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Sample records for multiple differentiation potential

  1. Multiple symbol differential detection

    NASA Technical Reports Server (NTRS)

    Divsalar, Dariush (Inventor); Simon, Marvin K. (Inventor)

    1991-01-01

    A differential detection technique for multiple phase shift keying (MPSK) signals is provided which uses a multiple symbol observation interval on the basis of which a joint decision is made regarding the phase of the received symbols. In accordance with the invention, a first difference phase is created between first and second received symbols. Next, the first difference phase is correlated with the possible values thereof to provide a first plurality of intermediate output signals. A second difference phase is next created between second and third received symbols. The second difference phase is correlated with plural possible values thereof to provide a second plurality of intermediate output signals. Next, a third difference phase is created between the first and third symbols. The third difference phase is correlated with plural possible values thereof to provide a third plurality of intermediate output signals. Each of the first plurality of intermediate outputs are combined with each of the second plurality of intermediate outputs and each of the third plurality of intermediate outputs to provide a plurality of possible output values. Finally, a joint decision is made by choosing from the plurality of possible output values the value which represents the best combined correlation of the first, second and third difference values with the possible values thereof.

  2. 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

  3. Multiple Intelligences for Differentiated Learning

    ERIC Educational Resources Information Center

    Williams, R. Bruce

    2007-01-01

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

  4. Multiple bit differential detection of offset QPSK

    NASA Technical Reports Server (NTRS)

    Simon, M.

    2003-01-01

    Analogous to multiple symbol differential detection of quadrature phase-shift-keying, a multiple bit differential detection scheme is described for offset QPSK that also exhibits continuous improvement in performance with increasing observation interval. Being derived from maximum-likelihood (ML) considerations, the proposed scheme is purported to be the most power efficient scheme for such a modulation and detection method.

  5. Evoked potentials in multiple sclerosis.

    PubMed

    Kraft, George H

    2013-11-01

    Before the development of magnetic resonance imaging (MRI), evoked potentials (EPs)-visual evoked potentials, somatosensory evoked potentials, and brain stem auditory evoked responses-were commonly used to determine a second site of disease in patients being evaluated for possible multiple sclerosis (MS). The identification of an area of the central nervous system showing abnormal conduction was used to supplement the abnormal signs identified on the physical examination-thus identifying the "multiple" in MS. This article is a brief overview of additional ways in which central nervous system (CNS) physiology-as measured by EPs-can still contribute value in the management of MS in the era of MRIs.

  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

    2016-11-01

    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. 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.

  9. Full potential multiple scattering theory

    SciTech Connect

    MacLaren, J.M.

    1994-10-20

    A practical method for performing self-consistent electronic structure calculations based upon full-potential multiple-scattering theory is presented. Solutions to the single site Schroedinger equation are obtained by solving coupled channel integral equations for a potential which is analytically continued out to the circumscribing sphere. This potential coincides with the full cell potential inside each atomic cell. Scattering matrices and wavefunctions for the full cell potential are obtained from surface Wronskian relations. The charge density is obtained from the single particle Green`s function. This Green`s function is computed using the cell scattering matrices and wavefunctions using the layer multiple scattering theory. Self consistent solutions require a solution at each iteration to the Poisson equation. The Poisson equation is solved using a variational cellular method. In the approach a local solution to each cell is augmented by adding a series of regular harmonics (solutions to Laplace`s equation). Minimizing the coulomb energy, subject to continuity of the potential across all cell boundary provides an expression for the coefficients of the regular harmonics. This method is applied to BCC Nb. Calculated properties converge well in angular momentum and show comparable accuracy to full potential linearized muffin-tin orbital calculations.

  10. 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…

  11. Multiple scattering theory for space filling potentials

    SciTech Connect

    Butler, W.H. ); Brown, R.G. . Dept. of Physics); Nesbet, R.K. . Almaden Research Center)

    1990-01-01

    Multiple scattering theory (MST) provides an efficient technique for solving the wave equation for the special case of muffin-tin potentials. Here MST is extended to treat space filling non-muffin tin potentials and its validity, accuracy and efficiency are tested by application of the two dimensional empty lattice test. For this test it is found that the traditional formulation of MST does not coverage as the number of partial waves is increased. A simple modification of MST, however, allows this problem to be solved exactly and efficiently. 15 refs., 3 tabs.

  12. 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.

  13. 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…

  14. [Differential diagnosis of dissociative identity disorder (multiple personality disorder)].

    PubMed

    Stübner, S; Völkl, G; Soyka, M

    1998-05-01

    Recently the concept of dissociative identity disorder (formerly known as multiple personality disorder) has attracted increasing public and scientific interest. However, it is rarely diagnosed in the clinical setting. the reported case of a 47-year-old woman with a history of child abuse demonstrates the problems of differential diagnosis. A number of psychopathologic symptoms pointed to a multiple personality disorder, but in the follow-up psychotic symptoms such as delusions, possible hallucinations and bizarre behavior clearly emerged. The differential diagnosis of dissociative identity disorder includes paranoid schizophrenia, as in the case described, borderline personality disorder, hysteria, simulation and the false memory syndrome. Finally, social and cultural factors have to be considered.

  15. Differentiation and transdifferentiation potentials of cancer stem cells

    PubMed Central

    Liu, Allan Yi; Ouyang, Gaoliang

    2015-01-01

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

  16. Differentiation and transdifferentiation potentials of cancer stem cells.

    PubMed

    Huang, Zhengjie; Wu, Tiantian; Liu, Allan Yi; Ouyang, Gaoliang

    2015-11-24

    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

  17. 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

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

    PubMed

    Weisfeld-Adams, James D; Katz Sand, Ilana B; Honce, Justin M; Lublin, Fred D

    2015-03-01

    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.

  19. 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.

  20. Multiple valued floating potentials of Langmuir probes

    NASA Technical Reports Server (NTRS)

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

    1988-01-01

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

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. Tanshinone II A, a multiple target neuroprotectant, promotes caveolae-dependent neuronal differentiation.

    PubMed

    Zhao, Yuming; Xu, Pingxiang; Hu, Shengquan; Du, Libo; Xu, Zhiqing; Zhang, Huan; Cui, Wei; Mak, Shinghung; Xu, Daping; Shen, Jianggang; Han, Yifan; Liu, Yang; Xue, Ming

    2015-10-15

    Neuron loss is one fundamental features of neurodegenerative diseases. Stimulating endogenous neurogenesis, especially neuronal differentiation, might potentially provide therapeutic effects to these diseases. In this study, tanshinone II A (TIIA), a multiple target neuroprotectant, was demonstrated to promote dose-dependent neuronal differentiation in three cell models of immortalized C17.2 neuronal stem cells, rat embryonic cortical neural stem cells (NSCs) and rat PC12 pheochromocytoma cells. In particular, TIIA exerted promising effects on NSCs even at the dose of 3 nM. In PC12 cells, TIIA activated mitogen-activated protein kinase 42/44 (MAPK42/44) and its downstream transcription factor, cAMP response element-binding protein (CREB). In addition, TIIA up-regulated the expressions of brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF). The MEK inhibitor and the antagonist to the receptors of NGF and BDNF could partially attenuate the differentiation effects, indicating that MAPK42/44 mediated BDNF and NGF signals were involved in TIIA's differentiation effects. Caveolin-1 (CAV-1), the major functional protein of membrane caveolae, plays critical roles in the endocytosis of exogenous materials. CAV1, which was activated by TIIA, might help TIIA transport across cell membrane to initiate its differentiation effects. It was proven by the evidences that suppressing the function of caveolin inhibited the differentiation effects of TIIA. Therefore, we concluded that TIIA promoted neuronal differentiation partially through MAPK42/44 mediated BDNF and NGF signals in a caveolae-dependent manner. PMID:26363255

  6. Securinine, a Myeloid Differentiation Agent with Therapeutic Potential for AML

    PubMed Central

    Gupta, Kalpana; Chakrabarti, Amitabha; Rana, Sonia; Ramdeo, Ritu; Roth, Bryan L.; Agarwal, Munna L.; Tse, William; Agarwal, Mukesh K.; Wald, David N.

    2011-01-01

    As the defining feature of Acute Myeloid Leukemia (AML) is a maturation arrest, a highly desirable therapeutic strategy is to induce leukemic cell maturation. This therapeutic strategy has the potential of avoiding the significant side effects that occur with the traditional AML therapeutics. We identified a natural compound securinine, as a leukemia differentiation-inducing agent. Securinine is a plant-derived alkaloid that has previously been used clinically as a therapeutic for primarily neurological related diseases. Securinine induces monocytic differentiation of a wide range of myeloid leukemia cell lines as well as primary leukemic patient samples. Securinine's clinical potential for AML can be seen from its ability to induce significant growth arrest in cell lines and patient samples as well as its activity in significantly impairing the growth of AML tumors in nude mice. In addition, securinine can synergize with currently employed agents such as ATRA and decitabine to induce differentiation. This study has revealed securinine induces differentiation through the activation of DNA damage signaling. Securinine is a promising new monocytic differentiation inducing agent for AML that has seen previous clinical use for non-related disorders. PMID:21731671

  7. 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

  8. 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.

  9. 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

  10. Computing derivatives of a gravity potential by using automatic differentiation

    NASA Astrophysics Data System (ADS)

    Abad, Alberto; Lacruz, Elvis

    2013-10-01

    A new method, based on automatic differentiation technique, has been proposed in this paper to compute the derivatives of the gravity potential. Using this method we can obtain derivatives up to any order. Instead of explicit expressions of the derivatives we use an iterative scheme to simultaneously compute the value of all the desired derivatives. The algorithm here presented can be easily parallelized by using OpenMP with the consequent improvement in CPU-time efficiency.

  11. Applying Metabolomics to differentiate amphibian responses to multiple stressors

    EPA Science Inventory

    Introduction/Objectives/Methods One of the biggest challenges in ecological risk assessment is determining the impact of multiple stressors on individual organisms and populations in ‘real world’ scenarios. Emerging ‘omic technologies, notably, metabolomics, pr...

  12. 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.

  13. 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

  14. 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

  15. 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…

  16. Multiple hormone-inducible enhancers as mediators of differential transcription.

    PubMed Central

    Toohey, M G; Morley, K L; Peterson, D O

    1986-01-01

    Sets of genes under a common regulatory control in a given cell type are often differentially transcribed. The possibility that this differential transcription can be modulated by the number or strength of cis-acting regulatory sequences associated with a given gene was tested by using the glucocorticoid-responsive enhancer element associated with the mouse mammary tumor virus promoter. Results indicate that differential levels of hormone-inducible gene expression can be modulated in an additive way by the number of glucocorticoid-responsive enhancers associated with this promoter. Realization of these effects shows little preference for position of the additional elements with respect to the promoter. When sequences that bind the glucocorticoid receptor in vitro with somewhat lower affinity than the enhancer were tested, these additive effects were not detected. The results support that differential transcription of genes subject to a common regulatory control can be mediated, at least in part, by the number or strength of their associated cis-acting regulatory sequences. Images PMID:3025659

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

    NASA Technical Reports Server (NTRS)

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

    2000-01-01

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

  18. System for measuring multiphase flow using multiple pressure differentials

    DOEpatents

    Fincke, James R.

    2003-01-01

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

  19. Computation of multiple Lie derivatives by algorithmic differentiation

    NASA Astrophysics Data System (ADS)

    Robenack, Klaus

    2008-04-01

    Lie derivatives are often used in nonlinear control and system theory. In general, these Lie derivatives are computed symbolically using computer algebra software. Although this approach is well-suited for small and medium-size problems, it is difficult to apply this technique to very complicated systems. We suggest an alternative method to compute the values of iterated and mixed Lie derivatives by algorithmic differentiation.

  20. 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…

  1. 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.

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. Multiple benign symmetric lipomatosis -- a differential diagnosis of obesity.

    PubMed

    Ardeleanu, V; Chicos, S; Georgescu, C; Tutunaru, D

    2013-01-01

    Benign symmetrical lipomatosis (BSL), or Madelung's disease, is a rare disease characterized by the progressive growth of diffuse, painless, non-enveloped symmetric lipomas. The etiology of this disease remains unknown, although it was associated in the medical literature with alcohol and nicotine abuse, metabolic disorders and a number of malignancies. It is assumed that there is a genetic predisposition for this affliction. The management in such cases is surgical removal of the lipomas, most times in several sessions, but this is often followed by relapse. However, surgical removal of the lipomas can provide satisfactory patient functionality and cosmetic results. The differential diagnosis is made with morbid obesity, Cushing syndrome, angiolipomatosis, encapsulated lipomas, neurofibromatosis, myxoid liposarcoma, lymphoma, salivary gland disease, Frolich and lipomatosis syndrome in patients infected with HIV. The current paper reports the case of a 55 year-old man, who presented with several large lipomatous masses, arranged symmetrically on the front and back of the trunk, and several smaller lipomas in the upper and lower limbs. Treatment consisted of resection of these lipomas in several sessions, without recurrence at one year after the last operation.

  8. 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

  9. Proteasome inhibition and its therapeutic potential in multiple myeloma

    PubMed Central

    Chari, Ajai; Mazumder, Amitabha; Jagannath, Sundar

    2010-01-01

    Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years. In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease. In this article, we briefly review the preclinical and clinical development of the drug as the underpinning for a systematic review of the large number of clinical trials that are beginning to shed some light on the full therapeutic potential of bortezomib in myeloma. We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma. PMID:21116326

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

    SciTech Connect

    Chen, Da-Ren; Cheng, Mengdawn

    2007-01-01

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

  11. Differential regulation of the multiple flagellins in spirochetes.

    PubMed

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

    2010-05-01

    The expression of flagellin genes in most bacteria is typically regulated by the flagellum-specific sigma(28) factor FliA, and an anti-sigma(28) 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 sigma(28), whereas the flaA and flaB3 genes are controlled by sigma(70). 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.

  12. 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…

  13. Increasing multiple myeloma mortality among the elderly: a manifestation of aging and differential survival.

    PubMed

    Riggs, J E

    1995-01-13

    Increasing multiple myeloma incidence and mortality among the elderly in industrialized nations has been attributed to associated environmental carcinogens. Age-specific multiple myeloma mortality rates in the United States from 1968 to 1989 were analyzed using the Strehler-Mildvan modification of the Gompertz relationship between aging and mortality. The results suggest that worsening environmental influences are not responsible for increasing multiple myeloma mortality among the elderly. Differential survival, a concept originally popularized by Charles Darwin, and its effect upon the surviving gene pool in an aging population is an alternative explanation for increasing multiple myeloma incidence and mortality in the elderly.

  14. PTHrP and Indian hedgehog control differentiation of growth plate chondrocytes at multiple steps.

    PubMed

    Kobayashi, Tatsuya; Chung, Ung-Il; Schipani, Ernestina; Starbuck, Michael; Karsenty, Gerard; Katagiri, Takenobu; Goad, Dale L; Lanske, Beate; Kronenberg, Henry M

    2002-06-01

    In developing murine growth plates, chondrocytes near the articular surface (periarticular chondrocytes) proliferate, differentiate into flat column-forming proliferating cells (columnar chondrocytes), stop dividing and finally differentiate into hypertrophic cells. Indian hedgehog (Ihh), which is predominantly expressed in prehypertrophic cells, stimulates expression of parathyroid hormone (PTH)-related peptide (PTHrP) which negatively regulates terminal chondrocyte differentiation through the PTH/PTHrP receptor (PPR). However, the roles of PTHrP and Ihh in regulating earlier steps in chondrocyte differentiation are unclear. We present novel mouse models with PPR abnormalities that help clarify these roles. In mice with chondrocyte-specific PPR ablation and mice with reduced PPR expression, chondrocyte differentiation was accelerated not only at the terminal step but also at an earlier step: periarticular to columnar differentiation. In these models, upregulation of Ihh action in the periarticular region was also observed. In the third model in which the PPR was disrupted in about 30% of columnar chondrocytes, Ihh action in the periarticular chondrocytes was upregulated because of ectopically differentiated hypertrophic chondrocytes that had lost PPR. Acceleration of periarticular to columnar differentiation was also noted in this mouse, while most of periarticular chondrocytes retained PPR signaling. These data suggest that Ihh positively controls differentiation of periarticular chondrocytes independently of PTHrP. Thus, chondrocyte differentiation is controlled at multiple steps by PTHrP and Ihh through the mutual regulation of their activities. PMID:12050144

  15. [Differential diagnosis of multiple pulmonary coin lesions--pulmonary hyaline granuloma].

    PubMed

    Banaschak, S; Müller, K M

    1996-02-01

    In addition to metastases, the differential diagnosis of pulmonary nodules also includes tuberculosis, sarcoidosis, and silicosis. Rarer diseases such as amyloid tumors, rheumatic nodules, and plasma-cell granulomas can, depending on the clinical situation, be the cause of this finding. For the example of the clinical picture of pulmonary hyalinizing granuloma, the differential diagnosis of multiple pulmonary nodules is illustrated under consideration of the pathognomonic, morphologic observations. PMID:8868595

  16. 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

  17. 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

  18. 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.

  19. 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

  20. 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

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

    ERIC Educational Resources Information Center

    Magis, David; De Boeck, Paul

    2011-01-01

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

  2. 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.

  3. 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.

  4. Application of automatic differentiation to trajectory optimization via direct multiple shooting

    NASA Astrophysics Data System (ADS)

    Garza, David Marcelo

    2003-10-01

    Automatic differentiation, also called computational differentiation and algorithmic differentiation, is the process of computing the derivatives or Taylor series of functions from the computer source code implementing the functions. To date, general-purpose trajectory optimization codes have relied on finite-differencing to compute the gradients needed by the nonlinear programming (NLP) algorithms within the codes. These codes typically support the selection of an arbitrary objective and constraint set from a library of a few hundred output variables. The use of automatic differentiation in these trajectory optimization programs can provide objective and constraint gradients to the same precision as the underlying functions without requiring the generation of hundreds of analytic derivative expressions by hand or via symbolic algebra packages. This work combines automatic differentiation with a direct multiple shooting method and uses the resulting method to solve a pair of example problems. The first is the well-known lunar launch problem, while the second is a launch vehicle ascent problem similar in complexity to that which would be computed by a program such as the Program to Optimize Simulated Trajectories (POST) for use in vehicle design studies. Results include comparisons of convergence behavior of the NLP problem and solution accuracy. Tests comparing the use of Euler angles versus quaternion elements as control variables demonstrate the versatility of automatic differentiation. For loose convergence levels automatic differentiation provided faster convergence than finite differencing on the launcher ascent problem. For tight accuracy requirements, automatic differentiation resulted in fewer major iterations on the lunar launch problem.

  5. 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

  6. Alignment estimation performances of merit function regression with differential wavefront sampling in multiple design configuration optimization

    NASA Astrophysics Data System (ADS)

    Oh, Eunsong; Kim, Sug-Whan; Cho, Seongick; Ryu, Joo-Hyung

    2011-10-01

    In our earlier study[12], we suggested a new alignment algorithm called Multiple Design Configuration Optimization (MDCO hereafter) method combining the merit function regression (MFR) computation with the differential wavefront sampling method (DWS). In this study, we report alignment state estimation performances of the method for three target optical systems (i.e. i) a two-mirror Cassegrain telescope of 58mm in diameter for deep space earth observation, ii) a three-mirror anastigmat of 210mm in aperture for ocean monitoring from the geostationary orbit, and iii) on-axis/off-axis pairs of a extremely large telescope of 27.4m in aperture). First we introduced known amounts of alignment state disturbances to the target optical system elements. Example alignment parameter ranges may include, but not limited to, from 800microns to 10mm in decenter, and from 0.1 to 1.0 degree in tilt. We then ran alignment state estimation simulation using MDCO, MFR and DWS. The simulation results show that MDCO yields much better estimation performance than MFR and DWS over the alignment disturbance level of up to 150 times larger than the required tolerances. In particular, with its simple single field measurement, MDCO exhibits greater practicality and application potentials for shop floor optical testing environment than MFR and DWS.

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

    USGS Publications Warehouse

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

    2013-01-01

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

  8. Selective oestrogen receptor modulators differentially potentiate brain mitochondrial function.

    PubMed

    Irwin, R W; Yao, J; To, J; Hamilton, R T; Cadenas, E; Brinton, R D

    2012-01-01

    The mitochondrial energy-transducing capacity of the brain is important for long-term neurological health and is influenced by endocrine hormone responsiveness. The present study aimed to determine the role of oestrogen receptor (ER) subtypes in regulating mitochondrial function using selective agonists for ERα (propylpyrazoletriol; PPT) and ERβ (diarylpropionitrile; DPN). Ovariectomised female rats were treated with 17β-oestradiol (E(2) ), PPT, DPN or vehicle control. Both ER selective agonists significantly increased the mitochondrial respiratory control ratio and cytochrome oxidase (COX) activity relative to vehicle. Western blots of purified whole brain mitochondria detected ERα and, to a greater extent, ERβ localisation. Pre-treatment with DPN, an ERβ agonist, significantly increased ERβ association with mitochondria. In the hippocampus, DPN activated mitochondrial DNA-encoded COX I expression, whereas PPT was ineffective, indicating that mechanistically ERβ, and not ERα, activated mitochondrial transcriptional machinery. Both selective ER agonists increased protein expression of nuclear DNA-encoded COX IV, suggesting that activation of ERβ or ERα is sufficient. Selective ER agonists up-regulated a panel of bioenergetic enzymes and antioxidant defence proteins. Up-regulated proteins included pyruvate dehydrogenase, ATP synthase, manganese superoxide dismutase and peroxiredoxin V. In vitro, whole cell metabolism was assessed in live primary cultured hippocampal neurones and mixed glia. The results of analyses conducted in vitro were consistent with data obtained in vivo. Furthermore, lipid peroxides, accumulated as a result of hormone deprivation, were significantly reduced by E(2) , PPT and DPN. These findings suggest that the activation of both ERα and ERβ is differentially required to potentiate mitochondrial function in brain. As active components in hormone therapy, synthetically designed oestrogens as well as natural phyto-oestrogen cocktails

  9. Convergent functional genomics of oligodendrocyte differentiation identifies multiple autoinhibitory signaling circuits.

    PubMed

    Gobert, Rosanna Pescini; Joubert, Lara; Curchod, Marie-Laure; Salvat, Catherine; Foucault, Isabelle; Jorand-Lebrun, Catherine; Lamarine, Marc; Peixoto, Hélène; Vignaud, Chloé; Frémaux, Christèle; Jomotte, Thérèse; Françon, Bernard; Alliod, Chantal; Bernasconi, Lilia; Abderrahim, Hadi; Perrin, Dominique; Bombrun, Agnes; Zanoguera, Francisca; Rommel, Christian; Hooft van Huijsduijnen, Rob

    2009-03-01

    Inadequate remyelination of brain white matter lesions has been associated with a failure of oligodendrocyte precursors to differentiate into mature, myelin-producing cells. In order to better understand which genes play a critical role in oligodendrocyte differentiation, we performed time-dependent, genome-wide gene expression studies of mouse Oli-neu cells as they differentiate into process-forming and myelin basic protein-producing cells, following treatment with three different agents. Our data indicate that different inducers activate distinct pathways that ultimately converge into the completely differentiated state, where regulated gene sets overlap maximally. In order to also gain insight into the functional role of genes that are regulated in this process, we silenced 88 of these genes using small interfering RNA and identified multiple repressors of spontaneous differentiation of Oli-neu, most of which were confirmed in rat primary oligodendrocyte precursors cells. Among these repressors were CNP, a well-known myelin constituent, and three phosphatases, each known to negatively control mitogen-activated protein kinase cascades. We show that a novel inhibitor for one of the identified genes, dual-specificity phosphatase DUSP10/MKP5, was also capable of inducing oligodendrocyte differentiation in primary oligodendrocyte precursors. Oligodendrocytic differentiation feedback loops may therefore yield pharmacological targets to treat disease related to dysfunctional myelin deposition.

  10. Convergent Functional Genomics of Oligodendrocyte Differentiation Identifies Multiple Autoinhibitory Signaling Circuits▿ †

    PubMed Central

    Pescini Gobert, Rosanna; Joubert, Lara; Curchod, Marie-Laure; Salvat, Catherine; Foucault, Isabelle; Jorand-Lebrun, Catherine; Lamarine, Marc; Peixoto, Hélène; Vignaud, Chloé; Frémaux, Christèle; Jomotte, Thérèse; Françon, Bernard; Alliod, Chantal; Bernasconi, Lilia; Abderrahim, Hadi; Perrin, Dominique; Bombrun, Agnes; Zanoguera, Francisca; Rommel, Christian; van Huijsduijnen, Rob Hooft

    2009-01-01

    Inadequate remyelination of brain white matter lesions has been associated with a failure of oligodendrocyte precursors to differentiate into mature, myelin-producing cells. In order to better understand which genes play a critical role in oligodendrocyte differentiation, we performed time-dependent, genome-wide gene expression studies of mouse Oli-neu cells as they differentiate into process-forming and myelin basic protein-producing cells, following treatment with three different agents. Our data indicate that different inducers activate distinct pathways that ultimately converge into the completely differentiated state, where regulated gene sets overlap maximally. In order to also gain insight into the functional role of genes that are regulated in this process, we silenced 88 of these genes using small interfering RNA and identified multiple repressors of spontaneous differentiation of Oli-neu, most of which were confirmed in rat primary oligodendrocyte precursors cells. Among these repressors were CNP, a well-known myelin constituent, and three phosphatases, each known to negatively control mitogen-activated protein kinase cascades. We show that a novel inhibitor for one of the identified genes, dual-specificity phosphatase DUSP10/MKP5, was also capable of inducing oligodendrocyte differentiation in primary oligodendrocyte precursors. Oligodendrocytic differentiation feedback loops may therefore yield pharmacological targets to treat disease related to dysfunctional myelin deposition. PMID:19139271

  11. 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

  12. Multiple-scattering effect on ozone retrieval from space-based differential absorption lidar measurements.

    PubMed

    Pal, S R; Bissonnette, L R

    1998-09-20

    Single-scattering and multiple-scattering lidar signals are calculated for a spaceborne differential absorption lidar system for global ozone measurements at the on and off wavelength pair at 305 and 315 nm. The effect of multiple scattering is found to be negligible on stratospheric and tropospheric ozone retrieval under background stratospheric aerosol. Under low-visibility conditions in the planetary boundary layer the presence of multiple scattering causes an overestimation in maritime aerosol and an underestimation in urban as well as in rural aerosol. This effect is also examined in three cirrus models. The multiple scattering does not permit accurate ozone retrieval within cirrus; however, below it the solution recovers somewhat with generally an underestimation depending on the type and density of cirrus. The effect of aerosol and Rayleigh extinction on the ozone retrieval is also discussed.

