-developed Golgi complexes, extensive endoplasmic reticulum, convolutions of the basolateral plasma membrane, and a primary cilium. Each exhibited succinate, phosphate, and Na,K- adenosine triphosphatase (ATPase) transport activity, as well as acidic dipeptide- and adenosine triphosphate-regulated mechanisms of ion transport. Transcripts for Na(+)-bicarbonate cotransporter, Na(+)-H(+) exchanger isoform 3, Na,K-ATPase, parathyroid hormone receptor, epidermal growth factor receptor, and vasopressin V2 receptor were identified. Furthermore, immunoreactive sodium phosphate cotransporter type II, vasopressin receptor V1a, and CLIC-1 (NCC27) were also identified. These well-differentiated, transport-competent cell lines demonstrated the growth, immortalization, and differentiation potential of normal, adult, human proximal tubule cells and consequently have wide applicability in cell biology and renal physiology. PMID:14748622

  7. The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis

    PubMed Central

    Auletta, Jeffery J; Bartholomew, Amelia M; Maziarz, Richard T; Deans, Robert J; Miller, Robert H; Lazarus, Hillard M; Cohen, Jeffrey A

    2012-01-01

    Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the CNS for which only partially effective therapies exist. Intense research defining the underlying immune pathophysiology is advancing both the understanding of MS as well as revealing potential targets for disease intervention. Mesenchymal stromal cell (MSC) therapy has the potential to modulate aberrant immune responses causing demyelination and axonal injury associated with MS, as well as to repair and restore damaged CNS tissue and cells. This article reviews the pathophysiology underlying MS, as well as providing a cutting-edge perspective into the field of MSC therapy based upon the experience of authors intrinsically involved in MS and MSC basic and translational science research. PMID:22642335

  8. Optical zero-differential pressure switch and its evaluation in a multiple pressure measuring system

    NASA Technical Reports Server (NTRS)

    Powell, J. A.

    1977-01-01

    The design of a clamped-diaphragm pressure switch is described in which diaphragm motion is detected by a simple fiber-optic displacement sensor. The switch was evaluated in a pressure measurement system where it detected the zero crossing of the differential pressure between a static test pressure and a tank pressure that was periodically ramped from near zero to fullscale gage pressure. With a ramping frequency of 1 hertz and a full-scale tank pressure of 69 N/sq cm gage (100 psig), the switch delay was as long as 2 milliseconds. Pressure measurement accuracies were 0.25 to 0.75 percent of full scale. Factors affecting switch performance are also discussed.

  9. Medicago truncatula symbiotic peptide NCR247 contributes to bacteroid differentiation through multiple mechanisms.

    PubMed

    Farkas, Attila; Marti, Gergely; Durg?, Hajnalka; Gyrgypl, Zoltn; Lima, Rui M; Medzihradszky, Katalin F; Kereszt, Attila; Mergaert, Peter; Kondorosi, va

    2014-04-01

    Symbiosis between rhizobia soil bacteria and legume plants results in the formation of root nodules where plant cells are fully packed with nitrogen fixing bacteria. In the host cells, the bacteria adapt to the intracellular environment and gain the ability for nitrogen fixation. Depending on the host plants, the symbiotic fate of bacteria can be either reversible or irreversible. In Medicago and related legume species, the bacteria undergo a host-directed multistep differentiation process culminating in the formation of elongated and branched polyploid bacteria with definitive loss of cell division ability. The plant factors are nodule-specific symbiotic peptides. Approximately 600 of them are nodule-specific cysteine-rich (NCR) peptides produced in the rhizobium-infected plant cells. NCRs are targeted to the endosymbionts, and concerted action of different sets of peptides governs different stages of endosymbiont maturation, whereas the symbiotic function of individual NCRs is unknown. This study focused on NCR247, a cationic peptide exhibiting in vitro antimicrobial activities. We show that NCR247 acts in those nodule cells where bacterial cell division is arrested and cell elongation begins. NCR247 penetrates the bacteria and forms complexes with many bacterial proteins. Interaction with FtsZ required for septum formation is one of the host interventions for inhibiting bacterial cell division. Complex formation with the ribosomal proteins affects translation and contributes to altered proteome and physiology of the endosymbiont. Binding to the chaperone GroEL amplifies the NCR247-modulated biological processes. We show that GroEL1 of Sinorhizobium meliloti is required for efficient infection, terminal differentiation, and nitrogen fixation. PMID:24706863

  10. Method and system for measuring multiphase flow using multiple pressure differentials

    DOEpatents

    Fincke, James R. (Idaho Falls, ID)

    2001-01-01

    An improved method and system for measuring a multiphase flow in a pressure flow meter. An extended throat venturi is used and pressure of the multiphase flow is measured at three or more positions in the venturi, which define two or more pressure differentials in the flow conduit. The differential pressures are then used to calculate the mass flow of the gas phase, the total mass flow, and the liquid phase. The method for determining the mass flow of the high void fraction fluid flow and the gas flow includes certain steps. The first step is calculating a gas density for the gas flow. The next two steps are finding a normalized gas mass flow rate through the venturi and computing a gas mass flow rate. The following step is estimating the gas velocity in the venturi tube throat. The next step is calculating the pressure drop experienced by the gas-phase due to work performed by the gas phase in accelerating the liquid phase between the upstream pressure measuring point and the pressure measuring point in the venturi throat. Another step is estimating the liquid velocity in the venturi throat using the calculated pressure drop experienced by the gas-phase due to work performed by the gas phase. Then the friction is computed between the liquid phase and a wall in the venturi tube. Finally, the total mass flow rate based on measured pressure in the venturi throat is calculated, and the mass flow rate of the liquid phase is calculated from the difference of the total mass flow rate and the gas mass flow rate.

  11. Medicago truncatula symbiotic peptide NCR247 contributes to bacteroid differentiation through multiple mechanisms

    PubMed Central

    Farkas, Attila; Marti, Gergely; Drg?, Hajnalka; Gyrgypl, Zoltn; Lima, Rui M.; Medzihradszky, Katalin F.; Kereszt, Attila; Mergaert, Peter; Kondorosi, va

    2014-01-01

    Symbiosis between rhizobia soil bacteria and legume plants results in the formation of root nodules where plant cells are fully packed with nitrogen fixing bacteria. In the host cells, the bacteria adapt to the intracellular environment and gain the ability for nitrogen fixation. Depending on the host plants, the symbiotic fate of bacteria can be either reversible or irreversible. In Medicago and related legume species, the bacteria undergo a host-directed multistep differentiation process culminating in the formation of elongated and branched polyploid bacteria with definitive loss of cell division ability. The plant factors are nodule-specific symbiotic peptides. Approximately 600 of them are nodule-specific cysteine-rich (NCR) peptides produced in the rhizobium-infected plant cells. NCRs are targeted to the endosymbionts, and concerted action of different sets of peptides governs different stages of endosymbiont maturation, whereas the symbiotic function of individual NCRs is unknown. This study focused on NCR247, a cationic peptide exhibiting in vitro antimicrobial activities. We show that NCR247 acts in those nodule cells where bacterial cell division is arrested and cell elongation begins. NCR247 penetrates the bacteria and forms complexes with many bacterial proteins. Interaction with FtsZ required for septum formation is one of the host interventions for inhibiting bacterial cell division. Complex formation with the ribosomal proteins affects translation and contributes to altered proteome and physiology of the endosymbiont. Binding to the chaperone GroEL amplifies the NCR247-modulated biological processes. We show that GroEL1 of Sinorhizobium meliloti is required for efficient infection, terminal differentiation, and nitrogen fixation. PMID:24706863

  12. Multiple breast cancer risk variants are associated with differential transcript isoform expression in tumors

    PubMed Central

    Caswell, Jennifer L.; Camarda, Roman; Zhou, Alicia Y.; Huntsman, Scott; Hu, Donglei; Brenner, Steven E.; Zaitlen, Noah; Goga, Andrei; Ziv, Elad

    2015-01-01

    Genome-wide association studies have identified over 70 single-nucleotide polymorphisms (SNPs) associated with breast cancer. A subset of these SNPs are associated with quantitative expression of nearby genes, but the functional effects of the majority remain unknown. We hypothesized that some risk SNPs may regulate alternative splicing. Using RNA-sequencing data from breast tumors and germline genotypes from The Cancer Genome Atlas, we tested the association between each risk SNP genotype and exon-, exonexon junction- or transcript-specific expression of nearby genes. Six SNPs were associated with differential transcript expression of seven nearby genes at FDR < 0.05 (BABAM1, DCLRE1B/PHTF1, PEX14, RAD51L1, SRGAP2D and STXBP4). We next developed a Bayesian approach to evaluate, for each SNP, the overlap between the signal of association with breast cancer and the signal of association with alternative splicing. At one locus (SRGAP2D), this method eliminated the possibility that the breast cancer risk and the alternate splicing event were due to the same causal SNP. Lastly, at two loci, we identified the likely causal SNP for the alternative splicing event, and at one, functionally validated the effect of that SNP on alternative splicing using a minigene reporter assay. Our results suggest that the regulation of differential transcript isoform expression is the functional mechanism of some breast cancer risk SNPs and that we can use these associations to identify causal SNPs, target genes and the specific transcripts that may mediate breast cancer risk. PMID:26472073

  13. Multiple breast cancer risk variants are associated with differential transcript isoform expression in tumors.

    PubMed

    Caswell, Jennifer L; Camarda, Roman; Zhou, Alicia Y; Huntsman, Scott; Hu, Donglei; Brenner, Steven E; Zaitlen, Noah; Goga, Andrei; Ziv, Elad

    2015-12-20

    Genome-wide association studies have identified over 70 single-nucleotide polymorphisms (SNPs) associated with breast cancer. A subset of these SNPs are associated with quantitative expression of nearby genes, but the functional effects of the majority remain unknown. We hypothesized that some risk SNPs may regulate alternative splicing. Using RNA-sequencing data from breast tumors and germline genotypes from The Cancer Genome Atlas, we tested the association between each risk SNP genotype and exon-, exon-exon junction- or transcript-specific expression of nearby genes. Six SNPs were associated with differential transcript expression of seven nearby genes at FDR < 0.05 (BABAM1, DCLRE1B/PHTF1, PEX14, RAD51L1, SRGAP2D and STXBP4). We next developed a Bayesian approach to evaluate, for each SNP, the overlap between the signal of association with breast cancer and the signal of association with alternative splicing. At one locus (SRGAP2D), this method eliminated the possibility that the breast cancer risk and the alternate splicing event were due to the same causal SNP. Lastly, at two loci, we identified the likely causal SNP for the alternative splicing event, and at one, functionally validated the effect of that SNP on alternative splicing using a minigene reporter assay. Our results suggest that the regulation of differential transcript isoform expression is the functional mechanism of some breast cancer risk SNPs and that we can use these associations to identify causal SNPs, target genes and the specific transcripts that may mediate breast cancer risk. PMID:26472073

  14. The SWI/SNF Chromatin Remodeling Complex Selectively Affects Multiple Aspects of Serotonergic Neuron Differentiation

    PubMed Central

    Weinberg, Peter; Flames, Nuria; Sawa, Hitoshi; Garriga, Gian; Hobert, Oliver

    2013-01-01

    Regulatory programs that control the specification of serotonergic neurons have been investigated by genetic mutant screens in the nematode Caenorhabditis elegans. Loss of a previously uncloned gene, ham-3, affects migration and serotonin antibody staining of the hermaphrodite-specific neuron (HSN) pair. We characterize these defects here in more detail, showing that the defects in serotonin antibody staining are paralleled by a loss of the transcription of all genes involved in serotonin synthesis and transport. This loss is specific to the HSN class as other serotonergic neurons appear to differentiate normally in ham-3 null mutants. Besides failing to migrate appropriately, the HSNs also display axon pathfinding defects in ham-3 mutants. However, the HSNs are still generated and express a subset of their terminal differentiation features in ham-3 null mutants, demonstrating that ham-3 is a specific regulator of select features of the HSNs. We show that ham-3 codes for the C. elegans ortholog of human BAF60, Drosophila Bap60, and yeast Swp73/Rsc6, which are subunits of the yeast SWI/SNF and vertebrate BAF chromatin remodeling complex. We show that the effect of ham-3 on serotonergic fate can be explained by ham-3 regulating the expression of the Spalt/SALL-type Zn finger transcription factor sem-4, a previously identified regulator of serotonin expression in HSNs and of the ham-2 Zn transcription factor, a previously identified regulator of HSN migration and axon outgrowth. Our findings provide the first evidence for the involvement of the BAF complex in the acquisition of terminal neuronal identity and constitute genetic proof by germline knockout that a BAF complex component can have cell-type-specific roles during development. PMID:23457234

  15. Multidimensional partial differential equation systems: Generating new systems via conservation laws, potentials, gauges, subsystems

    NASA Astrophysics Data System (ADS)

    Cheviakov, Alexei F.; Bluman, George W.

    2010-10-01

    For many systems of partial differential equations (PDEs), including nonlinear ones, one can construct nonlocally related PDE systems. In recent years, such nonlocally related systems have proven to be useful in applications. In particular, they have yielded systematically nonlocal symmetries, nonlocal conservation laws, noninvertible linearizations, and new exact solutions for many different PDE systems of interest. However, the overwhelming majority of new results and theoretical understanding pertain only to PDE systems with two independent variables. The situation for PDE systems with more than two independent variables turns out to be much more complicated due to gauge freedom relating potential variables. The current paper, together with the companion paper [A. F. Cheviakov and G. W. Bluman, J. Math. Phys. 51, 103522 (2010)], synthesizes and systematically extends known results for nonlocally related systems arising for multidimensional PDE systems, i.e., for PDE systems with three or more independent variables. The presented framework includes potential systems arising from lower-degree conservation laws of a given PDE system. Nonlocally related multidimensional PDE systems are discussed in terms of their construction, properties, and applications.

  16. Multiple evolutionary processes drive the patterns of genetic differentiation in a forest tree species complex

    PubMed Central

    Jones, Rebecca C; Steane, Dorothy A; Lavery, Martyn; Vaillancourt, Ren E; Potts, Brad M

    2013-01-01

    Forest trees frequently form species complexes, complicating taxonomic classification and gene pool management. This is certainly the case in Eucalyptus, and well exemplified by the Eucalyptus globulus complex. This ecologically and economically significant complex comprises four taxa (sspp. bicostata, globulus, maidenii, pseudoglobulus) that are geographically and morphologically distinct, but linked by extensive intergrade populations. To resolve their genetic affinities, nine microsatellites were used to genotype 1200 trees from throughout the natural range of the complex in Australia, representing 33 morphological core and intergrade populations. There was significant spatial genetic structure (FST = 0.10), but variation was continuous. High genetic diversity in southern ssp. maidenii indicates that this region is the center of origin. Genetic diversity decreases and population differentiation increases with distance from this area, suggesting that drift is a major evolutionary process. Many of the intergrade populations, along with other populations morphologically classified as ssp. pseudoglobulus or ssp. globulus, belong to a cryptic genetic entity that is genetically and geographically intermediate between core ssp. bicostata, ssp. maidenii, and ssp. globulus. Geography, rather than morphology, therefore, is the best predictor of overall genetic affinities within the complex and should be used to classify germplasm into management units for conservation and breeding purposes. PMID:23403692

  17. Geochemical consequences of flow differentiation in a multiple injection dike (Trinity ophiolite, N. California)

    USGS Publications Warehouse

    Brouxel, M.

    1991-01-01

    A clinopyroxene-rich dike of the Trinity ophiolite sheeted-dike complex shows three different magmatic pulses, probably injected in a short period of time (no well developed chilled margin) and important variations of the clinopyroxene and plagioclase percentages between its core (highly porphyritic) and margins (aphyric). This variation, interpreted as related to a flow differentiation phenomenon (mechanical phenocryst redistribution), has important geochemical consequences. It produces increases in the FeO, MgO, CaO, Cr and Ni contents from the margin to the core, together with increases in the clinopyroxene percentage, and decreases in the SiO2, Zr, Y, Nb and REE contents together with a decrease in the percentage of the fine-grained groundmass toward the core of the dike. This mineralogical redistribution, which also affects the incompatible trace element ratios because of the difference in plagioclase and clinopyroxene mineral/liquid partition coefficients, illustrate the importance of fractionation processes outside of a magma chamber. ?? 1991.

  18. Moving finite element method: Applications to general partial differential equations with multiple large gradients

    SciTech Connect

    Gelinas, R.J.; Doss, S.K.; Miller, K.

    1981-03-01

    The moving finite element (MFE) method has been reduced to practice in the automatic solution program DYLA for general systems of transient partial differential equations (PDEs) in 1-D. Several test examples are presented which illustrate the unique node movement and systematic control features which are intrinsic in the MFE method. Computational dilemmas of numerical diffusion, Gibbs overshooting and undershooting, zone tangling, and grid remap (or re-connection) aliasing, which occur frequently in conventional PDE methods, are essentially eliminated in the MFE mehtod. Arbitrarily large gradients (or shocks) can be solved with extremely high resolution and accuracy for non-coincident, or even counterdirected, propagating wavefronts. Boundary layers of arbitrarily small dimensions are solved with high accuracy simultaneously with the large-scale structures in reactive and non-reactive fluid calculations. The MFE method requires a small fraction of the grid nodes which are used in conventional PDE solution methods because the nodes migrate continuously and systematically to those positions where they are most needed in order to yield accurate PDE solutions on entire problem domains. Courant--Friedrichs--Lewy time-step limits are exceeded by wide margins (by factors of two to several thousand). Finally, the extension of the MFE method to 2-D is briefly discussed.

  19. miR-29b negatively regulates human osteoclastic cell differentiation and function: implications for the treatment of multiple myeloma-related bone disease.

    PubMed

    Rossi, Marco; Pitari, Maria Rita; Amodio, Nicola; Di Martino, Maria Teresa; Conforti, Francesco; Leone, Emanuela; Botta, Cirino; Paolino, Francesco Maria; Del Giudice, Teresa; Iuliano, Eleonora; Caraglia, Michele; Ferrarini, Manlio; Giordano, Antonio; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2013-07-01

    Skeletal homeostasis relies upon a fine tuning of osteoclast (OCL)-mediated bone resorption and osteoblast (OBL)-dependent bone formation. This balance is unsettled by multiple myeloma (MM) cells, which impair OBL function and stimulate OCLs to generate lytic lesions. Emerging experimental evidence is disclosing a key regulatory role of microRNAs (miRNAs) in the regulation of bone homeostasis suggesting the miRNA network as potential novel target for the treatment of MM-related bone disease (BD). Here, we report that miR-29b expression decreases progressively during human OCL differentiation in vitro. We found that lentiviral transduction of miR-29b into OCLs, even in the presence of MM cells, significantly impairs tartrate acid phosphatase (TRAcP) expression, lacunae generation, and collagen degradation, which are relevant hallmarks of OCL activity. Accordingly, expression of cathepsin K and metalloproteinase 9 (MMP9) as well as actin ring rearrangement were impaired in the presence of miR-29b. Moreover, we found that canonical targets C-FOS and metalloproteinase 2 are suppressed by constitutive miR-29b expression which also downregulated the master OCL transcription factor, NAFTc-1. Overall, these data indicate that enforced expression of miR-29b impairs OCL differentiation and overcomes OCL activation triggered by MM cells, providing a rationale for miR-29b-based treatment of MM-related BD. PMID:23254643

  20. Depletion of histone demethylase KDM2A enhanced the adipogenic and chondrogenic differentiation potentials of stem cells from apical papilla

    SciTech Connect

    Dong, Rui; Yao, Rui; Du, Juan; Wang, Songlin; Fan, Zhipeng

    2013-11-01

    Mesenchymal stem cells (MSCs) are a reliable resource for tissue regeneration, but the molecular mechanism underlying directed differentiation remains unclear; this has restricted potential MSC applications. The histone demethylase, lysine (K)-specific demethylase 2A (KDM2A), is evolutionarily conserved and ubiquitously expressed members of the JmjC-domain-containing histone demethylase family. A previous study determined that KDM2A can regulate the cell proliferation and osteo/dentinogenic differentiation of MSCs. It is not known whether KDM2A is involved in the other cell lineages differentiation of MSCs. Here, we show that depletion of KDM2A by short hairpin RNAs can enhance adipogenic and chondrogenic differentiation potentials in human stem cells from apical papilla (SCAPs). We found that the stemness-related genes, SOX2, and the embryonic stem cell master transcription factor, NANOG were significantly increased after silence of KDM2A in SCAPs. Moreover, we found that knock-down of the KDM2A co-factor, BCOR also up-regulated the mRNA levels of SOX2 and NANOG. Furthermore, Chromatin immunoprecipitation assays demonstrate that silence of KDM2A increased the histone H3 Lysine 4 (H3K4) trimethylation in the SOX2 and NANOG locus and regulates its expression. In conclusion, our results suggested that depletion of KDM2A enhanced the adipogenic and chondrogenic differentiation potentials of SCAPs by up-regulated SOX2 and NANOG, BCOR also involved in this regulation as co-factor, and provided useful information to understand the molecular mechanism underlying directed differentiation in MSCs. - Highlights: • Depletion of KDM2A enhances adipogenic/chondrogenic differentiation in SCAPs. • Depletion of KDM2A enhances the differentiation of SCAPs by activate SOX2 and NANOG. • Silence of KDM2A increases histone H3 Lysine 4 trimethylation in SOX2 and NANOG. • BCOR is co-factor of KDM2A involved in the differentiation regulation.

  1. Electrophilic PPAR? ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: a potentially novel therapy for corneal scarring.

    PubMed

    Kuriyan, A E; Lehmann, G M; Kulkarni, A A; Woeller, C F; Feldon, S E; Hindman, H B; Sime, P J; Huxlin, K R; Phipps, R P

    2012-01-01

    A critical component of corneal scarring is the TGF?-induced differentiation of corneal keratocytes into myofibroblasts. Inhibitors of this differentiation are potentially therapeutic for corneal scarring. In thisstudy, we tested the relative effectiveness and mechanisms of action of two electrophilic peroxisome proliferator-activated receptor gamma (PPAR?) ligands: cyano-3,12-dioxolean-1,9-dien-28-oic acid-methyl ester (CDDO-Me) and 15-deoxy-?(-12,14)-prostaglandin J(2) (15d-PGJ(2)) for inhibiting TGF?-induced myofibroblast differentiation invitro. TGF? was used to induce myofibroblast differentiation in cultured, primary human corneal fibroblasts. CDDO-Me and 15d-PGJ(2) were added to cultures to test their ability to inhibit this process. Myofibroblast differentiation was assessed by measuring the expression of myofibroblast-specific proteins (?SMA, collagen I, and fibronectin) and mRNA (?SMA and collagen III). The role of PPAR? in the inhibition of myofibroblast differentiation by these agents was tested in genetically and pharmacologically manipulated cells. Finally, we assayed the importance of electrophilicity in the actions of these agents on TGF?-induced ?SMA expression via Western blotting and immunofluorescence. Both electrophilic PPAR? ligands (CDDO-Me and 15d-PGJ(2)) potently inhibited TGF?-induced myofibroblast differentiation, but PPAR? was only partially required for inhibition of myofibroblast differentiation by either agent. Electrophilic PPAR? ligands were able to inhibit myofibroblast differentiation more potently than non-electrophilic PPAR? ligands, suggesting an important role of electrophilicity in this process. CDDO-Me and 15d-PGJ(2) are strong inhibitors of TGF?-induced corneal fibroblast to myofibroblast differentiation invitro, suggesting this class of agents as potential novel therapies for corneal scarring warranting further study in pre-clinical animal models. PMID:22178289

  2. Electrophilic PPAR? ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: A potentially novel therapy for corneal scarring

    PubMed Central

    Kuriyan, A.E.; Lehmann, G.M.; Kulkarni, A.A.; Woeller, C.F.; Feldon, S.E.; Hindman, H.B.; Sime, P.; Huxlin, K.R.; Phipps, R.P.

    2011-01-01

    A critical component of corneal scarring is the TGF?-induced differentiation of corneal keratocytes into myofibroblasts. Inhibitors of this differentiation are potentially therapeutic for corneal scarring. In this study, we tested the relative effectiveness and mechanisms of action of two electrophilic peroxisome proliferator-activated receptor gamma (PPAR?) ligands: cyano-3,12-dioxolean-1,9-dien-28-oic acid-metheyl ester (CDDO-Me) and 15-deoxy-?-12,14-prostaglandin J2 (15d-PGJ2) for inhibiting TGF?-induced myofibroblast differentiation in vitro. TGF? was used to induce myofibroblast differentiation in cultured, primary human corneal fibroblasts. CDDO-Me and 15d-PGJ2 were added to cultures to test their ability to inhibit this process. Myofibroblast differentiation was assessed by measuring the expression of myofibroblast-specific proteins (?SMA, collagen I, and fibronectin) and mRNA (?SMA and collagen III). The role of PPAR? in the inhibition of myofibroblast differentiation by these agents was tested in genetically and pharmacologically manipulated cells. Finally, we assayed the importance of electrophilicity in the actions of these agents on TGF?-induced ?SMA expression via Western blotting and immunofluorescence. Both electrophilic PPAR? ligands (CDDO-Me and 15d-PGJ2) potently inhibited TGF?-induced myofibroblast differentiation, but PPAR? was only partially required for inhibition of myofibroblast differentiation by either agent. Electrophilic PPAR? ligands were able to inhibit myofibroblast differentiation more potently than non-electrophilic PPAR? ligands, suggesting an important role of electrophilicity in this process. CDDO-Me and 15d-PGJ2 are strong inhibitors of TGF?-induced corneal fibroblast to myofibroblast differentiation in vitro, suggesting this class of agents as potential novel therapies for corneal scarring warranting further study in pre-clinical animal models. PMID:22178289

  3. Can Vestibular-Evoked Myogenic Potentials Help Differentiate Mnire Disease from Vestibular Migraine?

    PubMed Central

    Zuniga, M. Geraldine; Janky, Kristen L.; Schubert, Michael C.; Carey, John P.

    2013-01-01

    Objectives To characterize both cervical and ocular vestibular-evoked myogenic potential (cVEMP, oVEMP) responses to air-conducted sound (ACS) and midline taps in Mnire disease (MD), vestibular migraine (VM), and controls, as well as to determine if cVEMP or oVEMP responses can differentiate MD from VM. Study Design Prospective cohort study. Setting Tertiary referral center. Subjects and Methods Unilateral definite MD patients (n = 20), VM patients (n = 21) by modified Neuhauser criteria, and age-matched controls (n = 28). cVEMP testing used ACS (clicks), and oVEMP testing used ACS (clicks and 500-Hz tone bursts) and midline tap stimuli (reflex hammer and Mini-Shaker). Outcome parameters were cVEMP peak-to-peak amplitudes and oVEMP n10 amplitudes. Results Relative to controls, MD and VM groups both showed reduced click-evoked cVEMP (P < .001) and oVEMP (P < .001) amplitudes. Only the MD group showed reduction in tone-evoked amplitudes for oVEMP. Tone-evoked oVEMPs differentiated MD from controls (P = .001) and from VM (P = .007). The oVEMPs in response to the reflex hammer and Mini-Shaker midline taps showed no differences between groups (P > .210). Conclusions Using these techniques, VM and MD behaved similarly on most of the VEMP test battery. A link in their pathophysiology may be responsible for these responses. The data suggest a difference in 500-Hz tone burstevoked oVEMP responses between MD and MV as a group. However, no VEMP test that was investigated segregated individuals with MD from those with VM. PMID:22267492

  4. Melanocytic differentiation is present in a significant proportion of nonpigmented diffuse neurofibromas: a potential diagnostic pitfall.

    PubMed

    Piem, Joe; Nicholson, Kimberly M; Mraz, Jerica; Prieto, Victor G

    2013-08-01

    Whereas the pigmented (melanotic) variant of diffuse neurofibroma (DNF) with positivity for melanocytic markers is well recognized, expression of melanocytic markers in nonpigmented DNF has not been systematically studied. We analyzed 28 unselected consecutive DNFs for expression of melanocytic markers, including melan A, microphthalmia transcription factor (MITF), and HMB-45 antigen. For comparison, we also analyzed 40 localized skin neurofibromas and 7 intraneural neurofibromas. One case of nonpigmented DNF was analyzed by electron microscopy. Of the 28 DNFs studied by immunohistochemistry, 3 were pigmented and 25 nonpigmented. The 3 pigmented DNFs and 9 of 25 (36%) nonpigmented DNFs expressed melan A, MITF, and HMB-45 antigen. These markers were expressed either focally or more diffusely, typically in a minority of the lesional cells, and usually both in the dermal and subcutaneous portion of the DNF. Melan A was expressed in the largest number of the lesional cells (up to 50%), whereas only a small fraction of the melan A-positive cells (from 5% to 10% in most cases) also expressed HMB-45 antigen. None of the 47 non-DNFs expressed these markers. Ultrastructurally, melanosomes were present in some cells in nonpigmented DNF that expressed the melanocytic markers. Twenty-three of 28 (82%) DNFs, including 10 of 12 (83%) DNFs with melanocytic differentiation, were associated with neurofibromatosis type 1. Expression of melanocytic markers, including melan A, HMB-45 antigen, and MITF in DNF is a potential pitfall in differential diagnosis with melanocytic lesions that may clinically or histopathologically resemble DNF, in particular congenital melanocytic nevus with neurotization and neurofibroma-like melanoma. PMID:23715161

  5. Garlic Constituent Diallyl Trisulfide Prevents Development of Poorly-Differentiated Prostate Cancer and Pulmonary Metastasis Multiplicity in TRAMP Mice

    PubMed Central

    Singh, Shivendra V.; Powolny, Anna A.; Stan, Silvia D.; Xiao, Dong; Arlotti, Julie A.; Warin, Renaud; Hahm, Eun-Ryeong; Marynowski, Stanley W.; Bommareddy, Ajay; Potter, Douglas M.; Dhir, Rajiv

    2008-01-01

    Identification of agents that are non-toxic but can delay onset and/or progression of prostate cancer, which is the second leading cause of cancer-related deaths among men in the United States, is highly desirable. We now demonstrate that oral gavage of garlic constituent diallyl trisulfide (1 and 2 mg/d, thrice/week for thirteen weeks beginning at eight weeks of age) significantly inhibits progression to poorly-differentiated prostate carcinoma and pulmonary metastasis multiplicity in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice without any side effects. There was a trend of a decrease in average wet weights of the urogenital tract and prostate gland in 1 and 2 mg DATS-treated mice compared with controls (∼25-46% decrease in DATS-treated mice compared with controls). The incidence and the area of the dorsolateral prostate occupied by the poorly-differentiated carcinoma were significantly lower in both 1 and 2 mg DATS-treated mice compared with control mice. In addition, DATS administration resulted in a statistically significant decrease in pulmonary metastasis multiplicity compared with controls (P= 0.002). The dorsolateral prostate from DATS-treated TRAMP mice exhibited decreased cellular proliferation in association with induction of cyclinB1 and securin protein levels, and suppression of the expression of neuroendocrine marker synaptophysin. However, DATS administration did not have any appreciable effect on apoptosis induction, angiogenesis or natural killer and dendritic cell function. In conclusion, the results of the present study demonstrate, for the first time, that DATS administration prevents progression to invasive carcinoma and lung metastasis in TRAMP mice. PMID:19010926

  6. A Simple Differential Equation Associating Multiple Types of Probability Distributions in Characterization of Noninear Processes in Geosciences

    NASA Astrophysics Data System (ADS)

    Cheng, Q.

    2014-12-01

    Probability distributions or probability density functions are commonly used in geosciences for purposes ranging from characterization, estimation, prediction and assessment. Each type of probability distribution is found suitable for describing certain types of phenomena and processes, for example, the normal distribution is used, ensured by the classical Central Limit Theorem, to characterizing physical quantities summed many independent processes such as measurement errors, gamma distribution is frequently used to model waiting times, Pareto distribution to extreme events, power-law distribution to frequency-size distribution of earthquakes and inverse gamma distribution for self-organized criticality description of landslides. Understanding the associations of these types of probability distributions is essential not only for determining usage of these distributions but also for interpretation of the results. In this paper we demonstrate that a simple non-linear first order differential equation can be used to describe the decay function of probability density around the mean values. Assume the decay rate of probability density function is negatively proportional to the density itself or a power of the density, with a functional coefficient dependent on the value of the random variable. Applying Taylor series expansion to the coefficient function, the differential equation can be approximated by multiple simple dynamic systems, each with explicit solutions. These functions can be utilized either as separate and combined solutions to generate various commonly used probability distributions including but not limited to Gaussian, power-law, gamma, inverse gamma, Pareto, Weibull, Rayleigh, and Maxwell-Boltzmann distributions. The association of these types of distributions provides insight into multiple types of probability distributions commonly used in characterization of extreme events in nonlinear processes in geosciences.

  7. Breastmilk Is a Novel Source of Stem Cells with Multilineage Differentiation Potential

    PubMed Central

    Hassiotou, Foteini; Beltran, Adriana; Chetwynd, Ellen; Stuebe, Alison M; Twigger, Alecia-Jane; Metzger, Philipp; Trengove, Naomi; Lai, Ching Tat; Filgueira, Luis; Blancafort, Pilar; Hartmann, Peter E

    2012-01-01

    The mammary gland undergoes significant remodeling during pregnancy and lactation, which is fuelled by controlled mammary stem cell (MaSC) proliferation. The scarcity of human lactating breast tissue specimens and the low numbers and quiescent state of MaSCs in the resting breast have hindered understanding of both normal MaSC dynamics and the molecular determinants that drive their aberrant self-renewal in breast cancer. Here, we demonstrate that human breastmilk contains stem cells (hBSCs) with multilineage properties. Breastmilk cells from different donors displayed variable expression of pluripotency genes normally found in human embryonic stem cells (hESCs). These genes included the transcription factors (TFs) OCT4, SOX2, NANOG, known to constitute the core self-renewal circuitry of hESCs. When cultured in the presence of mouse embryonic feeder fibroblasts, a population of hBSCs exhibited an encapsulated ESC-like colony morphology and phenotype and could be passaged in secondary and tertiary clonogenic cultures. While self-renewal TFs were found silenced in the normal resting epithelium, they were dramatically upregulated in breastmilk cells cultured in 3D spheroid conditions. Furthermore, hBSCs differentiated in vitro into cell lineages from all three germ layers. These findings provide evidence that breastmilk represents a novel and noninvasive source of patient-specific stem cells with multilineage potential and establish a method for expansion of these cells in culture. They also highlight the potential of these cells to be used as novel models to understand adult stem cell plasticity and breast cancer, with potential use in bioengineering and tissue regeneration. Stem Cells2012;30:21642174 PMID:22865647

  8. Differential amplification, assembly, and relocation of multiple DNA sequences in human neuroblastomas and neuroblastoma cell lines.

    PubMed Central

    Shiloh, Y; Shipley, J; Brodeur, G M; Bruns, G; Korf, B; Donlon, T; Schreck, R R; Seeger, R; Sakai, K; Latt, S A

    1985-01-01

    DNA amplification, manifested by homogeneously staining regions in chromosomes and by extrachromosomal, double minute bodies, is characteristic of many neuroblastoma cell lines. Sequences recruited from a specific domain on the short arm of chromosome 2 (2p) are amplified in advanced-stage primary neuroblastomas, whereas sequences from distinctly different regions of 2p are amplified in the neuroblastoma cell line IMR-32. Five different DNA segments, which include the oncogene N-myc, three other fragments derived from the homogeneously staining region of the neuroblastoma cell line IMR-32, and a fifth fragment, derived from the neuroblastoma cell line NB-9, showed differential and variable amplification in 24 advanced-stage neuroblastoma tumors out of 112 tested specimens. All five fragments were mapped within the chromosomal region 2p23-2p25 by three different approaches. However, eight other fragments cloned from the homogeneously staining region of IMR-32 cells, which were not amplified in the tumor tissues examined, were mapped to two more proximal domains of 2p, thousands of kilobases apart from each other and from the chromosomal domain that is amplified in the tumors. These results establish the amplification, to different degrees, of a variable-sized segment of one domain near the terminus of 2p in advanced neuroblastomas. These tumors might ultimately be distinguished according to the pattern of amplification of DNA segments within this domain. The data presented also indicate the existence of a new and complex amplification mechanism in at least one neuroblastoma cell line (IMR-32), which involves not only relocation of DNA from specific genomic domains but also the formation of novel units by splicing together very distant DNA segments. Images PMID:3858848

  9. Differential pulse amplitude modulation for multiple-input single-output OWVLC

    NASA Astrophysics Data System (ADS)

    Yang, S. H.; Kwon, D. H.; Kim, S. J.; Son, Y. H.; Han, S. K.

    2015-01-01

    White light-emitting diodes (LEDs) are widely used for lighting due to their energy efficiency, eco-friendly, and small size than previously light sources such as incandescent, fluorescent bulbs and so on. Optical wireless visible light communication (OWVLC) based on LED merges lighting and communications in applications such as indoor lighting, traffic signals, vehicles, and underwater communications because LED can be easily modulated. However, physical bandwidth of LED is limited about several MHz by slow time constant of the phosphor and characteristics of device. Therefore, using the simplest modulation format which is non-return-zero on-off-keying (NRZ-OOK), the data rate reaches only to dozens Mbit/s. Thus, to improve the transmission capacity, optical filtering and pre-, post-equalizer are adapted. Also, high-speed wireless connectivity is implemented using spectrally efficient modulation methods: orthogonal frequency division multiplexing (OFDM) or discrete multi-tone (DMT). However, these modulation methods need additional digital signal processing such as FFT and IFFT, thus complexity of transmitter and receiver is increasing. To reduce the complexity of transmitter and receiver, we proposed a novel modulation scheme which is named differential pulse amplitude modulation. The proposed modulation scheme transmits different NRZ-OOK signals with same amplitude and unit time delay using each LED chip, respectively. The `N' parallel signals from LEDs are overlapped and directly detected at optical receiver. Received signal is demodulated by power difference between unit time slots. The proposed scheme can overcome the bandwidth limitation of LEDs and data rate can be improved according to number of LEDs without complex digital signal processing.

  10. Identification of potential biomarkers from microarray experiments using multiple criteria optimization

    PubMed Central

    Snchez-Pea, Matilde L; Isaza, Clara E; Prez-Morales, Jaileene; Rodrguez-Padilla, Cristina; Castro, Jos M; Cabrera-Ros, Mauricio

    2013-01-01

    Microarray experiments are capable of determining the relative expression of tens of thousands of genes simultaneously, thus resulting in very large databases. The analysis of these databases and the extraction of biologically relevant knowledge from them are challenging tasks. The identification of potential cancer biomarker genes is one of the most important aims for microarray analysis and, as such, has been widely targeted in the literature. However, identifying a set of these genes consistently across different experiments, researches, microarray platforms, or cancer types is still an elusive endeavor. Besides the inherent difficulty of the large and nonconstant variability in these experiments and the incommensurability between different microarray technologies, there is the issue of the users having to adjust a series of parameters that significantly affect the outcome of the analyses and that do not have a biological or medical meaning. In this study, the identification of potential cancer biomarkers from microarray data is casted as a multiple criteria optimization (MCO) problem. The efficient solutions to this problem, found here through data envelopment analysis (DEA), are associated to genes that are proposed as potential cancer biomarkers. The method does not require any parameter adjustment by the user, and thus fosters repeatability. The approach also allows the analysis of different microarray experiments, microarray platforms, and cancer types simultaneously. The results include the analysis of three publicly available microarray databases related to cervix cancer. This study points to the feasibility of modeling the selection of potential cancer biomarkers from microarray data as an MCO problem and solve it using DEA. Using MCO entails a new optic to the identification of potential cancer biomarkers as it does not require the definition of a threshold value to establish significance for a particular gene and the selection of a normalization procedure to compare different experiments is no longer necessary. PMID:23634293

  11. Reconstruction of multiple gastric electrical wave fronts using potential-based inverse methods

    NASA Astrophysics Data System (ADS)

    Kim, J. H. K.; Pullan, A. J.; Cheng, L. K.

    2012-08-01

    One approach for non-invasively characterizing gastric electrical activity, commonly used in the field of electrocardiography, involves solving an inverse problem whereby electrical potentials on the stomach surface are directly reconstructed from dense potential measurements on the skin surface. To investigate this problem, an anatomically realistic torso model and an electrical stomach model were used to simulate potentials on stomach and skin surfaces arising from normal gastric electrical activity. The effectiveness of the Greensite-Tikhonov or the Tikhonov inverse methods were compared under the presence of 10% Gaussian noise with either 84 or 204 body surface electrodes. The stability and accuracy of the Greensite-Tikhonov method were further investigated by introducing varying levels of Gaussian signal noise or by increasing or decreasing the size of the stomach by 10%. Results showed that the reconstructed solutions were able to represent the presence of propagating multiple wave fronts and the Greensite-Tikhonov method with 204 electrodes performed best (correlation coefficients of activation time: 90%; pacemaker localization error: 3 cm). The Greensite-Tikhonov method was stable with Gaussian noise levels up to 20% and 10% change in stomach size. The use of 204 rather than 84 body surface electrodes improved the performance; however, for all investigated cases, the Greensite-Tikhonov method outperformed the Tikhonov method.

  12. Reconstruction of multiple gastric electrical wave fronts using potential based inverse methods

    PubMed Central

    Kim, J HK; Pullan, A J; Cheng, L K

    2012-01-01

    One approach, commonly used in the field of electrocardiography, involves solving an inverse problem whereby electrical potentials on the stomach surface are directly reconstructed from dense potential measurements on the skin surface. To investigate this problem, an anatomically realistic torso model and an electrical stomach model were used to simulate potentials on stomach and skin surfaces arising from normal gastric electrical activity. The effectiveness of the Greensite-Tikhonov or the Tikhonov inverse methods were compared under the presence of 10% Gaussian noise with either 84 or 204 body surface electrodes. The stability and accuracy of the Greensite-Tikhonov method was further investigated by introducing varying levels of Gaussian signal noise or by increasing or decreasing the size of the stomach by 10%. Results showed that the reconstructed solutions were able to represent the presence of propagating multiple wave fronts and the Greensite-Tikhonov method with 204 electrodes performed best (Correlation coefficients of activation time: 90%; Pacemaker localization error: 3 cm). The Greensite-Tikhonov method was stable with Gaussian noise levels up to 20% and 10% change in stomach size. The use of 204 rather than 84 body surface electrodes improved the performance; however, for all investigated cases, the Greensite-Tikhonov method outperformed the Tikhonov method. PMID:22842812

  13. Barrier potential design criteria in multiple-quantum-well-based solar-cell structures

    NASA Astrophysics Data System (ADS)

    Mohaidat, Jihad M.; Shum, Kai; Wang, W. B.; Alfano, R. R.

    1994-11-01

    The barrier potential design criteria in multiple-quantum-well (MQW)-based solar-cell structures is reported for the purpose of achieving maximum efficiency. The time-dependent short-circuit current density at the collector side of various MQW solar-cell structures under resonant condition was numerically calculated using the time-dependent Schroedinger equation. The energy efficiency of solar cells based on the InAs/Ga(y)In(1-y)As and GaAs/Al(x)Ga(1-x)As MQW structues were compared when carriers are excited at a particular solar-energy band. Using InAs/Ga(y)In(1-y)As MQW structures it is found that a maximum energy efficiency can be achieved if the structure is designed with barrier potential of about 450 meV. The efficiency is found to decline linearly as the barrier potential increases for GaAs/Al(x)Ga(1-x)As MQW-structure-based solar cells.

  14. Barrier potential design criteria in multiple-quantum-well-based solar-cell structures

    NASA Technical Reports Server (NTRS)

    Mohaidat, Jihad M.; Shum, Kai; Wang, W. B.; Alfano, R. R.

    1994-01-01

    The barrier potential design criteria in multiple-quantum-well (MQW)-based solar-cell structures is reported for the purpose of achieving maximum efficiency. The time-dependent short-circuit current density at the collector side of various MQW solar-cell structures under resonant condition was numerically calculated using the time-dependent Schroedinger equation. The energy efficiency of solar cells based on the InAs/Ga(y)In(1-y)As and GaAs/Al(x)Ga(1-x)As MQW structues were compared when carriers are excited at a particular solar-energy band. Using InAs/Ga(y)In(1-y)As MQW structures it is found that a maximum energy efficiency can be achieved if the structure is designed with barrier potential of about 450 meV. The efficiency is found to decline linearly as the barrier potential increases for GaAs/Al(x)Ga(1-x)As MQW-structure-based solar cells.

  15. The p38 mitogen-activated protein kinase cascade modulates T helper type 17 differentiation and functionality in multiple sclerosis.

