Science.gov

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 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

  16. 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

  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. 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

  2. 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.

  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. 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

  6. 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

  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

    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 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

  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. 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

  9. 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.

  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. 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

  13. 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

  14. 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

  15. 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

  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. 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

  4. 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

  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

    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 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

  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. 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

  1. 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

  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. 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.

  4. 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

  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. 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

  8. 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

  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. 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.

  16. 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

  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. 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

  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 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

  5. 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

  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. 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.

  20. 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

  1. 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

  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

    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 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

  6. 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

  7. 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

  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. 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

  10. 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

  11. 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

  12. 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

  13. 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

  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. 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

  2. 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

  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. 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…

  5. 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.

  6. 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

  7. 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…

  8. 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

  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. 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

  17. 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

  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. 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. …

  4. 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…

  5. 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…

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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.

  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. 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

  15. 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

  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. 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.

  6. 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.

  7. 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

  8. 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

  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. 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.