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Sample records for multiple differentiation potential

  1. Visual evoked potentials to multiple temporal frequencies. Use in the differential diagnosis of optic neuropathy.

    PubMed

    Bobak, P; Friedman, R; Brigell, M; Goodwin, J; Anderson, R

    1988-07-01

    The usefulness of the visual evoked potential (VEP) in differential diagnosis increases when stimulus parameters such as check size and grating orientation are varied. In this study we varied the stimulation frequency. Temporal frequency-specific abnormalities were compared in three patient categories, including retrobulbar optic neuritis (eight patients), pseudotumor cerebri (11 patients), and thyroid eye disease (seven patients). All patients had minimal clinical evidence of optic nerve damage when tested. A 2.3 cycle-per-degree sinusoidal grating of 55% contrast was phase reversed at either 1 or 4 Hz. The P1 latency of the 1-Hz data and the phase at 8 Hz, the second harmonic of the 4-Hz input frequency, were measured. In retrobulbar neuritis, latency (phase) was severely abnormal at both temporal frequencies. In thyroid eye disease, VEP phase was abnormal at 8 Hz while the P1 latency was normal at 1 Hz. The P1 latency and phase were normal in most cases of pseudotumor cerebri. The results suggest differing mechanisms for damage in compressive vs primary demyelinating neuropathies. PMID:3390057

  2. Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells

    PubMed Central

    Tanno, Toshihiko; Lim, Yiting; Wang, Qiuju; Chesi, Marta; Bergsagel, P. Leif; Matthews, Geoff; Johnstone, Ricky W.; Ghosh, Nilanjan; Borrello, Ivan; Huff, Carol Ann

    2014-01-01

    Disease relapse remains a major factor limiting the survival of cancer patients. In the plasma cell malignancy multiple myeloma (MM), nearly all patients ultimately succumb to disease relapse and progression despite new therapies that have improved remission rates. Tumor regrowth indicates that clonogenic growth potential is continually maintained, but the determinants of self-renewal in MM are not well understood. Normal stem cells are regulated by extrinsic niche factors, and the tumor microenvironment (TME) may similarly influence tumor cell clonogenic growth and self-renewal. Growth differentiation factor 15 (GDF15) is aberrantly secreted by bone marrow stromal cells (BMSCs) in MM. We found that GDF15 is produced by BMSCs after direct contact with plasma cells and enhances the tumor-initiating potential and self-renewal of MM cells in a protein kinase B- and SRY (sex-determining region Y)-box–dependent manner. Moreover, GDF15 induces the expansion of MM tumor-initiating cells (TICs), and changes in the serum levels of GDF15 were associated with changes in the frequency of clonogenic MM cells and the progression-free survival of MM patients. These findings demonstrate that GDF15 plays a critical role in mediating the interaction among mature tumor cells, the TME, and TICs, and strategies targeting GDF15 may affect long-term clinical outcomes in MM. PMID:24345755

  3. Label-free morphology-based prediction of multiple differentiation potentials of human mesenchymal stem cells for early evaluation of intact cells.

    PubMed

    Sasaki, Hiroto; Takeuchi, Ichiro; Okada, Mai; Sawada, Rumi; Kanie, Kei; Kiyota, Yasujiro; Honda, Hiroyuki; Kato, Ryuji

    2014-01-01

    Precise quantification of cellular potential of stem cells, such as human bone marrow-derived mesenchymal stem cells (hBMSCs), is important for achieving stable and effective outcomes in clinical stem cell therapy. Here, we report a method for image-based prediction of the multiple differentiation potentials of hBMSCs. This method has four major advantages: (1) the cells used for potential prediction are fully intact, and therefore directly usable for clinical applications; (2) predictions of potentials are generated before differentiation cultures are initiated; (3) prediction of multiple potentials can be provided simultaneously for each sample; and (4) predictions of potentials yield quantitative values that correlate strongly with the experimental data. Our results show that the collapse of hBMSC differentiation potentials, triggered by in vitro expansion, can be quantitatively predicted far in advance by predicting multiple potentials, multi-lineage differentiation potentials (osteogenic, adipogenic, and chondrogenic) and population doubling potential using morphological features apparent during the first 4 days of expansion culture. In order to understand how such morphological features can be effective for advance predictions, we measured gene-expression profiles of the same early undifferentiated cells. Both senescence-related genes (p16 and p21) and cytoskeleton-related genes (PTK2, CD146, and CD49) already correlated to the decrease of potentials at this stage. To objectively compare the performance of morphology and gene expression for such early prediction, we tested a range of models using various combinations of features. Such comparison of predictive performances revealed that morphological features performed better overall than gene-expression profiles, balancing the predictive accuracy with the effort required for model construction. This benchmark list of various prediction models not only identifies the best morphological feature conversion

  4. Label-Free Morphology-Based Prediction of Multiple Differentiation Potentials of Human Mesenchymal Stem Cells for Early Evaluation of Intact Cells

    PubMed Central

    Sasaki, Hiroto; Takeuchi, Ichiro; Okada, Mai; Sawada, Rumi; Kanie, Kei; Kiyota, Yasujiro; Honda, Hiroyuki; Kato, Ryuji

    2014-01-01

    Precise quantification of cellular potential of stem cells, such as human bone marrow–derived mesenchymal stem cells (hBMSCs), is important for achieving stable and effective outcomes in clinical stem cell therapy. Here, we report a method for image-based prediction of the multiple differentiation potentials of hBMSCs. This method has four major advantages: (1) the cells used for potential prediction are fully intact, and therefore directly usable for clinical applications; (2) predictions of potentials are generated before differentiation cultures are initiated; (3) prediction of multiple potentials can be provided simultaneously for each sample; and (4) predictions of potentials yield quantitative values that correlate strongly with the experimental data. Our results show that the collapse of hBMSC differentiation potentials, triggered by in vitro expansion, can be quantitatively predicted far in advance by predicting multiple potentials, multi-lineage differentiation potentials (osteogenic, adipogenic, and chondrogenic) and population doubling potential using morphological features apparent during the first 4 days of expansion culture. In order to understand how such morphological features can be effective for advance predictions, we measured gene-expression profiles of the same early undifferentiated cells. Both senescence-related genes (p16 and p21) and cytoskeleton-related genes (PTK2, CD146, and CD49) already correlated to the decrease of potentials at this stage. To objectively compare the performance of morphology and gene expression for such early prediction, we tested a range of models using various combinations of features. Such comparison of predictive performances revealed that morphological features performed better overall than gene-expression profiles, balancing the predictive accuracy with the effort required for model construction. This benchmark list of various prediction models not only identifies the best morphological feature conversion

  5. 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…

  6. 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)

  7. Differential operator multiplication method for fractional differential equations

    NASA Astrophysics Data System (ADS)

    Tang, Shaoqiang; Ying, Yuping; Lian, Yanping; Lin, Stephen; Yang, Yibo; Wagner, Gregory J.; Liu, Wing Kam

    2016-08-01

    Fractional derivatives play a very important role in modeling physical phenomena involving long-range correlation effects. However, they raise challenges of computational cost and memory storage requirements when solved using current well developed numerical methods. In this paper, the differential operator multiplication method is proposed to address the issues by considering a reaction-advection-diffusion equation with a fractional derivative in time. The linear fractional differential equation is transformed into an integer order differential equation by the proposed method, which can fundamentally fix the aforementioned issues for select fractional differential equations. In such a transform, special attention should be paid to the initial conditions for the resulting differential equation of higher integer order. Through numerical experiments, we verify the proposed method for both fractional ordinary differential equations and partial differential equations.

  8. 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…

  9. MRI differential diagnosis of suspected multiple sclerosis.

    PubMed

    Chen, J J; Carletti, F; Young, V; Mckean, D; Quaghebeur, G

    2016-09-01

    Diagnosing multiple sclerosis (MS) can be very challenging owing to its variable clinical features and lack of a definitive test. Magnetic resonance imaging (MRI) is a core diagnostic tool in the detection of MS lesions and demonstration of spatial and temporal distribution of disease. Moreover, MRI plays a crucial role in the exclusion of alternative diagnoses of MS. The aim of this review is to describe the typical MRI features of MS and to present a series of common mimics of MS with emphasis on their distinguishing features from MS. PMID:27349475

  10. Differentiating single and multiple victim child sexual abuse cases: a research note considering social disorganization theory.

    PubMed

    Mustaine, Elizabeth Ehrhardt; Tewksbury, Richard; Corzine, Jay; Huff-Corzine, Lin

    2014-01-01

    This study examined the utility of social disorganization theory as an explanation for child sexual abuse with a focus on differentiating single and multiple victim cases. Drawing on 1,172 child sexual abuse cases (including 159 cases with multiple victims) in Orange County, Florida, from 2004 to 2006, the present study considered case characteristics and elements of social disorganization as potential predictors of child sexual abuse cases involving single and multiple victims. We found that social disorganization theory does not successfully predict the locations of multiple victim child sexual abuse incidents and is not useful for distinguishing between child sexual abuse incidents with single or multiple victims. PMID:24393089

  11. 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…

  12. Detection of Differential Item Functioning in Multiple Groups.

    ERIC Educational Resources Information Center

    Kim, Seock-Ho; And Others

    Detection of differential item functioning (DIF) is most often done between two groups of examinees under item response theory. It is sometimes important, however, to determine whether DIF is present in more than two groups. A method is presented for the detection of DIF in multiple groups. The method, the Q(sub j) statistic, is closely related to…

  13. 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

  14. 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

  15. 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.

  16. Differential and limited expression of mutant alleles in multiple myeloma

    PubMed Central

    Rashid, Naim U.; Sperling, Adam S.; Bolli, Niccolo; Wedge, David C.; Van Loo, Peter; Tai, Yu-Tzu; Shammas, Masood A.; Fulciniti, Mariateresa; Samur, Mehmet K.; Richardson, Paul G.; Magrangeas, Florence; Minvielle, Stephane; Futreal, P. Andrew; Anderson, Kenneth C.; Avet-Loiseau, Herve; Parmigiani, Giovanni

    2014-01-01

    Recent work has delineated mutational profiles in multiple myeloma and reported a median of 52 mutations per patient, as well as a set of commonly mutated genes across multiple patients. In this study, we have used deep sequencing of RNA from a subset of these patients to evaluate the proportion of expressed mutations. We find that the majority of previously identified mutations occur within genes with very low or no detectable expression. On average, 27% (range, 11% to 47%) of mutated alleles are found to be expressed, and among mutated genes that are expressed, there often is allele-specific expression where either the mutant or wild-type allele is suppressed. Even in the absence of an overall change in gene expression, the presence of differential allelic expression within malignant cells highlights the important contribution of RNA-sequencing in identifying clinically significant mutational changes relevant to our understanding of myeloma biology and also for therapeutic applications. PMID:25237203

  17. Differential and limited expression of mutant alleles in multiple myeloma.

    PubMed

    Rashid, Naim U; Sperling, Adam S; Bolli, Niccolo; Wedge, David C; Van Loo, Peter; Tai, Yu-Tzu; Shammas, Masood A; Fulciniti, Mariateresa; Samur, Mehmet K; Richardson, Paul G; Magrangeas, Florence; Minvielle, Stephane; Futreal, P Andrew; Anderson, Kenneth C; Avet-Loiseau, Herve; Campbell, Peter J; Parmigiani, Giovanni; Munshi, Nikhil C

    2014-11-13

    Recent work has delineated mutational profiles in multiple myeloma and reported a median of 52 mutations per patient, as well as a set of commonly mutated genes across multiple patients. In this study, we have used deep sequencing of RNA from a subset of these patients to evaluate the proportion of expressed mutations. We find that the majority of previously identified mutations occur within genes with very low or no detectable expression. On average, 27% (range, 11% to 47%) of mutated alleles are found to be expressed, and among mutated genes that are expressed, there often is allele-specific expression where either the mutant or wild-type allele is suppressed. Even in the absence of an overall change in gene expression, the presence of differential allelic expression within malignant cells highlights the important contribution of RNA-sequencing in identifying clinically significant mutational changes relevant to our understanding of myeloma biology and also for therapeutic applications. PMID:25237203

  18. 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.

  19. 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

  20. Adult mesenchymal stem cells: differentiation potential and therapeutic applications.

    PubMed

    Jackson, L; Jones, D R; Scotting, P; Sottile, V

    2007-01-01

    Adult mesenchymal stem cells (MSCs) are a population of multipotent cells found primarily in the bone marrow. They have long been known to be capable of osteogenic, adipogenic and chondrogenic differentiation and are currently the subject of a number of trials to assess their potential use in the clinic. Recently, the plasticity of these cells has come under close scrutiny as it has been suggested that they may have a differentiation potential beyond the mesenchymal lineage. Myogenic and in particular cardiomyogenic potential has been shown in vitro. MSCs have also been shown to have the ability to form neural cells both in vitro and in vivo, although the molecular mechanisms underlying these apparent transdifferentiation events are yet to be elucidated. We describe here the cellular characteristics and differentiation potential of MSCs, which represent a promising stem cell population for future applications in regenerative medicine. PMID:17495381

  1. Immunopathology: autoimmune glial diseases and differentiation from multiple sclerosis.

    PubMed

    Popescu, Bogdan F Gh; Lucchinetti, Claudia F

    2016-01-01

    While multiple sclerosis (MS) is often referred to as an autoimmune inflammatory demyelinating disease, neuromyelitis optica (NMO) is currently the only proven and well-characterized autoimmune disease affecting the glial cells. The target antigen is the water channel aquaporin-4 (AQP4), expressed on astrocytes, and antibodies against AQP4 (AQP4-IgG) are present in the serum of NMO patients. Clinical, serologic, cerebrospinal fluid, and neuroimaging criteria help differentiate NMO from other central nervous system inflammatory demyelinating disorders. Pathologically, the presence of dystrophic astrocytes, myelin vacuolation, granulocytic inflammatory infiltrates, vascular hyalinization, macrophages containing glial fibrillary acidic protein-positive debris and/or the absence of Creutzfeldt-Peters cells is more characteristic, but not specific, for NMO. These findings should prompt the neuropathologist to perform AQP4 immunohistochemistry, and recommend serologic testing for AQP4-IgG to exclude a diagnosis of NMO/NMO spectrum disorder (NMOSD). Loss of AQP4 on biopsied active demyelinating lesions and/or seropositivity for AQP4-IgG may confirm the diagnosis of NMO/NMOSD, which is important because treatments that are suitable for MS can aggravate NMO. Few other putative glial antigens have been postulated, but their pathogenic role remains to be demonstrated. PMID:27112673

  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. Physicochemical Control of Adult Stem Cell Differentiation: Shedding Light on Potential Molecular Mechanisms

    PubMed Central

    Titushkin, Igor; Sun, Shan; Shin, Jennifer; Cho, Michael

    2010-01-01

    Realization of the exciting potential for stem-cell-based biomedical and therapeutic applications, including tissue engineering, requires an understanding of the cell-cell and cell-environment interactions. To this end, recent efforts have been focused on the manipulation of adult stem cell differentiation using inductive soluble factors, designing suitable mechanical environments, and applying noninvasive physical forces. Although each of these different approaches has been successfully applied to regulate stem cell differentiation, it would be of great interest and importance to integrate and optimally combine a few or all of the physicochemical differentiation cues to induce synergistic stem cell differentiation. Furthermore, elucidation of molecular mechanisms that mediate the effects of multiple differentiation cues will enable the researcher to better manipulate stem cell behavior and response. PMID:20379388

  4. 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

  5. Curriculum Differentiation: Multiple Perspectives and Developments in Education

    ERIC Educational Resources Information Center

    Terwel, J.

    2005-01-01

    This paper examines curriculum differentiation (i.e. streaming or ability-grouping). After placing curriculum differentiation in an international perspective, it outlines the main conclusions from empirical research on differentiation over several decades. Against this empirical background, it describes and considers the three specific…

  6. Differential effects and glucocorticoid potentiation of bone morphogenetic protein action during rat osteoblast differentiation in vitro.

    PubMed

    Boden, S D; McCuaig, K; Hair, G; Racine, M; Titus, L; Wozney, J M; Nanes, M S

    1996-08-01

    Bone morphogenetic proteins (BMPs) induce cartilage and bone differentiation in vivo and promote osteoblast differentiation from calvarial and marrow stromal cell preparations. Functional differences between BMP-2, -4, and -6 are not well understood. Recent investigations find that these three closely related osteoinductive proteins may exert different effects in primary rat calvarial cell cultures, suggesting the possibility of unique functions in vivo. In this study, we use a fetal rat secondary calvarial cell culture system to examine the differential effects of BMP-2, -4, and -6 on early osteoblast differentiation. These cells do not spontaneously differentiate into osteoblasts, as do cells in primary calvarial cultures, but rather require exposure to a differentiation initiator such as glucocorticoid or BMP. We determined that BMP-6 is a 2- to 2.5-fold more potent inducer of osteoblast differentiation than BMP-2 or -4. BMP-6 induced the formation of more and larger bone nodules as well as increased osteocalcin secretion. The effects of all three of these BMPs were potentiated up to 10-fold by cotreatment or pretreatment with the glucocorticoid triamcinolone (Trm). The Trm effects were synergistic with those of BMP-2 or -4, suggesting that this glucocorticoid may increase the cell responsiveness to these BMPs. Finally, BMP-6 did not require either cotreatment or pretreatment with Trm to achieve greater amounts of osteoblast differentiation than seen with BMP-2 or BMP-4 treatment, suggesting that BMP-6 may act at an earlier stage of cell differentiation. PMID:8754767

  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. 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.

  9. Differentiation of multiple sclerosis subtypes: implications for treatment.

    PubMed

    Bitsch, Andreas; Brück, Wolfgang

    2002-01-01

    There has been tremendous progress in the immunomodulatory treatment of multiple sclerosis (MS) during recent years. With the introduction of interferon-beta, glatiramer acetate and mitoxantrone (recently registered for MS in the US), there are at least three therapeutic strategies that have proven effective in large phase III studies. However, not all patients with MS respond well to treatment with these drugs. This may largely be a consequence of disease heterogeneity. From a clinical perspective, patients with different disease courses show different treatment responses. Patients with relapsing-remitting MS are more likely to respond to immunomodulatory therapy than those with a progressive disease course. Studies of patients with secondary progressive MS have yielded inconsistent results and, so far, there has been no positive phase III study of immunomodulatory therapy in patients with primary progressive MS. Pathological evidence indicates that subtyping based on clinical findings alone does not reflect actual disease heterogeneity. In a large series of biopsy and autopsy specimens, at least four subtypes could be identified with respect to oligodendrocyte/myelin pathology and immunopathology. As long as the only method of identifying subtypes of disease is histopathology, differential therapy will remain a future goal. Thus, there is an urgent need for in vivo markers of immunopathogenesis in an individual patient that would allow treatment to be specifically directed towards a given pathological focus. However, at least from a theoretical point of view, some therapeutic approaches appear very attractive. Plasmapheresis and/or intravenous immunoglobulins could most plausibly be the best approach for the immunopathological subtype of MS, which is characterised by antibody and complement deposition next to demyelinated axons, in order to remove antibodies. The subtype of MS that is associated with heavy macrophage activation, T cell infiltration and expression

  10. Meta-Analysis of Differential Connectivity in Gene Co-Expression Networks in Multiple Sclerosis

    PubMed Central

    Creanza, Teresa Maria; Liguori, Maria; Liuni, Sabino; Nuzziello, Nicoletta; Ancona, Nicola

    2016-01-01

    Differential gene expression analyses to investigate multiple sclerosis (MS) molecular pathogenesis cannot detect genes harboring genetic and/or epigenetic modifications that change the gene functions without affecting their expression. Differential co-expression network approaches may capture changes in functional interactions resulting from these alterations. We re-analyzed 595 mRNA arrays from publicly available datasets by studying changes in gene co-expression networks in MS and in response to interferon (IFN)-β treatment. Interestingly, MS networks show a reduced connectivity relative to the healthy condition, and the treatment activates the transcription of genes and increases their connectivity in MS patients. Importantly, the analysis of changes in gene connectivity in MS patients provides new evidence of association for genes already implicated in MS by single-nucleotide polymorphism studies and that do not show differential expression. This is the case of amiloride-sensitive cation channel 1 neuronal (ACCN1) that shows a reduced number of interacting partners in MS networks, and it is known for its role in synaptic transmission and central nervous system (CNS) development. Furthermore, our study confirms a deregulation of the vitamin D system: among the transcription factors that potentially regulate the deregulated genes, we find TCF3 and SP1 that are both involved in vitamin D3-induced p27Kip1 expression. Unveiling differential network properties allows us to gain systems-level insights into disease mechanisms and may suggest putative targets for the treatment. PMID:27314336

  11. Meta-Analysis of Differential Connectivity in Gene Co-Expression Networks in Multiple Sclerosis.

    PubMed

    Creanza, Teresa Maria; Liguori, Maria; Liuni, Sabino; Nuzziello, Nicoletta; Ancona, Nicola

    2016-01-01

    Differential gene expression analyses to investigate multiple sclerosis (MS) molecular pathogenesis cannot detect genes harboring genetic and/or epigenetic modifications that change the gene functions without affecting their expression. Differential co-expression network approaches may capture changes in functional interactions resulting from these alterations. We re-analyzed 595 mRNA arrays from publicly available datasets by studying changes in gene co-expression networks in MS and in response to interferon (IFN)-β treatment. Interestingly, MS networks show a reduced connectivity relative to the healthy condition, and the treatment activates the transcription of genes and increases their connectivity in MS patients. Importantly, the analysis of changes in gene connectivity in MS patients provides new evidence of association for genes already implicated in MS by single-nucleotide polymorphism studies and that do not show differential expression. This is the case of amiloride-sensitive cation channel 1 neuronal (ACCN1) that shows a reduced number of interacting partners in MS networks, and it is known for its role in synaptic transmission and central nervous system (CNS) development. Furthermore, our study confirms a deregulation of the vitamin D system: among the transcription factors that potentially regulate the deregulated genes, we find TCF3 and SP1 that are both involved in vitamin D3-induced p27Kip1 expression. Unveiling differential network properties allows us to gain systems-level insights into disease mechanisms and may suggest putative targets for the treatment. PMID:27314336

  12. Glial-like differentiation potential of human mature adipocytes.

    PubMed

    Poloni, Antonella; Maurizi, Giulia; Foia, Federica; Mondini, Eleonora; Mattiucci, Domenico; Ambrogini, Patrizia; Lattanzi, Davide; Mancini, Stefania; Falconi, Massimo; Cinti, Saverio; Olivieri, Attilio; Leoni, Pietro

    2015-01-01

    The potential ability to differentiate dedifferentiated adipocytes into a neural lineage is attracting strong interest as an emerging method of producing model cells for the treatment of a variety of neurological diseases. Here, we describe the efficient conversion of dedifferentiated adipocytes into a neural-like cell population. These cells grew in neurosphere-like structures and expressed a high level of the early neuroectodermal marker Nestin. These neurospheres could proliferate and express stemness genes, suggesting that these cells could be committed to the neural lineage. After neural induction, NeuroD1, Sox1, Double Cortin, and Eno2 were not expressed. Patch clamp data did not reveal different electrophysiological properties, indicating the inability of these cells to differentiate into mature neurons. In contrast, the differentiated cells expressed a high level of CLDN11, as demonstrated using molecular method, and stained positively for the glial cell markers CLDN11 and GFAP, as demonstrated using immunocytochemistry. These data were confirmed by quantitative results for glial cell line-derived neurotrophic factor production, which showed a higher secretion level in neurospheres and the differentiated cells compared with the untreated cells. In conclusion, our data demonstrate morphological, molecular, and immunocytochemical evidence of initial neural differentiation of mature adipocytes, committing to a glial lineage. PMID:25007949

  13. Fully relativistic multiple scattering calculations for general potentials

    NASA Astrophysics Data System (ADS)

    Ebert, H.; Braun, J.; Ködderitzsch, D.; Mankovsky, S.

    2016-02-01

    The formal basis for fully relativistic Korringa-Kohn-Rostoker (KKR) or multiple scattering calculations for the electronic Green function in case of a general potential is discussed. Simple criteria are given to identify situations that require to distinguish between right- and left-hand-side solutions to the Dirac equation when setting up the electronic Green function. In addition, various technical aspects of an implementation of the relativistic KKR for general local and nonlocal potentials will be discussed.

  14. Multiple sclerosis: symptom equivalent to delayed visual evoked potential latency.

    PubMed

    Stenager, E; Jensen, K

    1990-10-01

    An investigation on the correlation between ability to read TV subtitles and the duration of visual evoked potential (VEP) latency in 14 patients with definite multiple sclerosis (MS), indicated that VEP latency in patients unable to read the TV subtitles was significantly delayed in comparison to that of patients who mastered this task. PMID:2275357

  15. 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-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

  16. 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

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

    PubMed Central

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

    2015-01-01

    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

  18. 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

  19. 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.

  20. 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…

  1. 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.

  2. Application of Differential Evolution Algorithm on Self-Potential Data

    PubMed Central

    Li, Xiangtao; Yin, Minghao

    2012-01-01

    Differential evolution (DE) is a population based evolutionary algorithm widely used for solving multidimensional global optimization problems over continuous spaces, and has been successfully used to solve several kinds of problems. In this paper, differential evolution is used for quantitative interpretation of self-potential data in geophysics. Six parameters are estimated including the electrical dipole moment, the depth of the source, the distance from the origin, the polarization angle and the regional coefficients. This study considers three kinds of data from Turkey: noise-free data, contaminated synthetic data, and Field example. The differential evolution and the corresponding model parameters are constructed as regards the number of the generations. Then, we show the vibration of the parameters at the vicinity of the low misfit area. Moreover, we show how the frequency distribution of each parameter is related to the number of the DE iteration. Experimental results show the DE can be used for solving the quantitative interpretation of self-potential data efficiently compared with previous methods. PMID:23240004

  3. 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

  4. THY-1 Receptor Expression Differentiates Cardiosphere-Derived Cells with Divergent Cardiogenic Differentiation Potential

    PubMed Central

    Gago-Lopez, Nuria; Awaji, Obinna; Zhang, Yiqiang; Ko, Christopher; Nsair, Ali; Liem, David; Stempien-Otero, April; MacLellan, W. Robb

    2014-01-01

    Summary Despite over a decade of intense research, the identity and differentiation potential of human adult cardiac progenitor cells (aCPC) remains controversial. Cardiospheres have been proposed as a means to expand aCPCs in vitro, but the identity of the progenitor cell within these 3D structures is unknown. We show that clones derived from cardiospheres could be subdivided based on expression of thymocyte differentiation antigen 1 (THY-1/CD90) into two distinct populations that exhibit divergent cardiac differentiation potential. One population, which is CD90+, expressed markers consistent with a mesenchymal/myofibroblast cell. The second clone type was CD90− and could form mature, functional myocytes with sarcomeres albeit at a very low rate. These two populations of cardiogenic clones displayed distinct cell surface markers and unique transcriptomes. Our study suggests that a rare aCPC exists in cardiospheres along with a mesenchymal/myofibroblast cell, which demonstrates incomplete cardiac myocyte differentiation. PMID:24936447

  5. 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-κB 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-κB 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

  6. Differentiation Potential of Urothelium from Patients with Benign Bladder Dysfunction

    PubMed Central

    Southgate, Jennifer; Varley, Claire L; Garthwaite, Mary AE; Hinley, Jennifer; Marsh, Fiona; Stahlschmidt, Jens; Trejdosiewicz, Ludwik K; Eardley, Ian

    2007-01-01

    Objective Benign dysfunctional bladder diseases encompass a number of poorly understood clinically-defined conditions, including interstitial cystitis (IC), idiopathic detrusor overactivity (IDO) and stress urinary incontinence (SUI). We developed a novel in vitro approach to test the hypothesis that failure of urothelial differentiation underlies the aetiopathology of IC, where there is evidence of compromised urinary barrier function. Materials and Methods Biopsy-derived urothelial cells from dysfunctional bladder biopsies were propagated as finite cell lines and examined for their capacity to undergo differentiation in vitro, as assessed by acquisition of a transitional cell morphology, a switch from a CK13lo/CK14hi to a CK13hi/CK14lo phenotype, expression of claudin 3, 4 and 5 proteins and induction of uroplakin gene transcription. Results 2/12 SUI cell lines showed early senescent changes in culture and were not characterised further; 1/7 IC, 1/5 IDO and a further 3 SUI cell lines displayed some evidence of senescence at passage 3. Of the IC-derived cell lines, 4/7 showed a near normal range of differentiation-associated responses, but the remainder of IC lines showed little or no response. A majority of IDO cell lines (4/5) showed a normal differentiation response, but at least 3/10 SUI cell lines showed some compromise of differentiation potential. Conclusion Our study supports the existence of a subset of IC patient in whom a failure of urothelial cytodifferentiation may contribute to the disease and provides a novel platform for investigating the cell biology of urothelium from SUI and other benign dysfunctional conditions. PMID:17537219

  7. 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-κB 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-κB 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

  8. System for measuring multiphase flow using multiple pressure differentials

    DOEpatents

    Fincke, James R.

    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.

  9. 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…

  10. 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

  11. 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

  12. 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

  13. Phonological fluency strategy of switching differentiates relapsing-remitting and secondary progressive multiple sclerosis patients.

    PubMed

    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

  14. [The differentiation potential of stem cells (the problem of plasticity)].

    PubMed

    Chertkov, I L; Drize, N I

    2005-01-01

    Numerous publications on the ability of adult stem cells to differentiate into the cells of various tissues, not always homodermic (stem cell flexibility), to contain serious methodic errors. The main flexibility phenomena, such as "transdifferentiation" of hemopoietic stem cells into hepatocytes, cardiomyocytes, beta-cells of islets of Langerhans, neurons etc., are caused not by a shift of the differentiation path, but by cell merging, resulting in appearance of hybrids with unusual markers of cells of non-hemopoietic origin. The second most frequent error is wrong identification of macrophages and lymphocytes, which are present in any tissue and have the donor's genotype in chimeras. Even when the cause of the error is unknown, the phenomenon of unusual cell formation is exclusively rare and never bears therapeutic potential. In general, it is at least too early to revise the main tenets of the stem cell doctrine. Embryonic stem cells are totipotent indeed; however, the time of their clinical use has not come yet. Attempts to induce their ordered differentiation keep on failing; they very often lead to formation of teratomas and, even if necessary cells such as hemopoietic stem cells are formed, they do not work after administration into an organism that has been exposed to radiation. Clinical use of embryonic stem cells do not seem possible in this decade. PMID:16320705

  15. 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 PKCα. 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 NFκB. 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

  16. 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

  17. A New Differential Logic-Compatible Multiple-Time Programmable Memory Cell

    NASA Astrophysics Data System (ADS)

    Yi-Hung Tsai,; Hsiao-Lan Yang,; Wun-Jie Lin,; Chrong Jung Lin,; Ya-Chin King,

    2010-04-01

    This work presents a novel differential n-channel logic-compatible multiple-time programmable (MTP) memory cell. This cell features double sensing window by a differential pair of floating gates, and therefore increases the retention lifetime of the nonvolatile memory effectively. Also, a self-selective programming (SSP) method is innovated in writing one pair differential data by a single cell without increasing any design or process complexity in peripheral circuit. The differential cell is a promising MTP solution to challenge thin floating gate oxide below 70 Å for 90 nm complementary metal-oxide-semiconductor (CMOS) node and beyond.

  18. Multiple sclerosis at menopause: Potential neuroprotective effects of estrogen.

    PubMed

    Christianson, Mindy S; Mensah, Virginia A; Shen, Wen

    2015-02-01

    Multiple sclerosis (MS) is an autoimmune demyelinating and neurodegenerative condition of the central nervous system that preferentially afflicts women more than men. Low estrogen states such as menopause and the postpartum period favor exacerbations of multiple sclerosis in women with the disease. Existing and emerging evidence suggests a role for estrogen in the alleviation of symptoms and reversal of pathology associated with MS. While clinical evidence is sparse regarding the benefit of estrogen therapy for women at risk for MS exacerbations, scientific data demonstrates that estrogen potentiates numerous neuroprotective effects on the central nervous system (CNS). Estrogens play a wide range of roles involved in MS disease pathophysiology, including increasing antiinflammatory cytokines, decreasing demyelination, and enhancing oxidative and energy producing processes in CNS cells. PMID:25544310

  19. 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

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

    PubMed

    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

  1. Differential ontogeny of multiple opioid receptors (mu, delta, and kappa)

    SciTech Connect

    Spain, J.W.; Roth, B.L.; Coscia, C.J.

    1985-03-01

    We investigated the postnatal ontogeny of opioid receptors in rat brain under assay conditions which, when combined with computerized analysis, effectively reflect the developmental profile of high affinity binding to mu, delta, and kappa subpopulations. Concentrations of mu sites were assessed with the selective ligand /sup 3/H-(D-ala2,mePhe4,gly-ol5)enkephalin (DAGO). The other two sites were analyzed in binding assays with less selective radioligands but in the presence of specific unlabeled ligands which suppress cross-reactivity. We utilized /sup 3/H-(D-ala2,D-leu5)enkephalin (DADL) in the presence of 10 nM DAGO to label delta sites and /sup 3/H-ethylketocyclazocine (EKC) in the presence of 100 nM DADL + 100 nM (D-ala2,mePhe4,Met(0)ol5)enkephalin to detect kappa receptors. After birth, the density (femtomoles per milligram of wet weight) of mu sites declined for several days and then rose sharply over the next 2 weeks, increasing 2-fold by adulthood. Delta (delta) sites appeared in the second week postnatal and increased more than 8-fold in the next 2 weeks. Levels of kappa receptors were relatively low at birth and increased slowly (2-fold, overall). Computerized analyses of binding data revealed that DAGO and DADL were binding to single populations of sites throughout the postnatal period. DAGO and EKC affinities did not fluctuate in this period, whereas DADL affinities were low for the first week and then rose to adult levels. In summary, mu, kappa, and delta receptors exhibit differential postnatal developmental profiles. The former two are present at birth, whereas the latter appears in the second week. The postnatal increase for all three sites appear to be preceded by the previously demonstrated emergence of opioid peptides.

  2. Differential effects of alcohol on working memory: distinguishing multiple processes.

    PubMed

    Saults, J Scott; Cowan, Nelson; Sher, Kenneth J; Moreno, Matthew V

    2007-12-01

    The authors assessed effects of alcohol consumption on different types of working memory (WM) tasks in an attempt to characterize the nature of alcohol effects on cognition. The WM tasks varied in 2 properties of materials to be retained in a 2-stimulus comparison procedure. Conditions included (a) spatial arrays of colors, (b) temporal sequences of colors, (c) spatial arrays of spoken digits, and (d) temporal sequences of spoken digits. Alcohol consumption impaired memory for auditory and visual sequences but not memory for simultaneous arrays of auditory or visual stimuli. These results suggest that processes needed to encode and maintain stimulus sequences, such as rehearsal, are more sensitive to alcohol intoxication than other WM mechanisms needed to maintain multiple concurrent items, such as focusing attention on them. These findings help to resolve disparate findings from prior research on alcohol's effect on WM and on divided attention. The results suggest that moderate doses of alcohol impair WM by affecting certain mnemonic strategies and executive processes rather than by shrinking the basic holding capacity of WM. PMID:18179311

  3. 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…

  4. Differential Regulation of the Multiple Flagellins in Spirochetes▿

    PubMed Central

    Li, Chunhao; Sal, Melanie; Marko, Michael; Charon, Nyles W.

    2010-01-01

    The expression of flagellin genes in most bacteria is typically regulated by the flagellum-specific sigma28 factor FliA, and an anti-sigma28 factor, FlgM. However, the regulatory hierarchy in several bacteria that have multiple flagellins is more complex. In these bacteria, the flagellin genes are often transcribed by at least two different sigma factors. The flagellar filament in spirochetes consists of one to three FlaB core proteins and at least one FlaA sheath protein. Here, the genetically amenable bacterium Brachyspira hyodysenteriae was used as a model spirochete to investigate the regulation of its four flagellin genes, flaA, flaB1, flaB2, and flaB3. We found that the flaB1 and flaB2 genes are regulated by sigma28, whereas the flaA and flaB3 genes are controlled by sigma70. The analysis of a flagellar motor switch fliG mutant further supported this proposition; in the mutant, the transcription of flaB1 and flaB2 was inhibited, but that of flaA and flaB3 was not. In addition, the continued expression of flaA and flaB3 in the mutant resulted in the formation of incomplete flagellar filaments that were hollow tubes and consisted primarily of FlaA. Finally, our recent studies have shown that each flagellin unit contributes to the stiffness of the periplasmic flagella, and this stiffness directly correlates with motility. The regulatory mechanism identified here should allow spirochetes to change the relative ratio of these flagellin proteins and, concomitantly, vary the stiffness of their flagellar filament. PMID:20304988

  5. Multiple Scattering Approach to Continuum State with Generally Shaped Potential

    SciTech Connect

    Hatada, Keisuke; Hayakawa, Kuniko; Tenore, Antonio; Benfatto, Maurizio; Natoli, Calogero

    2007-02-02

    We present a new scheme for solving the scattering problem for an arbitrarily shaped potential cell that avoids the well known convergence problems in the angular momentum expansion of the cell shape function. Tests of the method against analytically soluble separable model potentials, with and without shape truncation, have been performed with success. By a judicious choice of the shape of the cells partitioning the whole molecular space and use of empty cells when necessary, we set up a multiple scattering scheme that leads to a straightforward generalization of the same equations in the muffin-tin approximation. For example lmax in the angular momentum expansion can still be chosen according to the rule lmax {approx} kR, where R is the radius of the bounding sphere of the cell and all the matrices appearing in the theory are square matrices.

  6. Conditionally Immortalized Mouse Embryonic Fibroblasts Retain Proliferative Activity without Compromising Multipotent Differentiation Potential

    PubMed Central

    Huang, Enyi; Bi, Yang; Jiang, Wei; Luo, Xiaoji; Yang, Ke; Gao, Jian-Li; Gao, Yanhong; Luo, Qing; Shi, Qiong; Kim, Stephanie H.; Liu, Xing; Li, Mi; Hu, Ning; Liu, Hong; Cui, Jing; Zhang, Wenwen; Li, Ruidong; Chen, Xiang; Shen, Jikun; Kong, Yuhan; Zhang, Jiye; Wang, Jinhua; Luo, Jinyong; He, Bai-Cheng; Wang, Huicong; Reid, Russell R.; Luu, Hue H.; Haydon, Rex C.; Yang, Li; He, Tong-Chuan

    2012-01-01

    Mesenchymal stem cells (MSCs) are multipotent cells which reside in many tissues and can give rise to multiple lineages including bone, cartilage and adipose. Although MSCs have attracted significant attention for basic and translational research, primary MSCs have limited life span in culture which hampers MSCs' broader applications. Here, we investigate if mouse mesenchymal progenitors can be conditionally immortalized with SV40 large T antigen and maintain long-term cell proliferation without compromising their multipotency. Using the system which expresses SV40 large T antigen flanked with Cre/loxP sites, we demonstrate that mouse embryonic fibroblasts (MEFs) can be efficiently immortalized by SV40 large T antigen. The conditionally immortalized MEFs (iMEFs) exhibit an enhanced proliferative activity and maintain long-term cell proliferation, which can be reversed by Cre recombinase. The iMEFs express most MSC markers and retain multipotency as they can differentiate into osteogenic, chondrogenic and adipogenic lineages under appropriate differentiation conditions in vitro and in vivo. The removal of SV40 large T reduces the differentiation potential of iMEFs possibly due to the decreased progenitor expansion. Furthermore, the iMEFs are apparently not tumorigenic when they are subcutaneously injected into athymic nude mice. Thus, the conditionally immortalized iMEFs not only maintain long-term cell proliferation but also retain the ability to differentiate into multiple lineages. Our results suggest that the reversible immortalization strategy using SV40 large T antigen may be an efficient and safe approach to establishing long-term cell culture of primary mesenchymal progenitors for basic and translational research, as well as for potential clinical applications. PMID:22384246

  7. 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

  8. 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.

  9. Contrast Sensitivity versus Visual Evoked Potentials in Multiple Sclerosis

    PubMed Central

    Shandiz, Javad Heravian; Nourian, Abbas; Hossaini, Mercedeh Bahr; Moghaddam, Hadi Ostadi; yekta, Abbas-Ali; Sharifzadeh, Laleh; Marouzi, Parviz

    2010-01-01

    Purpose To compare the Cambridge contrast sensitivity (CS) test and visual evoked potentials (VEP) in detecting visual impairment in a population of visually symptomatic and asymptomatic patients affected by clinically definite multiple sclerosis (MS). Methods Fifty patients (100 eyes) presenting with MS and 25 healthy subjects (50 eyes) with normal corrected visual acuity were included in this study. CS was determined using the Cambridge Low Contrast Grating test and VEP was obtained in all eyes. Findings were evaluated in two age strata of 10–29 and 30–49 years. Results Of the 42 eyes in the 10–29 year age group, CS was abnormal in 22 (52%), VEP was also abnormal in 22 (52%), but only 12 eyes (28%) had visual symptoms. Of the 58 eyes in the 30–49 year group, CS was abnormal in 7 (12%), VEP was abnormal in 34 (58%), while only 11 eyes were symptomatic. No single test could detect all of the abnormal eyes. Conclusion The Cambridge Low Contrast Grating test is useful for detection of clinical and subclinical visual dysfunction especially in young patients with multiple sclerosis. Nevertheless, only a combination of CS and VEP tests can detect most cases of visual dysfunction associated with MS. PMID:22737353

  10. Characterization of Myelomonocytoid Progenitor Cells with Mesenchymal Differentiation Potential Obtained by Outgrowth from Pancreas Explants

    PubMed Central

    Roehrich, Marc-Estienne; Vassalli, Giuseppe

    2012-01-01

    Progenitor cells can be obtained by outgrowth from tissue explants during primary ex vivo tissue culture. We have isolated and characterized cells outgrown from neonatal mouse pancreatic explants. A relatively uniform population of cells showing a distinctive morphology emerged over time in culture. This population expressed monocyte/macrophage and hematopoietic markers (CD11b+ and CD45+), and some stromal-related markers (CD44+ and CD29+), but not mesenchymal stem cell (MSC)-defining markers (CD90− and CD105−) nor endothelial (CD31−) or stem cell-associated markers (CD133− and stem cell antigen-1; Sca-1−). Cells could be maintained in culture as a plastic-adherent monolayer in culture medium (MesenCult MSC) for more than 1 year. Cells spontaneously formed sphere clusters “pancreatospheres” which, however, were nonclonal. When cultured in appropriate media, cells differentiated into multiple mesenchymal lineages (fat, cartilage, and bone). Positive dithizone staining suggested that a subset of cells differentiated into insulin-producing cells. However, further studies are needed to characterize the endocrine potential of these cells. These findings indicate that a myelomonocytoid population from pancreatic explant outgrowths has mesenchymal differentiation potential. These results are in line with recent data onmonocyte-derivedmesenchymal progenitors (MOMPs). PMID:22953065

  11. Probabilistic delay differential equation modeling of event-related potentials.

    PubMed

    Ostwald, Dirk; Starke, Ludger

    2016-08-01

    "Dynamic causal models" (DCMs) are a promising approach in the analysis of functional neuroimaging data due to their biophysical interpretability and their consolidation of functional-segregative and functional-integrative propositions. In this theoretical note we are concerned with the DCM framework for electroencephalographically recorded event-related potentials (ERP-DCM). Intuitively, ERP-DCM combines deterministic dynamical neural mass models with dipole-based EEG forward models to describe the event-related scalp potential time-series over the entire electrode space. Since its inception, ERP-DCM has been successfully employed to capture the neural underpinnings of a wide range of neurocognitive phenomena. However, in spite of its empirical popularity, the technical literature on ERP-DCM remains somewhat patchy. A number of previous communications have detailed certain aspects of the approach, but no unified and coherent documentation exists. With this technical note, we aim to close this gap and to increase the technical accessibility of ERP-DCM. Specifically, this note makes the following novel contributions: firstly, we provide a unified and coherent review of the mathematical machinery of the latent and forward models constituting ERP-DCM by formulating the approach as a probabilistic latent delay differential equation model. Secondly, we emphasize the probabilistic nature of the model and its variational Bayesian inversion scheme by explicitly deriving the variational free energy function in terms of both the likelihood expectation and variance parameters. Thirdly, we detail and validate the estimation of the model with a special focus on the explicit form of the variational free energy function and introduce a conventional nonlinear optimization scheme for its maximization. Finally, we identify and discuss a number of computational issues which may be addressed in the future development of the approach. PMID:27114057

  12. 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

  13. 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

  14. 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…

  15. 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…

  16. Thyroid Hormone Potentially Benefits Multiple Sclerosis via Facilitating Remyelination.

    PubMed

    Zhang, Mao; Ma, Ziyi; Qin, Haochen; Yao, Zhongxiang

    2016-09-01

    Myelin destruction due to inflammatory damage of oligodendrocytes (OLs) in conjunction with axonal degeneration is one of the major histopathological hallmarks of multiple sclerosis (MS), a common autoimmune disorder affecting the central nervous system (CNS). Therapies over the last 20 years mainly focus on the immune system and, more specifically, on the modulation of immune cell behavior. It seems to be effective in MS with relapse, while it is of little benefit to progressive MS in which neurodegeneration following demyelination outweighs inflammation. Otherwise, remyelination, as a result of oligodendrocyte production from oligodendrocyte precursor cells (OPCs), is considered to be a potential target for the treatment of progressive MS. In this review, positive effects of remyelination on MS will be discussed in view of the critical role played by thyroid hormone (TH), focusing on the following points: (1) promising treatment of TH on MS that potentially targets to remyelination; (2) the active role of TH that is able to promote remyelination; (3) the regulative role of TH that works on endogenous stem and precursor cells; (4) the effect of TH on gene transcription; and (5) a working hypothesis which is developed that TH can alleviate MS by promoting remyelination, and the mechanism of which is its regulative role in gene transcription of OPCs. PMID:26243185

  17. 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

  18. 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

  19. 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

  20. Potential Risk Factors of Death in Multiple Trauma Patients

    PubMed Central

    Jelodar, Sina; Jafari, Peyman; Yadollahi, Mahnaz; Sabetian Jahromi, Golnar; Khalili, Hoseynali; Abbasi, Hamidreza; Bolandparvaz, Shahram; Paydar, Shahram

    2014-01-01

    Introduction: rauma has been recognized as one of the leading causes of death in many countries for decades. Reduction in mortality and morbidity rate of trauma cases is one of the most important attitudes in this field. Evaluation of different risk factors have been considered as the main goal of some studies. The purpose of this study was determining potential risk factors of death in trauma patients. Method: In a retrograde study, data of 740 patients admitted during three years (2009-2011) were studied. Demographic data (sex and age), clinical factors (blood pressure, pulse rate, respiratory rate, Glasgow coma scale (GCS)), trauma characteristics (location, type of injury, etc.), as well as outcome of patients were evaluated. Data analyses was done using SPSS 18.0. Stepwise multivariate regression analysis was used for recognition of independent predictive factors of death in multiple trauma patients. Results: Of those admitted, majority of patients were male (81.4%), 68% between 18 to 60 years, and 11.2% of them died during the course of treatment. Age; type of trauma; abnormal respiration rate, pulse rate, blood pressure; total GCS ≤8; abnormal pupil size; and head and neck; vertebral, and extremities fractures were obtained as significant predictive factor of death. GCS≤8, head and neck fracture, and abnormal pulse rate were independent death predictors. Conclusion: We identified GCS≤8, head and neck fracture, and abnormal pulse rate as predictive factors of mortality after trauma, which remained independent in the presence of all other factors and potentially treatable. PMID:26495375

  1. 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

  2. Protein Analysis of Sapienic Acid-Treated Porphyromonas gingivalis Suggests Differential Regulation of Multiple Metabolic Pathways

    PubMed Central

    Dawson, Deborah V.; Blanchette, Derek R.; Drake, David R.; Wertz, Philip W.; Brogden, Kim A.