    PubMed

    Di Mitri, Diletta; Sambucci, Manolo; Loiarro, Maria; De Bardi, Marco; Volpe, Elisabetta; Cencioni, Maria Teresa; Gasperini, Claudio; Centonze, Diego; Sette, Claudio; Akbar, Arne N; Borsellino, Giovanna; Battistini, Luca

    2015-10-01

    The p38 mitogen-activated protein kinase cascade is required for the induction of a T helper type 17 (Th17) -mediated autoimmune response, which underlies the development and progression of several autoimmune diseases, such as experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis (MS). However, the contribution of p38 phosphorylation to human Th cell differentiation has not been clarified. Here we demonstrate that the p38 signalling pathway is implicated in the generation of Th17 lymphocytes from human CD4(+) CD27(+) CD45RA(+) naive T cells, both in healthy donors and in patients affected by the relapsing-remitting form of MS. Our data also indicate that p38 activation is essential for interleukin-17 release from central memory lymphocytes and committed Th17 cell clones. Furthermore, CD4(+) T cells isolated from individuals with relapsing-remitting MS display an altered responsiveness of the p38 cascade, resulting in increased p38 phosphorylation upon stimulation. These findings suggest that the p38 signalling pathway, by modulating the Th17 differentiation and response, is involved in the pathogenesis of MS, and open new perspectives for the use of p38 inhibitors in the treatment of Th17-mediated autoimmune diseases. PMID:26095162

  16. Identification of Multiple Subsets of Ventral Interneurons and Differential Distribution along the Rostrocaudal Axis of the Developing Spinal Cord

    PubMed Central

    Francius, Cédric; Harris, Audrey; Rucchin, Vincent; Hendricks, Timothy J.; Stam, Floor J.; Barber, Melissa; Kurek, Dorota; Grosveld, Frank G.; Pierani, Alessandra; Goulding, Martyn; Clotman, Frédéric

    2013-01-01

    The spinal cord contains neuronal circuits termed Central Pattern Generators (CPGs) that coordinate rhythmic motor activities. CPG circuits consist of motor neurons and multiple interneuron cell types, many of which are derived from four distinct cardinal classes of ventral interneurons, called V0, V1, V2 and V3. While significant progress has been made on elucidating the molecular and genetic mechanisms that control ventral interneuron differentiation, little is known about their distribution along the antero-posterior axis of the spinal cord and their diversification. Here, we report that V0, V1 and V2 interneurons exhibit distinct organizational patterns at brachial, thoracic and lumbar levels of the developing spinal cord. In addition, we demonstrate that each cardinal class of ventral interneurons can be subdivided into several subsets according to the combinatorial expression of different sets of transcription factors, and that these subsets are differentially distributed along the rostrocaudal axis of the spinal cord. This comprehensive molecular profiling of ventral interneurons provides an important resource for investigating neuronal diversification in the developing spinal cord and for understanding the contribution of specific interneuron subsets on CPG circuits and motor control. PMID:23967072

  17. Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells.

    PubMed

    Cunnusamy, Khrishen; Baughman, Ethan J; Franco, Jorge; Ortega, Sterling B; Sinha, Sushmita; Chaudhary, Parul; Greenberg, Benjamin M; Frohman, Elliot M; Karandikar, Nitin J

    2014-01-01

    Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Although its etiology remains unknown, pathogenic T cells are thought to underlie MS immune pathology. We recently showed that MS patients harbor CNS-specific CD8+ Tregs that are deficient during disease relapse. We now demonstrate that CNS-specific CD8+ Tregs were cytolytic and could eliminate pathogenic CD4+ T cells. These CD8+ Tregs were present primarily in terminally differentiated (CD27-, CD45RO-) subset and their suppression was IFN?, perforin and granzyme B-dependent. Interestingly, MS patients with acute relapse displayed a significant loss in terminally differentiated CD8+ T cells, with a concurrent loss in expression of perforin and granzyme B. Pre-treatment of exacerbation-derived CD8+ T cells with IL-12 significantly restored suppressive capability of these cells through upregulation of granzyme B. Our studies uncover immune-suppressive mechanisms of CNS-specific CD8+ Tregs, and may contribute to design of novel immune therapies for MS. PMID:24657764

  18. Multiple-scattering Green-function method for space-filling cell potentials

    NASA Astrophysics Data System (ADS)

    Gonis, A.; Zhang, X.-G.; Nicholson, D. M.

    1989-07-01

    It is shown that the equations of multiple-scattering theory (MST) originally derived for scattering off collections of muffin-tin (MT) potentials, i.e., potential cells bounded by nonoverlapping spheres, remain valid in the case of arbitrarily shaped, nonoverlapping, and particularly space-filling potential cells. Specifically, it is shown that in the angular momentum representation the total scattering (transition) matrix, the Green function, the Bloch function for a translationally invariant material, and the Lloyd formula for the change in the integrated density of states have forms that are invariant with respect to the partition of a given potential into nonoverlapping cells, and with respect to the choice of the cell centers. An analytic proof is provided for the vanishing of near-field corrections (NFC's) long conjectured to arise when the spheres bounding individual cells overlap one another or adjacent potentials. Thus, the well-known MST expressions, originally derived for the case of MT potentials, for obtaining the solution of the Schrdinger equation and hence determining the band structure and the charge density of materials, ordered or disordered, are rigorously valid in the completely general case of arbitrarily shaped cells. The differences between this work and previous attempts to generalize MST to non-MT space-filling potentials are discussed. It is pointed out that in calculations involving non-MT potential cells, particular attention must be paid to the question of convergence of expansions in angular momentum eigenstates. This convergence is tested numerically in terms of cluster calculations and through the calculation of the electronic structure of elemental bcc Nb and fcc Zr and Rh. The results of the cluster calculations confirm the vanishing of NFC's in the cases studied, while the electronic-structure calculations indicate the rather rapid convergence that can be expected in applications of MST to close-packed structures. The conclusions that can be drawn from the analytic and computational aspects of the present work are summarized in the final section, along with our plans for future work.

  19. Valproic Acid Increases the Hepatic Differentiation Potential of Salivary Gland Cells

    PubMed Central

    Petrakova, O. S.; Ashapkin, V. V.; Shtratnikova, V. Y.; Kutueva, L. I.; Vorotelyak, E. A.; Borisov, M. A.; Terskikh, V. V.; Gvazava, I. G.; Vasiliev, A. V.

    2015-01-01

    The studies of cell plasticity and differentiation abilities are important problems in modern cellular biology. The use of histone deacetylase inhibitor - valproic acid is a promising approach to increasing the differentiation efficiency of various cell types. In this paper we investigate the ability of mouse submandibular salivary gland cells to differentiate into the hepatic direction and the effect of valproic acid on the efficiency of this differentiation. It was shown that the gene expression levels of hepatocyte markers (Aat, Afp, G6p, Pepck, Tat, Cyp3a13) and liver-enriched transcription factors (Hnf-3?, Hnf-3?, Hnf-4?, Hnf-6) were increased after differentiation in salivary gland cells. Valproic acid increases the specificity of hepatic differentiation, reducing the expression levels of the ductal (Krt19, Hhex1, Cyp7a1) and acinar (Ptf1a) markers. After valproic acid exposure, the efficiency of hepatic differentiation also increases, as evidenced by the increase in the gene expression level of Alb and Tdo, and increase in urea production by differentiated cells. No change was found in DNA methylation of the promoter regions of the genes; however, valproic acid treatment and subsequent hepatic differentiation largely affected the histone H3 methylation of liver-enriched genes. Thus, mouse submandibular salivary gland cells are capable of effective differentiation in the hepatic direction. Valproic acid increases the specificity and efficiency of the hepatic differentiation of these cells. PMID:26798494

  20. Differential Effects of Munc18s on Multiple Degranulation-Relevant Trans-SNARE Complexes

    PubMed Central

    Xu, Hao; Arnold, Matthew Grant; Kumar, Sushmitha Vijay

    2015-01-01

    Mast cell exocytosis, which includes compound degranulation and vesicle-associated piecemeal degranulation, requires multiple Q- and R- SNAREs. It is not clear how these SNAREs pair to form functional trans-SNARE complexes and how these trans-SNARE complexes are selectively regulated for fusion. Here we undertake a comprehensive examination of the capacity of two Q-SNARE subcomplexes (syntaxin3/SNAP-23 and syntaxin4/SNAP-23) to form fusogenic trans-SNARE complexes with each of the four granule-borne R-SNAREs (VAMP2, 3, 7, 8). We report the identification of at least six distinct trans-SNARE complexes under enhanced tethering conditions: i) VAMP2/syntaxin3/SNAP-23, ii) VAMP2/syntaxin4/SNAP-23, iii) VAMP3/syntaxin3/SNAP-23, iv) VAMP3/syntaxin4/SNAP-23, v) VAMP8/syntaxin3/SNAP-23, and vi) VAMP8/syntaxin4/SNAP-23. We show for the first time that Munc18a operates synergistically with SNAP-23-based non-neuronal SNARE complexes (i to iv) in lipid mixing, in contrast to Munc18b and c, which exhibit no positive effect on any SNARE combination tested. Pre-incubation with Munc18a renders the SNARE-dependent fusion reactions insensitive to the otherwise inhibitory R-SNARE cytoplasmic domains, suggesting a protective role of Munc18a for its cognate SNAREs. Our findings substantiate the recently discovered but unexpected requirement for Munc18a in mast cell exocytosis, and implicate post-translational modifications in Munc18b/c activation. PMID:26384026

  1. UAV based tree height estimation in apple orchards: potential of multiple approaches

    NASA Astrophysics Data System (ADS)

    Mejia-Aguilar, Abraham; Tomelleri, Enrico; Vilardi, Andrea; Zebisch, Marc

    2015-04-01

    Canopy height, as part of vegetation structure, is ecologically important for ecological studies on biomass, matter flows or meteorology. Measuring the growth of canopy can be undertaken by the use multiple remote sensing techniques. In this study, we firstly use data generated from an Unmanned Aerial Vehicles (UAV) with a simultaneous consumer-grade RGB and modified IR cameras, configured in nadir and multi-angle views to generate 3D models for Digital Surface Model (DSM) and Digital Terrain Models (DTM) in order to estimate tree height in apple orchards in South Tyrol, Italy. We evaluate the use of Ground Control Points (GCP) to minimize the error in scale and orientation. Then, we validate and compare the results of our primary data collection with data generated by geolocated field measurements over several selected tree species. Additionally, we compare DSM and DTM obtained from a recent 1-meter resolution LIDAR campaign (Light Detection and Ranging). The main purpose of this study is to contrast multiple estimation approaches and evaluate their utility for the estimation of canopy height, highlighting the use of UAV systems as a fast, reliable and non-expensive technique especially for small scale applications. The study is conducted in a homogenous tree canopy consisting of apple orchards located in Caldaro -South Tyrol, Italy. We end with proposing a potential low-cost and inexpensive application combining models for DSM from the UAV with DTM obtained from LIDAR for applications that should be updated frequently.

  2. Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair

    PubMed Central

    Markovic-Plese, Silva; Singh, Avtar K; Singh, Inderjit

    2009-01-01

    Statins as inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase are widely used as cholesterol-lowering drugs. Recent studies provide evidence that the anti-inflammatory activity of statins, which is independent of their cholesterol-lowering effects, may have potential therapeutic implications for neuroinflammatory diseases such as multiple sclerosis (MS), Alzheimers disease and brain tumors, as well as traumatic spinal cord and brain injuries. Studies with animal models of MS suggest that, in addition to immunomodulatory activities similar to the ones observed with approved MS medications, statin treatment also protects the BBB, protects against neurodegeneration and may also promote neurorepair. Although the initial human studies on statin treatment for MS are encouraging, prospective randomized clinical studies will be required to evaluate their efficacy in the larger patient population. PMID:20107624

  3. Perceived stress in multiple sclerosis: The potential role of mindfulness in health and wellbeing

    PubMed Central

    Senders, Angela; Bourdette, Dennis; Hanes, Douglas; Yadav, Vijayshree; Shinto, Lynne

    2014-01-01

    Stressful life events are associated with worsening neurological symptoms and decreased quality of life in multiple sclerosis (MS). Mindful-consciousness can alter the impact of stressful events and has potential to improve health outcomes in MS. This study evaluated the relationship between trait mindfulness and perceived stress, coping, and resilience in people with MS. Quality of life was assessed as a secondary outcome. 119 people with confirmed MS completed the Five-facet Mindfulness Questionnaire, Perceived Stress Scale, Brief Coping Orientation for Problem Experiences, Connor-Davidson Resilience Scale, and the SF-36. Greater trait mindfulness was significantly associated with decreased psychological stress, better coping skills, increased resilience, and higher quality of life. After controlling for confounders, mindfulness accounted for 25% of the variation in perceived stress scores and 44% of the variation in resilience scores. Results support further investigation of mindfulness training to enhance psychological resilience and improve wellbeing for those living with MS. PMID:24647090

  4. The potential of miRNAs as biomarkers for multiple myeloma.

    PubMed

    Rocci, Alberto; Hofmeister, Craig C; Pichiorri, Flavia

    2014-11-01

    Since the discovery of the link between miRNA and cancer, miRNAs have been investigated in virtually all tumors. Their ability to add a novel level of gene regulation and to target genes apparently not linked to each other has greatly intrigued researchers and physicians alike. In this review, the role of miRNAs in multiple myeloma (MM) is summarized, with particular attention to their potential as biomarkers. The promising role of circulating miRNAs in diagnosis and risk stratification is also discussed, as well as preliminary results of miRNA-based therapeutic approaches. Finally, the critical issues in miRNA analysis in MM and ongoing strategies to solve them are discussed. The ability to standardize miRNA analysis procedures will permit the inclusion of miRNA evaluation alongside available stratification tools, paving the way for personalized medicine in MM. PMID:25098410

  5. Energy-harvesting potential of multiple elastic structures in tandem arrangement

    NASA Astrophysics Data System (ADS)

    Yin, Bo; Luo, Haoxiang

    2011-11-01

    Vortex-induced flapping vibrations of elastic structures attached with piezoelectric materials, i.e., ``piezo-leaves'', have recently been explored for its potential application in wind energy harvesting (e.g., Li, Yuan, and Lipson, J. Appl. Phys., 2011). In this work, we explore the possibility of enhancing the structural vibration and energy harvesting performance of the generator by putting the leaves in tandem arrangement and within close range of hydrodynamic interaction. A two-dimensional model is developed, where two or more elastic plates are mounted in a cross flow. In the case of two plates, the numerical simulation shows that at a particular distance, the vibration of the downstream plate is greatly increased, and so is the energy level of the entire system. For multiple plates, we observed both synchronized and apparently chaotic vibration modes. The characteristics of the vortex interaction, plate deformation, and energetics will be presented for those coupling modes.

  6. Sequential dissection of multiple ionic currents in single cardiac myocytes under action potential-clamp

    PubMed Central

    Banyasz, Tamas; Horvath, Balazs; Jian, Zhong; Izu, Leighton T.; Chen-Izu, Ye

    2011-01-01

    The cardiac action potential (AP) is shaped by myriad ionic currents. In this study we develop an innovative AP-clamp Sequential Dissection technique to enable recording of multiple ionic currents in the single cell under AP-clamp. This new technique presents a significant step beyond the traditional way of recording only one current in any one cell. The ability to measure many currents in a single cell has revealed two hitherto unknown characteristics of the ionic currents in cardiac cells: coordination of currents within a cell and large variation of currents between cells. Hence, the AP-clamp Sequential Dissection method provides a unique and powerful tool for studying individual cell electrophysiology. PMID:21215755

  7. Percutaneous method for single-catheter multiple monophasic action potential recordings during magnetocardiographic mapping in spontaneously breathing rodents.

    PubMed

    Brisinda, Donatella; Sorbo, Anna Rita; Venuti, Angela; Fenici, Riccardo

    2012-03-01

    To test the feasibility of a novel method to combine magnetocardiographic (MCG) estimate of ventricular repolarization (VR) and multiple monophasic action potential (MultiMAP) recording in spontaneously breathing rodents with percutaneous sub-xyphoid epicardial placement of a MCG-compatible amagnetic catheter (AC), ten Wistar rats (WRs) and ten guinea pigs (GPs) were studied. Under fluoroscopic control, the AC was moved until four stable MAPs were recorded (fixed inter-electrode distance of 1.2 mm). 36-channel DC-SQUID (sensitivity 20 fT Hz(-)) were used for MCG mapping. MAPs, differentially amplified (BW: DC-500 Hz), were digitized at 1 kHz. AC pacing provided local ventricular effective refractory period (VERP) estimate. MAP duration (MAPd) was measured at 50% and 90% levels of repolarization. Simultaneous MCG mapping and MultiMAP recording were successful in all animals. Average MAPd50% and MAPd90% were shorter in WRs than in GPs (26.4 2.9 ms versus 110.6 14.3 ms and 60.7 5.4 ms versus 127.7 15.3 ms, respectively). VERP was 51 4.8 ms in WRs and 108.4 12.9 ms in GPs, respectively. The MAP amplitude was 16.9 4.5 in WRs and 16.2 4.2 in GPs. MAP and MCG parameters of VR were in good agreement. All animals survived the procedure. Two also survived a second invasive study; one was followed up until natural death at 52 months. Percutaneous MultiMAP recording is minimally invasive, usually avoids animal sacrifice, is compatible with simultaneous surface MCG mapping and might be used for experimental validation of MCG VR abnormality, to study the arrhythmogenic potential of new drugs and/or animal models of ventricular arrhythmias. PMID:22373565

  8. A Hybrid One-Way ANOVA Approach for the Robust and Efficient Estimation of Differential Gene Expression with Multiple Patterns

    PubMed Central

    Mollah, Mohammad Manir Hossain; Jamal, Rahman; Mokhtar, Norfilza Mohd; Harun, Roslan; Mollah, Md. Nurul Haque

    2015-01-01

    Background Identifying genes that are differentially expressed (DE) between two or more conditions with multiple patterns of expression is one of the primary objectives of gene expression data analysis. Several statistical approaches, including one-way analysis of variance (ANOVA), are used to identify DE genes. However, most of these methods provide misleading results for two or more conditions with multiple patterns of expression in the presence of outlying genes. In this paper, an attempt is made to develop a hybrid one-way ANOVA approach that unifies the robustness and efficiency of estimation using the minimum ?-divergence method to overcome some problems that arise in the existing robust methods for both small- and large-sample cases with multiple patterns of expression. Results The proposed method relies on a ?-weight function, which produces values between 0 and 1. The ?-weight function with ? = 0.2 is used as a measure of outlier detection. It assigns smaller weights (? 0) to outlying expressions and larger weights (? 1) to typical expressions. The distribution of the ?-weights is used to calculate the cut-off point, which is compared to the observed ?-weight of an expression to determine whether that gene expression is an outlier. This weight function plays a key role in unifying the robustness and efficiency of estimation in one-way ANOVA. Conclusion Analyses of simulated gene expression profiles revealed that all eight methods (ANOVA, SAM, LIMMA, EBarrays, eLNN, KW, robust BetaEB and proposed) perform almost identically for m = 2 conditions in the absence of outliers. However, the robust BetaEB method and the proposed method exhibited considerably better performance than the other six methods in the presence of outliers. In this case, the BetaEB method exhibited slightly better performance than the proposed method for the small-sample cases, but the the proposed method exhibited much better performance than the BetaEB method for both the small- and large-sample cases in the presence of more than 50% outlying genes. The proposed method also exhibited better performance than the other methods for m > 2 conditions with multiple patterns of expression, where the BetaEB was not extended for this condition. Therefore, the proposed approach would be more suitable and reliable on average for the identification of DE genes between two or more conditions with multiple patterns of expression. PMID:26413858

  9. Intracellular calcium transients in potentiated contractions induced by multiple extrasystolic beats in isolated perfused rat hearts.

    PubMed

    Kojima, S; Wu, S T; Wikman-Coffelt, J; Parmley, W W

    1994-09-01

    Mechanisms underlying contractile potentiation induced by multiple extrasystolic contractions (ESC) were evaluated with surface fluorometry in isolated perfused rat hearts loaded with Indo-1/AM. After baseline pacing with a 400 ms interval, 1-25 ESC were interposed with a regular 160 ms interval followed by the postextrasystolic beat with a 400 ms interval. With an increase in the ESC number, left ventricular developed pressure and peak positive dP/dt increased in an exponential manner, reaching a plateau, that was the same for 3 extracellular Ca2+ ([Ca2+]o; 0.55 (n = 9), 1.25 (n = 11) and 2.75 mM (n = 7). Increased [Ca2+]o shifted this relationship left and upward, and with 2.75 mM [Ca2+]o developed pressure and dP/dt decreased after the maximum potentiation was obtained. The relationship between the ESC number and the amplitude of the Indo-1 fluorescence (F400/F510; an index of intracellular Ca2+ ([Ca2+]i)) was also exponential and was shifted left and upward by high [Ca2+]o; however, it lacked the declining phase. Thus, the relationship between the amplitude of F400/F510 and developed pressure or dP/dt consisted of a positively linear part until the maximum potentiation was obtained and a negatively linear part with a further increase in the amplitude of F400/F510. This observation suggests that although contractile potentiation is mediated by increased [Ca2+]i transients, the maximum response might be determined by the responsiveness of the sarcomere. PMID:7530171

  10. Dispersal syndrome differentiation of Pinus armandii in Southwest China: Key elements of a potential selection mosaic

    NASA Astrophysics Data System (ADS)

    Chen, Fan; Chen, Jin

    2011-11-01

    Pinus armandii is a species of pine native to China with a wide geographical distribution and large-wingless seeds (about 300 mg). The study is to determine the variation in seed dispersal traits among populations within a relative small geographic scale and furthermore to explore if the trait differentiation results in the differences in dispersers, in particular nutcrackers ( Nucifraga caryocatactes) and scatter-hoarding rodents. We conducted studies at five sites at different elevations in northwest Yunnan Province. The study sites are separated by 10-200 km and divided into populations partly isolated by mountains and rivers. The cone and seed traits diverged significantly among the five study sites while the traits among individual trees at each site did not differ significantly. Nutcrackers and scatter-hoarding rodents presented conflicting preference in cone and seed traits: nutcrackers preferred smaller cones with smaller seeds, which increased the foraging efficiency of nutcrackers; while scatter-hoarding rodents tended to cache larger seeds. Consistent with variation in preferences by nutcrackers and scatter-hoarding rodents, in nutcracker-dominated sites, pines were characterized by smaller cones, smaller seeds, and thinner seed coats; while in sites where nutcrackers were not abundant, pines had relatively larger cones with larger seeds, which could enhance caching activities by scatter-hoarding rodents. The study provided some key elements for potential selection mosaic on cone and seed traits of a long-lived perennial tree among populations with limited geographical range.

  11. Potential nitrate pollution of groundwater in Germany: A supraregional differentiated model

    NASA Astrophysics Data System (ADS)

    Wendland, F.; Albert, H.; Bach, M.; Schmidt, R.

    1994-08-01

    Implemented on behalf of the Federal Ministry for Research and Technology (BMFT), a model is developed to trace the nutrient flow of nitrate in the soil and the groundwater on a supraregional scale. Research work is intended to indicate regionally differentiated hazardous potentials and thereby provide a basis for recommending comprehensive measures to protect groundwater in Germany. The adaption of the model to the hydrogeological and agricultural conditions of other states is possible in principle. This article focuses on the hydrogeological model parts. A high nitrate pollution of groundwater can be expected in all regions with intensive agricultural use of the topsoil. In particular, groundwater in solid rock areas is susceptible to nitrate pollution. There a rapid groundwater turnover and thus a short residence time for the groundwater in the aquifer is typical. Oxidizing aquifer conditions usually prevail in solid rock aquifers, preventing nitrate degradation. In many loose rock areas, in contrast, the groundwater has a low flow velocity and a long residence time in the aquifer. Because of a lack of free oxygen, a complete degradation of nitrate can occur, as long as iron sulfide compounds and/or organic carbon are available in the aquifer. A more detailed presentation of the whole research work is given in Wendland et al. (1993).

  12. Differentiation of human pluripotent stem cells into β-cells: Potential and challenges.

    PubMed

    Quiskamp, Nina; Bruin, Jennifer E; Kieffer, Timothy J

    2015-12-01

    Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) hold great potential as the basis for cell-based therapies of degenerative diseases, including diabetes. Current insulin-based therapies for diabetes do not prevent hyperglycaemia or the associated long-term organ damage. While transplantation of pancreatic islets can achieve insulin independence and improved glycemic control, it is limited by donor tissue scarcity, challenges of purifying islets from the pancreas, and the need for immunosuppression to prevent rejection of transplants. Large-scale production of β-cells from stem cells is a promising alternative. Recent years have seen considerable progress in the optimization of in vitro differentiation protocols to direct hESCs/iPSCs into mature insulin-secreting β-cells and clinical trials are now under way to test the safety and efficiency of hESC-derived pancreatic progenitor cells in patients with type 1 diabetes. Here, we discuss key milestones leading up to these trials in addition to recent developments and challenges for hESC/iPSC-based diabetes therapies and disease modeling. PMID:26696513

  13. Phenotypic identification of subclones in multiple myeloma with different chemoresistant, cytogenetic and clonogenic potential.

    PubMed

    Pano, T; Paiva, B; Sayagus, J M; Mota, I; Carvalheiro, T; Corchete, L A; Aires-Meja, I; Prez, J J; Sanchez, M L; Barcena, P; Ocio, E M; San-Segundo, L; Sarasquete, M E; Garca-Sanz, R; Vidriales, M-B; Oriol, A; Hernndez, M-T; Echeveste, M-A; Paiva, A; Blade, J; Lahuerta, J-J; Orfao, A; Mateos, M-V; Gutirrez, N C; San-Miguel, J F

    2015-05-01

    Knowledge about clonal diversity and selection is critical to understand multiple myeloma (MM) pathogenesis, chemoresistance and progression. If targeted therapy becomes reality, identification and monitoring of intraclonal plasma cell (PC) heterogeneity would become increasingly demanded. Here we investigated the kinetics of intraclonal heterogeneity among 116 MM patients using 23-marker multidimensional flow cytometry (MFC) and principal component analysis, at diagnosis and during minimal residual disease (MRD) monitoring. Distinct phenotypic subclones were observed in 35/116 (30%) newly diagnosed MM patients. In 10/35 patients, persistent MRD was detected after 9 induction cycles, and longitudinal comparison of patient-paired diagnostic vs MRD samples unraveled phenotypic clonal tiding after therapy in half (5/10) of the patients. After demonstrating selection of distinct phenotypic subsets by therapeutic pressure, we investigated whether distinct fluorescence-activated cell-sorted PC subclones had different clonogenic and cytogenetic profiles. In half (5/10) of the patients analyzed, distinct phenotypic subclones showed different clonogenic potential when co-cultured with stromal cells, and in 6/11 cases distinct phenotypic subclones displayed unique cytogenetic profiles by interphase fluorescence in situ hybridization, including selective del(17p13). Collectively, we unravel potential therapeutic selection of preexisting diagnostic phenotypic subclones during MRD monitoring; because phenotypically distinct PCs may show different clonogenic and cytogenetic profiles, identification and follow-up of unique phenotypic-genetic myeloma PC subclones may become relevant for tailored therapy. PMID:25388955

  14. Aproliferin--a human plasma protein that induces the irreversible loss of proliferative potential associated with terminal differentiation.

    PubMed Central

    Wier, M. L.; Scott, R. E.

    1986-01-01

    Cellular proliferation is regulated not only by the action of growth factors and growth inhibitors whose effects are reversible but also by factors that induce the irreversible loss of proliferative potential associated with the terminal event in cellular differentiation. The authors have employed 3T3 T mesenchymal stem cells as a model system to study the terminal event in cellular differentiation because in these cells' distinct nonterminal and terminal states of differentiation can be identified and because transition from the nonterminal to the terminal states of differentiation can be induced by human plasma. In this paper is reported the 20,000-fold purification of a component of human plasma that induces the terminal event in differentiation. This factor is shown to have an apparent molecular weight of approximately 45,000 and an isoelectric point of approximately 7.6. It is trypsin-sensitive, acid and heat-labile, and is resistant to treatment with dithiothreitol and alkali. The ability of this human plasma protein to induce the irreversible loss of proliferative potential associated with the terminal event in differentiation serves as the basis for its designation "aproliferin." The data in this paper in addition show that no other pharmacologic or physiologic agents have been identified that can mimic the biologic effect of aproliferin. Therefore, aproliferin appears to be a functionally distinct protein in human plasma. PMID:3799819

  15. Human Amniotic Fluid Mesenchymal Stem Cells from Second- and Third-Trimester Amniocentesis: Differentiation Potential, Molecular Signature, and Proteome Analysis

    PubMed Central

    Savickiene, Jurate; Treigyte, Grazina; Baronaite, Sandra; Valiuliene, Giedre; Kaupinis, Algirdas; Valius, Mindaugas; Arlauskiene, Audrone; Navakauskiene, Ruta

    2015-01-01

    Human amniotic fluid stem cells have become an attractive stem cell source for potential applications in regenerative medicine and tissue engineering. The aim of this study was to characterize amniotic fluid-derived mesenchymal stem cells (AF-MSCs) from second- and third-trimester of gestation. Using two-stage protocol, MSCs were successfully cultured and exhibited typical stem cell morphological, specific cell surface, and pluripotency markers characteristics. AF-MSCs differentiated into adipocytes, osteocytes, chondrocytes, myocytes, and neuronal cells, as determined by morphological changes, cell staining, and RT-qPCR showing the tissue-specific gene presence for differentiated cell lineages. Using SYNAPT G2 High Definition Mass Spectrometry technique approach, we performed for the first time the comparative proteomic analysis between undifferentiated AF-MSCs from late trimester of gestation and differentiated into myogenic, adipogenic, osteogenic, and neurogenic lineages. The analysis of the functional and expression patterns of 250 high abundance proteins selected from more than 1400 demonstrated the similar proteome of cultured and differentiated AF-MSCs but the unique changes in their expression profile during cell differentiation that may help the identification of key markers in differentiated cells. Our results provide evidence that human amniotic fluid of second- and third-trimester contains stem cells with multilineage potential and may be attractive source for clinical applications. PMID:26351462

  16. Multiple gradient echo propeller (MGREP) MRI: Technical development and potential applications

    NASA Astrophysics Data System (ADS)

    Poonawalla, Aziz Hatim

    The PROPELLER (Periodically Rotated Overlapping Parallel Lines with Enhanced Reconstruction) magnetic resonance imaging (MRI) technique has inherent advantages over other fast imaging methods, including robust motion correction, reduced image distortion, and resistance to off-resonance effects. These features make PROPELLER highly desirable for T2*-sensitive imaging, high-resolution diffusion imaging, and many other applications. However, PROPELLER has been predominantly implemented as a fast spin-echo (FSE) technique, which is insensitive to T2* contrast, and requires time-inefficient signal averaging to achieve adequate signal-to-noise ratio (SNR) for many applications. These issues presently constrain the potential clinical utility of FSE-based PROPELLER. In this research, our aim was to extend and enhance the potential applications of PROPELLER MRI by developing a novel multiple gradient echo PROPELLER (MGREP) technique that can overcome the aforementioned limitations. The MGREP pulse sequence was designed to acquire multiple gradient-echo images simultaneously, without any increase in total scan time or RF energy deposition relative to FSE-based PROPELLER. A new parameter was also introduced for direct user-control over gradient echo spacing, to allow variable sensitivity to T2* contrast. In parallel to pulse sequence development, an improved algorithm for motion correction was also developed and evaluated against the established method through extensive simulations. The potential advantages of MGREP over FSE-based PROPELLER were illustrated via three specific applications: (1) quantitative T2* measurement, (2) time-efficient signal averaging, and (3) high-resolution diffusion imaging. Relative to the FSE-PROPELLER method, the MGREP sequence was found to yield quantitative T2* values, increase SNR by 40% without any increase in acquisition time or RF energy deposition, and noticeably improve image quality in high-resolution diffusion maps. In addition, the new motion algorithm was found to improve the performance considerably in motion-artifact reduction. Overall, this work demonstrated a number of enhancements and extensions to existing PROPELLER techniques. The new technical capabilities of PROPELLER imaging, developed in this thesis research, are expected to serve as the foundation for further expanding the scope of PROPELLER applications.

  17. Sex and Genetic Factors Determine Osteoblastic Differentiation Potential of Murine Bone Marrow Stromal Cells

    PubMed Central

    Zanotti, Stefano; Kalajzic, Ivo; Aguila, Hector Leonardo; Canalis, Ernesto

    2014-01-01

    Sex and genetic factors determine skeletal mass, and we tested whether bone histomorphometric parameters were sexually dimorphic in femurs from 1 to 6 month old C57BL/6 mice. Trabecular bone volume declined more rapidly in female mice than in male littermates because of enhanced bone resorption. Although bone formation was not different between sexes, female mice exhibited a higher number of osteoblasts than male littermates, suggesting that osteoblasts from female mice may have a reduced ability to form bone. To determine the impact of sex on osteoblastogenesis, we investigated the potential for osteoblastic differentiation of bone marrow stromal cells from C57BL/6, Friend leukemia virus-B (FVB), C3H/HeJ and BALB/c mice of both sexes. Bone marrow stromal cells from female FVB, C57BL/6 and C3H/HeJ mice exhibited lower Alpl and Osteocalcin expression and alkaline phosphatase activity, and formed fewer mineralized nodules than cells from male littermates. Proliferative capacity was greater in cells from male than female C57BL/6, but not FVB, mice. Sorting of bone marrow stromal cells from mice expressing an ?-Smooth muscle actin-green fluorescent protein transgene, revealed a higher yield of mesenchymal stem cells in cultures from male mice than in those from female littermates. Sex had a modest impact on osteoblastic differentiation of mesenchymal stem cells. To determine the influence of sex and genetic factors on osteoblast function, calvarial osteoblasts were harvested from C57BL/6, FVB, C3H/HeJ and BALB/c mice. Alpl expression and activity were lower in osteoblasts from C57BL/6 and C3H/HeJ, but not FVB or BALB/c, female mice than in cells from littermates. Sex had no effect on osteoclastogenesis of bone marrow cultures of C57BL/6 mice, but osteoblasts from female mice exhibited higher Rankl and lower Opg expression than cells from male littermates. In conclusion, osteoblastogenesis is sexually dimorphic and influenced by genetic factors. PMID:24489784

  18. Population differentiation in a Mediterranean relict shrub: the potential role of local adaptation for coping with climate change.

    PubMed

    Lázaro-Nogal, Ana; Matesanz, Silvia; Hallik, Lea; Krasnova, Alisa; Traveset, Anna; Valladares, Fernando

    2016-04-01

    Plants can respond to climate change by either migrating, adapting to the new conditions or going extinct. Relict plant species of limited distribution can be especially vulnerable as they are usually composed of small and isolated populations, which may reduce their ability to cope with rapidly changing environmental conditions. The aim of this study was to assess the vulnerability of Cneorum tricoccon L. (Cneoraceae), a Mediterranean relict shrub of limited distribution, to a future drier climate. We evaluated population differentiation in functional traits related to drought tolerance across seven representative populations of the species' range. We measured morphological and physiological traits in both the field and the greenhouse under three water availability levels. Large phenotypic differences among populations were found under field conditions. All populations responded plastically to simulated drought, but they differed in mean trait values as well as in the slope of the phenotypic response. Particularly, dry-edge populations exhibited multiple functional traits that favored drought tolerance, such as more sclerophyllous leaves, strong stomatal control but high photosynthetic rates, which increases water use efficiency (iWUE), and an enhanced ability to accumulate sugars as osmolytes. Although drought decreased RGR in all populations, this reduction was smaller for populations from the dry edge. Our results suggest that dry-edge populations of this relict species are well adapted to drought, which could potentially mitigate the species' extinction risk under drier scenarios. Dry-edge populations not only have a great conservation value but can also change expectations from current species' distribution models. PMID:26662734

  19. Cervical and ocular vestibular evoked myogenic potentials in multiple sclerosis participants

    PubMed Central

    Parsa, Maryam Sadat; Mohammadkhani, Ghassem; Hajabolhassani, Fahimeh; Jalaee, Shohreh; Zakeri, Hassanali

    2015-01-01

    Background: Multiple sclerosis (MS) is a chronic neurological disease that affects brain and spinal cord. The infratentorial region contains the cerebellum and brainstem. Vestibular evoked myogenic potentials (VEMPs) are short-latency myogenic responses. Cervical vestibular evoked myogenic potential (cVEMP) is a manifestation of vestibulocolic reflex and ocular vestibular evoked myogenic potential (oVEMP) contributes to the linear vestibularocular reflex. The aim of this study was to evaluate cVEMP and oVEMP in MS patients with and without infratentorial plaques and compare the findings with normal controls. Methods: In this cross-sectional study, latency and amplitude of cVEMP and oVEMP were recorded in 15 healthy females with mean age of 31.139.27 years, 17 female MS patients with infratentorial plaque(s) and mean age of 29.888.93 years, and 17 female MS patients without infratentorial plaque(s) and mean age of 30.588.02 years. All patients underwent a complete clinical neurological evaluation and brain MRI scanning. Simple random sampling method was used in this study and data were analyzed using one way ANOVA through SPSS v22. Results: The latency of N1-P1 and P13 in MS participants with and without infratentorial plaques were significantly prolonged compared to normal controls (p<0.001). Additionally latency of P13- N23-N1 and P1 in MS patients with infratentorial plaques were significantly prolonged compared to patients without infratentorial plaques subjects (p<0.001). Conclusion: Abnormality of both cVEMP and oVEMP in MS patient with infratentorial plaque are more than that of MS patient without infratentorial plaque. Recording both ocular and cervical VEMPs are appropriate electrophysiologic methods assessing the function of both ascending and descending central vestibular pathways. PMID:26034721

  20. Developing Multiple Diverse Potential Designs for Heat Transfer Utilizing Graph Based Evolutionary Algorithms

    SciTech Connect

    David J. Muth Jr.

    2006-09-01

    This paper examines the use of graph based evolutionary algorithms (GBEAs) to find multiple acceptable solutions for heat transfer in engineering systems during the optimization process. GBEAs are a type of evolutionary algorithm (EA) in which a topology, or geography, is imposed on an evolving population of solutions. The rates at which solutions can spread within the population are controlled by the choice of topology. As in nature geography can be used to develop and sustain diversity within the solution population. Altering the choice of graph can create a more or less diverse population of potential solutions. The choice of graph can also affect the convergence rate for the EA and the number of mating events required for convergence. The engineering system examined in this paper is a biomass fueled cookstove used in developing nations for household cooking. In this cookstove wood is combusted in a small combustion chamber and the resulting hot gases are utilized to heat the stoves cooking surface. The spatial temperature profile of the cooking surface is determined by a series of baffles that direct the flow of hot gases. The optimization goal is to find baffle configurations that provide an even temperature distribution on the cooking surface. Often in engineering, the goal of optimization is not to find the single optimum solution but rather to identify a number of good solutions that can be used as a starting point for detailed engineering design. Because of this a key aspect of evolutionary optimization is the diversity of the solutions found. The key conclusion in this paper is that GBEAs can be used to create multiple good solutions needed to support engineering design.

  1. Edges of human embryonic stem cell colonies display distinct mechanical properties and differentiation potential.

    PubMed

    Rosowski, Kathryn A; Mertz, Aaron F; Norcross, Samuel; Dufresne, Eric R; Horsley, Valerie

    2015-01-01

    In order to understand the mechanisms that guide cell fate decisions during early human development, we closely examined the differentiation process in adherent colonies of human embryonic stem cells (hESCs). Live imaging of the differentiation process reveals that cells on the outer edge of the undifferentiated colony begin to differentiate first and remain on the perimeter of the colony to eventually form a band of differentiation. Strikingly, this band is of constant width in all colonies, independent of their size. Cells at the edge of undifferentiated colonies show distinct actin organization, greater myosin activity and stronger traction forces compared to cells in the interior of the colony. Increasing the number of cells at the edge of colonies by plating small colonies can increase differentiation efficiency. Our results suggest that human developmental decisions are influenced by cellular environments and can be dictated by colony geometry of hESCs. PMID:26391588

  2. Edges of human embryonic stem cell colonies display distinct mechanical properties and differentiation potential

    PubMed Central

    Rosowski, Kathryn A.; Mertz, Aaron F.; Norcross, Samuel; Dufresne, Eric R.; Horsley, Valerie

    2015-01-01

    In order to understand the mechanisms that guide cell fate decisions during early human development, we closely examined the differentiation process in adherent colonies of human embryonic stem cells (hESCs). Live imaging of the differentiation process reveals that cells on the outer edge of the undifferentiated colony begin to differentiate first and remain on the perimeter of the colony to eventually form a band of differentiation. Strikingly, this band is of constant width in all colonies, independent of their size. Cells at the edge of undifferentiated colonies show distinct actin organization, greater myosin activity and stronger traction forces compared to cells in the interior of the colony. Increasing the number of cells at the edge of colonies by plating small colonies can increase differentiation efficiency. Our results suggest that human developmental decisions are influenced by cellular environments and can be dictated by colony geometry of hESCs. PMID:26391588

  3. Secretome of Olfactory Mucosa Mesenchymal Stem Cell, a Multiple Potential Stem Cell.

    PubMed

    Ge, Lite; Jiang, Miao; Duan, Da; Wang, Zijun; Qi, Linyu; Teng, Xiaohua; Zhao, Zhenyu; Wang, Lei; Zhuo, Yi; Chen, Ping; He, Xijing; Lu, Ming

    2016-01-01

    Nasal olfactory mucosa mesenchymal stem cells (OM-MSCs) have the ability to promote regeneration in the nervous system in vivo. Moreover, with view to the potential for clinical application, OM-MSCs have the advantage of being easily accessible from patients and transplantable in an autologous manner, thus eliminating immune rejection and contentious ethical issues. So far, most studies have been focused on the role of OM-MSCs in central nervous system replacement. However, the secreted proteomics of OM-MSCs have not been reported yet. Here, proteins secreted by OM-MSCs cultured in serum-free conditions were separated on SDS-PAGE and identified by LC-MS/MS. As a result, a total of 274 secreted proteins were identified. These molecules are known to be important in neurotrophy, angiogenesis, cell growth, differentiation, and apoptosis, and inflammation which were highly correlated with the repair of central nervous system. The proteomic profiling of the OM-MSCs secretome might provide new insights into their nature in the neural recovery. However, proteomic analysis for clinical biomarkers of OM-MSCs needs to be further studied. PMID:26949398

  4. Secretome of Olfactory Mucosa Mesenchymal Stem Cell, a Multiple Potential Stem Cell

    PubMed Central

    Ge, Lite; Duan, Da; Wang, Zijun; Qi, Linyu; Teng, Xiaohua; Zhao, Zhenyu; Wang, Lei; Zhuo, Yi; Chen, Ping; He, Xijing; Lu, Ming

    2016-01-01

    Nasal olfactory mucosa mesenchymal stem cells (OM-MSCs) have the ability to promote regeneration in the nervous system in vivo. Moreover, with view to the potential for clinical application, OM-MSCs have the advantage of being easily accessible from patients and transplantable in an autologous manner, thus eliminating immune rejection and contentious ethical issues. So far, most studies have been focused on the role of OM-MSCs in central nervous system replacement. However, the secreted proteomics of OM-MSCs have not been reported yet. Here, proteins secreted by OM-MSCs cultured in serum-free conditions were separated on SDS-PAGE and identified by LC-MS/MS. As a result, a total of 274 secreted proteins were identified. These molecules are known to be important in neurotrophy, angiogenesis, cell growth, differentiation, and apoptosis, and inflammation which were highly correlated with the repair of central nervous system. The proteomic profiling of the OM-MSCs secretome might provide new insights into their nature in the neural recovery. However, proteomic analysis for clinical biomarkers of OM-MSCs needs to be further studied. PMID:26949398

  5. Differential Expression of Canonical (Classical) Transient Receptor Potential Channels in Guinea Pig Enteric Nervous System

    PubMed Central

    Liu, Sumei; Qu, Mei-Hua; Ren, Wei; Hu, Hong-Zhen; Gao, Na; Wang, Guo-Du; Wang, Xi-Yu; Fei, Guijun; Zuo, Fei; Xia, Yun; Wood, Jackie D.

    2008-01-01

    The canonical transient receptor potential (TRPC) family of ion channels is implicated in many neuronal processes including calcium homeostasis, membrane excitability, synaptic transmission and axon guidance. TRPC channels are postulated to be important in the functional neurobiology of the enteric nervous system (ENS); nevertheless, details for expression in the ENS are lacking. RT-PCR, Western blotting, and immunohistochemistry were used to study the expression and localization of TRPC channels. We found mRNA transcripts, protein on Western blots and immunoreactivity (IR) for TRPC1/3/4/6 expressed in the small intestinal ENS of adult guinea pigs. TRPC1/3/4/6-IR was localized to distinct subpopulations of enteric neurons and was differentially distributed between the myenteric and submucosal divisions of the ENS. TRPC1-IR was widely distributed and localized to neurons with cholinergic, calretinin, and nitrergic neuronal immunochemical codes in the myenteric plexus. It was localized to both cholinergic and non-cholinergic secretomotor neurons in the submucosal plexus. TRPC3-IR was found only in the submucosal plexus and was expressed exclusively by neuropeptide Y-IR neurons. TRPC4/6-IR was expressed in only a small population of myenteric neurons, but was abundantly expressed in the submucosal plexus. TRPC4/6-IR was coexpressed with both cholinergic and nitrergic neurochemical codes in the myenteric plexus. In the submucosal plexus, TRPC4/6-IR was expressed exclusively in non-cholinergic secretomotor neurons. No TRPC1/3/4/6-IR was found in calbindin-IR neurons. TRPC3/4/6-IR was widely expressed along varicose nerve fibers and colocalized with synaptophysin-IR at putative neurotransmitter release sites. Our results suggest important roles for TRPC channels in ENS physiology and neuronal regulation of gut function. PMID:18925632

  6. Tissue-engineered skin preserving the potential of epithelial cells to differentiate into hair after grafting.

    PubMed

    Larouche, Danielle; Cuffley, Kristine; Paquet, Claudie; Germain, Lucie

    2011-03-01

    The aim of this study was to evaluate whether tissue-engineered skin produced in vitro was able to sustain growth of hair follicles in vitro and after grafting. Different tissues were designed. Dissociated newborn mouse keratinocytes or newborn mouse hair buds (HBs) were added onto dermal constructs consisting of a tissue-engineered cell-derived matrix elaborated from either newborn mouse or adult human fibroblasts cultured with ascorbic acid. After 7-21 days of maturation at the air-liquid interface, no hair was noticed in vitro. Epidermal differentiation was observed in all tissue-engineered skin. However, human fibroblast-derived tissue-engineered dermis (hD) promoted a thicker epidermis than mouse fibroblast-derived tissue-engineered dermis (mD). In association with mD, HBs developed epithelial cyst-like inclusions presenting outer root sheath-like attributes. In contrast, epidermoid cyst-like inclusions lined by a stratified squamous epithelium were present in tissues composed of HBs and hD. After grafting, pilo-sebaceous units formed and hair grew in skin elaborated from HBs cultured 10-26 days submerged in culture medium in association with mD. However, the number of normal hair follicles decreased with longer culture time. This hair-forming capacity after grafting was not observed in tissues composed of hD overlaid with HBs. These results demonstrate that epithelial stem cells can be kept in vitro in a permissive tissue-engineered dermal environment without losing their potential to induce hair growth after grafting. PMID:20973750

  7. Gait Analysis at Multiple Speeds Reveals Differential Functional and Structural Outcomes in Response to Graded Spinal Cord Injury

    PubMed Central

    Krizsan-Agbas, Dora; Winter, Michelle K.; Eggimann, Linda S.; Meriwether, Judith; Berman, Nancy E.; McCarson, Kenneth E.