  13. Multiple positive solutions to a coupled systems of nonlinear fractional differential equations.

    PubMed

    Shah, Kamal; Khan, Rahmat Ali

    2016-01-01

    In this article, we study existence, uniqueness and nonexistence of positive solution to a highly nonlinear coupled system of fractional order differential equations. Necessary and sufficient conditions for the existence and uniqueness of positive solution are developed by using Perov's fixed point theorem for the considered problem. Further, we also established sufficient conditions for existence of multiplicity results for positive solutions. Also, we developed some conditions under which the considered coupled system of fractional order differential equations has no positive solution. Appropriate examples are also provided which demonstrate our results. PMID:27478733

  14. 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.

  15. 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.

  16. 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

  17. Differential prediction and the use of multiple predictors: the omitted variables problem.

    PubMed

    Sackett, Paul R; Laczo, Roxanne M; Lippe, Zachary P

    2003-12-01

    Moderated regression is widely used to examine differential prediction by race or gender. When using multiple predictors in a selection system, guidance as to whether differential prediction analysis should be conducted on each predictor individually, or on the set of predictors in combination, is lacking. Analyzing predictors individually creates the possibility of an omitted variable problem. Army Project A data were used to examine differential prediction by race with the use of personality measures for 79 predictor-criterion combinations. Traditional analysis indicated predictive bias by intercept in 45 instances and by slope in 7 instances; the inclusion of an Armed Services Vocational Aptitude Battery general factor as an additional predictor changed the conclusion in 32 cases for the intercept and in 3 cases for the slope.

  18. 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.

  19. Ab initio interionic potentials for UN by multiple lattice inversion

    NASA Astrophysics Data System (ADS)

    Chen, P. H.; Wang, X. L.; Lai, X. C.; Li, G.; Ao, B. Y.; Long, Y.

    2010-09-01

    Based on the Chen-Möbius lattice inversion and a series of pseudopotential total-energy curves, interionic pair potentials for UN were derived. By means of molecular dynamic (MD), we have examined this interionic potentials. Comparing with the experimental data, the thermal expansion coefficient and the compressibility were well reproduced by this potentials.

  20. 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

  1. Serum-free spheroid suspension culture maintains high proliferation and differentiation potentials of mesenchymal stem cells

    PubMed Central

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

    2016-01-01

    There have been many clinical trials recently using ex vivo-expanded human mesenchymal stem cells (MSCs) to treat several indications such as graft-versus-host disease, acute myocardial infarction, Crohn’s disease, and multiple sclerosis. However, the conventional 2-dimensional (2D) culture of MSCs is laborious and limited in scale potential. The large dosage requirement for many of the indications further exacerbates this manufacturing challenge. In contrast, spheroid MSC culture does not require a cell attachment surface and is amenable to large-scale suspension cell culture techniques, such as stirred-tank bioreactors. In this present study, we developed and optimized serum free media for culturing MSC spheroids. We used Design of Experiment (DoE)-based strategies to systematically evaluate media mixtures and a panel of different components. The optimization yielded two prototype media that could allow MSCs to form aggregates and proliferate in both static cultures and dynamic cultures. The expanded MSCs expressed the expected surface markers for mesenchymal cells (CD73, CD90 and CD105). In addition, the expanded cells demonstrated multipotency and differentiated to the osteocyte, chondrocyte and adipocyte lineages, which showed similar or enhanced differentiation levels compared with serum-containing adherent cultures. PMID:24616445

  2. Doubly differential single and multiple ionization of krypton by electron impact

    SciTech Connect

    Lucio, O. G. de; Gavin, J.; DuBois, R. D.

    2007-05-15

    Differential measurements for single and multiple ionization of Kr by 240 and 500 eV electron impact are presented. Using a pulsed extraction field, Kr{sup +}, Kr{sup 2+}, and Kr{sup 3+} ions were measured in coincidence with scattered electrons for energy losses up to 120 eV and scattering angles between 16 degree sign and 90 degree sign . Scaling properties of the doubly differential cross sections (DDCS) are investigated as a function of energy loss, scattering angle, and momentum transfer. It is shown that scaling the DDCS as outlined by Kim and Inokuti and plotting them versus a parameter consisting of the momentum transfer divided by the square root of the impact energy times 1-cos({theta}), where {theta} is the scattering angle, yielded similar curves, but with different magnitudes, for single and multiple ionization. Normalizing these curves together produced two universal curves, one appropriate for single and multiple electron emission at larger scattering angles ({theta}{>=}30 degree sign ) and one appropriate for small scattering angles ({theta}<30 degree sign )

  3. 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

  4. 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

  5. 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.

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

    PubMed

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

    2016-02-16

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

  7. 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.

  8. Differentiating between heat pain intensities: the combined effect of multiple autonomic parameters.

    PubMed

    Treister, Roi; Kliger, Mark; Zuckerman, Galit; Goor Aryeh, Itay; Eisenberg, Elon

    2012-09-01

    Although it is well known that pain induces changes in autonomic parameters, the extent to which these changes correlate with the experience of pain is under debate. The aim of the present study was to compare a combination of multiple autonomic parameters and each parameter alone in their ability to differentiate among 4 categories of pain intensity. Tonic heat stimuli (1minute) were individually adjusted to induce no pain, low, medium, and high pain in 45 healthy volunteers. Electrocardiogram, photoplethysmogram, and galvanic skin response were recorded, and the following parameters were calculated: heart rate; heart rate variability-high frequency (0.15 to 0.4Hz) spectral power; skin conductance level; number of skin conduction fluctuations; and photoplethysmographic pulse wave amplitude. A combination of parameters was created by fitting an ordinal cumulative logit model to the data and using linear coefficients of the model. Friedman test with post-hoc Wilcoxon test were used to compare between pain intensity categories for every parameter alone and for their linear combination. All of the parameters successfully differentiated between no pain and all other pain categories. However, none of the parameters differentiated between all 3 pain categories (i.e., low and medium; medium and high; low and high). In contrast, the linear combination of parameters significantly differentiated not only between pain and no pain, but also between all pain categories (P<.001 to .02). These results suggest that multiparameter approaches should be further investigated to make progress toward reliable autonomic-based pain assessment.

  9. 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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    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

    2015-05-30

    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.

  12. 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

  13. 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

  14. 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.

  15. 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.

  16. 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

  17. Smoldering multiple myeloma: present position and potential promises.

    PubMed

    Tageja, Nishant; Manasanch, Elisabet E; Korde, Neha; Kwok, Mary; Mailankody, Sham; Bhutani, Manisha; Roschewski, Mark; Landgren, Ola

    2014-01-01

    Since smoldering multiple myeloma (SMM) was first described over three decades ago based on a case series of six patients, its definition and our understanding of the entity have evolved considerably. The risk of progression to symptomatic myeloma (MM) varies greatly among individuals diagnosed with myeloma precursor disease. Epidemiologic, molecular, flow cytometric and radiological techniques have demonstrated that this transformation to MM from precursor states is not sudden but rather a continuous overlapping series of events with evidence of end-organ damage that could manifest in the earliest stages of disease. Contemporary antimyeloma therapies can yield rapid, deep, and durable responses with manageable toxicities, and molecular-cell-based measures are now available to rule out minimal residual disease. With this information, clinical studies with correlative measures can now be developed to test the fundamental hypothesis that intervention in early myeloma may provide a measurable clinical benefit to patients by either delaying progression or eradicating plasma cell clones. PMID:24112232

  18. 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

  19. 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.

  20. Somitogenesis clock-wave initiation requires differential decay and multiple binding sites for clock protein.

    PubMed

    Campanelli, Mark; Gedeon, Tomás

    2010-04-01

    Somitogenesis is a process common to all vertebrate embryos in which repeated blocks of cells arise from the presomitic mesoderm (PSM) to lay a foundational pattern for trunk and tail development. Somites form in the wake of passing waves of periodic gene expression that originate in the tailbud and sweep posteriorly across the PSM. Previous work has suggested that the waves result from a spatiotemporally graded control protein that affects the oscillation rate of clock-gene expression. With a minimally constructed mathematical model, we study the contribution of two control mechanisms to the initial formation of this gene-expression wave. We test four biologically motivated model scenarios with either one or two clock protein transcription binding sites, and with or without differential decay rates for clock protein monomers and dimers. We examine the sensitivity of wave formation with respect to multiple model parameters and robustness to heterogeneity in cell population. We find that only a model with both multiple binding sites and differential decay rates is able to reproduce experimentally observed waveforms. Our results show that the experimentally observed characteristics of somitogenesis wave initiation constrain the underlying genetic control mechanisms.

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

    PubMed Central

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

    2008-01-01

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

  2. 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

  3. 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

  4. Multiple roles for HOXA3 in regulating thymus and parathyroid differentiation and morphogenesis in mouse

    PubMed Central

    Chojnowski, Jena L.; Masuda, Kyoko; Trau, Heidi A.; Thomas, Kirk; Capecchi, Mario; Manley, Nancy R.

    2014-01-01

    Hoxa3 was the first Hox gene to be mutated by gene targeting in mice and is required for the development of multiple endoderm and neural crest cell (NCC)-derived structures in the pharyngeal region. Previous studies have shown that the Hoxa3 null mutant lacks third pharyngeal pouch derivatives, the thymus and parathyroids by E18.5, and organ-specific markers are absent or downregulated during initial organogenesis. Our current analysis of the Hoxa3 null mutant shows that organ-specific domains did undergo initial patterning, but the location and timing of key regional markers within the pouch, including Tbx1, Bmp4 and Fgf8, were altered. Expression of the parathyroid marker Gcm2 was initiated but was quickly downregulated and differentiation failed; by contrast, thymus markers were delayed but achieved normal levels, concurrent with complete loss through apoptosis. To determine the cell type-specific roles of Hoxa3 in third pharyngeal pouch development, we analyzed tissue-specific mutants using endoderm and/or NCC-specific Cre drivers. Simultaneous deletion with both drivers resulted in athymia at E18.5, similar to the null. By contrast, the individual tissue-specific Hoxa3 deletions resulted in small, ectopic thymi, although each had a unique phenotype. Hoxa3 was primarily required in NCCs for morphogenesis. In endoderm, Hoxa3 temporally regulated initiation of the thymus program and was required in a cell-autonomous manner for parathyroid differentiation. Furthermore, Hoxa3 was required for survival of third pharyngeal pouch-derived organs, but expression in either tissue was sufficient for this function. These data show that Hoxa3 has multiple complex and tissue-specific functions during patterning, differentiation and morphogenesis of the thymus and parathyroids. PMID:25249461

  5. 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…

  6. 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

  7. 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

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

    PubMed Central

    Deng, Shangkun; Sakurai, Akito

    2014-01-01

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

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

    PubMed

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

    2015-06-01

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

  10. 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

  11. 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

  12. Differential associations of early callous-unemotional, oppositional, and ADHD behaviors: multiple domains within early-starting conduct problems?

    PubMed Central

    Waller, Rebecca; Hyde, Luke W.; Grabell, Adam S.; Alves, Martha L.; Olson, Sheryl L.

    2016-01-01

    Background Early-starting child conduct problems (CP) are linked to the development of persistent antisocial behavior. Researchers have theorized multiple pathways to CP and that CP comprise separable domains, marked by callous unemotional (CU) behavior, oppositional behavior, or ADHD symptoms. However, a lack of empirical evidence exists from studies that have examined whether there are unique correlates of these domains. Methods We examined differential correlates of CU, oppositional, and ADHD behaviors during the preschool years to test their potentially distinct nomological networks. Multi-method data, including parent and teacher reports and observations of child behavior, were drawn from a prospective, longitudinal study of children assessed at age 3 and age 6 (N=240; 48% female). Results Dimensions of CU, oppositional and ADHD behaviors were separable within Confirmatory Factor Analyses across mother and father reports. There were differential associations between CU, oppositional, and ADHD behaviors and socioemotional, cognitive, and behavioral outcomes: CU behavior was uniquely related to lower moral regulation, guilt, and empathy. ADHD was uniquely related to lower attentional focusing and observed effortful control. Finally, CU behavior uniquely predicted increases in teacher-reported externalizing from ages 3–6 over and above covariates, and ADHD and oppositional behavior. Conclusions Consistent with theory, dimensions of CU, ADHD, and oppositional behavior demonstrated separable nomological networks representing separable facets within early-starting CP. PMID:25251938

  13. Differential use of multiple replication origins in the ribosomal DNA episome of the protozoan parasite Entamoeba histolytica.

    PubMed

    Ghosh, Soma; Satish, S; Tyagi, Sonika; Bhattacharya, Alok; Bhattacharya, Sudha

    2003-04-15

    The factors that control the initiation of eukaryotic DNA replication from defined origins (oris) on the chromosome remain incompletely resolved. Here we show that the circular rDNA episome of the human pathogen Entamoeba histolytica contains multiple potential oris, which are utilized in a differential manner. The primary ori in exponentially growing cells was mapped close to the promoter of rRNA genes in the upstream intergenic spacer (IGS) by two-dimensional gel electrophoresis. Replication initiated predominantly from the upstream IGS and terminated in the downstream IGS. However, when serum-starved cells were allowed to resume growth, the early oris which became activated were located in other parts of the molecule. Later the ori in the upstream IGS became activated, with concomitant silencing of the early oris. When the upstream IGS was located ectopically in an artificial plasmid, it again lost ori activity, while other parts of the rDNA episome could function as oris in this system. Therefore, the activation or silencing of the ori in this episome is context dependent, as is also the case with many eukaryotic replicons. This is the first replication origin to be mapped in this primitive protozoan and will provide an opportunity to define the factors involved in differential ori activity, and their comparison with metazoans. PMID:12682354

  14. 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

  15. Differential cerebro spinal fluid proteome investigation of Leber hereditary optic neuropathy (LHON) and multiple sclerosis.

    PubMed

    D'Aguanno, Simona; Barassi, Alessandra; Lupisella, Santina; d'eril, Gianlodovico Melzi; Del Boccio, Piero; Pieragostino, Damiana; Pallotti, Francesco; Carelli, Valerio; Valentino, Maria Lucia; Liguori, Rocco; Avoni, Patrizia; Bernardini, Sergio; Gambi, Domenico; Urbani, Andrea; Federici, Giorgio

    2008-01-01

    Leber's hereditary optic neuropathy (LHON) is a genetic disease leading to the loss of central vision and optic nerve atrophy. The existence of occasional cases of LHON patients developing a Multiple Sclerosis (MS)-like illness and the hypothesis that mtDNA variants may be involved in MS suggest the possibility of some common molecular mechanisms linking the two diseases. We have pursued a comparative proteomics approach on cerebrospinal fluid (CSF) samples from LHON and MS patients, as well as healthy donors by employing 2-DE gel separations coupled to MALDI-TOF-MS and nLC-MS/MS investigations. 7 protein spots showed significant differential distribution among the three groups. Both CSF of LHON or MS patients are characterized by lower level of transthyretin dimer adduct while a specific up regulation of Apo A-IV was detected in LHON CSF.

  16. 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.

  17. Regulation of the terminal event in cellular differentiation: biological mechanisms of the loss of proliferative potential

    PubMed Central

    1986-01-01

    Human plasma has been demonstrated to contain factors that induce the sequential expression of nonterminal and terminal adipocyte differentiation in 3T3 T mesenchymal stem cells. We now report the development of methods for the isolation of purified populations of nonterminally differentiated cells and terminally differentiated cells, and we show that it is possible to experimentally induce transition from the nonterminal to the terminal state of differentiation. With this model system it is therefore now possible to examine the biological and molecular processes associated with the terminal event in differentiation, i.e., the irreversible loss of proliferative potential. In this regard, we demonstrate that transition from the nonterminal to terminal state of differentiation is a complex metabolic process that consists of at least two steps and that this process can be triggered by pulse exposure to an inducer for approximately 12 h but that approximately 24-48 h is required for the process to be completed. The data also establish that induction of the terminal event in differentiation requires protein synthesis but not RNA and DNA synthesis. These and additional results suggest that loss of proliferative potential associated with the terminal event in cellular differentiation is a distinct regulatory process, and we suggest that defects in this regulatory process may be of etiological significance in the pathogenesis of specific human diseases, especially cancer. PMID:2422182

  18. 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

  19. Multiple Signaling Pathways Converge on the Cbfa1/Runx2 Transcription Factor to Regulate Osteoblast Differentiation

    PubMed Central

    Franceschi, Renny T.; Xiao, Guozhi; Jiang, Di; Gopalakrishnan, Rajaram; Yang, Shuying; Reith, Elizabeth

    2013-01-01

    The Cbfa1/Runx2 transcription factor is essential for osteoblast differentiation. However, levels of Runx2 are often not well correlated with its transcriptional activity suggesting that this factor must be activated either by covalent modification or through interactions with other nuclear components. Runx2 is phosphorylated and activated by the mitogen-activated protein kinase (MAPK) pathway. This pathway is stimulated in at least two ways: by binding of type I collagen to β2β1 integrins on the osteoblast surface and by treatment of cells with the osteogenic growth factor, FGF2. Protein kinase A (PKA) also may phosphorylate/activate Runx2 under certain conditions. Runx2 activity also is enhanced by factors known to stimulate specific signal transduction pathways such as PTH/PTHrP (signals through PKA and PKC pathways) and BMPs (Signal through Smad proteins). Interactions with Runx2 are complex involving both binding of distinct components such as AP-1 factors and Smads to separate sites on DNA, direct interactions between Runx2 and AP-1/Smad factors and MAPK or PKA-dependent Runx2 phosphorylation. These findings suggest that Runx2 plays a central role in coordinating multiple signals involved in osteoblast differentiation. PMID:12952183

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

    SciTech Connect

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

    1996-05-01

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

  1. Identifying differential expression in multiple SAGE libraries: an overdispersed log-linear model approach

    PubMed Central

    Lu, Jun; Tomfohr, John K; Kepler, Thomas B

    2005-01-01

    Background In testing for differential gene expression involving multiple serial analysis of gene expression (SAGE) libraries, it is critical to account for both between and within library variation. Several methods have been proposed, including the t test, tw test, and an overdispersed logistic regression approach. The merits of these tests, however, have not been fully evaluated. Questions still remain on whether further improvements can be made. Results In this article, we introduce an overdispersed log-linear model approach to analyzing SAGE; we evaluate and compare its performance with three other tests: the two-sample t test, tw test and another based on overdispersed logistic linear regression. Analysis of simulated and real datasets show that both the log-linear and logistic overdispersion methods generally perform better than the t and tw tests; the log-linear method is further found to have better performance than the logistic method, showing equal or higher statistical power over a range of parameter values and with different data distributions. Conclusion Overdispersed log-linear models provide an attractive and reliable framework for analyzing SAGE experiments involving multiple libraries. For convenience, the implementation of this method is available through a user-friendly web-interface available at . PMID:15987513

  2. 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

  3. 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

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

    SciTech Connect

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

    2012-12-10

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

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

    PubMed Central

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

    2009-01-01

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

  6. Clonal analysis of the differentiation potential of human adipose-derived adult stem cells.

    PubMed

    Guilak, Farshid; Lott, Kristen E; Awad, Hani A; Cao, Qiongfang; Hicok, Kevin C; Fermor, Beverley; Gimble, Jeffrey M

    2006-01-01

    Pools of human adipose-derived adult stem (hADAS) cells can exhibit multiple differentiated phenotypes under appropriate in vitro culture conditions. Because adipose tissue is abundant and easily accessible, hADAS cells offer a promising source of cells for tissue engineering and other cell-based therapies. However, it is unclear whether individual hADAS cells can give rise to multiple differentiated phenotypes or whether each phenotype arises from a subset of committed progenitor cells that exists within a heterogeneous population. The goal of this study was to test the hypothesis that single hADAS are multipotent at a clonal level. hADAS cells were isolated from liposuction waste, and ring cloning was performed to select cells derived from a single progenitor cell. Forty-five clones were expanded through four passages and then induced for adipogenesis, osteogenesis, chondrogenesis, and neurogenesis using lineage-specific differentiation media. Quantitative differentiation criteria for each lineage were determined using histological and biochemical analyses. Eighty one percent of the hADAS cell clones differentiated into at least one of the lineages. In addition, 52% of the hADAS cell clones differentiated into two or more of the lineages. More clones expressed phenotypes of osteoblasts (48%), chondrocytes (43%), and neuron-like cells (52%) than of adipocytes (12%), possibly due to the loss of adipogenic ability after repeated subcultures. The findings are consistent with the hypothesis that hADAS cells are a type of multipotent adult stem cell and not solely a mixed population of unipotent progenitor cells. However, it is important to exercise caution in interpreting these results until they are validated using functional in vivo assays.

  7. 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

  8. 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

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

    PubMed Central

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

    1996-01-01

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

  10. Differential effects of diltiazem on glutamate potentials and excitatory junctional potentials at the crayfish neuromuscular junction.

    PubMed Central

    Ishida, M; Shinozaki, H

    1980-01-01

    1. The effects of diltiazem on glutamate potentials and excitatory junctional potentials (e.j.p.s) were investigated in the crayfish neuromuscular junction. 2. When diltiazem (0.3 mM) was added to the perfusion fluid, the ionophoretic glutamate potential was reduced to about half, whereas the peak amplitude of successive e.j.p.s elicited by a train of pulses of 100/sec increased by about 2 times. 3. It was suggested that diltiazem was a non-competitive inhibitor of L-glutamate. The reduction of the response to applied glutamate was not due to the acceleration of desensitization of the glutamate receptor. The rate of recovery from desensitization was delayzed by diltiazem. 4. The increase in amplitude of e.j.p.s caused by diltiazem was due to the increase in membrane resistance. The quantum content and size of extracellular e.j.p.s were not affected by diltiazem. 5. It was substantiated using the micro-electrode technique that the glutamate sensitive area coincided with the neuromuscular junctional area. 6. The pharmacological difference between glutamate potentials and e.j.p.s revealed in the present study is difficult to explain on the glutamate transmitter hypothesis. One explanation worthy to be considered is that there are two pharmacologically different kinds of receptors sensitive to L-glutamate. PMID:7359406

  11. Differential School Effects among Low, Middle, and High Social Class Composition Schools: A Multiple Group, Multilevel Latent Growth Curve Analysis

    ERIC Educational Resources Information Center

    Palardy, Gregory J.

    2008-01-01

    This study uses large-scale survey data and a multiple group, multilevel latent growth curve model to examine differential school effects between low, middle, and high social class composition public schools. The results show that the effects of school inputs and school practices on learning differ across the 3 subpopulations. Moreover, student…

  12. 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

  13. 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

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

    PubMed Central

    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

  15. 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

  16. 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

  17. In vitro differentiation potential of human haematopoietic CD34(+) cells towards pancreatic β-cells.

    PubMed

    Sunitha, Manne Mudhu; Srikanth, Lokanathan; Santhosh Kumar, Pasupuleti; Chandrasekhar, Chodimella; Sarma, Potukuchi Venkata Gurunadha Krishna

    2016-10-01

    Haematopoietic stem cells (HSCs) possess multipotent ability to differentiate into various types of cells on providing appropriate niche. In the present study, the differentiating potential of human HSCs into β-cells of islets of langerhans was explored. Human HSCs were apheretically isolated from a donor and cultured. Phenotypic characterization of CD34 glycoprotein in the growing monolayer HSCs was confirmed by immunocytochemistry and flow cytometry techniques. HSCs were induced by selection with beta cell differentiating medium (BDM), which consists of epidermal growth factor (EGF), fibroblast growth factor (FGF), transferrin, Triiodo-l-Tyronine, nicotinamide and activin A. Distinct morphological changes of differentiated cells were observed on staining with dithizone (DTZ) and expression of PDX1, insulin and synaptophysin was confirmed by immunocytochemistry. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed distinct expression of specific β-cell markers, pancreatic and duodenal homeobox-1 (PDX1), glucose transporter-2 (GLUT-2), synaptophysin (SYP) and insulin (INS) in these differentiated cells compared to HSCs. Further, these cells exhibited elevated expression of INS gene at 10 mM glucose upon inducing with different glucose concentrations. The prominent feature of the obtained β-cells was the presence of glucose sensors, which was determined by glucokinase activity and high glucokinase activity compared with CD34(+) stem cells. These findings illustrate the differentiation of CD34(+) HSCs into β-cells of islets of langerhans. PMID:27514733

  18. 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

  19. Potential immunological consequences of pharmacological suppression of gastric acid production in patients with multiple sclerosis.

    PubMed

    Biswas, Sangita; Benedict, Stephen H; Lynch, Sharon G; LeVine, Steven M

    2012-06-07

    Corticosteroids are standard treatment for patients with multiple sclerosis experiencing acute relapse. Because dyspeptic pain is a common side effect of this intervention, patients can be given a histamine receptor-2 antagonist, proton pump inhibitor or antacid to prevent or ameliorate this disturbance. Additionally, patients with multiple sclerosis may be taking these medications independent of corticosteroid treatment. Interventions for gastric disturbances can influence the activation state of the immune system, a principal mediator of pathology in multiple sclerosis. Although histamine release promotes inflammation, activation of the histamine receptor-2 can suppress a proinflammatory immune response, and blocking histamine receptor-2 with an antagonist could shift the balance more towards immune stimulation. Studies utilizing an animal model of multiple sclerosis indicate that histamine receptor-2 antagonists potentially augment disease activity in patients with multiple sclerosis. In contrast, proton pump inhibitors appear to favor immune suppression, but have not been studied in models of multiple sclerosis. Antacids, histamine receptor-2 antagonists and proton pump inhibitors also could alter the intestinal microflora, which may indirectly lead to immune stimulation. Additionally, elevated gastric pH can promote the vitamin B12 deficiency that patients with multiple sclerosis are at risk of developing. Here, we review possible roles of gastric acid inhibitors on immunopathogenic mechanisms associated with multiple sclerosis.

  20. Potential immunological consequences of pharmacological suppression of gastric acid production in patients with multiple sclerosis

    PubMed Central

    2012-01-01

    Corticosteroids are standard treatment for patients with multiple sclerosis experiencing acute relapse. Because dyspeptic pain is a common side effect of this intervention, patients can be given a histamine receptor-2 antagonist, proton pump inhibitor or antacid to prevent or ameliorate this disturbance. Additionally, patients with multiple sclerosis may be taking these medications independent of corticosteroid treatment. Interventions for gastric disturbances can influence the activation state of the immune system, a principal mediator of pathology in multiple sclerosis. Although histamine release promotes inflammation, activation of the histamine receptor-2 can suppress a proinflammatory immune response, and blocking histamine receptor-2 with an antagonist could shift the balance more towards immune stimulation. Studies utilizing an animal model of multiple sclerosis indicate that histamine receptor-2 antagonists potentially augment disease activity in patients with multiple sclerosis. In contrast, proton pump inhibitors appear to favor immune suppression, but have not been studied in models of multiple sclerosis. Antacids, histamine receptor-2 antagonists and proton pump inhibitors also could alter the intestinal microflora, which may indirectly lead to immune stimulation. Additionally, elevated gastric pH can promote the vitamin B12 deficiency that patients with multiple sclerosis are at risk of developing. Here, we review possible roles of gastric acid inhibitors on immunopathogenic mechanisms associated with multiple sclerosis. PMID:22676575

  1. 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

  2. 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

  3. 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

  4. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis.