    2015-01-01

    ABSTRACT Lipids endogenous to skin and mucosal surfaces exhibit potent antimicrobial activity against Porphyromonas gingivalis, an important colonizer of the oral cavity implicated in periodontitis. Our previous work demonstrated the antimicrobial activity of the fatty acid sapienic acid (C16:1Δ6) against P. gingivalis and found that sapienic acid treatment alters both protein and lipid composition from those in controls. In this study, we further examined whole-cell protein differences between sapienic acid-treated bacteria and untreated controls, and we utilized open-source functional association and annotation programs to explore potential mechanisms for the antimicrobial activity of sapienic acid. Our analyses indicated that sapienic acid treatment induces a unique stress response in P. gingivalis resulting in differential expression of proteins involved in a variety of metabolic pathways. This network of differentially regulated proteins was enriched in protein-protein interactions (P = 2.98 × 10−8), including six KEGG pathways (P value ranges, 2.30 × 10−5 to 0.05) and four Gene Ontology (GO) molecular functions (P value ranges, 0.02 to 0.04), with multiple suggestive enriched relationships in KEGG pathways and GO molecular functions. Upregulated metabolic pathways suggest increases in energy production, lipid metabolism, iron acquisition and processing, and respiration. Combined with a suggested preferential metabolism of serine, which is necessary for fatty acid biosynthesis, these data support our previous findings that the site of sapienic acid antimicrobial activity is likely at the bacterial membrane. IMPORTANCE P. gingivalis is an important opportunistic pathogen implicated in periodontitis. Affecting nearly 50% of the population, periodontitis is treatable, but the resulting damage is irreversible and eventually progresses to tooth loss. There is a great need for natural products that can be used to treat and/or prevent the overgrowth of

  3. 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.

  4. 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

  5. "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

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. 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

  11. 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

  12. REST-VP16 activates multiple neuronal differentiation genes in human NT2 cells.

    PubMed

    Immaneni, A; Lawinger, P; Zhao, Z; Lu, W; Rastelli, L; Morris, J H; Majumder, S

    2000-09-01

    The RE1-silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF) can repress transcription of a battery of neuronal differentiation genes in non-neuronal cells by binding to a specific consensus DNA sequence present in their regulatory regions. However, REST/NRSF(-/-) mice suggest that the absence of REST/NRSF-dependent repression alone is not sufficient for the expression of these neuronal differentiation genes and that the presence of other promoter/enhancer-specific activators is required. Here we describe the construction of a recombinant transcription factor, REST-VP16, by replacing repressor domains of REST/NRSF with the activation domain of a viral activator VP16. In transient transfection experiments, REST-VP16 was found to operate through RE1 binding site/neuron-restrictive enhancer element (RE1/NRSE), activate plasmid-encoded neuronal promoters in various mammalian cell types and activate cellular REST/NRSF target genes, even in the absence of factors that are otherwise required to activate such genes. Efficient expression of REST-VP16 through adenoviral vectors in NT2 cells, which resemble human committed neuronal progenitor cells, was found to cause activation of multiple neuronal genes that are characteristic markers for neuronal differentiation. Thus, REST-VP16 could be used as a unique tool to study neuronal differentiation pathways and neuronal diseases that arise due to the deregulation of this process. PMID:10954611

  13. 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

  14. TEMPI: probabilistic modeling time-evolving differential PPI networks with multiPle information

    PubMed Central

    Kim, Yongsoo; Jang, Jin-Hyeok; Choi, Seungjin; Hwang, Daehee

    2014-01-01

    Motivation: Time-evolving differential protein–protein interaction (PPI) networks are essential to understand serial activation of differentially regulated (up- or downregulated) cellular processes (DRPs) and their interplays over time. Despite developments in the network inference, current methods are still limited in identifying temporal transition of structures of PPI networks, DRPs associated with the structural transition and the interplays among the DRPs over time. Results: Here, we present a probabilistic model for estimating Time-Evolving differential PPI networks with MultiPle Information (TEMPI). This model describes probabilistic relationships among network structures, time-course gene expression data and Gene Ontology biological processes (GOBPs). By maximizing the likelihood of the probabilistic model, TEMPI estimates jointly the time-evolving differential PPI networks (TDNs) describing temporal transition of PPI network structures together with serial activation of DRPs associated with transiting networks. This joint estimation enables us to interpret the TDNs in terms of temporal transition of the DRPs. To demonstrate the utility of TEMPI, we applied it to two time-course datasets. TEMPI identified the TDNs that correctly delineated temporal transition of DRPs and time-dependent associations between the DRPs. These TDNs provide hypotheses for mechanisms underlying serial activation of key DRPs and their temporal associations. Availability and implementation: Source code and sample data files are available at http://sbm.postech.ac.kr/tempi/sources.zip. Contact: seungjin@postech.ac.kr or dhwang@dgist.ac.kr Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25161233

  15. Imaging-based differential diagnosis between multiple system atrophy and Parkinson's disease.

    PubMed

    Sako, Wataru; Abe, Takashi; Murakami, Nagahisa; Miyazaki, Yoshimichi; Izumi, Yuishin; Harada, Masafumi; Kaji, Ryuji

    2016-09-15

    There are many tools for differentiating between multiple system atrophy with predominant parkinsonian features (MSA-P) and Parkinson's disease (PD). These include middle cerebellar peduncle (MCP) width, apparent diffusion coefficient (ADC) value of the putamen and cerebellum, and (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy images. We aimed to directly compare the above-mentioned methods, and to determine the optimal tool for differential diagnosis. Eleven patients with MSA-P and 36 patients with PD were enrolled. Of these, 7 patients with MSA-P and 14 patients with PD were chosen as background-matched subjects. We measured MCP width, ADC value of the putamen and cerebellum, and MIBG myocardial scintigraphy images. Area under curve (AUC) of receiver operating characteristic (ROC) was assessed to compare the above-mentioned methods. MCP width and ADC value of the putamen may be helpful for differentiating between MSA-P and PD relative to other methods in background-matched patients (MCP, AUC=0.95; putamen ADC, AUC=0.88; cerebellar ADC, AUC=0.70; MIBG, AUC=0.78). Similar AUCs were seen in all patients with different backgrounds. Our findings suggested that MCP width and ADC value of the putamen could be superior to ADC value of the cerebellum and MIBG uptake for differentiating between MSA-P and PD. PMID:27538610

  16. 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

  17. 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

  18. Yap1 Regulates Multiple Steps of Chondrocyte Differentiation during Skeletal Development and Bone Repair.

    PubMed

    Deng, Yujie; Wu, Ailing; Li, Pikshan; Li, Gang; Qin, Ling; Song, Hai; Mak, Kinglun Kingston

    2016-03-01

    Hippo signaling controls organ size and tissue regeneration in many organs, but its roles in chondrocyte differentiation and bone repair remain elusive. Here, we demonstrate that Yap1, an effector of Hippo pathway inhibits skeletal development, postnatal growth, and bone repair. We show that Yap1 regulates chondrocyte differentiation at multiple steps in which it promotes early chondrocyte proliferation but inhibits subsequent chondrocyte maturation both in vitro and in vivo. Mechanistically, we find that Yap1 requires Teads binding for direct regulation of Sox6 expression to promote chondrocyte proliferation. In contrast, Yap1 inhibits chondrocyte maturation by suppression of Col10a1 expression through interaction with Runx2. In addition, Yap1 also governs the initiation of fracture repair by inhibition of cartilaginous callus tissue formation. Taken together, our work provides insights into the mechanism by which Yap1 regulates endochondral ossification, which may help the development of therapeutic treatment for bone regeneration. PMID:26923596

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

    PubMed Central

    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

  20. 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

  1. 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.

  2. Proliferation and differentiation potential of chondrocytes from osteoarthritic patients

    PubMed Central

    Tallheden, Tommi; Bengtsson, Catherine; Brantsing, Camilla; Sjögren-Jansson, Eva; Carlsson, Lars; Peterson, Lars; Brittberg, Mats; Lindahl, Anders

    2005-01-01

    Autologous chondrocyte transplantation (ACT) has been shown, in long-term follow-up studies, to be a promising treatment for the repair of isolated cartilage lesions. The method is based on an implantation of in vitro expanded chondrocytes originating from a small cartilage biopsy harvested from a non-weight-bearing area within the joint. In patients with osteoarthritis (OA), there is a need for the resurfacing of large areas, which could potentially be made by using a scaffold in combination with culture-expanded cells. As a first step towards a cell-based therapy for OA, we therefore investigated the expansion and redifferentiation potential in vitro of chondrocytes isolated from patients undergoing total knee replacement. The results demonstrate that OA chondrocytes have a good proliferation potential and are able to redifferentiate in a three-dimensional pellet model. During the redifferentiation, the OA cells expressed increasing amounts of DNA and proteoglycans, and at day 14 the cells from all donors contained type II collagen-rich matrix. The accumulation of proteoglycans was in comparable amounts to those from ACT donors, whereas total collagen was significantly lower in all of the redifferentiated OA chondrocytes. When the OA chondrocytes were loaded into a scaffold based on hyaluronic acid, they bound to the scaffold and produced cartilage-specific matrix proteins. Thus, autologous chondrocytes are a potential source for the biological treatment of OA patients but the limited collagen synthesis of the OA chondrocytes needs to be further explained. PMID:15899043

  3. 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

  4. Multiple mesenteric well-differentiated liposarcoma complicated by purulent inflammation: A case report

    PubMed Central

    GAO, WEI; WANG, HUAIZHOU; LIU, JINYU; WANG, FUJIANG; DONG, JIANJUN; GENG, JUNZU

    2015-01-01

    Multiple mesenteric well-differentiated (WD) liposarcoma is an extremely rare entity. The present study describes a case of multiple mesenteric WD liposarcoma, complicated by purulent inflammation, in a 59-year-old male who presented with abdominal pain and pyrexia of unknown origin. A computed tomography scan of the abdomen revealed a large, non-encapsulated mass in the abdomino-pelvic cavity, which was characterized by two components, a main portion of fatty density and a non-adipose solid portion. A re-evaluated CT scan, performed eight days later, revealed an enlargement of the non-adipose mass. A laparotomy was performed, and numerous separated fatty nodules and masses of various sizes were identified within the mesentery of the small intestine. The histological findings were consistent with an adipocytic subtype of multiple mesenteric WD liposarcoma, with the largest of the tumors complicated by purulent inflammation. The multiplicity of these tumors and the concurrent purulent inflammation in the present case make it unique. PMID:25663908

  5. Recent advances and potential applications of modulated differential scanning calorimetry (mDSC) in drug development.

    PubMed

    Knopp, Matthias Manne; Löbmann, Korbinian; Elder, David P; Rades, Thomas; Holm, René

    2016-05-25

    Differential scanning calorimetry (DSC) is frequently the thermal analysis technique of choice within preformulation and formulation sciences because of its ability to provide detailed information about both the physical and energetic properties of a substance and/or formulation. However, conventional DSC has shortcomings with respect to weak transitions and overlapping events, which could be solved by the use of the more sophisticated modulated DSC (mDSC). mDSC has multiple potential applications within the pharmaceutical field and the present review provides an up-to-date overview of these applications. It is aimed to serve as a broad introduction to newcomers, and also as a valuable reference for those already practising in the field. Complex mDSC was introduced more than two decades ago and has been an important tool for the quantification of amorphous materials and development of freeze-dried formulations. However, as discussed in the present review, a number of other potential applications could also be relevant for the pharmaceutical scientist. PMID:26721421

  6. 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

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

    PubMed

    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

  8. Hepatocytic Differentiation Potential of Human Fetal Liver Mesenchymal Stem Cells: In Vitro and In Vivo Evaluation

    PubMed Central

    Hamidouche, Zahia; Sokal, Etienne; Charbord, Pierre

    2016-01-01

    In line with the search of effective stem cell population that would progress liver cell therapy and because the rate and differentiation potential of mesenchymal stem cells (MSC) decreases with age, the current study investigates the hepatogenic differentiation potential of human fetal liver MSCs (FL-MSCs). After isolation from 11-12 gestational weeks' human fetal livers, FL-MSCs were shown to express characteristic markers such as CD73, CD90, and CD146 and to display adipocytic and osteoblastic differentiation potential. Thereafter, we explored their hepatocytic differentiation potential using the hepatogenic protocol applied for adult human liver mesenchymal cells. FL-MSCs differentiated in this way displayed significant features of hepatocyte-like cells as demonstrated in vitro by the upregulated expression of specific hepatocytic markers and the induction of metabolic functions including CYP3A4 activity, indocyanine green uptake/release, and glucose 6-phosphatase activity. Following transplantation, naive and differentiated FL-MSC were engrafted into the hepatic parenchyma of newborn immunodeficient mice and differentiated in situ. Hence, FL-MSCs appeared to be interesting candidates to investigate the liver development at the mesenchymal compartment level. Standardization of their isolation, expansion, and differentiation may also support their use for liver cell-based therapy development. PMID:27057173

  9. 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

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

    PubMed

    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

  11. Retinoblastoma Protein Plays Multiple Essential Roles in the Terminal Differentiation of Sertoli Cells

    PubMed Central

    Nalam, Roopa L.; Andreu-Vieyra, Claudia; Braun, Robert E.; Akiyama, Haruhiko; Matzuk, Martin M.

    2009-01-01

    Retinoblastoma protein (RB) plays crucial roles in cell cycle control and cellular differentiation. Specifically, RB impairs the G1 to S phase transition by acting as a repressor of the E2F family of transcriptional activators while also contributing towards terminal differentiation by modulating the activity of tissue-specific transcription factors. To examine the role of RB in Sertoli cells, the androgen-dependant somatic support cell of the testis, we created a Sertoli cell-specific conditional knockout of Rb. Initially, loss of RB has no gross effect on Sertoli cell function because the mice are fertile with normal testis weights at 6 wk of age. However, by 10–14 wk of age, mutant mice demonstrate severe Sertoli cell dysfunction and infertility. We show that mutant mature Sertoli cells continue cycling with defective regulation of multiple E2F1- and androgen-regulated genes and concurrent activation of apoptotic and p53-regulated genes. The most striking defects in mature Sertoli cell function are increased permeability of the blood-testis barrier, impaired tissue remodeling, and defective germ cell-Sertoli cell interactions. Our results demonstrate that RB is essential for proper terminal differentiation of Sertoli cells. PMID:19819985

  12. [Multiple sclerosis: potential therapeutic options and update of ongoing studies].

    PubMed

    Wiendl, H; Lehmann, H C; Hohlfeld, R; Hartung, H-P; Kieseier, B C

    2004-06-01

    The therapeutic options for the treatment of multiple sclerosis (MS) have experienced enormous progress over recent years. Despite these encouraging developments, available therapies are only partially effective, and the ultimate goal of curing MS is still far from being attained. The improved understanding of the cellular and molecular mechanisms of MS (immune) pathogenesis together with recent shifts in paradigms led to a variety of new therapeutic targets and approaches. In addition to modulation of the inflammatory process, therapeutic approaches focussing on active neuroprotection, remyelinization, and regeneration have become increasingly important. Based on current concepts of the MS pathogenesis, this article summarizes new therapeutic approaches. Substances and strategies currently tested in clinical trials are reviewed. PMID:15257377

  13. Detecting Differential Item Functioning in the Japanese Version of the Multiple Affect Adjective Check List--Revised

    ERIC Educational Resources Information Center

    Yasuda, Tomoyuki; Lei, Pui-Wa; Suen, Hoi K.

    2007-01-01

    This study examines the differential item functioning (DIF) of the English version and the Japanese-translated version of the Multiple Affect Adjective Check List--Revised (MAACL-R) using the logistic regression (LR) procedure. The results of the LR are supplemented by multiple group confirmatory factor analysis (MGCFA). A total of five items are…

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

    PubMed Central

    Humphreys, William James Edward; Comerford, Eithne Josephine Veronica; Clegg, Peter David; Canty‐Laird, Elizabeth Gail

    2015-01-01

    ABSTRACT 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 33:849–858, 2015. PMID:25877997

  15. 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.

  16. Constitutive CD40 Signaling Calibrates Differentiation Outcomes in Responding B Cells via Multiple Molecular Pathways.

    PubMed

    Basu, Srijani; Kaw, Sheetal; D'Souza, Lucas; Vaidya, Tushar; Bal, Vineeta; Rath, Satyajit; George, Anna

    2016-08-01

    CD40 signaling during B cell activation is known to inhibit terminal differentiation and promote memory generation. Blimp-1 is essential for efficient plasma cell (PC) generation, and although CD40 signaling is known to inhibit Blimp-1 induction during B cell activation, the mechanisms involved have been unclear. We report that CD40 signaling induces miR-125b that targets Blimp-1 transcripts, and increases amounts of the ubiquitin ligase Hrd1 that targets BLIMP-1 protein for proteasomal degradation. CD40 signaling also inhibits the early unfolded protein response (UPR) of activated B cells that precedes the induction of terminal differentiation, and Hrd1 feeds into this pathway by targeting the core UPR component IRE-1α. Strikingly, CD40 signaling in the absence of BCR- or TLR-ligation also repressed Blimp-1 transcripts, suggesting that noncognate ligation of CD40 via T-B interactions may repress Blimp-1 in vivo. In support of this, we find that naive B cells purified from CD40-CD154 interaction-deficient mice express higher amounts of Blimp-1 and lower amounts of microRNAs and Hrd1. Higher basal amounts of Blimp-1 in naive CD40(-/-) B cells correlate with an increased tendency of the cells to undergo terminal differentiation upon LPS stimulation. Conversely, a 24-h exposure to CD40 ligation during LPS stimulation of wild-type B cells is sufficient to inhibit PC generation. The data show that CD40-mediated inhibition of PC generation is via engagement of multiple pathways that involve repression of Blimp-1 and inhibition of the UPR that prepares cells to become professional secretors. They also show that constitutive CD40 signaling in vivo involving bystander T-B interactions can calibrate B cell differentiation outcomes. PMID:27342845

  17. 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

  18. Polar/apolar compounds induce leukemia cell differentiation by modulating cell-surface potential.

    PubMed Central

    Arcangeli, A; Carlà, M; Del Bene, M R; Becchetti, A; Wanke, E; Olivotto, M

    1993-01-01

    The mechanism of action of polar/apolar inducers of cell differentiation, such as dimethyl sulfoxide and hexamethylene-bisacetamide, is still obscure. In this paper evidence is provided that their effects on murine erythroleukemia cells are modulated by various extracellular cations as a precise function of the cation effects on membrane surface potential. The interfacial effects of the inducers were directly measured on the charged electrode, showing that both dimethyl sulfoxide and hexamethylene-bisacetamide, at the effective concentrations for cell differentiation and within the physiological range of charge density, adsorb at the charged surface and produce a potential shift. A linear correlation was found between this shift and the inducer effects on cell differentiation. Besides offering a different interpretation of the mechanism of action of the inducers, these findings indicate that surface potential has a signaling function. They may also be relevant to cancer treatments based on tumor-cell commitment to terminal differentiation. Images Fig. 1 PMID:8516337

  19. RBC micromotors carrying multiple cargos towards potential theranostic applications.

    PubMed

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

    2015-08-28

    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. PMID:26214151

  20. Potential animal model of multiple chemical sensitivity with cholinergic supersensitivity.

    PubMed

    Overstreet, D H; Miller, C S; Janowsky, D S; Russell, R W

    1996-07-17

    Multiple Chemical Sensitivity (MCS) is a clinical phenomenon in which individuals, after acute or intermittent exposure to one or more chemicals, commonly organophosphate pesticides (OPs), become overly sensitive to a wide variety of chemically-unrelated compounds, which can include ethanol, caffeine and other psychotropic drugs. The Flinders Sensitive Line (FSL) rats were selectively bred to be more sensitive to the OP diisopropylfluorophosphate (DFP) compared to their control counterparts, the Flinders Resistant Line (FRL) rats. The present paper will summarize evidence which indicates that the FSL rats exhibit certain similarities to individuals with MCS. In addition to their greater sensitivity to DFP, the FSL rats are more sensitive to nicotine and the muscarinic agonists arecoline and oxotremorine, suggesting that the number of cholinergic receptors may be increased, a conclusion now supported by biochemical evidence. The FSL rats have also been found to exhibit enhanced responses to a variety of other drugs, including the serotonin agonists m-chlorophenylpiperazine and 8-OH-DPAT, the dopamine antagonist raclopride, the benzodiazepine diazepam, and ethanol. MCS patients report enhanced responses to many of these drugs, indicating some parallels between FSL rats and MCS patients. The FSL rats also exhibit reduced activity and appetite and increased REM sleep relative to their FRL controls. Because these behavioral features and the enhanced cholinergic responses are also observed in human depressives, the FSL rats have been proposed as a genetic animal model of depression. It has also been reported that MCS patients have a greater incidence of depression, both before and after onset of their chemical sensitivities, so cholinergic supersensitivity may be a state predisposing individuals to depressive disorders and/or MCS. Further exploration of the commonalities and differences between MCS patients, human depressives, and FSL rats will help to elucidate the

  1. Serum lactate as a novel potential biomarker in multiple sclerosis.

    PubMed

    Amorini, Angela M; Nociti, Viviana; Petzold, Axel; Gasperini, Claudio; Quartuccio, Esmeralda; Lazzarino, Giacomo; Di Pietro, Valentina; Belli, Antonio; Signoretti, Stefano; Vagnozzi, Roberto; Lazzarino, Giuseppe; Tavazzi, Barbara

    2014-07-01

    Multiple sclerosis (MS) is a primary inflammatory demyelinating disease associated with a probably secondary progressive neurodegenerative component. Impaired mitochondrial functioning has been hypothesized to drive neurodegeneration and to cause increased anaerobic metabolism in MS. The aim of our multicentre study was to determine whether MS patients had values of circulating lactate different from those of controls. Patients (n=613) were recruited, assessed for disability and clinically classified (relapsing-remitting, secondary progressive, primary progressive) at the Catholic University of Rome, Italy (n=281), at the MS Centre Amsterdam, The Netherlands (n=158) and at the S. Camillo Forlanini Hospital, Rome, Italy (n=174). Serum lactate levels were quantified spectrophotometrically with the analyst being blinded to all clinical information. In patients with MS serum lactate was three times higher (3.04±1.26mmol/l) than that of healthy controls (1.09±0.25mmol/l, p<0.0001) and increased across clinical groups, with higher levels in cases with a progressive than with a relapsing-remitting disease course. In addition, there was a linear correlation between serum lactate levels and the expanded disability scale (EDSS) (R(2)=0.419; p<0.001). These data support the hypothesis that mitochondrial dysfunction is an important feature in MS and of particular relevance to the neurodegenerative phase of the disease. Measurement of serum lactate in MS might be a relative inexpensive test for longitudinal monitoring of "virtual hypoxia" in MS and also a secondary outcome for treatment trials aimed to improve mitochondrial function in patients with MS. PMID:24726946

  2. Clonal multipotency and effect of long-term in vitro expansion on differentiation potential of human hair follicle derived mesenchymal stem cells

    PubMed Central

    Bajpai, Vivek K.; Mistriotis, Panagiotis; Andreadis, Stelios T.

    2011-01-01

    Hair follicle harbors a rich stem cell pool with mesenchymal lineage differentiation potential. Although previous studies with rodent cells demonstrated that hair follicle sheath and papilla cells possess multi-lineage differentiation potential, human hair follicle derived mesenchymal stem cells (hHF-MSCs) have not been characterized in detail in terms of their multipotency. In addition, it is not clear whether these cells are true stem cells that can differentiate along multiple lineages or whether they represent a collection of progenitor cells with restricted differentiation potential. Here we report that hHF-MSCs are highly proliferative cells that can be maintained in culture for ~45 population doublings before they start to show signs of cellular senescence. Under appropriate culture conditions, hHF-MSCs differentiated along the myogenic, osteogenic, adipogenic and chondrogenic lineages, as demonstrated by kinetic gene expression profiling and functional assays. Interestingly, the differentiation potential decreased with time in culture in a lineage-specific manner. Specifically, myogenesis and chondrogenesis showed a moderate decrease over time; osteogenesis was maximum at intermediate passages and adipogenesis was highly sensitive to long-term culture and was diminished at late passages. Finally, hHF-MSCs were clonally multipotent as the majority of hHF-MSCs clones (73%) demonstrated bi- or tri-lineage differentiation potential. These results suggest that hHF-MSCs may present an alternative source of easily accessible, autologous stem cells for tissue engineering and regenerative medicine. PMID:22099022

  3. Spinal Cord in Multiple Sclerosis: Magnetic Resonance Imaging Features and Differential Diagnosis.

    PubMed

    Rovira, Alex; Auger, Cristina

    2016-10-01

    Multiple sclerosis (MS) is an idiopathic inflammatory disorder of the central nervous system that affects not only the brain but also the spinal cord. In the diagnostic and monitoring process of MS, spinal cord magnetic resonance imaging (MRI) is not performed as commonly as brain MRI, mainly because of certain technical difficulties and the increase in total acquisition time. Nonetheless, spinal cord MRI findings are important to establish a prompt accurate diagnosis of MS, impart prognostic information, and provide valuable data for monitoring the disease course in certain cases. In this article, we discuss the technical aspects of spinal cord MRI, the typical MRI features of the spinal cord in MS, the clinical indications for this examination, and the differential diagnosis with other disorders that may produce similar clinical or MRI findings. PMID:27616313

  4. Linear differential equations and multiple zeta-values. III. Zeta(3)

    NASA Astrophysics Data System (ADS)

    Zakrzewski, Michał; Żoładek, Henryk

    2012-01-01

    We consider the hypergeometric equation (1 - t)∂t∂t∂g + x3g = 0, whose unique analytic solution φ1(t; x) = 1 + O(t) near t = 0 for t = 1 becomes a generating function for multiple zeta values φ1(1; x) = f3(x) = 1 - ζ(3)x3 + ζ(3, 3)x6 - …. We apply the so-called WKB method to study solutions of the hypergeometric equation for large x and we calculate corresponding Stokes matrices. We prove that the function f3(x) near x = ∞ is also expressed via WKB type functions which subject to some Stokes phenomenon. This implies that f3(x) satisfies a sixth order linear differential equation with irregular singularity at infinity.

  5. 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.

  6. Molecular chaperones: multiple functions, pathologies, and potential applications.

    PubMed

    Macario, Alberto J L; Conway de Macario, Everly

    2007-01-01

    Cell stressors are ubiquitous and frequent, challenging cells often, which leads to the stress response with activation of anti-stress mechanisms. These mechanisms involve a variety of molecules, including molecular chaperones also known as heat-shock proteins (Hsp). The chaperones treated in this article are proteins that assist other proteins to fold, refold, travel to their place of residence (cytosol, organelle, membrane, extracellular space), and translocate across membranes. Molecular chaperones participate in a variety of physiological processes and are widespread in organisms, tissues, and cells. It follows that chaperone failure will have an impact, possibly serious, on one or more cellular function, which may lead to disease. Chaperones must recognize and interact with proteins in need of assistance or client polypeptides (e.g., nascent at the ribosome, or partially denatured by stressors), and have to interact with other chaperones because the chaperoning mechanism involves teams of chaperone molecules, i.e., multimolecular assemblies or chaperone machines. Consequently, chaperone molecules have structural domains with distinctive functions: bind the client polypeptide, interact with other chaperone molecules to build a machine, and interact with other complexes that integrate the chaperoning network. Also, various chaperones have ATP-binding and ATPase sites because the chaperoning process requires as, a rule, energy from ATP hydrolysis. Alterations in any one of these domains due to a mutation or an aberrant post-translational modification can disrupt the chaperoning process and cause diseases termed chaperonopathies. This article presents the pathologic concept of chaperonopathy with examples, and discusses the potential of using chaperones (genes or proteins) in treatment (chaperonotherapy). In addition, emerging topics within the field of study of chaperones (chaperonology) are highlighted, e.g., genomics (chaperonomics), systems biology

  7. 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

  8. Differential and relaxed image foresting transform for graph-cut segmentation of multiple 3D objects.

    PubMed

    Moya, Nikolas; Falcão, Alexandre X; Ciesielski, Krzysztof C; Udupa, Jayaram K

    2014-01-01

    Graph-cut algorithms have been extensively investigated for interactive binary segmentation, when the simultaneous delineation of multiple objects can save considerable user's time. We present an algorithm (named DRIFT) for 3D multiple object segmentation based on seed voxels and Differential Image Foresting Transforms (DIFTs) with relaxation. DRIFT stands behind efficient implementations of some state-of-the-art methods. The user can add/remove markers (seed voxels) along a sequence of executions of the DRIFT algorithm to improve segmentation. Its first execution takes linear time with the image's size, while the subsequent executions for corrections take sublinear time in practice. At each execution, DRIFT first runs the DIFT algorithm, then it applies diffusion filtering to smooth boundaries between objects (and background) and, finally, it corrects possible objects' disconnection occurrences with respect to their seeds. We evaluate DRIFT in 3D CT-images of the thorax for segmenting the arterial system, esophagus, left pleural cavity, right pleural cavity, trachea and bronchi, and the venous system. PMID:25333179

  9. Effects of Medium Supplements on Proliferation, Differentiation Potential, and In Vitro Expansion of Mesenchymal Stem Cells

    PubMed Central

    Gharibi, Borzo

    2012-01-01

    Mesenchymal stem cells (MSCs) possess great potential for use in regenerative medicine. However, their clinical application may be limited by the ability to expand their cell numbers in vitro while maintaining their differential potentials and stem cell properties. Thus the aim of this study was to test the effect of a range of medium supplements on MSC self-renewal and differentiation potential. Cells were cultured until confluent and subcultured continuously until reaching senescence. Medium supplementation with fibroblast growth factor (FGF)-2, platelet-derived growth factor (PDGF)-BB, ascorbic acid (AA), and epidermal growth factor (EGF) both increased proliferation rate and markedly increased number of cell doublings before reaching senescence, with a greater than 1,000-fold increase in total cell numbers for AA, FGF-2, and PDGF-BB compared with control cultures. Long-term culture was associated with loss of osteogenic/adipocytic differentiation potential, particularly with FGF-2 supplementation but also with AA, EGF, and PDGF-BB. In addition FGF-2 resulted in reduction in expression of CD146 and alkaline phosphatase, but this was partially reversible on removal of the supplement. Cells expressed surface markers including CD146, CD105, CD44, CD90, and CD71 by flow cytometry throughout, and expression of these putative stem cell markers persisted even after loss of differentiation potentials. Overall, medium supplementation with FGF-2, AA, EGF, and PDGF-BB greatly enhanced the total in vitro expansion capacity of MSC cultures, although differentiation potentials were lost prior to reaching senescence. Loss of differentiation potential was not reflected by changes in stem cell surface marker expression. PMID:23197689

  10. Cellular diversity within embryonic stem cells: pluripotent clonal sublines show distinct differentiation potential

    PubMed Central

    Martinez, Yannick; Béna, Frédérique; Gimelli, Stefania; Tirefort, Diderik; Dubois-Dauphin, Michel; Krause, Karl-Heinz; Preynat-Seauve, Olivier

    2012-01-01

    Abstract Embryonic stem cells (ESC), derived from the early inner cell mass (ICM), are constituted of theoretically homogeneous pluripotent cells. Our study was designed to test this concept using experimental approaches that allowed characterization of progenies derived from single parental mouse ESC. Flow cytometry analysis showed that a fraction of ESC submitted to neural differentiation generates progenies that escape the desired phenotype. Live imaging of individual cells demonstrated significant variations in the capacity of parental ESC to generate neurons, raising the possibility of clonal diversity among ESC. To further substantiate this hypothesis, clonal sublines from ESC were generated by limit dilution. Transcriptome analysis of undifferentiated sublines showed marked differences in gene expression despite the fact that all clones expressed pluripotency markers. Sublines showed distinct differentiation potential, both in phenotypic differentiation assays and with respect to gene expression in embryoid bodies. Clones generated from another ESC line also showed individualities in their differentiation potential, demonstrating the wider applicability of these findings. Taken together, our observations demonstrate that pluripotent ESC consist of individual cell types with distinct differentiation potentials. These findings identify novel elements for the biological understanding of ESC and provide new tools with a major potential for their future in vitro and in vivo use. PMID:21535399

  11. Multiple Differential Networks Strategy Reveals Carboplatin and Melphalan-Induced Dynamic Module Changes in Retinoblastoma.

    PubMed

    Chen, Cui; Ma, Feng-Wei; Du, Cui-Yun; Wang, Ping

    2016-01-01

    BACKGROUND Retinoblastoma (RB) is the most common malignant tumor of the eye in childhood. The objective of this paper was to investigate carboplatin (CAR)- and melphalan (MEL)-induced dynamic module changes in RB based on multiple (M) differential networks, and to generate systems-level insights into RB progression. MATERIAL AND METHODS To achieve this goal, we constructed M-differential co-expression networks (DCNs), assigned a weight to each edge, and identified seed genes in M DCNs by ranking genes based on their topological features. Starting with seed genes, a module search was performed to explore candidate modules in CAR and MEL condition. M-DMs were detected according to significance evaluations of M-modules, which originated from refinement of candidate modules. Further, we revealed dynamic changes in M-DM activity and connectivity on the basis of significance of Module Connectivity Dynamic Score (MCDS). RESULTS In the present study, M=2, a total of 21 seed genes were obtained. By assessing module search, refinement, and evaluation, we gained 18 2-DMs. Moreover, 3 significant 2-DMs (Module 1, Module 2, and Module 3) with dynamic changes across CAR and MEL condition were determined, and we denoted them as dynamic modules. Module 1 had 27 nodes of which 6 were seed genes and 56 edges. Module 2 was composed of 28 nodes and 54 edges. A total of 28 nodes interacted with 45 edges presented in Module 3. CONCLUSIONS We have identified 3 dynamic modules with changes induced by CAR and MEL in RB, which might give insights in revealing molecular mechanism for RB therapy. PMID:27144687

  12. Tumorigenic potential is restored during differentiation in fusion-reprogrammed cancer cells

    PubMed Central

    Yao, J; Zhang, L; Hu, L; Guo, B; Hu, X; Borjigin, U; Wei, Z; Chen, Y; Lv, M; Lau, J T Y; Wang, X; Li, G; Hu, Y-P

    2016-01-01

    Detailed understanding of the mechanistic steps underlying tumor initiation and malignant progression is critical for insights of potentially novel therapeutic modalities. Cellular reprogramming is an approach of particular interest because it can provide a means to reset the differentiation state of the cancer cells and to revert these cells to a state of non-malignancy. Here, we investigated the relationship between cellular differentiation and malignant progression by the fusion of four independent mouse cancer cell lines from different tissues, each with differing developmental potentials, to pluripotent mouse embryonic stem (ES) cells. Fusion was accompanied by loss of differentiated properties of the four parental cancer cell lines and concomitant emergence of pluripotency, demonstrating the feasibility to reprogram the malignant and differentiative properties of cancer cells. However, the original malignant and differentiative phenotypes re-emerge upon withdrawal of the fused cells from the embryonic environment in which they were maintained. cDNA array analysis of the malignant hepatoma progression implicated a role for Foxa1, and silencing Foxa1 prevented the re-emergence of malignant and differentiation-associated gene expression. Our findings support the hypothesis that tumor progression results from deregulation of stem cells, and our approach provides a strategy to analyze possible mechanisms in the cancer initiation. PMID:27468690

  13. Morphology-based prediction of osteogenic differentiation potential of human mesenchymal stem cells.

    PubMed

    Matsuoka, Fumiko; Takeuchi, Ichiro; Agata, Hideki; Kagami, Hideaki; Shiono, Hirofumi; Kiyota, Yasujiro; Honda, Hiroyuki; Kato, Ryuji

    2013-01-01

    Human bone marrow mesenchymal stem cells (hBMSCs) are widely used cell source for clinical bone regeneration. Achieving the greatest therapeutic effect is dependent on the osteogenic differentiation potential of the stem cells to be implanted. However, there are still no practical methods to characterize such potential non-invasively or previously. Monitoring cellular morphology is a practical and non-invasive approach for evaluating osteogenic potential. Unfortunately, such image-based approaches had been historically qualitative and requiring experienced interpretation. By combining the non-invasive attributes of microscopy with the latest technology allowing higher throughput and quantitative imaging metrics, we studied the applicability of morphometric features to quantitatively predict cellular osteogenic potential. We applied computational machine learning, combining cell morphology features with their corresponding biochemical osteogenic assay results, to develop prediction model of osteogenic differentiation. Using a dataset of 9,990 images automatically acquired by BioStation CT during osteogenic differentiation culture of hBMSCs, 666 morphometric features were extracted as parameters. Two commonly used osteogenic markers, alkaline phosphatase (ALP) activity and calcium deposition were measured experimentally, and used as the true biological differentiation status to validate the prediction accuracy. Using time-course morphological features throughout differentiation culture, the prediction results highly correlated with the experimentally defined differentiation marker values (R>0.89 for both marker predictions). The clinical applicability of our morphology-based prediction was further examined with two scenarios: one using only historical cell images and the other using both historical images together with the patient's own cell images to predict a new patient's cellular potential. The prediction accuracy was found to be greatly enhanced by incorporation

  14. Gliotoxin potentiates osteoblast differentiation by inhibiting nuclear factor-κB signaling

    PubMed Central

    WANG, GUANGYE; ZHANG, XIAOHAI; YU, BAOQING; REN, KE

    2015-01-01

    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)-α. It has been demonstrated that TNF-α is able to inhibit osteoblast differentiation through the activation of nuclear factor (NF)-κB signaling. As a result of the critical role of TNF-α and NF-κB 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-κB inhibitor gliotoxin (GTX) in the regulation of osteoblast differentiation was evaluated. The non-toxic GTX doses were determined to be ≤3 μg/ml. It was revealed that GTX was able to block TNF-α-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 morphoge-netic protein-2-induced osteoblast differentiation. GTX was found to inhibit the accumulation of NF-κB protein p65 in the nucleus and reduce NF-κB transcriptional activity, suggesting that GTX potentiated osteoblast differentiation via the suppression of NF-κB signaling. PMID:25816130

  15. Multiple isoforms of mitochondrial glutathione S-transferases and their differential induction under oxidative stress.

    PubMed Central

    Raza, Haider; Robin, Marie-Anne; Fang, Ji-Kang; Avadhani, Narayan G

    2002-01-01

    The mitochondrial respiratory chain, which consumes approx. 85-90% of the oxygen utilized by cells, is a major source of reactive oxygen species (ROS). Mitochondrial genetic and biosynthetic systems are highly susceptible to ROS toxicity. Intramitochondrial glutathione (GSH) is a major defence against ROS. In the present study, we have investigated the nature of the glutathione S-transferase (GST) pool in mouse liver mitochondria, and have purified three distinct forms of GST: GSTA1-1 and GSTA4-4 of the Alpha family, and GSTM1-1 belonging to the Mu family. The mitochondrial localization of these multiple GSTs was confirmed using a combination of immunoblot analysis, protease protection assay, enzyme activity, N-terminal amino acid sequencing, peptide mapping and confocal immunofluorescence analysis. Additionally, exogenously added 4-hydroxynonenal (HNE), a reactive byproduct of lipid peroxidation, to COS cells differentially affected the cytosolic and mitochondrial GSH pools in a dose- and time-dependent manner. Our results show that HNE-mediated mitochondrial oxidative stress caused a decrease in the GSH pool, increased membrane lipid peroxidation, and increased levels of GSTs, glutathione peroxidase and Hsp70 (heat-shock protein 70). The HNE-induced oxidative stress persisted for longer in the mitochondrial compartment, where the recovery of GSH pool was slower than in the cytosolic compartment. Our study, for the first time, demonstrates the presence in mitochondria of multiple forms of GSTs that show molecular properties similar to those of their cytosolic counterparts. Our results suggest that mitochondrial GSTs may play an important role in defence against chemical and oxidative stress. PMID:12020353

  16. 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

  17. Donor age and cell passage affects differentiation potential of murine bone marrow-derived stem cells

    PubMed Central

    Kretlow, James D; Jin, Yu-Qing; Liu, Wei; Zhang, Wen Jie; Hong, Tan-Hui; Zhou, Guangdong; Baggett, L Scott; Mikos, Antonios G; Cao, Yilin

    2008-01-01

    Background Bone marrow-derived mesenchymal stem cells (BMSCs) are a widely researched adult stem cell population capable of differentiation into various lineages. Because many promising applications of tissue engineering require cell expansion following harvest and involve the treatment of diseases and conditions found in an aging population, the effect of donor age and ex vivo handling must be understood in order to develop clinical techniques and therapeutics based on these cells. Furthermore, there currently exists little understanding as to how these two factors may be influenced by one another. Results Differences in the adipogenic, chondrogenic, and osteogenic differentiation capacity of murine MSCs harvested from donor animals of different age and number of passages of these cells were observed. Cells from younger donors adhered to tissue culture polystyrene better and proliferated in greater number than those from older animals. Chondrogenic and osteogenic potential decreased with age for each group, and adipogenic differentiation decreased only in cells from the oldest donors. Significant decreases in differentiation potentials due to passage were observed as well for osteogenesis of BMSCs from the youngest donors and chondrogenesis of the cells from the oldest donors. Conclusion Both increasing age and the number of passages have lineage dependent effects on BMSC differentiation potential. Furthermore, there is an obvious interplay between donor age and cell passage that in the future must be accounted for when developing cell-based therapies for clinical use. PMID:18957087

  18. Histone demethylase KDM2B inhibits the chondrogenic differentiation potentials of stem cells from apical papilla.

    PubMed

    Wang, Jing-Jing; Dong, Rui; Wang, Li-Ping; Wang, Jin-Song; Du, Juan; Wang, Song-Lin; Shan, Zhao-Chen; Fan, Zhi-Peng

    2015-01-01

    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. Histone methylation, controlled by histone methyltransferases and demethylases, may play a key role in MSCs differentiation. Previous studies determined that KDM2B can regulate the cell proliferation and osteo/dentinogenic differentiation of MSCs. It is not known whether KDM2B is involved in the other cell lineages differentiation of MSCs. Here we used the stem cells from apical papilla (SCAPs) to study the role of KDM2B on the chondrogenic differentiation potentials in MSCs. In this study, Gain- and loss-of-function assays were applied to investigate the role of KDM2B on the chondrogenic differentiation. Alcian Blue Staining and Quantitative Analysis were used to investigate the synthesis of proteoglycans by chondrocytes. Real-time RT-PCR was used to detect the expressions of chondrogenesis related genes. The Alcian Blue staining and Quantitative Analysis results revealed that overexpression of KDM2B decreased the proteoglycans production, and real-time RT-PCR results showed that the expressions of the chondrogenic differentiation markers, COL1, COL2 and SOX9 were inhibited by overexpression of KDM2B in SCAPs. On the contrary, depletion of KDM2B increased the proteoglycans production, and inhibited the expressions of COL1, COL2 and SOX9. In conclusion, our results indicated that KDM2B is a negative regulator of chondrogenic differentiation in SCAPs and suggest that inhibition of KDM2B might improve MSC mediated cartilage regeneration. PMID:25932147

  19. Human Placenta-Derived CD146-Positive Mesenchymal Stromal Cells Display a Distinct Osteogenic Differentiation Potential.