    2014-01-01

    Abstract Open-field behavioral scoring is widely used to assess spinal cord injury (SCI) outcomes, but has limited usefulness in describing subtle changes important for posture and locomotion. Additional quantitative methods are needed to increase the resolution of locomotor outcome assessment. This study used gait analysis at multiple speeds (GAMS) across a range of mild-to-severe intensities of thoracic SCI in the rat. Overall, Basso, Beattie, and Bresnahan (BBB) scores and subscores were assessed, and detailed automated gait analysis was performed at three fixed walking speeds (3.5, 6.0, and 8.5?cm/sec). Variability in hindpaw brake, propel, and stance times were analyzed further by integrating across the stance phase of stepping cycles. Myelin staining of spinal cord sections was used to quantify white matter loss at the injury site. Varied SCI intensity produced graded deficits in BBB score, BBB subscores, and spinal cord white matter and total volume loss. GAMS measures of posture revealed decreased paw area, increased limb extension, altered stance width, and decreased values for integrated brake, propel, and stance. Measures of coordination revealed increased stride frequency concomitant with decreased stride length, resulting in deviation from consistent forelimb/hindlimb coordination. Alterations in posture and coordination were correlated to impact severity. GAMS results correlated highly with functional and histological measures and revealed differential relationships between sets of GAMS dynamics and cord total volume loss versus epicenter myelin loss. Automated gait analysis at multiple speeds is therefore a useful tool for quantifying nuanced changes in gait as an extension of histological and observational methods in assessing SCI outcomes. PMID:24405378

  8. Profile of elotuzumab and its potential in the treatment of multiple myeloma

    PubMed Central

    Liu, Yi-Chang; Szmania, Susann; van Rhee, Frits

    2015-01-01

    Although the introduction of novel drugs has improved outcome significantly in multiple myeloma (MM), many patients still eventually relapse. Monoclonal antibodies (mAbs) targeting MM-related antigens can complement currently available therapies. CS1 (also known as CD2 subunit 1, SLAMF7, CD319, and CRACC), a cell surface glycoprotein receptor that is a member of the signaling lymphocytic activation molecule (SLAM) family, is highly and nearly uniformly expressed in myeloma cells at the gene and protein level, but not expressed in other tissues, including hematopoietic stem cells, making CS1 a compelling target for the design of immunotherapies directed at MM. Elotuzumab (formerly HuLuc63), which is a humanized IgG1 mAb recognizing the extracellular region of human CS1, has been shown to be effective in preclinical and early stage clinical investigations, and its efficacy and safety will be further validated in ongoing Phase III trials. Integration of elotuzumab into multidrug therapeutic paradigms seems logical, as elotuzumab is more effective when combined with other agents, such as immunomodulatory drugs or proteasome inhibitors. The functional role of CS1 in MM pathogenesis and the consequences of elotuzumab on normal immune cells should be further investigated. Identification of potential biomarkers and exploration of resistance mechanisms are important issues for elotuzumab-based therapies, as is determining the best clinical placement of elotuzumab, not only in the relapsed/refractory setting but also in upfront therapy for high-risk frank MM, smoldering MM at high-risk of progression, and in maintenance regimens. This review will cover the biological characteristics of CS1 in normal immune cells and MM cells, the efficacy profile and mechanisms of action of elotuzumab from preclinical and clinical investigations, and its potential impact on the treatment of MM. PMID:26005365

  9. A brief exposure to tryptase or thrombin potentiates fibrocyte differentiation in the presence of serum or serum amyloid p.

    PubMed

    White, Michael J V; Galvis-Carvajal, Elkin; Gomer, Richard H

    2015-01-01

    A key question in both wound healing and fibrosis is the trigger for the initial formation of scar tissue. To help form scar tissue, circulating monocytes enter the tissue and differentiate into fibroblast-like cells called fibrocytes, but fibrocyte differentiation is strongly inhibited by the plasma protein serum amyloid P (SAP), and healthy tissues contain very few fibrocytes. In wounds and fibrotic lesions, mast cells degranulate to release tryptase, and thrombin mediates blood clotting in early wounds. Tryptase and thrombin are upregulated in wound healing and fibrotic lesions, and inhibition of these proteases attenuates fibrosis. We report that tryptase and thrombin potentiate human fibrocyte differentiation at biologically relevant concentrations and exposure times, even in the presence of concentrations of serum and SAP that normally completely inhibit fibrocyte differentiation. Fibrocyte potentiation by thrombin and tryptase is mediated by protease-activated receptors 1 and 2, respectively. Together, these results suggest that tryptase and thrombin may be an initial trigger to override SAP inhibition of fibrocyte differentiation to initiate scar tissue formation. PMID:25429068

  10. Impact of low oxygen tension on stemness, proliferation and differentiation potential of human adipose-derived stem cells

    SciTech Connect

    Choi, Jane Ru; Pingguan-Murphy, Belinda; Wan Abas, Wan Abu Bakar; Noor Azmi, Mat Adenan; Omar, Siti Zawiah; Chua, Kien Hui; Wan Safwani, Wan Kamarul Zaman

    2014-05-30

    Highlights: • Hypoxia maintains the stemness of adipose-derived stem cells (ASCs). • ASCs show an increased proliferation rate under low oxygen tension. • Oxygen level as low as 2% enhances the chondrogenic differentiation potential of ASCs. • HIF-1α may regulate the proliferation and differentiation activities of ASCs under hypoxia. - Abstract: Adipose-derived stem cells (ASCs) have been found adapted to a specific niche with low oxygen tension (hypoxia) in the body. As an important component of this niche, oxygen tension has been known to play a critical role in the maintenance of stem cell characteristics. However, the effect of O{sub 2} tension on their functional properties has not been well determined. In this study, we investigated the effects of O{sub 2} tension on ASCs stemness, differentiation and proliferation ability. Human ASCs were cultured under normoxia (21% O{sub 2}) and hypoxia (2% O{sub 2}). We found that hypoxia increased ASC stemness marker expression and proliferation rate without altering their morphology and surface markers. Low oxygen tension further enhances the chondrogenic differentiation ability, but reduces both adipogenic and osteogenic differentiation potential. These results might be correlated with the increased expression of HIF-1α under hypoxia. Taken together, we suggest that growing ASCs under 2% O{sub 2} tension may be important in expanding ASCs effectively while maintaining their functional properties for clinical therapy, particularly for the treatment of cartilage defects.

  11. A brief exposure to tryptase or thrombin potentiates fibrocyte differentiation in the presence of serum or SAP

    PubMed Central

    White, Michael J.V.; Galvis-Carvajal, Elkin; Gomer, Richard H.

    2014-01-01

    A key question in both wound healing and fibrosis is the trigger for the initial formation of scar tissue. To help form scar tissue, circulating monocytes enter the tissue and differentiate into fibroblast-like cells called fibrocytes, but fibrocyte differentiation is strongly inhibited by the plasma protein Serum Amyloid P (SAP), and healthy tissues contain very few fibrocytes. In wounds and fibrotic lesions, mast cells degranulate to release tryptase, and in early wounds thrombin mediates blood clotting. Tryptase and thrombin are upregulated in wound healing and fibrotic lesions, and inhibition of these proteases attenuates fibrosis. Here we report that tryptase and thrombin potentiate human fibrocyte differentiation at biologically relevant concentrations and exposure times, even in the presence of concentrations of serum and SAP that normally completely inhibit fibrocyte differentiation. The fibrocyte potentiation by thrombin and tryptase is mediated by protease-activated receptors 1 and 2, respectively. Together, these results suggest that tryptase and thrombin may be an initial trigger to override SAP inhibition of fibrocyte differentiation to initiate scar tissue formation. PMID:25429068

  12. Perceived stress in multiple sclerosis: the potential role of mindfulness in health and well-being.

    PubMed

    Senders, Angela; Bourdette, Dennis; Hanes, Douglas; Yadav, Vijayshree; Shinto, Lynne

    2014-04-01

    Stressful life events are associated with worsening neurological symptoms and decreased quality of life in multiple sclerosis (MS). Mindful consciousness can alter the impact of stressful events and has potential to improve health outcomes in MS. This study evaluated the relationship between trait mindfulness and perceived stress, coping, and resilience in people with MS. Quality of life was assessed as a secondary outcome. One hundred nineteen people with confirmed MS completed the Five-Facet Mindfulness Questionnaire, Perceived Stress Scale, Brief Coping Orientation for Problem Experiences, Connor-Davidson Resilience Scale, and Medical Outcome Study Short Form-36. Greater trait mindfulness was significantly associated with decreased psychological stress, better coping skills, increased resilience, and higher quality of life. After investigators controlled for confounders, mindfulness accounted for 25% of the variation in perceived stress scores and 44% of the variation in resilience scores. Results support further investigation of mindfulness training to enhance psychological resilience and improve well-being for those living with MS. PMID:24647090

  13. Multiple Spike Time Patterns Occur at Bifurcation Points of Membrane Potential Dynamics

    PubMed Central

    Toups, J. Vincent; Fellous, Jean-Marc; Thomas, Peter J.; Sejnowski, Terrence J.; Tiesinga, Paul H.

    2012-01-01

    The response of a neuron to repeated somatic fluctuating current injections in vitro can elicit a reliable and precisely timed sequence of action potentials. The set of responses obtained across trials can also be interpreted as the response of an ensemble of similar neurons receiving the same input, with the precise spike times representing synchronous volleys that would be effective in driving postsynaptic neurons. To study the reproducibility of the output spike times for different conditions that might occur in vivo, we somatically injected aperiodic current waveforms into cortical neurons in vitro and systematically varied the amplitude and DC offset of the fluctuations. As the amplitude of the fluctuations was increased, reliability increased and the spike times remained stable over a wide range of values. However, at specific values called bifurcation points, large shifts in the spike times were obtained in response to small changes in the stimulus, resulting in multiple spike patterns that were revealed using an unsupervised classification method. Increasing the DC offset, which mimicked an overall increase in network background activity, also revealed bifurcation points and increased the reliability. Furthermore, the spike times shifted earlier with increasing offset. Although the reliability was reduced at bifurcation points, a theoretical analysis showed that the information about the stimulus time course was increased because each of the spike time patterns contained different information about the input. PMID:23093916

  14. Overexpression of tetraspanins affects multiple myeloma cell survival and invasive potential.

    PubMed

    Tohami, Tali; Drucker, Liat; Shapiro, Hava; Radnay, Judith; Lishner, Michael

    2007-03-01

    Cellular interactions with microenvironmental components are critical in multiple myeloma (MM) and impede effective disease treatment. Membranal-embedded tetraspanins, associated with metastasis suppression, are underexpressed in MM. We aimed to investigate the consequences of CD81/CD82 tetraspanins over-expression in MM cell lines. CAG and RPMI 8226 were transfected with pEGFP-N1/C1 fusion vectors of CD81/CD82. Employing flow cytometry, immunocytochemistry, and activity assays we assessed transfected cells for: morphology, survival, death, caspases, cell cycle, proliferation, oxidative stress, adhesion, motility and invasion. Overexpressed CD81/CD82 pEGFP-N1 vectors reduced survival without elevation of pre-G1 or AnnexinV+/7AAD- and independently of caspases. Decreased Ki67 and elevated intracellular glutathione were detected. No perturbations in cell cycle distribution were observed. The pEGFP-C1 vectors of CD81/CD82 caused reduction of MM cell adherence with/without fibronectin, insulin-like growth factor (IGF)-I, and matrigel. They also reduced cell motility and attenuated invasion potential, expressed by reduced secreted MMP-9 activity. These novel findings delineate the significance of CD81/CD82 expression to MM cell survival and their negative effects on cell adhesion, motility, and invasion thus, supporting their role as tumor metastasis suppressors. PMID:17210782

  15. Multiple cone visual pigments and the potential for trichromatic colour vision in two species of elasmobranch.

    PubMed

    Hart, Nathan S; Lisney, Thomas J; Marshall, N Justin; Collin, Shaun P

    2004-12-01

    Elasmobranchs (sharks, skates and rays) are the modern descendents of the first jawed vertebrates and, as apex predators, often occupy the highest trophic levels of aquatic (predominantly marine) ecosystems. However, despite their crucial role in the structure of marine communities, their importance both to commercial and to recreational fisheries, and the inherent interest in their role in vertebrate evolution, very little is known about their visual capabilities, especially with regard to whether or not they have the potential for colour vision. Using microspectrophotometry, we show that the retinae of the giant shovelnose ray (Rhinobatos typus) and the eastern shovelnose ray (Aptychotrema rostrata) contain three spectrally distinct cone visual pigments with wavelengths of maximum absorbance (lambdamax) at 477, 502 and 561 nm and at 459, 492 and 553 nm, respectively. The retinae of R. typus and A. rostrata also contain a single type of rod visual pigment with lambdamax at 504 and 498 nm, respectively. R. typus, living in the same estuarine waters as A. rostrata, were found to have identical visual pigments to R. typus inhabiting coral reef flats, despite a considerable difference in habitat spectral radiance. This is the first time that multiple cone visual pigments have been measured directly in an elasmobranch. The finding raises the possibility that some species are able to discriminate colour--a visual ability traditionally thought to be lacking in this vertebrate class--and it is evident that the visual ecology of elasmobranchs is far more complex than once thought. PMID:15579554

  16. Endothelium Trans Differentiated from Wharton's Jelly Mesenchymal Cells Promote Tissue Regeneration: Potential Role of Soluble Pro-Angiogenic Factors

    PubMed Central

    Aguilera, Valeria; Briceo, Luis; Contreras, Hector; Lamperti, Liliana; Seplveda, Esperanza; Daz-Perez, Francisca; Len, Marcelo; Veas, Carlos; Maura, Rafael; Toledo, Jorge Roberto; Fernndez, Paulina; Covarrubias, Ambart; Zuiga, Felipe Andrs; Radojkovic, Claudia; Escudero, Carlos; Aguayo, Claudio

    2014-01-01

    Background Mesenchymal stem cells have a high capacity for trans-differentiation toward many adult cell types, including endothelial cells. Feto-placental tissue, such as Wharton's jelly is a potential source of mesenchymal stem cells with low immunogenic capacity; make them an excellent source of progenitor cells with a potential use for tissue repair. We evaluated whether administration of endothelial cells derived from mesenchymal stem cells isolated from Wharton's jelly (hWMSCs) can accelerate tissue repair in vivo. Methods Mesenchymal stem cells were isolated from human Wharton's jelly by digestion with collagenase type I. Endothelial trans-differentiation was induced for 14 (hWMSC-End14d) and 30 (hWMSC-End30d) days. Cell phenotyping was performed using mesenchymal (CD90, CD73, CD105) and endothelial (Tie-2, KDR, eNOS, ICAM-1) markers. Endothelial trans-differentiation was demonstrated by the expression of endothelial markers and their ability to synthesize nitric oxide (NO). Results hWMSCs can be differentiated into adipocytes, osteocytes, chondrocytes and endothelial cells. Moreover, these cells show high expression of CD73, CD90 and CD105 but low expression of endothelial markers prior to differentiation. hWMSCs-End express high levels of endothelial markers at 14 and 30 days of culture, and also they can synthesize NO. Injection of hWMSC-End30d in a mouse model of skin injury significantly accelerated wound healing compared with animals injected with undifferentiated hWMSC or injected with vehicle alone. These effects were also observed in animals that received conditioned media from hWMSC-End30d cultures. Conclusion These results demonstrate that mesenchymal stem cells isolated from Wharton's jelly can be cultured in vitro and trans-differentiated into endothelial cells. Differentiated hWMSC-End may promote neovascularization and tissue repair in vivo through the secretion of soluble pro-angiogenic factors. PMID:25412260

  17. Socioeconomic differentials in mortality risk among men screened for the Multiple Risk Factor Intervention Trial: I. White men.

    PubMed Central

    Smith, G D; Neaton, J D; Wentworth, D; Stamler, R; Stamler, J

    1996-01-01

    OBJECTIVES: This study examined socioeconomic differentials in risk of death from a number of specific causes in a large cohort of White men in the United States. METHODS: For 300 685 White men screened for the Multiple Risk Factor Intervention Trial between 1973 and 1975, data were collected on median income of White households in the zip code of residence, age, cigarette smoking, blood pressure, serum cholesterol, previous myocardial infarction, and drug treatment for diabetes. The 31 737 deaths that occurred over the 16-year follow-up period were grouped into specific causes and related to median White family income. RESULTS: There was an inverse association between age- adjusted all-cause mortality and median family income. There was no attenuation of this association over the follow-up period, and the association was similar for the 22 clinical centers carrying out the screening. The gradient was seen for many-but not all-of the specific causes of death. Other risk factors accounted for some of the association between income and coronary heart disease and smoking-related cancers. CONCLUSIONS: Socioeconomic position, as measured by median family income of area of residence, is an important determinant of mortality risk in White men. PMID:8604778

  18. Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke

    PubMed Central

    Bailey, Emma L; McBride, Martin W; Beattie, Wendy; McClure, John D; Graham, Delyth; Dominiczak, Anna F; Sudlow, Cathie LM; Smith, Colin; Wardlaw, Joanna M

    2014-01-01

    Aims Cerebral small vessel disease (SVD) causes a fifth of all strokes plus diffuse brain damage leading to cognitive decline, physical disabilities and dementia. The aetiology and pathogenesis of SVD are unknown, but largely attributed to hypertension or microatheroma. Methods We used the spontaneously hypertensive stroke-prone rat (SHRSP), the closest spontaneous experimental model of human SVD, and age-matched control rats kept under identical, non-salt-loaded conditions, to perform a blinded analysis of mRNA microarray, qRT-PCR and pathway analysis in two brain regions (frontal and mid-coronal) commonly affected by SVD in the SHRSP at age five, 16 and 21 weeks. Results We found gene expression abnormalities, with fold changes ranging from 2.5 to 59 for the 10 most differentially expressed genes, related to endothelial tight junctions (reduced), nitric oxide bioavailability (reduced), myelination (impaired), glial and microglial activity (increased), matrix proteins (impaired), vascular reactivity (impaired) and albumin (reduced), consistent with protein expression defects in the same rats. All were present at age 5 weeks thus predating blood pressure elevation. Neurological and inflammatory pathways were more affected than vascular functional pathways. Conclusions This set of defects, although individually modest, when acting in combination could explain the SHRSP's susceptibility to microvascular and brain injury, compared with control rats. Similar combined, individually modest, but multiple neurovascular unit defects, could explain susceptibility to spontaneous human SVD. PMID:24417612

  19. Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci.

    PubMed

    Andreassen, O A; Harbo, H F; Wang, Y; Thompson, W K; Schork, A J; Mattingsdal, M; Zuber, V; Bettella, F; Ripke, S; Kelsoe, J R; Kendler, K S; O'Donovan, M C; Sklar, P; McEvoy, L K; Desikan, R S; Lie, B A; Djurovic, S; Dale, A M

    2015-02-01

    Converging evidence implicates immune abnormalities in schizophrenia (SCZ), and recent genome-wide association studies (GWAS) have identified immune-related single-nucleotide polymorphisms (SNPs) associated with SCZ. Using the conditional false discovery rate (FDR) approach, we evaluated pleiotropy in SNPs associated with SCZ (n=21,856) and multiple sclerosis (MS) (n=43,879), an inflammatory, demyelinating disease of the central nervous system. Because SCZ and bipolar disorder (BD) show substantial clinical and genetic overlap, we also investigated pleiotropy between BD (n=16,731) and MS. We found significant genetic overlap between SCZ and MS and identified 21 independent loci associated with SCZ, conditioned on association with MS. This enrichment was driven by the major histocompatibility complex (MHC). Importantly, we detected the involvement of the same human leukocyte antigen (HLA) alleles in both SCZ and MS, but with an opposite directionality of effect of associated HLA alleles (that is, MS risk alleles were associated with decreased SCZ risk). In contrast, we found no genetic overlap between BD and MS. Considered together, our findings demonstrate genetic pleiotropy between SCZ and MS and suggest that the MHC signals may differentiate SCZ from BD susceptibility. PMID:24468824

  20. Multipotential differentiation of human urine-derived stem cells: potential for therapeutic applications in urology.

    PubMed

    Bharadwaj, Shantaram; Liu, Guihua; Shi, Yingai; Wu, Rongpei; Yang, Bin; He, Tongchuan; Fan, Yuxin; Lu, Xinyan; Zhou, Xiaobo; Liu, Hong; Atala, Anthony; Rohozinski, Jan; Zhang, Yuanyuan

    2013-09-01

    We sought to biologically characterize and identify a subpopulation of urine-derived stem cells (USCs) with the capacity for multipotent differentiation. We demonstrated that single USCs can expand to a large population with 60-70 population doublings. Nine of 15 individual USC clones expressed detectable levels of telomerase and have long telomeres. These cells expressed pericyte and mesenchymal stem cell markers. Upon induction with appropriate media in vitro, USCs differentiated into bladder-associated cell types, including functional urothelial and smooth muscle cell lineages. When the differentiated USCs were seeded onto a scaffold and subcutaneously implanted into nude mice, multilayered tissue-like structures formed consisting of urothelium and smooth muscle. Additionally, USCs were able to differentiate into endothelial, osteogenic, chondrogenic, adipogenic, skeletal myogenic, and neurogenic lineages but did not form teratomas during the 1-month study despite telomerase activity. USCs may be useful in cell-based therapies and tissue engineering applications, including urogenital reconstruction. PMID:23666768

  1. Multiple-Locus Variable-Number Tandem-Repeat Analysis Is a Suitable Tool for Differentiation of Mycoplasma hyopneumoniae Strains without Cultivation?

    PubMed Central

    Vranckx, K.; Maes, D.; Calus, D.; Villarreal, I.; Pasmans, F.; Haesebrouck, F.

    2011-01-01

    An assay based on multiple-locus variable-number tandem-repeat analysis allowed differentiating and studying diversity and persistence of Mycoplasma hyopneumoniae strains in pig herds without prior cultivation. The test had a discriminatory index of >0.99 and was applied reliably to porcine bronchoalveolar lavage fluid and tracheal swabs. PMID:21389157

  2. Microgravity Reduces the Differentiation and Regenerative Potential of Embryonic Stem Cells.

    PubMed

    Blaber, Elizabeth A; Finkelstein, Hayley; Dvorochkin, Natalya; Sato, Kevin Y; Yousuf, Rukhsana; Burns, Brendan P; Globus, Ruth K; Almeida, Eduardo A C

    2015-11-15

    Mechanical unloading in microgravity is thought to induce tissue degeneration by various mechanisms, including inhibition of regenerative stem cell differentiation. To address this hypothesis, we investigated the effects of microgravity on early lineage commitment of mouse embryonic stem cells (mESCs) using the embryoid body (EB) model of tissue differentiation. We found that exposure to microgravity for 15 days inhibits mESC differentiation and expression of terminal germ layer lineage markers in EBs. Additionally, microgravity-unloaded EBs retained stem cell self-renewal markers, suggesting that mechanical loading at Earth's gravity is required for normal differentiation of mESCs. Finally, cells recovered from microgravity-unloaded EBs and then cultured at Earth's gravity showed greater stemness, differentiating more readily into contractile cardiomyocyte colonies. These results indicate that mechanical unloading of stem cells in microgravity inhibits their differentiation and preserves stemness, possibly providing a cellular mechanistic basis for the inhibition of tissue regeneration in space and in disuse conditions on earth. PMID:26414276

  3. Cellular network entropy as the energy potential in Waddington's differentiation landscape

    NASA Astrophysics Data System (ADS)

    Banerji, Christopher R. S.; Miranda-Saavedra, Diego; Severini, Simone; Widschwendter, Martin; Enver, Tariq; Zhou, Joseph X.; Teschendorff, Andrew E.

    2013-10-01

    Differentiation is a key cellular process in normal tissue development that is significantly altered in cancer. Although molecular signatures characterising pluripotency and multipotency exist, there is, as yet, no single quantitative mark of a cellular sample's position in the global differentiation hierarchy. Here we adopt a systems view and consider the sample's network entropy, a measure of signaling pathway promiscuity, computable from a sample's genome-wide expression profile. We demonstrate that network entropy provides a quantitative, in-silico, readout of the average undifferentiated state of the profiled cells, recapitulating the known hierarchy of pluripotent, multipotent and differentiated cell types. Network entropy further exhibits dynamic changes in time course differentiation data, and in line with a sample's differentiation stage. In disease, network entropy predicts a higher level of cellular plasticity in cancer stem cell populations compared to ordinary cancer cells. Importantly, network entropy also allows identification of key differentiation pathways. Our results are consistent with the view that pluripotency is a statistical property defined at the cellular population level, correlating with intra-sample heterogeneity, and driven by the degree of signaling promiscuity in cells. In summary, network entropy provides a quantitative measure of a cell's undifferentiated state, defining its elevation in Waddington's landscape.

  4. Microgravity Reduces the Differentiation and Regenerative Potential of Embryonic Stem Cells

    PubMed Central

    Blaber, Elizabeth A.; Finkelstein, Hayley; Dvorochkin, Natalya; Sato, Kevin Y.; Yousuf, Rukhsana; Burns, Brendan P.; Globus, Ruth K.

    2015-01-01

    Mechanical unloading in microgravity is thought to induce tissue degeneration by various mechanisms, including inhibition of regenerative stem cell differentiation. To address this hypothesis, we investigated the effects of microgravity on early lineage commitment of mouse embryonic stem cells (mESCs) using the embryoid body (EB) model of tissue differentiation. We found that exposure to microgravity for 15 days inhibits mESC differentiation and expression of terminal germ layer lineage markers in EBs. Additionally, microgravity-unloaded EBs retained stem cell self-renewal markers, suggesting that mechanical loading at Earth's gravity is required for normal differentiation of mESCs. Finally, cells recovered from microgravity-unloaded EBs and then cultured at Earth's gravity showed greater stemness, differentiating more readily into contractile cardiomyocyte colonies. These results indicate that mechanical unloading of stem cells in microgravity inhibits their differentiation and preserves stemness, possibly providing a cellular mechanistic basis for the inhibition of tissue regeneration in space and in disuse conditions on earth. PMID:26414276

  5. Acute stimulation of mesenchymal stem cells with cigarette smoke extract affects their migration, differentiation, and paracrine potential.

    PubMed

    Wahl, Elizabeth A; Schenck, Thilo L; Machens, Hans-Günther; Egaña, J Tomás

    2016-01-01

    Mesenchymal stem cells (MSCs) are known to play a key role in tissue regeneration, while smoking cigarettes is described to impair it. This work focuses on the effect cigarette smoke extract (CSE) has on the migration, differentiation, and paracrine potential of human adipose derived MSCs (AdMSCs). To mimic native conditions in vitro, AdMSCs were cultured in either monolayer or three-dimensional pellet cultures. While constant exposure to high concentrations of CSE had lethal effects on AdMSCs, lower concentrations of CSE impaired cell migration when compared to control conditions. The secretion of key interleukins was downregulated when CSE was exposed to the cells at low concentrations. Moreover, in this work AdMSCs were exposed to CSE while simultaneously being induced to differentiate into adipocytes, osteoblasts, and chondrocytes to determine the effect of CSE on the cells potential to differentiate. While adipogenic differentiation showed no significant variation, AdMSCs exposed to osteogenic and chondrogenic supplements showed both early and late genetic level variation when acutely exposed to low concentrations of CSE. Our results indicate that even a small amount of cigarette smoke can have detrimental effects on the regenerative potential of MSCs. PMID:26976359

  6. Acute stimulation of mesenchymal stem cells with cigarette smoke extract affects their migration, differentiation, and paracrine potential

    PubMed Central

    Wahl, Elizabeth A.; Schenck, Thilo L.; Machens, Hans-Günther; Egaña, J. Tomás

    2016-01-01

    Mesenchymal stem cells (MSCs) are known to play a key role in tissue regeneration, while smoking cigarettes is described to impair it. This work focuses on the effect cigarette smoke extract (CSE) has on the migration, differentiation, and paracrine potential of human adipose derived MSCs (AdMSCs). To mimic native conditions in vitro, AdMSCs were cultured in either monolayer or three-dimensional pellet cultures. While constant exposure to high concentrations of CSE had lethal effects on AdMSCs, lower concentrations of CSE impaired cell migration when compared to control conditions. The secretion of key interleukins was downregulated when CSE was exposed to the cells at low concentrations. Moreover, in this work AdMSCs were exposed to CSE while simultaneously being induced to differentiate into adipocytes, osteoblasts, and chondrocytes to determine the effect of CSE on the cells potential to differentiate. While adipogenic differentiation showed no significant variation, AdMSCs exposed to osteogenic and chondrogenic supplements showed both early and late genetic level variation when acutely exposed to low concentrations of CSE. Our results indicate that even a small amount of cigarette smoke can have detrimental effects on the regenerative potential of MSCs. PMID:26976359

  7. Differentiation potentials of perivascular cells in the bone tissue remodeling zones under microgravity

    NASA Astrophysics Data System (ADS)

    Rodionova, Natalia; Katkova, Olena

    Adaptive remodeling processes in the skeleton bones occur in the close topographical interconnection with blood capillaries followed by perivascular cells. Radioautographic studies with 3Н- thymidine (Kimmel D.B., Fee W.S., 1980; Rodionova N.V., 1989, 2006) has shown that in osteogenesis zones there is sequential differentiation process of the perivascular cells into osteogenic ones. Using electron microscopy and cytochemistry we studied perivsacular cells in metaphysis of the rats femoral bones under conditions of modeling microgravity (28 days duration) and in femoral bonеs metaphyses of rats flown on board of the space laboratory (Spacelab - 2) It was revealed that population of the perivascular cells is not homogeneous in adaptive zones of the remodeling in both control and test groups (lowering support loading). This population comprises adjacent to endothelium little differentiated forms and isolated cells with differentiation features (specific volume of rough endoplasmic reticulum in cytoplasm is increased). Majority of the perivascular cells in the control group reveals reaction to alkaline phosphatase (marker of the osteogenic differentiation). In little differentiated cells this reaction is registered in nucleolus, nucleous and cytoplasm. In differentiating cells activity of the alkaline phosphatase is also detected on the outer surface of the cellular membrane. Unlike the control group in the bones of animals under microgravitaty reaction to the alkaline phosphatase is registered not for all cells of perivascular population. Part of the differentiating perivascular cells does not contain a product of the reaction. There is also visible trend of individual alkaline phosphatase containing perivascular cells amounts decrease (i.e. osteogenic cells-precursors). Under microgravity some little differentiated perivascular cells reveal destruction signs. Found decrease trend of the alkaline phosphatase containing cells (i.e. osteogenic cells) number in perivascular cells population. It is one of the mechanisms of the osteogenic process intensity decrease in bones due to lowering support loading on the bone skeleton. In particular this is confirmed by the fact that in the zones of adaptive remodeling we found fibroblasts and fibrosis zones - areas filled with non mineralized collagen fibrils on the bones surfaces. Hence it should be considered that lowering (removal) support loading slows down (or blocks) osteogenic differentiation of the perivascular cells part and stimulates differentiation of the fibroblast cells. Obtained data considered as one of the cellular mechanisms of the adaptive reactions development in spongy bone under microgravity which could lead to the bone mass loss.

  8. Bone-derived mesenchymal stromal cells from HIV transgenic mice exhibit altered proliferation, differentiation capacity and paracrine functions along with impaired therapeutic potential in kidney injury

    SciTech Connect

    Cheng, Kang; Rai, Partab; Lan, Xiqian; Plagov, Andrei; Malhotra, Ashwani; Gupta, Sanjeev; Singhal, Pravin C.

    2013-08-15

    Mesenchymal stem cells (MSCs) secrete paracrine factors that could be cytoprotective and serve roles in immunoregulation during tissue injury. Although MSCs express HIV receptors, and co-receptors, and are susceptible to HIV infection, whether HIV-1 may affect biological properties of MSCs needs more study. We evaluated cellular proliferation, differentiation and paracrine functions of MSCs isolated from compact bones of healthy control mice and Tg26 HIV-1 transgenic mice. The ability of MSCs to protect against cisplatin toxicity was studied in cultured renal tubular cells as well as in intact mice. We successfully isolated MSCs from healthy mice and Tg26 HIV-1 transgenic mice and found the latter expressed viral Nef, Vpu, NL4-3 and Vif genes. The proliferation and differentiation of Tg26 HIV-1 MSCs was inferior to MSCs from healthy mice. Moreover, transplantation of Tg26 HIV-1 MSCs less effectively improved outcomes compared with healthy MSCs in mice with acute kidney injury. Also, Tg26 HIV-1 MSCs secreted multiple cytokines, but at significantly lower levels than healthy MSCs, which resulted in failure of conditioned medium from these MSCs to protect cultured renal tubular cells from cisplatin toxicity. Therefore, HIV-1 had adverse biological effects on MSCs extending to their proliferation, differentiation, function, and therapeutic potential. These findings will help in advancing mechanistical insight in renal injury and repair in the setting of HIV-1 infection. -- Highlights: •MSCs isolated from HIV mice displayed HIV genes. •MSCs isolated from HIV mice exhibited attenuated growth and paracrine functions. •AKI mice with transplanted HIV-MSC displayed poor outcome. •HIV-1 MSC secreted multiple cytokines but at a lower level.

  9. Effects of long-term differential fertilization on eukaryotic microbial communities in an arable soil: a multiple barcoding approach.

    PubMed

    Lentendu, Guillaume; Wubet, Tesfaye; Chatzinotas, Antonis; Wilhelm, Christian; Buscot, Franois; Schlegel, Martin

    2014-07-01

    To understand the fine-scale effects of changes in nutrient availability on eukaryotic soil microorganisms communities, a multiple barcoding approach was used to analyse soil samples from four different treatments in a long-term fertilization experiment. We performed PCR amplification on soil DNA with primer pairs specifically targeting the 18S rRNA genes of all eukaryotes and three protist groups (Cercozoa, Chrysophyceae-Synurophyceae and Kinetoplastida) as well as the ITS gene of fungi and the 23S plastid rRNA gene of photoautotrophic microorganisms. Amplicons were pyrosequenced, and a total of 88,706 quality filtered reads were clustered into 1232 operational taxonomic units (OTU) across the six data sets. Comparisons of the taxonomic coverage achieved based on overlapping assignment of OTUs revealed that half of the eukaryotic taxa identified were missed by the universal eukaryotic barcoding marker. There were only little differences in OTU richness observed between organic- (farmyard manure), mineral- and nonfertilized soils. However, the community compositions appeared to be strongly structured by organic fertilization in all data sets other than that generated using the universal eukaryotic 18S rRNA gene primers, whereas mineral fertilization had only a minor effect. In addition, a co-occurrence based network analysis revealed complex potential interaction patterns between OTUs from different trophic levels, for example between fungivorous flagellates and fungi. Our results demonstrate that changes in pH, moisture and organic nutrients availability caused shifts in the composition of eukaryotic microbial communities at multiple trophic levels. PMID:24888892

  10. Differentiation of Equine Mesenchymal Stromal Cells into Cells of Neural Lineage: Potential for Clinical Applications

    PubMed Central

    Cruz Villagrán, Claudia; Amelse, Lisa; Neilsen, Nancy; Dunlap, John; Dhar, Madhu

    2014-01-01

    Mesenchymal stromal cells (MSCs) are able to differentiate into extramesodermal lineages, including neurons. Positive outcomes were obtained after transplantation of neurally induced MSCs in laboratory animals after nerve injury, but this is unknown in horses. Our objectives were to test the ability of equine MSCs to differentiate into cells of neural lineage in vitro, to assess differences in morphology and lineage-specific protein expression, and to investigate if horse age and cell passage number affected the ability to achieve differentiation. Bone marrow-derived MSCs were obtained from young and adult horses. Following demonstration of stemness, MSCs were neurally induced and microscopically assessed at different time points. Results showed that commercially available nitrogen-coated tissue culture plates supported proliferation and differentiation. Morphological changes were immediate and all the cells displayed a neural crest-like cell phenotype. Expression of neural progenitor proteins, was assessed via western blot or immunofluorescence. In our study, MSCs generated from young and middle-aged horses did not show differences in their ability to undergo differentiation. The effect of cell passage number, however, is inconsistent and further experiments are needed. Ongoing work is aimed at transdifferentiating these cells into Schwann cells for transplantation into a peripheral nerve injury model in horses. PMID:25506367

  11. Phosphoprotein enriched in astrocytes (PEA)-15: A potential therapeutic target in multiple disease states

    PubMed Central

    Greig, Fiona H.; Nixon, Graeme F.

    2014-01-01

    Phosphoprotein enriched in astrocytes-15 (PEA-15) is a cytoplasmic protein that sits at an important junction in intracellular signalling and can regulate diverse cellular processes, such as proliferation and apoptosis, dependent upon stimulation. Regulation of these processes occurs by virtue of the unique interaction of PEA-15 with other signalling proteins. PEA-15 acts as a cytoplasmic tether for the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) preventing nuclear localisation. In order to release ERK1/2, PEA-15 requires to be phosphorylated via several potential pathways. PEA-15 (and its phosphorylation state) therefore regulates many ERK1/2-dependent processes, including proliferation, via regulating ERK1/2 nuclear translocation. In addition, PEA-15 contains a death effector domain (DED) which allows interaction with other DED-containing proteins. PEA-15 can bind the DED-containing apoptotic adaptor molecule, Fas-associated death domain protein (FADD) which is also dependent on the phosphorylation status of PEA-15. PEA-15 binding of FADD can inhibit apoptosis as bound FADD cannot participate in the assembly of apoptotic signalling complexes. Through these proteinprotein interactions, PEA-15-regulated cellular effects have now been investigated in a number of disease-related studies. Changes in PEA-15 expression and regulation have been observed in diabetes mellitus, cancer, neurological disorders and the cardiovascular system. These changes have been suggested to contribute to the pathology related to each of these disease states. As such, new therapeutic targets based around PEA-15 and its associated interactions are now being uncovered and could provide novel avenues for treatment strategies in multiple diseases. PMID:24657708

  12. Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis.

    PubMed

    Sellebjerg, Finn; Cadavid, Diego; Steiner, Deborah; Villar, Luisa Maria; Reynolds, Richard; Mikol, Daniel

    2016-01-01

    Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) demyelinating disease and a leading cause of permanent disability. Patients most often present with a relapsing-remitting disease course, typically progressing over time to a phase of relentless advancement in secondary progressive MS (SPMS), for which approved disease-modifying therapies are limited. In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. In both forms of MS, active brain-tissue injury is associated with inflammation; but in SPMS, the inflammatory response occurs at least partly behind the blood-brain barrier and is followed by a cascade of events, including persistent microglial activation that may lead to chronic demyelination and neurodegeneration associated with irreversible disability. In patients with relapsing forms of MS, natalizumab therapy is known to significantly reduce intrathecal inflammatory responses which results in reductions in brain lesions and brain atrophy as well as beneficial effects on clinical measures, such as reduced frequency and severity of relapse and reduced accumulation of disability. Natalizumab treatment also reduces levels of cerebrospinal fluid chemokines and other biomarkers of intrathecal inflammation, axonal damage and demyelination, and has demonstrated the ability to reduce innate immune activation and intrathecal immunoglobulin synthesis in patients with MS. The efficacy of natalizumab therapy in SPMS is currently being investigated in a randomized, double-blind, placebo-controlled trial. PMID:26788129

  13. Potential role of soluble human leukocyte antigen-G molecules in multiple sclerosis.

    PubMed

    Fainardi, Enrico; Rizzo, Roberta; Castellazzi, Massimiliano; Stignani, Marina; Granieri, Enrico; Baricordi, Olavio Roberto

    2009-12-01

    Nonclassical human leukocyte antigen (HLA)-G antigens in soluble form (sHLA-G) have recently been suggested to have a potential role as immunomodulatory factors in multiple sclerosis (MS), a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system of unknown etiology and supposed autoimmune origin. In MS patients, sHLA-G levels were elevated in cerebrospinal fluid (CSF), intrathecally synthesized, predominantly represented by the HLA-G5 isoform and even more elevated in cases of inactive disease, as determined by magnetic resonance imaging. In MS, CSF sHLA-G concentrations were also related to the formation of an intrathecal anti-inflammatory microenvironment based on a positive correlation to CSF interleukin-10 titers and an inverse association to the levels of antiapoptotic sFas molecules in the CSF. Expression of HLA-G antigens was detected in microglia, macrophages, and endothelial cells within and around MS lesions and was enhanced in microglial cells by T-helper-1 proinflammatory cytokines. A novel subpopulation of naturally occurring CD4(+) and CD8(+) regulatory T cells expressing HLA-G1 and secreting HLA-G5 was identified in the CSF of MS patients. Taken together, these findings seem to indicate that sHLA-G antigens may be implicated in the termination of MS autoimmunity and associated with remission of the disease through their function as anti-inflammatory molecules. However, the mechanisms operating in the immunomodulatory circuit mediated by sHLA-G proteins remain to be clarified. PMID:19651179

  14. Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis

    PubMed Central

    Sellebjerg, Finn; Cadavid, Diego; Steiner, Deborah; Villar, Luisa Maria; Reynolds, Richard; Mikol, Daniel

    2016-01-01

    Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) demyelinating disease and a leading cause of permanent disability. Patients most often present with a relapsing–remitting disease course, typically progressing over time to a phase of relentless advancement in secondary progressive MS (SPMS), for which approved disease-modifying therapies are limited. In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. In both forms of MS, active brain-tissue injury is associated with inflammation; but in SPMS, the inflammatory response occurs at least partly behind the blood–brain barrier and is followed by a cascade of events, including persistent microglial activation that may lead to chronic demyelination and neurodegeneration associated with irreversible disability. In patients with relapsing forms of MS, natalizumab therapy is known to significantly reduce intrathecal inflammatory responses which results in reductions in brain lesions and brain atrophy as well as beneficial effects on clinical measures, such as reduced frequency and severity of relapse and reduced accumulation of disability. Natalizumab treatment also reduces levels of cerebrospinal fluid chemokines and other biomarkers of intrathecal inflammation, axonal damage and demyelination, and has demonstrated the ability to reduce innate immune activation and intrathecal immunoglobulin synthesis in patients with MS. The efficacy of natalizumab therapy in SPMS is currently being investigated in a randomized, double-blind, placebo-controlled trial. PMID:26788129

  15. "So Much Potential in Reading!" Developing Meaningful Literacy Routines for Students with Multiple Disabilities

    ERIC Educational Resources Information Center

    Fenlon, Amanda G.; McNabb, Jessica; Pidlypchak, Harmony

    2010-01-01

    Children with multiple disabilities, often experience challenges in communication, mobility, and learning. Despite these challenges, substantial research exists that documents successful educational methods and strategies for these students. Specifically, students with multiple disabilities have successfully been taught to use a voice output

  16. Identification of genes associated with the differentiation potential of adipose-derived stem cells to osteocytes or myocytes.

    PubMed

    Ren, Yizhong; Han, Changxu; Wang, Jingjuan; Jia, Yanbo; Kong, Lingyue; Eerdun, Tu; Wu, Lishuan; Jiang, Dianming

    2015-02-01

    Adipose-derived stem cells (ADSCs) have been considered as the optimal cells for regenerative medicine because ADSCs have the potential of multi-directional differentiation. To study the mechanisms of ADSCs differentiation, we analyzed microarray of GSE37329. GSE37329 was downloaded from Gene Expression Omnibus including 3 ADSCs, 2 ADSCs-derived osteocytes, and 2 ADSCs-derived myocytes samples. The differentially expressed genes (DEGs) were screened using limma package. Their underlying functions were predicted by gene ontology and pathway enrichment analyses. Besides, the interaction relationships of the proteins encoded by DEGs were obtained from STRING database, and protein-protein interaction (PPI) network was constructed using Cytoscape. Furthermore, modules analysis of PPI network was performed using MCODE in Cytoscape. We screened 662 and 484 DEG separately for the ADSCs-derived osteocytes and myocytes compared with ADSCs. There were 205 common up-regulated and 128 common down-regulated DEGs between the two groups. Function enrichment indicated that these common DEGs, especially, VEGFA, FGF2, and EGR1 may be related to cell differentiation. PPI network for common DEGs also suggested that VEGFA (degree = 29), FGF2 (degree = 17), and EGR1 (degree = 12) might be more important because they had higher connectivity degrees, and they might be involved in cell differentiation by interacting with other genes in module A (e.g., EGR1-NGF and EGR1-LEP), and B (e.g., VEGFA-PDGFD). Additionally, the IGF1 and BTG1 may be, respectively, specific for osteocytes and myocytes differentiation. VEGFA, PDGFD, FGF2, EGR1, NGF, LEP, IGF1, and BTG1 might serve as target genes in regulating ADSCs differentiation. PMID:25385480

  17. Comparisons of Differentiation Potential in Human Mesenchymal Stem Cells from Wharton's Jelly, Bone Marrow, and Pancreatic Tissues.