    PubMed

    Du, Changsheng; Liu, Chang; Kang, Jiuhong; Zhao, Guixian; Ye, Zhiqiang; Huang, Shichao; Li, Zhenxin; Wu, Zhiying; Pei, Gang

    2009-12-01

    Interleukin 17 (IL-17)-producing T helper cells (T(H)-17 cells) are increasingly recognized as key participants in various autoimmune diseases, including multiple sclerosis. Although sets of transcription factors and cytokines are known to regulate T(H)-17 differentiation, the role of noncoding RNA is poorly understood. Here we identify a T(H)-17 cell-associated microRNA, miR-326, whose expression was highly correlated with disease severity in patients with multiple sclerosis and mice with experimental autoimmune encephalomyelitis (EAE). In vivo silencing of miR-326 resulted in fewer T(H)-17 cells and mild EAE, and its overexpression led to more T(H)-17 cells and severe EAE. We also found that miR-326 promoted T(H)-17 differentiation by targeting Ets-1, a negative regulator of T(H)-17 differentiation. Our data show a critical role for microRNA in T(H)-17 differentiation and the pathogenesis of multiple sclerosis.

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

    PubMed

    Legartová, Soňa; Kozubek, Stanislav; Franek, Michal; Zdráhal, Zbyněk; Lochmanová, Gabriela; Martinet, Nadine; Bártová, Eva

    2014-04-01

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

  6. 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.

  7. 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

  8. 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.

  9. 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

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

    PubMed

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

    2014-08-26

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

  11. 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

  12. 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

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

    PubMed

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

    1979-03-01

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

  14. Differentially expressed genes in human peripheral blood as potential markers for statin response.

    PubMed

    Won, Hong-Hee; Kim, Suk Ran; Bang, Oh Young; Lee, Sang-Chol; Huh, Wooseong; Ko, Jae-Wook; Kim, Hyung-Gun; McLeod, Howard L; O'Connell, Thomas M; Kim, Jong-Won; Lee, Soo-Youn

    2012-02-01

    There is a considerable inter-individual variation in response to statin therapy and one third of patients do not meet their treatment goals. We aimed to identify differentially expressed genes that might be involved in the effects of statin treatment and to suggest potential markers to guide statin therapy. Forty-six healthy Korean subjects received atorvastatin; their whole-genome expression profiles in peripheral blood were analyzed before and after atorvastatin administration in relation with changes in lipid profiles. The expression patterns of the differentially expressed genes were also compared with the data of familial hypercholesterolemia (FH) patients and controls. Pairwise comparison analyses revealed differentially expressed genes involved in diverse biological processes and molecular functions related with immune responses. Atorvastain mainly affected antigen binding, immune or inflammatory response including interleukin pathways. Similar expression patterns of the genes were observed in patients with FH and controls. The Charcol-Leyden crystal (CLC), CCR2, CX3CR1, LRRN3, FOS, LDLR, HLA-DRB1, ERMN, and TCN1 genes were significantly associated with cholesterol levels or statin response. Interestingly, the CLC gene, which was significantly altered by atorvastatin administration and differentially expressed between FH patients and controls, showed much bigger change in high-responsive group than in low-responsive group. We identified differentially expressed genes that might be involved in mechanisms underlying the known pleiotropic effects of atorvastatin, baseline cholesterol levels, and drug response. Our findings suggest CLC as a new candidate marker for statin response, and further validation is needed.

  15. Yolk sac mesenchymal progenitor cells from New World mice (Necromys lasiurus) with multipotent differential potential.

    PubMed

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

    2014-01-01

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

  16. Neural differentiation potential of sympathoadrenal progenitors derived from fresh and cryopreserved neonatal porcine adrenal glands.

    PubMed

    Bozhok, G A; Sidorenko, O S; Plaksina, E M; Gurina, T M; Sukach, A N; Kholodnyy, V S; Ustichenko, V D; Bilyavskaya, S B; Bondarenko, T P; Legach, E I

    2016-10-01

    Stem/progenitor cells are thought to have the potential in the treatment of severe neurodegenerative diseases. Recently, sympathoadrenal progenitors expressing specific markers of neural crest derivatives and capable to differentiate into neurons were discovered in adult bovine and human adrenal glands, but there was no reported data on cryopreservation of sympathoadrenal progenitors. The aim of the present study was to examine the neural differentiation potential of sympathoadrenal progenitors derived from fresh and cryopreserved neonatal porcine adrenal glands. Considering impact of various initial state of frozen biomaterial on cell recovery, we carried out a comparative estimation of cryopreservation outcome both for adrenal tissue fragments and isolated primary cells. The estimation consisted of determining cell yield, viability, ability to adhere, proliferate and differentiate in vitro. Cells isolated from the fresh adrenal glands were cultured until confluence. A formation of sympathoadrenal progenitors-embedded spherical cell colonies, whose cells are differentiated then into βIII-tubulin-positive cells with neuron-like morphology, was observed on the monolayer. The colonies were well preserved after cryopreservation of cell culture with a cooling rate of 1 °C/min in the cryoprotectant media containing 5-15% of dimethylsulfoxide. Adrenal tissue fragments were cryopreserved in the presence of 10% dimethylsulfoxide at the cooling rates of 0.3; 1: 5; 40 and > 100 °C/min. Sympathoadrenal progenitors were recovered after cryopreservation with 0.3 °C/min cooling rate but not higher. PMID:27539465

  17. Neural differentiation potential of sympathoadrenal progenitors derived from fresh and cryopreserved neonatal porcine adrenal glands.

    PubMed

    Bozhok, G A; Sidorenko, O S; Plaksina, E M; Gurina, T M; Sukach, A N; Kholodnyy, V S; Ustichenko, V D; Bilyavskaya, S B; Bondarenko, T P; Legach, E I

    2016-10-01

    Stem/progenitor cells are thought to have the potential in the treatment of severe neurodegenerative diseases. Recently, sympathoadrenal progenitors expressing specific markers of neural crest derivatives and capable to differentiate into neurons were discovered in adult bovine and human adrenal glands, but there was no reported data on cryopreservation of sympathoadrenal progenitors. The aim of the present study was to examine the neural differentiation potential of sympathoadrenal progenitors derived from fresh and cryopreserved neonatal porcine adrenal glands. Considering impact of various initial state of frozen biomaterial on cell recovery, we carried out a comparative estimation of cryopreservation outcome both for adrenal tissue fragments and isolated primary cells. The estimation consisted of determining cell yield, viability, ability to adhere, proliferate and differentiate in vitro. Cells isolated from the fresh adrenal glands were cultured until confluence. A formation of sympathoadrenal progenitors-embedded spherical cell colonies, whose cells are differentiated then into βIII-tubulin-positive cells with neuron-like morphology, was observed on the monolayer. The colonies were well preserved after cryopreservation of cell culture with a cooling rate of 1 °C/min in the cryoprotectant media containing 5-15% of dimethylsulfoxide. Adrenal tissue fragments were cryopreserved in the presence of 10% dimethylsulfoxide at the cooling rates of 0.3; 1: 5; 40 and > 100 °C/min. Sympathoadrenal progenitors were recovered after cryopreservation with 0.3 °C/min cooling rate but not higher.

  18. 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.

  19. 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

  20. 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

  1. 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

  2. Cardiac differentiation potential of human induced pluripotent stem cells in a 3D self-assembling peptide scaffold.

    PubMed

    Puig-Sanvicens, Veronica A C; Semino, Carlos E; Zur Nieden, Nicole I

    2015-01-01

    In the past decade, various strategies for cardiac reparative medicine involving stem cells from multiple sources have been investigated. However, the intra-cardiac implantation of cells with contractile ability may seriously disrupt the cardiac syncytium and de-synchronize cardiac rhythm. For this reason, bioactive cardiac implants, consisting of stem cells embedded in biomaterials that act like band aids, have been exploited to repair the cardiac wall after myocardial infarction. For such bioactive implants to function properly after transplantation, the choice of biomaterial is equally important as the selection of the stem cell source. While adult stem cells have shown promising results, they have various disadvantages including low proliferative potential in vitro, which make their successful usage in human transplants difficult. As a first step towards the development of a bioactive cardiac patch, we investigate here the cardiac differentiation properties of human induced pluripotent stem cells (hiPSCs) when cultured with and without ascorbic acid (AA) and when embedded in RAD16-I, a biomaterial commonly used to develop cardiac implants. In adherent cultures and in the absence of RAD16-I, AA promotes the cardiac differentiation of hiPSCs by enhancing the expression of specific cardiac genes and proteins and by increasing the number of contracting clusters. In turn, embedding in peptide hydrogel based on RAD16-I interferes with the normal cardiac differentiation progression. Embedded hiPSCs up-regulate genes associated with early cardiogenesis by up to 105 times independently of the presence of AA. However, neither connexin 43 nor troponin I proteins, which are related with mature cardiomyocytes, were detected and no contraction was noted in the constructs. Future experiments will need to focus on characterizing the mature cardiac phenotype of these cells when implanted into infarcted myocardia and assess their regenerative potential in vivo. PMID:26707885

  3. Effect of body temperature on visual evoked potential delay and visual perception in multiple sclerosis.

    PubMed

    Regan, D; Murray, T J; Silver, R

    1977-11-01

    Seven multiple sclerosis patients were cooled and four heated, but evoked potential delay changed in only five out 11 experiments. Control limits were set by cooling eight and heating four control subjects. One patient gave anomalous results in that although heating degraded perceptual delay and visual acuity, and depressed the sine wave grating MTF, double-flash resolution was improved. An explanation is proposed in terms of the pattern of axonal demyelination. The medium frequency flicker evoked potential test seems to be a less reliable means of monitoring the progress of demyelination in multiple sclerosis patients than is double-flash campimetry or perceptual delay campimetry, although in some situations the objectivity of the evoked potential test would be advantageous.

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

    PubMed

    Zheng, Wei; Wang, Shi; Wang, Jianguo; Jin, Fang

    2015-10-01

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

  5. Role of membrane potential in the regulation of cell proliferation and differentiation.

    PubMed

    Sundelacruz, Sarah; Levin, Michael; Kaplan, David L

    2009-09-01

    Biophysical signaling, an integral regulator of long-term cell behavior in both excitable and non-excitable cell types, offers enormous potential for modulation of important cell functions. Of particular interest to current regenerative medicine efforts, we review several examples that support the functional role of transmembrane potential (V(mem)) in the regulation of proliferation and differentiation. Interestingly, distinct V(mem) controls are found in many cancer cell and precursor cell systems, which are known for their proliferative and differentiation capacities, respectively. Collectively, the data demonstrate that bioelectric properties can serve as markers for cell characterization and can control cell mitotic activity, cell cycle progression, and differentiation. The ability to control cell functions by modulating bioelectric properties such as V(mem) would be an invaluable tool for directing stem cell behavior toward therapeutic goals. Biophysical properties of stem cells have only recently begun to be studied and are thus in need of further characterization. Understanding the molecular and mechanistic basis of biophysical regulation will point the way toward novel ways to rationally direct cell functions, allowing us to capitalize upon the potential of biophysical signaling for regenerative medicine and tissue engineering. PMID:19562527

  6. The potential role of microRNAs in regulating gonadal sex differentiation in the chicken embryo.

    PubMed

    Cutting, Andrew D; Bannister, Stephanie C; Doran, Tim J; Sinclair, Andrew H; Tizard, Mark V L; Smith, Craig A

    2012-01-01

    Differential gene expression regulates tissue morphogenesis. The embryonic gonad is a good example, where the developmental decision to become an ovary or testis is governed by female- or male-specific gene expression. A number of genes have now been identified that control gonadal sex differentiation. However, the potential role of microRNAs (miRNAs) in ovarian and testicular pathways is unknown. In this review, we summarise our current understanding of gonadal differentiation and the possible involvement of miRNAs, using the chicken embryo as a model system. Chickens and other birds have a ZZ/ZW sex chromosome system, in which the female, ZW, is the heterogametic sex, and the male, ZZ, is homogametic (opposite to mammals). The Z-linked DMRT1 gene is thought to direct testis differentiation during embryonic life via a dosage-based mechanism. The conserved SOX9 gene is also likely to play a key role in testis formation. No master ovary determinant has yet been defined, but the autosomal FOXL2 and Aromatase genes are considered central. No miRNAs have been definitively shown to play a role in embryonic gonadal development in chickens or any other vertebrate species. Using next generation sequencing, we carried out an expression-based screen for miRNAs expressed in embryonic chicken gonads at the time of sexual differentiation. A number of miRNAs were identified, including several that showed sexually dimorphic expression. We validated a subset of miRNAs by qRT-PCR, and prediction algorithms were used to identify potential targets. We discuss the possible roles for these miRNAs in gonadal development and how these roles might be tested in the avian model.

  7. Molecular characterization and differential expression of multiple goose dopamine D2 receptors.

    PubMed

    Wang, Cui; Liu, Yi; Wang, Huiying; Wu, Huali; Gong, Shaoming; Chen, Weihu; He, Daqian

    2014-02-10

    Dopamine D2 receptor (DRD2) gene, a member of the dopamine receptors gene family, has been studied as a candidate gene for broodiness due to its special effects on avian prolactin secretion. Here, the genomic DNA and cDNA sequences of goose (Anser cygnoides) DRD2 gene were cloned and characterized for the first time. The goose DRD2 cDNA is 1353bp in length and encodes a protein of 450 amino acids. The length of goose DRD2 genomic DNA is 8350bp, including seven exons and six introns. We identified four goose DRD2 variants, which were generated due to alternative splicing. Bioinformatics analysis indicates that all the deduced DRD2 amino acid sequences contain seven putative transmembrane domains and four potential N-glycosylation sites. A phylogenetic tree based on amino acid sequences displays that the goose DRD2 protein is closely related to those of avian species. Semi-quantitative RT-PCR analysis demonstrates that the DRD2-1, DRD2-2 and DRD2-4 transcripts are differentially expressed in the pituitary, ovary, hypothalamus, as well as in the kidney, whereas the DRD2-3 transcript is widely expressed in all the examined tissues at different levels. Meanwhile, 54 single nucleotide polymorphisms (SNPs) and 4 insert-deletion (indel) variations were identified in the coding region and partial intron region of the goose DRD2 gene. Those findings will help us gain insight into the functions of the DRD2 gene in geese.

  8. 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.

  9. 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.

  10. MicroRNA Levels as Prognostic Markers for the Differentiation Potential of Human Mesenchymal Stromal Cell Donors.

    PubMed

    Georgi, Nicole; Taipaleenmaki, Hanna; Raiss, Christian C; Groen, Nathalie; Portalska, Karolina Janaeczek; van Blitterswijk, Clemens; de Boer, Jan; Post, Janine N; van Wijnen, Andre J; Karperien, Marcel

    2015-08-15

    The ability of human mesenchymal stromal/stem cells (hMSCs) to differentiate into various mesenchymal cell lineages makes them a promising cell source for the use in tissue repair strategies. Since the differentiation potential of hMSCs differs between donors, it is necessary to establish biomarkers for the identification of donors with high differentiation potential. In this study, we show that microRNA (miRNA) expression levels are effective for distinguishing donors with high differentiation potential from low differentiation potential. Twenty hMSC donors were initially tested for marker expression and differentiation potential. In particular, the chondrogenic differentiation potential was evaluated on the basis of histological matrix formation, mRNA expression levels of chondrogenic marker genes, and quantitative glycosaminoglycan deposition. Three donors out of twenty were identified as donors with high chondrogenic potential, whereas nine showed moderate and eight showed low chondrogenic potential. Expression profiles of miRNAs involved in chondrogenesis and cartilage homeostasis were used for the distinction between high-performance hMSCs and low-performance hMSCs. Global mRNA expression profiles of the donors before the onset of chondrogenic differentiation revealed minor differences in gene expression between low and high chondrogenic performers. However, analysis of miRNA expression during a 7-day differentiation period identified miR-210 and miR-630 as positive regulators of chondrogenesis. In contrast, miR-181 and miR-34a, which are negative regulators of chondrogenesis, were upregulated during differentiation in low-performing donors. In conclusion, profiling of hMSC donors for a specific panel of miRNAs may have a prognostic value for selecting donors with high differentiation potential to improve hMSC-based strategies for tissue regeneration.

  11. 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

  12. 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.

  13. 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

  14. 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

  15. Bioactivity and prognostic significance of growth differentiation factor GDF15 secreted by bone marrow mesenchymal stem cells in multiple myeloma.

    PubMed

    Corre, Jill; Labat, Elodie; Espagnolle, Nicolas; Hébraud, Benjamin; Avet-Loiseau, Hervé; Roussel, Murielle; Huynh, Anne; Gadelorge, Mélanie; Cordelier, Pierre; Klein, Bernard; Moreau, Philippe; Facon, Thierry; Fournié, Jean-Jacques; Attal, Michel; Bourin, Philippe

    2012-03-15

    Overexpression of growth differentiation factor 15 (GDF15) by bone marrow mesenchymal stem cells occurs widely in patients with multiple myeloma, but the pathophysiologic effects of GDF15 in this setting remain undefined. GDF15 has been described in numerous solid tumors but never in hematologic malignancies. In this study, we report that GDF15 significantly increases survival of stroma-dependent multiple myeloma cells including primary multiple myeloma cells. In particular, GDF15 conferred resistance to melphalan, bortezomib, and to a lesser extent, lenalidomide in both stroma-dependent and stroma-independent multiple myeloma cells. Akt-dependent signaling was critical to mediate the effects of GDF15, whereas Src and extracellular signal-regulated kinase 1/2 signaling pathways were not involved. Given these results, we tested the clinical significance of plasma concentrations of GDF15 (pGDF15) in 131 patients with multiple myeloma and found that it correlated with disease prognosis. Specifically, patients with high levels of pGDF15 had lower probabilities of event-free and overall survival 30 months after diagnosis than patients with low pGDF15 levels. Our findings suggest that tumor microenvironment-derived GDF15 is a key survival and chemoprotective factor for multiple myeloma cells, which is pathophysiologically linked to both initial parameters of the disease as well as patient survival.

  16. 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

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

    PubMed

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

    2015-11-01

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

  18. 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

  19. 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.

  20. 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

  1. 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).

  2. 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.

  3. 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

  4. Isolation, characterization and neural differentiation potential of amnion derived mesenchymal stem cells.

    PubMed

    Manochantr, Sirikul; Tantrawatpan, Chairat; Kheolamai, Pakpoom; U-pratya, Yaowaluk; Supokawej, Aungkura; Issaragrisil, Surapol

    2010-12-01

    Mesenchymal stem cells (MSCs) derived from amnion are considered to be adult stem cells that can be easily obtained in large quantities by a less invasive method in comparison to bone marrow-derived MSCs (BM-MSCs). However; the biological properties and the differentiation capacity of amnion-derived MSCs (AM-MSCs) are still poorly characterized. The objectives of this study were to isolate, characterize and explore the potential of AM-MSCs in differentiating toward neural lineage in comparison to those of BM-MSCs. To isolate AM-MSCs, amnion was digested with trypsin-EDTA and cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum. The expression profiles of several MSC markers were examined by flow cytometry. AM-MSCs from passage 3-5 were used for adipogenic, osteogenic and neural differentiation assays by culturing in appropriate induction media. The expression of several neural marker genes, including MAP-2, GFAP and beta-tubulin III in AM-MSCs was determined by quantitative real time-PCR. The expression of neural-specific markers, MAP-2 and beta-tubulin III, was subsequently confirmed by immunocytochemistry using confocal laser microscope. The results demonstrated that AM-MSCs could be easily expanded to 18-20 passages while maintaining the undifferentiated state and exhibiting MSC markers (CD73, CD90, and CD105) but do not express the hematopoietic markers (CD34 and CD45). Similar to BM-MSCs, AM-MSCs were able to differentiate to several mesodermal-lineages including adipocytes and osteoblasts. Moreover; these cells could be induced to differentiate to neuron-like cells as characterized by cell morphology and the expression of several neural markers including MAP-2, GFAP and beta-tubulin III. The present study demonstrated that AM-MSCs can be easily obtained and expanded in culture. These cells also have transdifferentiation capacity as evidenced by their neural differentiation potential. According to the results, amnion

  5. Relay Selection Based Double-Differential Transmission for Cooperative Networks with Multiple Carrier Frequency Offsets: Model, Analysis, and Optimization

    NASA Astrophysics Data System (ADS)

    Zhao, Kun; Zhang, Bangning; Pan, Kegang; Liu, Aijun; Guo, Daoxing

    2014-07-01

    Due to the distributed nature, cooperative networks are generally subject to multiple carrier frequency offsets (MCFOs), which make the channels time-varying and drastically degrade the system performance. In this paper, to address the MCFOs problem in detect-andforward (DetF) multi-relay cooperative networks, a robust relay selection (RS) based double-differential (DD) transmission scheme, termed RSDDT, is proposed, where the best relay is selected to forward the source's double-differentially modulated signals to the destination with the DetF protocol. The proposed RSDDT scheme can achieve excellent performance over fading channels in the presence of unknown MCFOs. Considering double-differential multiple phase-shift keying (DDMPSK) is applied, we first derive exact expressions for the outage probability and average bit error rate (BER) of the RSDDT scheme. Then, we look into the high signal-to-noise ratio (SNR) regime and present simple and informative asymptotic outage probability and average BER expressions, which reveal that the proposed scheme can achieve full diversity. Moreover, to further improve the BER performance of the RSDDT scheme, we investigate the optimum power allocation strategy among the source and the relay nodes, and simple analytical solutions are obtained. Numerical results are provided to corroborate the derived analytical expressions and it is demonstrated that the proposed optimum power allocation strategy offers substantial BER performance improvement over the equal power allocation strategy.

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

    SciTech Connect

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

    2012-07-15

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

  7. Aqueous ethanolic extract of Tinospora cordifolia as a potential candidate for differentiation based therapy of glioblastomas.

    PubMed

    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

  8. 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

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

    ERIC Educational Resources Information Center

    Rothbart, Mary K.

    2004-01-01

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

  10. 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…

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

    PubMed Central

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

    1992-01-01

    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. Images PMID:1448106

  12. 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.

  13. Using Multiple-Variable Matching to Identify Cultural Sources of Differential Item Functioning

    ERIC Educational Resources Information Center

    Wu, Amery D.; Ercikan, Kadriye

    2006-01-01

    Identifying the sources of differential item functioning (DIF) in international assessments is very challenging, because such sources are often nebulous and intertwined. Even though researchers frequently focus on test translation and content area, few actually go beyond these factors to investigate other cultural sources of DIF. This article…

  14. 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

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

    ERIC Educational Resources Information Center

    Vollmer, Timothy R.; And Others

    1992-01-01

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

  16. 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…

  17. 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.

  18. 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.

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

    PubMed

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

    2015-03-01

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

  20. Hypoxia converts the myogenic action of insulin-like growth factors into mitogenic action by differentially regulating multiple signaling pathways

    PubMed Central

    Ren, Hongxia; Accili, Domenico; Duan, Cunming

    2010-01-01

    Insulin-like growth factors (IGFs) stimulate myoblast proliferation and differentiation. It remains elusive how these mutually exclusive cellular responses are elicited by the same growth factor. Here we report that whereas IGF promotes myoblast differentiation under normoxia, it stimulates proliferation under hypoxia. Hypoxia activates the HIF-1 transcriptional program and knockdown of HIF-1α changes the mitogenic action of IGF into myogenic action under hypoxia. Conversely, overexpression of HIF-1α abolishes the myogenic effect of IGF under normoxia. Under normoxia, IGF activates the Akt-mTOR, p38, and Erk1/2 MAPK pathways. Hypoxia suppresses basal and IGF-induced Akt-mTOR and p38 activity, whereas it enhances and prolongs IGF-induced Erk1/2 activation in a HIF-1–dependent fashion. Activation of Akt-mTOR and p38 promotes myogenesis, and p38 also inhibits proliferation. Activation of Erk stimulates myoblast proliferation but inhibits differentiation. These results suggest that hypoxia converts the myogenic action of IGFs into mitogenic action by differentially regulating multiple signaling pathways via HIF-1-dependent mechanisms. Our findings provide a mechanistic explanation for the paradoxical actions of IGFs during myogenesis and reveal a novel mechanism by which cells sense and integrate growth factor signals and oxygen availability in their microenvironments. PMID:20231451

  1. Platelet Rich Concentrate Promotes Early Cellular Proliferation and Multiple Lineage Differentiation of Human Mesenchymal Stromal Cells In Vitro

    PubMed Central

    Shani, Samuel; Vasudevaraj Naveen, Sangeetha; 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

  2. Ultrafast differential transmission spectroscopy of excitonic transitions in InGaN/GaN multiple quantum wells

    NASA Astrophysics Data System (ADS)

    Chen, Fei; Cheung, M. C.; Sweeney, Paul M.; Kirkey, W. D.; Furis, M.; Cartwright, A. N.

    2003-04-01

    Room-temperature carrier dynamics in InGaN/GaN multiple quantum wells are studied by employing ultrafast pump-probe spectroscopy. Specifically, the observed differential spectral signatures are characteristic of changes in the absorption coefficient through both a reduction of the quantum-confined Stark shift due to the photoinduced in-well field screening (low carrier densities) and excitonic absorption quenching (high carrier densities). The comparison of the differential absorption spectra at different injected carrier densities allows us to separate field screening from excitonic bleaching. The estimated in-well field at the transition point between field screening and excitonic bleaching is consistent with the theoretical value of the piezoelectric field in the strained InGaN well.

  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. 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

  5. The 1985 Walter Hubert lecture. Malignant cell differentiation as a potential therapeutic approach.

    PubMed Central

    Sartorelli, A. C.