    PubMed

    Ulrich, Christine; Abruzzese, Tanja; Maerz, Jan K; Ruh, Manuel; Amend, Bastian; Benz, Karin; Rolauffs, Bernd; Abele, Harald; Hart, Melanie L; Aicher, Wilhelm K

    2015-07-01

    Mesenchymal stromal cells (MSCs) are multipotent cells that can be differentiated in vitro into a variety of cell types, including adipocytes or osteoblasts. Our recent studies indicated that a high expression of CD146 on MSCs from bone marrow correlates with their robust osteogenic differentiation potential. We therefore investigated if expression of CD146 on MSCs from the placenta correlates with a similar osteogenic differentiation potential. The MSCs were isolated specifically from the endometrial and fetal parts of human term placenta and expanded in separate cultures and compared with MSCs from bone marrow as controls. The expression of cell surface antigens was investigated by flow cytometry. Differentiation of MSCs was documented by cytochemistry and analysis of typical lineage marker genes. CD146-positive MSCs were separated from CD146-negative cells by magnet-assisted cell sorts (MACS). We report that the expression of CD146 is associated with a higher osteogenic differentiation potential in human placenta-derived MSCs (pMSCs) and the CD146(pos) pMSCs generated a mineralized extracellular matrix, whereas the CD146(neg) pMSCs failed to do so. In contrast, adipogenic and chondrogenic differentiation of pMSCs was not different in CD146(pos) compared with CD146(neg) pMSCs. Upon enrichment of pMSCs by MACS, the CD146(neg) and CD146(pos) populations maintained their expression levels for this antigen for several passages in vitro. We conclude that CD146(pos) pMSCs either respond to osteogenic stimuli more vividly or, alternatively, CD146(pos) pMSCs present a pMSC subset that is predetermined to differentiate into osteoblasts. PMID:25743703

  20. Kramers Moyal expansion for stochastic differential equations with single and multiple delays: Applications to financial physics and neurophysics

    NASA Astrophysics Data System (ADS)

    Frank, T. D.

    2007-01-01

    We present a generalized Kramers Moyal expansion for stochastic differential equations with single and multiple delays. In particular, we show that the delay Fokker Planck equation derived earlier in the literature is a special case of the proposed Kramers Moyal expansion. Applications for bond pricing and a self-inhibitory neuron model are discussed.

  1. In Vitro Differentiation Potential of Human Placenta Derived Cells into Skin Cells

    PubMed Central

    Mahmood, Ruhma; Choudhery, Mahmood S.; Mehmood, Azra; Khan, Shaheen N.; Riazuddin, Sheikh

    2015-01-01

    Skin autografting is the most viable and aesthetic technique for treatment of extensive burns; however, this practice has potential limitations. Harvesting cells from neonatal sources (such as placental tissue) is a simple, inexpensive, and noninvasive procedure. In the current study authors sought to evaluate in vitro potential of human placenta derived stem cells to develop into skin-like cells. After extensive washing, amniotic membrane and umbilical cord tissue were separated to harvest amniotic epithelial cells (AECs) and umbilical cord mesenchymal stem cells (UC-MSCs), respectively. Both types of cells were characterized for the expression of embryonic lineage markers and their growth characteristics were determined. AECs and UC-MSCs were induced to differentiate into keratinocytes-like and dermal fibroblasts-like cells, respectively. After induction, morphological changes were detected by microscopy. The differentiation potential was further assessed using immunostaining and RT-PCR analyses. AECs were positive for cytokeratins and E-Cadherin while UC-MSCs were positive for fibroblast specific makers. AECs differentiated into keratinocytes-like cells showed positive expression of keratinocyte specific cytokeratins, involucrin, and loricrin. UC-MSCs differentiated into dermal fibroblast-like cells indicated expression of collagen type 3, desmin, FGF-7, fibroblast activation protein alpha, procollagen-1, and vimentin. In conclusion, placenta is a potential source of cells to develop into skin-like cells. PMID:26229539

  2. Pyloric gland metaplasia/differentiation in multiple organ systems in a patient with Peutz-Jegher's syndrome.

    PubMed

    Kato, Noriko; Sugawara, Masato; Maeda, Kunihiko; Hosoya, Noriyuki; Motoyama, Teiichi

    2011-06-01

    Peutz-Jegher's syndrome (PJS) involves multiple organ systems and the development of hamartomatous, metaplastic, or neoplastic lesions of different cell lineages. Among them, glandular lesions are the most common, but their properties are obscure. We report here a 53-year-old woman with PJS who developed multiple hamartomatous polyps in the jejunum and mucinous glandular lesions in multiple organ systems: glandular metaplasia in the urinary bladder; lobular endocervical glandular hyperplasia in the uterine cervix; mucinous metaplasia in the right fallopian tube; mucinous adenoma in the left ovary. Histological and immunohistochemical analyses disclosed that all of the intestinal and extra-intestinal lesions were associated with pyloric gland metaplasia/differentiation across the organ systems. In the general population, the organs described above rarely or infrequently show pyloric gland phenotype, to say nothing of trans-organ involvement. It is strongly suggested that commitment to pyloric gland metaplasia/differentiation is closely associated with PJS. PMID:21615613

  3. Potential Effect of CD271 on Human Mesenchymal Stromal Cell Proliferation and Differentiation.

    PubMed

    Calabrese, Giovanna; Giuffrida, Raffaella; Lo Furno, Debora; Parrinello, Nunziatina Laura; Forte, Stefano; Gulino, Rosario; Colarossi, Cristina; Schinocca, Luciana Rita; Giuffrida, Rosario; Cardile, Venera; Memeo, Lorenzo

    2015-01-01

    The Low-Affinity Nerve Growth Factor Receptor (LNGFR), also known as CD271, is a member of the tumor necrosis factor receptor superfamily. The CD271 cell surface marker defines a subset of multipotential mesenchymal stromal cells and may be used to isolate and enrich cells derived from bone marrow aspirate. In this study, we compare the proliferative and differentiation potentials of CD271+ and CD271- mesenchymal stromal cells. Mesenchymal stromal cells were isolated from bone marrow aspirate and adipose tissue by plastic adherence and positive selection. The proliferation and differentiation potentials of CD271+ and CD271- mesenchymal stromal cells were assessed by inducing osteogenic, adipogenic and chondrogenic in vitro differentiation. Compared to CD271+, CD271- mesenchymal stromal cells showed a lower proliferation rate and a decreased ability to give rise to osteocytes, adipocytes and chondrocytes. Furthermore, we observed that CD271+ mesenchymal stromal cells isolated from adipose tissue displayed a higher efficiency of proliferation and trilineage differentiation compared to CD271+ mesenchymal stromal cells isolated from bone marrow samples, although the CD271 expression levels were comparable. In conclusion, these data show that both the presence of CD271 antigen and the source of mesenchymal stromal cells represent important factors in determining the ability of the cells to proliferate and differentiate. PMID:26184166

  4. 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

  5. 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

  6. Mesenchymal Stem Cells from Human Extra Ocular Muscle Harbor Neuroectodermal Differentiation Potential.

    PubMed

    Mawrie, Darilang; Kumar, Atul; Magdalene, Damaris; Bhattacharyya, Jina; Jaganathan, Bithiah Grace

    2016-01-01

    Mesenchymal stem cells (MSC) have been proposed as suitable candidates for cell therapy for neurological disorderssince they exhibit good neuronal differentiation capacity. However, for better therapeutic outcomes, it is necessary to isolate MSC from a suitable tissue sourcethat posses high neuronal differentiation. In this context, we isolated MSC from extra ocular muscle (EOM) tissue and tested the in vitro neuronal differentiation potential. In the current study, EOM tissue derived MSC were characterized and compared with bone marrow derived MSC. We found that EOM derived MSC proliferated as a monolayer and showed similarities in morphology, growth properties and cell surface marker expression with bone marrow derived MSC and expressed high levels of NES, OCT4, NANOG and SOX2 in its undifferentiated state. They also expressed embryonic cell surface marker SSEA4 and their intracellular mitochondrial distribution pattern was similar to that of multipotent stem cells. Although EOM derived MSC differentiated readily into adipocytes, osteocytes and chondrocytes, they differentiated more efficiently into neuroectodermal cells. The differentiation into neuroectodermal cellswas confirmed by the expression of neuronal markers NGFR and MAP2B. Thus, EOM derived MSC might be good candidates for stem cell based therapies for treating neurodegenerative diseases. PMID:27248788

  7. Mesenchymal Stem Cells from Human Extra Ocular Muscle Harbor Neuroectodermal Differentiation Potential

    PubMed Central

    Magdalene, Damaris; Bhattacharyya, Jina; Jaganathan, Bithiah Grace

    2016-01-01

    Mesenchymal stem cells (MSC) have been proposed as suitable candidates for cell therapy for neurological disorderssince they exhibit good neuronal differentiation capacity. However, for better therapeutic outcomes, it is necessary to isolate MSC from a suitable tissue sourcethat posses high neuronal differentiation. In this context, we isolated MSC from extra ocular muscle (EOM) tissue and tested the in vitro neuronal differentiation potential. In the current study, EOM tissue derived MSC were characterized and compared with bone marrow derived MSC. We found that EOM derived MSC proliferated as a monolayer and showed similarities in morphology, growth properties and cell surface marker expression with bone marrow derived MSC and expressed high levels of NES, OCT4, NANOG and SOX2 in its undifferentiated state. They also expressed embryonic cell surface marker SSEA4 and their intracellular mitochondrial distribution pattern was similar to that of multipotent stem cells. Although EOM derived MSC differentiated readily into adipocytes, osteocytes and chondrocytes, they differentiated more efficiently into neuroectodermal cells. The differentiation into neuroectodermal cellswas confirmed by the expression of neuronal markers NGFR and MAP2B. Thus, EOM derived MSC might be good candidates for stem cell based therapies for treating neurodegenerative diseases. PMID:27248788

  8. Acid Sensing Ion Channels (ASICs) in NS20Y cells - potential role in neuronal differentiation.

    PubMed

    O'Bryant, Zaven; Leng, Tiandong; Liu, Mingli; Inoue, Koichi; Vann, Kiara T; Xiong, Zhi-Gang

    2016-01-01

    Cultured neuronal cell lines can express properties of mature neurons if properly differentiated. Although the precise mechanisms underlying neuronal differentiation are not fully understood, the expression and activation of ion channels, particularly those of Ca(2+)-permeable channels, have been suggested to play a role. In this study, we explored the presence and characterized the properties of acid-sensing ion channels (ASICs) in NS20Y cells, a neuronal cell line previously used for the study of neuronal differentiation. In addition, the potential role of ASICs in cell differentiation was explored. Reverse Transcription Polymerase Chain Reaction and Western blot revealed the presence of ASIC1 subunits in these cells. Fast drops of extracellular pH activated transient inward currents which were blocked, in a dose dependent manner, by amiloride, a non-selective ASIC blocker, and by Psalmotoxin-1 (PcTX1), a specific inhibitor for homomeric ASIC1a and heteromeric ASIC1a/2b channels. Incubation of cells with PcTX1 significantly reduced the differentiation of NS20Y cells induced by cpt-cAMP, as evidenced by decreased neurite length, dendritic complexity, decreased expression of functional voltage gated Na(+) channels. Consistent with ASIC1a inhibition, ASIC1a knockdown with small interference RNA significantly attenuates cpt-cAMP-induced increase of neurite outgrowth. In summary, we described the presence of functional ASICs in NS20Y cells and demonstrate that ASIC1a plays a role in the differentiation of these cells. PMID:27342076

  9. Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer.

    PubMed

    Timperi, Eleonora; Pacella, Ilenia; Schinzari, Valeria; Focaccetti, Chiara; Sacco, Luca; Farelli, Francesco; Caronna, Roberto; Del Bene, Gabriella; Longo, Flavia; Ciardi, Antonio; Morelli, Sergio; Vestri, Anna Rita; Chirletti, Piero; Barnaba, Vincenzo; Piconese, Silvia

    2016-07-01

    Tregs can contribute to tumor progression by suppressing antitumor immunity. Exceptionally, in human colorectal cancer (CRC), Tregs are thought to exert beneficial roles in controlling pro-tumor chronic inflammation. The goal of our study was to characterize CRC-infiltrating Tregs at multiple levels, by phenotypical, molecular and functional evaluation of Tregs from the tumor site, compared to non-tumoral mucosa and peripheral blood of CRC patients. The frequency of Tregs was higher in mucosa than in blood, and further significantly increased in tumor. Ex vivo, those Tregs suppressed the proliferation of tumor-infiltrating CD8(+) and CD4(+) T cells. A differential compartmentalization was detected between Helios(high) and Helios(low) Treg subsets (thymus-derived versus peripherally induced): while Helios(low) Tregs were enriched in both sites, only Helios(high) Tregs accumulated significantly and specifically in tumors, displayed a highly demethylated TSDR region and contained high proportions of cells expressing CD39 and OX40, markers of activation and suppression. Besides the suppression of T cells, Tregs may contribute to CRC progression also through releasing IL-17, or differentiating into Tfr cells that potentially antagonize a protective Tfh response, events that were both detected in tumor-associated Tregs. Overall, our data indicate that Treg accumulation may contribute through multiple mechanisms to CRC establishment and progression. PMID:27622025

  10. 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

  11. 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

  12. Histone Deacetylase Inhibitors Enhance the Therapeutic Potential of Reovirus in Multiple Myeloma.

    PubMed

    Stiff, Andrew; Caserta, Enrico; Sborov, Douglas W; Nuovo, Gerard J; Mo, Xiaokui; Schlotter, Sarah Y; Canella, Alessandro; Smith, Emily; Badway, Joseph; Old, Matthew; Jaime-Ramirez, Alena Cristina; Yan, Pearlly; Benson, Don M; Byrd, John C; Baiocchi, Robert; Kaur, Balveen; Hofmeister, Craig C; Pichiorri, Flavia

    2016-05-01

    Multiple myeloma remains incurable and the majority of patients die within 5 years of diagnosis. Reolysin, the infusible form of human reovirus (RV), is a novel viral oncolytic therapy associated with antitumor activity likely resulting from direct oncolysis and a virus-mediated antitumor immune response. Results from our phase I clinical trial investigating single agent Reolysin in patients with relapsed multiple myeloma confirmed tolerability, but no objective responses were evident, likely because the virus selectively entered the multiple myeloma cells but did not actively replicate. To date, the precise mechanisms underlying the RV infectious life cycle and its ability to induce oncolysis in patients with multiple myeloma remain unknown. Here, we report that junctional adhesion molecule 1 (JAM-1), the cellular receptor for RV, is epigenetically regulated in multiple myeloma cells. Treatment of multiple myeloma cells with clinically relevant histone deacetylase inhibitors (HDACi) results in increased JAM-1 expression as well as increased histone acetylation and RNA polymerase II recruitment to its promoter. Furthermore, our data indicate that the combination of Reolysin with HDACi, potentiates RV killing activity of multiple myeloma cells in vitro and in vivo This study provides the molecular basis to use these agents as therapeutic tools to increase the efficacy of RV therapy in multiple myeloma. Mol Cancer Ther; 15(5); 830-41. ©2016 AACR. PMID:26809490

  13. The grain production potential assessment with Multiple Cropping Index (MCI) in China

    NASA Astrophysics Data System (ADS)

    Gao, Zhiqiang; Ning, Jicai; Gao, Wei

    2014-10-01

    This paper retrieved the information of cropland and MCI (Multiple Cropping Index) of China in 2000 and 2009 with SPOT NDVI time series data and utilized meteorological data and statistical data released by the state to calculate potential MCI and statistical MCI. Then, the MCI potential of China and grain production potential based on MCI were calculated in order to analyze the potential spatial distribution characteristics of MCI and the potential spatial pattern characteristics. The national mean MCI potentials in 2000 and 2009 are 0.485 and 0.506 respectively calculated with the remote sensing method and statistical method. And the grain productivity potentials of China based on MCI are 51% and 53% respectively. The improvement of MCI potential not only increases hydrothermal utilization rate and the utilization rate of cropland but also enormously enhances the food security degree of China and provides more available cropland area for the economic development.

  14. Ultrastructural assessment of the differentiation potential of human multipotent mesenchymal stromal cells.

    PubMed

    Pasquinelli, Gianandrea; Valente, Sabrina

    2013-10-01

    Mesenchymal stromal (stem) cells (MSCs) are defined by plastic adherent growth, multiple phenotype expressions, and tripotential mesodermal capability. The authors report examples where electron microscopy (EM) plays a role in stem cell research. MSCs isolated from human arteries are ultrastructurally heterogeneous and become more homogenous after plastic adhesion. EM shows a moderate complement of organelles, mainly mitochondria, rough endoplasmic reticulum, and glycogen aggregates. Clear vacuoles and vesicles are prominent when cells are recovered from plates using an enzymatic method. Since the mesengenic plasticity is the single most important criterion to define a cell as mesenchymal stromal, the authors induced experimentally adipogenic, leiomyogenic, cardiomyogenic, osteo-chondrogenic differentiations. In no case did EM reveal the achievement of complete differentiation. The authors obtained multivacuolated pre-adipocytes and never univacuolated adipocytes typical of mature white fat; myofibroblast and rhabdomyoblast morphotypes, where contractile filaments were not organized to form functional complexes, i.e., dense bodies and sarcomeres. Chondrogenesis and osteogenesis assays resulted in extracellular matrix changes. Collagen and proteoglycan filament/particle deposition was seen when chondrogenesis was promoted. Hydroxyapatite crystals, psammoma bodies, and plaque-like calcified matrix deposits were found in the osteogenic matrix. EM provides detailed structural information on the degree of differentiation induced in stem cells and demonstrates that the methods so far developed are not able to promote complete cell differentiation. These observations contribute to explain why clinical applications with hMSCs have produced results far lower than initial expectations. PMID:24047349

  15. Differential Frequency of CD8+ T Cell Subsets in Multiple Sclerosis Patients with Various Clinical Patterns.

    PubMed

    Salehi, Zahra; Doosti, Rozita; Beheshti, Masoumeh; Janzamin, Ehsan; Sahraian, Mohammad Ali; Izad, Maryam

    2016-01-01

    Recent evidence points to a pathogenic role for CD8+ cytotoxic T (Tc) cells in Multiple sclerosis (MS). Based on cytokine profile, Tc cells can be divided into different subsets: IFN-γ (Tc1), IL-4 (Tc2), IL-10 (Tc10), IL-17 (Tc17), IL-21 (Tc21), IL-22 (Tc22) and TNF-α producing cells. In this study we evaluated the frequency of Tc cell subsets and the serum level of Tc17 differentiation cytokines in MS patients with different clinical patterns. We analyzed Tc cell subsets percentage in peripheral blood of relapsing-remitting (RRMS) (n = 28), secondary-progressive (SPMS) (n = 10) and primary-progressive (PPMS) (n = 4) MS patients in comparison to healthy controls (n = 15) using flow cytometry. Serum level of TGF-β, IL-6 and IL-23 were measured by ELISA. We showed elevated levels of Tc1 and Tc17 cells in SPMS and RRMS patients in relapse phase, respectively (P = 0.04). Interestingly, the percentage of TNF-α producing CD8+ T cells in relapse and remission phase of RRMS and SPMS patients were higher than controls (P = 0.01, P = 0.004, P = 0.01, respectively) and Tc21 increased in remission phase of RRMS compared to SPMS (P = 0.03). We also found higher frequency of CD8+ IFN-γ+ TNF-α+ IL-17+ T cells in relapse phase of RRMS compared to remission phase, SPMS patients and controls (P = 0.01, P = 0.004 and P = 0.02, respectively). TGF- β increased in sera of RRMS patients in remission phase (P = 0.03) and SPMS (P = 0.05) compared to healthy subjects. Increased level of Tc17 and CD8+ IFN-γ+ TNF-α+ IL-17+ T cells in relapse phase highlights the critical role of IL-17 in RRMS pathogenesis. PMID:27467597

  16. Alternative promoter usage and differential expression of multiple transcripts of mouse Prkar1a gene.

    PubMed

    Banday, Abdul Rouf; Azim, Shafquat; Tabish, Mohammad

    2011-11-01

    Prkar1a gene encodes regulatory type 1 alpha subunit (RIα) of cAMP-dependent protein kinase (PKA) in mouse. The role of this gene has been implicated in Carney complex and many cancer types that suggest its involvement in physiological processes like cell cycle regulation, growth and/or proliferation. We have identified and sequenced partial cDNA clones encoding four alternatively spliced transcripts of mouse Prkar1a gene. These transcripts have alternate 5' UTR structure which results from splicing of three exons (designated as E1a, E1b, and E1c) to canonical exon 2. The designated transcripts T1, T2, T3, and T4 contain 5' UTR exons as E1c, E1a + E1b, E1a, and E1b, respectively. The transcript T1 corresponded to earlier reported transcript in GenBank. In silico study of genomic DNA sequence revealed three distinct promoter regions namely, P1, P2, and P3 upstream of the exons E1a, E1b, and E1c, respectively. P1 is non-CpG-related promoter but P2 and P3 are CpG-related promoters; however, all three are TATA less. RT-PCR analysis demonstrated the expression of all four transcripts in late postnatal stages; however, these were differentially regulated in early postnatal stages of 0.5 day, 3 day, and 15 day mice in different tissue types. Variations in expression of Prkar1a gene transcripts suggest their regulation from multiple promoters that respond to a variety of signals arising in or out of the cell in tissue and developmental stage-specific manner. PMID:21638026

  17. Differential Frequency of CD8+ T Cell Subsets in Multiple Sclerosis Patients with Various Clinical Patterns

    PubMed Central

    Salehi, Zahra; Doosti, Rozita; Beheshti, Masoumeh; Janzamin, Ehsan; Sahraian, Mohammad Ali; Izad, Maryam

    2016-01-01

    Recent evidence points to a pathogenic role for CD8+ cytotoxic T (Tc) cells in Multiple sclerosis (MS). Based on cytokine profile, Tc cells can be divided into different subsets: IFN-γ (Tc1), IL-4 (Tc2), IL-10 (Tc10), IL-17 (Tc17), IL-21 (Tc21), IL-22 (Tc22) and TNF-α producing cells. In this study we evaluated the frequency of Tc cell subsets and the serum level of Tc17 differentiation cytokines in MS patients with different clinical patterns. We analyzed Tc cell subsets percentage in peripheral blood of relapsing-remitting (RRMS) (n = 28), secondary-progressive (SPMS) (n = 10) and primary-progressive (PPMS) (n = 4) MS patients in comparison to healthy controls (n = 15) using flow cytometry. Serum level of TGF-β, IL-6 and IL-23 were measured by ELISA. We showed elevated levels of Tc1 and Tc17 cells in SPMS and RRMS patients in relapse phase, respectively (P = 0.04). Interestingly, the percentage of TNF-α producing CD8+ T cells in relapse and remission phase of RRMS and SPMS patients were higher than controls (P = 0.01, P = 0.004, P = 0.01, respectively) and Tc21 increased in remission phase of RRMS compared to SPMS (P = 0.03). We also found higher frequency of CD8+ IFN-γ+ TNF-α+ IL-17+ T cells in relapse phase of RRMS compared to remission phase, SPMS patients and controls (P = 0.01, P = 0.004 and P = 0.02, respectively). TGF- β increased in sera of RRMS patients in remission phase (P = 0.03) and SPMS (P = 0.05) compared to healthy subjects. Increased level of Tc17 and CD8+ IFN-γ+ TNF-α+ IL-17+ T cells in relapse phase highlights the critical role of IL-17 in RRMS pathogenesis. PMID:27467597

  18. 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.

  19. Potential mechanisms underlying ectodermal differentiation of Wharton's jelly mesenchymal stem cells.

    PubMed

    Jadalannagari, Sushma; Berry, Abigale M; Hopkins, Richard A; Bhavsar, Dhaval; Aljitawi, Omar S

    2016-09-16

    Wharton's jelly mesenchymal stem cells (WJMSCs) are being increasingly recognized for their ectodermal differentiation potential. Previously, we demonstrated that when WJMSC were seeded onto an acellular matrix material derived from Wharton's jelly and cultured in osteogenic induction media, generated CK19 positive cells and hair-like structures indicative of ectodermal differentiation of WJMSCs. In this manuscript, we examine the underlying mechanism behind this observation using a variety of microscopy and molecular biology techniques such as western blotting and qPCR. We demonstrate that these hair-like structures are associated with live cells that are positive for epithelial and mesenchymal markers such as cytokeratin-19 and α-smooth muscle actin, respectively. We also show that up-regulation of β-catenin and noggin, along with the expression of TGF-β and SMAD and inhibition of BMP4 could be the mechanism behind this ectodermal differentiation and hair-like structure formation. PMID:27501759

  20. 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-Mann–Whitney; 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 3 kb 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: [χ2; p = 0.004; OR (95% CI) = 0.50 (0.31-0.81)] and severity, since CC women presented lower MSSS scores than CT (U-Mann–Whitney; p = 0.039) or TT patients (U-Mann–Whitney; p = 0.031). Concordantly with the susceptibility conferred in women, rs6622139*T was associated with higher MSRV expression (U-Mann–Whitney; 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

  1. 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

  2. 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.

  3. 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

  4. Mycobacteriophage SWU1 gp39 can potentiate multiple antibiotics against Mycobacterium via altering the cell wall permeability.

    PubMed

    Li, Qiming; Zhou, Mingliang; Fan, Xiangyu; Yan, Jianlong; Li, Weimin; Xie, Jianping

    2016-01-01

    M. tuberculosis is intrinsically tolerant to many antibiotics largely due to the imperviousness of its unusual mycolic acid-containing cell wall to most antimicrobials. The emergence and increasingly widespread of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) revitalized keen interest in phage-inspired therapy. SWU1gp39 is a novel gene from mycobacteriophage SWU1 with unknown function. SWU1gp39 expressed in M. smegmatis conferred the host cell increased susceptibility to multiple antibiotics, including isoniazid, erythromycin, norfloxacin, ampicillin, ciprofloxacin, ofloxacin, rifampicin and vancomycin, and multiple environment stresses such as H2O2, heat shock, low pH and SDS. By using EtBr/Nile red uptake assays, WT-pAL-gp39 strain showed higher cell wall permeability than control strain WT-pAL. Moreover, the WT-pAL-gp39 strain produced more reactive oxygen species and reduced NAD(+)/NADH ratio. RNA-Seq transcriptomes of the WT-pAL-gp39 and WT-pAL revealed that the transcription of 867 genes was differentially regulated, including genes associated with lipid metabolism. Taken together, our results implicated that SWU1gp39, a novel gene from mycobacteriophage, disrupted the lipid metabolism of host and increased cell wall permeability, ultimately potentiated the efficacy of multiple antibiotics and stresses against mycobacteria. PMID:27350398

  5. Mycobacteriophage SWU1 gp39 can potentiate multiple antibiotics against Mycobacterium via altering the cell wall permeability

    PubMed Central

    Li, Qiming; Zhou, Mingliang; Fan, Xiangyu; Yan, Jianlong; Li, Weimin; Xie, Jianping

    2016-01-01

    M. tuberculosis is intrinsically tolerant to many antibiotics largely due to the imperviousness of its unusual mycolic acid-containing cell wall to most antimicrobials. The emergence and increasingly widespread of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) revitalized keen interest in phage-inspired therapy. SWU1gp39 is a novel gene from mycobacteriophage SWU1 with unknown function. SWU1gp39 expressed in M. smegmatis conferred the host cell increased susceptibility to multiple antibiotics, including isoniazid, erythromycin, norfloxacin, ampicillin, ciprofloxacin, ofloxacin, rifampicin and vancomycin, and multiple environment stresses such as H2O2, heat shock, low pH and SDS. By using EtBr/Nile red uptake assays, WT-pAL-gp39 strain showed higher cell wall permeability than control strain WT-pAL. Moreover, the WT-pAL-gp39 strain produced more reactive oxygen species and reduced NAD+/NADH ratio. RNA-Seq transcriptomes of the WT-pAL-gp39 and WT-pAL revealed that the transcription of 867 genes was differentially regulated, including genes associated with lipid metabolism. Taken together, our results implicated that SWU1gp39, a novel gene from mycobacteriophage, disrupted the lipid metabolism of host and increased cell wall permeability, ultimately potentiated the efficacy of multiple antibiotics and stresses against mycobacteria. PMID:27350398

  6. 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 Δ-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 Schrödinger 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

  7. RNAi Screen Reveals Potentially Novel Roles of Cytokines in Myoblast Differentiation

    PubMed Central

    Ge, Yejing; Waldemer, Rachel J.; Nalluri, Ramakrishna; Nuzzi, Paul D.; Chen, Jie

    2013-01-01

    Cytokines are cell-secreted signaling molecules that modulate various cellular functions, with the best-characterized roles in immune responses. The expression of numerous cytokines in skeletal muscle tissues and muscle cells has been reported, but their function in skeletal myogenesis, the formation of skeletal muscle, has been largely underexplored. To systematically examine the potential roles of cytokines in skeletal myogenesis, we undertook an RNAi screen of 134 mouse cytokine genes for their involvement in the differentiation of C2C12 myoblasts. Our results have uncovered 29 cytokines as strong candidates for novel myogenic regulators, potentially conferring positive and negative regulation at distinct stages of myogenesis. These candidates represent a diverse collection of cytokine families, including interleukins, TNF-related factors, and chemokines. Our findings suggest the fundamental importance of cytokines in the cell-autonomous regulation of myoblast differentiation, and may facilitate future identification of novel therapeutic targets for improving muscle regeneration and growth in health and diseases. PMID:23844157

  8. Potential Values of Incorporating a Multiple-Choice Question Construction in Physics Experimentation Instruction

    ERIC Educational Resources Information Center

    Yu, Fu-Yun; Liu, Yu-Hsin

    2005-01-01

    The potential value of a multiple-choice question-construction instructional strategy for the support of students' learning of physics experiments was examined in the study. Forty-two university freshmen participated in the study for a whole semester. A constant comparison method adopted to categorize students' qualitative data indicated that the…

  9. PAC1R agonist maxadilan enhances hADSC viability and neural differentiation potential.

    PubMed

    Guo, Xiaoling; Yu, Rongjie; Xu, Ying; Lian, Ruiling; Yu, Yankun; Cui, Zekai; Ji, Qingshan; Chen, Junhe; Li, Zhijie; Liu, Hongwei; Chen, Jiansu

    2016-05-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a structurally endogenous peptide with many biological roles. However, little is known about its presence or effects in human adipose-derived stem cells (hADSCs). In this study, the expression of PACAP type I receptor (PAC1R) was first confirmed in hADSCs. Maxadilan, a specific agonist of PAC1R, could increase hADSC proliferation as determined by Cell Counting Kit-8 and cell cycle analysis and promote migration as shown in wound-healing assays. Maxadilan also showed anti-apoptotic activity in hADSCs against serum withdrawal-induced apoptosis based on Annexin V/propidium iodide analysis and mitochondrial membrane potential assays. The anti-apoptotic effects of maxadilan correlated with the down-regulation of Cleaved Caspase 3 and Caspase 9 as well as up-regulation of Bcl-2. The chemical neural differentiation potential could be enhanced by maxadilan as indicated through quantitative PCR, Western blot and cell morphology analysis. Moreover, cytokine neural redifferentiation of hADSCs treated with maxadilan acquired stronger neuron-like functions with higher voltage-dependent tetrodotoxin-sensitive sodium currents, higher outward potassium currents and partial electrical impulses as determined using whole-cell patch clamp recordings. Maxadilan up-regulated the Wnt/β-catenin signalling pathway associated with dimer-dependent activity of PAC1R, promoting cell viability that was inhibited by XAV939, and it also activated the protein kinase A (PKA) signalling pathway associated with ligand-dependent activity of PAC1R, enhancing cell viability and neural differentiation potential that was inhibited by H-89. In summary, these results demonstrated that PAC1R is present in hADSCs, and maxadilan could enhance hADSC viability and neural differentiation potential in neural differentiation medium. PMID:26798992

  10. Mesenchymal precursor cells maintain the differentiation and proliferation potentials of breast epithelial cells

    PubMed Central

    2014-01-01

    Introduction Stromal-epithelial interactions play a fundamental role in tissue homeostasis, controlling cell proliferation and differentiation. Not surprisingly, aberrant stromal-epithelial interactions contribute to malignancies. Studies of the cellular and molecular mechanisms underlying these interactions require ex vivo experimental model systems that recapitulate the complexity of human tissue without compromising the differentiation and proliferation potentials of human primary cells. Methods We isolated and characterized human breast epithelial and mesenchymal precursors from reduction mammoplasty tissue and tagged them with lentiviral vectors. We assembled heterotypic co-cultures and compared mesenchymal and epithelial cells to cells in corresponding monocultures by analyzing growth, differentiation potentials, and gene expression profiles. Results We show that heterotypic culture of non-immortalized human primary breast epithelial and mesenchymal precursors maintains their proliferation and differentiation potentials and constrains their growth. We further describe the gene expression profiles of stromal and epithelial cells in co-cultures and monocultures and show increased expression of the tumor growth factor beta (TGFβ) family member inhibin beta A (INHBA) in mesenchymal cells grown as co-cultures compared with monocultures. Notably, overexpression of INHBA in mesenchymal cells increases colony formation potential of epithelial cells, suggesting that it contributes to the dynamic reciprocity between breast mesenchymal and epithelial cells. Conclusions The described heterotypic co-culture system will prove useful for further characterization of the molecular mechanisms mediating interactions between human normal or neoplastic breast epithelial cells and the stroma, and will provide a framework to test the relevance of the ever-increasing number of oncogenomic alterations identified in human breast cancer. PMID:24916766

  11. Selective AKR1C3 Inhibitors Potentiate Chemotherapeutic Activity in Multiple Acute Myeloid Leukemia (AML) Cell Lines.

    PubMed

    Verma, Kshitij; Zang, Tianzhu; Gupta, Nehal; Penning, Trevor M; Trippier, Paul C

    2016-08-11

    We report the design, synthesis, and evaluation of potent and selective inhibitors of aldo-keto reductase 1C3 (AKR1C3), an important enzyme in the regulatory pathway controlling proliferation, differentiation, and apoptosis in myeloid cells. Combination treatment with the nontoxic AKR1C3 inhibitors and etoposide or daunorubicin in acute myeloid leukemia cell lines, elicits a potent adjuvant effect, potentiating the cytotoxicity of etoposide by up to 6.25-fold and the cytotoxicity of daunorubicin by >10-fold. The results validate AKR1C3 inhibition as a common adjuvant target across multiple AML subtypes. These compounds in coadministration with chemotherapeutics in clinical use enhance therapeutic index and may avail chemotherapy as a treatment option to the pediatric and geriatric population currently unable to tolerate the side effects of cancer drug regimens. PMID:27563402

  12. Chemical and Physical Approaches to Extend the Replicative and Differentiation Potential of Stem Cells.

    PubMed

    Hwang, Eun Seong; Ok, Jeong Soo; Song, SeonBeom

    2016-06-01

    Cell therapies using mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) are increasing in regenerative medicine, with applications to a growing number of aging-associated dysfunctions and degenerations. For successful therapies, a certain mass of cells is needed, requiring extensive ex vivo expansion of the cells. However, the proliferation of both MSCs and EPCs is limited as a result of telomere shortening-induced senescence. As cells approach senescence, their proliferation slows down and differentiation potential decreases. Therefore, ways to delay senescence and extend the replicative lifespan these cells are needed. Certain proteins and pathways play key roles in determining the replicative lifespan by regulating ROS generation, damage accumulation, or telomere shortening. And, their agonists and gene activators exert positive effects on lifespan. In many of the treatments, importantly, the lifespan is extended with the retention of differentiation potential. Furthermore, certain culture conditions, including the use of specific atmospheric conditions and culture substrates, exert positive effects on not only the proliferation rate, but also the extent of proliferation and differentiation potential as well as lineage determination. These strategies and known underlying mechanisms are introduced in this review, with an evaluation of their pros and cons in order to facilitate safe and effective MSC expansion ex vivo. PMID:27085715

  13. Serum anti-GAGA4 IgM antibodies differentiate relapsing remitting and secondary progressive multiple sclerosis from primary progressive multiple sclerosis and other neurological diseases.

    PubMed

    Brettschneider, Johannes; Jaskowski, Troy D; Tumani, Hayrettin; Abdul, Sana; Husebye, Dee; Seraj, Haniah; Hill, Harry R; Fire, Ella; Spector, Larissa; Yarden, Jennifer; Dotan, Nir; Rose, John W

    2009-12-10

    The serum level of IgM antibodies against Glc(alpha1,4)Glc(alpha) (GAGA4) is higher in relapsing remitting multiple sclerosis (RRMS) compared to other neurological disease (OND) patients and healthy controls (HC). Detecting the level of anti-GAGA4 antibody by enzyme immunoassay and total IgM, we confirmed that anti-GAGA4 IgM can differentiate RRMS from OND patients and HC. Moreover, secondary progressive MS (SPMS) and RRMS patients have similar levels of anti-GAGA4 demonstrating the biomarker's presence throughout the disease. Interestingly, the anti-GAGA4 assay may also differentiate between primary progressive MS (PPMS) and RRMS/SPMS patients, since nearly all PPMS patients were negative for the assay. PMID:19879655

  14. A case of multiple evanescent white dot syndrome misdiagnosed as optic neuritis: Differential diagnosis for the neurologist

    PubMed Central

    Pellegrini, Francesco; Interlandi, Emanuela

    2016-01-01

    A 25-year-old female presented to a local hospital for acute onset of a central scotoma in the left visual field. She was visited by the neurologist, and a diagnosis of left retrobulbar optic neuritis was made. Magnetic resonance imaging scan was normal. Ophthalmic examination revealed a multiple evanescent white dot syndrome. After a description of the case, a brief differential diagnosis between these two entities is made. The neurologist should be aware of this uncommon condition. PMID:27114663

  15. About the notion of non-T-resonance and applications to topological multiplicity results for ODEs on differentiable manifolds

    NASA Astrophysics Data System (ADS)

    Bisconti, Luca; Spadini, Marco

    2015-12-01

    By using topological methods, mainly the degree of a tangent vector field, we establish multiplicity results for $T$-periodic solutions of parametrized $T$-periodic perturbations of autonomous ODEs on a differentiable manifold $M$. In order to provide insights into the key notion of $T$-resonance, we consider the elementary situations $M = \\mathbb{R}$ and $M = \\mathbb{R}^2$. So doing, we provide more comprehensive analysis of those cases and find improved conditions.

  16. Evoked potentials and contingent negative variation during treatment of multiple sclerosis with spinal cord stimulation.

    PubMed Central

    Sedgwick, E M; Illis, L S; Tallis, R C; Thornton, A R; Abraham, P; El-Negamy, E; Docherty, T B; Soar, J S; Spencer, S C; Taylor, F M

    1980-01-01

    Cervical somatosensory evoked potentials, brainstem evoked potentials, visual evoked potentials, and the cerebral contingent negative variation were recorded in patients with definite multiple sclerosis before, during, and after spinal cord stimulation. Improvements were seen in the cervical somatosensory and brainstem evoked potentials but neither the visual evoked potential nor the contingent negative variation changed in association with spinal cord stimulation. The results indicate that spinal cord stimulation acts at spinal and brainstem levels and that the clinical improvements seen in patients are caused by an action at these levels rather than by any cerebral arousal or motivational effect. The evoked potentials were not useful in predicting which patients were likely to respond to stimulation. PMID:7354352

  17. 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

  18. Label-free whole blood cell differentiation based on multiple frequency AC impedance and light scattering analysis in a micro flow cytometer.

    PubMed

    Simon, Peter; Frankowski, Marcin; Bock, Nicole; Neukammer, Jörg

    2016-06-21

    We developed a microfluidic sensor for label-free flow cytometric cell differentiation by combined multiple AC electrical impedance and light scattering analysis. The measured signals are correlated to cell volume, membrane capacity and optical properties of single cells. For an improved signal to noise ratio, the microfluidic sensor incorporates two electrode pairs for differential impedance detection. One-dimensional sheath flow focusing was implemented, which allows single particle analysis at kHz count rates. Various monodisperse particles and differentiation of leukocytes in haemolysed samples served to benchmark the microdevice applying combined AC impedance and side scatter analyses. In what follows, we demonstrate that AC impedance measurements at selected frequencies allow label-free discrimination of platelets, erythrocytes, monocytes, granulocytes and lymphocytes in whole blood samples involving dilution only. Immunofluorescence staining was applied to validate the results of the label-free cell analysis. Reliable differentiation and enumeration of cells in whole blood by AC impedance detection have the potential to support medical diagnosis for patients with haemolysis resistant erythrocytes or abnormally sensitive leucocytes, i.e. for patients suffering from anaemia or leukaemia. PMID:27229300

  19. TET1 knockdown inhibits the odontogenic differentiation potential of human dental pulp cells

    PubMed Central

    Rao, Li-Jia; Yi, Bai-Cheng; Li, Qi-Meng; Xu, Qiong

    2016-01-01

    Human dental pulp cells (hDPCs) possess the capacity to differentiate into odontoblast-like cells and generate reparative dentin in response to exogenous stimuli or injury. Ten–eleven translocation 1 (TET1) is a novel DNA methyldioxygenase that plays an important role in the promotion of DNA demethylation and transcriptional regulation in several cell lines. However, the role of TET1 in the biological functions of hDPCs is unknown. To investigate the effect of TET1 on the proliferation and odontogenic differentiation potential of hDPCs, a recombinant shRNA lentiviral vector was used to knock down TET1 expression in hDPCs. Following TET1 knockdown, TET1 was significantly downregulated at both the mRNA and protein levels. Proliferation of the hDPCs was suppressed in the TET1 knockdown groups. Alkaline phosphatase activity, the formation of mineralized nodules, and the expression levels of DSPP and DMP1 were all reduced in the TET1-knockdown hDPCs undergoing odontogenic differentiation. Based on these results, we concluded that TET1 knockdown can prevent the proliferation and odontogenic differentiation of hDPCs, which suggests that TET1 may play an important role in dental pulp repair and regeneration. PMID:27357322

  20. TET1 knockdown inhibits the odontogenic differentiation potential of human dental pulp cells.

    PubMed

    Rao, Li-Jia; Yi, Bai-Cheng; Li, Qi-Meng; Xu, Qiong

    2016-01-01

    Human dental pulp cells (hDPCs) possess the capacity to differentiate into odontoblast-like cells and generate reparative dentin in response to exogenous stimuli or injury. Ten-eleven translocation 1 (TET1) is a novel DNA methyldioxygenase that plays an important role in the promotion of DNA demethylation and transcriptional regulation in several cell lines. However, the role of TET1 in the biological functions of hDPCs is unknown. To investigate the effect of TET1 on the proliferation and odontogenic differentiation potential of hDPCs, a recombinant shRNA lentiviral vector was used to knock down TET1 expression in hDPCs. Following TET1 knockdown, TET1 was significantly downregulated at both the mRNA and protein levels. Proliferation of the hDPCs was suppressed in the TET1 knockdown groups. Alkaline phosphatase activity, the formation of mineralized nodules, and the expression levels of DSPP and DMP1 were all reduced in the TET1-knockdown hDPCs undergoing odontogenic differentiation. Based on these results, we concluded that TET1 knockdown can prevent the proliferation and odontogenic differentiation of hDPCs, which suggests that TET1 may play an important role in dental pulp repair and regeneration. PMID:27357322

  1. 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.