    PubMed

    Kao, Shih-Yi; Shyu, Jia-Fwu; Wang, Hwai-Shi; Lin, Chi-Hung; Su, Cheng-Hsi; Chen, Tien-Hua; Weng, Zen-Chung; Tsai, Pei-Jiun

    2015-01-01

    Background. Type 1 diabetes mellitus results from autoimmune destruction of ?-cells. Insulin-producing cells (IPCs) differentiated from mesenchymal stem cells (MSCs) in human tissues decrease blood glucose levels and improve survival in diabetic rats. We compared the differential ability and the curative effect of IPCs from three types of human tissue to determine the ideal source of cell therapy for diabetes. Methods. We induced MSCs from Wharton's jelly (WJ), bone marrow (BM), and surgically resected pancreatic tissue to differentiate into IPCs. The in vitro differential function of these IPCs was compared by insulin-to-DNA ratios and C-peptide levels after glucose challenge. In vivo curative effects of IPCs transplanted into diabetic rats were monitored by weekly blood glucose measurement. Results. WJ-MSCs showed better proliferation and differentiation potential than pancreatic MSCs and BM-MSCs. In vivo, WJ-IPCs significantly reduced blood glucose levels at first week after transplantation and maintained significant decrease till week 8. BM-IPCs reduced blood glucose levels at first week but gradually increased since week 3. In resected pancreas-IPCs group, blood glucose levels were significantly reduced till two weeks after transplantation and gradually increased since week 4. Conclusion. WJ-MSCs are the most promising stem cell source for ?-cell regeneration in diabetes treatment. PMID:26294917

  18. Comparisons of Differentiation Potential in Human Mesenchymal Stem Cells from Wharton's Jelly, Bone Marrow, and Pancreatic Tissues

    PubMed Central

    Kao, Shih-Yi; Shyu, Jia-Fwu; Wang, Hwai-Shi; Lin, Chi-Hung; Su, Cheng-Hsi; Chen, Tien-Hua; Weng, Zen-Chung; Tsai, Pei-Jiun

    2015-01-01

    Background. Type 1 diabetes mellitus results from autoimmune destruction of β-cells. Insulin-producing cells (IPCs) differentiated from mesenchymal stem cells (MSCs) in human tissues decrease blood glucose levels and improve survival in diabetic rats. We compared the differential ability and the curative effect of IPCs from three types of human tissue to determine the ideal source of cell therapy for diabetes. Methods. We induced MSCs from Wharton's jelly (WJ), bone marrow (BM), and surgically resected pancreatic tissue to differentiate into IPCs. The in vitro differential function of these IPCs was compared by insulin-to-DNA ratios and C-peptide levels after glucose challenge. In vivo curative effects of IPCs transplanted into diabetic rats were monitored by weekly blood glucose measurement. Results. WJ-MSCs showed better proliferation and differentiation potential than pancreatic MSCs and BM-MSCs. In vivo, WJ-IPCs significantly reduced blood glucose levels at first week after transplantation and maintained significant decrease till week 8. BM-IPCs reduced blood glucose levels at first week but gradually increased since week 3. In resected pancreas-IPCs group, blood glucose levels were significantly reduced till two weeks after transplantation and gradually increased since week 4. Conclusion. WJ-MSCs are the most promising stem cell source for β-cell regeneration in diabetes treatment. PMID:26294917

  19. Inverse differentiation pathway by multiple mafic magma refilling in the last magmatic activity of Nisyros Volcano, Greece

    NASA Astrophysics Data System (ADS)

    Braschi, Eleonora; Francalanci, Lorella; Vougioukalakis, Georges E.

    2012-07-01

    Based on detailed field, petrographic, chemical, and isotopic data, this paper shows that the youngest magmas of the active Nisyros volcano (South Aegean Arc, Greece) are an example of transition from rhyolitic to less evolved magmas by multiple refilling with mafic melts, triggering complex magma interaction processes. The final magmatic activity of Nisyros was characterized by sub-Plinian caldera-forming eruption (40 ka), emplacing the Upper Pumice (UP) rhyolitic deposits, followed by the extrusion of rhyodacitic post-caldera domes (about 31-10 ka). The latter are rich in magmatic enclaves with textural and compositional (basaltic-andesite to andesite) characteristics that reveal they are quenched portions of mafic magmas included in a cooler more evolved melt. Dome-lavas have different chemical, isotopic, and mineralogical characteristics from the enclaves. The latter have lower 87Sr/86Sr and higher 143Nd/144Nd values than dome-lavas. Silica contents and 87Sr/86Sr values decrease with time among dome-lavas and enclaves. Micro-scale mingling processes caused by enclave crumbling and by widespread mineral exchanges increase from the oldest to the youngest domes, together with enclave content. We demonstrate that the dome-lavas are multi-component magmas formed by progressive mingling/mixing processes between a rhyolitic component ( post-UP) and the enclave-forming mafic magmas refilling the felsic reservoir (from 15 wt.% to 40 wt.% of mafic component with time). We recognize that only the more evolved enclave magmas contribute to this process, in which recycling of cumulate plagioclase crystals is also involved. The post-UP end-member derives by fractional crystallization from the magmas leftover after the previous UP eruptions. The enclave magma differentiation develops mainly by fractional crystallization associated with multiple mixing with mafic melts changing their composition with time. A time-related picture of the relationships between dome-lavas and relative enclaves is proposed, suggesting a delay between a mafic magma input and the relative dome outpouring. We also infer that the magma viscosity reduction by re-heating allows dome extrusion without explosive activity.

  20. Changes in the Potential Multiple Cropping System in Response to Climate Change in China from 19602010

    PubMed Central

    Liu, Luo; Xu, Xinliang; Zhuang, Dafang; Chen, Xi; Li, Shuang

    2013-01-01

    The multiple cropping practice is essential to agriculture because it has been shown to significantly increase the grain yield and promote agricultural economic development. In this study, potential multiple cropping systems in China are calculated based on meteorological observation data by using the Agricultural Ecology Zone (AEZ) model. Following this, the changes in the potential cropping systems in response to climate change between the 1960s and the 2010s were subsequently analyzed. The results indicate that the changes of potential multiple cropping systems show tremendous heterogeneity in respect to the spatial pattern in China. A key finding is that the magnitude of change of the potential cropping systems showed a pattern of increase both from northern China to southern China and from western China to eastern China. Furthermore, the area found to be suitable only for single cropping decreased, while the area suitable for triple cropping increased significantly from the 1960s to the 2000s. During the studied period, the potential multiple cropping index (PMCI) gap between rain-fed and irrigated scenarios increased from 18% to 24%, which indicated noticeable growth of water supply limitations under the rain-fed scenario. The most significant finding of this research was that from the 1960s to the 2000s climate change had led to a significant increase of PMCI by 13% under irrigated scenario and 7% under rain-fed scenario across the whole of China. Furthermore, the growth of the annual mean temperature is identified as the main reason underlying the increase of PMCI. It has also been noticed that across China the changes of potential multiple cropping systems under climate change were different from region to region. PMID:24312511

  1. Differential usage of multiple brain-derived neurotrophic factor promoters in the rat brain following neuronal activation.

    PubMed Central

    Metsis, M; Timmusk, T; Arenas, E; Persson, H

    1993-01-01

    The rat brain-derived neurotropic factor (BDNF) gene consists of four 5' exons linked to separate promoters and one 3' exon encoding the prepro-BDNF protein. To gain insights into the regulation of BDNF mRNA expression, probes specific for the different 5' exons were used to study the expression of BDNF mRNA in the brain. Following a systemic injection of the glutamate analog kainic acid, exon I, II, and III mRNAs increased transiently in hippocampus and cerebral cortex. A modest increase was seen for exon IV, where a new transcription initiation site was induced by this treatment. Pretreatments with the N-methyl-D-aspartate (NMDA) receptor antagonist MK801 or the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitrosulfanoylbenzo(f)quinoxaline revealed two region-specific patterns of glutamate receptor-mediated regulation. The first pattern found in neocortex, piriform cortex, and amygdala involves regulation of BDNF exon I, II, and III mRNAs through NMDA and AMPA/kainate receptors. The second pattern found in the hippocampus involves regulation of BDNF exon I, II, and III mRNAs by high-affinity kainate or metabotropic receptors. Treatment with the gamma-aminobutyric acid subtype A (GABAA) receptor antagonist bicuculline increased exon I and III mRNAs in the denate gyrus, and the muscarinic receptor agonist pilocarpine increased exon I mRNA mainly in the neocortex. These data show that the four BDNF promoters allow multiple points of BDNF mRNA regulation and suggest that the activation of different subtypes of glutamate receptors differentially regulates the expression of BDNF exon-specific mRNAs in the brain. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8415610

  2. The differential algebra based multiple level fast multipole algorithm for 3D space charge field calculation and photoemission simulation

    DOE PAGESBeta

    None, None

    2015-09-28

    Coulomb interaction between charged particles inside a bunch is one of the most importance collective effects in beam dynamics, becoming even more significant as the energy of the particle beam is lowered to accommodate analytical and low-Z material imaging purposes such as in the time resolved Ultrafast Electron Microscope (UEM) development currently underway at Michigan State University. In addition, space charge effects are the key limiting factor in the development of ultrafast atomic resolution electron imaging and diffraction technologies and are also correlated with an irreversible growth in rms beam emittance due to fluctuating components of the nonlinear electron dynamics.more » In the short pulse regime used in the UEM, space charge effects also lead to virtual cathode formation in which the negative charge of the electrons emitted at earlier times, combined with the attractive surface field, hinders further emission of particles and causes a degradation of the pulse properties. Space charge and virtual cathode effects and their remediation are core issues for the development of the next generation of high-brightness UEMs. Since the analytical models are only applicable for special cases, numerical simulations, in addition to experiments, are usually necessary to accurately understand the space charge effect. In this paper we will introduce a grid-free differential algebra based multiple level fast multipole algorithm, which calculates the 3D space charge field for n charged particles in arbitrary distribution with an efficiency of O(n), and the implementation of the algorithm to a simulation code for space charge dominated photoemission processes.« less

  3. The differential algebra based multiple level fast multipole algorithm for 3D space charge field calculation and photoemission simulation

    SciTech Connect

    None, None

    2015-09-28

    Coulomb interaction between charged particles inside a bunch is one of the most importance collective effects in beam dynamics, becoming even more significant as the energy of the particle beam is lowered to accommodate analytical and low-Z material imaging purposes such as in the time resolved Ultrafast Electron Microscope (UEM) development currently underway at Michigan State University. In addition, space charge effects are the key limiting factor in the development of ultrafast atomic resolution electron imaging and diffraction technologies and are also correlated with an irreversible growth in rms beam emittance due to fluctuating components of the nonlinear electron dynamics. In the short pulse regime used in the UEM, space charge effects also lead to virtual cathode formation in which the negative charge of the electrons emitted at earlier times, combined with the attractive surface field, hinders further emission of particles and causes a degradation of the pulse properties. Space charge and virtual cathode effects and their remediation are core issues for the development of the next generation of high-brightness UEMs. Since the analytical models are only applicable for special cases, numerical simulations, in addition to experiments, are usually necessary to accurately understand the space charge effect. In this paper we will introduce a grid-free differential algebra based multiple level fast multipole algorithm, which calculates the 3D space charge field for n charged particles in arbitrary distribution with an efficiency of O(n), and the implementation of the algorithm to a simulation code for space charge dominated photoemission processes.

  4. Possibilities and Potential Barriers: Learning to Plan for Differentiated Instruction in Elementary Science

    ERIC Educational Resources Information Center

    Tobin, Ruthanne; Tippett, Christine D.

    2014-01-01

    Research indicates that differentiated practices enhance the likelihood of meeting the needs of students who find literacy learning challenging (Tobin & McInnes, 2008; Tomlinson, 2003). The aim of the professional development project described here was to leverage these findings and to build the foundation for future research exploring if

  5. Possibilities and Potential Barriers: Learning to Plan for Differentiated Instruction in Elementary Science

    ERIC Educational Resources Information Center

    Tobin, Ruthanne; Tippett, Christine D.

    2014-01-01

    Research indicates that differentiated practices enhance the likelihood of meeting the needs of students who find literacy learning challenging (Tobin & McInnes, 2008; Tomlinson, 2003). The aim of the professional development project described here was to leverage these findings and to build the foundation for future research exploring if…

  6. Recursive Partitioning to Identify Potential Causes of Differential Item Functioning in Cross-National Data

    ERIC Educational Resources Information Center

    Finch, W. Holmes; Hernández Finch, Maria E.; French, Brian F.

    2016-01-01

    Differential item functioning (DIF) assessment is key in score validation. When DIF is present scores may not accurately reflect the construct of interest for some groups of examinees, leading to incorrect conclusions from the scores. Given rising immigration, and the increased reliance of educational policymakers on cross-national assessments…

  7. Student Interactions with CD-ROM Storybooks: A Look at Potential Relationships between Multiple Intelligence Strengths and Levels of Interaction

    ERIC Educational Resources Information Center

    Huffman, Celia A.

    2012-01-01

    This study looked at the potential relationship that may exist between students' intelligence strengths, in particular their spatial and kinesthetic strengths, and their combined cognitive and metacognitive levels of interaction with a CD-ROM storybook. The multiple intelligence strengths of a sample of students, measured via the MIDAS/My

  8. PTSD and Comorbid Disorders in a Representative Sample of Adolescents: The Risk Associated with Multiple Exposures to Potentially Traumatic Events

    ERIC Educational Resources Information Center

    Macdonald, Alexandra; Danielson, Carla Kmett; Resnick, Heidi S.; Saunders, Benjamin E.; Kilpatrick, Dean G.

    2010-01-01

    Objective: This study compared the impact of multiple exposures to potentially traumatic events (PTEs), including sexual victimization, physical victimization, and witnessed violence, on posttraumatic stress disorder (PTSD) and comorbid conditions (i.e., major depressive episode [MDE], and substance use [SUD]). Methods: Participants were a

  9. The Effect of the Residual Ion Potential on the Fully Differential Cross Section of Helium for Ionization by Electron Impact

    SciTech Connect

    Toth, A.; Nagy, L.

    2011-10-03

    We have carried out calculations for the fully differential cross section of the ionization of helium by electron projectiles. In order to study the effect of the residual ion potential, we employed three models, and tested them for the coplanar and perpendicular plane geometry. In spite of the simplicity of our models, the results for the coplanar case are in fair agreement with the available experimental data. The results for the perpendicular geometry need more improvement.

  10. The Physical Characterization of the Potentially Hazardous Asteroid 2004 BL86: A Fragment of a Differentiated Asteroid

    NASA Astrophysics Data System (ADS)

    Reddy, Vishnu; Gary, Bruce L.; Sanchez, Juan A.; Takir, Driss; Thomas, Cristina A.; Hardersen, Paul S.; Ogmen, Yenal; Benni, Paul; Kaye, Thomas G.; Gregorio, Joao; Garlitz, Joe; Polishook, David; Le Corre, Lucille; Nathues, Andreas

    2015-09-01

    The physical characterization of potentially hazardous asteroids (PHAs) is important for impact hazard assessment and evaluating mitigation options. Close flybys of PHAs provide an opportunity to study their surface photometric and spectral properties that enable the identification of their source regions in the main asteroid belt. We observed PHA (357439) 2004 BL86 during a close flyby of the Earth at a distance of 1.2 million km (0.0080 AU) on 2015 January 26, with an array of ground-based telescopes to constrain its photometric and spectral properties. Lightcurve observations showed that the asteroid was a binary and subsequent radar observations confirmed the binary nature and gave a primary diameter of 300 m and a secondary diameter of 50-100 m. Our photometric observations were used to derive the phase curve of 2004 BL86 in the V-band. Two different photometric functions were fitted to this phase curve, the IAU H-G model and the Shevchenko model. From the fit of the H-G function we obtained an absolute magnitude of H = 19.51 0.02 and a slope parameter of G = 0.34 0.02. The Shevchenko function yielded an absolute magnitude of H = 19.03 0.07 and a phase coefficient b = 0.0225 0.0006. The phase coefficient was used to calculate the geometric albedo (Ag) using the relationship found by Belskaya & Schevchenko, obtaining a value of Ag = 40% 8% in the V-band. With the geometric albedo and the absolute magnitudes derived from the H-G and the Shevchenko functions we calculated the diameter (D) of 2004 BL86, obtaining D = 263 26 and D = 328 35 m, respectively. 2004 BL86 spectral band parameters and pyroxene chemistry are consistent with non-cumulate eucrite meteorites. A majority of these meteorites are derived from Vesta and are analogous with surface lava flows on a differentiated parent body. A non-diagnostic spectral curve match using the Modeling for Asteroids tool yielded a best-match with non-cumulate eucrite Bereba. Three other near-Earth asteroids (1993 VW, 1998 KK17, and 2000 XH44) that were observed by Burbine et al. also have spectral properties similar to 2004 BL86. The presence of eucrites with anomalous oxygen isotope ratios compared to the howardites, eucrites, and diogenites meteorites from Vesta suggests the possible presence of multiple differentiated bodies in the inner main belt or the contamination of Vestas surface with exogenic material. The spectral properties of both anomalous and Vestan eucrites are degenerate, making it difficult to identify the parent bodies of anomalous eucrites in the main belt and the NEO population using remote sensing. This makes it difficult to link 2004 BL86 directly to Vesta, although the Vesta family is the largest contributor of V-types to near-Earth space.

  11. Potential Factors for the Differentiation of ESCs/iPSCs Into Insulin-Producing Cells

    PubMed Central

    Tsugata, Takako; Nikoh, Naruo; Kin, Tatsuya; Saitoh, Issei; Noguchi, Yasufumi; Ueki, Hideo; Watanabe, Masami; James Shapiro, Andrew M.; Noguchi, Hirofumi

    2015-01-01

    The low efficiency of in vitro differentiation of human embryonic stem cells (ESCs) or human induced pluripotent stem cells (iPSCs) into insulin-producing cells thus creates a crucial hurdle for the clinical implementation of human pluripotent stem cells (PSCs). In this study, we investigated the key factors for the differentiation of PSCs into insulin-producing cells. We obtained microarray data of HUES8 and HUES6 from two GeneChips (GPL3921: Affymetrix HT Human Genome U133A Array, GPL570: Affymetrix Human Genome U133 Plus 2.0 Array) in a database of GEO (NCBI), since HUES8 can differentiate into pancreatic cells, while HUES6 hardly demonstrates any differentiation at all. The genes with more than fourfold higher expressions in HUES8 compared to HUES6 included RPS4Y1, DDX3Y, EIF1AY, GREM1, GATA6, and NLGN4Y. Since there were four genes, RPS4Y1, DDX3Y, EIF1AY, and NLGN4Y, on the Y chromosome and HUES8 was a male cell line and HUES6 was a female cell line, we excluded these genes in this study. On the other hand, genes with more than fourfold higher expressions in HUES6 compared to HUES8 included NLRP2, EGR1, and SMC3. We next compared iPSCs derived from pancreatic cells (PiPSCs) and iPSCs derived from fibroblasts (FiPSCs). PiPSCs differentiated into insulin-producing cells more easily than FiPSCs because of their epigenetic memory. The gene expressions of GREM1, GATA6, NLRP2, EGR1, and SMC3 in PiPSCs and FiPSCs were also investigated. The expression level of GREM1 and GATA6 in PiPSCs were higher than in FiPSCs. On the other hand, EGR1, which was lower in HUES8 than in HUES6, was predictably lower in PiPSCs than FiPSCs, while NLRP2 and SMC3 were higher in PiPSCs than FiPSCs. These data suggest that the expression of GATA6 and GREM1 and the inhibition of EGR1 may be important factors for the differentiation of PSCs into insulin-producing cells. PMID:26858897

  12. Transient Receptor Potential A1 Is a Sensory Receptor for Multiple Products of Oxidative Stress

    PubMed Central

    Andersson, David A.; Gentry, Clive; Moss, Sian; Bevan, Stuart

    2009-01-01

    Transient receptor potential A1 (TRPA1) is expressed in a subset of nociceptive sensory neurons where it acts as a sensor for environmental irritants, including acrolein, and some pungent plant ingredients such as allyl isothiocyanate and cinnamaldehyde. These exogenous compounds activate TRPA1 by covalent modification of cysteine residues. We have used electrophysiological methods and measurements of intracellular calcium concentration ([Ca2+]i) to show that TRPA1 is activated by several classes of endogenous thiolreactive molecules. TRPA1 was activated by hydrogen peroxide (H2O2; EC50, 230 μM), by endogenously occurring alkenyl aldehydes (EC50: 4-hydroxynonenal 19.9 μM, 4-oxo-nonenal 1.9 μM, 4-hydroxyhexenal 38.9 μM) and by the cyclopentenone prostaglandin, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, EC50: 5.6 μM). The effect of H2O2 was reversed by treatment with dithiothreitol indicating that H2O2 acts by promoting the formation of disulfide bonds whereas the actions of the alkenyl aldehydes and 15d-PGJ2 were not reversed, suggesting that these agents form Michael adducts. H2O2 and the naturally occurring alkenyl aldehydes and 15d-PGJ2 acted on a subset of isolated rat and mouse sensory neurons [~25% of rat dorsal root ganglion (DRG) and ~50% of nodose ganglion neurons] to evoke a depolarizing inward current and an increase in [Ca2+]i in TRPA1 expressing neurons. The abilities of H2O2, alkenyl aldehydes and 15d-PGJ2 to raise [Ca2+]i in mouse DRG neurons were greatly reduced in neurons from trpa1-/- mice. Furthermore, intraplantar injection of either H2O2 or 15d-PGJ2 evoked a nocifensive/pain response in wild-type mice, but not in trpa1-/- mice. These data demonstrate that multiple agents produced during episodes of oxidative stress can activate TRPA1 expressed in sensory neurons. PMID:18322093

  13. Contractile and intracellular Ca2+ decay in potentiated contractions following multiple extrasystolic beats.

    PubMed

    Kojima, S; Wu, S T; Wikman-Coffelt, J; Parmley, W W

    1995-08-01

    Developed pressure and intracellular Ca2+ ([Ca2+i) decay in postextrasystolic beats following multiple extrasystolic contractions (ESCs) was evaluated with surface fluorometry in atrioventricular-blocked perfused rat hearts loaded with Indo-1. After priming pacing at 400 ms intervals, 1-25 ESCs were interposed with a 160 ms interval, followed by 30 postextrasystolic beats with a 400 ms interval. Both left ventricular developed pressure and the amplitude of the Indo-1 fluorescence ratio (F400/F510: an index of [Ca2+]i) increased in a monoexponential manner with an increase in the number of ESCs. Both potentiated left ventricular developed pressure and the amplitude of F400/F510 transients returned to control in a monoexponential fashion. Consistent with this exponential decay, the relationship between developed pressure or the amplitude of F400/F510 transients in a postextrasystolic beat and that in the preceding beat was linear and the slope of a fitted line (recirculation fraction; RF) was evaluated as an index of rapidity of decay. The number of ESCs did not affect RF of developed pressure and the amplitude of F400/F510 transients. Reducing extracellular Ca2+ concentration (1.25 --> 0.55 mM), and perfusion with an acidic solution (pH = 6.8) significantly decreased RF of both developed pressure (0.85 +/- 0.06 --> 0.78 +/- P < 0.05 and 0.85 +/- 0.07 --> 0.78 +/- 0.06, n=8, P < 0.05, respectively) and the amplitude of F400/F510 (0.87 +/- 0.06 --> 0.78 +/- 0.05, P < 0.05, and 0.89 +/- 0.08 --> 0.78 +/- 0.07, P < 0.05, respectively). This study confirmed that, in all conditions evaluated, contractile decay was determined by [Ca2+]i decay and RF of contractile decay was an accurate estimate of [Ca2+]i decay in physiologically paced isolated perfused rat hearts. PMID:7585892

  14. Differential Regulation by Organic Compounds and Heavy Metals of Multiple Laccase Genes in the Aquatic Hyphomycete Clavariopsis aquatica

    PubMed Central

    Solé, Magali; Müller, Ines; Pecyna, Marek J.; Fetzer, Ingo; Harms, Hauke

    2012-01-01

    To advance the understanding of the molecular mechanisms controlling microbial activities involved in carbon cycling and mitigation of environmental pollution in freshwaters, the influence of heavy metals and natural as well as xenobiotic organic compounds on laccase gene expression was quantified using quantitative real-time PCR (qRT-PCR) in an exclusively aquatic fungus (the aquatic hyphomycete Clavariopsis aquatica) for the first time. Five putative laccase genes (lcc1 to lcc5) identified in C. aquatica were differentially expressed in response to the fungal growth stage and potential laccase inducers, with certain genes being upregulated by, e.g., the lignocellulose breakdown product vanillic acid, the endocrine disruptor technical nonylphenol, manganese, and zinc. lcc4 is inducible by vanillic acid and most likely encodes an extracellular laccase already excreted during the trophophase of the organism, suggesting a function during fungal substrate colonization. Surprisingly, unlike many laccases of terrestrial fungi, none of the C. aquatica laccase genes was found to be upregulated by copper. However, copper strongly increases extracellular laccase activity in C. aquatica, possibly due to stabilization of the copper-containing catalytic center of the enzyme. Copper was found to half-saturate laccase activity already at about 1.8 μM, in favor of a fungal adaptation to low copper concentrations of aquatic habitats. PMID:22544244

  15. Hypoxia increases Sca-1/CD44 co-expression in murine mesenchymal stem cells and enhances their adipogenic differentiation potential.

    PubMed

    Valorani, M G; Germani, A; Otto, W R; Harper, L; Biddle, A; Khoo, C P; Lin, W R; Hawa, M I; Tropel, P; Patrizi, M P; Pozzilli, P; Alison, M R

    2010-07-01

    Mesenchymal stem cells (MSCs) are usually cultured under normoxic conditions (21% oxygen). However, in vivo, the physiological "niches" for MSCs have a much lower oxygen tension. Because of their plasticity, stem cells are particularly sensitive to their environments, and oxygen tension is one developmentally important stimulus in stem cell biology and plays a role in the intricate balance between cellular proliferation and commitment towards differentiation. Therefore, we investigated here the effect of hypoxia (2% oxygen) on murine adipose tissue (AT) MSC proliferation and adipogenic differentiation. AT cells were obtained from the omental fat and AT-MSCs were selected for their ability to attach to the plastic dishes, and were grown under normoxic and hypoxic conditions. Prior exposure of MSCs to hypoxia led to a significant reduction of ex vivo expansion time, with significantly increased numbers of Sca-1(+) as well as Sca-1(+)/CD44(+)double-positive cells. Under low oxygen culture conditions, the AT-MSC number markedly increased and their adipogenic differentiation potential was reduced. Notably, the hypoxia-mediated inhibition of adipogenic differentiation was reversible: AT-MSCs pre-exposed to hypoxia when switched to normoxic conditions exhibited significantly higher adipogenic differentiation capacity compared to their pre-exposed normoxic-cultured counterparts. Accordingly, the expression of adipocyte-specific genes, peroxisome proliferator activated receptor gamma (Ppargamma), lipoprotein lipase (Lpl) and fatty acid binding protein 4 (Fabp4) were significantly enhanced in hypoxia pre-exposed AT-MSCs. In conclusion, pre-culturing MSCs under hypoxic culture conditions may represent a strategy to enhance MSC production, enrichment and adipogenic differentiation. PMID:20496083

  16. A qPCR ScoreCard quantifies the differentiation potential of human pluripotent stem cells.

    PubMed

    Tsankov, Alexander M; Akopian, Veronika; Pop, Ramona; Chetty, Sundari; Gifford, Casey A; Daheron, Laurence; Tsankova, Nadejda M; Meissner, Alexander

    2015-11-01

    Research on human pluripotent stem cells has been hampered by the lack of a standardized, quantitative, scalable assay of pluripotency. We previously described an assay called ScoreCard that used gene expression signatures to quantify differentiation efficiency. Here we report an improved version of the assay based on qPCR that enables faster, more quantitative assessment of functional pluripotency. We provide an in-depth characterization of the revised signature panel (commercially available as the TaqMan hPSC Scorecard Assay) through embryoid body and directed differentiation experiments as well as a detailed comparison to the teratoma assay. We further show that the improved ScoreCard enables a wider range of applications, such as screening of small molecules, genetic perturbations and assessment of culture conditions. Our approach can be extended beyond stem cell applications to characterize and assess the utility of other cell types and lineages. PMID:26501952

  17. Genetic Variability Overrides the Impact of Parental Cell Type and Determines iPSC Differentiation Potential

    PubMed Central

    Kyttälä, Aija; Moraghebi, Roksana; Valensisi, Cristina; Kettunen, Johannes; Andrus, Colin; Pasumarthy, Kalyan Kumar; Nakanishi, Mahito; Nishimura, Ken; Ohtaka, Manami; Weltner, Jere; Van Handel, Ben; Parkkonen, Olavi; Sinisalo, Juha; Jalanko, Anu; Hawkins, R. David; Woods, Niels-Bjarne; Otonkoski, Timo; Trokovic, Ras

    2016-01-01

    Summary Reports on the retention of somatic cell memory in induced pluripotent stem cells (iPSCs) have complicated the selection of the optimal cell type for the generation of iPSC biobanks. To address this issue we compared transcriptomic, epigenetic, and differentiation propensities of genetically matched human iPSCs derived from fibroblasts and blood, two tissues of the most practical relevance for biobanking. Our results show that iPSC lines derived from the same donor are highly similar to each other. However, genetic variation imparts a donor-specific expression and methylation profile in reprogrammed cells that leads to variable functional capacities of iPSC lines. Our results suggest that integration-free, bona fide iPSC lines from fibroblasts and blood can be combined in repositories to form biobanks. Due to the impact of genetic variation on iPSC differentiation, biobanks should contain cells from large numbers of donors. PMID:26777058

  18. Genetic Variability Overrides the Impact of Parental Cell Type and Determines iPSC Differentiation Potential.

    PubMed

    Kyttälä, Aija; Moraghebi, Roksana; Valensisi, Cristina; Kettunen, Johannes; Andrus, Colin; Pasumarthy, Kalyan Kumar; Nakanishi, Mahito; Nishimura, Ken; Ohtaka, Manami; Weltner, Jere; Van Handel, Ben; Parkkonen, Olavi; Sinisalo, Juha; Jalanko, Anu; Hawkins, R David; Woods, Niels-Bjarne; Otonkoski, Timo; Trokovic, Ras

    2016-02-01

    Reports on the retention of somatic cell memory in induced pluripotent stem cells (iPSCs) have complicated the selection of the optimal cell type for the generation of iPSC biobanks. To address this issue we compared transcriptomic, epigenetic, and differentiation propensities of genetically matched human iPSCs derived from fibroblasts and blood, two tissues of the most practical relevance for biobanking. Our results show that iPSC lines derived from the same donor are highly similar to each other. However, genetic variation imparts a donor-specific expression and methylation profile in reprogrammed cells that leads to variable functional capacities of iPSC lines. Our results suggest that integration-free, bona fide iPSC lines from fibroblasts and blood can be combined in repositories to form biobanks. Due to the impact of genetic variation on iPSC differentiation, biobanks should contain cells from large numbers of donors. PMID:26777058

  19. Quantitative Raman spectral changes of the differentiation of mesenchymal stem cells into islet-like cells by biochemical component analysis and multiple peak fitting

    NASA Astrophysics Data System (ADS)

    Su, Xin; Fang, Shaoyin; Zhang, Daosen; Zhang, Qinnan; He, Yingtian; Lu, Xiaoxu; Liu, Shengde; Zhong, Liyun

    2015-12-01

    Mesenchymal stem cells (MSCs) differentiate into islet-like cells, providing a possible solution for type I diabetes treatment. To search for the precise molecular mechanism of the directional differentiation of MSC-derived islet-like cells, biomolecular composition, and structural conformation information during MSC differentiation, is required. Because islet-like cells lack specific surface markers, the commonly employed immunostaining technique is not suitable for their identification, physical separation, and enrichment. Combining Raman spectroscopic data, a fitting accuracy-improved biochemical component analysis, and multiple peaks fitting approach, we identified the quantitative biochemical and intensity change of Raman peaks that show the differentiation of MSCs into islet-like cells. Along with increases in protein and glycogen content, and decreases in deoxyribonucleic acid and ribonucleic acid content, in islet-like cells relative to MSCs, it was found that a characteristic peak of insulin (665 cm-1) has twice the intensity in islet-like cells relative to MSCs, indicating differentiation of MSCs into islet-like cells was successful. Importantly, these Raman signatures provide useful information on the structural and pathological states during MSC differentiation and help to develop noninvasive and label-free Raman sorting methods for stem cells and their lineages.

  20. Localization and osteoblastic differentiation potential of neural crest-derived cells in oral tissues of adult mice.

    PubMed

    Ono, Miki; Suzawa, Tetsuo; Takami, Masamichi; Yamamoto, Gou; Hosono, Tomohiko; Yamada, Atsushi; Suzuki, Dai; Yoshimura, Kentaro; Watahiki, Junichi; Hayashi, Ryuhei; Arata, Satoru; Mishima, Kenji; Nishida, Kohji; Osumi, Noriko; Maki, Koutaro; Kamijo, Ryutaro

    2015-09-01

    In embryos, neural crest cells emerge from the dorsal region of the fusing neural tube and migrate throughout tissues to differentiate into various types of cells including osteoblasts. In adults, subsets of neural crest-derived cells (NCDCs) reside as stem cells and are considered to be useful cell sources for regenerative medicine strategies. Numerous studies have suggested that stem cells with a neural crest origin persist into adulthood, especially those within the mammalian craniofacial compartment. However, their distribution as well as capacity to differentiate into osteoblasts in adults is not fully understood. To analyze the precise distribution and characteristics of NCDCs in adult oral tissues, we utilized an established line of double transgenic (P0-Cre/CAG-CAT-EGFP) mice in which NCDCs express green fluorescent protein (GFP) throughout their life. GFP-positive cells were scattered like islands throughout tissues of the palate, gingiva, tongue, and buccal mucosa in adult mice, with those isolated from the latter shown to form spheres, typical cell clusters composed of stem cells, under low-adherent conditions. Furthermore, GFP-positive cells had markedly increased alkaline phosphatase (a marker enzyme of osteoblast differentiation) activity and mineralization as shown by alizarin red staining, in the presence of bone morphogenetic protein (BMP)-2. These results suggest that NCDCs reside in various adult oral tissues and possess potential to differentiate into osteoblastic cells. NCDCs in adults may be a useful cell source for bone regeneration strategies. PMID:26225748

  1. Measurements of jet multiplicity and differential production cross sections of Z +jets events in proton-proton collisions at ?{s }=7 TeV

    NASA Astrophysics Data System (ADS)