    1985-01-01

    Most drugs available for cancer chemotherapy exert their effects through cytodestruction. Although significant advances have been attained with these cytotoxic agents in several malignant diseases, response is often accompanied by significant morbidity and many common malignant tumours respond poorly to existing cytotoxic therapy. Development of chemotherapeutic agents with non-cytodestructive actions appears desirable. Considerable evidence exists which indicates that (a) the malignant state is not irreversible and represents a disease of altered maturation, and (b) some experimental tumour systems can be induced by chemical agents to differentiate to mature end-stage cells with no proliferative potential. Thus, it is conceivable that therapeutic agents can be developed which convert cancer cells to benign forms. To study the phenomenon of blocked maturation, squamous carcinoma SqCC/Y1 cells were employed in culture. Using this system it was possible to demonstrate that physiological levels of retinoic acid and epidermal growth factor were capable of preventing the differentiation of these malignant keratinocytes into a mature tissue-like structure. The terminal differentiation caused by certain antineoplastic agents was investigated in HL-60 promyelocytic leukaemia cells to provide information on the mechanism by which chemotherapeutic agents induce cells to by-pass a maturation block. The anthracyclines aclacinomycin A and marcellomycin were potent inhibitors of N-glycosidically linked glycoprotein biosynthesis and transferrin receptor activity, and active inducers of maturation; temporal studies suggested that the biochemical effects were associated with the differentiation process. 6-Thioguanine produced cytotoxicity in parental cells by forming analog nucleotide. In hypoxanthine-guanine phosphoribosyltransferase negative HL-60 cells the 6-thiopurine initiated maturation; this action was due to the free base (and possibly the deoxyribonucleoside), a finding

  6. 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

  7. [Differential diagnosis of the clinical picture of multiple sclerosis in MR tomography].

    PubMed

    Gowin, W; Mariss, G

    1986-09-01

    Magnetic resonance imaging (MRI) has the advantage of high sensitivity compared to other diagnostic imaging techniques in focal pathological lesions of the brain in multiple sclerosis patients. However, the specificity of this examination method is limited. Diseases of the central nervous system due to other, different causes could produce a similar magnetic resonance image. Clinically examined cases of malignant and toxic affections of the brain caused by inflammatory, degenerative, traumatic and vascular diseases are presented and compared with the changes occurring in multiple sclerosis.

  8. Investigation of potential ionic interactions between anionic and cationic polymethacrylates of multiple coatings of novel colonic delivery system.

    PubMed

    Gupta, Vishal K; Beckert, Thomas E; Deusch, Norbert J; Hariharan, Madhusudan; Price, James C

    2002-01-01

    The objective of this work was to investigate potential interactions between anionic (Eudragit FS) and cationic (Eudragit RL) polymethacrylates of multiple coatings of a novel colonic drug delivery system. Aqueous films of pure polymers Eudragit FS (FS) and Eudragit RL (RL) and their superimposedfilm (FS-RL) were cast on glass slabs. The potential ionic interactions were studied by analysing the dried films using differential scanning calorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), and nuclear magnetic resonance (NMR). The glass transition temperatures (Tg) of pure RL and FS were 60 degrees C and 22 degrees C, respectively; FS-RL showed two distinct glass transitions at 59 degrees C and 24 degrees C in the second heating cycle. In the 13C-MAS spectra of the samples in the solid state, no shifts of the resonance could be detected in the superimposed film compared with the pure polymers. The FT-IR spectra of the superimposed film did not show any significant shift of the bands of the -NMe3+ group of RL and the -COO- function of FS compared with the spectra of the pure polymers. No ionic interactions between anionic and cationic polymethacrylates were revealed by DSC, FT-IR, and NMR.

  9. 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

  10. Identification of Differentially Expressed Kinase and Screening Potential Anticancer Drugs in Papillary Thyroid Carcinoma

    PubMed Central

    Zhang, Huairong

    2016-01-01

    Aim. We aim to identify protein kinases involved in the pathophysiology of papillary thyroid carcinoma (PTC) in order to provide potential therapeutic targets for kinase inhibitors and unfold possible molecular mechanisms. Materials and Methods. The gene expression profile of GSE27155 was analyzed to identify differentially expressed genes and mapped onto human protein kinases database. Correlation of kinases with PTC was addressed by systematic literature search, GO and KEGG pathway analysis. Results. The functional enrichment analysis indicated that “mitogen-activated protein kinases pathway” expression was extremely enriched, followed by “neurotrophin signaling pathway,” “focal adhesion,” and “GnRH signaling pathway.” MAPK, SRC, PDGFRa, ErbB, and EGFR were significantly regulated to correct these pathways. Kinases investigated by the literature on carcinoma were considered to be potential novel molecular therapeutic target in PTC and application of corresponding kinase inhibitors could be possible therapeutic tool. Conclusion. SRC, MAPK, and EGFR were the most important differentially expressed kinases in PTC. Combined inhibitors may have high efficacy in PTC treatment by targeting these kinases. PMID:27703281

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

    PubMed

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

    2015-01-01

    Biocompatible polymer scaffolds are promising as potential carriers for the delivery of retinal progenitor cells (RPCs) in cell replacement therapy for the repair of damaged or diseased retinas. The primary goal of the present study was to investigate the effects of blended electrospun nanofibrous membranes of silk fibroin (SF) and poly(L-lactic acid-co-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

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. Multiple functions of Maf in the regulation of cellular development and differentiation

    PubMed Central

    Zhang, Chuan

    2015-01-01

    Summary Cellular muscular aponeurotic fibrosarcoma (c‐Maf) is a member of the large macrophage‐activating factor family. C‐Maf plays important roles in the morphogenetic processes and cellular differentiation of the lens, kidneys, liver, T cells and nervous system, and it is particularly important in pancreatic islet and erythroblastic island formation. However, the exact role of c‐Maf remains to be elucidated. In this review, we summarize the research to clarify the functions of c‐Maf in the cellular development and differentiation. The expression of c‐Maf is higher in pancreatic duct cells than in pancreatic islet cells. Therefore, we suggest that pancreatic duct cells may be converted to the functional insulin‐secreting cells by regulating c‐Maf. © 2015 National Natural Science Foundation of China. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd. PMID:26122665

  19. Reduction of multiple aberrant behaviors and concurrent development of self-care skills with differential reinforcement.

    PubMed

    Vollmer, T R; Iwata, B A; Smith, R G; Rodgers, T A

    1992-01-01

    A modified functional analysis was used to assess the behavioral function of a profoundly retarded man's self-injurious behavior (SIB). Results of that analysis showed that the behavior was most likely to occur in a demand context (self-care instructions) but was maintained by positive reinforcement in the form of attention and physical contact. The results of the functional analysis also prescribed a treatment involving differential reinforcement of alternative behavior (DRA). Further investigation showed that other aberrant behaviors, such as aggression and disruption, were members of the same functional response class as SIB. The differential reinforcement of alternative behavior (DRA) procedure effectively reduced those behaviors while compliance to a self-care acquisition task increased markedly. The results are discussed in terms of the importance of determining behavioral function prior to treatment.

  20. The HAND1 basic helix-loop-helix transcription factor regulates trophoblast differentiation via multiple mechanisms.

    PubMed

    Scott, I C; Anson-Cartwright, L; Riley, P; Reda, D; Cross, J C

    2000-01-01

    The basic helix-loop-helix (bHLH) transcription factor genes Hand1 and Mash2 are essential for placental development in mice. Hand1 promotes differentiation of trophoblast giant cells, whereas Mash2 is required for the maintenance of giant cell precursors, and its overexpression prevents giant cell differentiation. We found that Hand1 expression and Mash2 expression overlap in the ectoplacental cone and spongiotrophoblast, layers of the placenta that contain the giant cell precursors, indicating that the antagonistic activities of Hand1 and Mash2 must be coordinated. MASH2 and HAND1 both heterodimerize with E factors, bHLH proteins that are the DNA-binding partners for most class B bHLH factors and which are also expressed in the ectoplacental cone and spongiotrophoblast. In vitro, HAND1 could antagonize MASH2 function by competing for E-factor binding. However, the Hand1 mutant phenotype cannot be solely explained by ectopic activity of MASH2, as the Hand1 mutant phenotype was not altered by further mutation of Mash2. Interestingly, expression of E-factor genes (ITF2 and ALF1) was down-regulated in the trophoblast lineage prior to giant cell differentiation. Therefore, suppression of MASH2 function, required to allow giant cell differentiation, may occur in vivo by loss of its E-factor partner due to loss of its expression and/or competition from HAND1. In giant cells, where E-factor expression was not detected, HAND1 presumably associates with a different bHLH partner. This may account for the distinct functions of HAND1 in giant cells and their precursors. We conclude that development of the trophoblast lineage is regulated by the interacting functions of HAND1, MASH2, and their cofactors.

  1. 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…

  2. 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…

  3. 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

  4. 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

  5. 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.

  6. Ulinastatin - a newer potential therapeutic option for multiple organ dysfunction syndrome.

    PubMed

    Atal, Sarjana S; Atal, Shubham

    2016-03-01

    Despite significant improvements in medical and surgical management, multiple organ dysfunction syndrome (MODS) or multiple organ failure following conditions such as acute pancreatitis, severe sepsis, and traumatic, hemorrhagic, and endotoxin shocks is still accompanied with a high mortality rate. In light of the crucial role of immunologic derangement recently conceptualized in these conditions, ulinastatin, a urinary trypsin inhibitor, is considered as a potentially beneficial immunomodulator drug for MODS. Mechanisms involving protections against tissue organs and endothelial cell and anti-inflammatory effects by ulinastatin are dependent on the inhibition of polymorphonuclear leukocyte (PMN)-derived elastase, tumor necrosis factor α, and other pro-inflammatory cytokines and interleukins (IL-1, IL-6, and IL-8). Ulinastatin also suppresses the activation of PMN cells, macrophages, and platelets. Derived from these properties, ulinastatin has been investigated as a potential clinical therapy for indications including shock and pancreatitis and approved in Japan and China with ongoing clinical trials around the globe. Off-label potential uses of ulinastatin have been reported in preterm labor and hematological, hepatic, renal, and cardiovascular diseases including vasculitis syndromes such as Kawasaki disease.

  7. Histograms of the unitary evoked potential of the mouse diaphragm show multiple peaks.

    PubMed

    Kriebel, M E; Llados, F; Matteson, D R

    1982-01-01

    1. Two classes of miniature end-plate potentials (m.e.p.p.s) were recorded from diaphragm neuromuscular junctions. Amplitude histograms of both classes had multiple peaks that were integral multiples of the smallest peak (s-m.e.p.p.s). The smaller m.e.p.p.s formed the first three or four peaks of histograms and the number of m.e.p.p.s (skew-m.e.p.p.s) in each peak decreased, forming an over-all skewed distribution. The larger m.e.p.p.s (bell-m.e.p.p.s) formed a more-or-less bell-shaped distribution. The distribution of m.e.p.p.s varied from mainly skew- to mainly bell-m.e.p.p.s. In young adult mice the number of subunits composing the classical m.e.p.p.s varied between ten and fifteen at room temperature; at higher temperatures the range was from three to ten subunits.2. End-plate potentials (e.p.p.s) were reduced with cobalt ions (ca. 4 mm) until most nerve impulses failed to release transmitter. The amplitudes of ;unitary evoked potentials' were of the bell-m.e.p.p. class and histograms show integral multiple peaks that correspond to the peaks in histograms of the bell-m.e.p.p.s.3. The peaks in both m.e.p.p. and unitary e.p.p. histograms remained in the same position throughout the recording period and became more distinct as the sample size increased.4. The variance of the s-m.e.p.p. was estimated from the noise and measurement error and the variance of all peaks in the histograms. Most variance of the first peak (s-m.e.p.p.) was due to noise and measurement error.5. The integral peaks in the m.e.p.p. and ;unitary evoked potential' histograms are predicted with a probability density model based on the estimated variance of the s-m.e.p.p. and the assumption that larger potentials are composed of subunits the size of s-m.e.p.p.s. The data and model support the hypothesis that m.e.p.p.s and unitary potentials are composed of subunits.

  8. Neural differentiation potential of human bone marrow-derived mesenchymal stromal cells: misleading marker gene expression

    PubMed Central

    Montzka, Katrin; Lassonczyk, Nina; Tschöke, Beate; Neuss, Sabine; Führmann, Tobias; Franzen, Rachelle; Smeets, Ralf; Brook, Gary A; Wöltje, Michael

    2009-01-01

    Background In contrast to pluripotent embryonic stem cells, adult stem cells have been considered to be multipotent, being somewhat more restricted in their differentiation capacity and only giving rise to cell types related to their tissue of origin. Several studies, however, have reported that bone marrow-derived mesenchymal stromal cells (MSCs) are capable of transdifferentiating to neural cell types, effectively crossing normal lineage restriction boundaries. Such reports have been based on the detection of neural-related proteins by the differentiated MSCs. In order to assess the potential of human adult MSCs to undergo true differentiation to a neural lineage and to determine the degree of homogeneity between donor samples, we have used RT-PCR and immunocytochemistry to investigate the basal expression of a range of neural related mRNAs and proteins in populations of non-differentiated MSCs obtained from 4 donors. Results The expression analysis revealed that several of the commonly used marker genes from other studies like nestin, Enolase2 and microtubule associated protein 1b (MAP1b) are already expressed by undifferentiated human MSCs. Furthermore, mRNA for some of the neural-related transcription factors, e.g. Engrailed-1 and Nurr1 were also strongly expressed. However, several other neural-related mRNAs (e.g. DRD2, enolase2, NFL and MBP) could be identified, but not in all donor samples. Similarly, synaptic vesicle-related mRNA, STX1A could only be detected in 2 of the 4 undifferentiated donor hMSC samples. More significantly, each donor sample revealed a unique expression pattern, demonstrating a significant variation of marker expression. Conclusion The present study highlights the existence of an inter-donor variability of expression of neural-related markers in human MSC samples that has not previously been described. This donor-related heterogeneity might influence the reproducibility of transdifferentiation protocols as well as contributing to the

  9. 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.

  10. Retroperitoneal multiple lymphangioma with differential cyst contents causing hydronephrosis and biliary dilatation.

    PubMed

    Adachi, S; Maruyama, T; Suetomi, T; Morishita, Y; Otsuka, M; Todoroki, T; Fukao, K

    2001-01-01

    We report a 40-year-old woman with retroperitoneal multiple cystic lymphangioma. Multiple cystic lesions were found on both sides of the aorta in the retroperitoneal and right pelvic spaces. These thin-walled cysts gradually increased in size leading to left hydronephrosis and dilatation of the common bile duct with cholecystitis, requiring resection. Analysis of cystic contents revealed differences between the cysts. The right cyst contained high concentrations of amylase, 3429 U/L, while the left cyst contained high concentrations of triglyceride, 470 mg/dL. No reports of patients with idiopathic retroperitoneal cystic lymphangioma have described differences in cystic contents. Differences in cystic contents according to tumor location strongly suggest that the cause of retroperitoneal lymphangioma is a developmental malformation in which lymphangiectasia follows the failure of developing lymphatic tissue to establish normal communication with the remainder of the lymphatic system.

  11. [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

  12. [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.

  13. VSTM-v1, a potential myeloid differentiation antigen that is downregulated in bone marrow cells from myeloid leukemia patients.

    PubMed

    Xie, Min; Li, Ting; Li, Ning; Li, Jinlan; Yao, Qiumei; Han, Wenling; Ruan, Guorui

    2015-01-01

    Leukocyte differentiation antigens often represent important markers for the diagnosis, classification, prognosis, and therapeutic targeting of myeloid leukemia. Herein, we report a potential leukocyte differentiation antigen gene VSTM1 (V-set and transmembrane domain-containing 1) that was downregulated in bone marrow cells from leukemia patients and exhibited a higher degree of promoter methylation. The expression level of its predominant encoded product, VSTM1-v1, was positively correlated with myeloid cell maturation state. Restoration of VSTM1-v1 expression inhibited myeloid leukemia cells' growth. Therefore, VSTM1-v1 might represent an important myeloid leukocyte differentiation antigen and provide a potential target for the diagnosis and treatment of leukemia.

  14. BMP5 activates multiple signaling pathways and promotes chondrogenic differentiation in the ATDC5 growth plate model.

    PubMed

    Snelling, Sarah J B; Hulley, Philippa A; Loughlin, John

    2010-08-01

    The bone morphogenetic protein 5 (BMP5) participates in skeletal development but its direct effects on the function of growth plate chondrocytes during chondrogenesis have not been explored. We have investigated the signaling pathways activated by BMP5 and its effect on chondrogenic differentiation in the ATDC5 growth plate chondrocyte model. BMP5 transiently activated p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase signaling after 10 days of differentiation; sustained Smad and p38 MAPK signaling were seen after 15 days differentiation. All three pathways were activated by BMP5 in human adult articular chondrocytes. BMP5 alone and in combination with the chondrogenic enhancer, insulin, induced proteoglycan synthesis, aggrecan core protein 1 expression, and alkaline phosphatase activity. Upregulation of hypertrophic markers parathyroid receptor 1 and collagen type X alpha 1 occurred in BMP5-treated ATDC5 cultures. BMP5 is clearly chondrogenic and exhibits stage-specific regulation of multiple signaling pathways in this growth plate model. In particular, BMP5 accelerates expression of hypertrophy markers which is of relevance in both development and diseases such as osteoarthritis.

  15. 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

  16. CD44 in Differentiated Embryonic Stem Cells: Surface Expression and Transcripts Encoding Multiple Variants

    PubMed Central

    Haegel, Hélène; Dierich, Andrée

    1994-01-01

    Expression of the surface-adhesion molecule CD44 was investigated during the in vitro differentiation of the embryonic stem (ES) cell line D3. By immunofluorescence analysis, totipotent, undifferentiated ES cells did not show surface expression of CD44, although two transcripts of approximately 1.6 and 3.3 kb were detected on Northern blots. Following 1 week of differentiation in either suspension or substrate-attached cultures, CD44 appeared on the surface of some D3 cells, and synthesis of an additional 4.5 kb mRNA species was detected on Northern blots. At this stage, at least three distinct transcripts encoding CD44 variants were induced within the cultures, resulting from alternative splicing of additional exons in the variable domains of CD44. From PCR analysis, they all appeared to contain the variable exon v10, and two of them in addition contained v6. Taken together, these results suggest that CD44 may play a role in cell migration and adhesion in the early development of the mouse embryo. PMID:7542511

  17. Differential proteomics reveals multiple components in retrogradely transported axoplasm after nerve injury.

    PubMed

    Perlson, Eran; Medzihradszky, Katalin F; Darula, Zsuzsanna; Munno, David W; Syed, Naweed I; Burlingame, Alma L; Fainzilber, Mike

    2004-05-01

    Information on axonal damage is conveyed to neuronal cell bodies by a number of signaling modalities, including the post-translational modification of axoplasmic proteins. Retrograde transport of a subset of such proteins is thought to induce or enhance a regenerative response in the cell body. Here we report the use of a differential 2D-PAGE approach to identify injury-correlated retrogradely transported proteins in nerves of the mollusk Lymnaea. A comprehensive series of gels at different pI ranges allowed resolution of approximately 4000 spots by silver staining, and 172 of these were found to differ between lesioned versus control nerves. Mass spectrometric sequencing of 134 differential spots allowed their assignment to over 40 different proteins, some belonging to a vesicular ensemble blocked by the lesion and others comprising an up-regulated ensemble highly enriched in calpain cleavage products of an intermediate filament termed RGP51 (retrograde protein of 51 kDa). Inhibition of RGP51 expression by RNA interference inhibits regenerative outgrowth of adult Lymnaea neurons in culture. These results implicate regulated proteolysis in the formation of retrograde injury signaling complexes after nerve lesion and suggest that this signaling modality utilizes a wide range of protein components.

  18. 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.

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

    PubMed

    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

  20. 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

  1. Potential differentiation ability of gingiva originated human mesenchymal stem cell in the presence of tacrolimus

    PubMed Central

    Ha, Dong-Ho; Pathak, Shiva; Yong, Chul Soon; Kim, Jong Oh; Jeong, Jee-Heon; Park, Jun-Beom

    2016-01-01

    The aim of the present study is to evaluate the potential differentiation ability of gingiva originated human mesenchymal stem cell in the presence of tacrolimus. Tacrolimus-loaded poly(lactic-co-glycolic acid) microspheres were prepared using electrospraying technique. In vitro release study of tacrolimus-loaded poly(lactic-co-glycolic acid) microspheres was performed in phosphate-buffered saline (pH 7.4). Gingiva-derived stem cells were isolated and incubated with tacrolimus or tacrolimus-loaded microspheres. Release study of the microspheres revealed prolonged release profiles of tacrolimus without any significant initial burst release. The microsphere itself did not affect the morphology of the mesenchymal stem cells, and cell morphology was retained after incubation with microspheres loaded with tacrolimus at 1 μg/mL to 10 μg/mL. Cultures grown in the presence of microspheres loaded with tacrolimus at 1 μg/mL showed the highest mineralization. Alkaline phosphatase activity increased with an increase in incubation time. The highest expression of pSmad1/5 was achieved in the group receiving tacrolimus 0.1 μg/mL every third day, and the highest expression of osteocalcin was achieved in the group receiving 1 μg/mL every third day. Biodegradable poly(lactic-co-glycolic acid)-based microspheres loaded with tacrolimus promoted mineralization. Microspheres loaded with tacrolimus may be applied for increased osteoblastic differentiation. PMID:27721434

  2. 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

  3. 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.

  4. 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.

  5. Cigarette smoking hinders human periodontal ligament-derived stem cell proliferation, migration and differentiation potentials.

    PubMed

    Ng, Tsz Kin; Huang, Li; Cao, Di; Yip, Yolanda Wong-Ying; Tsang, Wai Ming; Yam, Gary Hin-Fai; Pang, Chi Pui; Cheung, Herman S

    2015-01-01

    Cigarette smoking contributes to the development of destructive periodontal diseases and delays its healing process. Our previous study demonstrated that nicotine, a major constituent in the cigarette smoke, inhibits the regenerative potentials of human periodontal ligament-derived stem cells (PDLSC) through microRNA (miRNA) regulation. In this study, we hypothesized that the delayed healing in cigarette smokers is caused by the afflicted regenerative potential of smoker PDLSC. We cultured PDLSC from teeth extracted from smokers and non-smokers. In smoker PDLSC, we found significantly reduced proliferation rate and retarded migration capabilities. Moreover, alkaline phosphatase activity, calcium deposition and acidic polysaccharide staining were reduced after BMP2-induced differentiation. In contrast, more lipid deposition was observed in adipogenic-induced smoker PDLSC. Furthermore, two nicotine-related miRNAs, hsa-miR-1305 (22.08 folds, p = 0.040) and hsa-miR-18b (15.56 folds, p = 0.018), were significantly upregulated in smoker PDLSC, suggesting these miRNAs might play an important role in the deteriorative effects on stem cells by cigarette smoke. Results of this study provide further evidences that cigarette smoking affects the regenerative potentials of human adult stem cells.

  6. 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

  7. 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.

  8. 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

  9. 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

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

    NASA Technical Reports Server (NTRS)

    Powell, J. A.

    1977-01-01

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

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

    DOEpatents

    Fincke, James R.

    2001-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    Ghezzi, A; Zaffaroni, M

    2001-11-01

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

  14. Differential Progression of Dysphagia in Heredity and Sporadic Ataxias Involving Multiple Systems.

    PubMed

    Isono, Chiharu; Hirano, Makito; Sakamoto, Hikaru; Ueno, Shuichi; Kusunoki, Susumu; Nakamura, Yusaku

    2015-01-01

    Sporadic ataxia affecting multiple systems, such as cerebellar, extrapyramidal, and autonomic systems, is known as multiple system atrophy cerebellar type (MSA-C), while similar multisystem involvements are seen in certain types of hereditary ataxia, such as spinocerebellar ataxia type 3 (SCA3). Dysphagia is a common symptom that can predispose to aspiration pneumonia, a major cause of death in patients with these diseases. Although the progressions of dysphagia in patients with MSA-C have been reported sporadically, those in SCA3 have not been reported. We retrospectively compared the results of repetitive videofluoroscopic examinations in patients with SCA3 (n = 6) and in those with MSA-C (n = 7). The result showed that the gross progression of dysphagia was significantly slower in patients with SCA3 than in those with MSA-C, but the maximum progression speeds were not significantly different. The dysphagia severities were not associated with impaired activity of daily living evaluated by the Barthel index in MSA-C, but were associated in SCA3. Despite the small number of patients enrolled, these data suggest that physicians should monitor swallowing functions in patients with SCA3 after mild dysphagia develops because it may progress as rapidly as it does in MSA-C.

  15. The potential use of adult stem cells for the treatment of multiple sclerosis and other neurodegenerative disorders.

    PubMed

    Slavin, Shimon; Kurkalli, Basan G S; Karussis, Dimitrios

    2008-11-01

    No specific treatment exists for patients with multiple sclerosis (MS) who fail to respond to conventional immunosuppressive and immunomodulating modalities. Furthermore, no method is available for regeneration of existing defect in the central nervous system (CNS). The ultimate goals of MS treatment, similarly to other autoimmune diseases, are twofold: first, to eliminate self-reactive lymphocytes and to prevent de novo development of self-reactivity by induction of self-tolerance. Second, attempting regeneration and repair of existing damage. In the case of MS, there is a need to stop the ongoing process of inflammation against the CNS by self-reactive lymphocytes thus facilitating spontaneous re-myelinization while in parallel attempt to recover existing neurological deficits caused by the autoimmune process resulting in demyelinization. Cell therapy stands out as the most rationale approach for neurological regeneration. In the absence of clinically applicable approaches involving the use of embryonic stem cells, we are investigating the feasibility and efficacy of enriched autologous mesenchymal stromal cells (MSC) injected intrathecally and intravenously to induce in situ immunomodulation and neuroprotection and possibly facilitate repair of the CNS in patients with MS and other neurodegenerative disorders. Our preclinical results suggest that bone marrow cells may provide a source of stem cells with a potential for migration into inflamed CNS and differentiate into cells expressing neuronal and glial cell markers. Based on the preclinical data, we are currently evaluating the safety of a similar therapeutic approach in a small group of patients with MS and other neurodegenerative diseases.

  16. Targeting IL-17A in Multiple Myeloma: A Potential Novel Therapeutic Approach in Myeloma

    PubMed Central

    Prabhala, Rao H.; Fulciniti, Mariateresa; Pelluru, Dheeraj; Rashid, Naim; Nigroiu, Andreea; Nanjappa, Puru; Pai, Christine; Lee, Saem; Prabhala, Nithya S.; Bandi, Rajya Lakshmi; Smith, Robert; Lazo-Kallanian, Suzan B.; Valet, Sonia; Raje, Noopur; Gold, Jason S.; Richardson, Paul G.; Daley, John F.; Anderson, Kenneth C.; Ettenberg, Seth A.; Di Padova, Franco; Munshi, Nikhil C.