  2. Multiple zone coal degasification potential in the Warrior coal field of Alabama

    SciTech Connect

    Graves, S.L.; Beavers, W.M.; Patton, A.

    1982-01-01

    The Upper Pottsville formation in the Warrior Coal Field of Alabama has six recognized groups of bituminous coal seams. Three of these groups, the Pratt, Mary Lee, and Black Creek consist of seams containing commercially significant quantities of methane. In parts of the Warrior Coal Field, where all three groups can be penetrated in one vertical borehole, the potential production from multiple zone completion wells can result in commercially profitable wells. Various open hole and through the casing completion procedures are being applied resulting in successful methane production from these multiple zone coal gas wells.

  3. 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 protein–protein 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 protein–protein 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

  4. Multiple Sclerosis Patient-Specific Primary Neurons Differentiated from Urinary Renal Epithelial Cells via Induced Pluripotent Stem Cells

    PubMed Central

    Massa, Megan G.; Gisevius, Barbara; Hirschberg, Sarah; Hinz, Lisa; Schmidt, Matthias; Gold, Ralf; Prochnow, Nora; Haghikia, Aiden

    2016-01-01

    As multiple sclerosis research progresses, it is pertinent to continue to develop suitable paradigms to allow for ever more sophisticated investigations. Animal models of multiple sclerosis, despite their continuing contributions to the field, may not be the most prudent for every experiment. Indeed, such may be either insufficient to reflect the functional impact of human genetic variations or unsuitable for drug screenings. Thus, we have established a cell- and patient-specific paradigm to provide an in vitro model within which to perform future genetic investigations. Renal proximal tubule epithelial cells were isolated from multiple sclerosis patients’ urine and transfected with pluripotency-inducing episomal factors. Subsequent induced pluripotent stem cells were formed into embryoid bodies selective for ectodermal lineage, resulting in neural tube-like rosettes and eventually neural progenitor cells. Differentiation of these precursors into primary neurons was achieved through a regimen of neurotrophic and other factors. These patient-specific primary neurons displayed typical morphology and functionality, also staining positive for mature neuronal markers. The development of such a non-invasive procedure devoid of permanent genetic manipulation during the course of differentiation, in the context of multiple sclerosis, provides an avenue for studies with a greater cell- and human-specific focus, specifically in the context of genetic contributions to neurodegeneration and drug discovery. PMID:27158987

  5. Multiple Sclerosis Patient-Specific Primary Neurons Differentiated from Urinary Renal Epithelial Cells via Induced Pluripotent Stem Cells.

    PubMed

    Massa, Megan G; Gisevius, Barbara; Hirschberg, Sarah; Hinz, Lisa; Schmidt, Matthias; Gold, Ralf; Prochnow, Nora; Haghikia, Aiden

    2016-01-01

    As multiple sclerosis research progresses, it is pertinent to continue to develop suitable paradigms to allow for ever more sophisticated investigations. Animal models of multiple sclerosis, despite their continuing contributions to the field, may not be the most prudent for every experiment. Indeed, such may be either insufficient to reflect the functional impact of human genetic variations or unsuitable for drug screenings. Thus, we have established a cell- and patient-specific paradigm to provide an in vitro model within which to perform future genetic investigations. Renal proximal tubule epithelial cells were isolated from multiple sclerosis patients' urine and transfected with pluripotency-inducing episomal factors. Subsequent induced pluripotent stem cells were formed into embryoid bodies selective for ectodermal lineage, resulting in neural tube-like rosettes and eventually neural progenitor cells. Differentiation of these precursors into primary neurons was achieved through a regimen of neurotrophic and other factors. These patient-specific primary neurons displayed typical morphology and functionality, also staining positive for mature neuronal markers. The development of such a non-invasive procedure devoid of permanent genetic manipulation during the course of differentiation, in the context of multiple sclerosis, provides an avenue for studies with a greater cell- and human-specific focus, specifically in the context of genetic contributions to neurodegeneration and drug discovery. PMID:27158987

  6. ABCG2 Is a Selectable Marker for Enhanced Multilineage Differentiation Potential in Periodontal Ligament Stem Cells

    PubMed Central

    Szepesi, Áron; Matula, Zsolt; Szigeti, Anna; Várady, György; Szabó, Gyula; Uher, Ferenc; Sarkadi, Balázs

    2015-01-01

    Periodontal ligament stem cells (PDLSCs) provide an important source for tissue regeneration and may become especially useful in the formation of osteogenic seeds. PDLSCs can be cultured, expanded, and differentiated in vitro; thus, they may be applied in the long-term treatment of the defects in the dental regions. Here we studied numerous potential markers allowing the selection of human PDLSCs with a maximum differentiation potential. We followed the expression of the ATP-binding cassette subfamily G member 2 (ABCG2) membrane transporter protein and isolated ABCG2-expressing cells by using a monoclonal antibody, recognizing the transporter at the cell surface in intact cells. The expression of the ABCG2 protein, corresponding to the so-called side-population phenotype in various tissue-derived stem cells, was found to be a useful marker for the selection of PDLSCs with enhanced osteogenic, chondrogenic, and adipogenic differentiation. These findings may have important applications in achieving efficient dental tissue regeneration by using stem cells from extracted teeth. PMID:25101689

  7. 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 (α1, α2 and β1; α5 and β3). 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

  8. Determination of spent nuclear fuel assembly multiplication with the differential die-away self-interrogation instrument

    NASA Astrophysics Data System (ADS)

    Kaplan, Alexis C.; Henzl, Vladimir; Menlove, Howard O.; Swinhoe, Martyn T.; Belian, Anthony P.; Flaska, Marek; Pozzi, Sara A.

    2014-09-01

    We present a novel method for determining the multiplication of a spent nuclear fuel assembly with a Differential Die-Away Self-Interrogation (DDSI) instrument. The signal, which is primarily created by thermal neutrons, is measured with four 3He detector banks surrounding a spent fuel assembly. The Rossi-alpha distribution (RAD) at early times reflects coincident events from single fissions as well as fission chains. Because of this fact, the early time domain contains information about both the fissile material and spontaneous fission material in the assembly being measured. A single exponential function fit to the early time domain of the RAD has a die-away time proportional to the spent fuel assembly (SFA) multiplication. This correlation was tested by simulating assay of 44 different SFAs with the DDSI instrument. The SFA multiplication was determined with a variance of 0.7%.

  9. Suprabasin, a novel epidermal differentiation marker and potential cornified envelope precursor.

    PubMed

    Park, Geon Tae; Lim, Susan E; Jang, Shyh-Ing; Morasso, Maria I

    2002-11-22

    The suprabasin gene is a novel gene expressed in mouse and human differentiating keratinocytes. We identified a partial cDNA encoding suprabasin using a suppression subtractive hybridization method between the proliferative basal and differentiating suprabasal populations of the mouse epidermis. A 3' gene-specific probe hybridized to transcripts of 0.7- and 2.2-kb pairs on Northern blots with specific detection in differentiated keratinocytes of stratified epithelia. The mouse gene was mapped to chromosome 7 by fluorescence in situ hybridization. This region is syntenic to human chromosome band 19q13.1, which contained the only region in the data bases with homology to the mouse suprabasin sequence. During embryonic mouse development, suprabasin mRNA was detected at day 15.5, coinciding with epidermal stratification. Suprabasin was detected in the suprabasal layers of the epithelia in the tongue, stomach, and epidermis. Differentiation of cultured primary epidermal keratinocytes with 0.12 mm Ca(2+) or 12-O-tetradecanoylphorbol-13-acetate treatment resulted in the induction of suprabasin. The 2.2-kb cDNA transcript encodes a protein of 72 kDa with a predicted isoelectric point of 6.85. The translated sequence has an amino-terminal domain, a central domain composed of repeats rich in glycine and alanine, and a carboxyl-terminal domain. The alternatively spliced 0.7-kb transcript encodes a smaller protein that shares the NH(2)- and COOH-terminal regions but lacks the repeat domain region. Cross-linking experiments indicate that suprabasin is a substrate for transglutaminase 2 and 3 activity. Altogether, these results indicate that the suprabasin protein potentially plays a role in the process of epidermal differentiation. PMID:12228223

  10. IL-12 directs further maturation of ex vivo differentiated NK cells with improved therapeutic potential.

    PubMed

    Lehmann, Dorit; Spanholtz, Jan; Sturtzel, Caterina; Tordoir, Marleen; Schlechta, Bernhard; Groenewegen, Dirk; Hofer, Erhard

    2014-01-01

    The possibility to modulate ex vivo human NK cell differentiation towards specific phenotypes will contribute to a better understanding of NK cell differentiation and facilitate tailored production of NK cells for immunotherapy. In this study, we show that addition of a specific low dose of IL-12 to an ex vivo NK cell differentiation system from cord blood CD34(+) stem cells will result in significantly increased proportions of cells with expression of CD62L as well as KIRs and CD16 which are preferentially expressed on mature CD56(dim) peripheral blood NK cells. In addition, the cells displayed decreased expression of receptors such as CCR6 and CXCR3, which are typically expressed to a lower extent by CD56(dim) than CD56(bright) peripheral blood NK cells. The increased number of CD62L and KIR positive cells prevailed in a population of CD33(+)NKG2A(+) NK cells, supporting that maturation occurs via this subtype. Among a series of transcription factors tested we found Gata3 and TOX to be significantly downregulated, whereas ID3 was upregulated in the IL-12-modulated ex vivo NK cells, implicating these factors in the observed changes. Importantly, the cells differentiated in the presence of IL-12 showed enhanced cytokine production and cytolytic activity against MHC class I negative and positive targets. Moreover, in line with the enhanced CD16 expression, these cells exhibited improved antibody-dependent cellular cytotoxicity for B-cell leukemia target cells in the presence of the clinically applied antibody rituximab. Altogether, these data provide evidence that IL-12 directs human ex vivo NK cell differentiation towards more mature NK cells with improved properties for potential cancer therapies. PMID:24498025

  11. 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

  12. Multiple specialised goose-type lysozymes potentially compensate for an exceptional lack of chicken-type lysozymes in Atlantic cod

    PubMed Central

    Seppola, Marit; Bakkemo, Kathrine Ryvold; Mikkelsen, Helene; Myrnes, Bjørnar; Helland, Ronny; Irwin, David M.; Nilsen, Inge W.

    2016-01-01

    Previous analyses of the Atlantic cod genome showed unique combinations of lacking and expanded number of genes for the immune system. The present study examined lysozyme activity, lysozyme gene distribution and expression in cod. Enzymatic assays employing specific bacterial lysozyme inhibitors provided evidence for presence of g-type, but unexpectedly not for c-type lysozyme activity. Database homology searches failed to identify any c-type lysozyme gene in the cod genome or in expressed sequence tags from cod. In contrast, we identified four g-type lysozyme genes (LygF1a-d) constitutively expressed, although differentially, in all cod organs examined. The active site glutamate residue is replaced by alanine in LygF1a, thus making it enzymatic inactive, while LygF1d was found in two active site variants carrying alanine or glutamate, respectively. In vitro and in vivo infection by the intracellular bacterium Francisella noatunensis gave a significantly reduced LygF1a and b expression but increased expression of the LygF1c and d genes as did also the interferon gamma (IFNγ) cytokine. These results demonstrate a lack of c-type lysozyme that is unprecedented among vertebrates. Our results further indicate that serial gene duplications have produced multiple differentially regulated cod g-type lysozymes with specialised functions potentially compensating for the lack of c-type lysozymes. PMID:27324690

  13. Multiple specialised goose-type lysozymes potentially compensate for an exceptional lack of chicken-type lysozymes in Atlantic cod.

    PubMed

    Seppola, Marit; Bakkemo, Kathrine Ryvold; Mikkelsen, Helene; Myrnes, Bjørnar; Helland, Ronny; Irwin, David M; Nilsen, Inge W

    2016-01-01

    Previous analyses of the Atlantic cod genome showed unique combinations of lacking and expanded number of genes for the immune system. The present study examined lysozyme activity, lysozyme gene distribution and expression in cod. Enzymatic assays employing specific bacterial lysozyme inhibitors provided evidence for presence of g-type, but unexpectedly not for c-type lysozyme activity. Database homology searches failed to identify any c-type lysozyme gene in the cod genome or in expressed sequence tags from cod. In contrast, we identified four g-type lysozyme genes (LygF1a-d) constitutively expressed, although differentially, in all cod organs examined. The active site glutamate residue is replaced by alanine in LygF1a, thus making it enzymatic inactive, while LygF1d was found in two active site variants carrying alanine or glutamate, respectively. In vitro and in vivo infection by the intracellular bacterium Francisella noatunensis gave a significantly reduced LygF1a and b expression but increased expression of the LygF1c and d genes as did also the interferon gamma (IFNγ) cytokine. These results demonstrate a lack of c-type lysozyme that is unprecedented among vertebrates. Our results further indicate that serial gene duplications have produced multiple differentially regulated cod g-type lysozymes with specialised functions potentially compensating for the lack of c-type lysozymes. PMID:27324690

  14. 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

  15. Multiscale renormalization group methods for effective potentials with multiple scalar fields

    NASA Astrophysics Data System (ADS)

    Wang, Zhi-Wei; Steele, Tom; McKeon, Gerry

    2015-04-01

    Conformally symmetric scalar extensions of the Standard Model are particular appealing to reveal the underlying mechanism for electroweak symmetry breaking and to provide dark matter candidates. The Gildener & Weinberg (GW) method is widely used in these models, but is limited to weakly coupled theories. In this talk, multi-scale renormalization group (RG) methods are reviewed and applied to the analysis of the effective potential for radiative symmetry breaking with multiple scalar fields, allowing an extension of the GW method beyond the weak coupling limit. A model containing two interacting real scalar fields is used as an example to illustrate these multi-scale RG methods. Extensions of these multi-scale methods for effective potentials in models containing multiple scalars with O(M) × O(N) symmetry will also be discussed. Reseach funded by NSERC (Natural Sciences and Engineering Research Council of Canada).

  16. 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.

  17. Aqueous Ethanolic Extract of Tinospora cordifolia as a Potential Candidate for Differentiation Based Therapy of Glioblastomas

    PubMed Central

    Mishra, Rachana; Kaur, Gurcharan

    2013-01-01

    Glioblastomas are the most aggressive primary brain tumors and their heterogeneity and complexity often renders them non responsive to various conventional treatments. Search for herbal products having potential anti-cancer activity is an active area of research in the Indian traditional system of medicine i.e., Ayurveda. Tinospora cordifolia, also named as ‘heavenly elixir’ is used in various ayurvedic decoctions as panacea to treat several body ailments. The current study investigated the anti-brain cancer potential of 50% ethanolic extract of Tinospora cordifolia (TCE) using C6 glioma cells. TCE significantly reduced cell proliferation in dose-dependent manner and induced differentiation in C6 glioma cells, resulting in astrocyte-like morphology as indicated by phase contrast images, GFAP expression and process outgrowth data of TCE treated cells which exhibited higher number and longer processes than untreated cells. Reduced proliferation of cells was accompanied by enhanced expression of senescence marker, mortalin and its translocation from perinuclear to pancytoplasmic spaces. Further, TCE showed anti-migratory and anti-invasive potential as depicted by wound scratch assay and reduced expression of plasticity markers NCAM and PSA-NCAM along with MMP-2 and 9. On analysis of the cell cycle and apoptotic markers, TCE treatment was seen to arrest the C6 cells in G0/G1 and G2/M phase, suppressing expression of G1/S phase specific protein cyclin D1 and anti-apoptotic protein Bcl-xL, thus supporting its anti-proliferative and apoptosis inducing potential. Present study provides the first evidence for the presence of anti-proliferative, differentiation-inducing and anti-migratory/anti-metastatic potential of TCE in glioma cells and possible signaling pathways involved in its mode of action. Our primary data suggests that TCE and its active components may prove to be promising phytotherapeutic interventions in gliobalstoma multiformae.  PMID:24205314

  18. 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.

  19. Optical Coherence Tomography versus Visual Evoked Potentials in detecting subclinical visual impairment in multiple sclerosis

    PubMed Central

    Grecescu, M

    2014-01-01

    Rationale. Visual impairment is one of the most common clinical manifestations of multiple sclerosis (MS). Some multiple sclerosis patients complain of poor vision although the Snellen visual acuity is 20/20. This study reveals that sensitive measurements like visual evoked potential (VEP) and optical coherence tomography (OCT) can evidence subclinical disturbances of visual pathway. These methods examine the relation between the visual function (VEP) and retinal nerve fiber layer (RNFL) thickness, as a structural biomarker for axonal loss in patients with multiple sclerosis (MS). The findings in this study indicate the utility of combining structural and functional testing in clinical research on patients with MS. Purpose. To detect visual impairment in a population of visually asymptomatic patients affected by clinically definite multiple sclerosis (MS) and to compare the utility of optical coherence tomography (OCT) versus visual evoked potentials (VEP). Material and methods. Fourteen patients (28 eyes) affected by clinically definite MS, without a history of optic neuritis and asymptomatic for visual disturbances, were initially fully examined (visual acuity, ocular fundus, biomicroscopy) from an ophthalmic point of view and then measured by OCT (RNFL thickness) and VEP. Patients with a history of glaucoma or other retinal or optic nerve disease were excluded. Results. Of fourteen patients (28 eyes), VEP was abnormal in 11 cases (78,57%) and OCT (RNFL thickness) was abnormal in 5 cases (35,71%), while 3 patients had no abnormalities on neither tests. Conclusions. Optical coherence tomography (OCT) is less sensitive than visual evoked potentials (VEPs) in detecting visual subclinical impairment in patients with multiple sclerosis (MS). VEP remains the preferred test for the detection of clinical and subclinical optic neuritis. OCT may provide complementary information to VEP in cases with clinical definite MS and represent a valuable research instrument for the

  20. 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

  1. 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

  2. Raman spectroscopic analysis of gunshot residue offering great potential for caliber differentiation.

    PubMed

    Bueno, Justin; Sikirzhytski, Vitali; Lednev, Igor K

    2012-05-15

    Near-infrared (NIR) Raman microspectroscopy combined with advanced statistics was used to differentiate gunshot residue (GSR) particles originating from different caliber ammunition. The firearm discharge process is analogous to a complex chemical reaction. The reagents of this process are represented by the chemical composition of the ammunition, firearm, and cartridge case. The specific firearm parameters determine the conditions of the reaction and thus the subsequent product, GSR. We found that Raman spectra collected from these products are characteristic for different caliber ammunition. GSR particles from 9 mm and 0.38 caliber ammunition, collected under identical discharge conditions, were used to demonstrate the capability of confocal Raman microspectroscopy for the discrimination and identification of GSR particles. The caliber differentiation algorithm is based on support vector machines (SVM) and partial least squares (PLS) discriminant analyses, validated by a leave-one-out cross-validation method. This study demonstrates for the first time that NIR Raman microspectroscopy has the potential for the reagentless differentiation of GSR based upon forensically relevant parameters, such as caliber size. When fully developed, this method should have a significant impact on the efficiency of crime scene investigations. PMID:22448891

  3. 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

  4. 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.

  5. Multiple mechanisms of interference between transformation and differentiation in thyroid cells.

    PubMed

    Francis-Lang, H; Zannini, M; De Felice, M; Berlingieri, M T; Fusco, A; Di Lauro, R

    1992-12-01

    Transformation of the thyroid cell line FRTL-5 results in loss or reduction of differentiation as measured by the expression of thyroglobulin and thyroperoxidase, two proteins whose genes are exclusively expressed in thyroid follicular cells. The biochemical mechanisms leading to this phenomenon were investigated in three cell lines obtained by transformation of FRTL-5 cells with Ki-ras, Ha-ras, and polyomavirus middle-T oncogenes. With the ras oncogenes, transformation leads to undetectable expression of the thyroglobulin and thyroperoxidase genes. However, the mechanisms responsible for the extinction of the differentiated phenotype seem to be different for the two ras oncogenes. In Ki-ras-transformed cells, the mRNA encoding TTF-1, a transcription factor controlling thyroglobulin and thyroperoxidase gene expression, is severely reduced. On the contrary, nearly wild-type levels of TTF-1 mRNA are detected in Ha-ras-transformed cells. Furthermore, overexpression of TTF-1 can activate transcription of the thyroglobulin promoter in Ki-ras-transformed cells, whereas it has no effect on thyroglobulin transcription in the Ha-ras-transformed line. Expression of polyoma middle-T antigen in thyroid cells leads to only a reduction of differentiation and does not severely affect either the activity or the amount of TTF-1. Another thyroid cell-specific transcription factor, TTF-2, is more sensitive to transformation, since it disappears in all three transformed lines, and probably contributes to the reduced expression of the differentiated phenotype. PMID:1448106

  6. 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

  7. 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…

  8. 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…

  9. Platelet rich concentrate promotes early cellular proliferation and multiple lineage differentiation of human mesenchymal stromal cells in vitro.

    PubMed

    Shani, Samuel; Ahmad, Raja Elina; Naveen, Sangeetha Vasudevaraj; Murali, Malliga Raman; Puvanan, Karunanithi; Abbas, Azlina Amir; Kamarul, Tunku

    2014-01-01

    Platelet rich concentrate (PRC) is a natural adjuvant that aids in human mesenchymal stromal cell (hMSC) proliferation in vitro; however, its role requires further exploration. This study was conducted to determine the optimal concentration of PRC required for achieving the maximal proliferation, and the need for activating the platelets to achieve this effect, and if PRC could independently induce early differentiation of hMSC. The gene expression of markers for osteocytes (ALP, RUNX2), chondrocytes (SOX9, COL2A1), and adipocytes (PPAR-γ) was determined at each time point in hMSC treated with 15% activated and nonactivated PRC since maximal proliferative effect was achieved at this concentration. The isolated PRC had approximately fourfold higher platelet count than whole blood. There was no significant difference in hMSC proliferation between the activated and nonactivated PRC. Only RUNX2 and SOX9 genes were upregulated throughout the 8 days. However, protein expression study showed formation of oil globules from day 4, significant increase in ALP at days 6 and 8 (P ≤ 0.05), and increased glycosaminoglycan levels at all time points (P < 0.05), suggesting the early differentiation of hMSC into osteogenic and adipogenic lineages. This study demonstrates that the use of PRC increased hMSC proliferation and induced early differentiation of hMSC into multiple mesenchymal lineages, without preactivation or addition of differentiation medium. PMID:25436230

  10. MicroRNA-125b promotes neuronal differentiation in human cells by repressing multiple targets.

    PubMed

    Le, Minh T N; Xie, Huangming; Zhou, Beiyan; Chia, Poh Hui; Rizk, Pamela; Um, Moonkyoung; Udolph, Gerald; Yang, Henry; Lim, Bing; Lodish, Harvey F

    2009-10-01

    MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression at the posttranscriptional level. Research on miRNAs has highlighted their importance in neural development, but the specific functions of neurally enriched miRNAs remain poorly understood. We report here the expression profile of miRNAs during neuronal differentiation in the human neuroblastoma cell line SH-SY5Y. Six miRNAs were significantly upregulated during differentiation induced by all-trans-retinoic acid and brain-derived neurotrophic factor. We demonstrated that the ectopic expression of either miR-124a or miR-125b increases the percentage of differentiated SH-SY5Y cells with neurite outgrowth. Subsequently, we focused our functional analysis on miR-125b and demonstrated the important role of this miRNA in both the spontaneous and induced differentiations of SH-SH5Y cells. miR-125b is also upregulated during the differentiation of human neural progenitor ReNcell VM cells, and miR-125b ectopic expression significantly promotes the neurite outgrowth of these cells. To identify the targets of miR-125b regulation, we profiled the global changes in gene expression following miR-125b ectopic expression in SH-SY5Y cells. miR-125b represses 164 genes that contain the seed match sequence of the miRNA and/or that are predicted to be direct targets of miR-125b by conventional methods. Pathway analysis suggests that a subset of miR-125b-repressed targets antagonizes neuronal genes in several neurogenic pathways, thereby mediating the positive effect of miR-125b on neuronal differentiation. We have further validated the binding of miR-125b to the miRNA response elements of 10 selected mRNA targets. Together, we report here for the first time the important role of miR-125b in human neuronal differentiation. PMID:19635812

  11. QoS differentiation scheme with multiple burst transmission and virtual resource reservation for optical burst switching networks

    NASA Astrophysics Data System (ADS)

    Arakawa, Yutaka; Yamanaka, Naoaki

    2007-08-01

    We propose what we believe to be a new scheme to provide basic quality of service (QoS) in optical burst switching networks. Our proposal consists of multiple burst transmission (MBT) and virtual resource reservation (VRR). With MBT, consecutive bursts headed to the same destination are serially transmitted, and, at the transmission of high-priority bursts, the wavelength resource reserved by the head burst is kept reserving for the following bursts. We call it VRR. Computer simulations show that our proposal offers a larger differentiation of burst loss than the conventional offset-based QoS differentiation scheme. Also, it can improve the burst loss rate of both high-priority and low-priority bursts. Moreover, it can minimize the burst loss rate of high-priority bursts even when the high-priority traffic occupies a large percentage of the network traffic. The proposed scheme can be applied to the future multiservice optical network architecture.

  12. RhoA inhibits neural differentiation in murine stem cells through multiple mechanisms.

    PubMed

    Yang, Junning; Wu, Chuanshen; Stefanescu, Ioana; Jakobsson, Lars; Chervoneva, Inna; Horowitz, Arie

    2016-01-01

    Spontaneous neural differentiation of embryonic stem cells is induced by Noggin-mediated inhibition of bone morphogenetic protein 4 (BMP4) signaling. RhoA is a guanosine triphosphatase (GTPase) that regulates cytoskeletal dynamics and gene expression, both of which control stem cell fate. We found that disruption of Syx, a gene encoding a RhoA-specific guanine nucleotide exchange factor, accelerated retinoic acid-induced neural differentiation in murine embryonic stem cells aggregated into embryoid bodies. Cells from Syx(+/+) and Syx(-/-) embryoid bodies had different abundances of proteins implicated in stem cell pluripotency. The differentiation-promoting proteins Noggin and RARγ (a retinoic acid receptor) were more abundant in cells of Syx(-/-) embryoid bodies, whereas the differentiation-suppressing proteins SIRT1 (a protein deacetylase) and the phosphorylated form of SMAD1 (the active form of this transcription factor) were more abundant in cells of Syx(+/+) embryoid bodies. These differences were blocked by the overexpression of constitutively active RhoA, indicating that the abundance of these proteins was maintained, at least in part, by RhoA activity. The peripheral stress fibers in cells from Syx(-/-) embryoid bodies were thinner than those in Syx(+/+) cells. Furthermore, less Noggin and fewer vesicles containing Rab3d, a GTPase that mediates Noggin trafficking, were detected in cells from Syx(-/-) embryoid bodies, which could result from increased Noggin exocytosis. These results suggested that, in addition to inhibiting Noggin transcription, RhoA activity in wild-type murine embryonic stem cells also prevented neural differentiation by limiting Noggin secretion. PMID:27460990

  13. 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

  14. 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.

  15. Numerical solution of potential flow about arbitrary 2-dimensional multiple bodies

    NASA Technical Reports Server (NTRS)

    Thompson, J. F.; Thames, F. C.

    1982-01-01

    A procedure for the finite-difference numerical solution of the lifting potential flow about any number of arbitrarily shaped bodies is given. The solution is based on a technique of automatic numerical generation of a curvilinear coordinate system having coordinate lines coincident with the contours of all bodies in the field, regardless of their shapes and number. The effects of all numerical parameters involved are analyzed and appropriate values are recommended. Comparisons with analytic solutions for single Karman-Trefftz airfoils and a circular cylinder pair show excellent agreement. The technique of application of the boundary-fitted coordinate systems to the numerical solution of partial differential equations is illustrated.

  16. 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 in vitro. 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

  17. 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-ε-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

  18. 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

  19. Multibeam long-path differential optical absorption spectroscopy instrument: a device for simultaneous measurements along multiple light paths.

    PubMed

    Pundt, Irene; Mettendorf, Kai Uwe

    2005-08-10

    A novel long-path differential optical absorption spectroscopy (DOAS) apparatus for measuring tropospheric trace gases and the first results from its use are presented: We call it the multibeam instrument. It is the first active DOAS device that emits several light beams simultaneously through only one telescope and with only one lamp as a light source, allowing simultaneous measurement along multiple light paths. In contrast to conventional DOAS instruments, several small mirrors are positioned near the lamp, creating multiple virtual light sources that emit one light beam each in one specific direction. The possibility of error due to scattering between the light beams is negligible. The trace-gas detection limits of NO2, SO2, O3, and H2CO are similar to those of the traditional long-path DOAS instrument. PMID:16114540

  20. Multiple negative differential conductance regions and inelastic phonon assisted tunneling in graphene/h -BN /graphene structures

    NASA Astrophysics Data System (ADS)

    Amorim, B.; Ribeiro, R. M.; Peres, N. M. R.

    2016-06-01

    In this paper we study in detail the effect of the rotational alignment between a hexagonal boron nitride (h -BN) slab and the graphene layers in the vertical current of a a graphene/h -BN /graphene device. We show how for small rotational angles, the transference of momentum by the h -BN crystal lattice leads to multiple peaks in the I -V curve of the device, giving origin to multiple regions displaying negative differential conductance. We also study the effect of scattering by phonons in the vertical current and see how the opening up of inelastic tunneling events allowed by spontaneous emission of optical phonons leads to sharp peaks in the second derivative of the current.

  1. Evoked potential changes in clinically definite multiple sclerosis: a two year follow up study.

    PubMed Central

    Walsh, J C; Garrick, R; Cameron, J; McLeod, J G

    1982-01-01

    Visual, spinal and somatosensory evoked potentials were performed on 56 patients with clinically definite multiple sclerosis at the beginning and end of a 2 1/2 year follow-up period. At the initial examination one or both visual evoked potentials were abnormal in all but nine patients (84%), five of whom had abnormalities of either spinal or somatosensory evoked responses; that is, one or more abnormal results were obtained from 52 of 56 (91%) patients. At the final examination there were abnormalities of one or more evoked potentials in 55 of the 56 (98%) patients. There was an increase in latency of the components of the evoked responses over the period; reduction in latency in individual patients was exceptional. The change in these electrophysiological measurements correlated with the increase in clinical disability of the group of patients over the period of study. PMID:7119812

  2. 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

    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

  3. 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…

  4. 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…

  5. Differential Daily Writing Contingencies and Performance on Major Multiple-Choice Exams

    ERIC Educational Resources Information Center

    Hautau, Briana; Turner, Haley C.; Carroll, Erin; Jaspers, Kathryn; Parker, Megan; Krohn, Katy; Williams, Robert L.

    2006-01-01

    On 4 of 7 days in each unit of an undergraduate human development course, students responded in writing to specific questions related to instructor notes previously made available to them. The study compared the effects of three writing contingencies on the quality of student writing and performance on major multiple-choice exams in the course. …

  6. Integrating prior knowledge in multiple testing under dependence with applications to detecting differential DNA methylation.

    PubMed

    Kuan, Pei Fen; Chiang, Derek Y

    2012-09-01

    DNA methylation has emerged as an important hallmark of epigenetics. Numerous platforms including tiling arrays and next generation sequencing, and experimental protocols are available for profiling DNA methylation. Similar to other tiling array data, DNA methylation data shares the characteristics of inherent correlation structure among nearby probes. However, unlike gene expression or protein DNA binding data, the varying CpG density which gives rise to CpG island, shore and shelf definition provides exogenous information in detecting differential methylation. This article aims to introduce a robust testing and probe ranking procedure based on a nonhomogeneous hidden Markov model that incorporates the above-mentioned features for detecting differential methylation. We revisit the seminal work of Sun and Cai (2009, Journal of the Royal Statistical Society: Series B (Statistical Methodology)71, 393-424) and propose modeling the nonnull using a nonparametric symmetric distribution in two-sided hypothesis testing. We show that this model improves probe ranking and is robust to model misspecification based on extensive simulation studies. We further illustrate that our proposed framework achieves good operating characteristics as compared to commonly used methods in real DNA methylation data that aims to detect differential methylation sites. PMID:22260651

  7. Cdk4 functions in multiple cell types to control Drosophila intestinal stem cell proliferation and differentiation

    PubMed Central

    Adlesic, Mojca; Frei, Christian; Frew, Ian J.

    2016-01-01

    ABSTRACT The proliferation of intestinal stem cells (ISCs) and differentiation of enteroblasts to form mature enteroendocrine cells and enterocytes in the Drosophila intestinal epithelium must be tightly regulated to maintain homeostasis. We show that genetic modulation of CyclinD/Cdk4 activity or mTOR-dependent signalling cell-autonomously regulates enterocyte growth, which influences ISC proliferation and enteroblast differentiation. Increased enterocyte growth results in higher numbers of ISCs and defective enterocyte growth reduces ISC abundance and proliferation in the midgut. Adult midguts deficient for Cdk4 show severe disruption of intestinal homeostasis characterised by decreased ISC self-renewal, enteroblast differentiation defects and low enteroendocrine cell and enterocyte numbers. The ISC/enteroblast phenotypes result from a combination of cell autonomous and non-autonomous requirements for Cdk4 function. One non-autonomous consequence of Cdk4-dependent deficient enterocyte growth is high expression of Delta in ISCs and Delta retention in enteroblasts. We postulate that aberrant activation of the Delta–Notch pathway is a possible partial cause of lost ISC stemness. These results support the idea that enterocytes contribute to a putative stem cell niche that maintains intestinal homeostasis in the Drosophila anterior midgut. PMID:26879465

  8. Cdk4 functions in multiple cell types to control Drosophila intestinal stem cell proliferation and differentiation.

    PubMed

    Adlesic, Mojca; Frei, Christian; Frew, Ian J

    2016-01-01

    The proliferation of intestinal stem cells (ISCs) and differentiation of enteroblasts to form mature enteroendocrine cells and enterocytes in the Drosophila intestinal epithelium must be tightly regulated to maintain homeostasis. We show that genetic modulation of CyclinD/Cdk4 activity or mTOR-dependent signalling cell-autonomously regulates enterocyte growth, which influences ISC proliferation and enteroblast differentiation. Increased enterocyte growth results in higher numbers of ISCs and defective enterocyte growth reduces ISC abundance and proliferation in the midgut. Adult midguts deficient for Cdk4 show severe disruption of intestinal homeostasis characterised by decreased ISC self-renewal, enteroblast differentiation defects and low enteroendocrine cell and enterocyte numbers. The ISC/enteroblast phenotypes result from a combination of cell autonomous and non-autonomous requirements for Cdk4 function. One non-autonomous consequence of Cdk4-dependent deficient enterocyte growth is high expression of Delta in ISCs and Delta retention in enteroblasts. We postulate that aberrant activation of the Delta-Notch pathway is a possible partial cause of lost ISC stemness. These results support the idea that enterocytes contribute to a putative stem cell niche that maintains intestinal homeostasis in the Drosophila anterior midgut. PMID:26879465

  9. Multiple zone coal degasification potential in Warrior coal field of Alabama

    SciTech Connect

    Graves, S.L.; Patton, A.F.; Beavers, W.M.

    1983-09-01

    The upper Pottsville Formation in the Warrior coal field of Alabama has seven recognized groups of bituminous coal seams. Three of these groups, the Pratt, Mary Lee, and Black Creek, consist of seams containing commercially significant quantities of methane. Each group has several seams within a vertical interval that, in many areas, can be stimulated collectively. In parts of the Warrior coal field, where all three groups can be penetrated in one vertical borehole, the potential production from multiple zone completion wells can result in commerically profitable wells. Various open-hole and through-the-casing completion procedures are being applied, resulting in successful methane production from these multiple zone coal gas wells.

  10. Multiple zone coal degasification potential in the Warrior coal field of Alabama

    SciTech Connect

    Graves, S.L.; Patton, A.F.; Beavers, W.M.

    1983-01-01

    The upper Pottsville Formation in the Warrior coal field of Alabama has 7 recognized groups of bituminous coal seams. Three of these groups, the Pratt, Mary Lee, and Black Creek, consist of seams containing commercially significant quantities of methane. Each group has several seams within a vertical interval that, in many areas, can be collectively stimulated. In parts of the Warrior coal field, where all 3 groups can be penetrated in one vertical borehole, the potential production from multiple zone completion wells can result in commercially profitable wells. Various open hole and through-the-casing completion procedures are being applied, resulting in successful methane production from these multiple-zone-coal-gas wells.

  11. 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.

  12. A multiple receiver - multiple transmitter VLF high-order differential analysis evaluation network for near real-time detection and discrimination of seismic-ionospheric precursor phenomena

    NASA Astrophysics Data System (ADS)

    Skeberis, Christos; Zaharis, Zaharias; Xenos, Thomas; Spatalas, Spyridon; Stratakis, Dimitrios; Maggipinto, Tommaso; Biagi, Pier francesco

    2016-04-01

    This study provides an evaluation of the application of high-order differential analysis on VLF signals on a multiple-receiver multiple-transmitter network. This application provides a method for near-real-time detection of disturbances that can be attributed to seismic-ionospheric precursor phenomena and can discriminate disturbances that could be classified as false positives and thus should be attributed to other geomagnetic influences. VLF data acquired in Thessaloniki, Greece (40.59N, 22,78E) Herakleion, Greece (35.31N, 25.10E), Nicosia, Cyprus (35.17N, 33.35E), Italy (42.42N, 13.08E) and transmitted by the VLF station in Tavolara, Italy (ICV station 40.923N, 9.731E) and the station in Keflavik, Iceland (ICE 64.02N, 22.57W) from January 2015 to January 2016 were used for the purpose of this paper. The receivers have been developed by Elettronika Srl and are part of the International Network for Frontier Research on Earthquake Precursors (INFREP). The process applied for this study has been further developed and is based on differential analysis. The signals undergo transformation using an enhanced version of the Hilbert Huang Transform, and relevant spectra are produced. On the product of this process, differential analysis is applied. Finally, the method produces the correlation coefficient of signals that are on the same path over an earthquake epicenter in order to highlight disturbances, and on the opposite can make comparisons with unrelated transmitted signals of different paths to eliminate disturbances that are not localized to the area of interest. This improvement provides a simple method of noise cancellation to signals that would otherwise be considered as false positives. A further evaluation of the method is provided with the presentation and discussion of sample results. The method seems to be a robust tool of analysis of VLF signals and also an automatic detection tool with built-in noise cancellation of outside disturbances.