    Khachatryan, V.; Sirunyan, A. M.; Tumasyan, A.; Adam, W.; Bergauer, T.; Dragicevic, M.; Er, J.; Fabjan, C.; Friedl, M.; Frhwirth, R.; Ghete, V. M.; Hartl, C.; Hrmann, N.; Hrubec, J.; Jeitler, M.; Kiesenhofer, W.; Knnz, V.; Krammer, M.; Krtschmer, I.; Liko, D.; Mikulec, I.; Rabady, D.; Rahbaran, B.; Rohringer, H.; Schfbeck, R.; Strauss, J.; Taurok, A.; Treberer-Treberspurg, W.; Waltenberger, W.; Wulz, C.-E.; Mossolov, V.; Shumeiko, N.; Suarez Gonzalez, J.; Alderweireldt, S.; Bansal, M.; Bansal, S.; Cornelis, T.; De Wolf, E. A.; Janssen, X.; Knutsson, A.; Luyckx, S.; Ochesanu, S.; Roland, B.; Rougny, R.; Van De Klundert, M.; Van Haevermaet, H.; Van Mechelen, P.; Van Remortel, N.; Van Spilbeeck, A.; Blekman, F.; Blyweert, S.; D'Hondt, J.; Daci, N.; Heracleous, N.; Keaveney, J.; Lowette, S.; Maes, M.; Olbrechts, A.; Python, Q.; Strom, D.; Tavernier, S.; Van Doninck, W.; Van Mulders, P.; Van Onsem, G. P.; Villella, I.; Caillol, C.; Clerbaux, B.; De Lentdecker, G.; Dobur, D.; Favart, L.; Gay, A. P. R.; Grebenyuk, A.; Lonard, A.; Mohammadi, A.; Perni, L.; Reis, T.; Seva, T.; Thomas, L.; Vander Velde, C.; Vanlaer, P.; Wang, J.; Adler, V.; Beernaert, K.; Benucci, L.; Cimmino, A.; Costantini, S.; Crucy, S.; Dildick, S.; Fagot, A.; Garcia, G.; Mccartin, J.; Ocampo Rios, A. A.; Ryckbosch, D.; Salva Diblen, S.; Sigamani, M.; Strobbe, N.; Thyssen, F.; Tytgat, M.; Yazgan, E.; Zaganidis, N.; Basegmez, S.; Beluffi, C.; Bruno, G.; Castello, R.; Caudron, A.; Ceard, L.; Da Silveira, G. G.; Delaere, C.; du Pree, T.; Favart, D.; Forthomme, L.; Giammanco, A.; Hollar, J.; Jez, P.; Komm, M.; Lemaitre, V.; Nuttens, C.; Pagano, D.; Perrini, L.; Pin, A.; Piotrzkowski, K.; Popov, A.; Quertenmont, L.; Selvaggi, M.; Vidal Marono, M.; Vizan Garcia, J. M.; Beliy, N.; Caebergs, T.; Daubie, E.; Hammad, G. H.; Ald Jnior, W. L.; Alves, G. A.; Brito, L.; Correa Martins Junior, M.; Dos Reis Martins, T.; Mora Herrera, C.; Pol, M. E.; Carvalho, W.; Chinellato, J.; Custdio, A.; Da Costa, E. M.; De Jesus Damiao, D.; De Oliveira Martins, C.; Fonseca De Souza, S.; Malbouisson, H.; Matos Figueiredo, D.; Mundim, L.; Nogima, H.; Prado Da Silva, W. L.; Santaolalla, J.; Santoro, A.; Sznajder, A.; Tonelli Manganote, E. J.; Vilela Pereira, A.; Bernardes, C. A.; Dogra, S.; Fernandez Perez Tomei, T. R.; Gregores, E. M.; Mercadante, P. G.; Novaes, S. F.; Padula, Sandra S.; Aleksandrov, A.; Genchev, V.; Iaydjiev, P.; Marinov, A.; Piperov, S.; Rodozov, M.; Stoykova, S.; Sultanov, G.; Tcholakov, V.; Vutova, M.; Dimitrov, A.; Glushkov, I.; Hadjiiska, R.; Kozhuharov, V.; Litov, L.; Pavlov, B.; Petkov, P.; Bian, J. G.; Chen, G. M.; Chen, H. S.; Chen, M.; Du, R.; Jiang, C. H.; Liang, S.; Plestina, R.; Tao, J.; Wang, X.; Wang, Z.; Asawatangtrakuldee, C.; Ban, Y.; Guo, Y.; Li, Q.; Li, W.; Liu, S.; Mao, Y.; Qian, S. J.; Wang, D.; Zhang, L.; Zou, W.; Avila, C.; Chaparro Sierra, L. F.; Florez, C.; Gomez, J. P.; Gomez Moreno, B.; Sanabria, J. C.; Godinovic, N.; Lelas, D.; Polic, D.; Puljak, I.; Antunovic, Z.; Kovac, M.; Brigljevic, V.; Kadija, K.; Luetic, J.; Mekterovic, D.; Sudic, L.; Attikis, A.; Mavromanolakis, G.; Mousa, J.; Nicolaou, C.; Ptochos, F.; Razis, P. A.; Bodlak, M.; Finger, M.; Finger, M.; Assran, Y.; Ellithi Kamel, A.; Mahmoud, M. A.; Radi, A.; Kadastik, M.; Murumaa, M.; Raidal, M.; Tiko, A.; Eerola, P.; Fedi, G.; Voutilainen, M.; Hrknen, J.; Karimki, V.; Kinnunen, R.; Kortelainen, M. J.; Lampn, T.; Lassila-Perini, K.; Lehti, S.; Lindn, T.; Luukka, P.; Menp, T.; Peltola, T.; Tuominen, E.; Tuominiemi, J.; Tuovinen, E.; Wendland, L.; Tuuva, T.; Besancon, M.; Couderc, F.; Dejardin, M.; Denegri, D.; Fabbro, B.; Faure, J. 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T.; Passaseo, M.; Pazzini, J.; Pegoraro, M.; Pozzobon, N.; Ronchese, P.; Simonetto, F.; Torassa, E.; Tosi, M.; Vanini, S.; Zotto, P.; Zucchetta, A.; Gabusi, M.; Ratti, S. P.; Riccardi, C.; Salvini, P.; Vitulo, P.; Biasini, M.; Bilei, G. M.; Ciangottini, D.; Fan, L.; Lariccia, P.; Mantovani, G.; Menichelli, M.; Romeo, F.; Saha, A.; Santocchia, A.; Spiezia, A.; Androsov, K.; Azzurri, P.; Bagliesi, G.; Bernardini, J.; Boccali, T.; Broccolo, G.; Castaldi, R.; Ciocci, M. A.; Dell'Orso, R.; Donato, S.; Fiori, F.; Fo, L.; Giassi, A.; Grippo, M. T.; Ligabue, F.; Lomtadze, T.; Martini, L.; Messineo, A.; Moon, C. S.; Palla, F.; Rizzi, A.; Savoy-Navarro, A.; Serban, A. T.; Spagnolo, P.; Squillacioti, P.; Tenchini, R.; Tonelli, G.; Venturi, A.; Verdini, P. G.; Vernieri, C.; Barone, L.; Cavallari, F.; D'imperio, G.; Del Re, D.; Diemoz, M.; Grassi, M.; Jorda, C.; Longo, E.; Margaroli, F.; Meridiani, P.; Micheli, F.; Nourbakhsh, S.; Organtini, G.; Paramatti, R.; Rahatlou, S.; Rovelli, C.; Santanastasio, F.; Soffi, L.; Traczyk, P.; Amapane, N.; Arcidiacono, R.; Argiro, S.; Arneodo, M.; Bellan, R.; Biino, C.; Cartiglia, N.; Casasso, S.; Costa, M.; Degano, A.; Demaria, N.; Finco, L.; Mariotti, C.; Maselli, S.; Migliore, E.; Monaco, V.; Musich, M.; Obertino, M. M.; Ortona, G.; Pacher, L.; Pastrone, N.; Pelliccioni, M.; Pinna Angioni, G. L.; Potenza, A.; Romero, A.; Ruspa, M.; Sacchi, R.; Solano, A.; Staiano, A.; Tamponi, U.; Belforte, S.; Candelise, V.; Casarsa, M.; Cossutti, F.; Della Ricca, G.; Gobbo, B.; La Licata, C.; Marone, M.; Montanino, D.; Scaini, D.; Schizzi, A.; Umer, T.; Zanetti, A.; Kropivnitskaya, A.; Nam, S. K.; Kim, D. H.; Kim, G. N.; Kim, M. S.; Kong, D. J.; Lee, S.; Oh, Y. D.; Park, H.; Sakharov, A.; Son, D. C.; Kim, T. J.; Kim, J. Y.; Song, S.; Choi, S.; Gyun, D.; Hong, B.; Jo, M.; Kim, H.; Kim, Y.; Lee, B.; Lee, K. S.; Park, S. K.; Roh, Y.; Choi, M.; Kim, J. H.; Park, I. C.; Park, S.; Ryu, G.; Ryu, M. S.; Choi, Y.; Choi, Y. K.; Goh, J.; Kim, D.; Kwon, E.; Lee, J.; Seo, H.; Yu, I.; Juodagalvis, A.; Komaragiri, J. R.; Md Ali, M. A. B.; Castilla-Valdez, H.; De La Cruz-Burelo, E.; Heredia-de La Cruz, I.; Lopez-Fernandez, R.; Sanchez-Hernandez, A.; Carrillo Moreno, S.; Vazquez Valencia, F.; Pedraza, I.; Salazar Ibarguen, H. A.; Casimiro Linares, E.; Morelos Pineda, A.; Krofcheck, D.; Butler, P. H.; Reucroft, S.; Ahmad, A.; Ahmad, M.; Hassan, Q.; Hoorani, H. R.; Khalid, S.; Khan, W. A.; Khurshid, T.; Shah, M. 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V.; Vinogradov, A.; Belyaev, A.; Boos, E.; Dubinin, M.; Dudko, L.; Ershov, A.; Gribushin, A.; Klyukhin, V.; Kodolova, O.; Lokhtin, I.; Obraztsov, S.; Petrushanko, S.; Savrin, V.; Snigirev, A.; Azhgirey, I.; Bayshev, I.; Bitioukov, S.; Kachanov, V.; Kalinin, A.; Konstantinov, D.; Krychkine, V.; Petrov, V.; Ryutin, R.; Sobol, A.; Tourtchanovitch, L.; Troshin, S.; Tyurin, N.; Uzunian, A.; Volkov, A.; Adzic, P.; Ekmedzic, M.; Milosevic, J.; Rekovic, V.; Alcaraz Maestre, J.; Battilana, C.; Calvo, E.; Cerrada, M.; Chamizo Llatas, M.; Colino, N.; De La Cruz, B.; Delgado Peris, A.; Domnguez Vzquez, D.; Escalante Del Valle, A.; Fernandez Bedoya, C.; Fernndez Ramos, J. P.; Flix, J.; Fouz, M. C.; Garcia-Abia, P.; Gonzalez Lopez, O.; Goy Lopez, S.; Hernandez, J. M.; Josa, M. I.; Merino, G.; Navarro De Martino, E.; Prez-Calero Yzquierdo, A.; Puerta Pelayo, J.; Quintario Olmeda, A.; Redondo, I.; Romero, L.; Soares, M. S.; Albajar, C.; de Trocniz, J. F.; Missiroli, M.; Moran, D.; Brun, H.; Cuevas, J.; Fernandez Menendez, J.; Folgueras, S.; Gonzalez Caballero, I.; Lloret Iglesias, L.; Brochero Cifuentes, J. A.; Cabrillo, I. J.; Calderon, A.; Duarte Campderros, J.; Fernandez, M.; Gomez, G.; Graziano, A.; Lopez Virto, A.; Marco, J.; Marco, R.; Martinez Rivero, C.; Matorras, F.; Munoz Sanchez, F. J.; Piedra Gomez, J.; Rodrigo, T.; Rodrguez-Marrero, A. Y.; Ruiz-Jimeno, A.; Scodellaro, L.; Vila, I.; Vilar Cortabitarte, R.; Abbaneo, D.; Auffray, E.; Auzinger, G.; Bachtis, M.; Baillon, P.; Ball, A. H.; Barney, D.; Benaglia, A.; Bendavid, J.; Benhabib, L.; Benitez, J. F.; Bernet, C.; Bianchi, G.; Bloch, P.; Bocci, A.; Bonato, A.; Bondu, O.; Botta, C.; Breuker, H.; Camporesi, T.; Cerminara, G.; Colafranceschi, S.; D'Alfonso, M.; d'Enterria, D.; Dabrowski, A.; David, A.; De Guio, F.; De Roeck, A.; De Visscher, S.; Dobson, M.; Dordevic, M.; Dupont-Sagorin, N.; Elliott-Peisert, A.; Eugster, J.; Franzoni, G.; Funk, W.; Gigi, D.; Gill, K.; Giordano, D.; Girone, M.; Glege, F.; Guida, R.; Gundacker, S.; Guthoff, M.; Hammer, J.; Hansen, M.; Harris, P.; Hegeman, J.; Innocente, V.; Janot, P.; Kousouris, K.; Krajczar, K.; Lecoq, P.; Loureno, C.; Magini, N.; Malgeri, L.; Mannelli, M.; Marrouche, J.; Masetti, L.; Meijers, F.; Mersi, S.; Meschi, E.; Moortgat, F.; Morovic, S.; Mulders, M.; Musella, P.; Orsini, L.; Pape, L.; Perez, E.; Perrozzi, L.; Petrilli, A.; Petrucciani, G.; Pfeiffer, A.; Pierini, M.; Pimi, M.; Piparo, D.; Plagge, M.; Racz, A.; Rolandi, G.; Rovere, M.; Sakulin, H.; Schfer, C.; Schwick, C.; Sharma, A.; Siegrist, P.; Silva, P.; Simon, M.; Sphicas, P.; Spiga, D.; Steggemann, J.; Stieger, B.; Stoye, M.; Treille, D.; Tsirou, A.; Veres, G. I.; Vlimant, J. R.; Wardle, N.; Whri, H. K.; Wollny, H.; Zeuner, W. D.; Bertl, W.; Deiters, K.; Erdmann, W.; Horisberger, R.; Ingram, Q.; Kaestli, H. C.; Kotlinski, D.; Langenegger, U.; Renker, D.; Rohe, T.; Bachmair, F.; Bni, L.; Bianchini, L.; Bortignon, P.; Buchmann, M. A.; Casal, B.; Chanon, N.; Deisher, A.; Dissertori, G.; Dittmar, M.; Doneg, M.; Dnser, M.; Eller, P.; Grab, C.; Hits, D.; Lustermann, W.; Mangano, B.; Marini, A. C.; Martinez Ruiz del Arbol, P.; Meister, D.; Mohr, N.; Ngeli, C.; Nessi-Tedaldi, F.; Pandolfi, F.; Pauss, F.; Peruzzi, M.; Quittnat, M.; Rebane, L.; Rossini, M.; Starodumov, A.; Takahashi, M.; Theofilatos, K.; Wallny, R.; Weber, H. A.; Amsler, C.; Canelli, M. F.; Chiochia, V.; De Cosa, A.; Hinzmann, A.; Hreus, T.; Kilminster, B.; Lange, C.; Millan Mejias, B.; Ngadiuba, J.; Robmann, P.; Ronga, F. J.; Taroni, S.; Verzetti, M.; Yang, Y.; Cardaci, M.; Chen, K. H.; Ferro, C.; Kuo, C. M.; Lin, W.; Lu, Y. J.; Volpe, R.; Yu, S. S.; Chang, P.; Chang, Y. H.; Chang, Y. W.; Chao, Y.; Chen, K. F.; Chen, P. H.; Dietz, C.; Grundler, U.; Hou, W.-S.; Kao, K. Y.; Lei, Y. J.; Liu, Y. F.; Lu, R.-S.; Majumder, D.; Petrakou, E.; Tzeng, Y. M.; Wilken, R.; Asavapibhop, B.; Srimanobhas, N.; Suwonjandee, N.; Adiguzel, A.; Bakirci, M. N.; Cerci, S.; Dozen, C.; Dumanoglu, I.; Eskut, E.; Girgis, S.; Gokbulut, G.; Gurpinar, E.; Hos, I.; Kangal, E. E.; Kayis Topaksu, A.; Onengut, G.; Ozdemir, K.; Ozturk, S.; Polatoz, A.; Sogut, K.; Sunar Cerci, D.; Tali, B.; Topakli, H.; Vergili, M.; Akin, I. V.; Bilin, B.; Bilmis, S.; Gamsizkan, H.; Karapinar, G.; Ocalan, K.; Sekmen, S.; Surat, U. E.; Yalvac, M.; Zeyrek, M.; Glmez, E.; Isildak, B.; Kaya, M.; Kaya, O.; Bahtiyar, H.; Barlas, E.; Cankocak, K.; Vardarl?, F. I.; Ycel, M.; Levchuk, L.; Sorokin, P.; Brooke, J. J.; Clement, E.; Cussans, D.; Flacher, H.; Frazier, R.; Goldstein, J.; Grimes, M.; Heath, G. P.; Heath, H. F.; Jacob, J.; Kreczko, L.; Lucas, C.; Meng, Z.; Newbold, D. M.; Paramesvaran, S.; Poll, A.; Senkin, S.; Smith, V. J.; Williams, T.; Bell, K. W.; Belyaev, A.; Brew, C.; Brown, R. M.; Cockerill, D. J. A.; Coughlan, J. A.; Harder, K.; Harper, S.; Olaiya, E.; Petyt, D.; Shepherd-Themistocleous, C. H.; Thea, A.; Tomalin, I. R.; Womersley, W. J.; Worm, S. D.; Baber, M.; Bainbridge, R.; Buchmuller, O.; Burton, D.; Colling, D.; Cripps, N.; Cutajar, M.; Dauncey, P.; Davies, G.; Della Negra, M.; Dunne, P.; Ferguson, W.; Fulcher, J.; Futyan, D.; Gilbert, A.; Hall, G.; Iles, G.; Jarvis, M.; Karapostoli, G.; Kenzie, M.; Lane, R.; Lucas, R.; Lyons, L.; Magnan, A.-M.; Malik, S.; Mathias, B.; Nash, J.; Nikitenko, A.; Pela, J.; Pesaresi, M.; Petridis, K.; Raymond, D. M.; Rogerson, S.; Rose, A.; Seez, C.; Sharp, P.; Tapper, A.; Vazquez Acosta, M.; Virdee, T.; Cole, J. E.; Hobson, P. R.; Khan, A.; Kyberd, P.; Leggat, D.; Leslie, D.; Martin, W.; Reid, I. D.; Symonds, P.; Teodorescu, L.; Turner, M.; Dittmann, J.; Hatakeyama, K.; Kasmi, A.; Liu, H.; Scarborough, T.; Charaf, O.; Cooper, S. I.; Henderson, C.; Rumerio, P.; Avetisyan, A.; Bose, T.; Fantasia, C.; Lawson, P.; Richardson, C.; Rohlf, J.; Sperka, D.; St. John, J.; Sulak, L.; Alimena, J.; Berry, E.; Bhattacharya, S.; Christopher, G.; Cutts, D.; Demiragli, Z.; Ferapontov, A.; Garabedian, A.; Heintz, U.; Kukartsev, G.; Laird, E.; Landsberg, G.; Luk, M.; Narain, M.; Segala, M.; Sinthuprasith, T.; Speer, T.; Swanson, J.; Breedon, R.; Breto, G.; Calderon De La Barca Sanchez, M.; Chauhan, S.; Chertok, M.; Conway, J.; Conway, R.; Cox, P. T.; Erbacher, R.; Gardner, M.; Ko, W.; Lander, R.; Miceli, T.; Mulhearn, M.; Pellett, D.; Pilot, J.; Ricci-Tam, F.; Searle, M.; Shalhout, S.; Smith, J.; Squires, M.; Stolp, D.; Tripathi, M.; Wilbur, S.; Yohay, R.; Cousins, R.; Everaerts, P.; Farrell, C.; Hauser, J.; Ignatenko, M.; Rakness, G.; Takasugi, E.; Valuev, V.; Weber, M.; Babb, J.; Burt, K.; Clare, R.; Ellison, J.; Gary, J. W.; Hanson, G.; Heilman, J.; Ivova Rikova, M.; Jandir, P.; Kennedy, E.; Lacroix, F.; Liu, H.; Long, O. R.; Luthra, A.; Malberti, M.; Nguyen, H.; Olmedo Negrete, M.; Shrinivas, A.; Sumowidagdo, S.; Wimpenny, S.; Andrews, W.; Branson, J. G.; Cerati, G. B.; Cittolin, S.; D'Agnolo, R. T.; Evans, D.; Holzner, A.; Kelley, R.; Klein, D.; Lebourgeois, M.; Letts, J.; Macneill, I.; Olivito, D.; Padhi, S.; Palmer, C.; Pieri, M.; Sani, M.; Sharma, V.; Simon, S.; Sudano, E.; Tadel, M.; Tu, Y.; Vartak, A.; Welke, C.; Wrthwein, F.; Yagil, A.; Yoo, J.; Barge, D.; Bradmiller-Feld, J.; Campagnari, C.; Danielson, T.; Dishaw, A.; Flowers, K.; Franco Sevilla, M.; Geffert, P.; George, C.; Golf, F.; Gouskos, L.; Incandela, J.; Justus, C.; Mccoll, N.; Richman, J.; Stuart, D.; To, W.; West, C.; Apresyan, A.; Bornheim, A.; Bunn, J.; Chen, Y.; Di Marco, E.; Duarte, J.; Mott, A.; Newman, H. B.; Pena, C.; Rogan, C.; Spiropulu, M.; Timciuc, V.; Wilkinson, R.; Xie, S.; Zhu, R. Y.; Azzolini, V.; Calamba, A.; Carlson, B.; Ferguson, T.; Iiyama, Y.; Paulini, M.; Russ, J.; Vogel, H.; Vorobiev, I.; Cumalat, J. P.; Ford, W. T.; Gaz, A.; Luiggi Lopez, E.; Nauenberg, U.; Smith, J. G.; Stenson, K.; Ulmer, K. A.; Wagner, S. R.; Alexander, J.; Chatterjee, A.; Chu, J.; Dittmer, S.; Eggert, N.; Mirman, N.; Nicolas Kaufman, G.; Patterson, J. R.; Ryd, A.; Salvati, E.; Skinnari, L.; Sun, W.; Teo, W. D.; Thom, J.; Thompson, J.; Tucker, J.; Weng, Y.; Winstrom, L.; Wittich, P.; Winn, D.; Abdullin, S.; Albrow, M.; Anderson, J.; Apollinari, G.; Bauerdick, L. A. T.; Beretvas, A.; Berryhill, J.; Bhat, P. C.; Burkett, K.; Butler, J. N.; Cheung, H. W. K.; Chlebana, F.; Cihangir, S.; Elvira, V. D.; Fisk, I.; Freeman, J.; Gao, Y.; Gottschalk, E.; Gray, L.; Green, D.; Grnendahl, S.; Gutsche, O.; Hanlon, J.; Hare, D.; Harris, R. M.; Hirschauer, J.; Hooberman, B.; Jindariani, S.; Johnson, M.; Joshi, U.; Kaadze, K.; Klima, B.; Kreis, B.; Kwan, S.; Linacre, J.; Lincoln, D.; Lipton, R.; Liu, T.; Lykken, J.; Maeshima, K.; Marraffino, J. M.; Martinez Outschoorn, V. I.; Maruyama, S.; Mason, D.; McBride, P.; Mishra, K.; Mrenna, S.; Musienko, Y.; Nahn, S.; Newman-Holmes, C.; O'Dell, V.; Prokofyev, O.; Sexton-Kennedy, E.; Sharma, S.; Soha, A.; Spalding, W. J.; Spiegel, L.; Taylor, L.; Tkaczyk, S.; Tran, N. V.; Uplegger, L.; Vaandering, E. W.; Vidal, R.; Whitbeck, A.; Whitmore, J.; Yang, F.; Acosta, D.; Avery, P.; Bourilkov, D.; Carver, M.; Cheng, T.; Curry, D.; Das, S.; De Gruttola, M.; Di Giovanni, G. P.; Field, R. D.; Fisher, M.; Furic, I. K.; Hugon, J.; Konigsberg, J.; Korytov, A.; Kypreos, T.; Low, J. F.; Matchev, K.; Milenovic, P.; Mitselmakher, G.; Muniz, L.; Rinkevicius, A.; Shchutska, L.; Snowball, M.; Yelton, J.; Zakaria, M.; Hewamanage, S.; Linn, S.; Markowitz, P.; Martinez, G.; Rodriguez, J. L.; Adams, T.; Askew, A.; Bochenek, J.; Diamond, B.; Haas, J.; Hagopian, S.; Hagopian, V.; Johnson, K. F.; Prosper, H.; Veeraraghavan, V.; Weinberg, M.; Baarmand, M. M.; Hohlmann, M.; Kalakhety, H.; Yumiceva, F.; Adams, M. R.; Apanasevich, L.; Bazterra, V. E.; Berry, D.; Betts, R. R.; Bucinskaite, I.; Cavanaugh, R.; Evdokimov, O.; Gauthier, L.; Gerber, C. E.; Hofman, D. J.; Khalatyan, S.; Kurt, P.; Moon, D. H.; O'Brien, C.; Silkworth, C.; Turner, P.; Varelas, N.; Albayrak, E. A.; Bilki, B.; Clarida, W.; Dilsiz, K.; Duru, F.; Haytmyradov, M.; Merlo, J.-P.; Mermerkaya, H.; Mestvirishvili, A.; Moeller, A.; Nachtman, J.; Ogul, H.; Onel, Y.; Ozok, F.; Penzo, A.; Rahmat, R.; Sen, S.; Tan, P.; Tiras, E.; Wetzel, J.; Yetkin, T.; Yi, K.; Barnett, B. A.; Blumenfeld, B.; Bolognesi, S.; Fehling, D.; Gritsan, A. V.; Maksimovic, P.; Martin, C.; Swartz, M.; Baringer, P.; Bean, A.; Benelli, G.; Bruner, C.; Gray, J.; Kenny, R. P.; Malek, M.; Murray, M.; Noonan, D.; Sanders, S.; Sekaric, J.; Stringer, R.; Wang, Q.; Wood, J. S.; Barfuss, A. F.; Chakaberia, I.; Ivanov, A.; Khalil, S.; Makouski, M.; Maravin, Y.; Saini, L. K.; Shrestha, S.; Skhirtladze, N.; Svintradze, I.; Gronberg, J.; Lange, D.; Rebassoo, F.; Wright, D.; Baden, A.; Belloni, A.; Calvert, B.; Eno, S. C.; Gomez, J. A.; Hadley, N. J.; Kellogg, R. G.; Kolberg, T.; Lu, Y.; Marionneau, M.; Mignerey, A. C.; Pedro, K.; Skuja, A.; Tonjes, M. B.; Tonwar, S. C.; Apyan, A.; Barbieri, R.; Bauer, G.; Busza, W.; Cali, I. A.; Chan, M.; Di Matteo, L.; Dutta, V.; Gomez Ceballos, G.; Goncharov, M.; Gulhan, D.; Klute, M.; Lai, Y. S.; Lee, Y.-J.; Levin, A.; Luckey, P. D.; Ma, T.; Paus, C.; Ralph, D.; Roland, C.; Roland, G.; Stephans, G. S. F.; Stckli, F.; Sumorok, K.; Velicanu, D.; Veverka, J.; Wyslouch, B.; Yang, M.; Zanetti, M.; Zhukova, V.; Dahmes, B.; Gude, A.; Kao, S. C.; Klapoetke, K.; Kubota, Y.; Mans, J.; Pastika, N.; Rusack, R.; Singovsky, A.; Tambe, N.; Turkewitz, J.; Acosta, J. G.; Oliveros, S.; Avdeeva, E.; Bloom, K.; Bose, S.; Claes, D. R.; Dominguez, A.; Gonzalez Suarez, R.; Keller, J.; Knowlton, D.; Kravchenko, I.; Lazo-Flores, J.; Malik, S.; Meier, F.; Snow, G. R.; Dolen, J.; Godshalk, A.; Iashvili, I.; Kharchilava, A.; Kumar, A.; Rappoccio, S.; Alverson, G.; Barberis, E.; Baumgartel, D.; Chasco, M.; Haley, J.; Massironi, A.; Morse, D. M.; Nash, D.; Orimoto, T.; Trocino, D.; Wang, R. J.; Wood, D.; Zhang, J.; Hahn, K. A.; Kubik, A.; Mucia, N.; Odell, N.; Pollack, B.; Pozdnyakov, A.; Schmitt, M.; Stoynev, S.; Sung, K.; Velasco, M.; Won, S.; Brinkerhoff, A.; Chan, K. M.; Drozdetskiy, A.; Hildreth, M.; Jessop, C.; Karmgard, D. J.; Kellams, N.; Lannon, K.; Luo, W.; Lynch, S.; Marinelli, N.; Pearson, T.; Planer, M.; Ruchti, R.; Valls, N.; Wayne, M.; Wolf, M.; Woodard, A.; Antonelli, L.; Brinson, J.; Bylsma, B.; Durkin, L. S.; Flowers, S.; Hill, C.; Hughes, R.; Kotov, K.; Ling, T. Y.; Puigh, D.; Rodenburg, M.; Smith, G.; Winer, B. L.; Wolfe, H.; Wulsin, H. W.; Driga, O.; Elmer, P.; Hebda, P.; Hunt, A.; Koay, S. A.; Lujan, P.; Marlow, D.; Medvedeva, T.; Mooney, M.; Olsen, J.; Pirou, P.; Quan, X.; Saka, H.; Stickland, D.; Tully, C.; Werner, J. S.; Zenz, S. C.; Zuranski, A.; Brownson, E.; Mendez, H.; Ramirez Vargas, J. E.; Alagoz, E.; Barnes, V. E.; Benedetti, D.; Bolla, G.; Bortoletto, D.; De Mattia, M.; Hu, Z.; Jha, M. K.; Jones, M.; Jung, K.; Kress, M.; Leonardo, N.; Lopes Pegna, D.; Maroussov, V.; Merkel, P.; Miller, D. H.; Neumeister, N.; Radburn-Smith, B. C.; Shi, X.; Shipsey, I.; Silvers, D.; Svyatkovskiy, A.; Wang, F.; Xie, W.; Xu, L.; Yoo, H. D.; Zablocki, J.; Zheng, Y.; Parashar, N.; Stupak, J.; Adair, A.; Akgun, B.; Ecklund, K. M.; Geurts, F. J. M.; Li, W.; Michlin, B.; Padley, B. P.; Redjimi, R.; Roberts, J.; Zabel, J.; Betchart, B.; Bodek, A.; Covarelli, R.; de Barbaro, P.; Demina, R.; Eshaq, Y.; Ferbel, T.; Garcia-Bellido, A.; Goldenzweig, P.; Han, J.; Harel, A.; Khukhunaishvili, A.; Petrillo, G.; Vishnevskiy, D.; Ciesielski, R.; Demortier, L.; Goulianos, K.; Lungu, G.; Mesropian, C.; Arora, S.; Barker, A.; Chou, J. P.; Contreras-Campana, C.; Contreras-Campana, E.; Duggan, D.; Ferencek, D.; Gershtein, Y.; Gray, R.; Halkiadakis, E.; Hidas, D.; Lath, A.; Panwalkar, S.; Park, M.; Patel, R.; Salur, S.; Schnetzer, S.; Somalwar, S.; Stone, R.; Thomas, S.; Thomassen, P.; Walker, M.; Rose, K.; Spanier, S.; York, A.; Bouhali, O.; Eusebi, R.; Flanagan, W.; Gilmore, J.; Kamon, T.; Khotilovich, V.; Krutelyov, V.; Montalvo, R.; Osipenkov, I.; Pakhotin, Y.; Perloff, A.; Roe, J.; Rose, A.; Safonov, A.; Sakuma, T.; Suarez, I.; Tatarinov, A.; Akchurin, N.; Cowden, C.; Damgov, J.; Dragoiu, C.; Dudero, P. R.; Faulkner, J.; Kovitanggoon, K.; Kunori, S.; Lee, S. W.; Libeiro, T.; Volobouev, I.; Appelt, E.; Delannoy, A. G.; Greene, S.; Gurrola, A.; Johns, W.; Maguire, C.; Mao, Y.; Melo, A.; Sharma, M.; Sheldon, P.; Snook, B.; Tuo, S.; Velkovska, J.; Arenton, M. W.; Boutle, S.; Cox, B.; Francis, B.; Goodell, J.; Hirosky, R.; Ledovskoy, A.; Li, H.; Lin, C.; Neu, C.; Wood, J.; Clarke, C.; Harr, R.; Karchin, P. E.; Kottachchi Kankanamge Don, C.; Lamichhane, P.; Sturdy, J.; Belknap, D. A.; Carlsmith, D.; Cepeda, M.; Dasu, S.; Dodd, L.; Duric, S.; Friis, E.; Hall-Wilton, R.; Herndon, M.; Herv, A.; Klabbers, P.; Lanaro, A.; Lazaridis, C.; Levine, A.; Loveless, R.; Mohapatra, A.; Ojalvo, I.; Perry, T.; Pierro, G. A.; Polese, G.; Ross, I.; Sarangi, T.; Savin, A.; Smith, W. H.; Vuosalo, C.; Woods, N.; CMS Collaboration

    2015-03-01

    Measurements of differential cross sections are presented for the production of a Z boson and at least one hadronic jet in proton-proton collisions at ?{s }=7 TeV , recorded by the CMS detector, using a data sample corresponding to an integrated luminosity of 4.9 fb-1 . The jet multiplicity distribution is measured for up to six jets. The differential cross sections are measured as a function of jet transverse momentum and pseudorapidity for the four highest transverse momentum jets. The distribution of the scalar sum of jet transverse momenta is also measured as a function of the jet multiplicity. The measurements are compared with theoretical predictions at leading and next-to-leading order in perturbative QCD.

  2. Progenitor tumours from Emu-bcl-2-myc transgenic mice have lymphomyeloid differentiation potential and reveal developmental differences in cell survival.

    PubMed Central

    Strasser, A; Elefanty, A G; Harris, A W; Cory, S

    1996-01-01

    Mice expressing both a bcl-2 and a myc transgene within the B lymphoid cell compartment invariably develop novel immature haemopoietic tumours. The likely cell of origin of these tumours was identified by a common pattern of cell surface marker expression on a subset of cells comprising approximately 1% of normal mouse bone marrow. The bcl-2-myc tumour cells could be induced to differentiate into either B lymphocytes or macrophages in culture with certain cytokines and feeder cells. Analysis of their progression into the B lymphoid lineage revealed that Igk locus transcription can precede Igh as well as Igk rearrangement. Surprisingly, the undifferentiated tumour cells died rapidly in culture, even in the presence of multiple cytokines, but they proliferated on monolayers of stromal cells derived from haemopoietic tissues. Thus, even with Bcl-2 levels that protect more differentiated cells, these immature bi-potential progenitor cells require a stromal-induced signal for survival. These results provide insight into the process of lineage commitment and suggest new levels of control of cell survival during early steps in haemopoietic development. Images PMID:8670887

  3. The potential role of subclinical Bordetella Pertussis colonization in the etiology of multiple sclerosis.

    PubMed

    Rubin, Keith; Glazer, Steven

    2016-04-01

    It is established that (1) subclinical Bordetella pertussis colonization of the nasopharynx persists in highly vaccinated populations, and (2) B. pertussis toxin is a potent adjuvant that, when co-administered with neural antigens, induces neuropathology in experimental autoimmune encephalomyelitis, the principle animal model of multiple sclerosis. Building on these observations with supporting epidemiologic and biologic evidence, we propose that, contrary to conventional wisdom that subclinical pertussis infections are innocuous to hosts, B. pertussis colonization is an important cause of multiple sclerosis. PMID:26724970

  4. A DELAY DIFFERENTIAL MODEL FOR EL NINO/SOUTHERN OSCILLATION (ENSO): PULLBACK ATTRACTORS, PHASE LOCKING, AND MULTIPLE SOLUTIONS

    NASA Astrophysics Data System (ADS)

    Chekroun, M. D.; Zaliapin, I.; Ghil, M.

    2009-12-01

    We consider a highly idealized model for El Nino/Southern Oscillation (ENSO) variability, previously studied by two of the co-authors. The model is governed by a delay differential equation for sea surface temperature T in the Tropical Pacific, and it combines two key mechanisms that participate in ENSO dynamics: delayed negative feedback and seasonal forcing. We perform a theoretical and numerical study of the model in the three-dimensional space of its physically relevant parameters: strength of seasonal forcing, atmosphere-ocean coupling, and propagation period of oceanic waves across the Tropical Pacific. Phase locking of model solutions to the periodic forcing is prevalent: the local maxima and minima of the solutions tend to occur at the same position within the seasonal cycle. Such phase locking is a key feature of the observed El Nino (warm) and La Nina (cold) events. The phasing of the extrema within the seasonal cycle depends sensitively on model parameters when forcing is weak. We also study co-existence of multiple solutions for fixed model parameters and describe the basins of attraction of the stable solutions within a one-dimensional manifold of constant initial model histories. We study next a two-dimensional manifold of solutions, given by initial histories that are piecewise constant, with a jump from T = a to T = 0 that occurs at time t = -b. To do so, we apply the concept of pullback attractor (PBA) in order to study the model dynamics in the model-parameter region where sensitivity to parameter values is high. Computation of the model's PBAs clearly demonstrates that its dynamics --- whether periodic or quasi-periodic --- occurs on a two-dimensional torus, within the three-dimensional space generated by the "product" of the two-dimensional manifold parameterized by (a,b) with the model variable T. This behavior reflects the competition between two oscillatory mechanisms: an external one due to the seasonal forsing and an internal one due to the delayed feedbacks. Such an interpretation is much harder to obtain from the complex, parameter-sensitive dynamics of the model using more traditional, theoretical and numerical, approaches.

  5. Multi-lineage differentiation and angiogenesis potentials of pigmented villonodular synovitis derived mesenchymal stem cells - pathological implication.

    PubMed

    Chiang, En-Rung; Ma, Hsiao-Li; Wang, Jung-Pan; Liu, Chien-Lin; Chen, Tain-Hsiung; Hung, Shih-Chieh

    2016-03-01

    Pigmented villonodular synovitis (PVNS) is a benign tissue proliferation characterized by its hyper-vascularity within the lesion. The true etiology and cell source of this disease entity still remain unclear. Mesenchymal stem cells (MSCs) exist in various tissues of human body. However, it has not been clarified whether MSCs could be isolated from tissue of PVNS. Here, we isolated MSCs from PVNS (PVNS-SCs), and by comparing to the MSCs from normal synovium (Syn-SCs) of the same individual, we investigated whether PVNS-SCs differed in the capacity for multi-differentiation and inducing angiogenesis. We first demonstrated that PVNS-SCs existed in the lesion of PVNS of three individuals. Moreover, we showed PVNS-SCs had better osteogenic differentiation potential than Syn-SCs, whereas Syn-SCs had better capacity for adipogenic and chondrogenic differentiation. By genome-wide analysis of gene expression profile using a complementary DNA microarray and comparing to Syn-SCs, we identified in PVNS-SCs a distinct gene expression profile characterized by up-regulation of genes involved in angiogenesis. In vitro and in vivo studies further confirmed that PVNS-SCs had better capacities for promoting angiogenesis. In summary, the identification of PVNS-SCs in PVNS tissue and their distinct angiogenic potential may help elucidate the underlying etiology of this disease. 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:395-403, 2016. PMID:26291329

  6. Equine Adipose-Derived Mesenchymal Stem Cells: Phenotype and Growth Characteristics, Gene Expression Profile and Differentiation Potentials

    PubMed Central

    Alipour, Faezeh; Parham, Abbas; Kazemi Mehrjerdi, Hossein; Dehghani, Hesam

    2015-01-01

    Objective Because of the therapeutic application of stem cells (SCs), isolation and characterization of different types of SCs, especially mesenchymal stem cells (MSCs), have gained considerable attention in recent studies. Adipose tissue is an abundant and accessible source of MSCs which can be used for tissue engineering and in particular for treatment of musculoskeletal disorders. This study was aimed to isolate and culture equine adipose-derived MSCs (AT-MSCs) from little amounts of fat tissue samples and determine some of their biological characteristics. Materials and Methods In this descriptive study, only 3-5 grams of fat tissue were collected from three crossbred mares. Immediately, cells were isolated by mechanical means and enzymatic digestion and were cultured in optimized conditions until passage 3 (P3). The cells at P3 were evaluated for proliferative capacities, expression of specific markers, and osteogenic, chondrogenic and adipogenic differentiation potentials. Results Results showed that the isolated cells were plastic adherent with a fibroblast-like phenotype. AT-MSCs exhibited expression of mesenchymal cluster of differentiation (CD) markers (CD29, CD44 and CD90) and not major histocompatibility complex II (MHC-II) and CD34 (hematopoietic marker). Cellular differentiation assays demonstrated the chondrogenic, adipogenic and osteogenic potential of the isolated cells. Conclusion Taken together, our findings reveal that equine MSCs can be obtained easily from little amounts of fat tissue which can be used in the future for regenerative purposes in veterinary medicine. PMID:25685736

  7. The potential to differentiate epidermis is unequally distributed in the AB lineage during early embryonic development in C. elegans.

    PubMed

    Gendreau, S B; Moskowitz, I P; Terns, R M; Rothman, J H

    1994-12-01

    In the early Caenorhabditis elegans embryo most of the ectoderm arises from the AB blastomere, one of the six founder cells. We report that nonequivalent blastomeres are generated at the third division round in the AB lineage. Each AB granddaughter divides to produce one cell that has the potential to make abundant epidermis and one that instead produces primarily nervous system. This unequal distribution of the potential to make epidermis occurs in an AB granddaughter that is isolated by laser-ablation of all other cells or during the development of an isolated AB blastomere in culture. The fidelity of this event is normally masked by a signal from the MS founder cell, which induces mesoderm in particular AB descendants. When MS induction is prevented by laser cell-ablation or by a mutation in the glp-1 gene, the epidermal fate map of the AB great granddaughters becomes left-right symmetrical. Cell lineage analyses demonstrate that, in fact, the AB lineage becomes entirely left-right symmetrical in the absence of MS induction. This accounts for the extra epidermal cells previously observed in a glp-1 mutant. Our results suggest that epidermal differentiation in the nematode may be controlled by a cell-autonomous mechanism that differentially allocates epidermal potential during AB development and that MS induction generates the left-right asymmetry in the fates of AB descendants in part by overriding this potential. PMID:7813794

  8. Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases

    PubMed Central

    D’Ambrosio, Daniele; Freedman, Mark S.; Prinz, Joerg

    2016-01-01

    The first oral treatment for relapsing multiple sclerosis, the nonselective sphingosine-1-phosphate receptor (S1PR) modulator fingolimod, led to identification of a pivotal role of sphingosine-1-phosphate and one of its five known receptors, S1P1R, in regulation of lymphocyte trafficking in multiple sclerosis. Modulation of S1P3R, initially thought to cause some of fingolimod’s side effects, prompted the search for novel compounds with high selectivity for S1P1R. Ponesimod is an orally active, selective S1P1R modulator that causes dose-dependent sequestration of lymphocytes in lymphoid organs. In contrast to the long half-life/slow elimination of fingolimod, ponesimod is eliminated within 1 week of discontinuation and its pharmacological effects are rapidly reversible. Clinical data in multiple sclerosis have shown a dose-dependent therapeutic effect of ponesimod and defined 20 mg as a daily dose with desired efficacy, and acceptable safety and tolerability. Phase II clinical data have also shown therapeutic efficacy of ponesimod in psoriasis. These findings have increased our understanding of psoriasis pathogenesis and suggest clinical utility of S1P1R modulation for treatment of various immune-mediated disorders. A gradual dose titration regimen was found to minimize the cardiac effects associated with initiation of ponesimod treatment. Selectivity for S1P1R, rapid onset and reversibility of pharmacological effects, and an optimized titration regimen differentiate ponesimod from fingolimod, and may lead to better safety and tolerability. Ponesimod is currently in phase III clinical development to assess efficacy and safety in relapsing multiple sclerosis. A phase II study is also ongoing to investigate the potential utility of ponesimod in chronic graft versus host disease. PMID:26770667

  9. Autocrine Action of Thrombospondin-2 Determines the Chondrogenic Differentiation Potential and Suppresses Hypertrophic Maturation of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells.

    PubMed

    Jeong, Sang Young; Ha, Jueun; Lee, Miyoung; Jin, Hye Jin; Kim, Dong Hyun; Choi, Soo Jin; Oh, Wonil; Yang, Yoon Sun; Kim, Jae-Sung; Kim, Byung-Gyu; Chang, Jeong Ho; Cho, Dong-Hyung; Jeon, Hong Bae

    2015-11-01

    Previous studies have shown that mesenchymal stem cell (MSC)-based therapies have varying efficacies for the treatment of various diseases, including cartilage defects. In this study, we demonstrated that the chondrogenic differentiation potential of human umbilical cord blood-derived MSCs (hUCB-MSCs) obtained from different individual donors varies, and we investigated the molecular basis for this variation. Microarray gene expression analysis identified thrombospondin-2 (TSP2) as a candidate gene underlying the interindividual variation in the chondrogenic differentiation potential of hUCB-MSCs. To assess the association between TSP-2 and the differentiation potential, we evaluated chondrogenic differentiation of hUCB-MSCs treated with TSP2 siRNA. In addition, we studied the effect of supplementing exogenous recombinant TSP-2 on TSP2 siRNA-treated hUCB-MSCs. We found that TSP-2 autocrinally promoted chondrogenic differentiation of hUCB-MSCs via the Notch signaling pathway, which was confirmed in MSCs from other sources such as bone marrow and adipose tissue. Interestingly, we observed that TSP-2 attenuated hypertrophy, which inevitably occurs during chondrogenic differentiation of hUCB-MSCs. Our findings indicated that the variable chondrogenic differentiation potential of MSCs obtained from different donors is influenced by the TSP-2 level in the differentiating cells. Thus, the TSP-2 level can be used as a marker to select MSCs with superior chondrogenic differentiation potential for use in cartilage regeneration therapy. PMID:26235673

  10. The Potential of Water Vapor & Precipitation Estimation with a Differential-frequency Radar

    NASA Technical Reports Server (NTRS)

    Meneghini, Robert; Liao, Liang; Tian, Lin

    2006-01-01

    In the presence of rain, the radar return powers from a three-frequency radar, with center frequency at 22.235 GHz and upper and lower frequencies chosen with equal water vapor absorption coefficients, can be used to estimate water vapor density and parameters of the precipitation. A linear combination of differential measurements between the center and lower frequencies on one hand and the upper and lower frequencies on the other provide an estimate of differential water vapor absorption. Conversely, the difference in radar reflectivity factors (in dB) between the upper and lower frequencies is independent of water vapor absorption and can be used to estimate the median mass diameter of the hydrometeors. For a down-looking radar, path-integrated estimates of water vapor absorption may be possible under rain-free as well as raining conditions by using the surface returns at the three frequencies. Cross-talk or interference between the precipitation and water vapor estimates depends on the frequency separation of the channels as well as on the phase state and the median mass diameter of the hydrometeors. Simulations of the retrieval of water vapor absorption show that the largest source of variability arises from the variance in the measured radar return powers while the largest biases occur in the mixed-phase region. Use of high pulse repetition frequencies and signal whitening methods may be needed to obtain the large number of independent samples required. Measurements over a fractional bandwidth, defined as the ratio of the difference between the upper and lower frequencies to the center frequency, up to about 0.2 should be passible in a differential frequency mode, where a single transceiver and antenna are used. Difficulties in frequency allocation may require alternative choices of frequency where the water vapor absorptions at the low and high frequencies are unequal. We consider the degradation in the retrieval accuracy when the frequencies are not optimum.

  11. In vivo differentiation potential of buffalo (Bubalus bubalis) embryonic stem cell.

    PubMed

    Verma, Om Prakash; Kumar, Rajesh; Nath, Amar; Sharma, Manjinder; Dubey, Pawan Kumar; Kumar, G Sai; Sharma, G Taru

    2012-06-01

    Embryonic stem cells (ESCs) derived from inner cell mass (ICM) of mammalian blastocyst are having indefinite proliferation and differentiation capability for any type of cell lineages. In the present study, ICMs of in vitro-derived buffalo blastocysts were cultured into two different culture systems using buffalo fetal fibroblast as somatic cell support and Matrigel as synthetic support to obtain pluripotent buffalo embryonic stem cell (buESC) colonies. Pluripotency of the ESCs were characterised through pluripotency markers whereas, their differentiation capability was assessed by teratoma assay using immuno-compromised mice. Cumulus ooccyte complexes from slaughter house-derived ovaries were subjected to in vitro maturation, in vitro fertilization and in vitro culture to generate blastocysts. Total 262 blastocysts were derived through IVEP with 11.83 % (31/262) hatching rate. To generate buESCs, 15 ICMs from hatched blastocysts were cultured on mitomycin-C-treated homologous fetal fibroblast feeder layer, whereas the leftover 16 ICMs were cultured on extra-cellular matrix (Matrigel). No significant differences were observed for primary ESCs colony formation between two culture systems. Primary colonies as well as passaged ESCs were characterised by alkaline phosphatase staining, karyotyping and expression of transcription-based stem cell markers, OCT-4 and cell surface antigens SSEA-4 and TRA-1-60. Batch of ESCs found positive for pluripotency markers and showing normal karyotype after fifteenth passage were inoculated into eight immuno-compromised mice through subcutaneous and intramuscular route. Subcutaneous route of inoculation was found to be better than intramuscular route. Developed teratomas were excised surgically and subjected to histological analysis. Histological findings revealed presence of all the three germinal layer derivatives in teratoma sections. Presence of germinal layer derivatives were further confirmed by reverse transcriptase-polymerase chain reaction for the presence of differentiation markers like nerve cell adhesion molecule, fetal liver kinase-1 and alpha-feto protein for ectoderm, mesoderm and endoderm, respectively. PMID:22678753

  12. Irradiation alters the differentiation potential of bone marrow mesenchymal stem cells.

    PubMed

    Wang, Yu; Zhu, Guoying; Wang, Jianping; Chen, Junxiang

    2016-01-01

    Bone injury following radiotherapy has been confirmed by epidemiological and animal studies. However, the underlying mechanism remains to be elucidated and no preventive or curative solution has been identified for this bone loss. The present study aimed to investigate the irradiation?altered osteogenesis and adipogenesis of bone marrow mesenchymal stem cells (BMSCs). BMSCs were derived and exposed to ??irradiation at doses of 0, 0.25, 0.5, 1, 2, 5 and 10Gy. Cell viability was assessed using a 3?(4,5?dimethylthiazol?2?yl)?2,5 diphenyl tetrazolium bromide assay, and clonal expansion invitro was detected by colony forming unit assessment. The osteogenic differentiation ability was demonstrated by alkaline phosphatase (ALP) activity, ALP staining and mineralization alizarin red staining, and the adipogenic differentiation ability was determined using OilOred staining. The osteogenesis?associated genes, RUNX2, ALP, osteocalcin (OCN) and adipogenesis?associated genes, PPAR?? and C/EBP?, were detected using reverse transcription?quantitative polymerase chain reaction analyses. The protein expression levels of RUNX2, ALP and PPAR?? were detected using western blotting. Compared with the control, significant decreases in the proliferation, ALP activity and mineralization ability of the BMSCs were observed in the ??irradiation group, with a high level of correlation with the exposure dose. However, no significant changes were observed in the area of OilredO positive staining. The mRNA levels of RUNX2, ALP and OCN were decreased (P<0.05), however, no significant changes were observed in the levels of C/EBP? and PPAR??. The protein expression levels of RUNX2 and ALP were decreased in the irradiated BMSCs, however, no significant difference was observed in the protein expression of PPAR??. Irradiation inhibited the osteogenic and adipogenic ability of the BMSCs, and the osteogenic differentiation was decreased. The results of the present study provided evidence to assist in further elucidating radiotherapy?associated side effects on the skeleton. PMID:26572960

  13. Investigation of potential of differential absorption Lidar techniques for remote sensing of atmospheric pollutants

    NASA Technical Reports Server (NTRS)

    Butler, C. F.; Shipley, S. T.; Allen, R. J.

    1981-01-01

    The NASA multipurpose differential absorption lidar (DIAL) system uses two high conversion efficiency dye lasers which are optically pumped by two frequency-doubled Nd:YAG lasers mounted rigidly on a supporting structure that also contains the transmitter, receiver, and data system. The DIAL system hardware design and data acquisition system are described. Timing diagrams, logic diagrams, and schematics, and the theory of operation of the control electronics are presented. Success in obtaining remote measurements of ozone profiles with an airborne systems is reported and results are analyzed.

  14. Greenhouse and Field Evaluation of Multiple Virus Resistant Lagenaria siceraria Lines Potentially useful for Watermelon Rootstocks

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In previous evaluations we identified numerous lines of bottle gourd (Lagenaria siceraria) with complete or partial resistance to Zucchini yellow mosaic virus (ZYMV). In the present study, we were interested in developing bottle gourd lines with multiple virus resistance that could be useful as roo...

  15. NOTES performed using multiple ports of entry: Current experience and potential implications for urologic applications.