    2015-01-01

    We have previously demonstrated that interleukin-17A (IL-17) producing Th17 cells are significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL-17A promotes MM cell growth via the expression of IL-17 receptor. In this study, we evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We observe significant inhibition of MM cell growth by AIN457 both in the presence and absence of BM stromal cells (BMSC). While IL-17A induces IL-6 production, AIN457 significantly down-regulated IL-6 production and MM cell-adhesion in MM-BMSC co-culture. AIN-457 also significantly inhibited osteoclast cell–differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN-457 weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared to isotype control mice. To understand the mechanism of action of anti-IL-17A mAb, we report here, that MM cells express IL-17A. We also observed that IL-17A knock-down inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN 457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease. PMID:26293646

  17. The Differentiation and Stress Response Factor XBP-1 Drives Multiple Myeloma Pathogenesis

    PubMed Central

    Carrasco, Daniel R.; Sukhdeo, Kumar; Protopopova, Marina; Sinha, Raktim; Enos, Miriam; Carrasco, Daniel E.; Zheng, Mei; Mani, Mala; Henderson, Joel; Pinkus, Geraldine S.; Munshi, Nikhil; Horner, James; Ivanova, Elena V.; Protopopov, Alexei; Anderson, Kenneth C.; Tonon, Giovanni; DePinho, Ronald A.

    2007-01-01

    Summary Multiple myeloma (MM) evolves from a highly prevalent premalignant condition termed MGUS. The factors underlying the malignant transformation of MGUS are unknown. We report a MGUS/MM phenotype in transgenic mice with Eμ-directed expression of the XBP-1 spliced isoform (XBP-1s), a factor governing unfolded protein/ER stress response and plasma-cell development. Eμ-XBP-1s elicited elevated serum Ig and skin alterations. With age, Eμ-xbp-1s transgenics develop features diagnostic of human MM, including bone lytic lesions and subendothelial Ig deposition. Furthermore, transcriptional profiles of Eμ-xbp-1s lymphoid and MM cells show aberrant expression of known human MM dysregulated genes. The similarities of this model with the human disease, coupled with documented frequent XBP-1s overexpression in human MM, serve to implicate XBP-1s dysregulation in MM pathogenesis. PMID:17418411

  18. Differential performance of Chinese volleyball athletes and nonathletes on a multiple-object tracking task.

    PubMed

    Zhang, Xuemin; Yan, Ming; Yangang, Liao

    2009-12-01

    The difference between athletes and nonathletes on the performance of a multiple-object tracking (MOT) task was examined. Participants were 17 national professional volleyball athletes and 20 age-matched nonathletes who were university students and attended basic volleyball training classes. Across trials, the number of distractors and the color and form of the targets were manipulated. A negative correlation was observed between the number of distractors and participants' reaction time. Further, all participants responded faster when the target color changed during a trial than when it remained consistent. Athletes had faster reaction time than nonathletes independent of the number of distractors or target manipulation. Male athletes also had faster overall reaction time than female athletes. The implications of these findings for athletic training are discussed. PMID:20178275

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

    PubMed

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

    2016-08-15

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

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

    PubMed

    Sánchez-Peña, Matilde L; Isaza, Clara E; Pérez-Morales, Jaileene; Rodríguez-Padilla, Cristina; Castro, José M; Cabrera-Ríos, Mauricio

    2013-04-01

    Microarray experiments are capable of determining the relative expression of tens of thousands of genes simultaneously, thus resulting in very large databases. The analysis of these databases and the extraction of biologically relevant knowledge from them are challenging tasks. The identification of potential cancer biomarker genes is one of the most important aims for microarray analysis and, as such, has been widely targeted in the literature. However, identifying a set of these genes consistently across different experiments, researches, microarray platforms, or cancer types is still an elusive endeavor. Besides the inherent difficulty of the large and nonconstant variability in these experiments and the incommensurability between different microarray technologies, there is the issue of the users having to adjust a series of parameters that significantly affect the outcome of the analyses and that do not have a biological or medical meaning. In this study, the identification of potential cancer biomarkers from microarray data is casted as a multiple criteria optimization (MCO) problem. The efficient solutions to this problem, found here through data envelopment analysis (DEA), are associated to genes that are proposed as potential cancer biomarkers. The method does not require any parameter adjustment by the user, and thus fosters repeatability. The approach also allows the analysis of different microarray experiments, microarray platforms, and cancer types simultaneously. The results include the analysis of three publicly available microarray databases related to cervix cancer. This study points to the feasibility of modeling the selection of potential cancer biomarkers from microarray data as an MCO problem and solve it using DEA. Using MCO entails a new optic to the identification of potential cancer biomarkers as it does not require the definition of a threshold value to establish significance for a particular gene and the selection of a normalization

  1. Simultaneous loss of multiple differentiated functions in aerial mycelium-negative isolates of streptomycetes.

    PubMed

    Redshaw, P A; McCann, P A; Pentella, M A; Pogell, B M

    1979-02-01

    Germination and outgrowth of spores of Streptomyces alboniger, Streptomyces scabies, and Streptomyces violaceus-ruber in the presence of intercalating dyes resulted in a high frequency (2 to 20%) of occurrence of aerial mycelium-negative (Amy-) isolates. Coincident with the appearance of the Amy- trait was the loss of several differentiated functions, including the characteristic pigments and earthy odor of the wild types. All S. alboniger, 27% of S. scabies, and 39% of the S. violaceus-ruber Amy- isolates were arginine auxotrophs. The missing enzyme step was identified as argininosuccinate synthetase by using a sensitive microassay for estimation of enzyme activity. The remainder of the S. scabies and S. violaceus-ruber isolates were prototrophs. In addition, S. alboniger Amy- isolates failed to produce or respond to the stimulator of aerial mycelium formation isolated from the wild type. The Amy- isolates did not revert to either Amy+ of Arg+. The lack of any detectable reversion, coupled with the high frequency of curing, supports the idea that a deletion of genetic material, possibly a plasmid, has occurred. PMID:422514

  2. Differential transcription of multiple forms of alpha-2-macroglobulin in carp (Cyprinus carpio) infected with parasites.

    PubMed

    Onara, Dalia F; Forlenza, Maria; Gonzalez, Santiago F; Rakus, Krzysztof Ł; Pilarczyk, Andrzej; Irnazarow, Ilgiz; Wiegertjes, Geert F

    2008-01-01

    Alpha-2-macroglobulin (a2M) is a non-specific protease inhibitor involved in host defense mechanisms, inhibiting both endogenous and exogenous proteases. It is unique among the plasma anti-proteases with respect to the diversity of proteases that it can inactivate. Carp a2M consists of an alpha and beta chain of which the first includes the bioactive regions. Previously, three a2M alpha chain sequences were reported for East-Asian common carp. We studied a2M alpha chain variability in European common carp and report the cloning of a fourth a2M alpha chain with distinct sequence diversity in the bait region. The role of a2M in the immune response to parasites was studied in the liver of carp infected with Trypanoplasma borreli or with Ichthyophthirius multifiliis. Quantitative gene transcription analysis showed a differential regulation of the four isoforms, most clearly seen in infections with I. multifiliis. A2M3 was the only a2M isoform with a highly upregulated transcription during infection, suggesting that this particular isoform is of foremost biological importance.

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

    USGS Publications Warehouse

    Brouxel, M.

    1991-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2012-08-01

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

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

    NASA Technical Reports Server (NTRS)

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

    1994-01-01

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

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

    PubMed Central

    Shibasaki, H; Kuroiwa, Y

    1982-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-04-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-04-01

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

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

    PubMed

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

    2016-05-13

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

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

    PubMed

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

    2016-05-13

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-01-01

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

  13. Differentiation between autism and multiple complex developmental disorder in response to psychosocial stress.

    PubMed

    Jansen, Lucres M C; Gispen-de Wied, Christine C; van der Gaag, Rutger-Jan; van Engeland, Herman

    2003-03-01

    Multiple Complex Developmental Disorder (MCDD) represents a distinct group within the autistic spectrum based on symptomatology. Unlike autistic children, part of MCDD children develop schizophrenia in adult life. Despite the differences, patients of both disorders are mainly characterized by abnormal reactions to their social environment. At the biological level, we showed in a previous study that MCDD children have a reduced cortisol response to psychosocial stress. Given the fact that autistic children clinically show more social impairments, it was hypothesized that they may have even further decreased cortisol responses to psychosocial stress than MCDD patients. Therefore, 10 autistic children were compared to 10 MCDD children and 12 healthy control children in their response to a psychosocial stressor, consisting of a public speaking task. In order to test whether any impairments in the biological stress response are specific for psychosocial stress, the autistic children were compared with 11 MCDD children and 15 control children in their response to a physical stressor, consisting of 10 min of bicycle exercise. Heart rate and salivary cortisol levels were used as indicators of response to the stress tests. Autistic children showed a relatively elevated cortisol response to psychosocial stress, in contrast to MCDD children who showed a reduced cortisol response. No differences in heart rate or cortisol responses to the physical stress test were found. The specific difference between autistic and MCDD children in their cortisol response to psychosocial stress indicates that the disturbed reactions to the social environment observed in these disorders may have different biological backgrounds.

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

    PubMed

    Pižem, Jože; Nicholson, Kimberly M; Mraz, Jerica; Prieto, Victor G

    2013-08-01

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

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

    SciTech Connect

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

    2013-11-01

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

  16. Electrophilic PPARγ ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: a potentially novel therapy for corneal scarring.

    PubMed

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

    2012-01-01

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

  17. Discovery and Characterization of Novel Allosteric Potentiators of M1 Muscarinic Receptors Reveals Multiple Modes of Activity

    PubMed Central

    Marlo, Joy E.; Niswender, Colleen M.; Days, Emily L.; Bridges, Thomas M.; Xiang, Yun; Rodriguez, Alice L.; Shirey, Jana K.; Brady, Ashley E.; Nalywajko, Tasha; Luo, Qingwei; Austin, Cheryl A.; Williams, Michael Baxter; Kim, Kwangho; Williams, Richard; Orton, Darren; Brown, H. Alex; Lindsley, Craig W.; Weaver, C. David; Conn, P. Jeffrey

    2009-01-01

    Activators of M1 muscarinic acetylcholine receptors (mAChRs) may provide novel treatments for schizophrenia and Alzheimer's disease. Unfortunately, the development of M1-active compounds has resulted in nonselective activation of the highly related M2 to M5 mAChR subtypes, which results in dose-limiting side effects. Using a functional screening approach, we identified several novel ligands that potentiated agonist activation of M1 with low micromolar potencies and induced 5-fold or greater leftward shifts of the acetylcholine (ACh) concentration-response curve. These ligands did not compete for binding at the ACh binding site, indicating that they modulate receptor activity by binding to allosteric sites. The two most selective compounds, cyclopentyl 1,6-dimethyl-4-(6-nitrobenzo[d][1,3]-dioxol-5-yl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (VU0090157) and (E)-2-(4-ethoxyphenylamino)-N′-((2-hydroxynaphthalen-1-yl)methylene)acetohydrazide (VU0029767), induced progressive shifts in ACh affinity at M1 that were consistent with their effects in a functional assay, suggesting that the mechanism for enhancement of M1 activity by these compounds is by increasing agonist affinity. These compounds were strikingly different, however, in their ability to potentiate responses at a mutant M1 receptor with decreased affinity for ACh and in their ability to affect responses of the allosteric M1 agonist, 1-[1′-(2-tolyl)-1,4′-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one. Furthermore, these two compounds were distinct in their abilities to potentiate M1-mediated activation of phosphoinositide hydrolysis and phospholipase D. The discovery of multiple structurally distinct positive allosteric modulators of M1 is an exciting advance in establishing the potential of allosteric modulators for selective activation of this receptor. These data also suggest that structurally diverse M1 potentiators may act by distinct mechanisms and differentially regulate receptor

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2012-06-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2016-07-01

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

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

    PubMed

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

    2015-01-01

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

  4. Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer

    PubMed Central

    Bilen, Mehmet Asim; Hess, Kenneth R.; Broaddus, Russell R.; Kopetz, Scott; Wei, Chongjuan; Pagliaro, Lance C.; Karam, Jose A.; Ward, John F.; Wood, Christopher G.; Rao, Priya; Tu, Zachary H.; General, Rosale; Chen, Adrienne H.; Nieto, Yago L.; Yeung, Sai‐ching J.; Lin, Sue‐Hwa; Logothetis, Christopher J.; Pisters, Louis L.

    2016-01-01

    BACKGROUND Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype. METHODS In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next‐generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations. RESULTS Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac‐seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected. CONCLUSIONS The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836–43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License

  5. The potential use of microcalorimetry in rapid differentiation between septic arthritis and other causes of arthritis.

    PubMed

    Yusuf, E; Hügle, T; Daikeler, T; Voide, C; Borens, O; Trampuz, A

    2015-03-01

    Current diagnostic methods in differentiating septic from non-septic arthritis are time-consuming (culture) or have limited sensitivity (Gram stain). Microcalorimetry is a novel method that can rapidly detect microorganisms by their heat production. We investigated the accuracy and time to detection of septic arthritis by using microcalorimetry. Patients older than 18 years of age with acute arthritis of native joints were prospectively included. Synovial fluid was aspirated and investigated by Gram stain, culture and microcalorimetry. The diagnosis of septic arthritis and non-septic arthritis were made by experienced rheumatologists or orthopaedic surgeons. Septic arthritis was diagnosed by considering the finding of acute arthritis together with findings such as positive Gram stain or positive culture of synovial fluid or positive blood culture. The sensitivity and specificity for diagnosing septic arthritis and the time to positivity of microcalorimetry were determined. Of 90 patients (mean age 64 years), nine had septic arthritis, of whom four (44 %) had positive Gram stain, six (67 %) positive synovial fluid culture and four (44 %) had positive blood culture. The sensitivity of microcalorimetry was 89 %, the specificity was 99 % and the mean detection time was 5.0 h (range, 2.2-8.0 h). Microcalorimetry is an accurate and rapid method for the diagnosis of septic arthritis. It has potential to be used in clinical practice in diagnosing septic arthritis.

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

    SciTech Connect

    David J. Muth Jr.

    2006-09-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  10. Verification of genes differentially expressed in neuroblastoma tumours: a study of potential tumour suppressor genes

    PubMed Central

    Thorell, Kaisa; Bergman, Annika; Carén, Helena; Nilsson, Staffan; Kogner, Per; Martinsson, Tommy; Abel, Frida

    2009-01-01

    Background One of the most striking features of the childhood malignancy neuroblastoma (NB) is its clinical heterogeneity. Although there is a great need for better clinical and biological markers to distinguish between tumours with different severity and to improve treatment, no clear-cut prognostic factors have been found. Also, no major NB tumour suppressor genes have been identified. Methods In this study we performed expression analysis by quantitative real-time PCR (QPCR) on primary NB tumours divided into two groups, of favourable and unfavourable outcome respectively. Candidate genes were selected on basis of lower expression in unfavourable tumour types compared to favourables in our microarray expression analysis. Selected genes were studied in two steps: (1) using TaqMan Low Density Arrays (TLDA) targeting 89 genes on a set of 12 NB tumour samples, and (2) 12 genes were selected from the TLDA analysis for verification using individual TaqMan assays in a new set of 13 NB tumour samples. Results By TLDA analysis, 81 out of 87 genes were found to be significantly differentially expressed between groups, of which 14 have previously been reported as having an altered gene expression in NB. In the second verification round, seven out of 12 transcripts showed significantly lower expression in unfavourable NB tumours, ATBF1, CACNA2D3, CNTNAP2, FUSIP1, GNB1, SLC35E2, and TFAP2B. The gene that showed the highest fold change in the TLDA analysis, POU4F2, was investigated for epigenetic changes (CpG methylation) and mutations in order to explore the cause of the differential expression. Moreover, the fragile site gene CNTNAP2 that showed the largest fold change in verification group 2 was investigated for structural aberrations by copy number analysis. However, the analyses of POU4F2 and CNTNAP2 showed no genetic alterations that could explain a lower expression in unfavourable NB tumours. Conclusion Through two steps of verification, seven transcripts were found to

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-08-01

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

  14. Event-related potentials and cognitive performance in multiple sclerosis patients with fatigue.

    PubMed

    Pokryszko-Dragan, Anna; Zagrajek, Mieszko; Slotwinski, Krzysztof; Bilinska, Malgorzata; Gruszka, Ewa; Podemski, Ryszard

    2016-09-01

    The aim of this study was to evaluate event-related potentials (ERP) and cognition in multiple sclerosis (MS) patients with regard to fatigue and disease-related variables. The study comprised 86 MS patients and 40 controls. Fatigue was assessed using the Fatigue Severity Scale (FSS/FSS-5) and the Modified Fatigue Impact Scale (MFIS/MFISmod). N200 and P300 components of auditory ERP were analyzed. Cognition was evaluated by means of Brief Repeatable Battery of Neuropsychological Tests (BRBNT). The results of ERP and BRBNT were compared between non-fatigued, moderately and severely fatigued MS patients and controls. P300 latency was significantly longer in the whole MS group and in the fatigued patients than in the controls. A positive correlation was found between P300 latency and MFIS/MFISmod results, independent from age and MS-related variables. The fatigued patients scored less than non-fatigued ones in tests evaluating memory, visuomotor abilities and attention. Results of these tests correlated significantly with fatigue measures, independently from MS-related variables. Fatigue in MS patients showed significant relationships with impairment within the memory and attention domains. Parameters of auditory ERP, as electrophysiological biomarkers of cognitive performance, were not independently linked to fatigue.

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

    Yang, Lei; Tan, Dewei; Piao, Hua

    2016-08-01

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

  17. Multiple gunshot suicides: potential for physical activity and medico-legal aspects.

    PubMed

    Karger, B; Brinkmann, B

    1997-01-01

    Out of 138 clearly defined gunshot suicides which were autopsied, 11 persons (8%) fired two or more gunshots to the body. From these 11, 5 cases involved 2 gunshots to the head where the bullets fired first had missed the brain. The trajectories were restricted to the chest in three cases and a combination of gunshots to the head and chest including two perforating heart wounds without immediate incapacitation occurred in three more cases. Reliable incapacitation is based on physiological effects (tissue disruption) and can only be achieved by decreasing the functioning capability of the CNS. This can be accomplished by direct disruption of brain tissue or indirectly by cerebral hypoxemia from massive bleeding. Targets of immediate incapacitation are restricted to certain CNS areas and targets of rapid incapacitation include the heart, the (thoracic) aorta and the pulmonary artery. Other major blood vessels and major organs (lungs, kidneys, liver, spleen) constitute targets of delayed incapacitation. This general classification can be derived from the literature and is illustrated by the cases presented. A thorough post mortem can exclude or quantify the potential for physical activity. Typical features of single gunshot suicides such as contact shots, classical entrance wound sites and soot/backspatter on a hand also occur in multiple gunshot suicides.

  18. Gait analysis at multiple speeds reveals differential functional and structural outcomes in response to graded spinal cord injury.

    PubMed

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

    2014-05-01

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

  19. Preservation of gene expression ratios among multiple complex cDNAs after PCR amplification: application to differential gene expression studies.

    PubMed

    Ji, W; Cai, L; Wright, M B; Walker, G; Salgam, P; Vater, A; Lindpaintner, K

    2000-01-01

    Comparative gene expression studies are often limited by low availability of tissue and poor quality of extractable mRNA. Collective PCR amplification of minute quantities of mRNA has great potential for overcoming these limitations. However, there remains significant concern about the effects of amplification on the absolute and relative abundance of individual mRNAs that could complicate subsequent gene expression studies. To address this problem, we systematically compared the relative abundance of many specific mRNAs from complex cDNA preparations (from tissue and cultured cells) both before and after amplification by PCR. Our results demonstrated that, as expected, the absolute abundance of different mRNAs in a cDNA library is altered in an unpredictable manner by PCR amplification. However, we found that the concentration ratios of specific mRNAs among different cDNA preparations were routinely well conserved after PCR amplification. Thus, for the purpose of comparative expression studies for specific mRNAs in two (or more) complex cDNAs, PCR-amplified cDNA is equally useful as unamplified cDNA. These results provide a rigorous experimental validation and offer a theoretical treatment to support the utility of PCR amplified cDNA for differential gene expression studies. We conclude that the inherent difficulties in performing differential screening studies such as gene chip and array analyses on limited amounts of biological materials can be overcome by a PCR amplification step without compromising data quality.

  20. Acupuncture: a potential modality for the treatment of auricular pruritus in Ramsay Hunt Syndrome with multiple cranial nerve lesions.

    PubMed

    Liu, Lan Ying; Wang, He Sheng; Sun, Jian Hua

    2015-03-01

    Auricular pruritus coexisted with multiple cranial nerve lesions in Ramsay Hunt syndrome has been rarely reported in the literature especially its treatment. However, auricular pruritus cannot be better improved along with the improvement of multiple cranial nerve lesions. We tried to solve the problem with acupuncture and got experience from it. The following 2 cases of Ramsay Hunt syndrome show a potential modality for the treatment of auricular pruritus with acupuncture.

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

    PubMed Central

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

    2016-01-01

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

  2. Potential Role of S100A8 in Cutaneous Squamous Cell Carcinoma Differentiation

    PubMed Central

    Shin, Jung-Min; Chang, In-Kyu; Lee, Young-Ho; Yeo, Min-Kyung; Kim, Jin-Man; Sohn, Kyung-Cheol; Im, Myung; Seo, Young-Joon; Kim, Chang-Deok; Lee, Jeung-Hoon

    2016-01-01

    Background S100A8 is differentially expressed in various cell types and is associated with a number of malignant disorders. S100A8 may affect tumor biology. However, its role in cutaneous squamous cell carcinoma (SCC) is not well established. Objective This study aims to investigate the relationship between S100A8 and cutaneous SCC development. Methods We performed immunohistochemical staining to detect S100A8 expression in facial skin specimens of premalignant actinic keratosis (AK), malignant SCC, and normal tissues. In addition, we utilized postconfluence and high calcium-induced differentiation in a culture system model. Furthermore, we constructed a recombinant adenovirus expressing GFP-tagged S100A8 to investigate the role of S100A8 in SCC cell differentiation. Results S100A8 was significantly overexpressed in human cutaneous SCC compared to that in normal and AK tissues. S100A8 was gradually upregulated in SCC cells in a post-confluence-induced differentiation model. Overexpression of S100A8 in SCC cells induced by adenoviral transduction led to increased expression levels of differentiation markers, such as loricrin, involucrin, and filaggrin. S100A8 overexpression also increased loricrin and involucrin luciferase activity. Conclusion S100A8 regulates cutaneous SCC differentiation and induces well-differentiated SCC formation in skin. PMID:27081264

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

    SciTech Connect

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

    2014-05-30

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

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

    PubMed Central

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

    2014-01-01

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

  5. The potential for a suite of isotope and chemical markers to differentiate sources of nitrate contamination: a review.

    PubMed

    Fenech, C; Rock, L; Nolan, K; Tobin, J; Morrissey, A

    2012-05-01

    Nitrate is naturally found within the environment as part of the nitrogen cycle. However, anthropogenic inputs have greatly increased nitrate loads within ground and surface waters. This has had a severe impact on aquatic ecosystems and has given rise to health considerations in humans and livestock. Therefore, the identification of nitrate sources is important in preserving water quality and achieving sustainability of our water resources. Nitrate sources can be determined based on the nitrate nitrogen (N) and oxygen (O) isotopic compositions (δ(15)N, δ(18)O). However, sewage and manure have overlapping δ(15)N and δ(18)O values making their differentiation on this basis problematic. The specific differentiation between sources of faecal contamination is of particular importance, because the risk to humans is usually considered higher from human faecal contamination (sewage) than from animal faecal contamination. This review summarises the current state of knowledge in using isotope tracers to differentiate various nitrate sources and identifies potential chemical tracers for differentiating sewage and manure. In particular, an in depth review of the current state of knowledge regarding the necessary considerations in using chemical markers, such as pharmaceuticals and food additives, to differentiate sewage and manure sources of nitrate contamination will be given, through an understanding of their use, occurrence and fate, in order to identify the most suitable potential chemical markers.

  6. Multiple, correlated covariates associated with differential item functioning (DIF): Accounting for language DIF when education levels differ across languages

    PubMed Central

    Gibbons, Laura E.; Crane, Paul K.; Mehta, Kala M.; Pedraza, Otto; Tang, Yuxiao; Manly, Jennifer J.; Narasimhalu, Kaavya; Teresi, Jeanne; Jones, Richard N.; Mungas, Dan

    2012-01-01

    Differential item functioning (DIF) occurs when a test item has different statistical properties in subgroups, controlling for the underlying ability measured by the test. DIF assessment is necessary when evaluating measurement bias in tests used across different language groups. However, other factors such as educational attainment can differ across language groups, and DIF due to these other factors may also exist. How to conduct DIF analyses in the presence of multiple, correlated factors remains largely unexplored. This study assessed DIF related to Spanish versus English language in a 44-item object naming test. Data come from a community-based sample of 1,755 Spanish- and English-speaking older adults. We compared simultaneous accounting, a new strategy for handling differences in educational attainment across language groups, with existing methods. Compared to other methods, simultaneously accounting for language- and education-related DIF yielded salient differences in some object naming scores, particularly for Spanish speakers with at least 9 years of education. Accounting for factors that vary across language groups can be important when assessing language DIF. The use of simultaneous accounting will be relevant to other cross-cultural studies in cognition and in other fields, including health-related quality of life. PMID:22900138

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

    PubMed

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

    2016-08-01

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

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

    PubMed

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

    2016-08-01

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

  9. Multipotential differentiation of human urine-derived stem cells: potential for therapeutic applications in urology.

    PubMed

    Bharadwaj, Shantaram; Liu, Guihua; Shi, Yingai; Wu, Rongpei; Yang, Bin; He, Tongchuan; Fan, Yuxin; Lu, Xinyan; Zhou, Xiaobo; Liu, Hong; Atala, Anthony; Rohozinski, Jan; Zhang, Yuanyuan

    2013-09-01

    We sought to biologically characterize and identify a subpopulation of urine-derived stem cells (USCs) with the capacity for multipotent differentiation. We demonstrated that single USCs can expand to a large population with 60-70 population doublings. Nine of 15 individual USC clones expressed detectable levels of telomerase and have long telomeres. These cells expressed pericyte and mesenchymal stem cell markers. Upon induction with appropriate media in vitro, USCs differentiated into bladder-associated cell types, including functional urothelial and smooth muscle cell lineages. When the differentiated USCs were seeded onto a scaffold and subcutaneously implanted into nude mice, multilayered tissue-like structures formed consisting of urothelium and smooth muscle. Additionally, USCs were able to differentiate into endothelial, osteogenic, chondrogenic, adipogenic, skeletal myogenic, and neurogenic lineages but did not form teratomas during the 1-month study despite telomerase activity. USCs may be useful in cell-based therapies and tissue engineering applications, including urogenital reconstruction.