  13. [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

  14. Identification of circulating microRNAs for the differential diagnosis of Parkinson's disease and Multiple System Atrophy

    PubMed Central

    Vallelunga, Annamaria; Ragusa, Marco; Di Mauro, Stefania; Iannitti, Tommaso; Pilleri, Manuela; Biundo, Roberta; Weis, Luca; Di Pietro, Cinzia; De Iuliis, Angela; Nicoletti, Alessandra; Zappia, Mario; Purrello, Michele; Antonini, Angelo

    2014-01-01

    Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder which may be misdiagnosed with atypical conditions such as Multiple System Atrophy (MSA), due to overlapping clinical features. MicroRNAs (miRNAs) are small non-coding RNAs with a key role in post-transcriptional gene regulation. We hypothesized that identification of a distinct set of circulating miRNAs (cmiRNAs) could distinguish patients affected by PD from MSA and healthy individuals. Results. Using TaqMan Low Density Array technology, we analyzed 754 miRNAs and found 9 cmiRNAs differentially expressed in PD and MSA patients compared to healthy controls. We also validated a set of 4 differentially expressed cmiRNAs in PD and MSA patients vs. controls. More specifically, miR-339-5p was downregulated, whereas miR-223*, miR-324-3p, and mir-24 were upregulated in both diseases. We found cmiRNAs specifically deregulated in PD (downregulation of miR-30c and miR-148b) and in MSA (upregulation of miR-148b). Finally, comparing MSA and PD, we identified 3 upregulated cmiRNAs in MSA serum (miR-24, miR-34b, miR-148b). Conclusions. Our results suggest that cmiRNA signatures discriminate PD from MSA patients and healthy controls and may be considered specific, non-invasive biomarkers for differential diagnosis. PMID:24959119

  15. 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

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

    PubMed

    Pipino, Caterina; Pandolfi, Assunta

    2015-05-26

    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

  17. Prolactin Pro-Differentiation Pathway in Triple Negative Breast Cancer: Impact on Prognosis and Potential Therapy

    PubMed Central

    López-Ozuna, Vanessa M.; Hachim, Ibrahim Y.; Hachim, Mahmood Y.; Lebrun, Jean-Jacques; Ali, Suhad

    2016-01-01

    Triple negative breast cancer (TNBC) is a heterogeneous disease associated with poor clinical outcome and lack of targeted therapy. Here we show that prolactin (PRL) and its signaling pathway serve as a sub-classifier and predictor of pro-differentiation therapy in TNBC. Using immunohistochemistry and various gene expression in silica analyses we observed that prolactin receptor (PRLR) protein and mRNA levels are down regulated in TNBC cases. In addition, examining correlation of PRLR gene expression with metagenes of TNBC subtypes (580 cases), we found that PRLR gene expression sub-classifies TNBC patients into a new subgroup (TNBC-PRLR) characterized by epithelial-luminal differentiation. Importantly, gene expression of PRL signaling pathway components individually (PRL, PRLR, Jak2 and Stat5a), or as a gene signature is able to predict TNBC patients with significantly better survival outcomes. As PRL hormone is a druggable target we determined the biological role of PRL in TNBC biology. Significantly, restoration/activation of PRL pathway in TNBC cells representative of mesenchymal or TNBC-PRLR subgroups led to induction of epithelial phenotype and suppression of tumorigenesis. Altogether, these results offer potential new modalities for TNBC stratification and development of personalized therapy based on PRL pathway activation. PMID:27480353

  18. 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

  19. Novel SCRG1/BST1 axis regulates self-renewal, migration, and osteogenic differentiation potential in mesenchymal stem cells

    PubMed Central

    Aomatsu, Emiko; Takahashi, Noriko; Sawada, Shunsuke; Okubo, Naoto; Hasegawa, Tomokazu; Taira, Masayuki; Miura, Hiroyuki; Ishisaki, Akira; Chosa, Naoyuki

    2014-01-01

    Human mesenchymal stem cells (hMSCs) remodel or regenerate various tissues through several mechanisms. Here, we identified the hMSC-secreted protein SCRG1 and its receptor BST1 as a positive regulator of self-renewal, migration, and osteogenic differentiation. SCRG1 and BST1 gene expression decreased during osteogenic differentiation of hMSCs. Intriguingly, SCRG1 maintained stem cell marker expression (Oct-4 and CD271/LNGFR) and the potentials of self-renewal, migration, and osteogenic differentiation, even at high passage numbers. Thus, the novel SCRG1/BST1 axis determines the fate of hMSCs by regulating their kinetic and differentiation potentials. Our findings provide a new perspective on methods for ex vivo expansion of hMSCs that maintain native stem cell potentials for bone-forming cell therapy. PMID:24413464

  20. Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation

    PubMed Central

    Zhang, Hongjie; Ables, Elizabeth Tweedie; Pope, Christine F.; Washington, M. Kay; Hipkens, Susan; Means, Anna L.; Path, Gunter; Costa, Robert H.; Seufert, Jochen; Leiter, Andrew B.; Magnuson, Mark A.; Gannon, Maureen

    2009-01-01

    Within the developing pancreas Hepatic Nuclear Factor 6 (HNF6) directly activates the pro-endocrine transcription factor, Ngn3. HNF6 and Ngn3 are each essential for endocrine differentiation and HNF6 is also required for embryonic duct development. Most HNF6−/− animals die as neonates, making it difficult to study later aspects of HNF6 function. Here, we describe, using conditional gene inactivation, that HNF6 has specific functions at different developmental stages in different pancreatic lineages. Loss of HNF6 from Ngn3-expressing cells (HNF6Δendo) resulted in fewer multipotent progenitor cells entering the endocrine lineage, but had no effect on β cell terminal differentiation. Early, pancreas-wide HNF6 inactivation (HNF6Δpanc) resulted in endocrine and ductal defects similar to those described for HNF6 global inactivation. However, all HNF6Δpanc animals survived to adulthood. HNF6Δpanc pancreata displayed increased ductal cell proliferation and metaplasia, as well as characteristics of pancreatitis, including up-regulation of CTGF, MMP7, and p8/Nupr1. Pancreatitis was most likely caused by defects in ductal primary cilia. In addition, expression of Prox1, a known regulator of pancreas development, was decreased in HNF6Δpanc pancreata. These data confirm that HNF6 has both early and late functions in the developing pancreas and is essential for maintenance of Ngn3 expression and proper pancreatic duct morphology. PMID:19766716

  1. Differential Dendritic Integration of Synaptic Potentials and Calcium in Cerebellar Interneurons.

    PubMed

    Tran-Van-Minh, Alexandra; Abrahamsson, Therése; Cathala, Laurence; DiGregorio, David A

    2016-08-17

    Dendritic voltage integration determines the transformation of synaptic inputs into output firing, while synaptic calcium integration drives plasticity mechanisms thought to underlie memory storage. Dendritic calcium integration has been shown to follow the same synaptic input-output relationship as dendritic voltage, but whether similar operations apply to neurons exhibiting sublinear voltage integration is unknown. We examined the properties and cellular mechanisms of these dendritic operations in cerebellar molecular layer interneurons using dendritic voltage and calcium imaging, in combination with synaptic stimulation or glutamate uncaging. We show that, while synaptic potentials summate sublinearly, concomitant dendritic calcium signals summate either linearly or supralinearly depending on the number of synapses activated. The supralinear dendritic calcium triggers a branch-specific, short-term suppression of neurotransmitter release that alters the pattern of synaptic activation. Thus, differential voltage and calcium integration permits dynamic regulation of neuronal input-output transformations without altering intrinsic nonlinear integration mechanisms. PMID:27537486

  2. Potential control of multiple sclerosis by cannabis and the endocannabinoid system.

    PubMed

    Pryce, Gareth; Baker, David

    2012-08-01

    For many years, multiple sclerosis (MS) patients have been self-medicating with illegal street cannabis to alleviate symptoms associated with MS. Data from animal models of MS and clinical studies have supported the anecdotal data that cannabis can improve symptoms such as limb spasticity, which are commonly associated with progressive MS, by the modulation of excessive neuronal signalling. This has lead to cannabis-based medicines being approved for the treatment of pain and spasticity in MS for the first time. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have activity, not only in symptom relief but also potentially in neuroprotective strategies which may slow disease progression and thus delay the onset of symptoms such as spasticity. This review appraises the current knowledge of cannabinoid biology particularly as it pertains to MS and outlines potential future therapeutic strategies for the treatment of disease progression in MS. PMID:22583441

  3. 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

  4. Potential of l-thyroxine to differentiate osteoblast-like cells via Angiopoietin1.

    PubMed

    Park, See-Hyoung; Lee, Jongsung; Kang, Mi-Ae; Moon, Young Jae; Wang, Sung Il; Kim, Kyoung Min; Park, Byung-Hyun; Jang, Kyu Yun; Kim, Jung Ryul

    2016-09-23

    Angiogenesis is closely associated with osteoblast differentiation. Previously, we demonstrated that bone formation can be accelerated by treatment with COMP-Angiopoietin1, a known angiogenic factor. Angiopoietin1 (Ang1) is a specific growth factor that generates stable and mature vasculature through the Tie2 receptor. In this study, we aimed to identify a novel drug that can activate endogenous Ang1 expression as a pharmacological treatment for bone formation. Therefore, Ang1 expression was examined in U2OS osteoblast-like cells treated with 770 drugs from a library of Food and Drug Administration (FDA)-approved drugs by using ELISA for Ang1. l-thyroxine was selected as a novel drug candidate. l-Thyroxine is a synthetic form of the hormone thyroxine, which is used to treat patients with hypothyroidism. Enzyme-linked immunosorbent assays (ELISAs) were performed to test whether Ang1 is induced in a dose-dependent manner in human osteoblast-like cell lines, U2OS and MG63. The effects of l-thyroxine on osteoblast differentiation and mineralization were evaluated by alkaline phosphatase (ALP) activity and Alizarin red s staining. To determine the molecular mechanism, the expression of proteins related to bone formation and differentiation, such as type I collagen (COL1A1), osteocalcin (OC), bone sialoprotein (BSP), distal-less homeobox 5 (Dlx5), Runt-related transcription factor 2 (Runx2), osterix (OSX), and ALP, was tested by Western blotting analysis. Consequently, l-thyroxine induced Ang1 expression in a dose-dependent manner in both U2OS and M63 cells, which was confirmed by ELISA and Western blotting. Also, l-thyroxine activated ALP activity in U2OS and MG63 cells as well as ALP expression. Furthermore, l-thyroxine enhanced the expression of COL1A1, Runx2, OC, BSP, Dlx5, and OSX mRNA and proteins. Taken together, we demonstrated that l-thyroxine increased Ang1 expression and induces bone formation, differentiation, and mineralization in U2OS and MG63 cell lines

  5. Potential Values of Incorporating a Multiple-Choice Question Construction in Physics Experimentation Instruction

    NASA Astrophysics Data System (ADS)

    Yu, Fu-Yun; Liu, Yu-Hsin

    2005-09-01

    The potential value of a multiple-choice question-construction instructional strategy for the support of students’ learning of physics experiments was examined in the study. Forty-two university freshmen participated in the study for a whole semester. A constant comparison method adopted to categorize students’ qualitative data indicated that the influences of multiple-choice question construction were evident in several significant ways (promoting constructive and productive studying habits; reflecting and previewing course-related materials; increasing in-group communication and interaction; breaking passive learning style and habits, etc.), which, worked together, not only enhanced students’ comprehension and retention of the obtained knowledge, but also helped distil a sense of empowerment and learning community within the participants. Analysis with one-group t-tests, using 3 as the expected mean, on quantitative data further found that students’ satisfaction toward past learning experience, and perceptions toward this strategy’s potentials for promoting learning were statistically significant at the 0.0005 level, while learning anxiety was not statistically significant. Suggestions for incorporating question-generation activities within classroom and topics for future studies were rendered.

  6. The potential of block copolymer's directed self-assembly for contact hole shrink and contact multiplication

    NASA Astrophysics Data System (ADS)

    Tiron, R.; Gharbi, A.; Argoud, M.; Chevalier, X.; Belledent, J.; Pimmenta Barros, P.; Servin, I.; Navarro, C.; Cunge, G.; Barnola, S.; Pain, L.; Asai, M.; Pieczulewski, C.

    2013-03-01

    The goal of this paper is to investigate the potential of Directed Self-Assembly (DSA) to address contact via level patterning, by either Critical Dimension (CD) shrink or contact multiplication. Using the 300mm pilot line available in LETI and Arkema materials, our approach is based on the graphoepitaxy of PS-b- PMMA block copolymers (BCP). The process consists in the following steps: a) the lithography of guiding patterns, b) the DSA of block copolymers and PMMA removal and finally c) the transfer of PS patterns into the under-layer by plasma etching. Several integration schemes using 193nm dry lithography are evaluated: negative tone development (NTD) resists, a tri-layer approach, frozen resists, etc. The advantages and limitations of each approach are reported. Furthermore, the impact of the BCP on the final patterns characteristics is investigated by tuning different parameters such as the molecular weight of the polymeric constituents and the interaction with the substrate. The optimization of the self-assembly process parameters in terms of film thickness or bake (temperature and time) is also reported. Finally, the transfer capabilities of the PS nanostructures in bulk silicon substrate by using plasma-etching are detailed. These results show that DSA has a high potential to be integrated directly into the conventional CMOS lithography process in order to achieve high-resolution contact holes. Furthermore, in order to prevent design restrictions, this approach may be extended to more complex structures with multiple contacts and nonhexagonal symmetries.

  7. Singularity analysis of multiple upward continuations to detect edges in potential field data

    NASA Astrophysics Data System (ADS)

    Chen, Z.; Cheng, Q.; Lovejoy, S.

    2012-12-01

    In geophysical applications, a number of filters are available to sharpen, de-noise or enhance the data in order to facilitate the interpretation. However, such filters are often implemented in the Fourier domain. Hence, they are not local, acting on all features simultaneously. Detecting strong gradients and edges in potential field data are one of the important tasks to infer geological structures indicating the edges of source bodies. Edges are identified by local singularity analysis combing multiple depth level upward continuations are provided by authors. Sources close to the surface induce short-wavelength anomalies in the signal, whereas sources deep underground induce long-wavelength anomalies in the signal. Upward continuation allows the data to be smooth, attenuates short wavelengths in the signal stronger than long wavelengths so as to highlight deep sources that might be hidden by shallow sources or noise. A useful of local singularity model based on multifractal theory suggested by Qiuming Cheng has gained significant attention in characterizing mineralization and predicting mineral deposits. Especially, this model has had impressive successes in the weak anomaly identification, interpolation for geochemical data. Thus, we create the multiple upward continuation grids of the observed potential field data at various heights. We recommend to add a small value to shift the raw data (>0), and reduce the magnetic data to the pole firstly or even convert it to pseudogravity. Then the singularity indexes are estimated by the multiple heights versus upward continuations under the power law. We take the airborne gravity data and aeromagnetic data in the East Tianshan mountains with desert cover area in Xinjiang province, China as a case study. The singularity spatial distribution for the gravity data in the East Tianshan mountains area indicates the regional deep faults and The singularity spatial distribution for the aeromagnetic data implies the probable

  8. Multiple gamma oscillations in the brain: a new strategy to differentiate functional correlates and P300 dynamics.

    PubMed

    Başar, Erol; Tülay, Elif; Güntekin, Bahar

    2015-03-01

    Brain oscillations in the gamma frequency band, - i.e. oscillations greater than 25 Hz - have attracted increasing attention over the last few decades in the research of sensory-cognitive processes. In the neuroscience research literature, a great number of reports aim to describe the functional correlates of oscillatory responses in the gamma frequency window. However, analysis using a broadband frequency window often leads to divergent functional interpretations and controversies. In order to provide a more exact approach, we have used a strategy by defining multiple frequency and multiple time windows according to the combined analysis of conventional power spectral windows, frequency adaptive multiple filters, and inter-trial coherence. The analysis in frequency windows of 25-30 Hz, 30-35 Hz, and 40-48 Hz enables the investigator to provide a distinction of cognitive and/or sensory responses. Moreover, according to topological differentiation and the consideration of neuroanatomic pathways, more reliable interpretations of gamma responses are reached. PMID:25660304

  9. Differentiation of agonist conformation and antagonist conformation in multiple opioid receptors.

    PubMed

    Ogawa, N; Yamawaki, Y; Kuroda, H; Nukina, I; Ofuji, T

    1981-12-11

    To differentiate the opiate (naloxone) receptor and the enkephalin receptor in rat brain, we solubilized the receptor molecules by detergent and determined the molecular weights by gel filtration. The receptor preparation was bound to [3H] naloxone or [3H] Met5-enkephalin, and was solubilized by Triton X-100. On gel chromatography with a Sepharose 6B column, the agonist and the antagonist conformation of opioid receptors eluted as molecules with the molecular weights of 240,000, and 120,000 and with Stokes' radii of 5.5 nm and 4.3 nm, respectively. Further, it was also disclosed that Na+ was bound to the antagonist conformation of opioid receptors but not to the agonist conformation. PMID:6275320

  10. 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-, 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

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

    DOEpatents

    Fincke, James R.

    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.

  12. Neurological manifestations of gastrointestinal disorders, with particular reference to the differential diagnosis of multiple sclerosis.

    PubMed

    Ghezzi, A; Zaffaroni, M

    2001-11-01

    Neurological manifestations of gastrointestinal disorders are described, with particular reference to those resembling multiple sclerosis (MS) on clinical or MRI grounds. Patients with celiac disease can present cerebellar ataxia, progressive myoclonic ataxia, myelopathy, or cerebral, brainstem and peripheral nerve involvement. Antigliadin antibodies can be found in subjects with neurological dysfunction of unknown cause, particularly in sporadic cerebellar ataxia ("gluten ataxia"). Patients with Whipple's disease can develop mental and psychiatric changes, supranuclear gaze palsy, upper motoneuron signs, hypothalamic dysfunction, cranial nerve abnormalities, seizures, ataxia, myorhythmia and sensory deficits. Neurological manifestations can complicate inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease) due to vascular or vasculitic mechanisms. Cases with both Crohn's disease and MS or cerebral vasculitis are described. Epilepsy, chronic inflammatory polyneuropathy, muscle involvement and myasthenia gravis are also reported. The central nervous system can be affected in patients with hepatitis C virus (HCV) infection because of vasculitis associated with HCV-related cryoglobulinemia. Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a disease caused by multiple deletions of mitochondrial DNA. It is characterized by peripheral neuropathy, ophthalmoplegia, deafness, leukoencephalopathy, and gastrointestinal symptoms due to visceral neuropathy. Neurological manifestations can be the consequence of vitamin B1, nicotinamide, vitamin B12, vitamin D, or vitamin E deficiency and from nutritional deficiency states following gastric surgery. PMID:11794474

  13. Rapid, accurate, and comparative differentiation of clinically and industrially relevant microorganisms via multiple vibrational spectroscopic fingerprinting.

    PubMed

    Muhamadali, Howbeer; Subaihi, Abdu; Mohammadtaheri, Mahsa; Xu, Yun; Ellis, David I; Ramanathan, Rajesh; Bansal, Vipul; Goodacre, Royston

    2016-08-15

    Despite the fact that various microorganisms (e.g., bacteria, fungi, viruses, etc.) have been linked with infectious diseases, their crucial role towards sustaining life on Earth is undeniable. The huge biodiversity, combined with the wide range of biochemical capabilities of these organisms, have always been the driving force behind their large number of current, and, as of yet, undiscovered future applications. The presence of such diversity could be said to expedite the need for the development of rapid, accurate and sensitive techniques which allow for the detection, differentiation, identification and classification of such organisms. In this study, we employed Fourier transform infrared (FT-IR), Raman, and surface enhanced Raman scattering (SERS) spectroscopies, as molecular whole-organism fingerprinting techniques, combined with multivariate statistical analysis approaches for the classification of a range of industrial, environmental or clinically relevant bacteria (P. aeruginosa, P. putida, E. coli, E. faecium, S. lividans, B. subtilis, B. cereus) and yeast (S. cerevisiae). Principal components-discriminant function analysis (PC-DFA) scores plots of the spectral data collected from all three techniques allowed for the clear differentiation of all the samples down to sub-species level. The partial least squares-discriminant analysis (PLS-DA) models generated using the SERS spectral data displayed lower accuracy (74.9%) when compared to those obtained from conventional Raman (97.8%) and FT-IR (96.2%) analyses. In addition, whilst background fluorescence was detected in Raman spectra for S. cerevisiae, this fluorescence was quenched when applying SERS to the same species, and conversely SERS appeared to introduce strong fluorescence when analysing P. putida. It is also worth noting that FT-IR analysis provided spectral data of high quality and reproducibility for the whole sample set, suggesting its applicability to a wider range of samples, and perhaps the

  14. 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.

  15. 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, René 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

  16. 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.

  17. 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

  18. 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;30:2164–2174 PMID:22865647

  19. The effects of cold atmospheric plasma on cell adhesion, differentiation, migration, apoptosis and drug sensitivity of multiple myeloma.

    PubMed

    Xu, Dehui; Luo, Xiaohui; Xu, Yujing; Cui, Qingjie; Yang, Yanjie; Liu, Dingxin; Chen, Hailan; Kong, Michael G

    2016-05-13

    Cold atmospheric plasma was shown to induce cell apoptosis in numerous tumor cells. Recently, some other biological effects, such as induction of membrane permeation and suppression of migration, were discovered by plasma treatment in some types of tumor cells. In this study, we investigated the biological effects of plasma treatment on multiple myeloma cells. We detected the detachment of adherent myeloma cells by plasma, and the detachment area was correlated with higher density of hydroxyl radical in the gas phase of the plasma. Meanwhile, plasma could promote myeloma differentiation by up-regulating Blimp-1 and XBP-1 expression. The migration ability was suppressed by plasma treatment through decreasing of MMP-2 and MMP-9 secretion. In addition, plasma could increase bortezomib sensitivity and induce myeloma cell apoptosis. Taking together, combination with plasma treatment may enhance current chemotherapy and probably improve the outcomes. PMID:27067049

  20. 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.

  1. 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.

  2. 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.

  3. Gender as a differential indicator of the employment discrimination experiences of Americans with multiple sclerosis.

    PubMed

    Rumrill, Phillip D; Roessler, Richard T; McMahon, Brian T; Hennessey, Mary L; Neath, Jeanne

    2007-01-01

    Information from the Integrated Mission System of the United States Equal Employment Opportunity Commission (EEOC) was used to investigate the employment discrimination experiences of women and men with multiple sclerosis (MS). Spanning the years 1992 to 2003, the EEOC database included 3,663 allegations of discrimination filed by 2,167 adults with MS. With respect to women and men with MS, the researchers examined the comparability of a) demographic characteristics; b) industry designations, locations, and size of employers; c) the nature of discrimination alleged; and d) the legal outcome or resolution of those allegations. On average, women and men with MS were in their early forties, with the majority of both groups being Caucasian. Both women and men were most likely to allege discrimination related to discharge and reasonable accommodations, although women were more likely to file harassment charges than men. Men with MS were more likely to allege discrimination regarding hiring and reinstatement. Women with MS were more likely to file allegations against employers in the service industries, and men were more likely to file allegations against employers in the construction, manufacturing, and wholesale industries. No gender differences were found in the geographic distribution of allegations. Both groups had comparable rates of merit closures (23% vs. 27%) as a result of the EEOC's investigatory process. Implications for rehabilitation counseling and employer-oriented interventions are discussed. PMID:18057570

  4. Pattern reversal visual evoked potentials in Japanese patients with multiple sclerosis.

    PubMed Central

    Shibasaki, H; Kuroiwa, Y

    1982-01-01

    Forty-seven Japanese patients with multiple sclerosis, 29 probable (clinically definite) and 18 possible, were studied by black-and-white checkerboard pattern reversal visual evoked potential and were compared with a control group of 20 healthy young adults. The major positive peak (P100) was found to be abnormal in 70% of all cases, 90% of probable cases and 39% of possible cases. P100 was delayed in 38% of all cases and was absent in 23% of all cases. None of the eyes showing a flat pattern response was in the acute stage of optic neuritis. The percentage of cases with no response (23% of all cases) was greater than any of the previously reported series from Western countries, substantiating the previously reported clinical features of oriental multiple sclerosis. The pattern response was absent only when testing eyes with severe visual impairment, whereas delayed latency of P100 was seen regardless of the severity of visual impairment, suggesting the usefulness of P100 latency for detecting subclinical optic nerve lesions. PMID:7161609

  5. 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.

  6. 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), Alzheimer’s 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

  7. The multiple time step r-RESPA procedure and polarizable potentials based on induced dipole moments

    NASA Astrophysics Data System (ADS)

    Masella, Michel

    In the present study, we present an accelerating scheme based on the reversible multiple time step r-RESPA method to be used in molecular dynamics simulations with polarizable potentials based on induced dipole moments. Even if the induced dipoles are estimated with an iterative self-consistent procedure, this scheme significantly reduces the CPU time needed to perform a molecular dynamics simulation, up to a factor 2, as compared to the Car-Parrinello method where additional dynamical variables are introduced for the treatment of the induced dipoles. The tests show that stable and reliable molecular dynamics trajectories can be generated with that scheme, and that the physical properties derived from the trajectories are equivalent to those computed with the classical all atom iterative approach and the Car-Parrinello one.

  8. 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

  9. Embryonic stem cell-specific microRNAs contribute to pluripotency by inhibiting regulators of multiple differentiation pathways.

    PubMed

    Gruber, Andreas J; Grandy, William A; Balwierz, Piotr J; Dimitrova, Yoana A; Pachkov, Mikhail; Ciaudo, Constance; Nimwegen, Erik van; Zavolan, Mihaela

    2014-08-01

    The findings that microRNAs (miRNAs) are essential for early development in many species and that embryonic miRNAs can reprogram somatic cells into induced pluripotent stem cells suggest that these miRNAs act directly on transcriptional and chromatin regulators of pluripotency. To elucidate the transcription regulatory networks immediately downstream of embryonic miRNAs, we extended the motif activity response analysis approach that infers the regulatory impact of both transcription factors (TFs) and miRNAs from genome-wide expression states. Applying this approach to multiple experimental data sets generated from mouse embryonic stem cells (ESCs) that did or did not express miRNAs of the ESC-specific miR-290-295 cluster, we identified multiple TFs that are direct miRNA targets, some of which are known to be active during cell differentiation. Our results provide new insights into the transcription regulatory network downstream of ESC-specific miRNAs, indicating that these miRNAs act on cell cycle and chromatin regulators at several levels and downregulate TFs that are involved in the innate immune response. PMID:25030899

  10. Embryonic stem cell-specific microRNAs contribute to pluripotency by inhibiting regulators of multiple differentiation pathways

    PubMed Central

    Gruber, Andreas J.; Grandy, William A.; Balwierz, Piotr J.; Dimitrova, Yoana A.; Pachkov, Mikhail; Ciaudo, Constance; van Nimwegen, Erik; Zavolan, Mihaela

    2014-01-01

    The findings that microRNAs (miRNAs) are essential for early development in many species and that embryonic miRNAs can reprogram somatic cells into induced pluripotent stem cells suggest that these miRNAs act directly on transcriptional and chromatin regulators of pluripotency. To elucidate the transcription regulatory networks immediately downstream of embryonic miRNAs, we extended the motif activity response analysis approach that infers the regulatory impact of both transcription factors (TFs) and miRNAs from genome-wide expression states. Applying this approach to multiple experimental data sets generated from mouse embryonic stem cells (ESCs) that did or did not express miRNAs of the ESC-specific miR-290-295 cluster, we identified multiple TFs that are direct miRNA targets, some of which are known to be active during cell differentiation. Our results provide new insights into the transcription regulatory network downstream of ESC-specific miRNAs, indicating that these miRNAs act on cell cycle and chromatin regulators at several levels and downregulate TFs that are involved in the innate immune response. PMID:25030899

  11. The TRPV5/6 calcium channels contain multiple calmodulin binding sites with differential binding properties.

    PubMed

    Kovalevskaya, Nadezda V; Bokhovchuk, Fedir M; Vuister, Geerten W

    2012-06-01

    The epithelial Ca(2+) channels TRPV5/6 (transient receptor potential vanilloid 5/6) are thoroughly regulated in order to fine-tune the amount of Ca(2+) reabsorption. Calmodulin has been shown to be involved into calcium-dependent inactivation of TRPV5/6 channels by binding directly to the distal C-terminal fragment of the channels (de Groot et al. in Mol Cell Biol 31:2845-2853, 12). Here, we investigate this binding in detail and find significant differences between TRPV5 and TRPV6. We also identify and characterize in vitro four other CaM binding fragments of TRPV5/6, which likely are also involved in TRPV5/6 channel regulation. The five CaM binding sites display diversity in binding modes, binding stoichiometries and binding affinities, which may fine-tune the response of the channels to varying Ca(2+)-concentrations. PMID:22354706

  12. Multiple plant-wax compounds record differential sources and ecosystem structure in large river catchments

    NASA Astrophysics Data System (ADS)

    Hemingway, Jordon D.; Schefuß, Enno; Dinga, Bienvenu Jean; Pryer, Helena; Galy, Valier V.

    2016-07-01

    n-alkanes better represent a catchment-integrated signal with minimal response to discharge seasonality. Comparison to published data on other large watersheds indicates that this phenomenon is not limited to the Congo River, and that analysis of multiple plant-wax lipid classes and chain lengths can be used to better resolve local vs. distal ecosystem structure in river catchments.

  13. Differential neural responses to humans vs. robots: an event-related potential study.

    PubMed

    Hirai, Masahiro; Hiraki, Kazuo

    2007-08-24

    Do we perceive humanoid robots as human beings? Recent neuroimaging studies have reported similarity in the neural processing of human and robot actions in the superior temporal sulcus area but a differential neural response in the premotor area. These studies suggest that the neural activity of the occipitotemporal region would not be affected by appearance information. Unlike those studies, in this study, by using the inversion effect as an index, we demonstrated for the first time that the appearance information of a presented action affects neural responses in the occipitotemporal region. In event-related potential (ERP) studies, the inversion effect is the phenomenon whereby an upright face- and body-sensitive ERP component in the occipitotemporal region is enhanced and delayed up to 200 ms in response to an inverted face and body, but not to an inverted object. We used three kinds of walking animation with different appearance information (human, robot, and point-light) as well as inverted stimuli of each appearance. The anatomical structure and walking speed of the presented stimuli were all identical. The results showed that the inversion effect occurred in the right occipitotemporal region only in response to human appearance, and not robotic and point-light appearances. That is, the amplitude of the inverted condition of human appearance was significantly larger than that of the upright condition only. Our results, which are contrary to other recent neuroimaging studies, suggested that appearance information affects the neural response in the occipitotemporal region. PMID:17658496

  14. 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).

  15. S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis.

    PubMed

    Barateiro, Andreia; Afonso, Vera; Santos, Gisela; Cerqueira, João José; Brites, Dora; van Horssen, Jack; Fernandes, Adelaide

    2016-08-01

    Multiple sclerosis (MS) pathology is characterized by neuroinflammation and demyelination. Recently, the inflammatory molecule S100B was identified in cerebrospinal fluid (CSF) and serum of MS patients. Although seen as an astrogliosis marker, lower/physiological levels of S100B are involved in oligodendrocyte differentiation/maturation. Nevertheless, increased S100B levels released upon injury may induce glial reactivity and oligodendrocyte demise, exacerbating tissue damage during an MS episode or delaying the following remyelination. Here, we aimed to unravel the functional role of S100B in the pathogenesis of MS. Elevated S100B levels were detected in the CSF of relapsing-remitting MS patients at diagnosis. Active demyelinating MS lesions showed increased expression of S100B and its receptor, the receptor for advanced glycation end products (RAGE), in the lesion area, while chronic active lesions displayed increased S100B in demyelinated areas with lower expression of RAGE in the rim. Interestingly, reactive astrocytes were identified as the predominant cellular source of S100B, whereas RAGE was expressed by activated microglia/macrophages. Using an ex vivo demyelinating model, cerebral organotypic slice cultures treated with lysophosphatidylcholine (LPC), we observed a marked elevation of S100B upon demyelination, which co-localized mostly with astrocytes. Inhibition of S100B action using a directed antibody reduced LPC-induced demyelination, prevented astrocyte reactivity and abrogated the expression of inflammatory and inflammasome-related molecules. Overall, high S100B expression in MS patient samples suggests its usefulness as a diagnostic biomarker for MS, while the beneficial outcome of its inhibition in our demyelinating model indicates S100B as an emerging therapeutic target in MS. PMID:26184632

  16. CCL27: Novel Cytokine with Potential Role in Pathogenesis of Multiple Sclerosis

    PubMed Central

    Khaiboullina, Svetlana F.; Gumerova, Aigul R.; Khafizova, Irina F.; Martynova, Ekaterina V.; Lombardi, Vincent C.; Bellusci, Saverio; Rizvanov, Albert A.

    2015-01-01

    Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of unknown etiology. Leukocyte infiltration of brain tissue and the subsequent inflammation, demyelination, axonal damage, and formation of sclerotic plaques is a hallmark of MS. Upregulation of proinflammatory cytokines has been suggested to play an essential role in regulating lymphocyte migration in MS. Here we present data on serum cytokine expression in MS cases. Increased serum levels of IL-17 and IL-23 were observed, suggesting activation of the Th17 population of immune effector cells. Additionally, increased levels of IL-22 were observed in the serum of those with acute phase MS. Unexpectedly, we observed an upregulation of the serum chemokine CCL27 in newly diagnosed and acute MS cases. CCL27 is an inflammatory chemokine associated with homing of memory T cells to sites of inflammation. Therefore, its upregulation in association with MS suggests a potential role in disease pathogenesis. Our data supports previous reports showing IL-17 and -23 upregulation in association with MS and potentially identify a previously unknown involvement for CCL27. PMID:26295034

  17. CCL27: Novel Cytokine with Potential Role in Pathogenesis of Multiple Sclerosis.

    PubMed

    Khaiboullina, Svetlana F; Gumerova, Aigul R; Khafizova, Irina F; Martynova, Ekaterina V; Lombardi, Vincent C; Bellusci, Saverio; Rizvanov, Albert A

    2015-01-01

    Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of unknown etiology. Leukocyte infiltration of brain tissue and the subsequent inflammation, demyelination, axonal damage, and formation of sclerotic plaques is a hallmark of MS. Upregulation of proinflammatory cytokines has been suggested to play an essential role in regulating lymphocyte migration in MS. Here we present data on serum cytokine expression in MS cases. Increased serum levels of IL-17 and IL-23 were observed, suggesting activation of the Th17 population of immune effector cells. Additionally, increased levels of IL-22 were observed in the serum of those with acute phase MS. Unexpectedly, we observed an upregulation of the serum chemokine CCL27 in newly diagnosed and acute MS cases. CCL27 is an inflammatory chemokine associated with homing of memory T cells to sites of inflammation. Therefore, its upregulation in association with MS suggests a potential role in disease pathogenesis. Our data supports previous reports showing IL-17 and -23 upregulation in association with MS and potentially identify a previously unknown involvement for CCL27. PMID:26295034

  18. 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

  19. Establishment and characterization of METON myoepithelioma cell line derived from human palatal myoepithelioma: apical reference to the diverse differentiation potential.

    PubMed

    Suzuki, Minako; Ishikawa, Hiroshi; Kawakami, Miyuki; Nakahara, Taka; Tanaka, Akira; Mataga, Izumi

    2013-12-01

    Myoepithelioma is an extremely rare condition that accounts for 1-1.5 % of salivary gland tumors. It was formerly regarded as a subtype of pleomorphic adenoma, in which myoepithelial structural components predominated, but was listed as a separate disease entity in the 1991 World Health Organization classification (Seifert in Histological typing of salivary gland tumours. Springer, Berlin, 1991). Its histology is highly varied and recurrence is frequent (El-Naggar et al. in J Larygol Otol 103:1192-1197, 1989), with cases of malignant transformation having been reported (Seifert in Histological typing of salivary gland tumours. Springer, Berlin, 1991; Barnes et al. in Pathology and Genetics of head and neck tumours. IARC Press, Lyon, 2005), making this a difficult tumor to control in many cases. This is thought to be due to the multiple differentiation potential of myoepithelial cells, but the details are unknown. There have been a number of reports of the establishment of cell lines (Shirasuna et al. Cancer. 45:297-305, 1980; Jaeger et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:663-667, 1997), but numerous points remain unclear. We established a myoepithelial cell line designated METON, and investigated its characteristics. METON consists of cells with two different morphologies: spindle-shaped cells and epithelial-like cells. Then. we also used single-cell cloning method to establish various subclones (epithelial-like, spindle-like, and mixed epithelial-like/spindle-like cell lines). Among these, pluripotency markers were expressed by the mixed epithelial-like/spindle-like cell lines. The newly established cell line expressing these pluripotency markers will be extremely useful for elucidating the diverse histologies of salivary gland tumors. PMID:23761224

  20. 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

  1. 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 stove’s 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 GBEA’s can be used to create multiple good solutions needed to support engineering design.

  2. 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

  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. Effects of Cryopreservation on the Cell Viability, Proliferative Capacity and Neuronal Differentiation Potential of Canine Bone Marrow Stromal Cells

    PubMed Central

    EDAMURA, Kazuya; NAKANO, Rei; FUJIMOTO, Kyohei; TESHIMA, Kenji; ASANO, Kazushi; TANAKA, Shigeo

    2013-01-01

    ABSTRACT We investigated the cell viability, proliferative capacity and neuronal differentiation potential of canine bone marrow stromal cells (BMSCs) after cryopreservation. BMSCs were cryopreserved using cryoprotectant solutions with 10% DMSO and 10% FBS (DF group) or without DMSO and FBS (DF-free group); fresh BMSCs were used as a control. The cell viability and proliferative capacity of BMSCs were similar in the DF-free and control groups, while those in the DF group were lower. In all groups, BMSCs differentiated into neuron-like cells that stained positive against neuron markers, and the mRNA expression levels of neuron markers increased after neuronal induction. In conclusion, cryopreservation with DF-free cryoprotectant solution did not diminish the cell viability, proliferative capacity or neuronal differentiation potential of canine BMSCs. PMID:24334862

  5. Fine-structure inelastic differential cross sections and B /sup 2/. sigma. potentials for the potassium rare gas interaction

    SciTech Connect

    Dueren, R.; Hasselbrink, E.; Hillrichs, G.

    1988-09-01

    Differential scattering cross sections for fine-structure inelastic collisions of potassium in its first excited state with various rare gases (Ne, Ar, Kr, and Xe) have been measured. This crossed molecular beams experiment uses cw-dye lasers for the excitation of the incident potassium beam and the detection of the fine-structure inelastic scattered potassium atoms. The collision energy has been varied between 92 and 199 meV. The differential cross sections exhibit for small collision energies Stueckelberg oscillations, which are due to interference of scattering on the attractive A /sup 2/Pi and the repulsive B /sup 2/..sigma.. potential. For higher collision energies these oscillations are missing at large angles. It is demonstrated that with the A /sup 2/Pi potential known from other sources the repulsive B /sup 2/..sigma.. potential can be determined. A shoulder in this repulsive potential is found to be responsible for the absence of the interference oscillations at higher scattering energies.

  6. Differential recognition of the multiple banded antigen isoforms across Ureaplasma parvum and Ureaplasma urealyticum species by monoclonal antibodies.

    PubMed

    Aboklaish, Ali F; Ahmed, Shatha; McAllister, Douglas; Cassell, Gail; Zheng, Xiaotian T; Spiller, Owen B

    2016-08-01

    Two separate species of Ureaplasma have been identified that infect humans: Ureaplasma parvum and Ureaplasma urealyticum. Most notably, these bacteria lack a cell wall and are the leading infectious organism associated with infection-related induction of preterm birth. Fourteen separate representative prototype bacterial strains, called serovars, are largely differentiated by the sequence of repeating units in the C-terminus of the major surface protein: multiple-banded antigen (MBA). Monoclonal antibodies that recognise single or small groups of serovars have been previously reported, but these reagents remain sequestered in individual research laboratories. Here we characterise a panel of commercially available monoclonal antibodies raised against the MBA and describe the first monoclonal antibody that cross-reacts by immunoblot with all serovars of U. parvum and U. urealyticum species. We also describe a recombinant MBA expressed by Escherichia coli which facilitated further characterisation by immunoblot and demonstrate immunohistochemistry of paraffin-embedded antigens. Immunoblot reactivity was validated against well characterised previously published monoclonal antibodies and individual commercial antibodies were found to recognise all U. parvum strains, only serovars 3 and 14 or only serovars 1 and 6, or all strains belonging to U. parvum and U. urealyticum. MBA mass was highly variable between strains, consistent with variation in the number of C-terminal repeats between strains. Antibody characterisation will enable future investigations to correlate severity of pathogenicity to MBA isoform number or mass, in addition to development of antibody-based diagnostics that will detect infection by all Ureaplasma species or alternately be able to differentiate between U. parvum, U. urealyticum or mixed infections. PMID:27208664

  7. Differential and tissue-specific regulation of the multiple rat c-erbA messenger RNA species by thyroid hormone.

    PubMed

    Hodin, R A; Lazar, M A; Chin, W W

    1990-01-01

    Thyroid hormone (T3) has been shown to regulate the level of its receptor in a number of tissues and cell lines. Recently, proteins encoded by the protooncogene c-erbA have been identified as T3 receptors. In the rat, four c-erbA gene products have been isolated, three of which, r-erbA alpha-1, r-erbA beta-1, and r-erbA beta-2, encode biologically active T3 receptors; the fourth, r-erbA alpha-2, may play an inhibitory role in T3 action. The present work examines the molecular nature of T3 receptor autoregulation using probes specific for each c-erbA mRNA. Rats were rendered hypothyroid with propylthiouracil and then treated with either saline or T3. Northern blot analyses reveal marked tissue-specific and differential regulation of the multiple c-erbA mRNAs by T3. In the pituitary the levels of r-erbA beta-1 mRNA increase, whereas the levels of the pituitary-specific r-erbA beta-2 mRNA decrease with T3 treatment. In heart, kidney, liver, and brain the levels of r-erbA beta-1 are unaffected by thyroidal status. The levels of both r-erbA alpha mRNAs decrease with T3 treatment in all tissues examined except for the brain, where there is no change. In addition, we find that changes in the mRNAs encoding specific subpopulations of T3 receptors do not always parallel changes in total nuclear T3 binding. Differential regulation of the specific c-erbA mRNA species could have important consequences for T3 action. PMID:2153150

  8. On the Differentiation of Foveal and Peripheral Early Visual Evoked Potentials.

    PubMed

    Hansen, Bruce C; Haun, Andrew M; Johnson, Aaron P; Ellemberg, Dave

    2016-07-01

    The C1 is one of the earliest visual evoked potentials observed following the onset of a patterned stimulus. The polarity of its peak is dependent on whether stimuli are presented in the upper or lower regions of the peripheral visual field, but has been argued to be negative for stimuli presented to the fovea. However, there has yet to be a systematic investigation into the extent to which the peripheral C1 (pC1) and foveal C1 (fC1) can be differentiated on the basis of response characteristics to different stimuli. The current study employed checkerboard patterns (Exp 1) and sinusoidal gratings of different spatial frequency (Exp 2) presented to the fovea or within one of the four quadrants of the peripheral visual field. The checkerboard stimuli yielded a sizable difference in peak component latency, with the fC1 peaking ~32 ms after the pC1. Further, the pC1 showed a band-pass response magnitude profile that peaked at 4 cycles per degree (cpd), whereas the fC1 was high-pass for spatial frequency, with a cut-off around 4 cpd. Finally, the scalp topographies of the pC1 and fC1 in both experiments differed greatly, with the fC1 being more posterior than the pC1. The results reported here call into question recent attempts to characterize general C1 processes without regard to whether stimuli are placed in the fovea or in the periphery. PMID:26868004

  9. Glycan Profiling Shows Unvaried N-Glycomes in MSC Clones with Distinct Differentiation Potentials

    PubMed Central

    Wilson, Katherine M.; Thomas-Oates, Jane E.; Genever, Paul G.; Ungar, Daniel

    2016-01-01

    Different cell types have different N-glycomes in mammals. This means that cellular differentiation is accompanied by changes in the N-glycan profile. Yet when the N-glycomes of cell types with differing fates diverge is unclear. We have investigated the N-glycan profiles of two different clonal populations of mesenchymal stromal cells (MSCs). One clone (Y101), when differentiated into osteoblasts, showed a marked shift in the glycan profile toward a higher abundance of complex N-glycans and more core fucosylation. Yet chemical inhibition of complex glycan formation during osteogenic differentiation did not prevent the formation of functional osteoblasts. However, the N-glycan profile of another MSC clone (Y202), which cannot differentiate into osteoblasts, was not significantly different from that of the clone that can. Interestingly, incubation of Y202 cells in osteogenic medium caused a similar reduction of oligomannose glycan content in this non-differentiating cell line. Our analysis implies that the N-glycome changes seen upon differentiation do not have direct functional links to the differentiation process. Thus N-glycans may instead be important for self-renewal rather than for cell fate determination. PMID:27303666

  10. Small Compound 6-O-Angeloylplenolin Induces Mitotic Arrest and Exhibits Therapeutic Potentials in Multiple Myeloma

    PubMed Central

    Liu, Ying; Chen, Xiao-Qin; Liang, Heng-Xing; Zhang, Feng-Xiang; Zhang, Bo; Jin, Jie; Chen, Yong-Long; Cheng, Yong-Xian; Zhou, Guang-Biao

    2011-01-01

    Background Multiple myeloma (MM) is a disease of cell cycle dysregulation while cell cycle modulation can be a target for MM therapy. In this study we investigated the effects and mechanisms of action of a sesquiterpene lactone 6-O-angeloylplenolin (6-OAP) on MM cells. Methodology/Principal Findings MM cells were exposed to 6-OAP and cell cycle distribution were analyzed. The role for cyclin B1 to play in 6-OAP-caused mitotic arrest was tested by specific siRNA analyses in U266 cells. MM.1S cells co-incubated with interleukin-6 (IL-6), insulin-like growth factor-I (IGF-I), or bone marrow stromal cells (BMSCs) were treated with 6-OAP. The effects of 6-OAP plus other drugs on MM.1S cells were evaluated. The in vivo therapeutic efficacy and pharmacokinetic features of 6-OAP were tested in nude mice bearing U266 cells and Sprague-Dawley rats, respectively. We found that 6-OAP suppressed the proliferation of dexamethasone-sensitive and dexamethasone-resistant cell lines and primary CD138+ MM cells. 6-OAP caused mitotic arrest, accompanied by activation of spindle assembly checkpoint and blockage of ubiquitiniation and subsequent proteasomal degradation of cyclin B1. Combined use of 6-OAP and bortezomib induced potentiated cytotoxicity with inactivation of ERK1/2 and activation of JNK1/2 and Casp-8/-3. 6-OAP overcame the protective effects of IL-6 and IGF-I on MM cells through inhibition of Jak2/Stat3 and Akt, respectively. 6-OAP inhibited BMSCs-facilitated MM cell expansion and TNF-α-induced NF-κB signal. Moreover, 6-OAP exhibited potent anti-MM activity in nude mice and favorable pharmacokinetics in rats. Conclusions/Significance These results indicate that 6-OAP is a new cell cycle inhibitor which shows therapeutic potentials for MM. PMID:21755010

  11. Early abnormalities of evoked potentials and future disability in patients with multiple sclerosis.

    PubMed

    Kallmann, B A; Fackelmann, S; Toyka, K V; Rieckmann, P; Reiners, K

    2006-02-01

    Evoked potentials (EP) have a role in making the diagnosis of multiple sclerosis (MS) but their implication for predicting the future disease course in MS is under debate. EP data of 94 MS patients examined at first presentation, and after five and ten years were retrospectively analysed. Patients were divided into two groups in relation to the prior duration of disease at the time point of first examination: group 1 patients (n=44) were first examined within two years after disease onset, and group 2 patients (n=50) at later time points. As primary measures sum scores were calculated for abnormalities of single and combined EP (visual (VEP), somatosensory (SEP), magnetic motor evoked potentials (MEP)). In patients examined early after disease onset (group 1), a significant predictive value for abnormal EP was found with MEP and SEP sum scores at first presentation correlating significantly with Expanded Disability Status Scale (EDSS) values after five years, while the VEP sum score was not. The cumulative number of abnormal MEP, SEP and VEP results also indicated higher degrees of disability (EDSS > or = 3.5) after five years. Combined pathological SEP and MEP findings at first presentation best predicted clinical disability (EDSS > or = 3.5) after five years (odds ratio 11.0). EP data and EDSS at first presentation were not significantly linked suggesting that EP abnormalities at least in part represented clinically silent lesions not mirrored by EDSS. For patients in later disease phases (group 2), no significant associations between EP data at first presentation and EDSS at five and ten years were detected. Together with clinical findings and MR imaging, combined EP data may help to identify patients at high risk of long-term clinical deterioration and guide decisions as to immunomodulatory treatment. PMID:16459720

  12. 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

  13. Teriflunomide, an inhibitor of dihydroorotate dehydrogenase for the potential oral treatment of multiple sclerosis.

    PubMed

    Palmer, Alan M

    2010-11-01

    Teriflunomide, being developed as a potential oral treatment for multiple sclerosis (MS) by sanofi-aventis, is the active metabolite of the rheumatoid arthritis drug leflunomide. Both teriflunomide and leflunomide are inhibitors of the mitochondrial enzyme dihydroorotate dehydrogenase, which is critically involved in pyrimidine synthesis. The production of activated T-cells largely depends on de novo pyrimidine synthesis, and thus pyrimidine depletion is thought to result in the inhibition of immune cell proliferation. Therapeutic efficacy of teriflunomide has been demonstrated in vivo in an experimental autoimmune encephalomyelitis model of MS using Dark Agouti rats. In a phase II, randomized, double-blind, placebo-controlled clinical trial of patients with relapsing-remitting MS, treatment with teriflunomide reduced the number of active lesions in the brain and preliminary evidence indicated a slowing in the development of disability. Recently reported data from the phase III TEMSO clinical trial support these initial findings. Compared with current therapies, teriflunomide has the advantage of oral administration. Thus, if good efficacy is demonstrated, teriflunomide may have a role to play in the future treatment of MS. PMID:21157651

  14. 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

  15. Myelin Basic Protein Citrullination in Multiple Sclerosis: A Potential Therapeutic Target for the Pathology.

    PubMed

    Yang, Lei; Tan, Dewei; Piao, Hua

    2016-08-01

    Multiple sclerosis (MS) is a multifactorial demyelinating disease characterized by neurodegenerative events and autoimmune response against myelin component. Citrullination or deimination, a post-translational modification of protein-bound arginine into citrulline, catalyzed by Ca(2+) dependent peptidylarginine deiminase enzyme (PAD), plays an essential role in physiological processes include gene expression regulation, apoptosis and the plasticity of the central nervous system, while aberrant citrullination can generate new epitopes, thus involving in the initiation and/or progression of autoimmune disorder like MS. Myelin basic protein (MBP) is the major myelin protein and is generally considered to maintain the stability of the myelin sheath. This review describes the MBP citrullination and its consequence, as well as offering further support for the "inside-out" hypothesis that MS is primarily a neurodegenerative disease with secondary inflammatory demyelination. In addition, it discusses the role of MBP citrullination in the immune inflammation and explores the potential of inhibition of PAD enzymes as a therapeutic strategy for the disease. PMID:27097548

  16. NICE technology appraisals: working with multiple levels of uncertainty and the potential for bias.

    PubMed

    Brown, Patrick; Calnan, Michael

    2013-05-01

    One of the key roles of the English National Institute for Health and Clinical Excellence (NICE) is technology appraisal. This essentially involves evaluating the cost effectiveness of pharmaceutical products and other technologies for use within the National Health Service. Based on a content analysis of key documents which shed light on the nature of appraisals, this paper draws attention to the multiple layers of uncertainty and complexity which are latent within the appraisal process, and the often socially constructed mechanisms for tackling these. Epistemic assumptions, bounded rationality and more explicitly relational forms of managing knowledge are applied to this end. These findings are discussed in the context of the literature highlighting the inherently social process of regulation. A framework is developed which posits the various forms of uncertainty, and responses to these, as potential conduits of regulatory bias-in need of further research. That NICE's authority is itself regulated by other actors within the regulatory regime, particularly the pharmaceutical industry, exposes it to the threat of regulatory capture. Following Lehoux, it is concluded that a more transparent and reflexive format for technological appraisals is necessary. This would enable a more robust, defensible form of decision-making and moreover enable NICE to preserve its legitimacy in the midst of pressures which threaten this. PMID:22198480

  17. 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

  18. 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.