    PubMed

    Lima, Estevao; Rolanda, Carla; Correia-Pinto, Jorge

    2009-05-01

    An isolated transgastric port raises serious limitations in performing natural orifice translumenal endoscopic surgery (NOTES) complex procedures in the urology field. In an attempt to overcome these limitations, several solutions has been advanced, such as the hybrid approach (adding a single abdominal port access) or the pure NOTES combined approach (joining multiple natural orifice ports). To review the current state of experimental and clinical results of multiple ports in NOTES, a literature search of PubMed was performed, seeking publications from January 2002 to 2008 on NOTES. In addition, we looked at pertinent abstracts of annual meetings of the American Urological Association, the European Association of Urology, and the World Congress of Endourology from 2007. Multiple ports of entry seem to be necessary, mainly for moderately complex procedures. Thus, we could find studies using the hybrid approach (combination of transgastric or transvaginal access with a single transabdominal port), or using the pure NOTES combined approach (transgastric and transvesical, transvaginal and transcolonic, or transgastric and transvaginal). There is still limited experience in humans using these approaches, and no comparative studies exist to date. It is predictable that for moderately complex procedures, we will need multiple ports, so the transvaginal-transabdominal (hybrid) approach is the most appealing, whereas in a pure NOTES perspective, the transgastric-transvesical approach seems to be the preferred approach. We are waiting for new equipment and instruments that are more appropriate for these novel techniques. PMID:19405809

  16. Homeobox B7 promotes the osteogenic differentiation potential of mesenchymal stem cells by activating RUNX2 and transcript of BSP

    PubMed Central

    Gao, Run-Tao; Zhan, Li-Ping; Meng, Cen; Zhang, Ning; Chang, Shi-Min; Yao, Rui; Li, Chong

    2015-01-01

    Mesenchymal stem cells (MSCs) are a reliable cell source for tissue regeneration. However, the molecular mechanisms underlying the directed differentiation of MSCs remain unclear; thus, their use is limited. Here, we investigate HOXB7 function in the osteogenic differentiation potentials of MSCs using stem cells from apical papilla (SCAPs) and bone marrow stem cells (BMSCs). The HOXB7 gene is highly expressed in BMSCs compared with dental tissue-derived MSCs. We found that, in vitro, over-expression of HOXB7 in SCAPs enhanced alkaline phosphatase (ALP) activity and mineralization. HOXB7 over-expression affected the mRNA expression of osteonectin (ON), collagen alpha-2(I) chain (COL1A2), bone sialoprotein (BSP), and osteocalcin (OCN), led to the expression of the key transcription factor, runt-related transcription factor 2 (RUNX2), and promoted SCAP osteogenic differentiation in vitro. The knock-down of HOXB7 inhibited ALP activity, mineralization, and the expression of ON, BSP, COL1A2, OCN, and RUNX2 in BMSCs in vitro. In addition, transplant experiments in nude mice confirmed that SCAP osteogenesis was triggered when HOXB7 was activated. Furthermore, Over-expression of HOXB7 significantly increased the levels of HOXB7 associated with the BSP promoter by ChIP assays. Taken together, these results indicate that HOXB7 enhances SCAP osteogenic differentiation by up-regulating RUNX2 and directly activating transcript of BSP. Thus, the activation of HOXB7 signaling might improve tissue regeneration mediated by MSCs. These results provide insight into the mechanism underlying the directed differentiation of MSCs. PMID:26379836

  17. Cellular mechanical properties reflect the differentiation potential of adipose-derived mesenchymal stem cells.

    PubMed

    Gonzlez-Cruz, Rafael D; Fonseca, Vera C; Darling, Eric M

    2012-06-12

    The mechanical properties of adipose-derived stem cell (ASC) clones correlate with their ability to produce tissue-specific metabolites, a finding that has dramatic implications for cell-based regenerative therapies. Autologous ASCs are an attractive cell source due to their immunogenicity and multipotent characteristics. However, for practical applications ASCs must first be purified from other cell types, a critical step which has proven difficult using surface-marker approaches. Alternative enrichment strategies identifying broad categories of tissue-specific cells are necessary for translational applications. One possibility developed in our lab uses single-cell mechanical properties as predictive biomarkers of ASC clonal differentiation capability. Elastic and viscoelastic properties of undifferentiated ASCs were tested via atomic force microscopy and correlated with lineage-specific metabolite production. Cell sorting simulations based on these "mechanical biomarkers" indicated they were predictive of differentiation capability and could be used to enrich for tissue-specific cells, which if implemented could dramatically improve the quality of regenerated tissues. PMID:22615348

  18. RNA sequencing reveals differentially expressed genes as potential diagnostic and prognostic indicators of gallbladder carcinoma

    PubMed Central

    Jiang, Mingming; Fang, Meng; Ji, Jun; Wang, Aihua; Wang, Mengmeng; Jiang, Xiaoqing; Gao, Chunfang

    2015-01-01

    Gallbladder carcinoma (GBC) is a rare tumor with a dismal survival rate overall. Hence, there is an urgent need for exploring more specific and sensitive biomarkers for the diagnosis and treatment of GBC. At first, amplified total RNAs from two paired GBC tumors and adjacent non-tumorous tissues (ANTTs) were subjected to RNA sequencing. 161 genes were identified differentially expressed between tumors and ANTTs. Functional enrichment analysis indicated that the up-regulated genes in tumor were primarily associated with signaling molecules and enzyme modulators, and mainly involved in cell cycles and pathways in cancer. Twelve differentially expressed genes (DEGs) were further confirmed in another independent cohort of 35 GBC patients. Expression levels of BIRC5, TK1, TNNT1 and MMP9 were found to be positively related to postoperative relapse. There was also a significant correlation between BIRC5 expression and tumor-node-metastasis (TNM) stage. Besides, we observed a positive correlation between serum CA199 concentration and the expression levels of TNNT1, MMP9 and CLIC3. Survival analysis revealed that GBC patients with high TK1 and MMP9 expression levels had worse prognosis. These identified DEGs might not only be promising biomarkers for GBC diagnosis and prognosis, but also expedite the discovery of novel therapeutic strategies. PMID:25970782

  19. Isolation, characterization and the multi-lineage differentiation potential of rabbit bone marrow-derived mesenchymal stem cells

    PubMed Central

    Tan, Sik-Loo; Ahmad, Tunku Sara; Selvaratnam, Lakshmi; Kamarul, Tunku

    2013-01-01

    Mesenchymal stem cells (MSCs) are recognized by their plastic adherent ability, fibroblastic-like appearance, expression of specific surface protein markers, and are defined by their ability to undergo multi-lineage differentiation. Although rabbit bone marrow-derived MSCs (rbMSCs) have been used extensively in previous studies especially in translational research, these cells have neither been defined morphologically and ultrastructurally, nor been compared with their counterparts in humans in their multi-lineage differentiation ability. A study was therefore conducted to define the morphology, surface marker proteins, ultrastructure and multi-lineage differentiation ability of rbMSCs. Herein, the primary rbMSC cultures of three adult New Zealand white rabbits (at least 4 months old) were used for three independent experiments. rbMSCs were isolated using the gradient-centrifugation method, an established technique for human MSCs (hMSCs) isolation. Cells were characterized by phase contrast microscopy observation, transmission electron microscopy analysis, reverse transcriptase-polymerase chain reaction (PCR) analysis, immunocytochemistry staining, flow cytometry, alamarBlue assay, histological staining and quantitative (q)PCR analysis. The isolated plastic adherent cells were in fibroblastic spindle-shape and possessed eccentric, irregular-shaped nuclei as well as rich inner cytoplasmic zones similar to that of hMSCs. The rbMSCs expressed CD29, CD44, CD73, CD81, CD90 and CD166, but were negative (or dim positive) for CD34, CD45, CD117 and HLD-DR. Despite having similar morphology and phenotypic expression, rbMSCs possessed significantly larger cell size but had a lower proliferation rate as compared with hMSCs. Using established protocols to differentiate hMSCs, rbMSCs underwent osteogenic, adipogenic and chondrogenic differentiation. Interestingly, differentiated rbMSCs demonstrated higher levels of osteogenic (Runx2) and chondrogenic (Sox9) gene expressions than that of hMSCs (P < 0.05). There was, however, no difference in the adipogenic (Ppar?) expressions between these cell types (P > 0.05). rbMSCs possess similar morphological characteristics to hMSCs, but have a higher potential for osteogenic and chondrogenic differentiation, despite having a lower cell proliferation rate than hMSCs. The characteristics reported here may be used as a comprehensive set of criteria to define or characterize rbMSCs. PMID:23510053

  20. Irradiation alters the differentiation potential of bone marrow mesenchymal stem cells

    PubMed Central

    WANG, YU; ZHU, GUOYING; WANG, JIANPING; CHEN, JUNXIANG

    2016-01-01

    Bone injury following radiotherapy has been confirmed by epidemiological and animal studies. However, the underlying mechanism remains to be elucidated and no preventive or curative solution has been identified for this bone loss. The present study aimed to investigate the irradiation-altered osteogenesis and adipogenesis of bone marrow mesenchymal stem cells (BMSCs). BMSCs were derived and exposed to γ-irradiation at doses of 0, 0.25, 0.5, 1, 2, 5 and 10 Gy. Cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay, and clonal expansion in vitro was detected by colony forming unit assessment. The osteogenic differentiation ability was demonstrated by alkaline phosphatase (ALP) activity, ALP staining and mineralization alizarin red staining, and the adipogenic differentiation ability was determined using Oil O red staining. The osteogenesis-associated genes, RUNX2, ALP, osteocalcin (OCN) and adipogenesis-associated genes, PPAR-γ and C/EBPα, were detected using reverse transcription-quantitative polymerase chain reaction analyses. The protein expression levels of RUNX2, ALP and PPAR-γ were detected using western blotting. Compared with the control, significant decreases in the proliferation, ALP activity and mineralization ability of the BMSCs were observed in the γ-irradiation group, with a high level of correlation with the exposure dose. However, no significant changes were observed in the area of Oil red O positive staining. The mRNA levels of RUNX2, ALP and OCN were decreased (P<0.05), however, no significant changes were observed in the levels of C/EBPα and PPAR-γ. The protein expression levels of RUNX2 and ALP were decreased in the irradiated BMSCs, however, no significant difference was observed in the protein expression of PPAR-γ. Irradiation inhibited the osteogenic and adipogenic ability of the BMSCs, and the osteogenic differentiation was decreased. The results of the present study provided evidence to assist in further elucidating radiotherapy-associated side effects on the skeleton. PMID:26572960

  1. Multiple negative differential resistance devices with ultra-high peak-to-valley current ratio for practical multi-valued logic and memory applications

    NASA Astrophysics Data System (ADS)

    Shin, Sunhae; Rok Kim, Kyung

    2015-06-01

    In this paper, we propose a novel multiple negative differential resistance (NDR) device with ultra-high peak-to-valley current ratio (PVCR) over 106 by combining tunnel diode with a conventional MOSFET, which suppresses the valley current with transistor off-leakage level. Band-to-band tunneling (BTBT) in tunnel junction provides the first peak, and the second peak and valley are generated from the suppression of diffusion current in tunnel diode by the off-state MOSFET. The multiple NDR curves can be controlled by doping concentration of tunnel junction and the threshold voltage of MOSFET. By using complementary multiple NDR devices, five-state memory is demonstrated only with six transistors.

  2. A case of multiple macronodular hepatic tuberculosis difficult to differentiate from hepatocellular carcinoma with intrahepatic metastasis: CT-guided fine needle aspiration biopsy confirmed the diagnosis.

    PubMed

    Zhang, Lei; Yang, Nai-Bin; Ni, Shun-Lan; Zhang, Sai-Nan; Shen, Chen-Bo; Lu, Ming-Qin

    2014-01-01

    Multiple macronodular hepatic tuberculosis is difficult to be differentiated from hepatocellular carcinoma with intrahepatic metastasis in clinical practice, especially when hepatitis B with or without liver cirrhosis coexists with it. Herein, we report a 30-year-old man with a 10-year history of hepatitis B and a family medical history of hepatocellular carcinoma related with hepatitis B that was finally diagnosed as multiple macronodular hepatic tuberculosis. Abdominal B-mode ultrasonography (US) and plain computed tomography (CT) revealed multiple unequal-sized nodules in the liver. CT-guided fine needle aspiration biopsy (FNAB) of the liver demonstrated a caseating granuloma with lymphocytes, multinucleate giant cells and epithelioid cells compatible with the diagnosis of tuberculosis and no hepatoma cells were detected. Thus, the diagnosis of hepatic tuberculosis was confirmed and hepatocellular carcinoma with intrahepatic metastasis was excluded. PMID:25550879

  3. Diagnostic potential of ancillary molecular testing in differentiation of benign and malignant thyroid nodules.

    PubMed

    Bhatia, Parisha; Deniwar, Ahmed; Friedlander, Paul; Aslam, Rizwan; Kandil, Emad

    2015-03-01

    Fine needle aspiration (FNA) cytology, being the mainstay to diagnose thyroid nodules, does not provide definitive results in a subset of patients. The use of molecular markers testing has been described as a useful aid in differentiation of thyroid nodules that present with an indeterminate cytodiagnosis. Molecular tests, such as the Afirma gene classifier, mutational assay and immunohistochemical markers have been increasingly used to further increase the accuracy and defer unnecessary surgeries for benign thyroid nodules. However, in light of the current literature, their emerging roles in clinical practice are limited due to financial and technical limitations. Nevertheless, their synergistic implementation can predict the risk of malignancy and yield an accurate diagnosis. This review discusses the clinical utility of various molecular tests done on FNA indeterminate nodules to avoid diagnostic thyroidectomies and warrant the need of future multi-Institutional studies. PMID:25750270

  4. The potential of panobinostat as a treatment option in patients with relapsed and refractory multiple myeloma

    PubMed Central

    Andreu-Vieyra, Claudia V.

    2014-01-01

    Panobinostat is an investigational and potent histone deacetylase inhibitor (HDACi) that has shown promise as an antimultiple myeloma agent in the preclinical setting. In this review, we discuss the rationale for the use of panobinostat as a combination therapy for multiple myeloma and provide an overview of recent and ongoing clinical trials testing the safety and efficacy of panobinostat for the treatment of the disease. PMID:25469210

  5. The potential of panobinostat as a treatment option in patients with relapsed and refractory multiple myeloma.

    PubMed

    Andreu-Vieyra, Claudia V; Berenson, James R

    2014-12-01

    Panobinostat is an investigational and potent histone deacetylase inhibitor (HDACi) that has shown promise as an antimultiple myeloma agent in the preclinical setting. In this review, we discuss the rationale for the use of panobinostat as a combination therapy for multiple myeloma and provide an overview of recent and ongoing clinical trials testing the safety and efficacy of panobinostat for the treatment of the disease. PMID:25469210

  6. Differentiation potential of germ line stem cells derived from the postnatal mouse ovary.

    PubMed

    Pacchiarotti, Jason; Maki, Chad; Ramos, Thomas; Marh, Joel; Howerton, Kyle; Wong, Jadelind; Pham, Jane; Anorve, Sandra; Chow, Yung-Chiong; Izadyar, Fariborz

    2010-03-01

    General belief in reproductive biology is that in most mammals female germ line stem cells are differentiated to primary oocytes during fetal development and oogenesis starts from a pool of primordial follicles after birth. This idea has been challenged previously by using follicle kinetics studies and demonstration of mitotically active germ cells in the postnatal mouse ovary (Johnson et al., 2004; Kerr et al., 2006; Zhang et al., 2008). However, the existence of a population of self-renewing ovarian germ line stem cells in postnatal mammals is still controversial (Eggan et al., 2006; Telfer et al., 2005; Gosden, 2004). Recently, production of offspring from a germ line stem cell line derived from the neonatal mouse ovary was reported (Zou et al., 2009). This report strongly supports the existence of germ line stem cells and their ability to expand in vitro. Recently, using a transgenic mouse model in which GFP is expressed under a germ cell-specific Oct-4 promoter, we isolated and generated multipotent cell lines from male germ line stem cells (Izadyar et al., 2008). Using the same strategy we isolated and derived cell lines from postnatal mouse ovary. Interestingly, ovarian germ line stem cells expanded in the same culture conditions as the male suggesting that they have similar requirements for their self-renewal. After 1 year of culture and many passages, ovarian germ line stem cells maintained their characteristics and telomerase activity, expressed germ cell and stem cell markers and revealed normal karyotype. As standard protocol for differentiation induction, these cells were aggregated and their ability to form embryoid bodies (EBs) was investigated. EBs generated in the presence of growth factors showed classical morphology and expressed specific markers for three germ layers. However, in the absence of growth promoting factors EBs were smaller and large cells with the morphological and molecular characteristics of oocytes were formed. This study shows the existence of a population of germ line stem cell in postnatal mouse ovary with multipotent characteristics. PMID:20138422

  7. UNAIDS multiple sexual partners core indicator: promoting sexual networks to reduce potential biases

    PubMed Central

    Dimbuene, Zacharie Tsala; Emina, Jacques B.O.; Sankoh, Osman

    2014-01-01

    UNAIDS proposed a set of core indicators for monitoring changes in the worldwide AIDS epidemic. This paper explores the validity and effectiveness of the multiple sexual partners core indicator, which is only partially captured with current available data. The paper also suggests an innovative approach for collecting more informative data that can be used to provide an accurate measure of the UNAIDSs multiple sexual partners core indicator. Specifically, the paper addresses three major limitations associated with the indicator when it is measured with respondents sexual behaviors. First, the indicator assumes that a persons risk of contracting HIV/AIDS/STIs is merely a function of his/her own sexual behavior. Second, the indicator does not account for a partners sexual history, which is very important in assessing an individuals risk level. Finally, the 12-month period used to define a persons risks can be misleading, especially because HIV/AIDS theoretically has a period of latency longer than a year. The paper concludes that, programmatically, improvements in data collection are a top priority for reducing the observed bias in the multiple sexual partners core indicator. PMID:24647127

  8. Placebo controlled pilot trial to study the remyelinating potential of intravenous immunoglobulins in multiple sclerosis

    PubMed Central

    Stangel, M.; Boegner, F.; Klatt, C.; Hofmeister, C.; Seyfert, S.

    2000-01-01

    Currently there is no treatment available to improve a stable deficit in multiple sclerosis. It was shown in animal models that intravenous immunoglobulins (IVIg) can enhance central nervous remyelination, and the first open trials were promising. We therefore conducted a double blind, placebo controlled pilot study to evaluate the effect of IVIg treatment in patients with multiple sclerosis with a stable clinical deficit. The primary outcome parameter was the change in central motor conduction time as an indirect measure of central myelination. Secondary outcome parameters were neurological examinations including the expanded disability status scale (EDSS), neurological rating scale (NRS), and manual muscle testing (MMT). Ten patients were treated first with placebo and then with IVIg (0.4 g/kg body weight on 5 consecutive days), the two treatments being separated by an interval of 6 weeks. There was no difference in the central motor conduction times measured before and 6 weeks after each treatment. Clinically there was a small improvement after IVIg treatment, but there was no significant difference when compared with placebo. In conclusion, our data do not support a role for IVIg in the remyelination of stable multiple sclerosis lesions as measured by central conduction time. The importance of the small clinical benefit is currently not clear.?? PMID:10601410

  9. Multiple Sclerosis: MicroRNA Expression Profiles Accurately Differentiate Patients with Relapsing-Remitting Disease from Healthy Controls

    PubMed Central

    Lange, Julia; Borries, Anne; Schroers, Hannah; Scheffler, Matthias; Lenhof, Hans-Peter; Ruprecht, Klemens; Meese, Eckart

    2009-01-01

    Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, which is heterogenous with respect to clinical manifestations and response to therapy. Identification of biomarkers appears desirable for an improved diagnosis of MS as well as for monitoring of disease activity and treatment response. MicroRNAs (miRNAs) are short non-coding RNAs, which have been shown to have the potential to serve as biomarkers for different human diseases, most notably cancer. Here, we analyzed the expression profiles of 866 human miRNAs. In detail, we investigated the miRNA expression in blood cells of 20 patients with relapsing-remitting MS (RRMS) and 19 healthy controls using a human miRNA microarray and the Geniom Real Time Analyzer (GRTA) platform. We identified 165 miRNAs that were significantly up- or downregulated in patients with RRMS as compared to healthy controls. The best single miRNA marker, hsa-miR-145, allowed discriminating MS from controls with a specificity of 89.5%, a sensitivity of 90.0%, and an accuracy of 89.7%. A set of 48 miRNAs that was evaluated by radial basis function kernel support vector machines and 10-fold cross validation yielded a specificity of 95%, a sensitivity of 97.6%, and an accuracy of 96.3%. While 43 of the 165 miRNAs deregulated in patients with MS have previously been related to other human diseases, the remaining 122 miRNAs are so far exclusively associated with MS. The implications of our study are twofold. The miRNA expression profiles in blood cells may serve as a biomarker for MS, and deregulation of miRNA expression may play a role in the pathogenesis of MS. PMID:19823682

  10. Comparison of Proliferative and Multilineage Differentiation Potential of Sheep Mesenchymal Stem Cells Derived from Bone Marrow, Liver, and Adipose Tissue

    PubMed Central

    Heidari, Banafsheh; Shirazi, Abolfazl; Akhondi, Mohammad Mehdi; Hassanpour, Hossein; Behzadi, Bahareh; Naderi, Mohammad Mehdi; Sarvari, Ali; Borjian, Sara

    2013-01-01

    Background Background: Despite major progress in our general knowledge related to the application of adult stem cells, finding alternative sources for bone marrow Mesenchymal Stem Cells (MSCs) has remained to be challenged. In this study successful isolation, multilineage differentiation, and proliferation potentials of sheep MSCs derived from bone marrow, adipose tissue, and liver were widely investigated. Methods The primary cell cultures were prepared form tissue samples obtained from sheep 30-35 day fetus. Passage-3 cells were plated either at varying cell densities or different serum concentrations for a week. The Population Doubling Time (PDT), growth curves, and Colony Forming Unit (CFU) of MSCs was determined. The stemness and trilineage differentiation potential of MSCs were analyzed by using molecullar and cytochemical staining approaches. The data was analyzed through one way ANOVA using SigmaStat (ver. 2). Results The highest PDT and lowest CFU were observed in adipose tissue group compared with other groups (p<0.001). Comparing different serum concentrations (5, 10, 15, and 20%), irrespective of cell sources, the highest proliferation rate was achieved in the presence of 20% serum (p<0.001). Additionally, there was an inverse relation between cell seeding density at culture initiation and proliferation rate, except for L-MSC at 300 cell seeding density. Conclusion All three sources of fetal sheep MSCs had the identical trilineage differentiation potential. The proliferative capacity of liver and bone marrow derived MSCs were similar at different cell seeding densities except for the higher fold increase in B-MSCs at 2700 cells/cm 2 density. Moreover, the adipose tissue derived MSCs had the lowest proliferative indices. PMID:23799179

  11. Exploring Potential Sources of Differential Vulnerability and Susceptibility in Risk From Environmental Hazards to Expand the Scope of Risk Assessment

    PubMed Central

    Bellinger, David; Glass, Thomas

    2011-01-01

    Genetic factors, other exposures, individual disease states and allostatic load, psychosocial stress, and socioeconomic position all have the potential to modify the response to environmental exposures. Moreover, many of these modifiers covary with the exposure, leading to much higher risks in some subgroups. These are not theoretical concerns; rather, all these patterns have already been demonstrated in studies of the effects of lead and air pollution. However, recent regulatory impact assessments for these exposures have generally not incorporated these findings. Therefore, differential risk and vulnerability is a critically important but neglected area within risk assessment, and should be incorporated in the future. PMID:22021315

  12. Sexual differentiation in the distribution potential of northern jaguars (Panthera onca)

    USGS Publications Warehouse

    Boydston, Erin E.; Lopez Gonzalez, Carlos A.

    2005-01-01

    We estimated the potential geographic distribution of jaguars in the southwestern United States and northwestern Mexico by modeling the jaguar ecological niche from occurrence records. We modeled separately the distribution of males and females, assuming records of females probably represented established home ranges while male records likely included dispersal movements. The predicted distribution for males was larger than that for females. Eastern Sonora appeared capable for supporting male and female jaguars with potential range expansion into southeastern Arizona. New Mexico and Chihuahua contained environmental characteristics primarily limited to the male niche and thus may be areas into which males occasionally disperse.

  13. Determination of the potential of induced pluripotent stem cells to differentiate into mouse nucleus pulposus cells in vitro.

    PubMed

    Liu, K; Chen, Z; Luo, X W; Song, G Q; Wang, P; Li, X D; Zhao, M; Han, X W; Bai, Y G; Yang, Z L; Feng, G

    2015-01-01

    We determined the potential for induced pluripotent stem (iPS) cells to differentiate into nucleus pulposus (NP)-like cells in mice. iPS cells were generated from tail-tip fibroblasts. We used a pellet culture model with the aim of determining the applicability of iPS cell-based therapy to intervertebral disc degeneration (IVD). The cell pellet was cultured in an NP cell basal medium comprising Dulbecco's modified Eagle's medium supplemented with transforming growth factor beta 1, dexamethasone, ascorbate-2-phosphate, and 1% ITS-Premix. The pellet was evaluated by quantitative reverse transcription polymerase chain reaction, immunohistochemical staining, and biochemical composition. The differentiation of iPS cells into NP cells was demonstrated by the protein and mRNA expression levels of proteoglycan, collagen II, aggrecan, and CD24. Furthermore, increased hydroxyproline content and dimethylmethylene blue staining demonstrated that the collagen II and glycosaminoglycan content in the NP cells increased with time. We have shown that cultured mouse iPS cells can be induced to differentiate into NP cells. Such proof-of-concept opens up the possibility of producing patient-specific NP cells in a relatively simple and straightforward manner with high efficiency. We are confident that such cells could be immediately useful for the study of IVD disease. PMID:26505389

  14. Event-Related Potentials and Consonant Differentiation in Newborns with Familial Risk for Dyslexia.

    ERIC Educational Resources Information Center

    Guttorm, Tomi K.; Leppanen, Paavo H. T.; Richardson, Ulla; Lyytinen, Heikki

    2001-01-01

    This study examined event-related potentials (ERPs) to synthetic consonant-vowel syllables from 26 newborns with familial risk for dyslexia and 23 control infants participating in a longitudinal study of dyslexia. Results indicated that the cortical electric activation evoked by speech elements differed between children with and without risk for…

  15. Exposure to Potentially Traumatic Events in Early Childhood: Differential Links to Emergent Psychopathology

    ERIC Educational Resources Information Center

    Briggs-Gowan, Margaret J.; Carter, Alice S.; Clark, Roseanne; Augustyn, Marilyn; McCarthy, Kimberly J.; Ford, Julian D.

    2010-01-01

    Research NeedsObjective: To examine associations between exposure to potentially traumatic events (PTEs) and clinical patterns of symptoms and disorders in preschool children. Method: Two hundred and thirteen referred and non-referred children, ages 24 to 48 months (MN = 34.9, SD = 6.7 months) were studied. Lifetime exposure to PTEs (family

  16. Visualization of the electrostatic potential distribution in both polar ionospheres using multiple satellite measurements

    SciTech Connect

    Hairston, M.R.; Heelis, R.A.; Rich, F.J.

    1995-01-01

    During the time from December 1991 through March 1992, there were four operational DMSP satellites in polar orbit. All four satellites carried the Special Sensor-Ions, Electrons, Scintillation (SSIES) plasma package which included an ion drift meter. Data from the drift meter, combined with the magnetic field data, allowed the calculation of the electrostatic potential in the ionosphere along the satellite`s path. Simultaneous polar coverage by four satellites was unprecedented, providing researchers with almost continuous monitoring of the potential distribution in both hemispheres for the four month period. Combining the magnitude and location of the potential data from each of the four satellites in order to examine the varying potential distribution pattern in both hemispheres presented a major challenge in data visualization. The problem was solved by developing a three-dimensional presentation of the data where the potentials are color coded and represented by the vertical dimension. This paper presents examples from a computer animation of several days of data demonstrating evolution of the size and shape of the potential distribution, along with how these changes correspond to variations in other geophysical parameters, such as the IMF orientation and the K{sub p} index.

  17. Visualization of the electrostatic potential distribution in both polar ionospheres using multiple satellite measurements

    NASA Technical Reports Server (NTRS)

    Hairston, Marc R.; Heelis, Roderick A.; Rich, Frederick J.

    1995-01-01

    During the time from December 1991 through March 1992, there were four operational DMSP satellites in polar orbit. All four satellites carried the Special Sensor-Ions, Electrons, Scintillation (SSIES) plasma package which included an ion drift meter. Data from the drift meter, combined with the magnetic field data, allowed the calculation of the electrostatic potential in the ionosphere along the satellite's path. Simultaneous polar coverage by four satellites was unprecedented, providing researchers with almost continuous monitoring of the potential distribution in both hemispheres for the four month period. Combining the magnitude and location of the potential data from each of the four satellites in order to examine the varying potential distribution pattern in both hemispheres presented a major challenge in data visualization. The problem was solved by developing a three-dimensional presentation of the data where the potentials are color coded and represented by the vertical dimension. This paper presents examples from a computer animation of several days of data demonstrating evolution of the size and shape of the potential distribution, along with how these changes correspond to variations in other geophysical parameters, such as the IMF orientation and the K(sub p) index.

  18. p16 Expression in Fat Necrosis: A Potential Diagnostic Pitfall in the Evaluation of Differentiated Adipocytic Neoplasms.

    PubMed

    Ng, Wen; Messiou, Christina; Smith, Myles; Thway, Khin

    2015-10-01

    Distinguishing well-differentiated liposarcoma (WDL) from lipoma is of clinical and prognostic importance, but can be difficult on imaging and histology alone. WDL characteristically harbor amplifications of the MDM2 and CDK4 cell cycle oncogenes and overexpress the cell cycle regulator p16. Fluorescence in situ hybridization (FISH) to assess for MDM2 and CDK4 gene amplification is the diagnostic gold standard, and immunohistochemistry for the overexpressed MDM2 and CDK4 proteins is also useful but may not be routinely offered by pathology laboratories. p16 immunohistochemistry is a sensitive marker for WDL and is in the repertoire of most laboratories, and it has been suggested as a useful method of distinguishing WDL from lipomas when other ancillary modalities are not readily available. We describe a case of a large retroperitoneal adipocytic mass occurring in a 27-year-old male, which was clinically and radiologically in keeping with WDL. Histologically this was a differentiated adipocytic neoplasm with prominent fibrous septa and fat necrosis, more suggestive of retroperitoneal lipoma. Immunohistochemistry showed diffuse, strong nuclear expression of p16 in the areas of fat necrosis. However, CDK4 was negative and the lesion lacked evidence of MDM2 amplification with FISH. Diffuse expression of p16 in areas of fat necrosis in large or deep lipomas highlights the potential for diagnostic misinterpretation as well differentiated liposarcoma, and we therefore emphasize that p16 immunohistochemistry should always be interpreted as part of a panel with CDK4 +/- MDM2 in the differential diagnosis of WDL and lipoma. PMID:26173427

  19. Comparative analysis of neural differentiation potential in human mesenchymal stem cells derived from chorion and adult bone marrow.

    PubMed

    Ziadlou, Reihane; Shahhoseini, Maryam; Safari, Fatemeh; Sayahpour, Forugh-Azam; Nemati, Shiva; Eslaminejad, Mohamadreza Baghaban

    2015-11-01

    The finding of a reliable and abundant source of stem cells for the replacement of missing neurons in nervous system diseases requires extensive characterization of neural-differentiation-associated markers in stem cells from various sources. Chorion-derived stem cells from the human placenta have recently been described as an abundant, ethically acceptable, and easily accessible source of cells that are not limited in the same way as bone marrow (BM) mesenchymal stem cells (MSCs). We have isolated and cultured chorion MSCs (C-MSCs) and compared their proliferative capacity, multipotency, and neural differentiation ability with BM-MSCs. C-MSCs showed a higher proliferative capacity compared with BM-MSCs. The expression and histone modification of Nestin, as a marker for neural stem/progenitor cells, was evaluated quantitatively between the two groups. The Nestin expression level in C-MSCs was significantly higher than that in BM-MSCs. Notably, modifications of lys9, lys4, and lys27 of histone H3 agreed with the remarkable higher expression of Nestin in C-MSCs than in BM-MSCs. Furthermore, after neural differentiation of MSCs upon retinoic acid induction, both immunocytochemical and flow cytometry analyses demonstrated that the expression of neural marker genes was significantly higher in neural-induced C-MSCs compared with BM-MSCs. Mature neuron marker genes were also expressed at a significantly higher level in C-MSCs than in BM-MSCs. Thus, C-MSCs have a greater potential than BM-MSCs for differentiation to neural cell lineages and can be regarded as a promising source of stem cells for the cell therapy of neurological disorders. PMID:26022335

  20. Mitochondrial DNA of Anisakis simplex s.s. as a potential tool for differentiating populations.

    PubMed

    Kijewska, Agnieszka; Dzido, Joanna; Rokicki, Jerzy

    2009-12-01

    Anisakis simplex s.s. specimens from Gadus morhua, Gadus ogac, Reinhardtius hippoglossoides, Clupea harengus, Micromesistius poutassou, Pleurogrammus monopterygius, and Oncorhynchus nerka, caught in the north Atlantic and Pacific, were examined. Identity of the parasite species was confirmed using a molecular key. All specimens were used for amplifying a part of the non-coding sequence of the AT-rich region, flanked by the nad6-nad4L-trnW-trnE-rrnS-trnS2, and trnN-trnY-nad1 genes. This part of the mtDNA was chosen as a promising fragment, which could yield information regarding population differentiation. The number of samples and their geographical origin was sufficient to compare the 2 regions. The Bayesian analysis provided strong support for a population split into 2 groups, one representing A. simplex s.s. samples from the Pacific, and the other representing all the Atlantic samples. It is highly probable that observed subpopulations were constituted after the connection between the Atlantic and Pacific had been closed and movement between these 2 oceans was prevented. PMID:19530887

  1. Human Chorionic Stem Cells: Podocyte Differentiation and Potential for the Treatment of Alport Syndrome.

    PubMed

    Moschidou, Dafni; Corcelli, Michelangelo; Hau, Kwan-Leong; Ekwalla, Victoria J; Behmoaras, Jacques V; De Coppi, Paolo; David, Anna L; Bou-Gharios, George; Cook, H Terence; Pusey, Charles D; Fisk, Nicholas M; Guillot, Pascale V

    2016-03-01

    Alport syndrome (AS) is a hereditary glomerulopathy caused by a mutation in type IV collagen genes, which disrupts glomerular basement membrane, leading to progressive glomerulosclerosis and end-stage renal failure. There is at present no cure for AS, and cell-based therapies offer promise to improve renal function. In this study, we found that human first trimester fetal chorionic stem cells (CSC) are able to migrate to glomeruli and differentiate down the podocyte lineage in vitro and in vivo. When transplanted into 7-week-old Alport 129Sv-Col4α3(tm1Dec)/J (-/-) mice, a single intraperitoneal injection of CSC significantly lowered blood urea and urine proteinuria levels over the ensuing 2 weeks. In addition, nearly two-thirds of transplanted -/- mice maintained their weight above the 80% welfare threshold, with both males and females weighing more than age-matched nontransplanted -/- mice. This was associated with less renal cortical fibrosis and interstitial inflammation compared to nontransplanted mice as shown by reduction in murine CD4, CD68, and CD45.2 cells. Transplanted CSC homed to glomeruli, where they expressed CR1, VEGFA, SYNAPTOPODIN, CD2AP, and PODOCIN at the RNA level and produced PODOCIN, CD2AP, and COLIVα3 proteins in nontransplanted -/- mice, indicating that CSC have adopted a podocyte phenotype. Together, these data indicate that CSC may be used to delay progression of renal pathology by a combination of anti-inflammatory effects and replacement of the defective resident podocytes. PMID:26728561

  2. Reduced numbers of switched memory B cells with high terminal differentiation potential in Down syndrome

    PubMed Central

    Carsetti, Rita; Valentini, Diletta; Marcellini, Valentina; Scarsella, Marco; Marasco, Emiliano; Giustini, Ferruccio; Bartuli, Andrea; Villani, Alberto; Ugazio, Alberto G

    2015-01-01

    Children with Down syndrome (DS) have increased susceptibility to infections and a high frequency of leukemia and autoimmune disorders, suggesting that immunodeficiency and immune dysfunction are integral parts of the syndrome. A reduction in B-cell numbers has been reported, associated with moderate immunodeficiency and normal immunoglobulin levels. Here, we compared B-cell populations of 19 children with DS with those in healthy age-matched controls. We found that all steps of peripheral B-cell development are altered in DS, with a more severe defect during the later stages of B-cell development. Transitional and mature-naïve B-cell numbers are reduced by 50% whereas switched memory B cells represent 10–15% of the numbers in age-matched controls. Serum IgM levels were slightly reduced, but all other immunoglobulin isotypes were in the normal range. The frequency of switched memory B cells specific for vaccine antigens was significantly lower in affected children than in their equivalently vaccinated siblings. In vitro switched memory B cells of patients with DS have an increased ability to differentiate into antibody-forming cells in response to TLR9 signals. Tailored vaccination schedules increasing the number of switched memory B cells may improve protection and reduce the risk of death from infection in DS. PMID:25472482

  3. Differential action potentials and firing patterns in injured and uninjured small dorsal root ganglion neurons after nerve injury.

    PubMed

    Zhang, Xu-Feng; Zhu, Chang Z; Thimmapaya, Rama; Choi, Won S; Honore, Prisca; Scott, Victoria E; Kroeger, Paul E; Sullivan, James P; Faltynek, Connie R; Gopalakrishnan, Murali; Shieh, Char-Chang

    2004-05-29

    The profile of tetrodotoxin sensitive (TTX-S) and resistant (TTX-R) Na(+) channels and their contribution to action potentials and firing patterns were studied in isolated small dorsal root ganglion (DRG) neurons after L5/L6 spinal nerve ligation (SNL). Total TTX-R Na(+) currents and Na(v) 1.8 mRNA were reduced in injured L5 DRG neurons 14 days after SNL. In contrast, TTX-R Na(+)currents and Na(v) 1.8 mRNA were upregulated in uninjured L4 DRG neurons after SNL. Voltage-dependent inactivation of TTX-R Na(+) channels in these neurons was shifted to hyperpolarized potentials by 4 mV. Two types of neurons were identified in injured L5 DRG neurons after SNL. Type I neurons (57%) had significantly lower threshold but exhibited normal resting membrane potential (RMP) and action potential amplitude. Type II neurons (43%) had significantly smaller action potential amplitude but retained similar RMP and threshold to those from sham rats. None of the injured neurons could generate repetitive firing. In the presence of TTX, only 26% of injured neurons could generate action potentials that had smaller amplitude, higher threshold, and higher rheobase compared with sham rats. In contrast, action potentials and firing patterns in uninjured L4 DRG neurons after SNL, in the presence or absence of TTX, were not affected. These results suggest that TTX-R Na(+) channels play important roles in regulating action potentials and firing patterns in small DRG neurons and that downregulation in injured neurons and upregulation in uninjured neurons confer differential roles in shaping electrogenesis, and perhaps pain transmission, in these neurons. PMID:15120592

  4. SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway

    PubMed Central

    Wu, Ching-Shyi; Ouyang, Jian; Mori, Eiichiro; Nguyen, Hai Dang; Maréchal, Alexandre; Hallet, Alexander; Chen, David J.; Zou, Lee

    2014-01-01

    The ATR (ATM [ataxia telangiectasia-mutated]- and Rad3-related) checkpoint is a crucial DNA damage signaling pathway. While the ATR pathway is known to transmit DNA damage signals through the ATR–Chk1 kinase cascade, whether post-translational modifications other than phosphorylation are important for this pathway remains largely unknown. Here, we show that protein SUMOylation plays a key role in the ATR pathway. ATRIP, the regulatory partner of ATR, is modified by SUMO2/3 at K234 and K289. An ATRIP mutant lacking the SUMOylation sites fails to localize to DNA damage and support ATR activation efficiently. Surprisingly, the ATRIP SUMOylation mutant is compromised in the interaction with a protein group, rather than a single protein, in the ATR pathway. Multiple ATRIP-interacting proteins, including ATR, RPA70, TopBP1, and the MRE11–RAD50–NBS1 complex, exhibit reduced binding to the ATRIP SUMOylation mutant in cells and display affinity for SUMO2 chains in vitro, suggesting that they bind not only ATRIP but also SUMO. Fusion of a SUMO2 chain to the ATRIP SUMOylation mutant enhances its interaction with the protein group and partially suppresses its localization and functional defects, revealing that ATRIP SUMOylation promotes ATR activation by providing a unique type of protein glue that boosts multiple protein interactions along the ATR pathway. PMID:24990965

  5. The effect of low static magnetic field on osteogenic and adipogenic differentiation potential of human adipose stromal/stem cells

    NASA Astrophysics Data System (ADS)

    Marędziak, Monika; Śmieszek, Agnieszka; Tomaszewski, Krzysztof A.; Lewandowski, Daniel; Marycz, Krzysztof

    2016-01-01

    The aim of this work was to investigate the effects of static magnetic field (SMF) on the osteogenic properties of human adipose derived mesenchymal stem cells (hASCs). In this study in seven days viability assay we examined the impact of SMF on cells proliferation rate, population doubling time, and ability to form single-cell derived colonies. We have also examined cells' morphology, ultrastructure and osteogenic properties on the protein as well as mRNA level. We established a complex approach, which enabled us to obtain information about SMF and hASCs potential in the context of differentiation into osteogenic and adipogenic lineages. We demonstrated that SMF enhances both viability and osteogenic properties of hASCs through higher proliferation factor and shorter population doubling time. We have also observed asymmetrically positioned nuclei and organelles after SMF exposition. With regards to osteogenic properties we observed increased levels of osteogenic markers i.e. osteopontin, osteocalcin and increased ability to form osteonodules with positive reaction to Alizarin Red dye. We have also shown that SMF besides enhancing osteogenic properties of hASCs, simultaneously decreases their ability to differentiate into adipogenic lineage. Our results clearly show a direct influence of SMF on the osteogenic potential of hASCs. These results provide key insights into the role of SMF on their cellular fate and properties.

  6. Hydrogen gas treatment prolongs replicative lifespan of bone marrow multipotential stromal cells in vitro while preserving differentiation and paracrine potentials

    SciTech Connect

    Kawasaki, Haruhisa; Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210 ; Guan, Jianjun; Tamama, Kenichi; Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210; Center for Stem Cell and Regenerative Medicine, The Ohio State University, Columbus, OH 43210

    2010-07-02

    Cell therapy with bone marrow multipotential stromal cells/mesenchymal stem cells (MSCs) represents a promising approach in the field of regenerative medicine. Low frequency of MSCs in adult bone marrow necessitates ex vivo expansion of MSCs after harvest; however, such a manipulation causes cellular senescence with loss of differentiation, proliferative, and therapeutic potentials of MSCs. Hydrogen molecules have been shown to exert organ protective effects through selective reduction of hydroxyl radicals. As oxidative stress is one of the key insults promoting cell senescence in vivo as well as in vitro, we hypothesized that hydrogen molecules prevent senescent process during MSC expansion. Addition of 3% hydrogen gas enhanced preservation of colony forming early progenitor cells within MSC preparation and prolonged the in vitro replicative lifespan of MSCs without losing differentiation potentials and paracrine capabilities. Interestingly, 3% hydrogen gas treatment did not decrease hydroxyl radical, protein carbonyl, and 8-hydroxydeoxyguanosine, suggesting that scavenging hydroxyl radical might not be responsible for these effects of hydrogen gas in this study.

  7. The N3 potential compared to sound and galvanic vestibular evoked myogenic potential in healthy subjects and in multiple sclerosis patients.

    PubMed

    Versino, Maurizio; Ranza, Laura; Colnaghi, Silvia; Alloni, Roberto; Callieco, Roberto; Romani, Alfredo; Bergamaschi, Roberto; Pichiecchio, Anna; Bastianello, Stefano; Cosi, Vittorio

    2007-01-01

    Both sound (s-) and galvanic (g-) vestibular-evoked myogenic potential (VEMP) enable us to study the saccular pathways. However, the VEMP can be abnormal for non-vestibular factors, such as insufficient activation of the sterno-cleido-mastoid (SCM) muscle or a lesion that involves the accessory nucleus and/or nerve or the SCM muscle. These drawbacks do not affect another technique that evaluates the saccular function: the N3 potential. We recorded both the s- and the g-VEMP and the N3 potential in a group of 31 healthy subjects to establish a reference range. The N3 potential and the s-VEMP were recordable bilaterally from all the subjects, whereas the g-VEMP was undetectable uni- or bilaterally in 7 subjects. The latency and amplitude values of the s-VEMP did not differ from those of the g-VEMP. For all three techniques, the latency and amplitude values from the right and from the left recording and/or stimulation side were the same. We suggest using normative latency and amplitude values based on the mean and ratio of the right- and left-side values. The s-VEMP, the N3 potential and the auditory evoked response (ABR) were compared in 15 subjects suffering from multiple sclerosis. The three techniques detected a similar number of abnormalities, but these abnormalities were not correlated. This suggests that these different techniques should be regarded as complementary in evaluating saccular function. PMID:18219103

  8. The checkpoint kinase inhibitor AZD7762 potentiates chemotherapy-induced apoptosis of p53-mutated multiple myeloma cells.

    PubMed

    Landau, Heather J; McNeely, Samuel C; Nair, Jayasree S; Comenzo, Raymond L; Asai, Takashi; Friedman, Hillel; Jhanwar, Suresh C; Nimer, Stephen D; Schwartz, Gary K

    2012-08-01

    DNA cross-linking agents are frequently used in the treatment of multiple myeloma-generating lesions, which activate checkpoint kinase 1 (Chk1), a critical transducer of the DNA damage response. Chk1 activation promotes cell survival by regulating cell-cycle arrest and DNA repair following genotoxic stress. The ability of AZD7762, an ATP-competitive Chk1/2 inhibitor to increase the efficacy of the DNA-damaging agents bendamustine, melphalan, and doxorubicin was examined using four human myeloma cell lines, KMS-12-BM, KMS-12-PE, RPMI-8226, and U266B1. The in vitro activity of AZD7762 as monotherapy and combined with alkylating agents and the "novel" drug bortezomib was evaluated by studying its effects on cytotoxicity, signaling, and apoptotic pathways. The Chk1/2 inhibitor AZD7762 potentiated the antiproliferative effects of bendamustine, melphalan, and doxorubicin but not bortezomib in multiple myeloma cell lines that were p53-deficient. Increased ?H2AX staining in cells treated with bendamustine or melphalan plus AZD7762 indicates a greater degree of DNA damage with combined therapy. Abrogation of the G(2)-M checkpoint by AZD7762 resulted in mitotic catastrophe with ensuing apoptosis evidenced by PARP and caspase-3 cleavage. In summary, the cytotoxic effects of bendamustine, melphalan and doxorubicin on p53-deficient multiple myeloma cell lines were enhanced by the coadministration of AZD7762. These data provide a rationale for testing these combinations in patients with relapsed and/or refractory multiple myeloma. PMID:22653969

  9. Detection of multiple potentially pathogenic bacteria in Matang mangrove estuaries, Malaysia.

    PubMed

    Ghaderpour, Aziz; Mohd Nasori, Khairul Nazrin; Chew, Li Lee; Chong, Ving Ching; Thong, Kwai Lin; Chai, Lay Ching

    2014-06-15

    The deltaic estuarine system of the Matang Mangrove Forest Reserve of Malaysia is a site where several human settlements and brackish water aquaculture have been established. Here, we evaluated the level of fecal indicator bacteria (FIB) and the presence of potentially pathogenic bacteria in the surface water and sediments. Higher levels of FIB were detected at downstream sampling sites from the fishing village, indicating it as a possible source of anthropogenic pollution to the estuary. Enterococci levels in the estuarine sediments were higher than in the surface water, while total coliforms and E. coli in the estuarine sediments were not detected in all samples. Also, various types of potentially pathogenic bacteria, including Klebsiella pneumoniae, Serratia marcescens and Enterobacter cloacae were isolated. The results indicate that the Matang estuarine system is contaminated with various types of potential human bacterial pathogens which might pose a health risk to the public. PMID:24820641

  10. Exploring the multiple biotechnological potential of halophilic microorganisms isolated from two Argentinean salterns.