  10. Microgravity Reduces the Differentiation and Regenerative Potential of Embryonic Stem Cells

    PubMed Central

    Blaber, Elizabeth A.; Finkelstein, Hayley; Dvorochkin, Natalya; Sato, Kevin Y.; Yousuf, Rukhsana; Burns, Brendan P.; Globus, Ruth K.

    2015-01-01

    Mechanical unloading in microgravity is thought to induce tissue degeneration by various mechanisms, including inhibition of regenerative stem cell differentiation. To address this hypothesis, we investigated the effects of microgravity on early lineage commitment of mouse embryonic stem cells (mESCs) using the embryoid body (EB) model of tissue differentiation. We found that exposure to microgravity for 15 days inhibits mESC differentiation and expression of terminal germ layer lineage markers in EBs. Additionally, microgravity-unloaded EBs retained stem cell self-renewal markers, suggesting that mechanical loading at Earth's gravity is required for normal differentiation of mESCs. Finally, cells recovered from microgravity-unloaded EBs and then cultured at Earth's gravity showed greater stemness, differentiating more readily into contractile cardiomyocyte colonies. These results indicate that mechanical unloading of stem cells in microgravity inhibits their differentiation and preserves stemness, possibly providing a cellular mechanistic basis for the inhibition of tissue regeneration in space and in disuse conditions on earth. PMID:26414276

  11. Cellular network entropy as the energy potential in Waddington's differentiation landscape.

    PubMed

    Banerji, Christopher R S; Miranda-Saavedra, Diego; Severini, Simone; Widschwendter, Martin; Enver, Tariq; Zhou, Joseph X; Teschendorff, Andrew E

    2013-10-24

    Differentiation is a key cellular process in normal tissue development that is significantly altered in cancer. Although molecular signatures characterising pluripotency and multipotency exist, there is, as yet, no single quantitative mark of a cellular sample's position in the global differentiation hierarchy. Here we adopt a systems view and consider the sample's network entropy, a measure of signaling pathway promiscuity, computable from a sample's genome-wide expression profile. We demonstrate that network entropy provides a quantitative, in-silico, readout of the average undifferentiated state of the profiled cells, recapitulating the known hierarchy of pluripotent, multipotent and differentiated cell types. Network entropy further exhibits dynamic changes in time course differentiation data, and in line with a sample's differentiation stage. In disease, network entropy predicts a higher level of cellular plasticity in cancer stem cell populations compared to ordinary cancer cells. Importantly, network entropy also allows identification of key differentiation pathways. Our results are consistent with the view that pluripotency is a statistical property defined at the cellular population level, correlating with intra-sample heterogeneity, and driven by the degree of signaling promiscuity in cells. In summary, network entropy provides a quantitative measure of a cell's undifferentiated state, defining its elevation in Waddington's landscape.

  12. Microgravity Reduces the Differentiation and Regenerative Potential of Embryonic Stem Cells.

    PubMed

    Blaber, Elizabeth A; Finkelstein, Hayley; Dvorochkin, Natalya; Sato, Kevin Y; Yousuf, Rukhsana; Burns, Brendan P; Globus, Ruth K; Almeida, Eduardo A C

    2015-11-15

    Mechanical unloading in microgravity is thought to induce tissue degeneration by various mechanisms, including inhibition of regenerative stem cell differentiation. To address this hypothesis, we investigated the effects of microgravity on early lineage commitment of mouse embryonic stem cells (mESCs) using the embryoid body (EB) model of tissue differentiation. We found that exposure to microgravity for 15 days inhibits mESC differentiation and expression of terminal germ layer lineage markers in EBs. Additionally, microgravity-unloaded EBs retained stem cell self-renewal markers, suggesting that mechanical loading at Earth's gravity is required for normal differentiation of mESCs. Finally, cells recovered from microgravity-unloaded EBs and then cultured at Earth's gravity showed greater stemness, differentiating more readily into contractile cardiomyocyte colonies. These results indicate that mechanical unloading of stem cells in microgravity inhibits their differentiation and preserves stemness, possibly providing a cellular mechanistic basis for the inhibition of tissue regeneration in space and in disuse conditions on earth. PMID:26414276

  13. Microgravity Reduces the Differentiation and Regenerative Potential of Embryonic Stem Cells.

    PubMed

    Blaber, Elizabeth A; Finkelstein, Hayley; Dvorochkin, Natalya; Sato, Kevin Y; Yousuf, Rukhsana; Burns, Brendan P; Globus, Ruth K; Almeida, Eduardo A C

    2015-11-15

    Mechanical unloading in microgravity is thought to induce tissue degeneration by various mechanisms, including inhibition of regenerative stem cell differentiation. To address this hypothesis, we investigated the effects of microgravity on early lineage commitment of mouse embryonic stem cells (mESCs) using the embryoid body (EB) model of tissue differentiation. We found that exposure to microgravity for 15 days inhibits mESC differentiation and expression of terminal germ layer lineage markers in EBs. Additionally, microgravity-unloaded EBs retained stem cell self-renewal markers, suggesting that mechanical loading at Earth's gravity is required for normal differentiation of mESCs. Finally, cells recovered from microgravity-unloaded EBs and then cultured at Earth's gravity showed greater stemness, differentiating more readily into contractile cardiomyocyte colonies. These results indicate that mechanical unloading of stem cells in microgravity inhibits their differentiation and preserves stemness, possibly providing a cellular mechanistic basis for the inhibition of tissue regeneration in space and in disuse conditions on earth.

  14. Acute stimulation of mesenchymal stem cells with cigarette smoke extract affects their migration, differentiation, and paracrine potential

    PubMed Central

    Wahl, Elizabeth A.; Schenck, Thilo L.; Machens, Hans-Günther; Egaña, J. Tomás

    2016-01-01

    Mesenchymal stem cells (MSCs) are known to play a key role in tissue regeneration, while smoking cigarettes is described to impair it. This work focuses on the effect cigarette smoke extract (CSE) has on the migration, differentiation, and paracrine potential of human adipose derived MSCs (AdMSCs). To mimic native conditions in vitro, AdMSCs were cultured in either monolayer or three-dimensional pellet cultures. While constant exposure to high concentrations of CSE had lethal effects on AdMSCs, lower concentrations of CSE impaired cell migration when compared to control conditions. The secretion of key interleukins was downregulated when CSE was exposed to the cells at low concentrations. Moreover, in this work AdMSCs were exposed to CSE while simultaneously being induced to differentiate into adipocytes, osteoblasts, and chondrocytes to determine the effect of CSE on the cells potential to differentiate. While adipogenic differentiation showed no significant variation, AdMSCs exposed to osteogenic and chondrogenic supplements showed both early and late genetic level variation when acutely exposed to low concentrations of CSE. Our results indicate that even a small amount of cigarette smoke can have detrimental effects on the regenerative potential of MSCs. PMID:26976359

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

    PubMed

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

    2016-06-01

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

  16. Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis.

    PubMed

    Sellebjerg, Finn; Cadavid, Diego; Steiner, Deborah; Villar, Luisa Maria; Reynolds, Richard; Mikol, Daniel

    2016-01-01

    Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) demyelinating disease and a leading cause of permanent disability. Patients most often present with a relapsing-remitting disease course, typically progressing over time to a phase of relentless advancement in secondary progressive MS (SPMS), for which approved disease-modifying therapies are limited. In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. In both forms of MS, active brain-tissue injury is associated with inflammation; but in SPMS, the inflammatory response occurs at least partly behind the blood-brain barrier and is followed by a cascade of events, including persistent microglial activation that may lead to chronic demyelination and neurodegeneration associated with irreversible disability. In patients with relapsing forms of MS, natalizumab therapy is known to significantly reduce intrathecal inflammatory responses which results in reductions in brain lesions and brain atrophy as well as beneficial effects on clinical measures, such as reduced frequency and severity of relapse and reduced accumulation of disability. Natalizumab treatment also reduces levels of cerebrospinal fluid chemokines and other biomarkers of intrathecal inflammation, axonal damage and demyelination, and has demonstrated the ability to reduce innate immune activation and intrathecal immunoglobulin synthesis in patients with MS. The efficacy of natalizumab therapy in SPMS is currently being investigated in a randomized, double-blind, placebo-controlled trial. PMID:26788129

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

    NASA Astrophysics Data System (ADS)

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

    2015-12-01

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

  18. Phosphoprotein enriched in astrocytes (PEA)-15: A potential therapeutic target in multiple disease states

    PubMed Central

    Greig, Fiona H.; Nixon, Graeme F.

    2014-01-01

    Phosphoprotein enriched in astrocytes-15 (PEA-15) is a cytoplasmic protein that sits at an important junction in intracellular signalling and can regulate diverse cellular processes, such as proliferation and apoptosis, dependent upon stimulation. Regulation of these processes occurs by virtue of the unique interaction of PEA-15 with other signalling proteins. PEA-15 acts as a cytoplasmic tether for the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) preventing nuclear localisation. In order to release ERK1/2, PEA-15 requires to be phosphorylated via several potential pathways. PEA-15 (and its phosphorylation state) therefore regulates many ERK1/2-dependent processes, including proliferation, via regulating ERK1/2 nuclear translocation. In addition, PEA-15 contains a death effector domain (DED) which allows interaction with other DED-containing proteins. PEA-15 can bind the DED-containing apoptotic adaptor molecule, Fas-associated death domain protein (FADD) which is also dependent on the phosphorylation status of PEA-15. PEA-15 binding of FADD can inhibit apoptosis as bound FADD cannot participate in the assembly of apoptotic signalling complexes. Through these protein–protein interactions, PEA-15-regulated cellular effects have now been investigated in a number of disease-related studies. Changes in PEA-15 expression and regulation have been observed in diabetes mellitus, cancer, neurological disorders and the cardiovascular system. These changes have been suggested to contribute to the pathology related to each of these disease states. As such, new therapeutic targets based around PEA-15 and its associated interactions are now being uncovered and could provide novel avenues for treatment strategies in multiple diseases. PMID:24657708

  19. Multiple extrema in the intermolecular potential and the phase diagram of protein solutions.

    PubMed

    Brandon, Simon; Katsonis, Panagiotis; Vekilov, Peter G

    2006-06-01

    Recent experiments have revealed several surprising features of the phase equilibria in protein solutions: liquid-liquid phase separation which is, in some cases, metastable with respect to the liquid-solid equilibrium, and in others-unobservable; widely varying crystallization enthalpies, including completely athermal crystallization; the co-existence of several crystalline polymorphs; and others. Other studies have shown that the solvent molecules at the hydrophobic and polar patches on the protein molecular surfaces are structured, introducing repulsive forces at surface separations equal to several water molecule sizes. In search of a causal link between the latter and former findings, we apply Monte Carlo simulation techniques in the investigation of phase diagrams associated with globular biological molecules in solution. We account for the solvent structuring via short-range isotropic two-body intermolecular potentials exhibiting multiple extrema. We show that the introduction of a repulsive maximum or a secondary attractive minimum at separations longer than the primary attractive minimum has dramatic effects on the phase diagram: liquid-liquid separation curves are driven to lower or higher temperatures, the sensitivity of the solubility curve (liquidus) to temperature, i.e., the enthalpy of crystallization, is significantly reduced or enhanced, metastable liquid-liquid separation may become stable and vice versa, and both low- and high-density crystalline phases are observed. The similarity of these features of the simulated phase behavior to those observed experimentally suggests that at least some of the mysteries of the protein phase equilibria may be due to the structuring of the solvent around the protein molecular surfaces. Another conclusion is that at least some of the dense liquids seen in protein solutions may be stable and not metastable with respect to a solid phase.

  20. Characterizing the existing and potential structural space of proteins by large-scale multiple loop permutations.

    PubMed

    Dai, Liang; Zhou, Yaoqi

    2011-05-01

    Worldwide structural genomics projects are increasing structure coverage of sequence space but have not significantly expanded the protein structure space itself (i.e., number of unique structural folds) since 2007. Discovering new structural folds experimentally by directed evolution and random recombination of secondary-structure blocks is also proved rarely successful. Meanwhile, previous computational efforts for large-scale mapping of protein structure space are limited to simple model proteins and led to an inconclusive answer on the completeness of the existing observed protein structure space. Here, we build novel protein structures by extending naturally occurring circular (single-loop) permutation to multiple loop permutations (MLPs). These structures are clustered by structural similarity measure called TM-score. The computational technique allows us to produce different structural clusters on the same naturally occurring, packed, stable core but with alternatively connected secondary-structure segments. A large-scale MLP of 2936 domains from structural classification of protein domains reproduces those existing structural clusters (63%) mostly as hubs for many nonredundant sequences and illustrates newly discovered novel clusters as islands adopted by a few sequences only. Results further show that there exist a significant number of novel potentially stable clusters for medium-size or large-size single-domain proteins, in particular, >100 amino acid residues, that are either not yet adopted by nature or adopted only by a few sequences. This study suggests that MLP provides a simple yet highly effective tool for engineering and design of novel protein structures (including naturally knotted proteins). The implication of recovering new-fold targets from critical assessment of structure prediction techniques (CASP) by MLP on template-based structure prediction is also discussed. Our MLP structures are available for download at the publication page of the

  1. "So Much Potential in Reading!" Developing Meaningful Literacy Routines for Students with Multiple Disabilities

    ERIC Educational Resources Information Center

    Fenlon, Amanda G.; McNabb, Jessica; Pidlypchak, Harmony

    2010-01-01

    Children with multiple disabilities, often experience challenges in communication, mobility, and learning. Despite these challenges, substantial research exists that documents successful educational methods and strategies for these students. Specifically, students with multiple disabilities have successfully been taught to use a voice output…

  2. Differentiation potentials of perivascular cells in the bone tissue remodeling zones under microgravity

    NASA Astrophysics Data System (ADS)

    Rodionova, Natalia; Katkova, Olena

    Adaptive remodeling processes in the skeleton bones occur in the close topographical interconnection with blood capillaries followed by perivascular cells. Radioautographic studies with 3Н- thymidine (Kimmel D.B., Fee W.S., 1980; Rodionova N.V., 1989, 2006) has shown that in osteogenesis zones there is sequential differentiation process of the perivascular cells into osteogenic ones. Using electron microscopy and cytochemistry we studied perivsacular cells in metaphysis of the rats femoral bones under conditions of modeling microgravity (28 days duration) and in femoral bonеs metaphyses of rats flown on board of the space laboratory (Spacelab - 2) It was revealed that population of the perivascular cells is not homogeneous in adaptive zones of the remodeling in both control and test groups (lowering support loading). This population comprises adjacent to endothelium little differentiated forms and isolated cells with differentiation features (specific volume of rough endoplasmic reticulum in cytoplasm is increased). Majority of the perivascular cells in the control group reveals reaction to alkaline phosphatase (marker of the osteogenic differentiation). In little differentiated cells this reaction is registered in nucleolus, nucleous and cytoplasm. In differentiating cells activity of the alkaline phosphatase is also detected on the outer surface of the cellular membrane. Unlike the control group in the bones of animals under microgravitaty reaction to the alkaline phosphatase is registered not for all cells of perivascular population. Part of the differentiating perivascular cells does not contain a product of the reaction. There is also visible trend of individual alkaline phosphatase containing perivascular cells amounts decrease (i.e. osteogenic cells-precursors). Under microgravity some little differentiated perivascular cells reveal destruction signs. Found decrease trend of the alkaline phosphatase containing cells (i.e. osteogenic cells) number in

  3. Effects of long-term differential fertilization on eukaryotic microbial communities in an arable soil: a multiple barcoding approach.

    PubMed

    Lentendu, Guillaume; Wubet, Tesfaye; Chatzinotas, Antonis; Wilhelm, Christian; Buscot, François; Schlegel, Martin

    2014-07-01

    To understand the fine-scale effects of changes in nutrient availability on eukaryotic soil microorganisms communities, a multiple barcoding approach was used to analyse soil samples from four different treatments in a long-term fertilization experiment. We performed PCR amplification on soil DNA with primer pairs specifically targeting the 18S rRNA genes of all eukaryotes and three protist groups (Cercozoa, Chrysophyceae-Synurophyceae and Kinetoplastida) as well as the ITS gene of fungi and the 23S plastid rRNA gene of photoautotrophic microorganisms. Amplicons were pyrosequenced, and a total of 88,706 quality filtered reads were clustered into 1232 operational taxonomic units (OTU) across the six data sets. Comparisons of the taxonomic coverage achieved based on overlapping assignment of OTUs revealed that half of the eukaryotic taxa identified were missed by the universal eukaryotic barcoding marker. There were only little differences in OTU richness observed between organic- (farmyard manure), mineral- and nonfertilized soils. However, the community compositions appeared to be strongly structured by organic fertilization in all data sets other than that generated using the universal eukaryotic 18S rRNA gene primers, whereas mineral fertilization had only a minor effect. In addition, a co-occurrence based network analysis revealed complex potential interaction patterns between OTUs from different trophic levels, for example between fungivorous flagellates and fungi. Our results demonstrate that changes in pH, moisture and organic nutrients availability caused shifts in the composition of eukaryotic microbial communities at multiple trophic levels.

  4. Bone-derived mesenchymal stromal cells from HIV transgenic mice exhibit altered proliferation, differentiation capacity and paracrine functions along with impaired therapeutic potential in kidney injury

    SciTech Connect

    Cheng, Kang; Rai, Partab; Lan, Xiqian; Plagov, Andrei; Malhotra, Ashwani; Gupta, Sanjeev; Singhal, Pravin C.

    2013-08-15

    Mesenchymal stem cells (MSCs) secrete paracrine factors that could be cytoprotective and serve roles in immunoregulation during tissue injury. Although MSCs express HIV receptors, and co-receptors, and are susceptible to HIV infection, whether HIV-1 may affect biological properties of MSCs needs more study. We evaluated cellular proliferation, differentiation and paracrine functions of MSCs isolated from compact bones of healthy control mice and Tg26 HIV-1 transgenic mice. The ability of MSCs to protect against cisplatin toxicity was studied in cultured renal tubular cells as well as in intact mice. We successfully isolated MSCs from healthy mice and Tg26 HIV-1 transgenic mice and found the latter expressed viral Nef, Vpu, NL4-3 and Vif genes. The proliferation and differentiation of Tg26 HIV-1 MSCs was inferior to MSCs from healthy mice. Moreover, transplantation of Tg26 HIV-1 MSCs less effectively improved outcomes compared with healthy MSCs in mice with acute kidney injury. Also, Tg26 HIV-1 MSCs secreted multiple cytokines, but at significantly lower levels than healthy MSCs, which resulted in failure of conditioned medium from these MSCs to protect cultured renal tubular cells from cisplatin toxicity. Therefore, HIV-1 had adverse biological effects on MSCs extending to their proliferation, differentiation, function, and therapeutic potential. These findings will help in advancing mechanistical insight in renal injury and repair in the setting of HIV-1 infection. -- Highlights: •MSCs isolated from HIV mice displayed HIV genes. •MSCs isolated from HIV mice exhibited attenuated growth and paracrine functions. •AKI mice with transplanted HIV-MSC displayed poor outcome. •HIV-1 MSC secreted multiple cytokines but at a lower level.

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

    PubMed

    Abhishek, Sinha; Palamadai Krishnan, Suresh

    2016-01-01

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

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

    PubMed

    Abhishek, Sinha; Palamadai Krishnan, Suresh

    2016-01-01

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

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

    PubMed Central

    Abhishek, Sinha; Palamadai Krishnan, Suresh

    2016-01-01

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

  8. TGF-beta signaling potentiates differentiation of embryonic stem cells to Pdx-1 expressing endodermal cells.

    PubMed

    Shiraki, Nobuaki; Lai, Cheng-Jung; Hishikari, Yosuke; Kume, Shoen

    2005-06-01

    Embryonic stem (ES) cells have the capacity to differentiate to every cell type that constitutes fetal or adult tissues. To trace and quantitatively assess the differentiation of ES cells into gut endodermal cells, we used an ES cell line with the lacZ gene inserted into the pdx-1 locus. Targeted mutations of pdx-1 in mice demonstrate that pdx-1 is required for pancreatic and rostral duodenal development; therefore, pdx-1 serves as an excellent early gut regional specific marker. When these ES cells were differentiated by removal of leukemia inhibitory factor (LIF), only fractional cells turned into lacZ positive, which indicates pancreatic-duodenal differentiation. Co-cultivation of ES cells with pancreatic rudiments induced a significant increase in the proportion of lacZ positive cell numbers and this increase was further enhanced by forced expression of a chick putative endoderm inducer gene, cmix. Transforming growth factor (TGF)-beta2 mimicked the effects of pancreatic rudiments and this effect was enhanced by cmix expression. Expression analysis showed over-expression of cmix induced endodermal marker genes. These data indicate that one can make use of this knowledge on molecular events of embryonic development to drive ES cells to differentiate into pdx-1 expressing endodermal cells in vitro.

  9. The Drosophila Transcription Factor Dimmed Affects Neuronal Growth and Differentiation in Multiple Ways Depending on Neuron Type and Developmental Stage

    PubMed Central

    Liu, Yiting; Luo, Jiangnan; Nässel, Dick R.

    2016-01-01

    Growth of postmitotic neurons occurs during different stages of development, including metamorphosis, and may also be part of neuronal plasticity and regeneration. Recently we showed that growth of post-mitotic neuroendocrine cells expressing the basic helix loop helix (bHLH) transcription factor Dimmed (Dimm) in Drosophila could be regulated by insulin/IGF signaling and the insulin receptor (dInR). Dimm is also known to confer a secretory phenotype to neuroendocrine cells and can be part of a combinatorial code specifying terminal differentiation in peptidergic neurons. To further understand the mechanisms of Dimm function we ectopically expressed Dimm or Dimm together with dInR in a wide range of Dimm positive and Dimm negative peptidergic neurons, sensory neurons, interneurons, motor neurons, and gut endocrine cells. We provide further evidence that dInR mediated cell growth occurs in a Dimm dependent manner and that one source of insulin-like peptide (DILP) for dInR mediated cell growth in the CNS is DILP6 from glial cells. Expressing both Dimm and dInR in Dimm negative neurons induced growth of cell bodies, whereas dInR alone did not. We also found that Dimm alone can regulate cell growth depending on specific cell type. This may be explained by the finding that the dInR is a direct target of Dimm. Conditional gene targeting experiments showed that Dimm alone could affect cell growth in certain neuron types during metamorphosis or in the adult stage. Another important finding was that ectopic Dimm inhibits apoptosis of several types of neurons normally destined for programmed cell death (PCD). Taken together our results suggest that Dimm plays multiple transcriptional roles at different developmental stages in a cell type-specific manner. In some cell types ectopic Dimm may act together with resident combinatorial code transcription factors and affect terminal differentiation, as well as act in transcriptional networks that participate in long term maintenance

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

    SciTech Connect

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

    2007-08-17

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

  11. Matrix-mediated retention of osteogenic differentiation potential by human adult bone marrow stromal cells during ex vivo expansion.

    PubMed

    Mauney, Joshua R; Kaplan, David L; Volloch, Vladimir

    2004-07-01

    During prolonged cultivation ex vivo, adult bone marrow stromal stem cells (BMSCs) undergo two probably interdependent processes, replicative aging and a decline in differentiation potential. Recently, our results with primary human fibroblasts indicated that growth on denatured collagen (DC) matrix results in the reduction of the rate of cellular aging. The present study has been undertaken to test whether the growth of human BMSCs under the same conditions would translate into preservation of cellular aging-attenuated functions, such as the ability to express HSP70 in response to stress as well as of osteogenic differentiation potential. We report here that growth of BMSCs on a DC matrix versus tissue culture polystyrene significantly reduced one of the main manifestations of cellular aging, the attenuation of the ability to express a major protective stress response component, HSP70, increased the proliferation capacity of ex vivo expanded BMSCs, reduced the rate of morphological changes, and resulted in a dramatic increase in the retention of the potential to express osteogenic-specific functions and markers upon treatment with osteogenic stimulants. BMSCs are a promising and increasingly important cell source for tissue engineering as well as cell and gene therapeutic strategies. For use of BMSCs in these applications, ex vivo expansion is necessary to obtain a sufficient, therapeutically useful, number of cells; however, this results in the loss of differentiation potential. This problem is especially acute in older patients where more extensive in vitro expansion of smaller number of stem/progenitor cells is needed. The finding that growth on certain biomaterials preserves aging-attenuated functions, enhances proliferation capacity, and maintains differentiation potential of BMSCs indicates a promising approach to address this problem.

  12. Inverse differentiation pathway by multiple mafic magma refilling in the last magmatic activity of Nisyros Volcano, Greece

    NASA Astrophysics Data System (ADS)

    Braschi, Eleonora; Francalanci, Lorella; Vougioukalakis, Georges E.

    2012-07-01

    Based on detailed field, petrographic, chemical, and isotopic data, this paper shows that the youngest magmas of the active Nisyros volcano (South Aegean Arc, Greece) are an example of transition from rhyolitic to less evolved magmas by multiple refilling with mafic melts, triggering complex magma interaction processes. The final magmatic activity of Nisyros was characterized by sub-Plinian caldera-forming eruption (40 ka), emplacing the Upper Pumice (UP) rhyolitic deposits, followed by the extrusion of rhyodacitic post-caldera domes (about 31-10 ka). The latter are rich in magmatic enclaves with textural and compositional (basaltic-andesite to andesite) characteristics that reveal they are quenched portions of mafic magmas included in a cooler more evolved melt. Dome-lavas have different chemical, isotopic, and mineralogical characteristics from the enclaves. The latter have lower 87Sr/86Sr and higher 143Nd/144Nd values than dome-lavas. Silica contents and 87Sr/86Sr values decrease with time among dome-lavas and enclaves. Micro-scale mingling processes caused by enclave crumbling and by widespread mineral exchanges increase from the oldest to the youngest domes, together with enclave content. We demonstrate that the dome-lavas are multi-component magmas formed by progressive mingling/mixing processes between a rhyolitic component ( post-UP) and the enclave-forming mafic magmas refilling the felsic reservoir (from 15 wt.% to 40 wt.% of mafic component with time). We recognize that only the more evolved enclave magmas contribute to this process, in which recycling of cumulate plagioclase crystals is also involved. The post-UP end-member derives by fractional crystallization from the magmas leftover after the previous UP eruptions. The enclave magma differentiation develops mainly by fractional crystallization associated with multiple mixing with mafic melts changing their composition with time. A time-related picture of the relationships between dome-lavas and

  13. Student Interactions with CD-ROM Storybooks: A Look at Potential Relationships between Multiple Intelligence Strengths and Levels of Interaction

    ERIC Educational Resources Information Center

    Huffman, Celia A.