  19. 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

  20. 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

  1. 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

  2. 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.

  3. Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci

    PubMed Central

    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

    2015-01-01

    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

  4. 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

  5. Doubly differential measurements for multiple ionization of argon by electron impact: Comparison with positron impact and photoionization

    SciTech Connect

    Santos, A.C.F.; Hasan, A.; Yates, T.; DuBois, R.D.

    2003-05-01

    Doubly differential cross sections for single and multiple ionization of Ar have been measured for 500, 750, and 1000 eV electron impact. The cross sections were measured as a function of projectile energy loss and scattering angle. The energy loss range was 0-85% of the initial projectile energy and scattering angles were between {+-}22 deg. The data were put on an absolute scale by normalizing to total ionization cross sections available in the literature and found to be in good agreement with the absolute electron impact cross sections from DuBois and Rudd. For 750 eV impact, a comparison was made between the present electron impact data and positron impact data obtained using the same experimental conditions. The same energy dependence and yields for single ionization were found for both electron and positron impact. On the other hand, the double- and triple-ionization yields are smaller for positron impact as compared to electron impact. Comparisons with photoionization data showed that for outer shell ionization the fractions of double and triple ionization of argon by photon impact are in quite good agreement with the present electron impact data.

  6. Photoreflectance and differential surface photovoltage studies of δ-doped GaAs/AlAs multiple quantum wells

    NASA Astrophysics Data System (ADS)

    Cechavičius, Bronislovas; Kavaliauskas, Julius; Krivaite, Gene; Seliuta, Dalius; Valusis, Gintaras; Halsall, Matthew P.; Steer, Matthew J.; Harrison, Paul

    2005-08-01

    We measured the photoreflectance (PR) and wavelength-modulated differential surface photovoltage (DSPV) spectra of δ-doped GaAs/AlAs multiple quantum wells (MQW) with different well widths and doping levels. We demonstrated that PR and DSPV are powerful contactless tools for the characterization of MQW structures. We observed Franz-Keldysh oscillations in the PR spectra, which enabled us to determine the built-in electric fields in the GaAs/AlAs MQW structures. As it turned out, in the GaAs buffedcap layers the field strength is in the range of 18-20 kV/cm. It was found that a buried interface rather than the structure surface very probably governs the SPV effect. Sharp features associated with excitonic optical transitions were revealed in both, PR and DSPV spectra. From the line shape analysis of the modulation spectra, we estimated optical transition energies and broadening parameters. The energy levels and interband transition energies calculated by the transfer matrix method are in good agreement with the experimental values. The influence of the doping on the broadening of exciton resonances was observed and investigated.

  7. A multiple RT-PCR assay for simultaneous detection and differentiation of latent viruses and apscarviroids in apple trees.

    PubMed

    Hao, Lu; Xie, Jipeng; Chen, Shanyi; Wang, Shaojie; Gong, Zhuoqun; Ling, Kai-Shu; Guo, Liyun; Fan, Zaifeng; Zhou, Tao

    2016-08-01

    Apple chlorotic leaf spot virus (ACLSV), Apple stem grooving virus (ASGV), and Apple stem pitting virus (ASPV) are three latent viruses frequently occurring in apple trees worldwide. In field orchards, these viruses are frequently found in a mixed infection with viroids in the genus Apscarviroid, including Apple scar skin viroid, and Apple dimple fruit viroid. Together these viruses and viroids could cause serious damage to apple fruit production worldwide. Rapid and efficient detection methods are pivotal to identify and select the virus-free propagation material for healthy apple orchard management. In this study a multiplex Reverse Transcription-PCR (RT-PCR) was developed and optimized for simultaneous detection and differentiation of the three latent viruses and apscarviroids. With newly designed specific primers for ACLSV, ASGV, APSV, and EF-1α (as an internal control), and a pair of degenerate primers for apscarviroids, optimized parameters for multiplex RT-PCR were determined. The resulting PCR products from each target virus and viroid could be easily identified because their product sizes differ by at least a 100bp. The multiplex RT-PCR method is expected to detect different variants of the viruses as the test results showed that a variety of isolates from different regions in China gave positive results. To the best of our knowledge, this multiplex RT-PCR assay is the first to simultaneously detect multiple viruses and viroids infecting apple trees in a single reaction tube. This assay, therefore, offers a useful tool for routine certification and quarantine programs. PMID:27054889

  8. 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

  9. 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

  10. 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

  11. 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.

  12. Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease.

    PubMed

    Eda, Homare; Santo, Loredana; Wein, Marc N; Hu, Dorothy Z; Cirstea, Diana D; Nemani, Neeharika; Tai, Yu-Tzu; Raines, Sarah E; Kuhstoss, Stuart Allen; Munshi, Nikhil C; Kronenberg, Henry M; Raje, Noopur S

    2016-06-01

    Sclerostin is a potent inhibitor of osteoblastogenesis. Interestingly, newly diagnosed multiple myeloma (MM) patients have high levels of circulating sclerostin that correlate with disease stage and fractures. However, the source and impact of sclerostin in MM remains to be defined. Our goal was to determine the role of sclerostin in the biology of MM and its bone microenvironment as well as investigate the effect of targeting sclerostin with a neutralizing antibody (scl-Ab) in MM bone disease. Here we confirm increased sclerostin levels in MM compared with precursor disease states like monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM. Furthermore, we found that a humanized MM xenograft mouse model bearing human MM cells (NOD-SCID.CB17 male mice injected intravenously with 2.5 million of MM1.S-Luc-GFP cells) demonstrated significantly higher concentrations of mouse-derived sclerostin, suggesting a microenvironmental source of sclerostin. Associated with the increased sclerostin levels, activated β-catenin expression levels were lower than normal in MM mouse bone marrow. Importantly, a high-affinity grade scl-Ab reversed osteolytic bone disease in this animal model. Because scl-Ab did not demonstrate significant in vitro anti-MM activity, we combined it with the proteasome inhibitor carfilzomib. Our data demonstrated that this combination therapy significantly inhibited tumor burden and improved bone disease in our in vivo MM mouse model. In agreement with our in vivo data, sclerostin expression was noted in marrow stromal cells and osteoblasts of MM patient bone marrow samples. Moreover, MM cells stimulated sclerostin expression in immature osteoblasts while inhibiting osteoblast differentiation in vitro. This was in part regulated by Dkk-1 secreted by MM cells and is a potential mechanism contributing to the osteoblast dysfunction noted in MM. Our data confirm the role of sclerostin as a potential therapeutic target in MM bone disease

  13. Epidermal Differentiation Complex: A Review on Its Epigenetic Regulation and Potential Drug Targets.

    PubMed

    Abhishek, Sinha; Palamadai Krishnan, Suresh

    2016-01-01

    The primary feature of the mammalian skin includes the hair follicle, inter-follicular epidermis and the sebaceous glands, all of which form pilo-sebaceous units. The epidermal protective layer undergoes an ordered/programmed process of proliferation and differentiation, ultimately culminating in the formation of a cornified envelope consisting of enucleated corneocytes. These terminally differentiated cells slough off in a cyclic manner and this process is regulated via induction or repression of epidermal differentiation complex (EDC) genes. These genes, spanning 2 Mb region of human chromosome 1q21, play a crucial role in epidermal development, through various mechanisms. Each of these mechanisms employs a unique chromatin re-modelling factor or an epigenetic modifier. These factors act to regulate epidermal differentiation singly and/or in combination. Diseases like psoriasis and cancer exhibit aberrations in proliferation and differentiation through, in part, dysregulation in these epigenetic mechanisms. Knowledge of the existing mechanisms in the physiological and the aforesaid pathological contexts may not only facilitate drug development, it also can make refinements to the existing drug delivery systems. PMID:27054112

  14. Endocrine-committed progenitor cells retain their differentiation potential in the absence of neurogenin-3 expression

    PubMed Central

    Prasadan, Krishna; Tulachan, Sidhartha; Guo, Ping; Shiota, Chiyo; Shah, Sohail; Gittes, George

    2016-01-01

    Neurogenin-3 (ngn-3) expression is critical for endocrine development in the developing pancreas. We found that when ngn-3 was inhibited in an E11.5 pancreas, using either morpholino antisense or siRNA, it led to a significant decrease in endocrine differentiation after seven days in culture. Endocrine differentiation was rescued when ngn-3 inhibition was withdrawn after three days of culture, suggesting that the embryonic pancreas retains progenitor cells with the ability to differentiate into endocrine cell types when ngn-3 expression recurs. To determine whether the rescue phenomenon observed after withdrawing ngn-3 antisense treatment was the result of the original endocrine-committed cells reinitiating endocrine differentiation, or was instead due to new recruitment of later progenitor cells, we blocked ngn-3 expression for only the last four days of a seven-day culture. Here, insulin-positive differentiation was slightly reduced, but there was a normal number of glucagon-positive cells. In addition, there was an increase in SOX9-positive cells in ngn-3 inhibited, as well as in ngn-3 rescued pancreata, with a significant proportion of these SOX9-positive cells co-localized with DBA, an early ductal marker. This increased number of cells with co-localization of SOX9 and DBA could indicate an increased numbers of endocrine progenitor cells. PMID:20471370

  15. Epidermal Differentiation Complex: A Review on Its Epigenetic Regulation and Potential Drug Targets

    PubMed Central

    Abhishek, Sinha; Palamadai Krishnan, Suresh

    2016-01-01

    The primary feature of the mammalian skin includes the hair follicle, inter-follicular epidermis and the sebaceous glands, all of which form pilo-sebaceous units. The epidermal protective layer undergoes an ordered/programmed process of proliferation and differentiation, ultimately culminating in the formation of a cornified envelope consisting of enucleated corneocytes. These terminally differentiated cells slough off in a cyclic manner and this process is regulated via induction or repression of epidermal differentiation complex (EDC) genes. These genes, spanning 2 Mb region of human chromosome 1q21, play a crucial role in epidermal development, through various mechanisms. Each of these mechanisms employs a unique chromatin re-modelling factor or an epigenetic modifier. These factors act to regulate epidermal differentiation singly and/or in combination. Diseases like psoriasis and cancer exhibit aberrations in proliferation and differentiation through, in part, dysregulation in these epigenetic mechanisms. Knowledge of the existing mechanisms in the physiological and the aforesaid pathological contexts may not only facilitate drug development, it also can make refinements to the existing drug delivery systems. PMID:27054112

  16. 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

  17. Interleukin-1β promotes long-term potentiation in patients with multiple sclerosis.

    PubMed

    Mori, Francesco; Nisticò, Robert; Mandolesi, Georgia; Piccinin, Sonia; Mango, Dalila; Kusayanagi, Hajime; Berretta, Nicola; Bergami, Alessandra; Gentile, Antonietta; Musella, Alessandra; Nicoletti, Carolina G; Nicoletti, Ferdinando; Buttari, Fabio; Mercuri, Nicola B; Martino, Gianvito; Furlan, Roberto; Centonze, Diego

    2014-03-01

    The immune system shapes synaptic transmission and plasticity in experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis (MS). These synaptic adaptations are believed to drive recovery of function after brain lesions, and also learning and memory deficits and excitotoxic neurodegeneration; whether inflammation influences synaptic plasticity in MS patients is less clear. In a cohort of 59 patients with MS, we found that continuous theta-burst transcranial magnetic stimulation did not induce the expected long-term depression (LTD)-like synaptic phenomenon, but caused persisting enhancement of brain cortical excitability. The amplitude of this long-term potentiation (LTP)-like synaptic phenomenon correlated with the concentration of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the cerebrospinal fluid. In MS and EAE, the brain and spinal cord are typically enriched of CD3(+) T lymphocyte infiltrates, which are, along with activated microglia and astroglia, a major cause of inflammation. Here, we found a correlation between the presence of infiltrating T lymphocytes in the hippocampus of EAE mice and synaptic plasticity alterations. We observed that T lymphocytes from EAE, but not from control mice, release IL-1β and promote LTP appearance over LTD, thereby mimicking the facilitated LTP induction observed in the cortex of MS patients. EAE-specific T lymphocytes were able to suppress GABAergic transmission in an IL-1β-dependent manner, providing a possible synaptic mechanism able to lower the threshold of LTP induction in MS brains. Moreover, in vivo blockade of IL-1β signaling resulted in inflammation and synaptopathy recovery in EAE hippocampus. These data provide novel insights into the pathophysiology of MS. PMID:23892937

  18. Assessments of Maize Yield Potential in the Korean Peninsula Using Multiple Crop Models

    NASA Astrophysics Data System (ADS)

    Kim, S. H.; Myoung, B.; Lim, C. H.; Lee, S. G.; Lee, W. K.; Kafatos, M.

    2015-12-01

    The Korean Peninsular has unique agricultural environments due to the differences in the political and socio-economical systems between the Republic of Korea (SK, hereafter) and the Democratic Peoples' Republic of Korea (NK, hereafter). NK has been suffering from the lack of food supplies caused by natural disasters, land degradation and failed political system. The neighboring developed country SK has a better agricultural system but very low food self-sufficiency rate (around 1% of maize). Maize is an important crop in both countries since it is staple food for NK and SK is No. 2 maize importing country in the world after Japan. Therefore evaluating maize yield potential (Yp) in the two distinct regions is essential to assess food security under climate change and variability. In this study, we have utilized multiple process-based crop models capable of regional-scale assessments to evaluate maize Yp over the Korean Peninsula - the GIS version of EPIC model (GEPIC) and APSIM model that can be expanded to regional scales (APSIM regions). First we evaluated model performance and skill for 20 years from 1991 to 2010 using reanalysis data (Local Data Assimilation and Prediction System (LDAPS); 1.5km resolution) and observed data. Each model's performances were compared over different regions within the Korean Peninsula of different regional climate characteristics. To quantify the major influence of individual climate variables, we also conducted a sensitivity test using 20 years of climatology. Lastly, a multi-model ensemble analysis was performed to reduce crop model uncertainties. The results will provide valuable information for estimating the climate change or variability impacts on Yp over the Korean Peninsula.

  19. 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

  20. Potential Benefits of Nintendo Wii Fit Among People with Multiple Sclerosis

    PubMed Central

    Finlayson, Marcia

    2011-01-01

    We examined the potential of Nintendo Wii Fit (Nintendo Co, Ltd, Kyoto, Japan) to increase physical activity (PA) behavior and health among people with multiple sclerosis (MS). The study consisted of a repeated-measures design with a baseline control period and involved 30 people with MS who had the ability to walk 25 feet with or without a cane (26 individuals were included in the analyses). Nintendo Wii was set up in the homes of participants, who were prescribed a Wii Fit exercise program lasting 14 weeks, 3 days a week. The Physical Activity and Disability Survey, Modified Fatigue Impact Scale, and 36-item Short Form Health Status Survey were administered three times before participants gained access to Wii Fit (control period, at 2-week intervals), and three times after they received Wii Fit (posttest 1: immediately after; posttest 2: 7 weeks after; posttest 3: 14 weeks after). Mobility, balance, strength, and weight were assessed at the first pretest, immediately prior to obtaining access to Wii Fit, and 7 weeks after obtaining access to Wii Fit. Results from the questionnaires indicated that PA significantly improved at week 7, but at week 14, PA levels declined relative to week 7 and the difference was no longer significant compared with the control period. Physical assessments indicated that balance and strength significantly improved at week 7. One adverse event was reported (repetitive knee injury). Physical assessments indicated that people with MS may be able to improve their fitness levels by using Wii Fit. Future studies should incorporate behavior change strategies to promote long-term use of Wii Fit, and explore whether individuals with more severe symptoms of MS can safely use Wii Fit. PMID:24453702

  1. "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…

  2. Hyaluronan preserves the proliferation and differentiation potentials of long-term cultured murine adipose-derived stromal cells

    SciTech Connect

    Chen, P.-Y.; Huang, Lynn L.H. . E-mail: lynn@mail.ncku.edu.tw; Hsieh, H.-J. . E-mail: hjhsieh@ntu.edu.tw

    2007-08-17

    For long-term culture, murine adipose-derived stromal cells (mADSCs) at latter passages demonstrated a marked decline in proliferative activity, exhibited senescent morphology and reduced differentiation potentials, particularly osteogenesis. To extend the lifespan of mADSCs, two culture conditions containing hyaluronan (HA) was compared in our study, one as a culture medium supplement (SHA), and the other where HA was pre-coated on culture surface (CHA). mADSCs cultivated with SHA exhibited a prolonged lifespan, reduced cellular senescence, and enhanced osteogenic potential compared to regular culture condition (control). Upon CHA treatment, mADSCs tended to form cell aggregates with gradual growth profiles, while their differentiation activities remained similar to SHA groups. After transferring mADSCs from CHA to control surface, they were shown to have an extended lifespan and an increase of osteogenic potential. Our results suggested that HA can be useful for preserving the proliferation and differentiation potentials of long-term cultured mADSCs.

  3. Determination of the interatomic potential from elastic differential cross sections at fixed energy: Functional sensitivity analysis approach

    SciTech Connect

    Ho, T.; Rabitz, H.

    1989-02-01

    Elastic differential cross sections in atomic crossed beam experiments contain detailed information about the underlying interatomic potentials. The functional sensitivity density of the cross sections with respect to the potential deltasigma(theta)/deltaV(R) reveals such information and has been implemented in an iterative inversion procedure, analogous to that of the Newton--Raphson technique. The stability of the inversion is achieved with the use of the regularization method of Tikhonov and Miller. It is shown that given a set of well resolved and noise-free differential cross section data within a limited angular range and given a reasonable starting reference potential, the recovered potential accurately resembles the desired one in the important region, i.e., the region to which the scattering data are sensitive. The region of importance depends upon the collision energy relative to the well depth of the potential under study; usually a higher collision energy penetrates deeper into the repulsive part of the potential and thus accordingly yields a more accurate potential in that part. The inversion procedure produces also a quality function indicating the well determined radial region. Moreover, the extracted potential is quite independent of the functional form of the reference potential in contrast to curve fitting approaches. As illustrations, the model inert gas systems He--Ne and Ne--Ar have been considered. For collision energies within an order of magnitude of the associated potential well depth, the attractive part of the potential can be determined to high precision provided that scattering data at small enough angles are available.

  4. Comparison of chromosome centromere topology in differentiating cells with myogenic potential.

    PubMed

    Mikołajczak, Bartosz; Wiland, Ewa; Rozwadowska, Natalia; Rucinski, Marek; Mietkiewski, Tomasz; Kurpisz, Maciej

    2009-01-01

    Chromosome territories (CT's) constitute the critical element of the intranuclear architecture. Position of these compartmentalized structures plays an important role in functioning of entire genome. Present study was to examine whether the centromeres position of chromosomes 4, X and Y can be changed during differentiation from myoblasts to myotubes. Topological analysis of these centromeres was based on two-dimensional fluorescent hybridization in situ (2D-FISH). During differentiation process the majority of X chromosome centromeres analyzed shifted to the peripheral part of a nucleus and similar phenomenon was observed with one of the chromosome 4 centromeres. Completely different tendency was noticed when investigating the location of the chromosome Y centromeres. Centromeres of this chromosome migrated to the centre of a nucleus. The results obtained demonstrated visible changes in chromosome topology along the myogenic stem cells differentiation. PMID:20164021

  5. 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

  6. Comparative Evaluation for Potential Differentiation of Endothelial Progenitor Cells and Mesenchymal Stem Cells into Endothelial-Like Cells

    PubMed Central

    Sabry, Dina; Noh, Olfat; Samir, Mai

    2016-01-01

    Understanding the mechanisms of vascular remodeling could lead to more effective treatments for ischemic conditions. We aimed to compare between the abilities of both human Wharton jelly derived mesenchymal stem cells (hMSCs) and human cord blood endothelial progenitor cells (hEPCs) and CD34+ to induce angiogenesis in vitro. hMSCs, hEPCs, and CD34+ were isolated from human umbilical cord blood using microbead (MiniMacs). The cells characterization was assessed by flow cytometry following culture and real-time PCR for vascular endothelial growth factor receptor 2 (VEGFR2) and von Willebrand factor (vWF) to prove stem cells differentiation. The study revealed successful isolation of hEPCs, CD34+, and hMSCs. The hMSCs were identified by gaining CD29+ and CD44+ using FACS analysis. The hEPCs were identified by having CD133+, CD34+, and KDR. The potential ability of hEPCs and CD34+ to differentiate into endothelial-like cells was more than hMSCs. This finding was assessed morphologically in culture and by higher significant VEGFR2 and vWF genes expression (p<0.05) in differentiated hEPCs and CD34+ compared to differentiated hMSCs. hEPCs and CD34+ differentiation into endothelial-like cells were much better than that of hMSCs. PMID:27426085

  7. 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

  8. 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…

  9. Human keratinocyte growth and differentiation on acellular porcine dermal matrix in relation to wound healing potential.

    PubMed

    Zajicek, Robert; Mandys, Vaclav; Mestak, Ondrej; Sevcik, Jan; Königova, Radana; Matouskova, Eva

    2012-01-01

    A number of implantable biomaterials derived from animal tissues are now used in modern surgery. Xe-Derma is a dry, sterile, acellular porcine dermis. It has a remarkable healing effect on burns and other wounds. Our hypothesis was that the natural biological structure of Xe-Derma plays an important role in keratinocyte proliferation and formation of epidermal architecture in vitro as well as in vivo. The bioactivity of Xe-Derma was studied by a cell culture assay. We analyzed growth and differentiation of human keratinocytes cultured in vitro on Xe-Derma, and we compared the results with formation of neoepidermis in the deep dermal wounds treated with Xe-Derma. Keratinocytes cultured on Xe-Derma submerged in the culture medium achieved confluence in 7-10 days. After lifting the cultures to the air-liquid interface, the keratinocytes were stratified and differentiated within one week, forming an epidermis with basal, spinous, granular, and stratum corneum layers. Immunohistochemical detection of high-molecular weight cytokeratins (HMW CKs), CD29, p63, and involucrin confirmed the similarity of organization and differentiation of the cultured epidermal cells to the normal epidermis. The results suggest that the firm natural structure of Xe-Derma stimulates proliferation and differentiation of human primary keratinocytes and by this way improves wound healing. PMID:22629190

  10. Potential Sources of Differential Item Functioning in the Adaptation of Tests

    ERIC Educational Resources Information Center

    Elosua, Paula; Lopez-Jauregui, Alicia

    2007-01-01

    This report shows a classification of differential item functioning (DIF) sources that have an effect on the adaptation of tests. This classification is based on linguistic and cultural criteria. Four general DIF sources are distinguished: cultural relevance, translation problems, morph syntactical differences, and semantic differences. The…

  11. 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…

  12. 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…

  13. 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…

  14. 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.

  15. 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

  16. A label-free high throughput resistive-pulse sensor for simultaneous differentiation and measurement of multiple particle-laden analytes

    NASA Astrophysics Data System (ADS)

    Jagtiani, Ashish V.; Sawant, Rupesh; Zhe, Jiang

    2006-08-01

    We describe an all-electronic, label-free, resistive-pulse sensor that utilizes multiple microchannels for parallel detection, counting and differentiation of multiple biological particles simultaneously. Four particle solutions, including 20 µm and 40 µm polymethacrylate particles, Juniper Scopulorum (Rocky Mountain Juniper) pollen and Populus deltidoes (Eastern Cottonwood) pollen, were loaded to the four peripheral reservoirs, respectively, and were driven to the central reservoir through four microchannels, all operating simultaneously for particle detection and counting. Experiments demonstrated that this sensor was able to differentiate and count multiple particle solutions simultaneously through its four microchannels fabricated on polymer membranes. Thus the sensing throughput has been improved significantly in contrast to typical Coulter counters without sacrificing accuracy, sensitivity and reliability. Furthermore, the experimental results also proved the feasibility of differentiating various pollens from polymethacrylate microparticles with the multi-channel resistive-pulse sensor. The differentiation is based on difference in size and surface charge for the bioparticles, with no need for labeling of samples. Possible improvements and extensions to other biological particle detection are discussed.

  17. 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.

  18. Cardiac Adipose-Derived Stem Cells Exhibit High Differentiation Potential to Cardiovascular Cells in C57BL/6 Mice.

    PubMed

    Nagata, Hiroki; Ii, Masaaki; Kohbayashi, Eiko; Hoshiga, Masaaki; Hanafusa, Toshiaki; Asahi, Michio

    2016-02-01

    Adipose-derived stem cells (AdSCs) have recently been shown to differentiate into cardiovascular lineage cells. However, little is known about the fat tissue origin-dependent differences in AdSC function and differentiation potential. AdSC-rich cells were isolated from subcutaneous, visceral, cardiac (CA), and subscapular adipose tissue from mice and their characteristics analyzed. After four different AdSC types were cultured with specific differentiation medium, immunocytochemical analysis was performed for the assessment of differentiation into cardiovascular cells. We then examined the in vitro differentiation capacity and therapeutic potential of AdSCs in ischemic myocardium using a mouse myocardial infarction model. The cell density and proliferation activity of CA-derived AdSCs were significantly increased compared with the other adipose tissue-derived AdSCs. Immunocytochemistry showed that CA-derived AdSCs had the highest appearance rates of markers for endothelial cells, vascular smooth muscle cells, and cardiomyocytes among the AdSCs. Systemic transfusion of CA-derived AdSCs exhibited the highest cardiac functional recovery after myocardial infarction and the high frequency of the recruitment to ischemic myocardium. Moreover, long-term follow-up of the recruited CA-derived AdSCs frequently expressed cardiovascular cell markers compared with the other adipose tissue-derived AdSCs. Cardiac adipose tissue could be an ideal source for isolation of therapeutically effective AdSCs for cardiac regeneration in ischemic heart diseases. Significance: The present study found that cardiac adipose-derived stem cells have a high potential to differentiate into cardiovascular lineage cells (i.e., cardiomyocytes, endothelial cells, and vascular smooth muscle cells) compared with stem cells derived from other adipose tissue such as subcutaneous, visceral, and subscapular adipose tissue. Notably, only a small number of supracardiac adipose-derived stem cells that were

  19. The Differential Hormonal Milieu of Morning versus Evening May Have an Impact on Muscle Hypertrophic Potential.

    PubMed

    Burley, Simon D; Whittingham-Dowd, Jayde; Allen, Jeremy; Grosset, Jean-Francois; Onambele-Pearson, Gladys L

    2016-01-01

    Substantial gains in muscle strength and hypertrophy are clearly associated with the routine performance of resistance training. What is less evident is the optimal timing of the resistance training stimulus to elicit these significant functional and structural skeletal muscle changes. Therefore, this investigation determined the impact of a single bout of resistance training performed either in the morning or evening upon acute anabolic signalling (insulin-like growth factor-binding protein-3 (IGFBP-3), myogenic index and differentiation) and catabolic processes (cortisol). Twenty-four male participants (age 21.4±1.9yrs, mass 83.7±13.7kg) with no sustained resistance training experience were allocated to a resistance exercise group (REP). Sixteen of the 24 participants were randomly selected to perform an additional non-exercising control group (CP) protocol. REP performed two bouts of resistance exercise (80% 1RM) in the morning (AM: 0800 hrs) and evening (PM: 1800 hrs), with the sessions separated by a minimum of 72 hours. Venous blood was collected immediately prior to, and 5 min after, each resistance exercise and control sessions. Serum cortisol and IGFBP-3 levels, myogenic index, myotube width, were determined at each sampling period. All data are reported as mean ± SEM, statistical significance was set at P≤0.05. As expected a significant reduction in evening cortisol concentration was observed at pre (AM: 98.4±10.5, PM: 49.8±4.4 ng/ml, P<0.001) and post (AM: 98.0±9.0, PM: 52.7±6.0 ng/ml, P<0.001) exercise. Interestingly, individual cortisol differences pre vs post exercise indicate a time-of-day effect (AM difference: -2±2.6%, PM difference: 14.0±6.7%, P = 0.03). A time-of-day related elevation in serum IGFBP-3 (AM: 3274.9 ± 345.2, PM: 3605.1 ± 367.5, p = 0.032) was also evident. Pre exercise myogenic index (AM: 8.0±0.6%, PM: 16.8±1.1%) and myotube width (AM: 48.0±3.0, PM: 71.6±1.9 μm) were significantly elevated (P<0.001) in the evening

  20. Lovastatin Decreases the Expression of CD133 and Influences the Differentiation Potential of Human Embryonic Stem Cells

    PubMed Central

    Kallas-Kivi, Ade

    2016-01-01

    The lipophilic statin lovastatin decreases cholesterol synthesis and is a safe and effective treatment for the prevention of cardiovascular diseases. Growing evidence points at antitumor potential of lovastatin. Therefore, understanding the molecular mechanism of lovastatin function in different cell types is critical to effective therapy design. In this study, we investigated the effects of lovastatin on the differentiation potential of human embryonic stem (hES) cells (H9 cell line). Multiparameter flow cytometric assay was used to detect changes in the expression of transcription factors characteristic of hES cells. We found that lovastatin treatment delayed NANOG downregulation during ectodermal and endodermal differentiation. Likewise, expression of ectodermal (SOX1 and OTX2) and endodermal (GATA4 and FOXA2) markers was higher in treated cells. Exposure of hES cells to lovastatin led to a minor decrease in the expression of SSEA-3 and a significant reduction in CD133 expression. Treated cells also formed fewer embryoid bodies than control cells. By analyzing hES with and without CD133, we discovered that CD133 expression is required for proper formation of embryoid bodies. In conclusion, lovastatin reduced the heterogeneity of hES cells and impaired their differentiation potential. PMID:27247576

  1. 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

  2. Potential Factors for the Differentiation of ESCs/iPSCs Into Insulin-Producing Cells.

    PubMed

    Tsugata, Takako; Nikoh, Naruo; Kin, Tatsuya; Saitoh, Issei; Noguchi, Yasufumi; Ueki, Hideo; Watanabe, Masami; James Shapiro, Andrew M; Noguchi, Hirofumi

    2015-02-01

    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

  3. 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

  4. An improved ScoreCard to assess the differentiation potential of human pluripotent stem cells

    PubMed Central

    Tsankov, Alexander M.; Akopian, Veronika; Pop, Ramona; Chetty, Sundari; Gifford, Casey A.; Daheron, Laurence; Melton, Douglas A.; Tsankova, Nadejda M.; Meissner, Alexander

    2015-01-01

    Research on human pluripotent stem cells has been hampered by the lack of a standardized, quantitative, scalable assay of pluripotency. We have 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 through embryoid body and directed differentiation experiments as well as a detailed comparison to the teratoma assay. We also show that the improved ScoreCard enables applications such as screening of small molecules, genetic perturbations and assessment of culture conditions. Beyond stem cell applications, this approach can in principle be extended to other cell types and lineages. PMID:26501952

  5. 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

  6. 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

  7. Potential role of epigenetic mechanisms in regulation of trophoblast differentiation, migration, and invasion in the human placenta.

    PubMed

    Kohan-Ghadr, Hamid-Reza; Kadam, Leena; Jain, Chandni; Armant, D Randall; Drewlo, Sascha

    2016-03-01

    The proper establishment and organogenesis of the placenta is crucial for intrauterine fetal growth and development. Endometrial invasion by the extravillous trophoblast cells, as well as formation of the syncytiotrophoblast (STB), are of vital importance for placental function. Trophoblast migration and invasion is often compared to tumor metastasis, which uses many of the same molecular mechanisms. However, unlike cancer cells, both initiation and the extent of trophoblast invasion are tightly regulated by feto-maternal cross-talk, which when perturbed, results in a wide range of abnormalities. Multiple factors control the trophoblast, including cytokines and hormones, which are subject to transcriptional regulatory networks. The relevance of epigenetics in transcriptional regulation of trophoblast differentiation and invasion, as well as in the onset of placenta-related pregnancy disorders, became recognized decades ago. Although, there has been tremendous progress in uncovering the molecular foundation of placental development, there is still much to be learned about the epigenetic machinery, and its role in trophoblast differentiation and invasion. This review will provide an overview of the epigenetic control of trophoblast differentiation and invasion. It will also highlight the major epigenetic mechanisms involved in pregnancy complications related to placental deficiencies. PMID:26745760

  8. Potential role of epigenetic mechanisms in regulation of trophoblast differentiation, migration, and invasion in the human placenta

    PubMed Central

    Kohan-Ghadr, Hamid-Reza; Kadam, Leena; Jain, Chandni; Armant, D. Randall; Drewlo, Sascha

    2016-01-01

    ABSTRACT The proper establishment and organogenesis of the placenta is crucial for intrauterine fetal growth and development. Endometrial invasion by the extravillous trophoblast cells, as well as formation of the syncytiotrophoblast (STB), are of vital importance for placental function. Trophoblast migration and invasion is often compared to tumor metastasis, which uses many of the same molecular mechanisms. However, unlike cancer cells, both initiation and the extent of trophoblast invasion are tightly regulated by feto-maternal cross-talk, which when perturbed, results in a wide range of abnormalities. Multiple factors control the trophoblast, including cytokines and hormones, which are subject to transcriptional regulatory networks. The relevance of epigenetics in transcriptional regulation of trophoblast differentiation and invasion, as well as in the onset of placenta-related pregnancy disorders, became recognized decades ago. Although, there has been tremendous progress in uncovering the molecular foundation of placental development, there is still much to be learned about the epigenetic machinery, and its role in trophoblast differentiation and invasion. This review will provide an overview of the epigenetic control of trophoblast differentiation and invasion. It will also highlight the major epigenetic mechanisms involved in pregnancy complications related to placental deficiencies. PMID:26745760

  9. Differentiation and regeneration potential of mesenchymal progenitor cells derived from traumatized muscle tissue.

    PubMed

    Jackson, Wesley M; Lozito, Thomas P; Djouad, Farida; Kuhn, Nastaran Z; Nesti, Leon J; Tuan, Rocky S

    2011-11-01

    Mesenchymal stem cell (MSC) therapy is a promising approach to promote tissue regeneration by either differentiating the MSCs into the desired cell type or by using their trophic functions to promote endogenous tissue repair. These strategies of regenerative medicine are limited by the availability of MSCs at the point of clinical care. Our laboratory has recently identified multipotent mesenchymal progenitor cells (MPCs) in traumatically injured muscle tissue, and the objective of this study was to compare these cells to a typical population of bone marrow derived MSCs. Our hypothesis was that the MPCs exhibit multilineage differentiation and expression of trophic properties that make functionally them equivalent to bone marrow derived MSCs for tissue regeneration therapies. Quantitative evaluation of their proliferation, metabolic activity, expression of characteristic cell-surface markers and baseline gene expression profile demonstrate substantial similarity between the two cell types. The MPCs were capable of differentiation into osteoblasts, adipocytes and chondrocytes, but they appeared to demonstrate limited lineage commitment compared to the bone marrow derived MSCs. The MPCs also exhibited trophic (i.e. immunoregulatory and pro-angiogenic) properties that were comparable to those of MSCs. These results suggest that the traumatized muscle derived MPCs may not be a direct substitute for bone marrow derived MSCs. However, because of their availability and abundance, particularly following orthopaedic injuries when traumatized muscle is available to harvest autologous cells, MPCs are a promising cell source for regenerative medicine therapies designed to take advantage of their trophic properties. PMID:21129154

  10. Crucial transcription factors in tendon development and differentiation: their potential for tendon regeneration.

    PubMed

    Liu, Huanhuan; Zhu, Shouan; Zhang, Can; Lu, Ping; Hu, Jiajie; Yin, Zi; Ma, Yue; Chen, Xiao; OuYang, Hongwei

    2014-05-01

    Tendons that connect muscles to bone are often the targets of sports injuries. The currently unsatisfactory state of tendon repair is largely attributable to the limited understanding of basic tendon biology. A number of tendon lineage-related transcription factors have recently been uncovered and provide clues for the better understanding of tendon development. Scleraxis and Mohawk have been identified as critical transcription factors in tendon development and differentiation. Other transcription factors, such as Sox9 and Egr1/2, have also been recently reported to be involved in tendon development. However, the molecular mechanisms and application of these transcription factors remain largely unclear and this prohibits their use in tendon therapy. Here, we systematically review and analyze recent findings and our own data concerning tendon transcription factors and tendon regeneration. Based on these findings, we provide interaction and temporal programming maps of transcription factors, as a basis for future tendon therapy. Finally, we discuss future directions for tendon regeneration with differentiation and trans-differentiation approaches based on transcription factors. PMID:24705622

  11. Microtubules are potential regulators of growth-plate chondrocyte differentiation and hypertrophy.

    PubMed

    Farquharson, C; Lester, D; Seawright, E; Jefferies, D; Houston, B

    1999-10-01

    Terminal differentiation of growth-plate chondrocytes is accompanied by the acquisition of a spherical morphology and a large increase in cell volume. These changes are likely to be associated with rearrangement of the cytoskeleton, but little information on this aspect of chondrocyte hypertrophy is available. We report a role for microtubules in the control of chondrocyte maturation and hypertrophy. Chick growth-plate chondrocytes were fractionated into five maturationally distinct populations by Percoll density gradient centrifugation, and agarose gel differential display analysis was performed. We identified a 1200 bp cDNA fragment derived from a transcript that was most highly expressed in the hypertrophic chondrocytes. After cloning and sequencing, FASTA and BLAST analysis revealed 100% identity to chick beta7-tubulin. Differential expression was confirmed in a reverse transcription-polymerase chain reaction (RT-PCR) assay using specific primers for a 343 bp fragment from the 3' untranslated region of beta7-tubulin. Beta7-tubulin was upregulated three-fold in fully hypertrophic chondrocytes compared with the other four fractions, which all had similar levels of expression. Immunocytochemical localization of beta-tubulin in chick growth-plate sections demonstrated little staining in the chondrocytes of the proliferating zone, but intense cytoplasmic staining was present in the large hypertrophic chondrocytes. In cell culture studies, the addition of colchicine (10(-6) mol/L) resulted in a higher rate of [3H]-thymidine uptake (36.0%; p < 0.001), but lower amounts of alkaline phosphatase activity (69.1%; p < 0.001), collagen (49.1%; p < 0.01), and glycosaminoglycan (43.3%; p < 0.01) accumulation within the cell-matrix layer. Further evidence for the involvement of microtubules in chondrocyte differentiation and hypertrophy was obtained by morphological assessment of colchicine-treated growth-plate explant cultures. A partial failure of chondrocyte hypertrophy was

  12. Extension of the spectral element method for stability analysis of time-periodic delay-differential equations with multiple and distributed delays

    NASA Astrophysics Data System (ADS)

    Lehotzky, David; Insperger, Tamas; Stepan, Gabor

    2016-06-01

    The spectral element method was introduced by Khasawneh and Mann (2013) for the stability analysis of time-periodic delay-differential equations (DDEs) with multiple delays. In this paper, this method is generalized for time-periodic DDEs with multiple delays and distributed delay. For this general case, an explicit formula is given for the construction of the matrix approximation of the monodromy operator. The derived formula enables the algorithmic application of the method to DDEs with general combinations of delays for arbitrary point sets and test functions. Stability analysis is demonstrated for specific case studies, and the computation code is provided for a complex example.

  13. 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.

  14. 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

  15. Multiple grid method for the calculation of potential flow around three dimensional bodies

    NASA Astrophysics Data System (ADS)

    Wolff, H.

    1982-01-01

    The classical approach of representation of the solution by means of a doublet distribution on the boundary of the domain is considered. From the boundary condition, a Fredholm integral equation for the doublet distribution, mu, is obtained. By a piecewise constant function, mu is approximated. This numerical method results in a nonsparse system that is solved by a multiple grid iterative process. The convergence rate of this process is discussed and its performance is compared with the Jacobi iterative process. For flow around an ellipsoid, the multiple grid process turns out to be much more efficient than the Jacobi iterative process.

  16. 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.; Erö, J.; Fabjan, C.; Friedl, M.; Frühwirth, R.; Ghete, V. M.; Hartl, C.; Hörmann, N.; Hrubec, J.; Jeitler, M.; Kiesenhofer, W.; Knünz, V.; Krammer, M.; Krätschmer, I.; Liko, D.; Mikulec, I.; Rabady, D.; Rahbaran, B.; Rohringer, H.; Schöfbeck, 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.; Léonard, A.; Mohammadi, A.; Perniè, 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.; Aldá Júnior, W. L.; Alves, G. 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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.; Fanò, 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.; Foà, 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. 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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.; Lourenço, 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.; Pimiä, M.; Piparo, D.; Plagge, M.; Racz, A.; Rolandi, G.; Rovere, M.; Sakulin, H.; Schäfer, 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.; Wöhri, 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.; Bäni, L.; Bianchini, L.; Bortignon, P.; Buchmann, M. A.; Casal, B.; Chanon, N.; Deisher, A.; Dissertori, G.; Dittmar, M.; Donegà, M.; Dünser, M.; Eller, P.; Grab, C.; Hits, D.; Lustermann, W.; Mangano, B.; Marini, A. C.; Martinez Ruiz del Arbol, P.; Meister, D.; Mohr, N.; Nägeli, 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.; Gülmez, E.; Isildak, B.; Kaya, M.; Kaya, O.; Bahtiyar, H.; Barlas, E.; Cankocak, K.; Vardarlı, F. I.; Yücel, 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.; Würthwein, 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.; Grünendahl, 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.; Stöckli, 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.; Piroué, 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.; Hervé, 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.

  17. 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

  18. Agent based modeling of the effects of potential treatments over the blood-brain barrier in multiple sclerosis.

    PubMed

    Pennisi, Marzio; Russo, Giulia; Motta, Santo; Pappalardo, Francesco

    2015-12-01

    Multiple sclerosis is a disease of the central nervous system that involves the destruction of the insulating sheath of axons, causing severe disabilities. Since the etiology of the disease is not yet fully understood, the use of novel techniques that may help to understand the disease, to suggest potential therapies and to test the effects of candidate treatments is highly advisable. To this end we developed an agent based model that demonstrated its ability to reproduce the typical oscillatory behavior observed in the most common form of multiple sclerosis, relapsing-remitting multiple sclerosis. The model has then been used to test the potential beneficial effects of vitamin D over the disease. Many scientific studies underlined the importance of the blood-brain barrier and of the mechanisms that influence its permeability on the development of the disease. In the present paper we further extend our previously developed model with a mechanism that mimics the blood-brain barrier behavior. The goal of our work is to suggest the best strategies to follow for developing new potential treatments that intervene in the blood-brain barrier. Results suggest that the best treatments should potentially prevent the opening of the blood-brain barrier, as treatments that help in recovering the blood-brain barrier functionality could be less effective. PMID:26343337

  19. 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.