    PubMed

    Nercessian, Débora; Di Meglio, Leonardo; De Castro, Rosana; Paggi, Roberto

    2015-11-01

    The biodiversity and biotechnological potential of microbes from central Argentinean halophilic environments have been poorly explored. Salitral Negro and Colorada Grande salterns are neutral hypersaline basins exploded for NaCl extraction. As part of an ecological analysis of these environments, two bacterial and seven archaeal representatives were isolated, identified and examined for their biotechnological potential. The presence of hydrolases (proteases, amylases, lipases, cellulases and nucleases) and bioactive molecules (surfactants and antimicrobial compounds) was screened. While all the isolates exhibited at least one of the tested activities or biocompounds, the species belonging to Haloarcula genus were the most active, also producing antimicrobial compounds against their counterparts. In general, the biosurfactants were more effective against olive oil and aromatic compounds than detergents (SDS or Triton X-100). Our results demonstrate the broad spectrum of activities with biotechnological potential exhibited by the microorganisms inhabiting the Argentinean salterns and reinforce the importance of screening pristine extreme environments to discover interesting/novel bioactive molecules. PMID:26369649

  11. Review of teriflunomide and its potential in the treatment of multiple sclerosis

    PubMed Central

    Warnke, Clemens; Meyer zu Hrste, Gerd; Hartung, Hans-Peter; Stve, Olaf; Kieseier, Bernd C

    2009-01-01

    In the light of new cases of progressive multifocal leukoencephalopathy and induced autoimmunity in multiple sclerosis (MS) patients who received treatment with upcoming disease-modifying immunosuppressant drugs with a highly specific mode of action such as natalizumab, rituximab, or alemtuzumab, alternative oral treatment options for a subgroup of less severely affected MS patients are a major focus of drug development. These agents are currently investigated in phase III clinical trials and some of them are characterized by a favorable safety profile. With an emphasis on teriflunomide, the active metabolite of an immunosuppressant approved for the treatment of rheumatoid arthritis since 1998, a number of oral treatment options for patients with MS are discussed. PMID:19557143

  12. Potential nosocomial acquisition of epidemic Listeria monocytogenes presenting as multiple brain abscesses resembling nocardiosis

    PubMed Central

    Stefanovic, Aleksandra; Reid, James; Nadon, A Celine; Grant, Jennifer

    2010-01-01

    Listerial brain abscesses are rare, and are found mostly in patients with underlying hematological malignancies or solid-organ transplants. A case of a patient with Crohns disease and multiple brain abscesses involving the left cerebellum and right sylvian fissure is described. The Gram stain and histopathology of the cerebellar abscess revealed Gram-positive, beaded rods suggestive of Nocardia. However, on culture, Listeria monocytogenes was identified. Listeria may appear Gram-variable and has been misidentified as streptococci, enterococci and diphtheroids. The present case is the first reported case of L monocytogenes resembling Nocardia on both microbiological and histopathological assessment. Reported cases of listerial brain abscesses are sporadic, while the current case was part of a nationwide listerial outbreak linked to consumption of contaminated deli meats. Broad antimicrobial therapy (including antilisterial coverage) in immunosuppressed patients presenting with brain abscess is crucial, until cultures confirm the identification of the organism. PMID:21358887

  13. Potential impact of B cells on T cell function in multiple sclerosis.

    PubMed

    Ireland, Sara; Monson, Nancy

    2011-01-01

    Multiple sclerosis is a chronic debilitating autoimmune disease of the central nervous system. The contribution of B cells in the pathoetiology of MS has recently been highlighted by the emergence of rituximab, an anti-CD20 monoclonal antibody that specifically depletes B cells, as a potent immunomodulatory therapy for the treatment of MS. However, a clearer understanding of the impact B cells have on the neuro-inflammatory component of MS pathogenesis is needed in order to develop novel therapeutics whose affects on B cells would be beneficial and not harmful. Since T cells are known mediators of the pathology of MS, the goal of this review is to summarize what is known about the interactions between B cells and T cells, and how current and emerging immunotherapies may impact B-T cell interactions in MS. PMID:22096636

  14. The potential role of B cell-targeted therapies in multiple sclerosis.

    PubMed

    Boster, Aaron; Ankeny, Daniel P; Racke, Michael K

    2010-12-24

    Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Until recently, most therapeutic interventions have targeted T cells in the treatment of MS. Recent data show that B cells also have a role in the pathogenesis of MS. The cerebrospinal fluid and CNS of MS patients contain B cells, plasma cells and immunoglobulins, and recent data indicate that B cells are involved in antigen presentation and T-cell activation, cytokine production, antibody secretion, demyelination and remyelination in MS. These advances in the understanding of B cells and their role in the pathophysiology of MS provide a strong rationale for B cell-targeted therapies. Recent clinical trials with rituximab highlight the possibility that B cells should be an important therapeutic target in patients with MS. PMID:21142258

  15. Endoplasmic reticulum stress response as a potential therapeutic target in multiple sclerosis

    PubMed Central

    Getts, Meghann Teague; Getts, Daniel R.; Kohm, Adam P.; Miller, Stephen D

    2010-01-01

    Summary Multiple Sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system (CNS). Since current treatments are aimed at nonspecifically down-regulating inflammation and natural mechanisms of repair and remyelination within the CNS are inadequate for recovery of function, MS patients presently only have available treatments that delay symptom progression. The complex nature of this disease means that only multifaceted treatments hold the promise of a cure. Recent studies indicate that the ER stress response, a cellular pathway that allows a cell to survive and recover from a stressful event, could be elicited to help the myelin-generating and myelin-support cells of the CNS survive inflammatory insult. PMID:20357912

  16. Existence and multiplicity of solutions for Kirchhoff-type equation with radial potentials in {R3}

    NASA Astrophysics Data System (ADS)

    Li, Anran; Su, Jiabao

    2015-12-01

    In this paper, we deal with the Kirchhoff-type equation -[1+intlimits_{{{R}}^3} (|nabla u|^2+V(x)u^2)dx ][Δ u+V(x)u] = λ Q(x) f(u), quad xin {{R}}^3, quad quad quad {(P)_λ} u(x)→ 0, quad as |x|→ ∞ , where {λ > 0}, V and Q are radial functions, which can be vanishing or coercive at infinity. With assumptions on f just in a neighborhood of the origin, existence and multiplicity of nontrivial radial solutions are obtained via variational methods. In particular, if f is sublinear and odd near the origin, we obtain infinitely many solutions of {(P)_λ} for any {λ > 0}.

  17. Acrolein detection: potential theranostic utility in multiple sclerosis and spinal cord injury

    PubMed Central

    Tully, Melissa; Zheng, Lingxing; Shi, Riyi

    2015-01-01

    Oxidative stress has been implicated as a major pathological process underlying CNS disease and trauma. More specifically, acrolein, an unsaturated aldehyde, produced by way of lipid peroxidation, has been shown to play a crucial role in initiating and perpetuating detrimental effects associated with multiple sclerosis and spinal cord injury. In light of these findings, quantification of acrolein levels both systemically and locally could allow for the use of acrolein as a biomarker to aid in diagnosis and guide treatment regimens. The three main approaches currently available are acrolein derivatization followed byLC/GCMS, application of an acrolein antibody and subsequent immunoblotting, and the 3-hydroxypropylmercapturic acid-based method. Of these three strategies, the 3-hydroxypropylmercapturic acid-based method is the least invasive allowing for rapid translation of acrolein detection into a clinical setting. PMID:24831349

  18. DNA repair pathways in human multiple myeloma: role in oncogenesis and potential targets for treatment.

    PubMed

    Gourzones-Dmitriev, Claire; Kassambara, Alboukadel; Sahota, Surinder; Rme, Thierry; Moreaux, Jrme; Bourquard, Pascal; Hose, Dirk; Pasero, Philippe; Constantinou, Angelos; Klein, Bernard

    2013-09-01

    Every day, cells are faced with thousands of DNA lesions, which have to be repaired to preserve cell survival and function. DNA repair is more or less accurate and could result in genomic instability and cancer. We review here the current knowledge of the links between molecular features, treatment, and DNA repair in multiple myeloma (MM), a disease characterized by the accumulation of malignant plasma cells producing a monoclonal immunoglobulin. Genetic instability and abnormalities are two hallmarks of MM cells and aberrant DNA repair pathways are involved in disease onset, primary translocations in MM cells, and MM progression. Two major drugs currently used to treat MM, the alkylating agent Melphalan and the proteasome inhibitor Bortezomib act directly on DNA repair pathways, which are involved in response to treatment and resistance. A better knowledge of DNA repair pathways in MM could help to target them, thus improving disease treatment. PMID:23966156

  19. Pharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic

    PubMed Central

    Way, Sharon W.; Podojil, Joseph R.; Clayton, Benjamin L.; Zaremba, Anita; Collins, Tassie L.; Kunjamma, Rejani B.; Robinson, Andrew P.; Brugarolas, Pedro; Miller, Robert H.; Miller, Stephen D.; Popko, Brian

    2015-01-01

    Oligodendrocyte death contributes to the pathogenesis of the inflammatory demyelinating disease multiple sclerosis (MS). Nevertheless, current MS therapies are mainly immunomodulatory and have demonstrated limited ability to inhibit MS progression. Protection of oligodendrocytes is therefore a desirable strategy for alleviating disease. Here we demonstrate that enhancement of the integrated stress response using the FDA-approved drug guanabenz increases oligodendrocyte survival in culture and prevents hypomyelination in cerebellar explants in the presence of interferon-?, a pro-inflammatory cytokine implicated in MS pathogenesis. In vivo, guanabenz treatment protects against oligodendrocyte loss caused by CNS-specific expression of interferon-?. In a mouse model of MS, experimental autoimmune encephalomyelitis, guanabenz alleviates clinical symptoms, which correlates with increased oligodendrocyte survival and diminished CNS CD4+ T cell accumulation. Moreover, guanabenz ameliorates relapse in relapsing-remitting experimental autoimmune encephalomyelitis. Our results provide support for a MS therapy that enhances the integrated stress response to protect oligodendrocytes against the inflammatory CNS environment. PMID:25766071

  20. The potential diagnostic power of extracellular vesicle analysis for multiple myeloma.

    PubMed

    Canella, Alessandro; Harshman, Sean W; Radomska, Hanna S; Freitas, Michael A; Pichiorri, Flavia

    2016-03-01

    Multiple myeloma (MM) is a hematologic malignancy of plasma cells (PCs). In the United States, MM accounts for approximately 1% of all diagnoses and 2% of all cancer-related deaths. Although MM is a treatable disease, most patients eventually relapse, and despite the development of numerous treatment options it is still considered incurable. Mechanisms of communication between MM-PCs and bone marrow microenvironment, including cell-cell contacts and release of pro-survival factors, promote cancer cell survival and drug resistance. Recently, the importance of extracellular vesicles (EVs) as mechanisms of communication between MM cells and other cells in the microenvironment has been reported. In this review, the authors provide the update on the biology and clinical aspects of EVs in MM. PMID:26671731

  1. Proteomic Profiling in Multiple Sclerosis Clinical Courses Reveals Potential Biomarkers of Neurodegeneration

    PubMed Central

    Liguori, Maria; Qualtieri, Antonio; Tortorella, Carla; Direnzo, Vita; Bagal, Angelo; Mastrapasqua, Mariangela; Spadafora, Patrizia; Trojano, Maria

    2014-01-01

    The aim of our project was to perform an exploratory analysis of the cerebrospinal fluid (CSF) proteomic profiles of Multiple Sclerosis (MS) patients, collected in different phases of their clinical course, in order to investigate the existence of peculiar profiles characterizing the different MS phenotypes. The study was carried out on 24 Clinically Isolated Syndrome (CIS), 16 Relapsing Remitting (RR) MS, 11 Progressive (Pr) MS patients. The CSF samples were analysed using the Matrix Assisted Laser Desorption Ionisation Time Of Flight (MALDI-TOF) mass spectrometer in linear mode geometry and in delayed extraction mode (m/z range: 100025000 Da). Peak lists were imported for normalization and statistical analysis. CSF data were correlated with demographic, clinical and MRI parameters. The evaluation of MALDI-TOF spectra revealed 348 peak signals with relative intensity ?1% in the study range. The peak intensity of the signals corresponding to Secretogranin II and Protein 7B2 were significantly upregulated in RRMS patients compared to PrMS (p<0.05), whereas the signals of Fibrinogen and Fibrinopeptide A were significantly downregulated in CIS compared to PrMS patients (p<0.04). Additionally, the intensity of the Tymosin ?4 peak was the only signal to be significantly discriminated between the CIS and RRMS patients (p?=?0.013). Although with caution due to the relatively small size of the study populations, and considering that not all the findings remained significant after adjustment for multiple comparisons, in our opinion this mass spectrometry evaluation confirms that this technique may provide useful and important information to improve our understanding of the complex pathogenesis of MS. PMID:25098164

  2. Multiple Continua Simulations of Thermal-Hydrological-Chemical Processes in the Potential Repository at Yucca Mountain, Nevada

    NASA Astrophysics Data System (ADS)

    Painter, S.; Pabalan, R. T.; Sun, A. Y.

    2005-12-01

    Numerical simulation of nonisothermal, multiphase flow and associated reactive transport in fractured rock is an important tool for evaluating the performance of a potential repository for high-level nuclear waste at Yucca Mountain, Nevada. A dual continuum representation has emerged as the standard approach for modeling processes in the unsaturated zone near emplacement tunnels. In the dual continuum representation, the fracture network is modeled as an equivalent continuum that interacts with a second continuum representing the matrix system. The principal limitation of the dual continuum approach is that it neglects gradients in pressure, temperature, saturation, and concentration within the matrix blocks. The dual continuum model is understood to be an accurate approximation for steady-state or weakly transient situations, but the accuracy of the representation is unclear for strongly heated transient situations. Thermal-hydrological-chemical simulations using the dual continuum model have been compared with simulations using the more general multiple interacting continua (MINC) model (Pruess and Narasimhan, 1985). In the MINC model, multiple interacting continua are used to represent the matrix system. Both the MINC and dual continuum simulations use the computer code MULTIFLO Version 2.0.1 (Lichtner and Seth, 1996; Painter and Seth, 2003), and consider multiple aqueous species and multiple minerals. The MINC simulations result in lower matrix pressures and drier fractures near the potential emplacement tunnels. Precipitation of amorphous silica in fractures is reduced in the MINC model. This abstract was prepared to document work performed by the Center for Nuclear Waste Regulatory Analyses (CNWRA) and its contractors for the Nuclear Regulatory Commission (NRC) under Contract No. NRC-02-02-012. The activities reported here were performed on behalf of the NRC Office of Nuclear Material Safety and Safeguards, Division of High-Level Waste Repository Safety. This abstract is an independent product of the CNWRA and does not necessarily reflect the view or regulatory position of NRC.

  3. Equine mesenchymal stem cells from bone marrow, adipose tissue and umbilical cord: immunophenotypic characterization and differentiation potential

    PubMed Central

    2014-01-01

    Introduction Studies with mesenchymal stem cells (MSCs) are increasing due to their immunomodulatory, anti-inflammatory and tissue regenerative properties. However, there is still no agreement about the best source of equine MSCs for a bank for allogeneic therapy. The aim of this study was to evaluate the cell culture and immunophenotypic characteristics and differentiation potential of equine MSCs from bone marrow (BM-MSCs), adipose tissue (AT-MSCs) and umbilical cord (UC-MSCs) under identical in vitro conditions, to compare these sources for research or an allogeneic therapy cell bank. Methods The BM-MSCs, AT-MSCs and UC-MSCs were cultured and evaluated in vitro for their osteogenic, adipogenic and chondrogenic differentiation potential. Additionally, MSCs were assessed for CD105, CD44, CD34, CD90 and MHC-II markers by flow cytometry, and MHC-II was also assessed by immunocytochemistry. To interpret the flow cytometry results, statistical analysis was performed using ANOVA. Results The harvesting and culturing procedures of BM-MSCs, AT-MSCs and UC-MSCs were feasible, with an average cell growth until the third passage of 25days for BM-MSCs, 15days for AT-MSCs and 26days for UC-MSCs. MSCs from all sources were able to differentiate into osteogenic (after 10days for BM-MSCs and AT-MSCs and 15days for UC-MSCs), adipogenic (after 8days for BM-MSCs and AT-MSCs and 15days for UC-MSCs) and chondrogenic (after 21days for BM-MSCs, AT-MSCs and UC-MSCs) lineages. MSCs showed high expression of CD105, CD44 and CD90 and low or negative expression of CD34 and MHC-II. The MHC-II was not detected by immunocytochemistry techniques in any of the MSCs studied. Conclusions The BM, AT and UC are feasible sources for harvesting equine MSCs, and their immunophenotypic and multipotency characteristics attained minimal criteria for defining MSCs. Due to the low expression of MHC-II by MSCs, all of the sources could be used in clinical trials involving allogeneic therapy in horses. However, the BM-MSCs and AT-MSCs showed fastest in vitro differentiation and AT-MSCs showed highest cell growth until third passage. These findings suggest that BM and AT may be preferable for cell banking purposes. PMID:24559797

  4. Quantifying the dispersal potential of seagrass vegetative fragments: A comparison of multiple subtropical species

    NASA Astrophysics Data System (ADS)

    Weatherall, E. J.; Jackson, E. L.; Hendry, R. A.; Campbell, M. L.

    2016-02-01

    Seagrass meadows are threatened by anthropogenic and natural disturbances on both a local and global scale. Understanding the potential for seagrasses to disperse, connecting populations separated by unsuitable habitat is important to assess the resilience of regional populations. This study investigated the relative dispersal potential of vegetative fragments of seagrass from five subtropical species (Zostera muelleri, Halodule uninervis, Halophila ovalis, Halophila spinulosa, Halophila decipiens). Five questions were examined: 1) do vegetative fragments of different species settle at different velocities; 2) does a species morphometric variables influence settling velocities; 3) is a species settling velocity related to the species local distribution; 4) does temperature stress affect settling velocity; and 5) what is the composition and potential viability of seagrass fragments floating in the bay. A proportional distribution index for each species was determined using data from a habitat prediction model. It was found that H. spinulosa settled significantly faster than the remaining species and Z. muelleri settled the slowest. Variables influencing settling velocity included rhizome length, weight and surface area. In both Z. muelleri and H. ovalis settling velocities were significantly greater at higher temperatures (although there was no significant difference between approximately 5 and 10 °C above ambient temperature). H. uninervis was not significantly influenced by temperature. There was a significant negative correlation between species settling velocities and their distribution.

  5. Multiple benign symmetric lipomatosis--a differential diagnosis of obesity. Is there a rationale for fibrate treatment?

    PubMed

    Zeitler, Heike; Ulrich-Merzenich, Gudrun; Richter, Dirk Frank; Vetter, Hans; Walger, Peter

    2008-10-01

    Multiple benign symmetric lipomatosis (MSL) is characterized by a rapid progression of multiple, symmetric nonencapsulated fat masses in the face, neck, and extremities. The lipomas are thought to be the result of defective brown adipose tissue (BAT). In up to 90% MSL is associated with chronic alcohol abuse. Prognosis depends on the concomitant presence of a neuropathy with a mortality of 25.8%. Therapeutic options are limited to alcohol abstinence and surgical interventions. We report here about a 53-year-old MSL patient who increased his body weight by 37 kg over 10 years. Multiple lipectomies were performed, but disease progressed. We treated him with fenofibrates (200 mg/day). Disease progression discontinued and circumferences of abdominal adipose tissue reduced. Fibrates, peroxisome proliferator-activated receptor alpha (PPAR alpha) agonists, are pleiotropic hypolipidemic drugs, and might have worked by suppression of protein expressions involved in the architecture of BAT keeping it in a quiescent state. PMID:18528737

  6. Multiple benign symmetric lipomatosis--a differential diagnosis of obesity: is there a rationale for fibrate treatment?

    PubMed

    Heike, Zeitler; Gudrun, Ulrich-Merzenich; Frank, Richter Dirk; Vetter, Hans; Walger, Peter

    2008-02-01

    Multiple benign symmetric lipomatosis (MSL) is characterized by a rapid progression of multiple, symmetric nonencapsulated fat masses in face, neck, and extremities. The lipomas are thought to be the result of defective brown adipose tissue (BAT). In up to 90%, MSL is associated with chronic alcohol abuse. Prognosis depends on the concomitant presence of a neuropathy with a mortality of 25.8%. Therapeutic options are limited to alcohol abstinence and surgical interventions. We report here about a 53-year-old MSL patient who increased his body weight by 37 kg over 10 years. Multiple lipectomies were performed but disease progressed. We treated him with fenofibrates (200 mg/day). Disease progression discontinued, and circumferences of abdominal adipose tissue reduced. Fibrates, peroxisome proliferator-activated receptor alpha agonists, are pleiotropic hypolipidemic drugs and might have worked by suppression of protein expressions involved in the architecture of BAT keeping it in a quiescent state. PMID:18175197

  7. Lipidome analysis in multiple sclerosis reveals protein lipoxidative damage as a potential pathogenic mechanism.

    PubMed

    Gonzalo, Hugo; Brieva, Luis; Tatzber, Franz; Jov, Mariona; Cacabelos, Daniel; Cassany, Anna; Lanau-Angulo, Lucia; Boada, Jordi; Serrano, Jos C E; Gonzlez, Cristina; Hernndez, Lourdes; Peralta, Slvia; Pamplona, Reinald; Portero-Otin, Manuel

    2012-11-01

    Metabolomic and lipidomic analyses have been used for the profiling of neurodegenerative processes, both in targeted and untargeted approaches. In this work we have applied these techniques to the study of CSF samples of multiple sclerosis (MS) patients (n = 9), compared with samples of non-MS individuals (n = 9) using mass-spectrometry. We have used western-blot and analyzed cell culture to confirm pathogenic pathways suggested by mass-spectrometric measurements. The results of the untargeted approach of metabolomics and lipidomics suggest the existence of several metabolites and lipids discriminating both populations. Applying targeted lipidomic analyses focused to a pathogenic pathway in MS, oxidative stress, reveal that the lipid peroxidation marker 8-iso-prostaglandin F2? is increased in CSF from MS patients. Furthermore, as lipid peroxidation exerts its pathogenical effects through protein modification, we studied the incidence of protein lipoxidation, revealing specific increases in carboxymethylated, neuroketal and malondialdehyde-mediated protein modifications in proteins of CSF from MS patients, despite the absence of their precursors glyoxal and methylglyoxal. Finally, we report that the level of neuroketal-modified proteins correlated with a hitherto unknown increased amount of autoantibodies against lipid peroxidation-modified proteins in CSF, without compensation by signaling induced by lipid peroxidation via peroxisome proliferator-activated receptor ? (PPAR?). The results, despite the limitation of being obtained in a small population, strongly suggest that autoimmunity against in situ produced epitopes derived from lipid peroxidation can be a relevant pathogenic factor in MS. PMID:22924648

  8. Potential role of stress and sensitization in the development and expression of multiple chemical sensitivity.

    PubMed Central

    Sorg, B A; Prasad, B M

    1997-01-01

    Chemical sensitivity in humans may be an acquired disorder in which individuals become increasingly sensitive to chemicals in the environment. It is hypothesized that in individuals with multiple chemical sensitivity (MCS), a sensitization process has occurred that is akin to behavioral sensitization and kindling observed in rodents. In the rodent sensitization model, repeated exposure to stress or drugs of abuse enhances behavioral and neurochemical responses to subsequent stimuli (stress or drugs of abuse). Kindling is a form of sensitization in which repeated application of electrical stimuli applied to the brain at low levels culminates in the induction of full-blown seizures when the same stimulus is applied at a later time. A similar sensitization of specific limbic pathways in the brain may occur in individuals with MCS. The time-dependent nature of sensitization and kindling and the role of stress in the development of sensitization are discussed in the context of rodent models, with an emphasis on application of these models to human studies of MCS. PMID:9167981

  9. Genetic polymorphisms related to vitamin D and the therapeutic potential of vitamin D in multiple sclerosis.

    PubMed

    Niino, Masaaki; Miyazaki, Yusei

    2015-05-01

    Vitamin D receptors (VDRs), which are responsible for most vitamin D functions, are expressed on various immune cells. Vitamin D is considered to be a potent immunomodulator. A variety of cells in the central nervous system (CNS) also express VDRs; thus, vitamin D may play a role in the regulation of neurodegeneration and repair processes within the CNS. Considered together with epidemiological studies, low vitamin D status is reckoned to be one of the risk factors for multiple sclerosis (MS). Further, vitamin D is considered to be a possible treatment for MS. However, previous clinical trials with small cohorts have not demonstrated significant effects of vitamin D in MS. Current ongoing clinical trials with large cohorts could provide answers with respect to the clinical effects of vitamin D in MS. However, genetic studies have suggested that genes associated with vitamin D, including VDRs, are susceptible genes for MS. Vitamin D needs to be considered from the perspective of the interaction between vitamin-D-related genetic factors and environmental factors affecting vitamin D levels. PMID:25798693

  10. Is T-bet a potential therapeutic target in multiple sclerosis?

    PubMed

    Racke, Michael K; Yang, Yuhong; Lovett-Racke, Amy E

    2014-08-01

    Treatments for multiple sclerosis (MS) have changed over the past years as our understanding of immunology and neuroscience has evolved. Experimental autoimmune encephalomyelitis (EAE) continues to remain the major model for MS and has been a major vehicle in the development of new therapeutic targets for MS, including new agents such as natalizumab, fingolimod, and dimethyl fumarate. As progress in the molecular understanding of immunology continues, many observations in EAE are pursued with the ultimate goal of defining the pathophysiology of MS and development of innovative treatments for the disease. Although many consider MS to be a T cell-mediated autoimmune disease directed against myelin antigens, the exact cause of the disease is still unknown. For many years, it was thought that myelin-specific T cells that secreted interferon-γ and were proinflammatory were the major T cell subset that mediated the disease, but recent studies on the cytokine phenotype of pathogenic T cells in EAE and MS have opened debate on this issue. Work over the past several years suggests that the transcription factor T-bet appears to be an important factor in T cell encephalitogenicity; however, recent data suggest that it is also dispensable in certain situations, particularly for Th17 cells. Understanding the molecular mechanisms responsible for T cell encephalitogenicity in MS and other autoimmune diseases will be essential in the development of specific therapies for these inflammatory diseases. PMID:25084179

  11. Potential role of FLT3-ligand in the angiogenic process of multiple myeloma.

    PubMed

    Kokonozaki, M; Tsirakis, G; Devetzoglou, M; Kyriakaki, S; Antonakis, A; Vyzoukaki, R; Pappa, C A; Tzardi, M; Alexandrakis, M G

    2015-12-01

    The aim of the study was to evaluate serum levels of FLT3-ligand (FLT3-L), a soluble molecule in bone marrow (BM), participating actively in hematopoiesis, in relation with angiogenic factors in multiple myeloma (MM) patients. We measured, in 70 patients with active MM and in 38 of them who responded to conventional therapy, serum levels of FLT3-L, along with known angiogenic factors, such as VEGF, endoglin, TNF-alpha and HGF (with ELISA) and BM microvascular density (MVD), estimating the immunohistochemical expression of CD31. All pre-treatment values were higher in active MM patients compared to controls (p<0.001 for all cases), in parallel with both International Staging System and Durie-Salmon stages (p<0.001 for all cases). Moreover, levels of FLT3-L correlated positively with all soluble angiogenic factors, as well with MVD (p<0.0001 for all cases). Post-treatment values of FLT3-L decreased significantly in responders to therapy (p<0.001). The underlying relation of MM angiogenesis with FLT3-L may result from the fact that BM microvasculature is a major source of FLT3-L, both in BM niche and probably in peripheral blood. Our results suggest that serum levels of FLT3-L may be used as angiogenic marker in MM patients. PMID:26521986

  12. The potential role of iNKT cells in experimental allergic encephalitis and multiple sclerosis.

    PubMed

    Roozbeh, Maryam; Mohammadpour, Hemn; Azizi, Gholamreza; Ghobadzadeh, Samira; Mirshafiey, Abbas

    2014-04-01

    Multiple sclerosis (MS) is an autoimmune disorder associated with neurological signs and chronic inflammatory demyelination of the central nervous system (CNS). MS has been thought as Th1 (T helper) and Th17 cells mediated disease, but cells of the innate immune system play an important role both in the initiation and progression of MS. The invariant Natural Killer T (iNKT) cells are the unique innate lymphocytes subtype involved in inflammation and autoimmune disorders and secretes cytokines such as interferon gamma (IFN-?), Interleukin (IL)-10, IL-4 and IL-13. A reduction in number or defect in function of iNKT cells has been associated with an increased prevalence of autoimmune disorders indicating that iNKT cells have an immune-regulatory role in autoimmune disorders. Also, the protective role of iNKT cells has been extensively studied in EAE and the results of these studies show that iNKT cells might be a target for therapeutic purposes, but needs more extensive studies of their biology. In this review, we will attempt to show the protective role of iNKT cells in the pathogenesis of EAE and human disease. PMID:24601677

  13. A Combination of Culture Conditions and Gene Expression Analysis Can Be Used to Investigate and Predict hES Cell Differentiation Potential towards Male Gonadal Cells

    PubMed Central

    Kjartansdóttir, Kristín Rós; Reda, Ahmed; Panula, Sarita; Day, Kelly; Hultenby, Kjell; Söder, Olle; Hovatta, Outi; Stukenborg, Jan-Bernd

    2015-01-01

    Human embryonic stem cell differentiation towards various cell types belonging to ecto-, endo- and mesodermal cell lineages has been demonstrated, with high efficiency rates using standardized differentiation protocols. However, germ cell differentiation from human embryonic stem cells has been very inefficient so far. Even though the influence of various growth factors has been evaluated, the gene expression of different cell lines in relation to their differentiation potential has not yet been extensively examined. In this study, the potential of three male human embryonic stem cell lines to differentiate towards male gonadal cells was explored by analysing their gene expression profiles. The human embryonic stem cell lines were cultured for 14 days as monolayers on supporting human foreskin fibroblasts or as spheres in suspension, and were differentiated using BMP7, or spontaneous differentiation by omitting exogenous FGF2. TLDA analysis revealed that in the undifferentiated state, these cell lines have diverse mRNA profiles and exhibit significantly different potentials for differentiation towards the cell types present in the male gonads. This potential was associated with important factors directing the fate of the male primordial germ cells in vivo to form gonocytes, such as SOX17 or genes involved in the NODAL/ACTIVIN pathway, for example. Stimulation with BMP7 in suspension culture resulted in up-regulation of cytoplasmic SOX9 protein expression in all three lines. The observation that human embryonic stem cells differentiate towards germ and somatic cells after spontaneous and BMP7-induced stimulation in suspension emphasizes the important role of somatic cells in germ cell differentiation in vitro. PMID:26630562

  14. Redox potential tuning through differential quinone binding in the photosynthetic reaction center of Rhodobacter sphaeroides.

    PubMed

    Vermaas, Josh V; Taguchi, Alexander T; Dikanov, Sergei A; Wraight, Colin A; Tajkhorshid, Emad

    2015-03-31

    Ubiquinone forms an integral part of the electron transport chain in cellular respiration and photosynthesis across a vast number of organisms. Prior experimental results have shown that the photosynthetic reaction center (RC) from Rhodobacter sphaeroides is only fully functional with a limited set of methoxy-bearing quinones, suggesting that specific interactions with this substituent are required to drive electron transport and the formation of quinol. The nature of these interactions has yet to be determined. Through parameterization of a CHARMM-compatible quinone force field and subsequent molecular dynamics simulations of the quinone-bound RC, we have investigated and characterized the interactions of the protein with the quinones in the Q(A) and Q(B) sites using both equilibrium simulation and thermodynamic integration. In particular, we identify a specific interaction between the 2-methoxy group of ubiquinone in the Q(B) site and the amide nitrogen of GlyL225 that we implicate in locking the orientation of the 2-methoxy group, thereby tuning the redox potential difference between the quinones occupying the Q(A) and Q(B) sites. Disruption of this interaction leads to weaker binding in a ubiquinone analogue that lacks a 2-methoxy group, a finding supported by reverse electron transfer electron paramagnetic resonance experiments of the Q(A)?Q(B)? biradical and competitive binding assays. PMID:25734689

  15. Endometrial Cancer Side-Population Cells Show Prominent Migration and Have a Potential to Differentiate into the Mesenchymal Cell Lineage

    PubMed Central

    Kato, Kiyoko; Takao, Tomoka; Kuboyama, Ayumi; Tanaka, Yoshihiro; Ohgami, Tatsuhiro; Yamaguchi, Shinichiro; Adachi, Sawako; Yoneda, Tomoko; Ueoka, Yousuke; Kato, Keiji; Hayashi, Shinichi; Asanoma, Kazuo; Wake, Norio

    2010-01-01

    Cancer stem-like cell subpopulations, referred to as “side-population” (SP) cells, have been identified in several tumors based on their ability to efflux the fluorescent dye Hoechst 33342. Although SP cells have been identified in the normal human endometrium and endometrial cancer, little is known about their characteristics. In this study, we isolated and characterized the SP cells in human endometrial cancer cells and in rat endometrial cells expressing oncogenic human K-Ras protein. These SP cells showed i) reduction in the expression levels of differentiation markers; ii) long-term proliferative capacity of the cell cultures; iii) self-renewal capacity in vitro; iv) enhancement of migration, lamellipodia, and, uropodia formation; and v) enhanced tumorigenicity. In nude mice, SP cells formed large, invasive tumors, which were composed of both tumor cells and stromal-like cells with enriched extracellular matrix. The expression levels of vimentin, α-smooth muscle actin, and collagen III were enhanced in SP tumors compared with the levels in non-SP tumors. In addition, analysis of microdissected samples and fluorescence in situ hybridization of Hec1-SP-tumors showed that the stromal-like cells with enriched extracellular matrix contained human DNA, confirming that the stromal-like cells were derived from the inoculated cells. Moreober, in a Matrigel assay, SP cells differentiated into α-smooth muscle actin-expressing cells. These findings demonstrate that SP cells have cancer stem-like cell features, including the potential to differentiate into the mesenchymal cell lineage. PMID:20008133

  16. MiRNAs with Apoptosis Regulating Potential Are Differentially Expressed in Chronic Exercise-Induced Physiologically Hypertrophied Hearts

    PubMed Central

    Ramprasath, Tharmarajan; Kalpana, Krishnan

    2015-01-01

    Physiological cardiac hypertrophy is an adaptive mechanism, induced during chronic exercise. As it is reversible and not associated with cardiomyocyte death, it is considered as a natural tactic to prevent cardiac dysfunction and failure. Though, different studies revealed the importance of microRNAs (miRNAs) in pathological hypertrophy, their role during physiological hypertrophy is largely unexplored. Hence, this study is aimed at revealing the global expression profile of miRNAs during physiological cardiac hypertrophy. Chronic swimming protocol continuously for eight weeks resulted in induction of physiological hypertrophy in rats and histopathology revealed the absence of tissue damage, apoptosis or fibrosis. Subsequently, the total RNA was isolated and small RNA sequencing was executed. Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during physiological hypertrophy. The expression profile of the significantly differentially expressed miRNAs was validated by qPCR. In silico prediction of target genes by miRanda, miRdB and TargetScan and subsequent qPCR analysis unraveled that miRNAs including miR-99b, miR-100, miR-19b, miR-10, miR-208a, miR-133, miR-191a, miR-22, miR-30e and miR-181a are targeting the genes that primarily regulate cell proliferation and cell death. Gene ontology and pathway mapping showed that the differentially expressed miRNAs and their target genes were mapped to apoptosis and cell death pathways principally via PI3K/Akt/mTOR and MAPK signaling. In summary, our data indicates that regulation of these miRNAs with apoptosis regulating potential can be one of the major key factors in determining pathological or physiological hypertrophy by controlling fibrosis, apoptosis and cell death mechanisms. PMID:25793527

  17. Differential Vocational Rehabilitation Service Patterns Related to the Job Retention and Job-Seeking Needs of Individuals with Multiple Sclerosis

    ERIC Educational Resources Information Center

    Tansey, Timothy N.; Strauser, David; Frain, Michael P.; Bishop, Malachy; Chiu, Chung-Yi; Kaya, Cahit; Chan, Fong

    2015-01-01

    The experience of living with multiple sclerosis (MS) can have a profound effect on employment. The impact of MS is a complex interaction of personal, medical, functional, financial, and psychosocial variables that ultimately results in up to 80% of persons with MS leaving their jobs within 10 years of their diagnosis. The aim of this study was to

  18. Knockdown of Human TCF4 Affects Multiple Signaling Pathways Involved in Cell Survival, Epithelial to Mesenchymal Transition and Neuronal Differentiation

    PubMed Central

    Forrest, Marc P.; Waite, Adrian J.; Martin-Rendon, Enca; Blake, Derek J.

    2013-01-01

    Haploinsufficiency of TCF4 causes Pitt-Hopkins syndrome (PTHS): a severe form of mental retardation with phenotypic similarities to Angelman, Mowat-Wilson and Rett syndromes. Genome-wide association studies have also found that common variants in TCF4 are associated with an increased risk of schizophrenia. Although TCF4 is transcription factor, little is known about TCF4-regulated processes in the brain. In this study we used genome-wide expression profiling to determine the effects of acute TCF4 knockdown on gene expression in SH-SY5Y neuroblastoma cells. We identified 1204 gene expression changes (494 upregulated, 710 downregulated) in TCF4 knockdown cells. Pathway and enrichment analysis on the differentially expressed genes in TCF4-knockdown cells identified an over-representation of genes involved in TGF-? signaling, epithelial to mesenchymal transition (EMT) and apoptosis. Among the most significantly differentially expressed genes were the EMT regulators, SNAI2 and DEC1 and the proneural genes, NEUROG2 and ASCL1. Altered expression of several mental retardation genes such as UBE3A (Angelman Syndrome), ZEB2 (Mowat-Wilson Syndrome) and MEF2C was also found in TCF4-depleted cells. These data suggest that TCF4 regulates a number of convergent signaling pathways involved in cell differentiation and survival in addition to a subset of clinically important mental retardation genes. PMID:24058414

  19. hTERT gene immortalized human adipose-derived stem cells and its multiple differentiations: a preliminary investigation.

    PubMed

    Wang, L; Song, K; Qu, X; Wang, H; Zhu, H; Xu, X; Zhang, M; Tang, Y; Yang, X

    2013-03-01

    Human adipose-derived adult stem cells (hADSCs) can express human telomerase reverse transcriptase phenotypes under an appropriate culture condition. Because adipose tissue is abundant and easily accessible, hADSCs offer a promising source of stem cells for tissue engineering application and other cell-based therapies. However, the shortage of cells number and the difficulty to proliferate, known as the "Hayflick limit" in vitro, limit their further clinical application. Here, hADSCs were transfected with human telomerase reverse transcriptase (hTERT) gene by the lentiviral vector to prolong the lifespan of stem cells and even immortalize them. Following to this, the cellular properties and functionalities of the transfected cell lines were assayed. The results demonstrated that hADSCs had been successfully transfected with hTERT gene (hTERT-ADSCs). Then, hTERT-ADSCs were initially selected by G418 and subsequently expanded over 20 passages in vitro. Moreover, the qualitative and quantitative differentiation criteria for 20 passages of hTERT-ADSCs also demonstrated that hTERT-ADSCs could differentiate into osteogenesis, chondrogenesis, and adipogenesis phenotypes in lineage-specific differentiation media. These findings confirmed that this transfection could prolong the lifespan of hADSCs. PMID:23322249

  20. Clinicopathological significance and potential drug target of p15INK4B in multiple myeloma.

    PubMed

    Li, Jun; Bi, Lintao; Lin, Yumei; Lu, Zhenxia; Hou, Gang

    2014-01-01

    Multiple myeloma (MM) is a clonal malignancy characterized by the proliferation of malignant plasma cells in the bone marrow and the production of monoclonal immunoglobulin. In addition to genetic changes, gene hypermethylation is an alternative mechanism of tumor suppressor gene inactivation in MM. The cyclin-dependent kinase inhibitor 1 (CDKN2B or p15(INK4B) ) gene lies adjacent to the tumor suppressor gene, cyclin-dependent kinase inhibitor 2 (CDKN2A), and is frequently mutated and deleted in a wide variety of tumors, including MM. However, there is a lack of systematic analysis of p15 epigenetic modification such as methylation in MM from different studies that can provide more powerful estimation of an effect. In this study, we have systematically reviewed the studies of p15(INK4B) promoter methylation in MM and quantified the association between p15(INK4B) promoter methylation and MM using meta-analysis methods. We observed that the frequency of p15(INK4B) methylation is significantly higher in MM patients than in normal healthy controls. The pooled odds ratio (OR) from ten studies including 394 MM and 99 normal individuals is 0.08, while confidence interval (CI) is 0.03-0.21 (P<0.00001). This indicates that p15(INK4B) inactivation through methylation plays an important role in the pathogenesis of MM. In addition, the frequency of p15(INK4B) methylation was significantly higher in patients with MM than in those with asymptomatic monoclonal gammopathy of undetermined significance. The pooled OR from four studies is 0.40, 95% CI =0.21-0.78 (P=0.007). These results suggest that silencing of p15(INK4B) gene expression by epigenetic modification such as promoter hypermethylation plays a role not only in the initiation of MM but also in plasma cell malignant transformation, disease progression, and development. PMID:25382971

  1. Increases in intracellular calcium via activation of potentially multiple phospholipase C isozymes in mouse olfactory neurons

    PubMed Central

    Szebenyi, Steven A.; Ogura, Tatsuya; Sathyanesan, Aaron; AlMatrouk, Abdullah K.; Chang, Justin; Lin, Weihong

    2014-01-01

    Phospholipase C (PLC) and internal Ca2+ stores are involved in a variety of cellular functions. However, our understanding of PLC in mammalian olfactory sensory neurons (OSNs) is generally limited to its controversial role in odor transduction. Here we employed single-cell Ca2+ imaging and molecular approaches to investigate PLC-mediated Ca2+ responses and its isozyme gene transcript expression. We found that the pan-PLC activator m-3M3FBS (25 ?M) induces intracellular Ca2+ increases in vast majority of isolated mouse OSNs tested. Both the response amplitude and percent responding cells depend on m-3M3FBS concentrations. In contrast, the inactive analog o-3M3FBS fails to induce Ca2+ responses. The m-3M3FBS-induced Ca2+ increase is blocked by the PLC inhibitor U73122, while its inactive analog U73433 has no effect. Removal of extracellular Ca2+ does not change significantly the m-3M3FBS-induced Ca2+ response amplitude. Additionally, in the absence of external Ca2+, we found that a subset of OSNs respond to an odorant mixture with small Ca2+ increases, which are significantly suppressed by U73122. Furthermore, using reverse transcription polymerase chain reaction and real-time quantitative polymerase chain reaction, we found that multiple PLC isozyme gene transcripts are expressed in olfactory turbinate tissue in various levels. Using RNA in situ hybridization analysis, we further show expression of ?4, ?1, ?2 gene transcripts in OSNs. Taken together, our results establish that PLC isozymes are potent enzymes for mobilizing intracellular Ca2+ in mouse OSNs and provide molecular insight for PLC isozymes-mediated complex cell signaling and regulation in the peripheral olfactory epithelium. PMID:25374507

  2. Coinhibitory molecule PD-1 as a potential target for the immunotherapy of multiple myeloma.

    PubMed

    Atanackovic, D; Luetkens, T; Kröger, N

    2014-05-01

    The adaptive immune system is clearly capable of recognizing and attacking malignant plasma cells in patients with multiple myeloma (MM). However, MM patients evidence severe defects of humoral and cellular immunity, and it is likely that the profound immune dysregulation typical for this malignancy contributes to its eventual escape from natural immune control. One of the factors responsible for the immune dysfunction in MM might be the programmed death 1 (PD-1) protein. The physiological role of PD-1 is to guarantee T-cell homeostasis by limiting T-cell activation and proliferation. Accordingly, binding of the ligand PD-L1 to PD-1 expressed on the surface of activated T cells delivers an inhibitory signal, reducing cytokine production and proliferation. Using the same mechanism, PD-L1/PD-1 interactions have been shown in a number of animal models to confer tumor escape from immune control. Recently, clinical trials have suggested a significant therapeutic impact of PD-1/PD-L inhibition on a variety of solid tumors-for example, by the application of monoclonal antibodies. We show here that based on (1) the broad expression of PD-1 and its ligands in the microenvironment of myeloma, (2) data indicating an important role of the PD-1 pathway in the immune evasion by MM cells and (3) preclinical results providing a strong rationale for therapeutic PD-1/PD-L inhibition in this malignancy, MM may be very well suited for immunotherapy, for example, a monoclonal antibody, targeting PD-1 and/or its ligands. PMID:24153012

  3. EpsteinBarr virus and multiple sclerosis: potential opportunities for immunotherapy

    PubMed Central

    Pender, Michael P; Burrows, Scott R

    2014-01-01

    Multiple sclerosis (MS) is a common chronic inflammatory demyelinating disease of the central nervous system (CNS) causing progressive disability. Many observations implicate EpsteinBarr virus (EBV) in the pathogenesis of MS, namely universal EBV seropositivity, high anti-EBV antibody levels, alterations in EBV-specific CD8+ T-cell immunity, increased spontaneous EBV-induced transformation of peripheral blood B cells, increased shedding of EBV from saliva and accumulation of EBV-infected B cells and plasma cells in the brain. Several mechanisms have been postulated to explain the role of EBV in the development of MS including cross-reactivity between EBV and CNS antigens, bystander damage to the CNS by EBV-specific CD8+ T cells, activation of innate immunity by EBV-encoded small RNA molecules in the CNS, expression of ?B-crystallin in EBV-infected B cells leading to a CD4+ T-cell response against oligodendrocyte-derived ?B-crystallin and EBV infection of autoreactive B cells, which produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells in the CNS. The rapidly accumulating evidence for a pathogenic role of EBV in MS provides ground for optimism that it might be possible to prevent and cure MS by effectively controlling EBV infection through vaccination, antiviral drugs or treatment with EBV-specific cytotoxic CD8+ T cells. Adoptive immunotherapy with in vitro-expanded autologous EBV-specific CD8+ T cells directed against viral latent proteins was recently used to treat a patient with secondary progressive MS. Following the therapy, there was clinical improvement, decreased disease activity on magnetic resonance imaging and reduced intrathecal immunoglobulin production. PMID:25505955

  4. Seeking balance: Potentiation and inhibition of multiple sclerosis autoimmune responses by IL-6 and IL-10.

    PubMed

    Ireland, Sara J; Monson, Nancy L; Davis, Laurie S

    2015-06-01

    The cytokines IL-6 and IL-10 are produced by cells of the adaptive and innate arms of the immune system and they appear to play key roles in genetically diverse autoimmune diseases such as relapsing remitting multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Whereas previous intense investigations focused on the generation of autoantibodies and their contribution to immune-mediated pathogenesis in these diseases; more recent attention has focused on the roles of cytokines such as IL-6 and IL-10. In response to pathogens, antigen presenting cells (APC), including B cells, produce IL-6 and IL-10 in order to up-or down-regulate immune cell activation and effector responses. Evidence of elevated levels of the proinflammatory cytokine IL-6 has been routinely observed during inflammatory responses and in a number of autoimmune diseases. Our recent studies suggest that MS peripheral blood B cells secrete higher quantities of IL-6 and less IL-10 than B cells from healthy controls. Persistent production of IL-6, in turn, contributes to T cell expansion and the functional hyperactivity of APC such as MS B cells. Altered B cell activity can have a profound impact on resultant T cell effector functions. Enhanced signaling through the IL-6 receptor can effectively inhibit cytolytic activity, induce T cell resistance to IL-10-mediated immunosuppression and increase skewing of autoreactive T cells to a pathogenic Th17 phenotype. Our recent findings and studies by others support a role for the indirect attenuation of B cell responses by Glatiramer acetate (GA) therapy. Our studies suggest that GA therapy temporarily permits homeostatic regulatory mechanisms to be reinstated. Future studies of mechanisms underlying dysregulated B cell cytokine production could lead to the identification of novel targets for improved immunoregulatory therapies for autoimmune diseases. PMID:25794663

  5. The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects

    PubMed Central

    Sorensen, Per Soelberg; Blinkenberg, Morten

    2016-01-01

    B cells play a central role in the pathogenesis in multiple sclerosis (MS), being involved in the activation of proinflammatory T cells, secretion of proinflammatory cytokines, and production of autoantibodies directed against myelin. Hence, the usage of B-cell-depleting monoclonal antibodies as therapy for autoimmune diseases including MS lay near at hand. Rituximab was the first therapeutic B-cell-depleting chimeric monoclonal antibody to be used successfully in MS. Ocrelizumab, a second-generation humanized anti-CD20 antibody, was explored in a large phase II, randomized, placebo-controlled multicentre trial in patients with relapsing–remitting disease. Compared with placebo, two doses of ocrelizumab (600 and 2000 mg on days 1 and 15) showed a pronounced effect on disease activity seen in magnetic resonance imaging (MRI) as gadolinium-enhanced lesions (89% and 96% relative reduction, both p < 0.001) and also had a significant effect on relapses. In exploratory analyses, both doses of ocrelizumab had better effect on gadolinium-enhanced lesions than interferon beta-1a intramuscularly that was used as a reference arm. Adverse effects were mainly infusion-related reactions, in particular during the first infusion. Serious infections occurred at similar rates in ocrelizumab and placebo-treated patients, and no opportunistic infections were reported. However, progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with anti-CD20 monoclonal antibodies for other indications. Other anti-CD20 monoclonal antibodies have been tested as treatments for MS, including ofatumumab that has shown beneficial results in placebo-controlled phase II trials in patients with relapsing–remitting MS. Ocrelizumab is now in phase III development for the treatment of relapsing–remitting MS, as well as primary progressive MS, and the results of ongoing clinical trials are eagerly awaited and will determine the place of ocrelizumab in the armamentarium of MS therapies. PMID:26788130

  6. Shrub encroachment impacts the potential for multiple use conflicts on public land.

    PubMed

    Burkinshaw, Angela M; Bork, Edward W

    2009-09-01

    Public rangelands in North America are typically managed under a multiple use policy that includes livestock grazing and wildlife management. In this article we report on the landscape level extent of grassland loss to shrub encroachment in a portion of the Rocky Mountain Forest Reserve in southwestern Alberta, Canada, and review the associated implications for simultaneously supporting livestock and wildlife populations while maintaining range health on this diminishing vegetation type. Digitized aerial photographs of 12 km of valley bottom from 1958 and 1974 were co-registered to ortho-rectified digital imagery taken in 1998, and an un-supervised classification used to determine areas associated with grassland and shrubland in each year. Field data from 2002 were over-layed using GPS coordinates to refine the classification using a calibration-validation procedure. Over the 40-year study period, open grasslands declined from 1,111 ha in 1958 to 465 ha in 1998, representing a 58% decrease. Using mean production data for grass and shrub dominated areas we then quantified aggregate changes in grazing capacity of both primary (grassland) and secondary (shrubland) habitats for livestock and wildlife. Total declines in grazing capacity from 1958 to 1998 totaled 2,744 Animal Unit Months (AUMs) of forage (-39%), including a 58% decrease in primary (i.e., open grassland) range, which was only partly offset by the availability of 1,357 AUMs within less productive and less accessible shrubland habitats. Our results indicate shrub encroachment has been extensive and significantly reduced forage availability to domestic livestock and wildlife, and will increase the difficulty of conserving remaining grasslands. Although current grazing capacities remain marginally above those specified by regulated grazing policies, it is clear that continued habitat change and decreases in forage availability are likely to threaten the condition of remaining grasslands. Unless shrub encroachment is arrested or grassland restoration initiated, reductions in aggregate ungulate numbers may be necessary. PMID:19588191

  7. Shrub Encroachment Impacts the Potential for Multiple Use Conflicts on Public Land

    NASA Astrophysics Data System (ADS)

    Burkinshaw, Angela M.; Bork, Edward W.