    2012-01-01

    This study looked at the potential relationship that may exist between students' intelligence strengths, in particular their spatial and kinesthetic strengths, and their combined cognitive and metacognitive levels of interaction with a CD-ROM storybook. The multiple intelligence strengths of a sample of students, measured via the MIDAS/My…

  14. PTSD and Comorbid Disorders in a Representative Sample of Adolescents: The Risk Associated with Multiple Exposures to Potentially Traumatic Events

    ERIC Educational Resources Information Center

    Macdonald, Alexandra; Danielson, Carla Kmett; Resnick, Heidi S.; Saunders, Benjamin E.; Kilpatrick, Dean G.

    2010-01-01

    Objective: This study compared the impact of multiple exposures to potentially traumatic events (PTEs), including sexual victimization, physical victimization, and witnessed violence, on posttraumatic stress disorder (PTSD) and comorbid conditions (i.e., major depressive episode [MDE], and substance use [SUD]). Methods: Participants were a…

  15. Directed differentiation into neural lineages and therapeutic potential of porcine embryonic stem cells in rat Parkinson's disease model.

    PubMed

    Yang, Jenn-Rong; Liao, Chia-Hsin; Pang, Cheng-Yoong; Huang, Lynn Ling-Huei; Lin, Yu-Ting; Chen, Yi-Ling; Shiue, Yow-Ling; Chen, Lih-Ren

    2010-08-01

    This study was conducted to direct porcine embryonic stem (pES) cells differentiating into neural lineages and to investigate therapeutic potential of GFP-expressing pES (pES/GFP(+)) in the rat model of Parkinson's disease (PD). Directed differentiation of pES into neural lineages was induced by suspension culture in medium containing RA, SHH, and FGF combinations without going through embryoid body formation. A high yield of nestin-expressing neural precursors was found in all treatments on day 2 after the 12-day induction. On day 6 after replating, more than 86.2 and 83.4% of the differentiated cells stained positively for NFL and MAP2, respectively. The expression of TH, ChAT, and GABA specific markers were also observed in these NFL-positive neural cells. The undifferentiated pES/GFP(+) cells and their neuronal differentiation derivatives were transplanted into the Sprague-Dawley (SD) rat's brain, and their survival and development was determined by using live animal fluorescence optical imaging system every 15 days. The results showed that fluorescent signals from the injection site of SD rats' brain could be detected through the experimental period of 3 months. The level of fluorescent signal detected in the treatment group was twofold that of the control group. The results of behavior analysis showed that PD rats exhibited stably decreased asymmetric rotations after transplantation with pES/GFP(+)-derived D18 neuronal progenitors. The dopaminergic differentiation of grafted cells in the brain was further confirmed by immunohistochemical staining with anti-TH, anti-DA, and anti-DAT antibodies. These results suggested that the differentiation approach we developed would direct pES cells to differentiate into neural lineages and benefit the development of novel therapeutics involving stem cell transplantation.

  16. Comparisons of Differentiation Potential in Human Mesenchymal Stem Cells from Wharton's Jelly, Bone Marrow, and Pancreatic Tissues

    PubMed Central

    Kao, Shih-Yi; Shyu, Jia-Fwu; Wang, Hwai-Shi; Lin, Chi-Hung; Su, Cheng-Hsi; Chen, Tien-Hua; Weng, Zen-Chung; Tsai, Pei-Jiun

    2015-01-01

    Background. Type 1 diabetes mellitus results from autoimmune destruction of β-cells. Insulin-producing cells (IPCs) differentiated from mesenchymal stem cells (MSCs) in human tissues decrease blood glucose levels and improve survival in diabetic rats. We compared the differential ability and the curative effect of IPCs from three types of human tissue to determine the ideal source of cell therapy for diabetes. Methods. We induced MSCs from Wharton's jelly (WJ), bone marrow (BM), and surgically resected pancreatic tissue to differentiate into IPCs. The in vitro differential function of these IPCs was compared by insulin-to-DNA ratios and C-peptide levels after glucose challenge. In vivo curative effects of IPCs transplanted into diabetic rats were monitored by weekly blood glucose measurement. Results. WJ-MSCs showed better proliferation and differentiation potential than pancreatic MSCs and BM-MSCs. In vivo, WJ-IPCs significantly reduced blood glucose levels at first week after transplantation and maintained significant decrease till week 8. BM-IPCs reduced blood glucose levels at first week but gradually increased since week 3. In resected pancreas-IPCs group, blood glucose levels were significantly reduced till two weeks after transplantation and gradually increased since week 4. Conclusion. WJ-MSCs are the most promising stem cell source for β-cell regeneration in diabetes treatment. PMID:26294917

  17. The potential role of subclinical Bordetella Pertussis colonization in the etiology of multiple sclerosis.

    PubMed

    Rubin, Keith; Glazer, Steven

    2016-04-01

    It is established that (1) subclinical Bordetella pertussis colonization of the nasopharynx persists in highly vaccinated populations, and (2) B. pertussis toxin is a potent adjuvant that, when co-administered with neural antigens, induces neuropathology in experimental autoimmune encephalomyelitis, the principle animal model of multiple sclerosis. Building on these observations with supporting epidemiologic and biologic evidence, we propose that, contrary to conventional wisdom that subclinical pertussis infections are innocuous to hosts, B. pertussis colonization is an important cause of multiple sclerosis.

  18. The differential algebra based multiple level fast multipole algorithm for 3D space charge field calculation and photoemission simulation

    DOE PAGES

    None, None

    2015-09-28

    Coulomb interaction between charged particles inside a bunch is one of the most importance collective effects in beam dynamics, becoming even more significant as the energy of the particle beam is lowered to accommodate analytical and low-Z material imaging purposes such as in the time resolved Ultrafast Electron Microscope (UEM) development currently underway at Michigan State University. In addition, space charge effects are the key limiting factor in the development of ultrafast atomic resolution electron imaging and diffraction technologies and are also correlated with an irreversible growth in rms beam emittance due to fluctuating components of the nonlinear electron dynamics.more » In the short pulse regime used in the UEM, space charge effects also lead to virtual cathode formation in which the negative charge of the electrons emitted at earlier times, combined with the attractive surface field, hinders further emission of particles and causes a degradation of the pulse properties. Space charge and virtual cathode effects and their remediation are core issues for the development of the next generation of high-brightness UEMs. Since the analytical models are only applicable for special cases, numerical simulations, in addition to experiments, are usually necessary to accurately understand the space charge effect. In this paper we will introduce a grid-free differential algebra based multiple level fast multipole algorithm, which calculates the 3D space charge field for n charged particles in arbitrary distribution with an efficiency of O(n), and the implementation of the algorithm to a simulation code for space charge dominated photoemission processes.« less

  19. The differential algebra based multiple level fast multipole algorithm for 3D space charge field calculation and photoemission simulation

    SciTech Connect

    None, None

    2015-09-28

    Coulomb interaction between charged particles inside a bunch is one of the most importance collective effects in beam dynamics, becoming even more significant as the energy of the particle beam is lowered to accommodate analytical and low-Z material imaging purposes such as in the time resolved Ultrafast Electron Microscope (UEM) development currently underway at Michigan State University. In addition, space charge effects are the key limiting factor in the development of ultrafast atomic resolution electron imaging and diffraction technologies and are also correlated with an irreversible growth in rms beam emittance due to fluctuating components of the nonlinear electron dynamics. In the short pulse regime used in the UEM, space charge effects also lead to virtual cathode formation in which the negative charge of the electrons emitted at earlier times, combined with the attractive surface field, hinders further emission of particles and causes a degradation of the pulse properties. Space charge and virtual cathode effects and their remediation are core issues for the development of the next generation of high-brightness UEMs. Since the analytical models are only applicable for special cases, numerical simulations, in addition to experiments, are usually necessary to accurately understand the space charge effect. In this paper we will introduce a grid-free differential algebra based multiple level fast multipole algorithm, which calculates the 3D space charge field for n charged particles in arbitrary distribution with an efficiency of O(n), and the implementation of the algorithm to a simulation code for space charge dominated photoemission processes.

  20. Multiple nicotine training doses in mice as a basis for differentiating the effects of smoking cessation aids

    PubMed Central

    Cunningham, Colin S.; McMahon, Lance R.

    2013-01-01

    Rationale Receptor mechanisms underlying the behavioral effects of clinically used nicotinic acetylcholine receptor agonists have not been fully established. Objective Drug discrimination was used to compare receptor mechanisms underlying the effects of smoking cessation aids. Methods Separate groups of male C57BL/6J mice discriminated 0.56, 1, or 1.78 mg/kg of nicotine base. Nicotine, varenicline, and cytisine were administered alone, in combination with each other, and in combination with mecamylamine and dihydro-β-erythroidine (DHβE). Midazolam and morphine were tested to examine sensitivity to non-nicotinics. Results The ED50 value of nicotine to produce discriminative stimulus effects systematically increased as training dose increased. Varenicline and cytisine did not fully substitute for nicotine and, as compared with nicotine, their ED50 values varied less systematically as a function of nicotine training dose. Morphine did not substitute for nicotine, whereas midazolam substituted for the low and not the higher training doses of nicotine. As training dose increased, the dose of mecamylamine needed to produce a significant rightward shift in the nicotine dose-effect function also increased. DHβE antagonized nicotine in animals discriminating the smallest dose of nicotine. Varenicline did not antagonize the effects of nicotine, whereas cytisine produced a modest though significant antagonism of nicotine. Conclusions These results suggest that differences in pharmacologic mechanism between nicotine, varenicline, and cytisine include not only differences in efficacy at a common subtype of nicotinic acetylcholine receptor, but also differential affinity and/or efficacy at multiple receptor subtypes. PMID:23494230

  1. Differential usage of multiple brain-derived neurotrophic factor promoters in the rat brain following neuronal activation.

    PubMed Central

    Metsis, M; Timmusk, T; Arenas, E; Persson, H

    1993-01-01

    The rat brain-derived neurotropic factor (BDNF) gene consists of four 5' exons linked to separate promoters and one 3' exon encoding the prepro-BDNF protein. To gain insights into the regulation of BDNF mRNA expression, probes specific for the different 5' exons were used to study the expression of BDNF mRNA in the brain. Following a systemic injection of the glutamate analog kainic acid, exon I, II, and III mRNAs increased transiently in hippocampus and cerebral cortex. A modest increase was seen for exon IV, where a new transcription initiation site was induced by this treatment. Pretreatments with the N-methyl-D-aspartate (NMDA) receptor antagonist MK801 or the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitrosulfanoylbenzo(f)quinoxaline revealed two region-specific patterns of glutamate receptor-mediated regulation. The first pattern found in neocortex, piriform cortex, and amygdala involves regulation of BDNF exon I, II, and III mRNAs through NMDA and AMPA/kainate receptors. The second pattern found in the hippocampus involves regulation of BDNF exon I, II, and III mRNAs by high-affinity kainate or metabotropic receptors. Treatment with the gamma-aminobutyric acid subtype A (GABAA) receptor antagonist bicuculline increased exon I and III mRNAs in the denate gyrus, and the muscarinic receptor agonist pilocarpine increased exon I mRNA mainly in the neocortex. These data show that the four BDNF promoters allow multiple points of BDNF mRNA regulation and suggest that the activation of different subtypes of glutamate receptors differentially regulates the expression of BDNF exon-specific mRNAs in the brain. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8415610

  2. The efficacy and safety of daclizumab and its potential role in the treatment of multiple sclerosis

    PubMed Central

    2014-01-01

    Daclizumab is a humanized monoclonal antibody of the immunoglobulin G1 (IgG1) isotype that binds to the α-subunit (CD25) of the high-affinity interleukin-2 (IL-2) receptor expressed on activated T cells and CD4+CD25+FoxP3+ regulatory T cells. Based on the assumption that it would block the activation and expansion of autoreactive T cells that are central to the immune pathogenesis of multiple sclerosis (MS), daclizumab was tested in several small open-label clinical trials in MS and demonstrated a profound inhibition of inflammatory disease activity. Surprisingly, accompanying mechanistic studies revealed that the most important biological effect of daclizumab was rather a dramatic expansion and activation of immunoregulatory CD56bright natural-killer (NK) cells that correlated with treatment response, while there was no or only minor effect on peripheral T-cell activation and function. These CD56bright NK cells were able to gain access to the central nervous system in MS and kill autologous activated T cells. Additional and relatively large phase IIb clinical trials showed that daclizumab, as add-on or monotherapy in relapsing–remitting (RR) MS, was highly effective in reducing relapse rate, disability progression, and the number and volume of gadolinium-enhancing, T1 and T2 lesions on brain magnetic resonance imaging (MRI), and reproduced the expansion of CD56bright NK cells as a biomarker for daclizumab activity. Daclizumab is generally very well tolerated and has shown a favorable adverse event (AE) profile in transplant recipients. However, several potentially serious and newly emerging AEs (mainly infections, skin reactions, elevated liver function tests and autoimmune phenomena in several body organs) may require strict safety monitoring programs in future clinical practice and place daclizumab together with other new and highly effective MS drugs as a second-line therapy. Ongoing phase III clinical trials in RRMS are expected to provide definite

  3. Recursive Partitioning to Identify Potential Causes of Differential Item Functioning in Cross-National Data

    ERIC Educational Resources Information Center

    Finch, W. Holmes; Hernández Finch, Maria E.; French, Brian F.

    2016-01-01

    Differential item functioning (DIF) assessment is key in score validation. When DIF is present scores may not accurately reflect the construct of interest for some groups of examinees, leading to incorrect conclusions from the scores. Given rising immigration, and the increased reliance of educational policymakers on cross-national assessments…

  4. Possibilities and Potential Barriers: Learning to Plan for Differentiated Instruction in Elementary Science

    ERIC Educational Resources Information Center

    Tobin, Ruthanne; Tippett, Christine D.

    2014-01-01

    Research indicates that differentiated practices enhance the likelihood of meeting the needs of students who find literacy learning challenging (Tobin & McInnes, 2008; Tomlinson, 2003). The aim of the professional development project described here was to leverage these findings and to build the foundation for future research exploring if…

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

    Allen, Jeremy; Grosset, Jean-Francois

    2016-01-01

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

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

    PubMed

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

    2016-02-01

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

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

    PubMed Central

    Kallas-Kivi, Ade

    2016-01-01

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

  9. Differential Regulation by Organic Compounds and Heavy Metals of Multiple Laccase Genes in the Aquatic Hyphomycete Clavariopsis aquatica

    PubMed Central

    Solé, Magali; Müller, Ines; Pecyna, Marek J.; Fetzer, Ingo; Harms, Hauke

    2012-01-01

    To advance the understanding of the molecular mechanisms controlling microbial activities involved in carbon cycling and mitigation of environmental pollution in freshwaters, the influence of heavy metals and natural as well as xenobiotic organic compounds on laccase gene expression was quantified using quantitative real-time PCR (qRT-PCR) in an exclusively aquatic fungus (the aquatic hyphomycete Clavariopsis aquatica) for the first time. Five putative laccase genes (lcc1 to lcc5) identified in C. aquatica were differentially expressed in response to the fungal growth stage and potential laccase inducers, with certain genes being upregulated by, e.g., the lignocellulose breakdown product vanillic acid, the endocrine disruptor technical nonylphenol, manganese, and zinc. lcc4 is inducible by vanillic acid and most likely encodes an extracellular laccase already excreted during the trophophase of the organism, suggesting a function during fungal substrate colonization. Surprisingly, unlike many laccases of terrestrial fungi, none of the C. aquatica laccase genes was found to be upregulated by copper. However, copper strongly increases extracellular laccase activity in C. aquatica, possibly due to stabilization of the copper-containing catalytic center of the enzyme. Copper was found to half-saturate laccase activity already at about 1.8 μM, in favor of a fungal adaptation to low copper concentrations of aquatic habitats. PMID:22544244

  10. The Physical Characterization of the Potentially Hazardous Asteroid 2004 BL86: A Fragment of a Differentiated Asteroid

    NASA Astrophysics Data System (ADS)

    Reddy, Vishnu; Gary, Bruce L.; Sanchez, Juan A.; Takir, Driss; Thomas, Cristina A.; Hardersen, Paul S.; Ogmen, Yenal; Benni, Paul; Kaye, Thomas G.; Gregorio, Joao; Garlitz, Joe; Polishook, David; Le Corre, Lucille; Nathues, Andreas

    2015-09-01

    The physical characterization of potentially hazardous asteroids (PHAs) is important for impact hazard assessment and evaluating mitigation options. Close flybys of PHAs provide an opportunity to study their surface photometric and spectral properties that enable the identification of their source regions in the main asteroid belt. We observed PHA (357439) 2004 BL86 during a close flyby of the Earth at a distance of 1.2 million km (0.0080 AU) on 2015 January 26, with an array of ground-based telescopes to constrain its photometric and spectral properties. Lightcurve observations showed that the asteroid was a binary and subsequent radar observations confirmed the binary nature and gave a primary diameter of 300 m and a secondary diameter of 50-100 m. Our photometric observations were used to derive the phase curve of 2004 BL86 in the V-band. Two different photometric functions were fitted to this phase curve, the IAU H-G model and the Shevchenko model. From the fit of the H-G function we obtained an absolute magnitude of H = 19.51 ± 0.02 and a slope parameter of G = 0.34 ± 0.02. The Shevchenko function yielded an absolute magnitude of H = 19.03 ± 0.07 and a phase coefficient b = 0.0225 ± 0.0006. The phase coefficient was used to calculate the geometric albedo (Ag) using the relationship found by Belskaya & Schevchenko, obtaining a value of Ag = 40% ± 8% in the V-band. With the geometric albedo and the absolute magnitudes derived from the H-G and the Shevchenko functions we calculated the diameter (D) of 2004 BL86, obtaining D = 263 ± 26 and D = 328 ± 35 m, respectively. 2004 BL86 spectral band parameters and pyroxene chemistry are consistent with non-cumulate eucrite meteorites. A majority of these meteorites are derived from Vesta and are analogous with surface lava flows on a differentiated parent body. A non-diagnostic spectral curve match using the Modeling for Asteroids tool yielded a best-match with non-cumulate eucrite Bereba. Three other near

  11. THE PHYSICAL CHARACTERIZATION OF THE POTENTIALLY HAZARDOUS ASTEROID 2004 BL86: A FRAGMENT OF A DIFFERENTIATED ASTEROID

    SciTech Connect

    Reddy, Vishnu; Sanchez, Juan A.; Takir, Driss; Corre, Lucille Le; Gary, Bruce L.; Thomas, Cristina A.; Hardersen, Paul S.; Ogmen, Yenal; Benni, Paul; Kaye, Thomas G.; Gregorio, Joao; Garlitz, Joe; Polishook, David; Nathues, Andreas

    2015-09-20

    The physical characterization of potentially hazardous asteroids (PHAs) is important for impact hazard assessment and evaluating mitigation options. Close flybys of PHAs provide an opportunity to study their surface photometric and spectral properties that enable the identification of their source regions in the main asteroid belt. We observed PHA (357439) 2004 BL86 during a close flyby of the Earth at a distance of 1.2 million km (0.0080 AU) on 2015 January 26, with an array of ground-based telescopes to constrain its photometric and spectral properties. Lightcurve observations showed that the asteroid was a binary and subsequent radar observations confirmed the binary nature and gave a primary diameter of 300 m and a secondary diameter of 50–100 m. Our photometric observations were used to derive the phase curve of 2004 BL86 in the V-band. Two different photometric functions were fitted to this phase curve, the IAU H–G model and the Shevchenko model. From the fit of the H–G function we obtained an absolute magnitude of H = 19.51 ± 0.02 and a slope parameter of G = 0.34 ± 0.02. The Shevchenko function yielded an absolute magnitude of H = 19.03 ± 0.07 and a phase coefficient b = 0.0225 ± 0.0006. The phase coefficient was used to calculate the geometric albedo (Ag) using the relationship found by Belskaya and Schevchenko, obtaining a value of Ag = 40% ± 8% in the V-band. With the geometric albedo and the absolute magnitudes derived from the H–G and the Shevchenko functions we calculated the diameter (D) of 2004 BL86, obtaining D = 263 ± 26 and D = 328 ± 35 m, respectively. 2004 BL86 spectral band parameters and pyroxene chemistry are consistent with non-cumulate eucrite meteorites. A majority of these meteorites are derived from Vesta and are analogous with surface lava flows on a differentiated parent body. A non-diagnostic spectral curve match using the Modeling for Asteroids tool yielded a best-match with non-cumulate eucrite Bereba. Three other

  12. The Potential Role of T Helper Cell 22 and IL-22 in Immunopathogenesis of Multiple Sclerosis

    PubMed Central

    Fard, Nazanin Arjomand; Azizi, Gholamreza

    2016-01-01

    Multiple sclerosis is a complex disease with many different immune cells involved in its pathogenesis. Newly identified T helper cell 22 (Th22) is a subset of CD4+ T cells with specific properties apart from other known CD4+ T cell subsets with distinguished function and gene expression. Th22 cells are characterized by production of a distinct profile of effector cytokines, including interleukin (IL)-22, IL-13, and tumor necrosis factor-α (TNF- α). The frequency of Th22 and related cytokine IL-22 are increased in various autoimmune diseases. Recently, several studies have reported the changes in frequency and function of Th22 in multiple sclerosis. This review discusses the role of Th22 and its cytokine IL-22 in the immunopathogenesis of multiple sclerosis disease. PMID:27672486

  13. The Potential Role of T Helper Cell 22 and IL-22 in Immunopathogenesis of Multiple Sclerosis.

    PubMed

    Fard, Nazanin Arjomand; Azizi, Gholamreza; Mirshafiey, Abbas

    2016-01-01

    Multiple sclerosis is a complex disease with many different immune cells involved in its pathogenesis. Newly identified T helper cell 22 (Th22) is a subset of CD4(+) T cells with specific properties apart from other known CD4(+) T cell subsets with distinguished function and gene expression. Th22 cells are characterized by production of a distinct profile of effector cytokines, including interleukin (IL)-22, IL-13, and tumor necrosis factor-α (TNF- α). The frequency of Th22 and related cytokine IL-22 are increased in various autoimmune diseases. Recently, several studies have reported the changes in frequency and function of Th22 in multiple sclerosis. This review discusses the role of Th22 and its cytokine IL-22 in the immunopathogenesis of multiple sclerosis disease. PMID:27672486

  14. A Multiple Regression Analysis of Family Factors Affecting the Potential for Alcoholism in College Students.

    ERIC Educational Resources Information Center

    Pardeck, John T.

    1991-01-01

    Explored the effects of the family system on the potential for alcoholism in 209 college students. Findings showed that students' gender, race, and how often they consumed alcohol were unrelated to the potential for alcoholism; however, perceived conflict in the students' family of origin appeared to increase potential. (Author/PVV)

  15. A qPCR ScoreCard quantifies the differentiation potential of human pluripotent stem cells.

    PubMed

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

    2015-11-01

    Research on human pluripotent stem cells has been hampered by the lack of a standardized, quantitative, scalable assay of pluripotency. We previously described an assay called ScoreCard that used gene expression signatures to quantify differentiation efficiency. Here we report an improved version of the assay based on qPCR that enables faster, more quantitative assessment of functional pluripotency. We provide an in-depth characterization of the revised signature panel (commercially available as the TaqMan hPSC Scorecard Assay) through embryoid body and directed differentiation experiments as well as a detailed comparison to the teratoma assay. We further show that the improved ScoreCard enables a wider range of applications, such as screening of small molecules, genetic perturbations and assessment of culture conditions. Our approach can be extended beyond stem cell applications to characterize and assess the utility of other cell types and lineages. PMID:26501952

  16. Molecular mechanisms and potentials for differentiating inner ear stem cells into sensory hair cells.

    PubMed

    Liu, Quanwen; Chen, Ping; Wang, Jinfu

    2014-06-15

    In mammals, hair cells may be damaged or lost due to genetic mutation, infectious disease, chemical ototoxicity, noise and other factors, causing permanent sensorineural deafness. Regeneration of hair cells is a basic pre-requisite for recovery of hearing in deaf animals. The inner ear stem cells in the organ of Corti and vestibular utricle are the most ideal precursors for regeneration of inner ear hair cells. This review highlights some recent findings concerning the proliferation and differentiation of inner ear stem cells. The differentiation of inner ear stem cells into hair cells involves a series of signaling pathways and regulatory factors. This paper offers a comprehensive analysis of the related studies. PMID:24680894

  17. Genetic Variability Overrides the Impact of Parental Cell Type and Determines iPSC Differentiation Potential

    PubMed Central

    Kyttälä, Aija; Moraghebi, Roksana; Valensisi, Cristina; Kettunen, Johannes; Andrus, Colin; Pasumarthy, Kalyan Kumar; Nakanishi, Mahito; Nishimura, Ken; Ohtaka, Manami; Weltner, Jere; Van Handel, Ben; Parkkonen, Olavi; Sinisalo, Juha; Jalanko, Anu; Hawkins, R. David; Woods, Niels-Bjarne; Otonkoski, Timo; Trokovic, Ras

    2016-01-01

    Summary Reports on the retention of somatic cell memory in induced pluripotent stem cells (iPSCs) have complicated the selection of the optimal cell type for the generation of iPSC biobanks. To address this issue we compared transcriptomic, epigenetic, and differentiation propensities of genetically matched human iPSCs derived from fibroblasts and blood, two tissues of the most practical relevance for biobanking. Our results show that iPSC lines derived from the same donor are highly similar to each other. However, genetic variation imparts a donor-specific expression and methylation profile in reprogrammed cells that leads to variable functional capacities of iPSC lines. Our results suggest that integration-free, bona fide iPSC lines from fibroblasts and blood can be combined in repositories to form biobanks. Due to the impact of genetic variation on iPSC differentiation, biobanks should contain cells from large numbers of donors. PMID:26777058

  18. [Potentialities of MRI in the differential diagnosis of peripheral lung cancer and inflammatory changes].

    PubMed

    Gamova, E V; Nudnov, N V

    2006-01-01

    The paper analyzes the authors' own data of chest magnetic resonance imaging (MRI) in 62 patients with verified peripheral lung cancer and different inflammatory changes (round pneumonic focuses, abscesses, etc.). The MRI signs of peripheral lung cancer are systematized. The additional capacities of contrast enhancement are analyzed. The MRI semiotics of different inflammatory changes has been developed. The differential diagnostic criteria for recognizing peripheral lung cancer and inflammatory changes have been also elaborated.

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

    PubMed Central

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

    2016-01-01

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

  20. Myeloma-specific multiple peptides able to generate cytotoxic T lymphocytes: A potential therapeutic application in multiple myeloma and other plasma cell disorders

    PubMed Central

    Bae, Jooeun; Smith, Robert; Daley, John; Mimura, Naoya; Tai, Yu-Tzu; Anderson, Kenneth C.; Munshi, Nikhil C.