  20. Potential role of differentially expressed lncRNAs in the pathogenesis of oral squamous cell carcinoma.

    PubMed

    Zhang, Shanchuan; Tian, Lili; Ma, Penghua; Sun, Qiang; Zhang, Kai; GuanchaoWang; Liu, Hongchen; Xu, Baohua

    2015-10-01

    Long non-coding RNAs (lncRNAs) have recently attracted more attention about the role in a broad range of biological processes and complex cancers. We aimed to identify differentially expressed lncRNAs that play an important role in the pathogenesis of oral squamous cell carcinoma (OSCC). Microarray data GSE25099 consisting of 57 samples from patients with OSCC and 22 normal samples were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) and lncRNAs were identified between OSCC samples and control using samr package in R and noncoder software. Co-expression network was constructed for lncRNAs and candidate target DEGs, followed by functional and pathway enrichment analysis using the Database for Annotation, Visualization and Integrated Discovery online tool. OSCC-related genes were screened by Genetic-Association-DB-Database analysis, and then protein-protein interaction (PPI) network construction of OSCC-related and co-expressed genes. Bioinformatic analysis revealed that there were 998 DEGs and 160 differentially expressed lncRNAs between OSCC and normal control. We found LOC100130547, FTH1P3, PDIA3F and GTF2IRD2P1 targeted most of DEGs. Predicted targets-related functional annotation showed significant changes in inflammation-related functions and Toll-like receptor signaling pathway. By further conducting PPI network with lncRNA co-expressed DEGs, we found that OSCC-associated genes including MMP1 (matrix metallopeptidase), MMP3, MMP9, PLAU (plasminogen activator, urokinase) and IL8 (interleukin 8) were targeted by FTH1P3, PDIA3F and GTF2IRD2P1. Our results indicate that lncRNAs FTH1P3, PDIA3F and GTF2IRD2P1 may responsible for progression and metastasis of OSCC via targeting MMP1, MMP3, MMP9, PLAU and IL8 which are key regulators of tumorigenesis. PMID:26276270

  1. Downregulation of H19 improves the differentiation potential of mouse parthenogenetic embryonic stem cells.

    PubMed

    Ragina, Neli P; Schlosser, Karianne; Knott, Jason G; Senagore, Patricia K; Swiatek, Pamela J; Chang, Eun Ah; Fakhouri, Walid D; Schutte, Brian C; Kiupel, Matti; Cibelli, Jose B

    2012-05-01

    Parthenogenetic embryonic stem cells (P-ESCs) offer an alternative source of pluripotent cells, which hold great promise for autologous transplantation and regenerative medicine. P-ESCs have been successfully derived from blastocysts of several mammalian species. However, compared with biparental embryonic stem cells (B-ESCs), P-ESCs are limited in their ability to fully differentiate into all 3 germ layers. For example, it has been observed that there is a differentiation bias toward ectoderm derivatives at the expense of endoderm and mesoderm derivatives-muscle in particular-in chimeric embryos, teratomas, and embryoid bodies. In the present study we found that H19 expression was highly upregulated in P-ESCs with more than 6-fold overexpression compared with B-ESCs. Thus, we hypothesized that manipulation of the H19 gene in P-ESCs would alleviate their limitations and allow them to function like B-ESCs. To test this hypothesis we employed a small hairpin RNA approach to reduce the amount of H19 transcripts in mouse P-ESCs. We found that downregulation of H19 led to an increase of mesoderm-derived muscle and endoderm in P-ESCs teratomas similar to that observed in B-ESCs teratomas. This phenomenon coincided with upregulation of mesoderm-specific genes such as Myf5, Myf6, and MyoD. Moreover, H19 downregulated P-ESCs differentiated into a higher percentage of beating cardiomyocytes compared with control P-ESCs. Collectively, these results suggest that P-ESCs are amenable to molecular modifications that bring them functionally closer to true ESCs. PMID:21793658

  2. Downregulation of H19 Improves the Differentiation Potential of Mouse Parthenogenetic Embryonic Stem Cells

    PubMed Central

    Ragina, Neli P.; Schlosser, Karianne; Knott, Jason G.; Senagore, Patricia K.; Swiatek, Pamela J.; Chang, Eun Ah; Fakhouri, Walid D.; Schutte, Brian C.; Kiupel, Matti

    2012-01-01

    Parthenogenetic embryonic stem cells (P-ESCs) offer an alternative source of pluripotent cells, which hold great promise for autologous transplantation and regenerative medicine. P-ESCs have been successfully derived from blastocysts of several mammalian species. However, compared with biparental embryonic stem cells (B-ESCs), P-ESCs are limited in their ability to fully differentiate into all 3 germ layers. For example, it has been observed that there is a differentiation bias toward ectoderm derivatives at the expense of endoderm and mesoderm derivatives—muscle in particular—in chimeric embryos, teratomas, and embryoid bodies. In the present study we found that H19 expression was highly upregulated in P-ESCs with more than 6-fold overexpression compared with B-ESCs. Thus, we hypothesized that manipulation of the H19 gene in P-ESCs would alleviate their limitations and allow them to function like B-ESCs. To test this hypothesis we employed a small hairpin RNA approach to reduce the amount of H19 transcripts in mouse P-ESCs. We found that downregulation of H19 led to an increase of mesoderm-derived muscle and endoderm in P-ESCs teratomas similar to that observed in B-ESCs teratomas. This phenomenon coincided with upregulation of mesoderm-specific genes such as Myf5, Myf6, and MyoD. Moreover, H19 downregulated P-ESCs differentiated into a higher percentage of beating cardiomyocytes compared with control P-ESCs. Collectively, these results suggest that P-ESCs are amenable to molecular modifications that bring them functionally closer to true ESCs. PMID:21793658

  3. 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

  4. Differential charging of high-voltage spacecraft: The equilibrium potential of insulated surfaces

    NASA Astrophysics Data System (ADS)

    Katz, I.; Mandell, M. J.

    1982-06-01

    A theory is presented for the steady-state potential of insulated surfaces near exposed high voltages. The term 'insulated surfaces' is used to mean either dielectric surfaces of electrically isolated metallic surfaces. The potential is bounded below by the zero of the material's I-V curve assuming total suppression of secondary electrons, and above by assuming total extraction of secondaries. Within these bounds, the material's surface potential is determined consistently with the solution to Poisson's equation external to the vehicle. The theory is compared with rocket experiments and with SCATHA satellite data. Also, an explanation is suggested for the observed 'snapover' of solar cell coverslips from near plasma ground potential to near the potential of positively biased interconnects with increasing bias voltage.

  5. Differential charging of high-voltage spacecraft - The equilibrium potential of insulated surfaces

    NASA Technical Reports Server (NTRS)

    Katz, I.; Mandell, M. J.

    1982-01-01

    A theory is presented for the steady-state potential of insulated surfaces near exposed high voltages. The term 'insulated surfaces' is used to mean either dielectric surfaces or electrically isolated metallic surfaces. The potential is bounded below by the zero of the material's I-V curve assuming total suppression of secondary electrons, and above by assuming total extraction of secondaries. Within these bounds, the material's surface potential is determined consistently with the solution to Poisson's equation external to the vehicle. The theory is compared with rocket experiments and with SCATHA satellite data. Also, an explanation is suggested for the observed 'snapover' of solar cell coverslips from near plasma ground potential to near the potential of positively biased interconnects with increasing bias voltage.

  6. 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.

  7. 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...

  8. 5-azacytidine improves the osteogenic differentiation potential of aged human adipose-derived mesenchymal stem cells by DNA demethylation.

    PubMed

    Yan, Xueying; Ehnert, Sabrina; Culmes, Mihaela; Bachmann, Anastasia; Seeliger, Claudine; Schyschka, Lilianna; Wang, Zhiyong; Rahmanian-Schwarz, Afshin; Stöckle, Ulrich; De Sousa, Paul A; Pelisek, Jaroslav; Nussler, Andreas K

    2014-01-01

    The therapeutic value of adipose-derived mesenchymal stem cells (Ad-MSCs) for bone regeneration is critically discussed. A possible reason for reduced osteogenic potential may be an age-related deterioration of the Ad-MSCs. In long term in vitro culture, epigenomic changes in DNA methylation are known to cause gene silencing, affecting stem cell growth as well as the differentiation potential. In this study, we observed an age-related decline in proliferation of primary human Ad-MSCs. Decreased Nanog, Oct4 and Lin28A and increased Sox2 gene-expression was accompanied by an impaired osteogenic differentiation potential of Ad-MSCs isolated from old donors (>60 a) as compared to Ad-MSCs isolated from younger donors (<45 a). 5-hydroxymethylcytosine (5 hmC) and 5-methylcytonsine (5 mC) distribution as well as TET gene expression were evaluated to assess the evidence of active DNA demethylation. We observed a decrease of 5 hmC in Ad-MSCs from older donors. Incubation of these cells with 5-Azacytidine induced proliferation and improved the osteogenic differentiation potential in these cells. The increase in AP activity and matrix mineralization was associated with an increased presence of 5 hmC as well as with an increased TET2 and TET3 gene expression. Our data show, for the first time, a decrease of DNA hydroxymethylation in Ad-MSCs which correlates with donor-age and that treatment with 5-Azacytidine provides an approach which could be used to rejuvenate Ad-MSCs from aged donors. PMID:24603866

  9. 5-Azacytidine Improves the Osteogenic Differentiation Potential of Aged Human Adipose-Derived Mesenchymal Stem Cells by DNA Demethylation

    PubMed Central

    Culmes, Mihaela; Bachmann, Anastasia; Seeliger, Claudine; Schyschka, Lilianna; Wang, Zhiyong; Rahmanian-Schwarz, Afshin; Stöckle, Ulrich; De Sousa, Paul A.; Pelisek, Jaroslav; Nussler, Andreas K.

    2014-01-01

    The therapeutic value of adipose-derived mesenchymal stem cells (Ad-MSCs) for bone regeneration is critically discussed. A possible reason for reduced osteogenic potential may be an age-related deterioration of the Ad-MSCs. In long term in vitro culture, epigenomic changes in DNA methylation are known to cause gene silencing, affecting stem cell growth as well as the differentiation potential. In this study, we observed an age-related decline in proliferation of primary human Ad-MSCs. Decreased Nanog, Oct4 and Lin28A and increased Sox2 gene-expression was accompanied by an impaired osteogenic differentiation potential of Ad-MSCs isolated from old donors (>60 a) as compared to Ad-MSCs isolated from younger donors (<45 a). 5-hydroxymethylcytosine (5 hmC) and 5-methylcytonsine (5 mC) distribution as well as TET gene expression were evaluated to assess the evidence of active DNA demethylation. We observed a decrease of 5 hmC in Ad-MSCs from older donors. Incubation of these cells with 5-Azacytidine induced proliferation and improved the osteogenic differentiation potential in these cells. The increase in AP activity and matrix mineralization was associated with an increased presence of 5 hmC as well as with an increased TET2 and TET3 gene expression. Our data show, for the first time, a decrease of DNA hydroxymethylation in Ad-MSCs which correlates with donor-age and that treatment with 5-Azacytidine provides an approach which could be used to rejuvenate Ad-MSCs from aged donors. PMID:24603866

  10. Myogenic differentiation potential of human tonsil-derived mesenchymal stem cells and their potential for use to promote skeletal muscle regeneration

    PubMed Central

    PARK, SAEYOUNG; CHOI, YOONYOUNG; JUNG, NAMHEE; YU, YEONSIL; RYU, KYUNG-HA; KIM, HAN SU; JO, INHO; CHOI, BYUNG-OK; JUNG, SUNG-CHUL

    2016-01-01

    Stem cells are regarded as an important source of cells which may be used to promote the regeneration of skeletal muscle (SKM) which has been damaged due to defects in the organization of muscle tissue caused by congenital diseases, trauma or tumor removal. In particular, mesenchymal stem cells (MSCs), which require less invasive harvesting techniques, represent a valuable source of cells for stem cell therapy. In the present study, we demonstrated that human tonsil-derived MSCs (T-MSCs) may differentiate into myogenic cells in vitro and that the transplantation of myoblasts and myocytes generated from human T-MSCs mediates the recovery of muscle function in vivo. In order to induce myogenic differentiation, the T-MSC-derived spheres were cultured in Dulbecco's modified Eagle's medium/nutrient mixture F-12 (DMEM/F-12) supplemented with 1 ng/ml transforming growth factor-β, non-essential amino acids and insulin-transferrin-selenium for 4 days followed by culture in myogenic induction medium [low-glucose DMEM containing 2% fetal bovine serum (FBS) and 10 ng/ml insulin-like growth factor 1 (IGF1)] for 14 days. The T-MSCs sequentially differentiated into myoblasts and skeletal myocytes, as evidenced by the increased expression of skeletal myogenesis-related markers [including α-actinin, troponin I type 1 (TNNI1) and myogenin] and the formation of myotubes in vitro. The in situ transplantation of T-MSCs into mice with a partial myectomy of the right gastrocnemius muscle enhanced muscle function, as demonstrated by gait assessment (footprint analysis), and restored the shape of SKM without forming teratomas. Thus, T-MSCs may differentiate into myogenic cells and effectively regenerate SKM following injury. These results demonstrate the therapeutic potential of T-MSCs to promote SKM regeneration following injury. PMID:27035161

  11. Myogenic differentiation potential of human tonsil-derived mesenchymal stem cells and their potential for use to promote skeletal muscle regeneration.

    PubMed

    Park, Saeyoung; Choi, Yoonyoung; Jung, Namhee; Yu, Yeonsil; Ryu, Kyung-Ha; Kim, Han Su; Jo, Inho; Choi, Byung-Ok; Jung, Sung-Chul

    2016-05-01

    Stem cells are regarded as an important source of cells which may be used to promote the regeneration of skeletal muscle (SKM) which has been damaged due to defects in the organization of muscle tissue caused by congenital diseases, trauma or tumor removal. In particular, mesenchymal stem cells (MSCs), which require less invasive harvesting techniques, represent a valuable source of cells for stem cell therapy. In the present study, we demonstrated that human tonsil-derived MSCs (T-MSCs) may differentiate into myogenic cells in vitro and that the transplantation of myoblasts and myocytes generated from human T-MSCs mediates the recovery of muscle function in vivo. In order to induce myogenic differentiation, the T-MSC-derived spheres were cultured in Dulbecco's modified Eagle's medium/nutrient mixture F-12 (DMEM/F‑12) supplemented with 1 ng/ml transforming growth factor-β, non-essential amino acids and insulin‑transferrin-selenium for 4 days followed by culture in myogenic induction medium [low-glucose DMEM containing 2% fetal bovine serum (FBS) and 10 ng/ml insulin‑like growth factor 1 (IGF1)] for 14 days. The T-MSCs sequentially differentiated into myoblasts and skeletal myocytes, as evidenced by the increased expression of skeletal myogenesis-related markers [including α-actinin, troponin I type 1 (TNNI1) and myogenin] and the formation of myotubes in vitro. The in situ transplantation of T-MSCs into mice with a partial myectomy of the right gastrocnemius muscle enhanced muscle function, as demonstrated by gait assessment (footprint analysis), and restored the shape of SKM without forming teratomas. Thus, T-MSCs may differentiate into myogenic cells and effectively regenerate SKM following injury. These results demonstrate the therapeutic potential of T-MSCs to promote SKM regeneration following injury. PMID:27035161

  12. Differentiation of porcine mesenchymal stem cells into epithelial cells as a potential therapeutic application to facilitate epithelial regeneration.

    PubMed

    Kokubun, Kelsey; Pankajakshan, Divya; Kim, Min-Jung; Agrawal, Devendra K

    2016-02-01

    Epithelial denudation is one of the characteristics of chronic asthma. To restore its functions, the airway epithelium has to rapidly repair the injuries and regenerate its structure and integrity. Mesenchymal stem cells (MSCs) have the ability to differentiate into many cell lineages. However, the differentiation of MSCs into epithelial cells has not been fully studied. Here, we examined the differentiation of MSCs into epithelial cells using three different media compositions with various growth supplementations. The MSCs were isolated from porcine bone marrow by density gradient centrifugation. The isolated MSCs were CD11(-) CD34(-) CD45(-) CD44(+) CD90(+) and CD105(+) by immunostaining and flow cytometry. MSCs were stimulated with EpiGRO (Millipore), BEpiCM (ScienCell) and AECGM (PromoCell) media for 5 and 10 days, and epithelial differentiation was assessed by qPCR (keratin 14, 18 and EpCAM), fluorometry (cytokeratin 7-8, cytokeratin 14-15-16-19 and EpCAM), western blot analysis (pancytokeratin, EpCAM) and flow cytometry (cytokeratin 7-8, cytokeratin 14-15-16-19 and EpCAM). The functional marker MUC1 was also assessed after 10 days of air-liquid interface (ALI) culture in optimized media. Cells cultured in BEpiCM containing fibroblast growth factor and prostaglandin E2 showed the highest expression of the epithelial markers: CK7-8 (85.90%); CK-14-15-16-19 (10.14%); and EpCAM (64.61%). The cells also expressed functional marker MUC1 after ALI culture. The differentiated MSCs when cultured in BEpiCM medium ex vivo in a bioreactor on a decellularized trachea for 10 days retained the epithelial-like phenotype. In conclusion, porcine bone marrow-derived MSCs demonstrate commitment to the epithelial lineage and might be a potential therapy for facilitating the repair of denuded airway epithelium. PMID:23696537

  13. Potential role of herbal remedies in stem cell therapy: proliferation and differentiation of human mesenchymal stromal cells.

    PubMed

    Udalamaththa, Vindya Lankika; Jayasinghe, Chanika Dilumi; Udagama, Preethi Vidya

    2016-01-01

    Stem cell therapy has revolutionized modern clinical therapy with the potential of stem cells to differentiate into many different cell types which may help to replace different cell lines of an organism. Innumerous trials are carried out to merge new scientific knowledge and techniques with traditional herbal extracts that may result in less toxic, affordable, and highly available natural alternative therapeutics. Currently, mesenchyamal stromal cell (MSC) lines are treated with individual and mixtures of crude herbal extracts, as well as with purified compounds from herbal extracts, to investigate the mechanisms and effects of these on stem cell growth and differentiation. Human MSCs (hMSCs) possess multilineage, i.e., osteogenic, neurogenic, adipogenic, chondrogenic, and myogenic, differentiation abilities. The proliferative and differentiation properties of hMSCs treated with herbal extracts have shown promise in diseases such as osteoporosis, neurodegenerative disorders, and other tissue degenerative disorders. Well characterized herbal extracts that result in increased rates of tissue regeneration may be used in both stem cell therapy and tissue engineering for replacement therapy, where the use of scaffolds and vesicles with enhanced attaching and proliferative properties could be highly advantageous in the latter. Although the clinical application of herbal extracts is still in progress due to the variability and complexity of bioactive constituents, standardized herbal preparations will strengthen their application in the clinical context. We have critically reviewed the proliferative and differentiation effects of individual herbal extracts on hMSCs mainly derived from bone marrow and elaborated on the plausible underlying mechanisms of action. To be fruitfully used in reparative and regenerative therapy, future directions in this area of study should (i) make use of hMSCs derived from different non-traditional sources, including medical waste material

  14. 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

  15. X-ray induced alterations in the differentiation and mineralization potential of murine preosteoblastic cells

    NASA Astrophysics Data System (ADS)

    Hu, Yueyuan; Lau, Patrick; Baumstark-Khan, Christa; Hellweg, Christine E.; Reitz, Günther

    2012-05-01

    To evaluate the effects of ionizing radiation (IR) on murine preosteoblastic cell differentiation, we directed OCT-1 cells to the osteoblastic lineage by treatment with a combination of β-glycerophosphate (β-GP), ascorbic acid (AA), and dexamethasone (Dex). In vitro mineralization was evaluated based on histochemical staining and quantification of the hydroxyapatite content of the extracellular bone matrix. Expression of mRNA encoding Runx2, transforming growth factor β1 (TGF-β1), osteocalcin (OCN), and p21CDKN1A was analyzed. Exposure to IR reduced the growth rate and diminished cell survival of OCT-1 cells under standard conditions. Notably, calcium content analysis revealed that deposition of mineralized matrix increased significantly under osteogenic conditions after X-ray exposure in a time-dependent manner. In this study, higher radiation doses exert significant overall effects on TGF-β1, OCN, and p21CDKN1A gene expression, suggesting that gene expression following X-ray treatment is affected in a dose-dependent manner. Additionally, we verified that Runx2 was suppressed within 24 h after irradiation at 2 and 4 Gy. Although further studies are required to verify the molecular mechanism, our observations strongly suggest that treatment with IR markedly alters the differentiation and mineralization process of preosteoblastic cells.

  16. New potential markers of in vitro tomato morphogenesis identified by mRNA differential display.

    PubMed

    Torelli, A; Soragni, E; Bolchi, A; Petrucco, S; Ottonello, S; Branca, C

    1996-12-01

    The identification of plant genes involved in early phases of in vitro morphogenesis can not only contribute to our understanding of the processes underlying growth regulator-controlled determination, but also provide novel markers for evaluating the outcome of in vitro regeneration experiments. To search for such genes and to monitor changes in gene expression accompanying in vitro regeneration, we have adapted the mRNA differential display technique to the comparative analysis of a model system of tomato cotyledons that can be driven selectively toward either shoot or callus formation by means of previously determined growth regulator supplementations. Hormone-independent transcriptional modulation (mainly down-regulation) has been found to be the most common event, indicating that a non-specific reprogramming of gene expression quantitatively predominates during the early phases of in vitro culture. However, cDNA fragments representative of genes that are either down-regulated or induced in a programme-specific manner could also be identified, and two of them (G35, G36) were further characterized. One of these cDNA fragments, G35, corresponds to an mRNA that is down-regulated much earlier in callus- (day 2) than in shoot-determined explants (day 6). The other, G36, identifies an mRNA that is transiently expressed in shoot-determined explants only, well before any macroscopic signs of differentiation become apparent, and thus exhibits typical features of a morphogenetic marker. PMID:8980540

  17. Exendin-4 induces cell adhesion and differentiation and counteracts the invasive potential of human neuroblastoma cells.

    PubMed

    Luciani, Paola; Deledda, Cristiana; Benvenuti, Susanna; Squecco, Roberta; Cellai, Ilaria; Fibbi, Benedetta; Marone, Ilaria Maddalena; Giuliani, Corinna; Modi, Giulia; Francini, Fabio; Vannelli, Gabriella Barbara; Peri, Alessandro

    2013-01-01

    Exendin-4 is a molecule currently used, in its synthetic form exenatide, for the treatment of type 2 diabetes mellitus. Exendin-4 binds and activates the Glucagon-Like Peptide-1 Receptor (GLP-1R), thus inducing insulin release. More recently, additional biological properties have been associated to molecules that belong to the GLP-1 family. For instance, Peptide YY and Vasoactive Intestinal Peptide have been found to affect cell adhesion and migration and our previous data have shown a considerable actin cytoskeleton rearrangement after exendin-4 treatment. However, no data are currently available on the effects of exendin-4 on tumor cell motility. The aim of this study was to investigate the effects of this molecule on cell adhesion, differentiation and migration in two neuroblastoma cell lines, SH-SY5Y and SK-N-AS. We first demonstrated, by Extra Cellular Matrix cell adhesion arrays, that exendin-4 increased cell adhesion, in particular on a vitronectin substrate. Subsequently, we found that this molecule induced a more differentiated phenotype, as assessed by i) the evaluation of neurite-like protrusions in 3D cell cultures, ii) the analysis of the expression of neuronal markers and iii) electrophysiological studies. Furthermore, we demonstrated that exendin-4 reduced cell migration and counteracted anchorage-independent growth in neuroblastoma cells. Overall, these data indicate for the first time that exendin-4 may have anti-tumoral properties. PMID:23990978

  18. The potential role of elastography in differentiating between endometrial polyps and submucosal fibroids: a preliminary study

    PubMed Central

    2015-01-01

    Endometrial polyps and submucosal fibroids are common causes of abnormal uterine bleeding (AUB) and less commonly infertility. The prevalence of such intrauterine lesions increases with age during the reproductive years, and usually decreases after menopause. The first-line imaging examination in the diagnosis of endometrial polyps as well as submucosal fibroidsis ultrasound, but its accuracy is not obvious. Elastography is an ultrasound-based imaging modality that is used to assess the stiffness of examined tissues. Considering the fact that endometrial polyps derive from soft endometrial tissue and submucosal fibroids are made of hard muscle tissue, elastography seems a perfect tool to differentiate between such lesions. I present two groups of patients with AUB and intrauterine lesions suspected on ultrasound. In the first group of patients, elastography showed that the stiffness of the lesion was similar to the endometrium and softer than the myometrium. During hysteroscopies endometrial polyps were removed. In the second group of patients, elastography showed that the stiffness of the lesion was similar to the myometrium and harder than the endometrium. During hysteroscopies submucosal fibroids were removed. In both groups, the diagnosis was confirmed by the pathological examination in all cases. It was demonstrated that with the use of elastography it is possible to assess the stiffness of intrauterine lesions, which may be useful in differentiating between endometrial polyps and submucosal fibroids. PMID:26327901

  19. The potential role of elastography in differentiating between endometrial polyps and submucosal fibroids: a preliminary study.

    PubMed

    Woźniak, Sławomir

    2015-06-01

    Endometrial polyps and submucosal fibroids are common causes of abnormal uterine bleeding (AUB) and less commonly infertility. The prevalence of such intrauterine lesions increases with age during the reproductive years, and usually decreases after menopause. The first-line imaging examination in the diagnosis of endometrial polyps as well as submucosal fibroidsis ultrasound, but its accuracy is not obvious. Elastography is an ultrasound-based imaging modality that is used to assess the stiffness of examined tissues. Considering the fact that endometrial polyps derive from soft endometrial tissue and submucosal fibroids are made of hard muscle tissue, elastography seems a perfect tool to differentiate between such lesions. I present two groups of patients with AUB and intrauterine lesions suspected on ultrasound. In the first group of patients, elastography showed that the stiffness of the lesion was similar to the endometrium and softer than the myometrium. During hysteroscopies endometrial polyps were removed. In the second group of patients, elastography showed that the stiffness of the lesion was similar to the myometrium and harder than the endometrium. During hysteroscopies submucosal fibroids were removed. In both groups, the diagnosis was confirmed by the pathological examination in all cases. It was demonstrated that with the use of elastography it is possible to assess the stiffness of intrauterine lesions, which may be useful in differentiating between endometrial polyps and submucosal fibroids. PMID:26327901

  20. Effect of isolation methodology on stem cell properties and multilineage differentiation potential of human dental pulp stem cells.

    PubMed

    Hilkens, P; Gervois, P; Fanton, Y; Vanormelingen, J; Martens, W; Struys, T; Politis, C; Lambrichts, I; Bronckaers, A

    2013-07-01

    Dental pulp stem cells (DPSCs) are an attractive alternative mesenchymal stem cell (MSC) source because of their isolation simplicity compared with the more invasive methods associated with harvesting other MSC sources. However, the isolation method to be favored for obtaining DPSC cultures remains under discussion. This study compares the stem cell properties and multilineage differentiation potential of DPSCs obtained by the two most widely adapted isolation procedures. DPSCs were isolated either by enzymatic digestion of the pulp tissue (DPSC-EZ) or by the explant method (DPSC-OG), while keeping the culture media constant throughout all experiments and in both isolation methods. Assessment of the stem cell properties of DPSC-EZ and DPSC-OG showed no significant differences between the two groups with regard to proliferation rate and colony formation. Phenotype analysis indicated that DPSC-EZ and DPSC-OG were positive for CD29, CD44, CD90, CD105, CD117 and CD146 expression without any significant differences. The multilineage differentiation potential of both stem cell types was confirmed by using standard immuno(histo/cyto)chemical staining together with an in-depth ultrastructural analysis by means of transmission electron microscopy. Our results indicate that both DPSC-EZ and DPSC-OG could be successfully differentiated into adipogenic, chrondrogenic and osteogenic cell types, although the adipogenic differentiation of both stem cell populations was incomplete. The data suggest that both the enzymatic digestion and outgrowth method can be applied to obtain a suitable autologous DPSC resource for tissue replacement therapies of both bone and cartilage. PMID:23715720

  1. 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

    than that of hMSCs (P < 0.05). There was, however, no difference in the adipogenic (Pparγ) 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

  2. 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

  3. 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

  4. Discovery and initial verification of differentially abundant proteins between multiple sclerosis patients and controls using iTRAQ and SID-SRM.

    PubMed

    Kroksveen, Ann C; Aasebø, Elise; Vethe, Heidrun; Van Pesch, Vincent; Franciotta, Diego; Teunissen, Charlotte E; Ulvik, Rune J; Vedeler, Christian; Myhr, Kjell-Morten; Barsnes, Harald; Berven, Frode S

    2013-01-14

    In the present study, we aimed to discover cerebrospinal fluid (CSF) proteins with significant abundance difference between early multiple sclerosis patients and controls, and do an initial verification of these proteins using selected reaction monitoring (SRM). iTRAQ and Orbitrap MS were used to compare the CSF proteome of patients with clinically isolated syndrome (CIS) (n=5), patients with relapsing-remitting multiple sclerosis that had CIS at the time of lumbar puncture (n=5), and controls with other inflammatory neurological disease (n=5). Of more than 1200 identified proteins, five proteins were identified with significant abundance difference between the patients and controls. In the initial verification using SRM we analyzed a larger patient and control cohort (n=132) and also included proteins reported as differentially abundant in multiple sclerosis in the literature. We found significant abundance difference for 11 proteins after verification, of which the five proteins alpha-1-antichymotrypsin, contactin-1, apolipoprotein D, clusterin, and kallikrein-6 were significantly differentially abundant in several of the group comparisons. This initial study form the basis for further biomarker verification studies in even larger sample cohorts, to determine if these proteins have relevance as diagnostic or prognostic biomarkers for multiple sclerosis. PMID:23059536

  5. 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

  6. The myocardial regenerative potential of three-dimensional engineered cardiac tissues composed of multiple human iPS cell-derived cardiovascular cell lineages.

    PubMed

    Masumoto, Hidetoshi; Nakane, Takeichiro; Tinney, Joseph P; Yuan, Fangping; Ye, Fei; Kowalski, William J; Minakata, Kenji; Sakata, Ryuzo; Yamashita, Jun K; Keller, Bradley B

    2016-01-01

    Human induced pluripotent stem cells (hiPSCs) are a robust source for cardiac regenerative therapy due to their potential to support autologous and allogeneic transplant paradigms. The in vitro generation of three-dimensional myocardial tissue constructs using biomaterials as an implantable hiPSC-derived myocardium provides a path to realize sustainable myocardial regeneration. We generated engineered cardiac tissues (ECTs) from three cellular compositions of cardiomyocytes (CMs), endothelial cells (ECs), and vascular mural cells (MCs) differentiated from hiPSCs. We then determined the impact of cell composition on ECT structural and functional properties. In vitro force measurement showed that CM+EC+MC ECTs possessed preferential electromechanical properties versus ECTs without vascular cells indicating that incorporation of vascular cells augmented tissue maturation and function. The inclusion of MCs facilitated more mature CM sarcomeric structure, preferential alignment, and activated multiple tissue maturation pathways. The CM+EC+MC ECTs implanted onto infarcted, immune tolerant rat hearts engrafted, displayed both host and graft-derived vasculature, and ameliorated myocardial dysfunction. Thus, a composition of CMs and multiple vascular lineages derived from hiPSCs and incorporated into ECTs promotes functional maturation and demonstrates myocardial replacement and perfusion relevant for clinical translation. PMID:27435115

  7. The myocardial regenerative potential of three-dimensional engineered cardiac tissues composed of multiple human iPS cell-derived cardiovascular cell lineages

    PubMed Central

    Masumoto, Hidetoshi; Nakane, Takeichiro; Tinney, Joseph P.; Yuan, Fangping; Ye, Fei; Kowalski, William J.; Minakata, Kenji; Sakata, Ryuzo; Yamashita, Jun K.; Keller, Bradley B.

    2016-01-01

    Human induced pluripotent stem cells (hiPSCs) are a robust source for cardiac regenerative therapy due to their potential to support autologous and allogeneic transplant paradigms. The in vitro generation of three-dimensional myocardial tissue constructs using biomaterials as an implantable hiPSC-derived myocardium provides a path to realize sustainable myocardial regeneration. We generated engineered cardiac tissues (ECTs) from three cellular compositions of cardiomyocytes (CMs), endothelial cells (ECs), and vascular mural cells (MCs) differentiated from hiPSCs. We then determined the impact of cell composition on ECT structural and functional properties. In vitro force measurement showed that CM+EC+MC ECTs possessed preferential electromechanical properties versus ECTs without vascular cells indicating that incorporation of vascular cells augmented tissue maturation and function. The inclusion of MCs facilitated more mature CM sarcomeric structure, preferential alignment, and activated multiple tissue maturation pathways. The CM+EC+MC ECTs implanted onto infarcted, immune tolerant rat hearts engrafted, displayed both host and graft-derived vasculature, and ameliorated myocardial dysfunction. Thus, a composition of CMs and multiple vascular lineages derived from hiPSCs and incorporated into ECTs promotes functional maturation and demonstrates myocardial replacement and perfusion relevant for clinical translation. PMID:27435115

  8. Expression profiling shows differential molecular pathways and provides potential new diagnostic biomarkers for colorectal serrated adenocarcinoma.

    PubMed

    Conesa-Zamora, Pablo; García-Solano, José; García-García, Francisco; Turpin, María Del Carmen; Trujillo-Santos, Javier; Torres-Moreno, Daniel; Oviedo-Ramírez, Isabel; Carbonell-Muñoz, Rosa; Muñoz-Delgado, Encarnación; Rodriguez-Braun, Edith; Conesa, Ana; Pérez-Guillermo, Miguel

    2013-01-15

    Serrated adenocarcinoma (SAC) is a recently recognized colorectal cancer (CRC) subtype accounting for 7.5 to 8.7% of CRCs. It has been shown that SAC has a poorer prognosis and has different molecular and immunohistochemical features compared with conventional carcinoma (CC) but, to date, only one previous study has analyzed its mRNA expression profile by microarray. Using a different microarray platform, we have studied the molecular signature of 11 SACs and compared it with that of 15 matched CC with the aim of discerning the functions which characterize SAC biology and validating, at the mRNA and protein level, the most differentially expressed genes which were also tested using a validation set of 70 SACs and 70 CCs to assess their diagnostic and prognostic values. Microarray data showed a higher representation of morphogenesis-, hypoxia-, cytoskeleton- and vesicle transport-related functions and also an overexpression of fascin1 (actin-bundling protein associated with invasion) and the antiapoptotic gene hippocalcin in SAC all of which were validated both by quantitative real-time PCR (qPCR) and immunohistochemistry. Fascin1 expression was statistically associated with KRAS mutation with 88.6% sensitivity and 85.7% specificity for SAC diagnosis and the positivity of fascin1 or hippocalcin was highly suggestive of SAC diagnosis (sensitivity = 100%). Evaluation of these markers in CRCs showing histological and molecular characteristics of high-level microsatellite instability (MSI-H) also helped to distinguish SACs from MSI-H CRCs. Molecular profiling demonstrates that SAC shows activation of distinct signaling pathways and that immunohistochemical fascin1 and hippocalcin expression can be reliably used for its differentiation from other CRC subtypes. PMID:22696308

  9. 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.

  10. 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

  11. Multiple sclerosis: microRNA expression profiles accurately differentiate patients with relapsing-remitting disease from healthy controls.

    PubMed

    Keller, Andreas; Leidinger, Petra; 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

  12. 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

  13. 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.

  14. Evaluation of osteoinductive and endothelial differentiation potential of Platelet-Rich Plasma incorporated Gelatin-Nanohydroxyapatite Fibrous Matrix.

    PubMed

    J, Anjana; Kuttappan, Shruthy; Keyan, Kripa S; Nair, Manitha B

    2016-05-01

    In this study, platelet-rich plasma (PRP) was incorporated into gelatin-nanohydroxyapatite fibrous scaffold in two forms (PRP gel as coating on the scaffold [PCSC] and PRP powder within the scaffold [PCSL] and investigated for (a) growth factor release; (b) stability of scaffold at different temperature; (c) stability of scaffold before and after ETO sterilization; and (d) osteogenic and endothelial differentiation potential using mesenchymal stem cells (MSCs). PCSC demonstrated a high and burst growth factor release initially followed by a gradual reduction in its concentration, while PCSL showed a steady state release pattern for 30 days. The stability of growth factors released from PCSL was not altered either through ETO sterilization or through its storage at different temperature. PRP-loaded scaffolds induced the differentiation of MSCs into osteogenic and endothelial lineage without providing any induction factors in the cell culture medium and the differentiation rate was significantly higher when compared to the scaffolds devoid of PRP. PCSC performed better than PCSL. In general, PRP in combination with composite fibrous scaffold could be a promising candidate for bone tissue engineering applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 771-781, 2016. PMID:26821772

  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. Negative differential conductivity in quantum well with complex potential profile for electron-phonon scattering

    NASA Astrophysics Data System (ADS)

    Figarova, S. R.; Hasiyeva, G. N.; Figarov, V. R.

    2016-04-01

    The effect of phonon scattering on electrical conductivity (EC) of 2D electron gas in quantum well (QW) systems with a complicated potential profile is described. Dependence of QW electrical conductivity on QW parameters (such as QW width, Fermi level positions etc.) when phonon scattering is employed has been calculated. NDC in EC when it varies with width of the QW has been found.

  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. 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.

  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. Human Adipose Stem Cells Differentiated on Braided Polylactide Scaffolds Is a Potential Approach for Tendon Tissue Engineering.

    PubMed

    Vuornos, Kaisa; Björninen, Miina; Talvitie, Elina; Paakinaho, Kaarlo; Kellomäki, Minna; Huhtala, Heini; Miettinen, Susanna; Seppänen-Kaijansinkko, Riitta; Haimi, Suvi

    2016-03-01

    Growing number of musculoskeletal defects increases the demand for engineered tendon. Our aim was to find an efficient strategy to produce tendon-like matrix in vitro. To allow efficient differentiation of human adipose stem cells (hASCs) toward tendon tissue, we tested different medium compositions, biomaterials, and scaffold structures in preliminary tests. This is the first study to report that medium supplementation with 50 ng/mL of growth and differentiation factor-5 (GDF-5) and 280 μM l-ascorbic acid are essential for tenogenic differentiation of hASCs. Tenogenic medium (TM) was shown to significantly enhance tendon-like matrix production of hASCs compared to other tested media groups. Cell adhesion, proliferation, and tenogenic differentiation of hASCs were supported on braided poly(l/d)lactide (PLA) 96l/4d copolymer filament scaffolds in TM condition compared to foamed poly(l-lactide-co-ɛ-caprolactone) (PLCL) 70L/30CL scaffolds. A uniform cell layer formed on braided PLA 96/4 scaffolds when hASCs were cultured in TM compared to maintenance medium (MM) condition after 14 days of culture. Furthermore, total collagen content and gene expression of tenogenic marker genes were significantly higher in TM condition after 2 weeks of culture. The elastic modulus of PLA 96/4 scaffold was more similar to the elastic modulus reported for native Achilles tendon. Our study showed that the optimized TM is needed for efficient and rapid in vitro tenogenic extracellular matrix production of hASCs. PLA 96/4 scaffolds together with TM significantly stimulated hASCs, thus demonstrating the potential clinical relevance of this novel and emerging approach to tendon injury treatments in the future. PMID:26919401

  1. The Potential of Menstrual Blood-Derived Stem Cells in Differentiation to Epidermal Lineage: A Preliminary Report

    PubMed Central

    Faramarzi, Hossein; Mehrabani, Davood; Fard, Maryam; Akhavan, Maryam; Zare, Sona; Bakhshalizadeh, Shabnam; Manafi, Amir; Kazemnejad, Somaieh; Shirazi, Reza

    2016-01-01

    BACKGROUND Menstrual blood-derived stem cells (MenSCs) are a novel source of stem cells that can be easily isolated non-invasively from female volunteered donor without ethical consideration. These mesenchymal-like stem cells have high rate of proliferation and possess multi lineage differentiation potency. This study was undertaken to isolate the MenSCs and assess their potential in differentiation into epidermal lineage. METHODS About 5-10 ml of menstrual blood (MB) was collected using sterile Diva cups inserted into vagina during menstruation from volunteered healthy fertile women aged between 22-30 years. MB was transferred into Falcon tubes containing phosphate buffered saline (PBS) without Ca2+ or Mg2+ supplemented with 2.5 µg/ml fungizone, 100 µg/mL streptomycin, 100 U/mL penicillin and 0.5 mM EDTA. Mononuclear cells were separated using Ficoll-Hypaque density gradient centrifugation and washed out in PBS. The cell pellet was suspended in DMEM-F12 medium supplemented with 10% FBS and cultured in tissue culture plates. The isolated cells were co-cultured with keratinocytes derived from the foreskin of healthy newborn male aged 2-10 months who was a candidate for circumcision for differentiation into epidermal lineage. RESULTS The isolated MenSCs were adhered to the plate and exhibited spindle-shaped morphology. Flow cytometric analysis revealed the expression of mesenchymal markers of CD10, CD29, CD73, and CD105 and lack of hematopoietic stem cells markers. An early success in derivation of epidermal lineage from MenSCs was visible. CONCLUSION The MenSCs are a real source to design differentiation to epidermal cells that can be used non-invasively in various dermatological lesions and diseases. PMID:27308237

  2. Transthyretin as a potential biomarker for the differential diagnosis between lung cancer and lung infection

    PubMed Central

    DING, HONGMEI; LIU, JIANHUA; XUE, RONG; ZHAO, PENG; QIN, YI; ZHENG, FANG; SUN, XUGUO

    2014-01-01

    Satisfactory biomarkers for screening and early diagnosis of lung cancer remain scarce and require further investigation. The aim of the present study was to examine the changes of the biochemical and protein composition in the serum and pleural effusion from lung cancer and lung infection (bacterial pneumonia) patients. A total of 92 patients with lung cancer, 38 with bacterial pneumonia and 42 healthy controls were enrolled in the study. The serum levels of cholesterol, apolipoprotein A and transthyretin (TTR) in the lung cancer patients were higher than that of the lung infection patients (P<0.05). The levels of TTR were higher, whereas the activity of adenosine deaminase (ADA) was lower in the pleural effusion from the lung cancer patients compared to the lung infection patients (P<0.05). Furthermore, the pleural effusion/serum TTR ratios in the lung cancer patients were higher, whereas the ratios of ADA were lower (P<0.05). By matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis, four major peaks corresponding to native TTR, Sul-TTR, Cys-TTR and Cysgly-TTR were observed in the serum of the lung cancer and lung infection patients. A significant increase was found in the proportion of Cysgly-TTR in the pleural effusion from the patients with lung cancer. The data indicated that a combination of pleural effusion/serum TTR ratios and modified TTR may be beneficial for the differential diagnosis between lung cancer and lung infection. PMID:25054025

  3. 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

  4. A Sox2 distal enhancer cluster regulates embryonic stem cell differentiation potential.

    PubMed

    Zhou, Harry Y; Katsman, Yulia; Dhaliwal, Navroop K; Davidson, Scott; Macpherson, Neil N; Sakthidevi, Moorthy; Collura, Felicia; Mitchell, Jennifer A

    2014-12-15

    The Sox2 transcription factor must be robustly transcribed in embryonic stem (ES) cells to maintain pluripotency. Two gene-proximal enhancers, Sox2 regulatory region 1 (SRR1) and SRR2, display activity in reporter assays, but deleting SRR1 has no effect on pluripotency. We identified and functionally validated the sequences required for Sox2 transcription based on a computational model that predicted transcriptional enhancer elements within 130 kb of Sox2. Our reporter assays revealed three novel enhancers--SRR18, SRR107, and SRR111--that, through the formation of chromatin loops, form a chromatin complex with the Sox2 promoter in ES cells. Using the CRISPR/Cas9 system and F1 ES cells (Mus musculus(129) × Mus castaneus), we generated heterozygous deletions of each enhancer region, revealing that only the distal cluster containing SRR107 and SRR111, located >100 kb downstream from Sox2, is required for cis-regulation of Sox2 in ES cells. Furthermore, homozygous deletion of this distal Sox2 control region (SCR) caused significant reduction in Sox2 mRNA and protein levels, loss of ES cell colony morphology, genome-wide changes in gene expression, and impaired neuroectodermal formation upon spontaneous differentiation to embryoid bodies. Together, these data identify a distal control region essential for Sox2 transcription in ES cells. PMID:25512558

  5. Noggin inactivation affects the number and differentiation potential of muscle progenitor cells in vivo.

    PubMed

    Costamagna, Domiziana; Mommaerts, Hendrik; Sampaolesi, Maurilio; Tylzanowski, Przemko

    2016-01-01

    Inactivation of Noggin, a secreted antagonist of Bone Morphogenetic Proteins (BMPs), in mice leads, among others, to severe malformations of the appendicular skeleton and defective skeletal muscle fibers. To determine the molecular basis of the phenotype, we carried out a histomorphological and molecular analysis of developing muscles Noggin(-/-) mice. We show that in 18.5 dpc embryos there is a marked reduction in muscle fiber size and a failure of nuclei migration towards the cell membrane. Molecularly, the absence of Noggin results in an increased BMP signaling in muscle tissue as shown by the increase in SMAD1/5/8 phosphorylation, concomitant with the induction of BMP target genes such as Id1, 2, 3 as well as Msx1. Finally, upon removal of Noggin, the number of mesenchymal Pax7(+) muscle precursor cells is reduced and they are more prone to differentiate into adipocytes in vitro. Thus, our results highlight the importance of Noggin/BMP balance for myogenic commitment of early fetal progenitor cells. PMID:27573479

  6. Noggin inactivation affects the number and differentiation potential of muscle progenitor cells in vivo

    PubMed Central

    Costamagna, Domiziana; Mommaerts, Hendrik; Sampaolesi, Maurilio; Tylzanowski, Przemko

    2016-01-01

    Inactivation of Noggin, a secreted antagonist of Bone Morphogenetic Proteins (BMPs), in mice leads, among others, to severe malformations of the appendicular skeleton and defective skeletal muscle fibers. To determine the molecular basis of the phenotype, we carried out a histomorphological and molecular analysis of developing muscles Noggin−/− mice. We show that in 18.5 dpc embryos there is a marked reduction in muscle fiber size and a failure of nuclei migration towards the cell membrane. Molecularly, the absence of Noggin results in an increased BMP signaling in muscle tissue as shown by the increase in SMAD1/5/8 phosphorylation, concomitant with the induction of BMP target genes such as Id1, 2, 3 as well as Msx1. Finally, upon removal of Noggin, the number of mesenchymal Pax7+ muscle precursor cells is reduced and they are more prone to differentiate into adipocytes in vitro. Thus, our results highlight the importance of Noggin/BMP balance for myogenic commitment of early fetal progenitor cells. PMID:27573479

  7. Evoked response study tool: a portable, rugged system for single and multiple auditory evoked potential measurements.

    PubMed

    Finneran, James J

    2009-07-01

    Although the potential of using portable auditory evoked potential systems for field testing of stranded cetaceans has been long recognized, commercial systems for evoked potential measurements generally do not possess the bandwidth required for testing odontocete cetaceans and are not suitable for field use. As a result, there have been a number of efforts to develop portable evoked potential systems for field testing of cetaceans. This paper presents another such system, called the evoked response study tool (EVREST). EVREST is a Windows-based hardware/software system designed for calibrating sound stimuli and recording and analyzing transient and steady-state evoked potentials. The EVREST software features a graphical user interface, real-time analysis and visualization of recorded data, a variety of stimulus options, and a high level of automation. The system hardware is portable, rugged, battery-powered, and possesses a bandwidth that encompasses the audible range of echolocating odontocetes, making the system suitable for field testing of stranded or rehabilitating cetaceans. PMID:19603907

  8. Adapted physical exercise enhances activation and differentiation potential of satellite cells in the skeletal muscle of old mice.