    2009-09-01

    Public rangelands in North America are typically managed under a multiple use policy that includes livestock grazing and wildlife management. In this article we report on the landscape level extent of grassland loss to shrub encroachment in a portion of the Rocky Mountain Forest Reserve in southwestern Alberta, Canada, and review the associated implications for simultaneously supporting livestock and wildlife populations while maintaining range health on this diminishing vegetation type. Digitized aerial photographs of 12 km of valley bottom from 1958 and 1974 were co-registered to ortho-rectified digital imagery taken in 1998, and an un-supervised classification used to determine areas associated with grassland and shrubland in each year. Field data from 2002 were over-layed using GPS coordinates to refine the classification using a calibration-validation procedure. Over the 40-year study period, open grasslands declined from 1,111 ha in 1958 to 465 ha in 1998, representing a 58% decrease. Using mean production data for grass and shrub dominated areas we then quantified aggregate changes in grazing capacity of both primary (grassland) and secondary (shrubland) habitats for livestock and wildlife. Total declines in grazing capacity from 1958 to 1998 totaled 2,744 Animal Unit Months (AUMs) of forage (-39%), including a 58% decrease in primary (i.e., open grassland) range, which was only partly offset by the availability of 1,357 AUMs within less productive and less accessible shrubland habitats. Our results indicate shrub encroachment has been extensive and significantly reduced forage availability to domestic livestock and wildlife, and will increase the difficulty of conserving remaining grasslands. Although current grazing capacities remain marginally above those specified by regulated grazing policies, it is clear that continued habitat change and decreases in forage availability are likely to threaten the condition of remaining grasslands. Unless shrub encroachment is arrested or grassland restoration initiated, reductions in aggregate ungulate numbers may be necessary.

  8. Impairment of heme synthesis in myelin as potential trigger of multiple sclerosis.

    PubMed

    Morelli, Alessandro; Ravera, Silvia; Calzia, Daniela; Panfoli, Isabella

    2012-06-01

    The pathogenesis of multiple sclerosis (MS), a disease characterized by demyelination and subsequent axonal degeneration, is as yet unknown. Also, the nature of the disease is as yet not established, since doubts have been cast on its autoimmune origin. Genetic and environmental factors have been implied in MS, leading to the idea of an overall multifactorial origin. An unexpected role in energizing the axon has been reported for myelin, supposed to be the site of consumption of most of oxygen in brain. Myelin would be able to perform oxidative phosphorylation to supply the axons with ATP, thanks to the expression therein of mitochondrial F(o)F(1)-ATP synthase, and respiratory chains. Interestingly, myelin expresses the pathway of heme synthesis, hence of cytochromes, that rely on heme group, in turn depending on Fe availability. Poisoning by these pollutants shares the common characteristic to bring about demyelination both in animal models and in man. Carbon monoxide (CO) and lead poisoning which cause functional imbalance of the heme group, as well as of heme synthesis, cause myelin damage. On the other hand, a lack of essential metals such as iron and copper, produces dramatic myelin decrease. Myelin is a primary target, of iron shortage, indicating that in myelin Fe-dependent processes are more active than in other tissues. The predominant spread of MS in industrialized countries where pollution by heavy metals, and CO poisoning is widespread, suggests a relationship among toxic action of metal pollutants and MS. According to the present hypothesis, MS can be primarily triggered by environmental factors acting on a genetic susceptibility, while the immune response may be a consequence of a primary oxidative damage due to reactive oxygen species produced consequently to an imbalance of cytochromes and respiratory chains in the sheath. PMID:22398388

  9. The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects.

    PubMed

    Sorensen, Per Soelberg; Blinkenberg, Morten

    2016-01-01

    B cells play a central role in the pathogenesis in multiple sclerosis (MS), being involved in the activation of proinflammatory T cells, secretion of proinflammatory cytokines, and production of autoantibodies directed against myelin. Hence, the usage of B-cell-depleting monoclonal antibodies as therapy for autoimmune diseases including MS lay near at hand. Rituximab was the first therapeutic B-cell-depleting chimeric monoclonal antibody to be used successfully in MS. Ocrelizumab, a second-generation humanized anti-CD20 antibody, was explored in a large phase II, randomized, placebo-controlled multicentre trial in patients with relapsing-remitting disease. Compared with placebo, two doses of ocrelizumab (600 and 2000 mg on days 1 and 15) showed a pronounced effect on disease activity seen in magnetic resonance imaging (MRI) as gadolinium-enhanced lesions (89% and 96% relative reduction, both p < 0.001) and also had a significant effect on relapses. In exploratory analyses, both doses of ocrelizumab had better effect on gadolinium-enhanced lesions than interferon beta-1a intramuscularly that was used as a reference arm. Adverse effects were mainly infusion-related reactions, in particular during the first infusion. Serious infections occurred at similar rates in ocrelizumab and placebo-treated patients, and no opportunistic infections were reported. However, progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with anti-CD20 monoclonal antibodies for other indications. Other anti-CD20 monoclonal antibodies have been tested as treatments for MS, including ofatumumab that has shown beneficial results in placebo-controlled phase II trials in patients with relapsing-remitting MS. Ocrelizumab is now in phase III development for the treatment of relapsing-remitting MS, as well as primary progressive MS, and the results of ongoing clinical trials are eagerly awaited and will determine the place of ocrelizumab in the armamentarium of MS therapies. PMID:26788130

  10. Differential Radiosensitizing Potential of Temozolomide in MGMT Promoter Methylated Glioblastoma Multiforme Cell Lines

    SciTech Connect

    Nifterik, Krista A. van; Berg, Jaap van den; Stalpers, Lukas J.A.; Lafleur, M. Vincent M.; Leenstra, Sieger; Slotman, Ben J.; Hulsebos, Theo J.M.; Sminia, Peter

    2007-11-15

    Purpose: To investigate the radiosensitizing potential of temozolomide (TMZ) for human glioblastoma multiforme (GBM) cell lines using single-dose and fractionated {gamma}-irradiation. Methods and Materials: Three genetically characterized human GBM cell lines (AMC-3046, VU-109, and VU-122) were exposed to various single (0-6 Gy) and daily fractionated doses (2 Gy per fraction) of {gamma}-irradiation. Repeated TMZ doses were given before and concurrent with irradiation treatment. Immediately plated clonogenic cell-survival curves were determined for both the single-dose and the fractionated irradiation experiments. To establish the net effect of clonogenic cell survival and cell proliferation, growth curves were determined, expressed as the number of surviving cells. Results: All three cell lines showed MGMT promoter methylation, lacked MGMT protein expression, and were sensitive to TMZ. The isotoxic TMZ concentrations used were in a clinically feasible range of 10 {mu}mol/L (AMC-3046), 3 {mu}mol/L (VU-109), and 2.5 {mu}mol/L (VU-122). Temozolomide was able to radiosensitize two cell lines (AMC 3046 and VU-122) using single-dose irradiation. A reduction in the number of surviving cells after treatment with the combination of TMZ and fractionated irradiation was seen in all three cell lines, but only AMC 3046 showed a radiosensitizing effect. Conclusions: This study on TMZ-sensitive GBM cell lines shows that TMZ can act as a radiosensitizer and is at least additive to {gamma}-irradiation. Enhancement of the radiation response by TMZ seems to be independent of the epigenetically silenced MGMT gen000.

  11. An interneuron progenitor maintains neurogenic potential in vivo and differentiates into GABAergic interneurons after transplantation in the postnatal rat brain

    PubMed Central

    Wang, Qi; Hong, Peiwei; Gao, Hui; Chen, Yuntian; Yang, Qi; Jiang, Mei; Li, Hedong

    2016-01-01

    Dysfunction of cortical GABAergic interneurons are involved in numerous neurological disorders including epilepsy, schizophrenia and autism; and replenishment of these cells by transplantation strategy has proven to be a feasible and effective method to help revert the symptoms in several animal models. To develop methodology of generating transplantable GABAergic interneurons for therapy, we previously reported the isolation of a v-myc-induced GABAergic interneuron progenitor clone GE6 from embryonic ganglionic eminence (GE). These cells can proliferate and form functional inhibitory synapses in culture. Here, we tested their differentiation behavior in vivo by transplanting them into the postnatal rat forebrain. We found that GE6 cells migrate extensively in the neonatal forebrain and differentiate into both neurons and glia, but preferentially into neurons when compared with a sister progenitor clone CTX8. The neurogenic potential of GE6 cells is also maintained after transplantation into a non-permissive environment such as adult cortex or when treated with inflammatory cytokine in culture. The GE6-derived neurons were able to mature in vivo as GABAergic interneurons expressing GABAergic, not glutamatergic, presynaptic puncta. Finally, we propose that v-myc-induced human interneuron progenitor clones could be an alternative cell source of transplantable GABAergic interneurons for treating related neurological diseases in future clinic. PMID:26750620

  12. Contribution of Vestibular-Evoked Myogenic Potential (VEMP) testing in the assessment and the differential diagnosis of otosclerosis

    PubMed Central

    Tramontani, Ourania; Gkoritsa, Eleni; Ferekidis, Eleftherios; Korres, Stavros G.

    2014-01-01

    Background The aim of this prospective clinical study was to evaluate the clinical importance of Vestibular-Evoked Myogenic Potentials (VEMPs) in the assessment and differential diagnosis of otosclerosis and otologic diseases characterized by “pseudo-conductive” components. We also investigated the clinical appearance of balance disorders in patients with otosclerosis by correlating VEMP results with the findings of caloric testing and pure tone audiometry(PTA). Material/Methods Air-conducted(AC) 4-PTA, bone-conducted(BC) 4-PTA, air-bone Gap(ABG), AC, BC tone burst evoked VEMP, and calorics were measured preoperatively in 126 otosclerotic ears. Results The response rate of the AC-VEMPs and BC-VEMPs was 29.36% and 44.03%, respectively. Statistical differences were found between the means of ABG, AC 4-PTA, and BC 4-PTA in the otosclerotic ears in relation to AC-VEMP elicitability. About one-third of patients presented with disequilibrium. A statistically significant interaction was found between calorics and dizziness in relation to PTA thresholds. No relationship was found between calorics and dizziness with VEMPs responses. Conclusions AC and BC VEMPs can be elicited in ears with otosclerosis. AC-VEMP is more vulnerable to conductive hearing loss. Evaluation of AC-VEMP thresholds can be added in the diagnostic work-up of otosclerosis in case of doubt, enhancing differential diagnosis in patients with air-bone gaps. Otosclerosis is not a cause of canal paresis or vertigo. PMID:24509900

  13. The AP-1 transcription factor component Fosl2 potentiates the rate of myocardial differentiation from the zebrafish second heart field.

    PubMed

    Jahangiri, Leila; Sharpe, Michka; Novikov, Natasha; González-Rosa, Juan Manuel; Borikova, Asya; Nevis, Kathleen; Paffett-Lugassy, Noelle; Zhao, Long; Adams, Meghan; Guner-Ataman, Burcu; Burns, Caroline E; Burns, C Geoffrey

    2016-01-01

    The vertebrate heart forms through successive phases of cardiomyocyte differentiation. Initially, cardiomyocytes derived from first heart field (FHF) progenitors assemble the linear heart tube. Thereafter, second heart field (SHF) progenitors differentiate into cardiomyocytes that are accreted to the poles of the heart tube over a well-defined developmental window. Although heart tube elongation deficiencies lead to life-threatening congenital heart defects, the variables controlling the initiation, rate and duration of myocardial accretion remain obscure. Here, we demonstrate that the AP-1 transcription factor, Fos-like antigen 2 (Fosl2), potentiates the rate of myocardial accretion from the zebrafish SHF. fosl2 mutants initiate accretion appropriately, but cardiomyocyte production is sluggish, resulting in a ventricular deficit coupled with an accumulation of SHF progenitors. Surprisingly, mutant embryos eventually correct the myocardial deficit by extending the accretion window. Overexpression of Fosl2 also compromises production of SHF-derived ventricular cardiomyocytes, a phenotype that is consistent with precocious depletion of the progenitor pool. Our data implicate Fosl2 in promoting the progenitor to cardiomyocyte transition and uncover the existence of regulatory mechanisms to ensure appropriate SHF-mediated cardiomyocyte contribution irrespective of embryonic stage. PMID:26732840

  14. An interneuron progenitor maintains neurogenic potential in vivo and differentiates into GABAergic interneurons after transplantation in the postnatal rat brain.

    PubMed

    Wang, Qi; Hong, Peiwei; Gao, Hui; Chen, Yuntian; Yang, Qi; Jiang, Mei; Li, Hedong

    2016-01-01

    Dysfunction of cortical GABAergic interneurons are involved in numerous neurological disorders including epilepsy, schizophrenia and autism; and replenishment of these cells by transplantation strategy has proven to be a feasible and effective method to help revert the symptoms in several animal models. To develop methodology of generating transplantable GABAergic interneurons for therapy, we previously reported the isolation of a v-myc-induced GABAergic interneuron progenitor clone GE6 from embryonic ganglionic eminence (GE). These cells can proliferate and form functional inhibitory synapses in culture. Here, we tested their differentiation behavior in vivo by transplanting them into the postnatal rat forebrain. We found that GE6 cells migrate extensively in the neonatal forebrain and differentiate into both neurons and glia, but preferentially into neurons when compared with a sister progenitor clone CTX8. The neurogenic potential of GE6 cells is also maintained after transplantation into a non-permissive environment such as adult cortex or when treated with inflammatory cytokine in culture. The GE6-derived neurons were able to mature in vivo as GABAergic interneurons expressing GABAergic, not glutamatergic, presynaptic puncta. Finally, we propose that v-myc-induced human interneuron progenitor clones could be an alternative cell source of transplantable GABAergic interneurons for treating related neurological diseases in future clinic. PMID:26750620

  15. Differential osteogenic potential of human adipose-derived stem cells co-cultured with human osteoblasts on polymeric microfiber scaffolds.

    PubMed

    Rozila, Ismail; Azari, Pedram; Munirah, Sha'ban; Wan Safwani, Wan Kamarul Zaman; Gan, Seng Neon; Nur Azurah, Abdul Ghani; Jahendran, Jeevanan; Pingguan-Murphy, Belinda; Chua, Kien Hui

    2016-02-01

    The osteogenic potential of human adipose-derived stem cells (HADSCs) co-cultured with human osteoblasts (HOBs) using selected HADSCs/HOBs ratios of 1:1, 2:1, and 1:2, respectively, is evaluated. The HADSCs/HOBs were seeded on electrospun three-dimensional poly[(R)-3-hydroxybutyric acid] (PHB) blended with bovine-derived hydroxyapatite (BHA). Monocultures of HADSCs and HOBs were used as control groups. The effects of PHB-BHA scaffold on cell proliferation and cell morphology were assessed by AlamarBlue assay and field emission scanning electron microscopy. Cell differentiation, cell mineralization, and osteogenic-related gene expression of co-culture HADSCs/HOBs were examined by alkaline phosphatase (ALP) assay, alizarin Red S assay, and quantitative real time PCR, respectively. The results showed that co-culture of HADSCs/HOBs, 1:1 grown into PHB-BHA promoted better cell adhesion, displayed a significant higher cell proliferation, higher production of ALP, extracellular mineralization and osteogenic-related gene expression of run-related transcription factor, bone sialoprotein, osteopontin, and osteocalcin compared to other co-culture groups. This result also suggests that the use of electrospun PHB-BHA in a co-culture HADSCs/HOBs system may serve as promising approach to facilitate osteogenic differentiation activity of HADSCs through direct cell-to-cell contact with HOBs. 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 377-387, 2016. PMID:26414782

  16. Loss of the osteogenic differentiation potential during senescence is limited to bone progenitor cells and is dependent on p53.

    PubMed

    Despars, Genevive; Carbonneau, Cynthia L; Bardeau, Pascal; Coutu, Daniel L; Beausjour, Christian M

    2013-01-01

    DNA damage can lead to the induction of cellular senescence. In particular, we showed that exposure to ionizing radiation (IR) leads to the senescence of bone marrow-derived multipotent stromal cells (MSC) and osteoblast-like stromal cells (OB-SC), a phenotype associated with bone loss. The mechanism by which IR leads to bone dysfunction is not fully understood. One possibility involves that DNA damage-induced senescence limits the regeneration of bone progenitor cells. Another possibility entails that bone dysfunction arises from the inability of accumulating senescent cells to fulfill their physiological function. Indeed, we show here that exposure to IR prevented the differentiation and mineralization functions of MSC, an effect we found was limited to this population as more differentiated OB-SC could still form mineralize nodules. This is in contrast to adipogenesis, which was inhibited in both IR-induced senescent MSC and 3T3-L1 pre-adipocytes. Furthermore, we demonstrate that IR-induced loss of osteogenic potential in MSC was p53-dependent, a phenotype that correlates with the inability to upregulate key osteogenic transcription factors. These results are the first to demonstrate that senescence impacts osteogenesis in a cell type dependent manner and suggest that the accumulation of senescent osteoblasts is unlikely to significantly contribute to bone dysfunction in a cell autonomous manner. PMID:24009740

  17. Loss of the Osteogenic Differentiation Potential during Senescence Is Limited to Bone Progenitor Cells and Is Dependent on p53

    PubMed Central

    Despars, Genevive; Carbonneau, Cynthia L.; Bardeau, Pascal; Coutu, Daniel L.; Beausjour, Christian M.

    2013-01-01

    DNA damage can lead to the induction of cellular senescence. In particular, we showed that exposure to ionizing radiation (IR) leads to the senescence of bone marrow-derived multipotent stromal cells (MSC) and osteoblast-like stromal cells (OBSC), a phenotype associated with bone loss. The mechanism by which IR leads to bone dysfunction is not fully understood. One possibility involves that DNA damage-induced senescence limits the regeneration of bone progenitor cells. Another possibility entails that bone dysfunction arises from the inability of accumulating senescent cells to fulfill their physiological function. Indeed, we show here that exposure to IR prevented the differentiation and mineralization functions of MSC, an effect we found was limited to this population as more differentiated OBSC could still form mineralize nodules. This is in contrast to adipogenesis, which was inhibited in both IR-induced senescent MSC and 3T3-L1 pre-adipocytes. Furthermore, we demonstrate that IR-induced loss of osteogenic potential in MSC was p53-dependent, a phenotype that correlates with the inability to upregulate key osteogenic transcription factors. These results are the first to demonstrate that senescence impacts osteogenesis in a cell type dependent manner and suggest that the accumulation of senescent osteoblasts is unlikely to significantly contribute to bone dysfunction in a cell autonomous manner. PMID:24009740

  18. A generalized Grubbs-Beck test statistic for detecting multiple potentially influential low outliers in flood series

    USGS Publications Warehouse

    Cohn, T.A.; England, J.F.; Berenbrock, C.E.; Mason, R.R.; Stedinger, J.R.; Lamontagne, J.R.

    2013-01-01

    he Grubbs-Beck test is recommended by the federal guidelines for detection of low outliers in flood flow frequency computation in the United States. This paper presents a generalization of the Grubbs-Beck test for normal data (similar to the Rosner (1983) test; see also Spencer and McCuen (1996)) that can provide a consistent standard for identifying multiple potentially influential low flows. In cases where low outliers have been identified, they can be represented as “less-than” values, and a frequency distribution can be developed using censored-data statistical techniques, such as the Expected Moments Algorithm. This approach can improve the fit of the right-hand tail of a frequency distribution and provide protection from lack-of-fit due to unimportant but potentially influential low flows (PILFs) in a flood series, thus making the flood frequency analysis procedure more robust.

  19. Growth Differentiation Factor-15 (GDF-15) is a potential marker of radiation response and radiation sensitivity.

    PubMed

    Sndor, Nikolett; Schilling-Tth, Boglrka; Kis, Enik?; Benedek, Anett; Lumniczky, Katalin; Sfrny, Gza; Hegyesi, Hargita

    2015-11-01

    We have investigated the importance of GDF-15 (secreted cytokine belonging to the TGF-? superfamily) in low and high dose radiation-induced cellular responses. A telomerase immortalized human fibroblast cell line (F11hT) was used in the experiments. A lentiviral system encoding small hairpin RNAs (shRNA) was used to establish GDF-15 silenced cells. Secreted GDF-15 levels were measured in culture medium by ELISA. Cell cycle analysis was performed by flow cytometry. The experiments demonstrated that in irradiated human fibroblasts GDF-15 expression increased with dose starting from 100mGy. Elevated GDF-15 expression was not detected in bystander cells. The potential role of GDF-15 in radiation response was investigated by silencing GDF-15 in immortalized human fibroblasts with five different shRNA encoded in lentiviral vectors. Cell lines with considerably reduced GDF-15 levels presented increased radiation sensitivity, while a cell line with elevated GDF-15 was more radiation resistant than wild type cells. We have investigated how the reduced GDF-15 levels alter the response of several known radiation inducible genes. In F11hT-shGDF-15 cells the basal expression level of CDKN1A was unaltered relative to F11hT cells, while GADD45A and TGF-?1 mRNA levels were slightly higher, and TP53INP1 was considerably reduced. The radiation-induced expression of TP53INP1 was lower in the silenced than in wild type fibroblast cells. Cell cycle analysis indicated that radiation-induced early G2/M arrest was abrogated in GDF-15 silenced cells. Moreover, radiation-induced bystander effect was less pronounced in GDF-15 silenced fibroblasts. In conclusion, the results suggest that GDF-15 works as a radiation inducible radiation resistance increasing factor in normal human fibroblast cells, acts by regulating the radiation-induced transcription of several genes and might serve as a radiation-induced early biomarker in exposed cells. PMID:26520384

  20. The heterodimeric sweet taste receptor has multiple potential ligand binding sites.

    PubMed

    Cui, Meng; Jiang, Peihua; Maillet, Emeline; Max, Marianna; Margolskee, Robert F; Osman, Roman

    2006-01-01

    The sweet taste receptor is a heterodimer of two G protein coupled receptors, T1R2 and T1R3. This discovery has increased our understanding at the molecular level of the mechanisms underlying sweet taste. Previous experimental studies using sweet receptor chimeras and mutants show that there are at least three potential binding sites in this heterodimeric receptor. Receptor activity toward the artificial sweeteners aspartame and neotame depends on residues in the amino terminal domain of human T1R2. In contrast, receptor activity toward the sweetener cyclamate and the sweet taste inhibitor lactisole depends on residues within the transmembrane domain of human T1R3. Furthermore, receptor activity toward the sweet protein brazzein depends on the cysteine rich domain of human T1R3. Although crystal structures are not available for the sweet taste receptor, useful homology models can be developed based on appropriate templates. The amino terminal domain, cysteine rich domain and transmembrane helix domain of T1R2 and T1R3 have been modeled based on the crystal structures of metabotropic glutamate receptor type 1, tumor necrosis factor receptor, and bovine rhodopsin, respectively. We have used homology models of the sweet taste receptors, molecular docking of sweet ligands to the receptors, and site-directed mutagenesis of the receptors to identify potential ligand binding sites of the sweet taste receptor. These studies have led to a better understanding of the structure and function of this heterodimeric receptor, and can act as a guide for rational structure-based design of novel non-caloric sweeteners, which can be used in the fighting against obesity and diabetes. PMID:17168764

  1. Multiple Pathogens Including Potential New Species in Tick Vectors in Côte d’Ivoire

    PubMed Central

    Ehounoud, Cyrille Bilé; Yao, Kouassi Patrick; Dahmani, Mustapha; Achi, Yaba Louise; Amanzougaghene, Nadia; Kacou N’Douba, Adèle; N’Guessan, Jean David; Raoult, Didier; Fenollar, Florence; Mediannikov, Oleg

    2016-01-01

    Background Our study aimed to assess the presence of different pathogens in ticks collected in two regions in Côte d’Ivoire. Methodology/Principal Findings Real-time PCR and standard PCR assays coupled to sequencing were used. Three hundred and seventy eight (378) ticks (170 Amblyomma variegatum, 161 Rhipicepalus microplus, 3 Rhipicephalus senegalensis, 27 Hyalomma truncatum, 16 Hyalomma marginatum rufipes, and 1 Hyalomma impressum) were identified and analyzed. We identified as pathogenic bacteria, Rickettsia africae in Am. variegatum (90%), Rh. microplus (10%) and Hyalomma spp. (9%), Rickettsia aeschlimannii in Hyalomma spp. (23%), Rickettsia massiliae in Rh. senegalensis (33%) as well as Coxiella burnetii in 0.2%, Borrelia sp. in 0.2%, Anaplasma centrale in 0.2%, Anaplasma marginale in 0.5%, and Ehrlichia ruminantium in 0.5% of all ticks. Potential new species of Borrelia, Anaplasma, and Wolbachia were detected. Candidatus Borrelia africana and Candidatus Borrelia ivorensis (detected in three ticks) are phylogenetically distant from both the relapsing fever group and Lyme disease group borreliae; both were detected in Am. variegatum. Four new genotypes of bacteria from the Anaplasmataceae family were identified, namely Candidatus Anaplasma ivorensis (detected in three ticks), Candidatus Ehrlichia urmitei (in nine ticks), Candidatus Ehrlichia rustica (in four ticks), and Candidatus Wolbachia ivorensis (in one tick). Conclusions/Significance For the first time, we demonstrate the presence of different pathogens such as R. aeschlimannii, C. burnetii, Borrelia sp., A. centrale, A. marginale, and E. ruminantium in ticks in Côte d’Ivoire as well as potential new species of unknown pathogenicity. PMID:26771308

  2. Embryonic Stem Cells Derived from In Vivo or In Vitro-Generated Murine Blastocysts Display Similar Transcriptome and Differentiation Potential

    PubMed Central

    Simbulan, Rhodel K.; Di Santo, Marlea; Liu, Xiaowei; Lin, Wingka; Donjacour, Annemarie; Maltepe, Emin; Shenoy, Archana; Borini, Andrea; Rinaudo, Paolo

    2015-01-01

    The use of assisted reproductive technologies (ART) such as in vitro fertilization (IVF) has resulted in the birth of more than 5 million children. While children conceived by these technologies are generally healthy, there is conflicting evidence suggesting an increase in adult-onset complications like glucose intolerance and high blood pressure in IVF children. Animal models indicate similar potential risks. It remains unclear what molecular mechanisms may be operating during in vitro culture to predispose the embryo to these diseases. One of the limitations faced by investigators is the paucity of the material in the preimplantation embryo to test for molecular analysis. To address this problem, we generated mouse embryonic stem cells (mESC) from blastocysts conceived after natural mating (mESCFB) or after IVF, using optimal (KSOM + 5% O2; mESCKAA) and suboptimal (Whittens Medium, + 20% O2, mESCWM) conditions. All three groups of embryos showed similar behavior during both derivation and differentiation into their respective mESC lines. Unsupervised hierarchical clustering of microarray data showed that blastocyst culture does not affect the transcriptome of derived mESCs. Transcriptomic changes previously observed in the inner cell mass (ICM) of embryos derived in the same conditions were not present in mESCs, regardless of method of conception or culture medium, suggesting that mESC do not fully maintain a memory of the events occurring prior to their derivation. We conclude that the fertilization method or culture media used to generate blastocysts does not affect differentiation potential, morphology and transcriptome of mESCs. PMID:25723476

  3. Long-Term Potentiation Promotes Proliferation/Survival and Neuronal Differentiation of Neural Stem/Progenitor Cells

    PubMed Central

    Cho, Taesup; Ryu, Jae K.; Taghibiglou, Changiz; Ge, Yuan; Chan, Allen W.; Liu, Lidong; Lu, Jie; McLarnon, James G.; Wang, Yu Tian

    2013-01-01

    Neural stem cell (NSC) replacement therapy is considered a promising cell replacement therapy for various neurodegenerative diseases. However, the low rate of NSC survival and neurogenesis currently limits its clinical potential. Here, we examined if hippocampal long-term potentiation (LTP), one of the most well characterized forms of synaptic plasticity, promotes neurogenesis by facilitating proliferation/survival and neuronal differentiation of NSCs. We found that the induction of hippocampal LTP significantly facilitates proliferation/survival and neuronal differentiation of both endogenous neural progenitor cells (NPCs) and exogenously transplanted NSCs in the hippocampus in rats. These effects were eliminated by preventing LTP induction by pharmacological blockade of the N-methyl-D-aspartate glutamate receptor (NMDAR) via systemic application of the receptor antagonist, 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP). Moreover, using a NPC-neuron co-culture system, we were able to demonstrate that the LTP-promoted NPC neurogenesis is at least in part mediated by a LTP-increased neuronal release of brain-derived neurotrophic factor (BDNF) and its consequent activation of tropomysosin receptor kinase B (TrkB) receptors on NSCs. Our results indicate that LTP promotes the neurogenesis of both endogenous and exogenously transplanted NSCs in the brain. The study suggests that pre-conditioning of the host brain receiving area with a LTP-inducing deep brain stimulation protocol prior to NSC transplantation may increase the likelihood of success of using NSC transplantation as an effective cell therapy for various neurodegenerative diseases. PMID:24146937

  4. Potential role of multiple carbon fixation pathways during lipid accumulation in Phaeodactylum tricornutum

    PubMed Central

    2012-01-01

    Background Phaeodactylum tricornutum is a unicellular diatom in the class Bacillariophyceae. The full genome has been sequenced (<30?Mb), and approximately 20 to 30% triacylglyceride (TAG) accumulation on a dry cell basis has been reported under different growth conditions. To elucidate P. tricornutum gene expression profiles during nutrient-deprivation and lipid-accumulation, cell cultures were grown with a nitrate to phosphate ratio of 20:1 (N:P) and whole-genome transcripts were monitored over time via RNA-sequence determination. Results The specific Nile Red (NR) fluorescence (NR fluorescence per cell) increased over time; however, the increase in NR fluorescence was initiated before external nitrate was completely exhausted. Exogenous phosphate was depleted before nitrate, and these results indicated that the depletion of exogenous phosphate might be an early trigger for lipid accumulation that is magnified upon nitrate depletion. As expected, many of the genes associated with nitrate and phosphate utilization were up-expressed. The diatom-specific cyclins cyc7 and cyc10 were down-expressed during the nutrient-deplete state, and cyclin B1 was up-expressed during lipid-accumulation after growth cessation. While many of the genes associated with the C3 pathway for photosynthetic carbon reduction were not significantly altered, genes involved in a putative C4 pathway for photosynthetic carbon assimilation were up-expressed as the cells depleted nitrate, phosphate, and exogenous dissolved inorganic carbon (DIC) levels. P. tricornutum has multiple, putative carbonic anhydrases, but only two were significantly up-expressed (2-fold and 4-fold) at the last time point when exogenous DIC levels had increased after the cessation of growth. Alternative pathways that could utilize HCO3- were also suggested by the gene expression profiles (e.g., putative propionyl-CoA and methylmalonyl-CoA decarboxylases). Conclusions The results indicate that P. tricornutum continued carbon dioxide reduction when population growth was arrested and different carbon-concentrating mechanisms were used dependent upon exogenous DIC levels. Based upon overall low gene expression levels for fatty acid synthesis, the results also suggest that the build-up of precursors to the acetyl-CoA carboxylases may play a more significant role in TAG synthesis rather than the actual enzyme levels of acetyl-CoA carboxylases per se. The presented insights into the types and timing of cellular responses to inorganic carbon will help maximize photoautotrophic carbon flow to lipid accumulation. PMID:22672912

  5. Expression profiling of the RPE in zebrafish smarca4 mutant revealed altered signals that potentially affect RPE and retinal differentiation

    PubMed Central

    Ma, Ping; Collery, Ross; Trowbridge, Sara; Zhong, Wenxuan; Leung, Yuk Fai

    2014-01-01

    Purpose The purpose of this study was to develop a framework for analyzing retinal pigment epithelium (RPE) expression profiles from zebrafish eye mutants. Methods The fish model we used was SWI/SNF-related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (smarca4), a retinal dystrophic mutant with a previously described retinal phenotype and expression profiles. Histological and Affymetrix GeneChip analyses were conducted to characterize the RPE defects and underlying differential expression, respectively. Results Histological analysis revealed that smarca4 RPE was formed, but its differentiation was abnormal. In particular, ultrastructural analysis of smarca4 RPE by transmission electron microscopy demonstrated several defects in melanogenesis. The nature of these defects also suggests that the cytoskeletal dynamics, which are tightly linked with melanogenesis, were impaired in smarca4 RPE. To compare the expression profile of normal wild-type (WT) and smarca4 RPE, the gene expression profiles of microdissected retinas and RPE-attached retinas were measured with Affymetrix GeneChip analysis. The RPE expression values were then estimated from these samples by subtracting the retinal expression values from the expression values of the RPE-attached retinas. A factorial analysis was conducted using the expression values of the RPE, retinal, and whole-embryo samples. Specific rules (contrasts) were built using the coefficients of the resulting fitted models to select for three groups of genes: 1) smarca4-regulated RPE genes, 2) smarca4-regulated retinal genes, and 3) smarca4-regulated RPE genes that are not differentially expressed in the retina. Interestingly, the third group consists of 39 genes that are highly related to cytoskeletal dynamics, melanogenesis, and paracrine and intracellular signal transduction. Conclusions Our analytical framework provides an experimental approach to identify differentially-regulated genes in the retina and the RPE of zebrafish mutants in which both of these tissues are affected by the underlying mutation. Specifically, we have used the method to identify a group of 39 genes that can potentially explain the melanogenesis defect in the smarca4 RPE. In addition, several genes in this group are secreted signaling molecules. Thus, this observation further implicates that the smarca4 RPE might play a role in the retinal dystrophic phenotype in smarca4. PMID:24426776

  6. Determination of Pu content in a Spent Fuel Assembly by Measuring Passive Total Neutron count rate and Multiplication with the Differential Die-Away Instrument

    SciTech Connect

    Henzl, Vladimir; Croft, Stephen; Swinhoe, Martyn T.; Tobin, Stephen J.

    2012-07-13

    Inspired by approach of Bignan and Martin-Didier (ESARDA 1991) we introduce novel (instrument independent) approach based on multiplication and passive neutron. Based on simulations of SFL-1 the accuracy of determination of {sup tot}Pu content with new approach is {approx}1.3-1.5%. Method applicable for DDA instrument, since it can measure both multiplication and passive neutron count rate. Comparison of pro's & con's of measuring/determining of {sup 239}Pu{sub eff} and {sup tot}Pu suggests a potential for enhanced diversion detection sensitivity.

  7. Preservation of Differentiation and Clonogenic Potential of Human Hematopoietic Stem and Progenitor Cells during Lyophilization and Ambient Storage

    PubMed Central

    Buchanan, Sandhya S.; Pyatt, David W.; Carpenter, John F.

    2010-01-01

    Progenitor cell therapies show great promise, but their potential for clinical applications requires improved storage and transportation. Desiccated cells stored at ambient temperature would provide economic and practical advantages over approaches employing cell freezing and subzero temperature storage. The objectives of this study were to assess a method for loading the stabilizing sugar, trehalose, into hematopoietic stem and progenitor cells (HPC) and to evaluate the effects of subsequent freeze-drying and storage at ambient temperature on differentiation and clonogenic potential. HPC were isolated from human umbilical cord blood and loaded with trehalose using an endogenous cell surface receptor, termed P2Z. Solution containing trehalose-loaded HPC was placed into vials, which were transferred to a tray freeze-dryer and removed during each step of the freeze-drying process to assess differentiation and clonogenic potential. Control groups for these experiments were freshly isolated HPC. Control cells formed 1450±230 CFU-GM, 430±140 BFU-E, and 50±40 CFU-GEMM per 50 µL. Compared to the values for the control cells, there was no statistical difference observed for cells removed at the end of the freezing step or at the end of primary drying. There was a gradual decrease in the number of CFU-GM and BFU-E for cells removed at different temperatures during secondary drying; however, there were no significant differences in the number of CFU-GEMM. To determine storage stability of lyophilized HPC, cells were stored for 4 weeks at 25°C in the dark. Cells reconstituted immediately after lyophilization produced 580±90 CFU-GM (∼40%, relative to unprocessed controls p<0.0001), 170±70 BFU-E (∼40%, p<0.0001), and 41±22 CFU-GEMM (∼82%, p = 0.4171), and cells reconstituted after 28 days at room temperature produced 513±170 CFU-GM (∼35%, relative to unprocessed controls, p<0.0001), 112±68 BFU-E (∼26%, p<0.0001), and 36±17 CFU-GEMM (∼82%, p = 0.2164) These studies are the first to document high level retention of CFU-GEMM following lyophilization and storage for 4 weeks at 25°C. This type of flexible storage stability would potentially permit the ability to ship and store HPC without the need for refrigeration. PMID:20824143

  8. The Potential of TaqMan Array Cards for Detection of Multiple Biological Agents by Real-Time PCR

    PubMed Central

    Rachwal, Phillip A.; Rose, Helen L.; Cox, Victoria; Lukaszewski, Roman A.; Murch, Amber L.; Weller, Simon A.

    2012-01-01

    The TaqMan Array Card architecture, normally used for gene expression studies, was evaluated for its potential to detect multiple bacterial agents by real-time PCR. Ten PCR assays targeting five biological agents (Bacillus anthracis, Burkholderia mallei, Burkholderia pseudomallei, Francisella tularensis, and Yersinia pestis) were incorporated onto Array Cards. A comparison of PCR performance of each PCR in Array Card and singleplex format was conducted using DNA extracted from pure bacterial cultures. When 100 fg of agent DNA was added to Array Card channels the following levels of agent detection (where at least one agent PCR replicate returned a positive result) were observed: Y. pestis 100%, B. mallei & F. tularensis 93%; B. anthracis 71%; B. pseudomallei 43%. For B. mallei & pseudomallei detection the BPM2 PCR, which detects both species, outperformed PCR assays specific to each organism indicating identification of the respective species would not be reproducible at the 100 fg level. Near 100% levels of detection were observed when 100 fg of DNA was added to each PCR in singleplex format with singleplex PCRs also returning sporadic positives at the 10 fg per PCR level. Before evaluating the use of Array Cards for the testing of environmental and clinical sample types, with potential levels of background DNA and PCR inhibitors, users would therefore have to accept a 10-fold reduction in sensitivity of PCR assays on the Array Card format, in order to benefit for the capacity to test multiple samples for multiple agents. A two PCR per agent strategy would allow the testing of 7 samples for the presence of 11 biological agents or 3 samples for 23 biological agents per card (with negative control channels). PMID:22540014

  9. Differential Gene Expression in the Siphonophore Nanomia bijuga (Cnidaria) Assessed with Multiple Next-Generation Sequencing Workflows

    PubMed Central

    Siebert, Stefan; Robinson, Mark D.; Tintori, Sophia C.; Goetz, Freya; Helm, Rebecca R.; Smith, Stephen A.; Shaner, Nathan; Haddock, Steven H. D.; Dunn, Casey W.

    2011-01-01

    We investigated differential gene expression between functionally specialized feeding polyps and swimming medusae in the siphonophore Nanomia bijuga (Cnidaria) with a hybrid long-read/short-read sequencing strategy. We assembled a set of partial gene reference sequences from long-read data (Roche 454), and generated short-read sequences from replicated tissue samples that were mapped to the references to quantify expression. We collected and compared expression data with three short-read expression workflows that differ in sample preparation, sequencing technology, and mapping tools. These workflows were Illumina mRNA-Seq, which generates sequence reads from random locations along each transcript, and two tag-based approaches, SOLiD SAGE and Helicos DGE, which generate reads from particular tag sites. Differences in expression results across workflows were mostly due to the differential impact of missing data in the partial reference sequences. When all 454-derived gene reference sequences were considered, Illumina mRNA-Seq detected more than twice as many differentially expressed (DE) reference sequences as the tag-based workflows. This discrepancy was largely due to missing tag sites in the partial reference that led to false negatives in the tag-based workflows. When only the subset of reference sequences that unambiguously have tag sites was considered, we found broad congruence across workflows, and they all identified a similar set of DE sequences. Our results are promising in several regards for gene expression studies in non-model organisms. First, we demonstrate that a hybrid long-read/short-read sequencing strategy is an effective way to collect gene expression data when an annotated genome sequence is not available. Second, our replicated sampling indicates that expression profiles are highly consistent across field-collected animals in this case. Third, the impacts of partial reference sequences on the ability to detect DE can be mitigated through workflow choice and deeper reference sequencing. PMID:21829563

  10. Differential gene expression in the siphonophore Nanomia bijuga (Cnidaria) assessed with multiple next-generation sequencing workflows.

    PubMed

    Siebert, Stefan; Robinson, Mark D; Tintori, Sophia C; Goetz, Freya; Helm, Rebecca R; Smith, Stephen A; Shaner, Nathan; Haddock, Steven H D; Dunn, Casey W

    2011-01-01

    We investigated differential gene expression between functionally specialized feeding polyps and swimming medusae in the siphonophore Nanomia bijuga (Cnidaria) with a hybrid long-read/short-read sequencing strategy. We assembled a set of partial gene reference sequences from long-read data (Roche 454), and generated short-read sequences from replicated tissue samples that were mapped to the references to quantify expression. We collected and compared expression data with three short-read expression workflows that differ in sample preparation, sequencing technology, and mapping tools. These workflows were Illumina mRNA-Seq, which generates sequence reads from random locations along each transcript, and two tag-based approaches, SOLiD SAGE and Helicos DGE, which generate reads from particular tag sites. Differences in expression results across workflows were mostly due to the differential impact of missing data in the partial reference sequences. When all 454-derived gene reference sequences were considered, Illumina mRNA-Seq detected more than twice as many differentially expressed (DE) reference sequences as the tag-based workflows. This discrepancy was largely due to missing tag sites in the partial reference that led to false negatives in the tag-based workflows. When only the subset of reference sequences that unambiguously have tag sites was considered, we found broad congruence across workflows, and they all identified a similar set of DE sequences. Our results are promising in several regards for gene expression studies in non-model organisms. First, we demonstrate that a hybrid long-read/short-read sequencing strategy is an effective way to collect gene expression data when an annotated genome sequence is not available. Second, our replicated sampling indicates that expression profiles are highly consistent across field-collected animals in this case. Third, the impacts of partial reference sequences on the ability to detect DE can be mitigated through workflow choice and deeper reference sequencing. PMID:21829563

  11. Exercise body surface potential mapping in single and multiple coronary artery disease

    SciTech Connect

    Montague, T.J.; Witkowski, F.X.; Miller, R.M.; Johnstone, D.E.; MacKenzie, R.B.; Spencer, C.A.; Horacek, B.M. )

    1990-06-01

    Body surface ST integral maps were recorded in 36 coronary artery disease (CAD) patients at: rest; peak, angina-limited exercise; and, 1 and 5 min of recovery. They were compared to maps