    PubMed

    Cisterna, Barbara; Giagnacovo, Marzia; Costanzo, Manuela; Fattoretti, Patrizia; Zancanaro, Carlo; Pellicciari, Carlo; Malatesta, Manuela

    2016-05-01

    During ageing, a progressive loss of skeletal muscle mass and a decrease in muscle strength and endurance take place, in the condition termed sarcopenia. The mechanisms of sarcopenia are complex and still unclear; however, it is known that muscle atrophy is associated with a decline in the number and/or efficiency of satellite cells, the main contributors to muscle regeneration. Physical exercise proved beneficial in sarcopenia; however, knowledge of the effect of adapted physical exercise on the myogenic properties of satellite cells in aged muscles is limited. In this study the amount and activation state of satellite cells as well as their proliferation and differentiation potential were assessed in situ by morphology, morphometry and immunocytochemistry at light and transmission electron microscopy on 28-month-old mice submitted to adapted aerobic physical exercise on a treadmill. Sedentary age-matched mice served as controls, and sedentary adult mice were used as a reference for an unperturbed control at an age when the capability of muscle regeneration is still high. The effect of physical exercise in aged muscles was further analysed by comparing the myogenic potential of satellite cells isolated from old running and old sedentary mice using an in vitro system that allows observation of the differentiation process under controlled experimental conditions. The results of this ex vivo and in vitro study demonstrated that adapted physical exercise increases the number and activation of satellite cells as well as their capability to differentiate into structurally and functionally correct myotubes (even though the age-related impairment in myotube formation is not fully reversed): this evidence further supports adapted physical exercise as a powerful, non-pharmacological approach to counteract sarcopenia and the age-related deterioration of satellite cell capabilities even at very advanced age. PMID:26739770

  9. 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

  10. Hydrogen gas treatment prolongs replicative lifespan of bone marrow multipotential stromal cells in vitro while preserving differentiation and paracrine potentials

    SciTech Connect

    Kawasaki, Haruhisa; Guan, Jianjun; Tamama, Kenichi

    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.

  11. 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.

  12. Photoelectron drift and multiplication due to surface potential gradient - An application for solar power arrays

    NASA Astrophysics Data System (ADS)

    Suh, P. K.; Stauber, M. C.

    1980-01-01

    The drift of photoelectrons in a surface potential gradient, together with their resultant energy enhancement and drift current application by secondary emission and backscattering, is examined taking into account the screening of the surface potential by the space plasma environment. Specific results are presented for parameters representative of a large photovoltaic array, for different values of the voltage gradient. It is found that the surface drift current resulting from photoelectrons is substantially larger than the direct photoelectric emissions. On the other hand, the effective drift current tends to be insignificant compared to the array current itself.

  13. 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}.

  14. Potential nosocomial acquisition of epidemic Listeria monocytogenes presenting as multiple brain abscesses resembling nocardiosis.

    PubMed

    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 Crohn's 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

  15. Proteomic profiling in multiple sclerosis clinical courses reveals potential biomarkers of neurodegeneration.

    PubMed

    Liguori, Maria; Qualtieri, Antonio; Tortorella, Carla; Direnzo, Vita; Bagalà, 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: 1000-25000 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 β4 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

  16. ALDH1B1 is a potential stem / progenitor marker for multiple pancreas progenitor pools

    PubMed Central

    Ioannou, Marilia; Serafimidis, Ioannis; Arnes, Luis; Sussel, Lori; Singh, Surendra; Vasiliou, Vasilis; Gavalas, Anthony

    2013-01-01

    Aldehyde Dehydrogenase (ALDH) genes are increasingly associated with stem / progenitor cell status but their role in the maintenance of pluripotency remains uncertain. In a screen conducted for downstream Ngn3 target genes using ES derived pancreas progenitors we identified Aldh1b1, encoding a mitochondrial enzyme, as one of the genes strongly up regulated in response to Ngn3 expression. We found both by in situ hybridization and immunofluorescence using a specific antibody that ALDH1B1 is exclusively expressed in the emerging pancreatic buds of the early embryo (9.5 dpc) in a Pdx1 dependent manner. Around the time of secondary transition, ALDH1B1 expression was restricted in the tip tripotent progenitors of the branching epithelium and in a subset of the trunk epithelium. Expression in the latter was Ngn3 dependent. Subsequently, ALDH1B1 expression persisted only in the tip cells that become restricted to the exocrine lineage and declined rapidly as these cells mature. In the adult pancreas we identified rare ALDH1B1+ cells that become abundant following pancreas injury in either the caerulein or streptozotocin paradigms. Blocking ALDH catalytic activity in pancreas embryonic explants resulted in reduced size of the explants and accelerated differentiation suggesting for the first time that ALDH activity may be necessary in the developing pancreas for the maintenance and expansion of progenitor pools. PMID:23142317

  17. 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 25 days for BM-MSCs, 15 days for AT-MSCs and 26 days for UC-MSCs. MSCs from all sources were able to differentiate into osteogenic (after 10 days for BM-MSCs and AT-MSCs and 15 days for UC-MSCs), adipogenic (after 8 days for BM-MSCs and AT-MSCs and 15 days for UC-MSCs) and chondrogenic (after 21 days 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

  18. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders.

    PubMed

    Campos, Alline Cristina; Moreira, Fabricio Araújo; Gomes, Felipe Villela; Del Bel, Elaine Aparecida; Guimarães, Francisco Silveira

    2012-12-01

    Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ(9)-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca(2+)) increase, etc.), on CBD behavioural effects. PMID:23108553

  19. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders

    PubMed Central

    Campos, Alline Cristina; Moreira, Fabricio Araújo; Gomes, Felipe Villela; Del Bel, Elaine Aparecida; Guimarães, Francisco Silveira

    2012-01-01

    Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ9-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca2+) increase, etc.), on CBD behavioural effects. PMID:23108553

  20. 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.

  1. Differential bioaccumulation of potentially toxic elements in benthic and pelagic food chains in Lake Baikal.

    PubMed

    Ciesielski, Tomasz M; Pastukhov, Mikhail V; Leeves, Sara A; Farkas, Julia; Lierhagen, Syverin; Poletaeva, Vera I; Jenssen, Bjørn M

    2016-08-01

    Lake Baikal is located in eastern Siberia in the center of a vast mountain region. Even though the lake is regarded as a unique and pristine ecosystem, there are existing sources of anthropogenic pollution to the lake. In this study, the concentrations of the potentially toxic trace elements As, Cd, Pb, Hg, and Se were analyzed in water, plankton, invertebrates, and fish from riverine and pelagic influenced sites in Lake Baikal. Concentrations of Cd, Hg, Pb and Se in Lake Baikal water and biota were low, while concentrations of As were similar or slightly higher compared to in other freshwater ecosystems. The bioaccumulation potential of the trace elements in both the pelagic and the benthic ecosystems differed between the Selenga Shallows (riverine influence) and the Listvenichnyĭ Bay (pelagic influence). Despite the one order of magnitude higher water concentrations of Pb in the Selenga Shallows, Pb concentrations were significantly higher in both pelagic and benthic fish from the Listvenichnyĭ Bay. A similar trend was observed for Cd, Hg, and Se. The identified enhanced bioavailability of contaminants in the pelagic influenced Listvenichnyĭ Bay may be attributed to a lower abundance of natural ligands for contaminant complexation. Hg was found to biomagnify in both benthic and pelagic Baikal food chains, while As, Cd, and Pb were biodiluted. At both locations, Hg concentrations were around seven times higher in benthic than in pelagic fish, while pelagic fish had two times higher As concentrations compared to benthic fish. The calculated Se/Hg molar ratios revealed that, even though Lake Baikal is located in a Se-deficient region, Se is still present in excess over Hg and therefore the probability of Hg induced toxicity in the endemic fish species of Lake Baikal is assumed to be low. PMID:27130338

  2. Serum Parathyroid Hormone Is a New Potential Risk Factor in Multiple Myeloma

    PubMed Central

    Won, Eun-Jeong; Kim, Hye-Ran; Choi, Hyun-Jung; Park, Hye-Ri; Shin, Jong-Hee; Suh, Soon-Pal; Ryang, Dong-Wook; Shin, Myung-Geun

    2014-01-01

    We hypothesized that serum PTH might be associated with various clinicopathological parameters in multiple myeloma (MM). So we investigated the implications of serum PTH in MM patients and the relationship with other risk factors of MM. A total of 115 patients who were newly diagnosed with MM were enrolled. Serum PTH level was 24.7 ± 34.9 (ranged 0.0–284.1) pg/mL. Serum levels of IgG, IgM, FLC-lambda, albumin, and LDH were in positive correlation with serum PTH. Compared to non-high PTH (<68.3 pg/mL) group, the hazard ratio (HR) for overall survival was higher for group with high PTH level (≥68.3 pg/mL) (HR, 1.710). Furthermore, the patient group with high PTH level showed inferior progression-free survival than non-high PTH group (P = 0.056). Interestingly, subgroup analysis showed that serum PTH level at diagnosis was associated with risk factors and clinical outcome in MM patients, especially in complete remission group, transplantation cases, ISS stage II cases, and cases without chromosome abnormality. In conclusion, this study showed that blood PTH level in MM at diagnosis was associated with risk factors and clinical outcome in MM patients. PMID:24967406

  3. 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

  4. Potential effect of resonant scattering from multiple swimbladders on audition in juvenile fish

    NASA Astrophysics Data System (ADS)

    Hastings, Mardi C.

    2003-04-01

    The swimbladder, a gas-filled chamber in the abdominal cavity of most bony fishes, is a hydrostatic organ that enables fish to maintain neutral buoyancy; however, it also responds to acoustic pressure and radiates a secondary acoustic field that enhances detection capability of the inner ear. Recent experiments have indicated that resonant response of the swimbladder may control the auditory bandwidth in at least four species of fish [Hastings et al., J. Acoust. Soc. Am. 110, 2640 (2001)]. The auditory bandwidths of these fishes, however, do not change appreciably while they grow even though the resonance frequency of the swimbladder decreases with increasing body length. Results of an analysis inspired by Feiullade et al. [J. Acoust. Soc. Am. 112, 2206 (2002)] show that the downward shift and broadening associated with resonance of the aggregate scattered field from multiple fish is perhaps sufficient enough to account for this discrepancy. Effects of resonant characteristics of a single swimbladder, fish length, and number of fish on the changes in the collective scattered field are presented. Thus the resonant scattered field created by relatively large schools of juvenile fish may enhance their auditory capability.

  5. Astrocytes as potential targets to suppress inflammatory demyelinating lesions in multiple sclerosis.

    PubMed

    De Keyser, Jacques; Laureys, Guy; Demol, Frauke; Wilczak, Nadine; Mostert, Jop; Clinckers, Ralph

    2010-11-01

    A hallmark of multiple sclerosis (MS) is the occurrence of focal inflammatory demyelinating lesions in the central nervous system. The prevailing view that activated anti-myelin T cells inherently mediate these lesions has been challenged after observations that these T cells, which are part of the normal immune repertoire, can also intermittently become activated in healthy people and subjects with other diseases. Astrocytes in the white matter of subjects with MS are deficient in beta(2) adrenergic receptors. Stimulation of beta(2) adrenergic receptors increases cAMP, leading to activation of protein kinase A (PKA). beta(2) adrenergic receptor deficiency will reduce the suppressive action of PKA on coactivator class II transactivator (CIITA), which is a key regulator of interferon gamma-induced major histocompatibility (MHC) class II molecule transcription. The expression of MHC class II may deviate astrocytes to function as facultative antigen presenting cells, which can then initiate the inflammatory cascade. In a proof of concept study in MS subjects it was shown that fluoxetine, which activates PKA in astrocytes, reduced the development of focal inflammatory lesions. If confirmed and extended by additional studies, suppressing the antigen presenting capacity of astrocytes could be a novel therapeutic option for the treatment of MS. PMID:20178822

  6. Relativistic Green's Functions in Full-Potential Multiple-Scattering Theory

    NASA Astrophysics Data System (ADS)

    Liu, Xianglin; Wang, Yang; Eisenbach, Markus; Stocks, G. Malcolm

    The Green's functions play a central role in MST based KKR method. Obtaining the Green's functions by solving the Dirac equation is appealing since it naturally incorporated the electron spin and the spin-orbit coupling effects. Here we implemented the full-potential relativistic KKR method using a technique called the sine and cosine matrices formalism. The charge density and the density of states of some pure element crystals have been calculated. Different expressions of the Green's functions have been investigated for numerical benefits.

  7. 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

  8. 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

    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

  9. Triterpene saponosides from Lysimachia ciliata differentially attenuate invasive potential of prostate cancer cells.

    PubMed

    Koczurkiewicz, Paulina; Podolak, Irma; Skrzeczyńska-Moncznik, Joanna; Sarna, Michał; Wójcik, Katarzyna Anna; Ryszawy, Damian; Galanty, Agnieszka; Lasota, Sławomir; Madeja, Zbigniew; Czyż, Jarosław; Michalik, Marta

    2013-10-25

    Neither androgen ablation nor chemotherapeutic agents are effective in reducing the risk of prostate cancer progression. On the other hand, multifaceted effects of phytochemicals, such as triterpene saponins, on cancer cells have been suggested. A promising safety and tolerability profile indicate their possible application in the treatment of advanced prostate cancers. We analyzed the specificity, selectivity and versatility of desglucoanagalloside B effects on human prostate cancer cells derived from prostate cancer metastases to brain (DU-145 cells) and bone (PC-3 cells). Prominent growth arrest and apoptotic response of both cell types was observed in the presence of sub-micromolar desglucoanagalloside B concentrations. This was accompanied by cytochrome c release and caspase 3/7 activation. A relatively low cytostatic and pro-apoptotic response of cancer cells to a desglucoanagalloside B analog, anagallosaponin IV, illustrated the specificity of the effects of desglucoanagalloside B, whereas the low sensitivity of normal prostate PNT2 cells to desglucoanagalloside B showed the selectivity of its action. Inhibition of cancer cell motility was observed in the presence of both saponins, however only desglucoanagalloside B attenuated cancer cell invasive potential, predominantly through an effect on cell elastic properties. These data demonstrate the versatility of its effects on prostate cancer cells. In contrast to PNT2 cells, cancer cells tested in this study were relatively resistant to mitoxantrone. The multifaceted action of desglucoanagalloside B on basic cellular traits, crucial for prostate cancer progression, opens perspectives for elaboration of combined palliative therapies and new prostate cancer prophylaxis regimens. PMID:23954719

  10. CD123 immunostaining patterns in systemic mastocytosis: differential expression in disease subgroups and potential prognostic value.

    PubMed

    Pardanani, A; Reichard, K K; Zblewski, D; Abdelrahman, R A; Wassie, E A; Morice Ii, W G; Brooks, C; Grogg, K L; Hanson, C A; Tefferi, A; Chen, D

    2016-04-01

    CD123 is the α-subunit of the interleukin-3 receptor; it represents a potential therapeutic target in systemic mastocytosis (SM) given its absent expression on normal/reactive mast cells (MCs) and aberrant expression on neoplastic MCs. We studied 58 SM patients to define CD123 expression patterns by immunohistochemistry and its clinical significance. Two hematopathologists independently scored bone marrow slides using predefined histologic parameters. In all, 23 patients had indolent SM (ISM), 10 aggressive SM (ASM), 23 SM with associated hematological neoplasm (SM-AHN) and 2 had mast cell leukemia (MCL). MC_CD123 expression was demonstrable in 37 (64%) cases; expression rates were 100%, 61%, 57% and 0% in ASM, ISM, SM-AHN and MCL, respectively (P=0.02). Focal proliferation of plasmacytoid dendritic cells (PDCs) around MC aggregates, suggesting a tumor-promoting role for PDCs, was noted in 44 (76%) cases, and was significantly higher in CD123-positive versus -negative cases (87% versus 50%, P=0.005). CD123 expression and its staining intensity had prognostic value in SM-chronic myelomonocytic leukemia and nonindolent SM patients, respectively. These observations suggest that targeting CD123 in SM may have direct (via MCs) and indirect (via PDCs) antitumor effects and clinical trials to that effect require laboratory correlative studies to address the observed target expression heterogeneity. PMID:26678095

  11. Early differential sensitivity of evoked-potentials to local and global shape during the perception of three-dimensional objects.

    PubMed

    Leek, E Charles; Roberts, Mark; Oliver, Zoe J; Cristino, Filipe; Pegna, Alan J

    2016-08-01

    Here we investigated the time course underlying differential processing of local and global shape information during the perception of complex three-dimensional (3D) objects. Observers made shape matching judgments about pairs of sequentially presented multi-part novel objects. Event-related potentials (ERPs) were used to measure perceptual sensitivity to 3D shape differences in terms of local part structure and global shape configuration - based on predictions derived from hierarchical structural description models of object recognition. There were three types of different object trials in which stimulus pairs (1) shared local parts but differed in global shape configuration; (2) contained different local parts but shared global configuration or (3) shared neither local parts nor global configuration. Analyses of the ERP data showed differential amplitude modulation as a function of shape similarity as early as the N1 component between 146-215ms post-stimulus onset. These negative amplitude deflections were more similar between objects sharing global shape configuration than local part structure. Differentiation among all stimulus types was reflected in N2 amplitude modulations between 276-330ms. sLORETA inverse solutions showed stronger involvement of left occipitotemporal areas during the N1 for object discrimination weighted towards local part structure. The results suggest that the perception of 3D object shape involves parallel processing of information at local and global scales. This processing is characterised by relatively slow derivation of 'fine-grained' local shape structure, and fast derivation of 'coarse-grained' global shape configuration. We propose that the rapid early derivation of global shape attributes underlies the observed patterns of N1 amplitude modulations. PMID:27396674

  12. Erythropoietin is involved in the angiogenic potential of bone marrow macrophages in multiple myeloma.

    PubMed

    De Luisi, Annunziata; Binetti, Laura; Ria, Roberto; Ruggieri, Simona; Berardi, Simona; Catacchio, Ivana; Racanelli, Vito; Pavone, Vincenzo; Rossini, Bernardo; Vacca, Angelo; Ribatti, Domenico

    2013-10-01

    Erythropoietin (Epo) is the crucial cytokine regulator of red blood cell production, and recombinant human erythropoietin (rHuEpo) is widely used in clinical practice for the treatment of anemia, primarily in kidney disease and in cancer. Increasing evidence suggests several biological roles for Epo and its receptor, Epo-R, unrelated to erythropoiesis, including angiogenesis. Epo-R has been found expressed in various non-haematopoietic cells and tissues, and in cancer cells. Here, we detected the expression of Epo-R in bone marrow-derived macrophages (BMMAs) from multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) patients and assessed whether Epo/Epo-R axis plays a role in MM macrophage-mediated angiogenesis. We found that Epo-R is over-expressed in BMMAs from MM patients with active disease compared to MGUS patients. The treatment of BMMAs with rHuEpo significantly increased the expression and secretion of key pro-angiogenic mediators, such as vascular endothelial growth factor, hepatocyte growth factor and monocyte chemotactic protein (MCP-1/CCL-2), through activation of JAK2/STAT5 and PI3 K/Akt pathways. In addition, the conditioned media harvested from rHuEpo-treated BMMAs enhanced bone marrow-derived endothelial cell migration and capillary morphogenesis in vitro, and induced angiogenesis in the chorioallantoic membrane of chick embryos in vivo. Furthermore, we found an increase in the circulating levels of several pro-angiogenic cytokines in serum of MM patients with anemia under treatment with Epo. Our findings highlight the direct effect of rHuEpo on macrophage-mediated production of pro-angiogenic factors, suggesting that Epo/Epo-R pathway may be involved in the regulation of angiogenic response occurring in MM. PMID:23881169

  13. 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

  14. 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.

  15. 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

  16. 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

  17. Novel immortalized human fetal liver cell line, cBAL111, has the potential to differentiate into functional hepatocytes

    PubMed Central

    Deurholt, Tanja; van Til, Niek P; Chhatta, Aniska A; ten Bloemendaal, Lysbeth; Schwartlander, Ruth; Payne, Catherine; Plevris, John N; Sauer, Igor M; Chamuleau, Robert AFM; Elferink, Ronald PJ Oude; Seppen, Jurgen; Hoekstra, Ruurdtje

    2009-01-01

    Background A clonal cell line that combines both stable hepatic function and proliferation capacity is desirable for in vitro applications that depend on hepatic function, such as pharmacological or toxicological assays and bioartificial liver systems. Here we describe the generation and characterization of a clonal human cell line for in vitro hepatocyte applications. Results Cell clones derived from human fetal liver cells were immortalized by over-expression of telomerase reverse transcriptase. The resulting cell line, cBAL111, displayed hepatic functionality similar to the parental cells prior to immortalization, and did not grow in soft agar. Cell line cBAL111 expressed markers of immature hepatocytes, like glutathione S transferase and cytokeratin 19, as well as progenitor cell marker CD146 and was negative for lidocaine elimination. On the other hand, the cBAL111 cells produced urea, albumin and cytokeratin 18 and eliminated galactose. In contrast to hepatic cell lines NKNT-3 and HepG2, all hepatic functions were expressed in cBAL111, although there was considerable variation in their levels compared with primary mature hepatocytes. When transplanted in the spleen of immunodeficient mice, cBAL111 engrafted into the liver and partly differentiated into hepatocytes showing expression of human albumin and carbamoylphosphate synthetase without signs of cell fusion. Conclusion This novel liver cell line has the potential to differentiate into mature hepatocytes to be used for in vitro hepatocyte applications. PMID:19845959

  18. IGF1 potentiates BMP9-induced osteogenic differentiation in mesenchymal stem cells through the enhancement of BMP/Smad signaling

    PubMed Central

    Chen, Liang; Zou, Xiang; Zhang, Ran-Xi; Pi, Chang-Jun; Wu, Nian; Yin, Liang-Jun; Deng, Zhong-Liang

    2016-01-01

    Engineered bone tissue is thought to be the ideal alternative for bone grafts in the treatment of related bone diseases. BMP9 has been demonstrated as one of the most osteogenic factors, and enhancement of BMP9-induced osteogenesis will greatly accelerate the development of bone tissue engineering. Here, we investigated the effect of insulin-like growth factor 1 (IGF1) on BMP9-induced osteogenic differentiation, and unveiled a possible molecular mechanism underling this process. We found that IGF1 and BMP9 are both detectable in mesenchymal stem cells (MSCs). Exogenous expression of IGF1 potentiates BMP9-induced alkaline phosphatase (ALP), matrix mineralization, and ectopic bone formation. Similarly, IGF1 enhances BMP9-induced endochondral ossification. Mechanistically, we found that IGF1 increases BMP9-induced activation of BMP/Smad signaling in MSCs. Our findings demonstrate that IGF1 can enhance BMP9-induced osteogenic differentiation in MSCs, and that this effect may be mediated by the enhancement of the BMP/Smad signaling transduction triggered by BMP9. [BMB Reports 2016; 49(2): 122-127] PMID:26645636

  19. 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. PMID:26414782

  20. Low Oxygen Modulates Multiple Signaling Pathways, Increasing Self-Renewal, While Decreasing Differentiation, Senescence, and Apoptosis in Stromal MIAMI Cells.

    PubMed

    Rios, Carmen; D'Ippolito, Gianluca; Curtis, Kevin M; Delcroix, Gaëtan J-R; Gomez, Lourdes A; El Hokayem, Jimmy; Rieger, Megan; Parrondo, Ricardo; de Las Pozas, Alicia; Perez-Stable, Carlos; Howard, Guy A; Schiller, Paul C

    2016-06-01

    Human bone marrow multipotent mesenchymal stromal cell (hMSC) number decreases with aging. Subpopulations of hMSCs can differentiate into cells found in bone, vasculature, cartilage, gut, and other tissues and participate in their repair. Maintaining throughout adult life such cell subpopulations should help prevent or delay the onset of age-related degenerative conditions. Low oxygen tension, the physiological environment in progenitor cell-rich regions of the bone marrow microarchitecture, stimulates the self-renewal of marrow-isolated adult multilineage inducible (MIAMI) cells and expression of Sox2, Nanog, Oct4a nuclear accumulation, Notch intracellular domain, notch target genes, neuronal transcriptional repressor element 1 (RE1)-silencing transcription factor (REST), and hypoxia-inducible factor-1 alpha (HIF-1α), and additionally, by decreasing the expression of (i) the proapoptotic proteins, apoptosis-inducing factor (AIF) and Bak, and (ii) senescence-associated p53 expression and β-galactosidase activity. Furthermore, low oxygen increases canonical Wnt pathway signaling coreceptor Lrp5 expression, and PI3K/Akt pathway activation. Lrp5 inhibition decreases self-renewal marker Sox2 mRNA, Oct4a nuclear accumulation, and cell numbers. Wortmannin-mediated PI3K/Akt pathway inhibition leads to increased osteoblastic differentiation at both low and high oxygen tension. We demonstrate that low oxygen stimulates a complex signaling network involving PI3K/Akt, Notch, and canonical Wnt pathways, which mediate the observed increase in nuclear Oct4a and REST, with simultaneous decrease in p53, AIF, and Bak. Collectively, these pathway activations contribute to increased self-renewal with concomitant decreased differentiation, cell cycle arrest, apoptosis, and/or senescence in MIAMI cells. Importantly, the PI3K/Akt pathway plays a central mechanistic role in the oxygen tension-regulated self-renewal versus osteoblastic differentiation of progenitor cells. PMID:27059084

  1. 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…

  2. 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-β 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

  3. A generalized Grubbs-Beck test statistic for detecting multiple potentially influential low outliers in flood series

    NASA Astrophysics Data System (ADS)

    Cohn, T. A.; England, J. F.; Berenbrock, C. E.; Mason, R. R.; Stedinger, J. R.; Lamontagne, J. R.

    2013-08-01

    The 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.

  4. 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.

  5. Angular distributions of electrons photoemitted from core levels of oriented diatomic molecules: Multiple scattering theory in non-spherical potentials

    SciTech Connect

    Diez Muino, R.; Rolles, D.; Garcia de Abajo, F.J.; Fadley, C.S.; Van Hove, M.A.

    2001-09-06

    We use multiple scattering in non-spherical potentials (MSNSP) to calculate the angular distributions of electrons photoemitted from the 1s-shells of CO and N2 gas-phase molecules with fixed-in-space orientations. For low photoelectron kinetic energies (E<50 eV), as appropriate to certain shape-resonances, the electron scattering must be represented by non-spherical scattering potentials, which are naturally included in our formalism. Our calculations accurately reproduce the experimental angular patterns recently measured by several groups, including those at the shape-resonance energies. The MSNSP theory thus enhances the sensitivity to spatial electronic distribution and dynamics, paving the way toward their determination from experiment.

  6. A methanotroph-based biorefinery: Potential scenarios for generating multiple products from a single fermentation.

    PubMed

    Strong, P J; Kalyuzhnaya, M; Silverman, J; Clarke, W P

    2016-09-01

    Methane, a carbon source for methanotrophic bacteria, is the principal component of natural gas and is produced during anaerobic digestion of organic matter (biogas). Methanotrophs are a viable source of single cell protein (feed supplement) and can produce various products, since they accumulate osmolytes (e.g. ectoine, sucrose), phospholipids (potential biofuels) and biopolymers (polyhydroxybutyrate, glycogen), among others. Other cell components, such as surface layers, metal chelating proteins (methanobactin), enzymes (methane monooxygenase) or heterologous proteins hold promise as future products. Here, scenarios are presented where ectoine, polyhydroxybutyrate or protein G are synthesised as the primary product, in conjunction with a variety of ancillary products that could enhance process viability. Single or dual-stage processes and volumetric requirements for bioreactors are discussed, in terms of an annual biomass output of 1000 tonnesyear(-1). Product yields are discussed in relation to methane and oxygen consumption and organic waste generation. PMID:27146469

  7. Arsenite oxidizing multiple metal resistant bacteria isolated from industrial effluent: their potential use in wastewater treatment.

    PubMed

    Naureen, Ayesha; Rehman, Abdul

    2016-08-01

    Arsenite oxidizing bacteria, isolated from industrial wastewater, showed high resistance against arsenite (40 mM) and other heavy metals (10 mM Pb; 8 mM Cd; 6 mM Cr; 10 mM Cu and 26.6 mM As(5+)). Bacterial isolates were characterized, on the basis of morphological, biochemical and 16S rRNA ribotyping, as Bacillus cereus (1.1S) and Acinetobacter junii (1.3S). The optimum temperature and pH for the growth of both strains were found to be 37 °C and 7. Both the strains showed maximum growth after 24 h of incubation. The predominant form of arsenite oxidase was extracellular in B. cereus while in A. junii both types of activities, intracellular and extracellular, were found. The extracellular aresenite oxidase activity was found to be 730 and 750 µM/m for B. cereus and A. junii, respectively. The arsenite oxidase from both bacterial strains showed maximum activity at 37 °C, pH 7 and enhanced in the presence of Zn(2+). The presence of two protein bands with molecular weight of approximately 70 and 14 kDa in the presence of arsenic points out a possible role in arsenite oxidation. Arsenite oxidation potential of B. cereus and A. junii was determined up to 92 and 88 % in industrial wastewater after 6 days of incubation. The bacterial treated wastewater improved the growth of Vigna radiata as compared to the untreated wastewater. It indicates that these bacterial strains may find some potential applications in wastewater treatment systems to transform toxic arsenite into less toxic form, arsenate. PMID:27339314

  8. 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

  9. 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

  10. Public health implications of Acanthamoeba and multiple potential opportunistic pathogens in roof-harvested rainwater tanks.

    PubMed

    Hamilton, K A; Ahmed, W; Palmer, A; Sidhu, J P S; Hodgers, L; Toze, S; Haas, C N

    2016-10-01

    A study of six potential opportunistic pathogens (Acanthamoeba spp., Legionella spp., Legionella longbeachae, Pseudomonas aeruginosa, Mycobacterium avium and Mycobacterium intracellulare) and an accidental human pathogen (Legionella pneumophila) in 134 roof-harvested rainwater (RHRW) tank samples was conducted using quantitative PCR (qPCR). All five opportunistic pathogens and accidental pathogen L. pneumophila were detected in rainwater tanks except Legionella longbeachae. Concentrations ranged up to 3.1×10(6) gene copies per L rainwater for Legionella spp., 9.6×10(5) gene copies per L for P. aeruginosa, 6.8×10(5) gene copies per L for M. intracellulare, 6.6×10(5) gene copies per L for Acanthamoeba spp., 1.1×10(5) gene copies per L for M. avium, and 9.8×10(3) gene copies per L for L. pneumophila. Among the organisms tested, Legionella spp. (99% tanks) were the most prevalent followed by M. intracellulare (78%). A survey of tank-owners provided data on rainwater end-uses. Fecal indicator bacteria (FIB) Escherichia coli and Enterococcus spp. were enumerated using culture-based methods, and assessed for correlations with opportunistic pathogens and L. pneumophila tested in this study. Opportunistic pathogens did not correlate well with FIB except E. coli vs. Legionella spp. (tau=0.151, P=0.009) and E. coli vs. M. intracellulare (tau=0.14, P=0.015). However, M. avium weakly correlated with both L. pneumophila (Kendall's tau=0.017, P=0.006) and M. intracellulare (tau=0.088, P=0.027), and Legionella spp. also weakly correlated with M. intracellulare (tau=0.128, P=0.028). The presence of these potential opportunistic pathogens in tank water may present health risks from both the potable and non-potable uses documented from the current survey data. PMID:27336236

  11. Specific effect of the HLDF differentiation factor on the cytokine production potential of immunocompetent blood cells in stomach adenocarcinoma.

    PubMed

    Autenshlyus, A I; Kunts, T A; Mikhaylova, E S; Varaksin, N A; Bogachuk, A P; Lipkin, V M

    2016-07-01

    The cytokine production potential of immunocompetent cells from the blood of stomach adenocarcinoma patients was analyzed after the pretreatment of cells with the HLDF differentiation factor with subsequent exposure to polyclonal activators (HLDF+PA). IL-1β, IL-1Ra, TNFα, IL-2, IL-6, IL-8, IL-10, IL-17, IL-18, IL-18BPa, IFNγ, G-CSF, and GM-CSF were quantified in the supernatants after precipitation of the cells. Specific effects of HLDF+PA were manifested as an increase in the production of IL-8, IL-17, and GM-CSF due to suppression of Th1-dependent immune reactions in a Th17-mediated mechanism that is a part of a broader functional antagonism of Th1 and Th17 lymphocyte subpopulations. PMID:27595831

  12. Diagnostic potential of near-infrared Raman spectroscopy in the stomach: differentiating dysplasia from normal tissue

    PubMed Central

    Teh, S K; Zheng, W; Ho, K Y; Teh, M; Yeoh, K G; Huang, Z

    2008-01-01

    diagnostic algorithm can be derived from the PCA-LDA technique. Therefore, NIR Raman spectroscopy in conjunction with multivariate statistical technique has potential for rapid diagnosis of dysplasia in the stomach based on the optical evaluation of spectral features of biomolecules. PMID:18195711

  13. Growth Differentiation Factor-15 (GDF-15) is a potential marker of radiation response and radiation sensitivity.

    PubMed

    Sándor, Nikolett; Schilling-Tóth, Boglárka; Kis, Enikő; Benedek, Anett; Lumniczky, Katalin; Sáfrány, Géza; Hegyesi, Hargita

    2015-11-01

    We have investigated the importance of GDF-15 (secreted cytokine belonging to the TGF-β 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-β1 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

  14. 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

  15. Enhanced Osteogenic and Vasculogenic Differentiation Potential of Human Adipose Stem Cells on Biphasic Calcium Phosphate Scaffolds in Fibrin Gels.

    PubMed

    van Esterik, Fransisca A S; Zandieh-Doulabi, Behrouz; Kleverlaan, Cornelis J; Klein-Nulend, Jenneke

    2016-01-01

    For bone tissue engineering synthetic biphasic calcium phosphate (BCP) with a hydroxyapatite/β-tricalcium phosphate (HA/β-TCP) ratio of 60/40 (BCP60/40) is successfully clinically applied, but the high percentage of HA may hamper efficient scaffold remodelling. Whether BCP with a lower HA/β-TCP ratio (BCP20/80) is more desirable is still unclear. Vascular development is needed before osteogenesis can occur. We aimed to test the osteogenic and/or vasculogenic differentiation potential as well as degradation of composites consisting of human adipose stem cells (ASCs) seeded on BCP60/40 or BCP20/80 incorporated in fibrin gels that trigger neovascularization for bone regeneration. ASC attachment to BCP60/40 and BCP20/80 within 30 min was similar (>93%). After 11 days of culture BCP20/80-based composites showed increased alkaline phosphatase activity and DMP1 gene expression, but not RUNX2 and osteonectin expression, compared to BCP60/40-based composites. BCP20/80-based composites also showed enhanced expression of the vasculogenic markers CD31 and VEGF189, but not VEGF165 and endothelin-1. Collagen-1 and collagen-3 expression was similar in both composites. Fibrin degradation was increased in BCP20/80-based composites at day 7. In conclusion, BCP20/80-based composites showed enhanced osteogenic and vasculogenic differentiation potential compared to BCP60/40-based composites in vitro, suggesting that BCP20/80-based composites might be more promising for in vivo bone augmentation than BCP60/40-based composites. PMID:27547223

  16. Genistein induces adipogenic differentiation in human bone marrow mesenchymal stem cells and suppresses their osteogenic potential by upregulating PPARγ

    PubMed Central

    ZHANG, LI-YAN; XUE, HAO-GANG; CHEN, JI-YING; CHAI, WEI; NI, MING

    2016-01-01

    Genistein is a soy isoflavone that exists in the form of an aglycone. It is the primary active component in soy isoflavone and has a number of biological activities (anti-inflammatory and anti-oxidative). However, the specific effect of genistein on human bone marrow mesenchymal stem cells (BMSCs) remains unclear. In the present study, the mechanism underlying the effect of genistein on the suppression of BMSC adipogenic differentiation and the enhancement of osteogenic potential was investigated using an MTT assay. It was observed that genistein significantly increased BMSC cell proliferation in a time- and dose-dependent manner (P<0.01). In addition, reverse transcription-quantitative polymerase chain reaction revealed that genistein significantly inhibited the expression of runt-related transcription factor 2 (Runx2), type I collagen (Col I) and osteocalcin (OC; P<0.01). Furthermore, 20 µm genistein significantly inhibited the activity of alkaline phosphatase (ALP) and increased the activity of triglycerides (TGs) increased (P<0.01) as determined by an enzyme-linked immunosorbent assay. Finally, western blotting revealed that BMSC pretreatment with 20 µm genistein significantly increased peroxisome proliferator-activated receptor γ (PPARγ) protein expression (P<0.01). This suggests that the downregulation of PPARγ may significantly reduce the effect of genistein on cell proliferation, suppress the expression of Runx2, Col I and OC mRNA, and reduce ALP and promote TG activity in BMSCs. Thus, the results of the present study conclude that genistein induces adipogenic differentiation in human BMSCs and suppresses their osteogenic potential by upregulating the expression of PPARγ. In conclusion, genistein may be a promising candidate drug for treatment against osteogenesis. PMID:27168816

  17. Enhanced Osteogenic and Vasculogenic Differentiation Potential of Human Adipose Stem Cells on Biphasic Calcium Phosphate Scaffolds in Fibrin Gels

    PubMed Central

    2016-01-01

    For bone tissue engineering synthetic biphasic calcium phosphate (BCP) with a hydroxyapatite/β-tricalcium phosphate (HA/β-TCP) ratio of 60/40 (BCP60/40) is successfully clinically applied, but the high percentage of HA may hamper efficient scaffold remodelling. Whether BCP with a lower HA/β-TCP ratio (BCP20/80) is more desirable is still unclear. Vascular development is needed before osteogenesis can occur. We aimed to test the osteogenic and/or vasculogenic differentiation potential as well as degradation of composites consisting of human adipose stem cells (ASCs) seeded on BCP60/40 or BCP20/80 incorporated in fibrin gels that trigger neovascularization for bone regeneration. ASC attachment to BCP60/40 and BCP20/80 within 30 min was similar (>93%). After 11 days of culture BCP20/80-based composites showed increased alkaline phosphatase activity and DMP1 gene expression, but not RUNX2 and osteonectin expression, compared to BCP60/40-based composites. BCP20/80-based composites also showed enhanced expression of the vasculogenic markers CD31 and VEGF189, but not VEGF165 and endothelin-1. Collagen-1 and collagen-3 expression was similar in both composites. Fibrin degradation was increased in BCP20/80-based composites at day 7. In conclusion, BCP20/80-based composites showed enhanced osteogenic and vasculogenic differentiation potential compared to BCP60/40-based composites in vitro, suggesting that BCP20/80-based composites might be more promising for in vivo bone augmentation than BCP60/40-based composites. PMID:27547223

  18. 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 γH2AX 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

  19. Linking potential denitrification rates to microbial gene abundances in multiple boreal ecosystems

    NASA Astrophysics Data System (ADS)

    Petersen, D. G.; Blazewicz, S.; Herman, D. J.; Firestone, M. K.; Waldrop, M. P.

    2010-12-01

    The composition and functioning of boreal ecosystems are vulnerable to changes in climate, leading to changes in season length, fire regimes, and soil moisture status. To investigate the influence of vegetation and soil moisture on microbial nitrogen cycling several disparate boreal ecosystems was studied. The two primary objectives were to: (1) determine whether process rates could be predicted solely from soil physical and chemical characteristics and (2) determine if the abundance of functional genes could be an additional explanatory variable. Surface soils were sampled along an elevation-driven hydrologic gradient at the Bonanza Creek LTER that corresponds with five plant communities typical of interior Alaska. The plant communities included a black spruce stand, a deciduous stand, a tussock grassland, an emergent fen, and a rich fen. We examined the chemical composition of the surface organic moss and soil, measured gross N-mineralization, potential rates of nitrification and denitrification (DEA), and abundances of several functional groups of microorganisms from soil cores collected in mid summer. We used quantitative PCR to assess the gene abundances of ammonia oxidizers and denitrifiers based on a functional gene approach. Here, we focus on potential denitrification rates (PDR), and abundance of denitrifyers carrying NirS and NirK genes (nitrate reductase) and NosZ genes (nitrous oxide reductase). PDR increased dramatically with increasing soil moisture along the gradient, from 1 mg N/m2/h at the dry black spruce site to 300 mg N/m2/h in the rich fen, which is very high compared to other poorly drained soil environments. PDR were linearly related to the abundance of functional genes from the microorganisms responsible for this process. Abundances of NirS, NirK and NosZ genes correlated significantly to PDR (r2 = 0.61 p < 0.0001, r2 = 0.45 p < 0.0003, r2 = 0.81 p < 0.0001, respectively). In addition, PDR were better explained by functional gene abundances

  20. Preservation of differentiation and clonogenic potential of human hematopoietic stem and progenitor cells during lyophilization and ambient storage.

    PubMed

    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 microL. Compared to the values for the control cells, there was no statistical difference observed for cells removed