    2013-01-01

    Purpose The efficacy of peptide vaccines may be enhanced by stimulating immune cells with multiple peptides derived from distinct tumor-associated antigens. We have evaluated the heteroclitic XBP1 US184–192 (YISPWILAV), heteroclitic XBP1 SP367–375 (YLFPQLISV), native CD138260–268 (GLVGLIFAV), and native CS1239–247 (SLFVLGLFL) peptides, which have strong HLA-A2 affinity and immunogenicity in combination, for their ability to elicit multiple myeloma antigen-specific responses. Experimental Design Multipeptide-specific cytotoxic T lymphocytes (MP-CTL) were generated by the stimulation of CD3+ T lymphocytes from HLA-A2+ individuals with either autologous mature dendritic cells or T2 cells pulsed with a cocktail of these four peptides. Results The peptide cocktail did not compromise tumor antigen-specific activity of CTL. MP-CTL displayed increased total, effector memory (CCR7−CD45RO+), and activated (CD69+) CD3+CD8+ T lymphocytes. In addition, MP-CTL demonstrated IFN-γ production, cell proliferation, and cytotoxicity against HLA-A2+ multiple myeloma cells, including HLA-A2+ MM patients’ cells. Importantly, MP-CTL showed specific responses in functional assays to each relevant peptide, but not to an irrelevant HLA-A2 specific CMV pp65 (NLVPMVATV) peptide. Conclusions These results highlight the potential therapeutic application of vaccination with a cocktail of HLA-A2 specific peptides to induce CTL with a broad spectrum of immune responses against multiple myeloma antigens. PMID:22753586

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

    NASA Astrophysics Data System (ADS)

    Lehotzky, David; Insperger, Tamas; Stepan, Gabor

    2016-06-01

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

  2. Greenhouse and Field Evaluation of Multiple Virus Resistant Lagenaria siceraria Lines Potentially useful for Watermelon Rootstocks

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In previous evaluations we identified numerous lines of bottle gourd (Lagenaria siceraria) with complete or partial resistance to Zucchini yellow mosaic virus (ZYMV). In the present study, we were interested in developing bottle gourd lines with multiple virus resistance that could be useful as roo...

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

    PubMed

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

    2015-12-01

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

  4. Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases

    PubMed Central

    D’Ambrosio, Daniele; Freedman, Mark S.; Prinz, Joerg

    2016-01-01

    The first oral treatment for relapsing multiple sclerosis, the nonselective sphingosine-1-phosphate receptor (S1PR) modulator fingolimod, led to identification of a pivotal role of sphingosine-1-phosphate and one of its five known receptors, S1P1R, in regulation of lymphocyte trafficking in multiple sclerosis. Modulation of S1P3R, initially thought to cause some of fingolimod’s side effects, prompted the search for novel compounds with high selectivity for S1P1R. Ponesimod is an orally active, selective S1P1R modulator that causes dose-dependent sequestration of lymphocytes in lymphoid organs. In contrast to the long half-life/slow elimination of fingolimod, ponesimod is eliminated within 1 week of discontinuation and its pharmacological effects are rapidly reversible. Clinical data in multiple sclerosis have shown a dose-dependent therapeutic effect of ponesimod and defined 20 mg as a daily dose with desired efficacy, and acceptable safety and tolerability. Phase II clinical data have also shown therapeutic efficacy of ponesimod in psoriasis. These findings have increased our understanding of psoriasis pathogenesis and suggest clinical utility of S1P1R modulation for treatment of various immune-mediated disorders. A gradual dose titration regimen was found to minimize the cardiac effects associated with initiation of ponesimod treatment. Selectivity for S1P1R, rapid onset and reversibility of pharmacological effects, and an optimized titration regimen differentiate ponesimod from fingolimod, and may lead to better safety and tolerability. Ponesimod is currently in phase III clinical development to assess efficacy and safety in relapsing multiple sclerosis. A phase II study is also ongoing to investigate the potential utility of ponesimod in chronic graft versus host disease. PMID:26770667

  5. Quantitative Raman spectral changes of the differentiation of mesenchymal stem cells into islet-like cells by biochemical component analysis and multiple peak fitting

    NASA Astrophysics Data System (ADS)

    Su, Xin; Fang, Shaoyin; Zhang, Daosen; Zhang, Qinnan; He, Yingtian; Lu, Xiaoxu; Liu, Shengde; Zhong, Liyun

    2015-12-01

    Mesenchymal stem cells (MSCs) differentiate into islet-like cells, providing a possible solution for type I diabetes treatment. To search for the precise molecular mechanism of the directional differentiation of MSC-derived islet-like cells, biomolecular composition, and structural conformation information during MSC differentiation, is required. Because islet-like cells lack specific surface markers, the commonly employed immunostaining technique is not suitable for their identification, physical separation, and enrichment. Combining Raman spectroscopic data, a fitting accuracy-improved biochemical component analysis, and multiple peaks fitting approach, we identified the quantitative biochemical and intensity change of Raman peaks that show the differentiation of MSCs into islet-like cells. Along with increases in protein and glycogen content, and decreases in deoxyribonucleic acid and ribonucleic acid content, in islet-like cells relative to MSCs, it was found that a characteristic peak of insulin (665 cm-1) has twice the intensity in islet-like cells relative to MSCs, indicating differentiation of MSCs into islet-like cells was successful. Importantly, these Raman signatures provide useful information on the structural and pathological states during MSC differentiation and help to develop noninvasive and label-free Raman sorting methods for stem cells and their lineages.

  6. Localization and osteoblastic differentiation potential of neural crest-derived cells in oral tissues of adult mice.

    PubMed

    Ono, Miki; Suzawa, Tetsuo; Takami, Masamichi; Yamamoto, Gou; Hosono, Tomohiko; Yamada, Atsushi; Suzuki, Dai; Yoshimura, Kentaro; Watahiki, Junichi; Hayashi, Ryuhei; Arata, Satoru; Mishima, Kenji; Nishida, Kohji; Osumi, Noriko; Maki, Koutaro; Kamijo, Ryutaro

    2015-09-01

    In embryos, neural crest cells emerge from the dorsal region of the fusing neural tube and migrate throughout tissues to differentiate into various types of cells including osteoblasts. In adults, subsets of neural crest-derived cells (NCDCs) reside as stem cells and are considered to be useful cell sources for regenerative medicine strategies. Numerous studies have suggested that stem cells with a neural crest origin persist into adulthood, especially those within the mammalian craniofacial compartment. However, their distribution as well as capacity to differentiate into osteoblasts in adults is not fully understood. To analyze the precise distribution and characteristics of NCDCs in adult oral tissues, we utilized an established line of double transgenic (P0-Cre/CAG-CAT-EGFP) mice in which NCDCs express green fluorescent protein (GFP) throughout their life. GFP-positive cells were scattered like islands throughout tissues of the palate, gingiva, tongue, and buccal mucosa in adult mice, with those isolated from the latter shown to form spheres, typical cell clusters composed of stem cells, under low-adherent conditions. Furthermore, GFP-positive cells had markedly increased alkaline phosphatase (a marker enzyme of osteoblast differentiation) activity and mineralization as shown by alizarin red staining, in the presence of bone morphogenetic protein (BMP)-2. These results suggest that NCDCs reside in various adult oral tissues and possess potential to differentiate into osteoblastic cells. NCDCs in adults may be a useful cell source for bone regeneration strategies.

  7. Statistically Differentiating between Interaction and Nonlinearity in Multiple Regression Analysis: A Monte Carlo Investigation of a Recommended Strategy.

    ERIC Educational Resources Information Center

    Kromrey, Jeffrey D.; Foster-Johnson, Lynn

    1999-01-01

    Shows that the procedure recommended by D. Lubinski and L. Humphreys (1990) for differentiating between moderated and nonlinear regression models evidences statistical problems characteristic of stepwise procedures. Interprets Monte Carlo results in terms of the researchers' need to differentiate between exploratory and confirmatory aspects of…

  8. Progenitor tumours from Emu-bcl-2-myc transgenic mice have lymphomyeloid differentiation potential and reveal developmental differences in cell survival.

    PubMed Central

    Strasser, A; Elefanty, A G; Harris, A W; Cory, S

    1996-01-01

    Mice expressing both a bcl-2 and a myc transgene within the B lymphoid cell compartment invariably develop novel immature haemopoietic tumours. The likely cell of origin of these tumours was identified by a common pattern of cell surface marker expression on a subset of cells comprising approximately 1% of normal mouse bone marrow. The bcl-2-myc tumour cells could be induced to differentiate into either B lymphocytes or macrophages in culture with certain cytokines and feeder cells. Analysis of their progression into the B lymphoid lineage revealed that Igk locus transcription can precede Igh as well as Igk rearrangement. Surprisingly, the undifferentiated tumour cells died rapidly in culture, even in the presence of multiple cytokines, but they proliferated on monolayers of stromal cells derived from haemopoietic tissues. Thus, even with Bcl-2 levels that protect more differentiated cells, these immature bi-potential progenitor cells require a stromal-induced signal for survival. These results provide insight into the process of lineage commitment and suggest new levels of control of cell survival during early steps in haemopoietic development. Images PMID:8670887

  9. Stem cells from umbilical cord blood do have myogenic potential, with and without differentiation induction in vitro

    PubMed Central

    Jazedje, Tatiana; Secco, Mariane; Vieira, Natássia M; Zucconi, Eder; Gollop, Thomaz R; Vainzof, Mariz; Zatz, Mayana

    2009-01-01

    The dystrophin gene, located at Xp21, codifies dystrophin, which is part of a protein complex responsible for the membrane stability of muscle cells. Its absence on muscle causes Duchenne Muscular Dystrophy (DMD), a severe disorder, while a defect of muscle dystrophin causes Becker Muscular Dystrophy (DMB), a milder disease. The replacement of the defective muscle through stem cells transplantation is a possible future treatment for these patients. Our objective was to analyze the potential of CD34+ stem cells from umbilical cord blood to differentiate in muscle cells and express dystrophin, in vitro. Protein expression was analyzed by Immunofluorescence, Western Blotting (WB) and Reverse Transcriptase – Polymerase Chain Reaction (RT-PCR). CD34+ stem cells and myoblasts from a DMD affected patient started to fuse with muscle cells immediately after co-cultures establishment. Differentiation in mature myotubes was observed after 15 days and dystrophin-positive regions were detected through Immunofluorescence analysis. However, WB or RT-PCR analysis did not detect the presence of normal dystrophin in co-cultures of CD34+ and DMD or DMB affected patients' muscle cells. In contrast, some CD34+ stem cells differentiated in dystrophin producers' muscle cells, what was observed by WB, reinforcing that this progenitor cell has the potential to originate muscle dystrophin in vitro, and not just in vivo like reported before. PMID:19144182

  10. Establishment from Shope carcinoma induced in an inbred rabbit of culture cell lines with various potentials for differentiation and tumorigenicity.

    PubMed

    Seto, A; Isono, T; Inoue, M; Yamade, I; Ogawa, K

    1991-08-01

    Shope papillomas induced by cottontail rabbit papilloma-virus (CRPV) in domestic rabbits frequently regress spontaneously or, failing to do so, convert into squamous cell carcinomas at a high rate. This papilloma-carcinoma complex in rabbits provides an experimental model for human papillo-mavirus-associated malignancies. The aim of this study was to prepare an experimental system in inbred rabbits by establishing culture cell lines of the tumor. Squamous cell carcinoma developed from a Shope papilloma that had been induced 6 months previously by inoculating CRPV into an inbred B/J rabbit. By in vitro culturing of the tumor cells, cell lines with potentials for terminal differentiation and tumorigenicity were established. Cloning yielded sublines that varied in these potentials and possessed episomal and integrated CRPV genomes as revealed by Southern hybridization in both one- and two-dimensional electrophoresis. Major CRPV-specific transcripts were similarly observed both in well-differentiated and in poorly differentiated sublines. Immunofluorescence with syngeneic rabbit antibody against tumor-specific antigens localized such antigens mainly in the nuclei of the cells of these sublines. This experimental system allows experiments that were not feasible in randomly bred rabbits. PMID:1649230

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

    PubMed

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

    2015-10-01

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

  12. The Potential of Water Vapor & Precipitation Estimation with a Differential-frequency Radar

    NASA Technical Reports Server (NTRS)

    Meneghini, Robert; Liao, Liang; Tian, Lin

    2006-01-01

    In the presence of rain, the radar return powers from a three-frequency radar, with center frequency at 22.235 GHz and upper and lower frequencies chosen with equal water vapor absorption coefficients, can be used to estimate water vapor density and parameters of the precipitation. A linear combination of differential measurements between the center and lower frequencies on one hand and the upper and lower frequencies on the other provide an estimate of differential water vapor absorption. Conversely, the difference in radar reflectivity factors (in dB) between the upper and lower frequencies is independent of water vapor absorption and can be used to estimate the median mass diameter of the hydrometeors. For a down-looking radar, path-integrated estimates of water vapor absorption may be possible under rain-free as well as raining conditions by using the surface returns at the three frequencies. Cross-talk or interference between the precipitation and water vapor estimates depends on the frequency separation of the channels as well as on the phase state and the median mass diameter of the hydrometeors. Simulations of the retrieval of water vapor absorption show that the largest source of variability arises from the variance in the measured radar return powers while the largest biases occur in the mixed-phase region. Use of high pulse repetition frequencies and signal whitening methods may be needed to obtain the large number of independent samples required. Measurements over a fractional bandwidth, defined as the ratio of the difference between the upper and lower frequencies to the center frequency, up to about 0.2 should be passible in a differential frequency mode, where a single transceiver and antenna are used. Difficulties in frequency allocation may require alternative choices of frequency where the water vapor absorptions at the low and high frequencies are unequal. We consider the degradation in the retrieval accuracy when the frequencies are not optimum.

  13. In vivo differentiation potential of buffalo (Bubalus bubalis) embryonic stem cell.

    PubMed

    Verma, Om Prakash; Kumar, Rajesh; Nath, Amar; Sharma, Manjinder; Dubey, Pawan Kumar; Kumar, G Sai; Sharma, G Taru

    2012-06-01

    Embryonic stem cells (ESCs) derived from inner cell mass (ICM) of mammalian blastocyst are having indefinite proliferation and differentiation capability for any type of cell lineages. In the present study, ICMs of in vitro-derived buffalo blastocysts were cultured into two different culture systems using buffalo fetal fibroblast as somatic cell support and Matrigel as synthetic support to obtain pluripotent buffalo embryonic stem cell (buESC) colonies. Pluripotency of the ESCs were characterised through pluripotency markers whereas, their differentiation capability was assessed by teratoma assay using immuno-compromised mice. Cumulus ooccyte complexes from slaughter house-derived ovaries were subjected to in vitro maturation, in vitro fertilization and in vitro culture to generate blastocysts. Total 262 blastocysts were derived through IVEP with 11.83 % (31/262) hatching rate. To generate buESCs, 15 ICMs from hatched blastocysts were cultured on mitomycin-C-treated homologous fetal fibroblast feeder layer, whereas the leftover 16 ICMs were cultured on extra-cellular matrix (Matrigel). No significant differences were observed for primary ESCs colony formation between two culture systems. Primary colonies as well as passaged ESCs were characterised by alkaline phosphatase staining, karyotyping and expression of transcription-based stem cell markers, OCT-4 and cell surface antigens SSEA-4 and TRA-1-60. Batch of ESCs found positive for pluripotency markers and showing normal karyotype after fifteenth passage were inoculated into eight immuno-compromised mice through subcutaneous and intramuscular route. Subcutaneous route of inoculation was found to be better than intramuscular route. Developed teratomas were excised surgically and subjected to histological analysis. Histological findings revealed presence of all the three germinal layer derivatives in teratoma sections. Presence of germinal layer derivatives were further confirmed by reverse transcriptase

  14. Investigation of potential of differential absorption Lidar techniques for remote sensing of atmospheric pollutants

    NASA Technical Reports Server (NTRS)

    Butler, C. F.; Shipley, S. T.; Allen, R. J.

    1981-01-01

    The NASA multipurpose differential absorption lidar (DIAL) system uses two high conversion efficiency dye lasers which are optically pumped by two frequency-doubled Nd:YAG lasers mounted rigidly on a supporting structure that also contains the transmitter, receiver, and data system. The DIAL system hardware design and data acquisition system are described. Timing diagrams, logic diagrams, and schematics, and the theory of operation of the control electronics are presented. Success in obtaining remote measurements of ozone profiles with an airborne systems is reported and results are analyzed.

  15. Differential Detection of Potentially Hazardous Fusarium Species in Wheat Grains by an Electronic Nose

    PubMed Central

    Eifler, Jakob; Martinelli, Eugenio; Santonico, Marco; Capuano, Rosamaria; Schild, Detlev; Di Natale, Corrado

    2011-01-01

    Fungal infestation on wheat is an increasingly grave nutritional problem in many countries worldwide. Fusarium species are especially harmful pathogens due to their toxic metabolites. In this work we studied volatile compounds released by F. cerealis, F. graminearum, F. culmorum and F. redolens using SPME-GC/MS. By using an electronic nose we were able to differentiate between infected and non-infected wheat grains in the post-harvest chain. Our electronic nose was capable of distinguishing between four wheat Fusaria species with an accuracy higher than 80%. PMID:21695232

  16. Autocrine Action of Thrombospondin-2 Determines the Chondrogenic Differentiation Potential and Suppresses Hypertrophic Maturation of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells.

    PubMed

    Jeong, Sang Young; Ha, Jueun; Lee, Miyoung; Jin, Hye Jin; Kim, Dong Hyun; Choi, Soo Jin; Oh, Wonil; Yang, Yoon Sun; Kim, Jae-Sung; Kim, Byung-Gyu; Chang, Jeong Ho; Cho, Dong-Hyung; Jeon, Hong Bae

    2015-11-01

    Previous studies have shown that mesenchymal stem cell (MSC)-based therapies have varying efficacies for the treatment of various diseases, including cartilage defects. In this study, we demonstrated that the chondrogenic differentiation potential of human umbilical cord blood-derived MSCs (hUCB-MSCs) obtained from different individual donors varies, and we investigated the molecular basis for this variation. Microarray gene expression analysis identified thrombospondin-2 (TSP2) as a candidate gene underlying the interindividual variation in the chondrogenic differentiation potential of hUCB-MSCs. To assess the association between TSP-2 and the differentiation potential, we evaluated chondrogenic differentiation of hUCB-MSCs treated with TSP2 siRNA. In addition, we studied the effect of supplementing exogenous recombinant TSP-2 on TSP2 siRNA-treated hUCB-MSCs. We found that TSP-2 autocrinally promoted chondrogenic differentiation of hUCB-MSCs via the Notch signaling pathway, which was confirmed in MSCs from other sources such as bone marrow and adipose tissue. Interestingly, we observed that TSP-2 attenuated hypertrophy, which inevitably occurs during chondrogenic differentiation of hUCB-MSCs. Our findings indicated that the variable chondrogenic differentiation potential of MSCs obtained from different donors is influenced by the TSP-2 level in the differentiating cells. Thus, the TSP-2 level can be used as a marker to select MSCs with superior chondrogenic differentiation potential for use in cartilage regeneration therapy. PMID:26235673

  17. Differential Effect of Cholesterol and Its Biosynthetic Precursors on Membrane Dipole Potential

    PubMed Central

    Haldar, Sourav; Kanaparthi, Ravi Kumar; Samanta, Anunay; Chattopadhyay, Amitabha

    2012-01-01

    Dipole potential is the potential difference within the membrane bilayer, which originates due to the nonrandom arrangement of lipid dipoles and water molecules at the membrane interface. Cholesterol, a representative sterol in higher eukaryotic membranes, is known to increase membrane dipole potential. In this work, we explored the effects of immediate (7-DHC and desmosterol) and evolutionary (ergosterol) precursors of cholesterol on membrane dipole potential, monitored by the dual wavelength ratiometric approach utilizing the probe di-8-ANEPPS. Our results show that the effect of these precursors on membrane dipole potential is very different from that observed with cholesterol, although the structural differences among them are subtle. These results assume relevance, since accumulation of cholesterol precursors due to defective cholesterol biosynthesis has been reported to result in several inherited metabolic disorders such as the Smith-Lemli-Opitz syndrome. Interestingly, cholesterol (and its precursors) has a negligible effect on dipole potential in polyunsaturated membranes. We interpret these results in terms of noncanonical orientation of cholesterol in these membranes. Our results constitute the first report on the effect of biosynthetic and evolutionary precursors of cholesterol on dipole potential, and imply that a subtle change in sterol structure can significantly alter the dipolar field at the membrane interface. PMID:22500756

  18. UNAIDS 'multiple sexual partners' core indicator: promoting sexual networks to reduce potential biases.

    PubMed

    Dimbuene, Zacharie Tsala; Emina, Jacques B O; Sankoh, Osman

    2014-01-01

    UNAIDS proposed a set of core indicators for monitoring changes in the worldwide AIDS epidemic. This paper explores the validity and effectiveness of the 'multiple sexual partners' core indicator, which is only partially captured with current available data. The paper also suggests an innovative approach for collecting more informative data that can be used to provide an accurate measure of the UNAIDS's 'multiple sexual partners' core indicator. Specifically, the paper addresses three major limitations associated with the indicator when it is measured with respondents' sexual behaviors. First, the indicator assumes that a person's risk of contracting HIV/AIDS/STIs is merely a function of his/her own sexual behavior. Second, the indicator does not account for a partner's sexual history, which is very important in assessing an individual's risk level. Finally, the 12-month period used to define a person's risks can be misleading, especially because HIV/AIDS theoretically has a period of latency longer than a year. The paper concludes that, programmatically, improvements in data collection are a top priority for reducing the observed bias in the 'multiple sexual partners' core indicator.

  19. Potential for Pancreatic Maturation of Differentiating Human Embryonic Stem Cells Is Sensitive to the Specific Pathway of Definitive Endoderm Commitment

    PubMed Central

    Jaramillo, Maria; Mathew, Shibin; Task, Keith; Barner, Sierra; Banerjee, Ipsita

    2014-01-01

    This study provides a detailed experimental and mathematical analysis of the impact of the initial pathway of definitive endoderm (DE) induction on later stages of pancreatic maturation. Human embryonic stem cells (hESCs) were induced to insulin-producing cells following a directed-differentiation approach. DE was induced following four alternative pathway modulations. DE derivatives obtained from these alternate pathways were subjected to pancreatic progenitor (PP) induction and maturation and analyzed at each stage. Results indicate that late stage maturation is influenced by the initial pathway of DE commitment. Detailed quantitative analysis revealed WNT3A and FGF2 induced DE cells showed highest expression of insulin, are closely aligned in gene expression patterning and have a closer resemblance to pancreatic organogenesis. Conversely, BMP4 at DE induction gave most divergent differentiation dynamics with lowest insulin upregulation, but highest glucagon upregulation. Additionally, we have concluded that early analysis of PP markers is indicative of its potential for pancreatic maturation. PMID:24743345

  20. Potential therapeutic applications of differentiated induced pluripotent stem cells (iPSCs) in the treatment of neurodegenerative diseases.

    PubMed

    Gao, Aijing; Peng, Yuhua; Deng, Yulin; Qing, Hong

    2013-01-01

    Difficulties in realizing persistent neurogenesis, inabilities in modeling pathogenesis of most cases, and a shortage of disease material for screening therapeutic agents restrict our progress to overcome challenges presented by neurodegenerative diseases. We propose that reprogramming primary somatic cells of patients into induced pluripotent stem cells (iPSCs) provides a new avenue to overcome these impediments. Their abilities in self-renewal and differentiation into various cell types will enable disease investigation and drug development. In this review, we introduce efficient approaches to generate iPSCs and distinct iPSCs differentiation stages, and critically discuss paradigms of iPSCs technology application to investigate neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Although iPSCs technology is in its infancy and faces many obstacles, it has great potential in helping to identify therapeutic targets for treating neurodegenerative diseases.

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

    PubMed Central

    2015-01-01

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

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

    PubMed

    Woźniak, Sławomir

    2015-06-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2012-05-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-08-11

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

  6. Homeobox B7 promotes the osteogenic differentiation potential of mesenchymal stem cells by activating RUNX2 and transcript of BSP

    PubMed Central

    Gao, Run-Tao; Zhan, Li-Ping; Meng, Cen; Zhang, Ning; Chang, Shi-Min; Yao, Rui; Li, Chong

    2015-01-01

    Mesenchymal stem cells (MSCs) are a reliable cell source for tissue regeneration. However, the molecular mechanisms underlying the directed differentiation of MSCs remain unclear; thus, their use is limited. Here, we investigate HOXB7 function in the osteogenic differentiation potentials of MSCs using stem cells from apical papilla (SCAPs) and bone marrow stem cells (BMSCs). The HOXB7 gene is highly expressed in BMSCs compared with dental tissue-derived MSCs. We found that, in vitro, over-expression of HOXB7 in SCAPs enhanced alkaline phosphatase (ALP) activity and mineralization. HOXB7 over-expression affected the mRNA expression of osteonectin (ON), collagen alpha-2(I) chain (COL1A2), bone sialoprotein (BSP), and osteocalcin (OCN), led to the expression of the key transcription factor, runt-related transcription factor 2 (RUNX2), and promoted SCAP osteogenic differentiation in vitro. The knock-down of HOXB7 inhibited ALP activity, mineralization, and the expression of ON, BSP, COL1A2, OCN, and RUNX2 in BMSCs in vitro. In addition, transplant experiments in nude mice confirmed that SCAP osteogenesis was triggered when HOXB7 was activated. Furthermore, Over-expression of HOXB7 significantly increased the levels of HOXB7 associated with the BSP promoter by ChIP assays. Taken together, these results indicate that HOXB7 enhances SCAP osteogenic differentiation by up-regulating RUNX2 and directly activating transcript of BSP. Thus, the activation of HOXB7 signaling might improve tissue regeneration mediated by MSCs. These results provide insight into the mechanism underlying the directed differentiation of MSCs. PMID:26379836

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

    PubMed

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

    2016-01-01

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

  8. Chitosan scaffolds induce human dental pulp stem cells to neural differentiation: potential roles for spinal cord injury therapy.

    PubMed

    Zhang, Jinlong; Lu, Xiaohui; Feng, Guijuan; Gu, Zhifeng; Sun, Yuyu; Bao, Guofeng; Xu, Guanhua; Lu, Yuanzhou; Chen, Jiajia; Xu, Lingfeng; Feng, Xingmei; Cui, Zhiming

    2016-10-01

    Cell-based transplantation strategies hold great potential for spinal cord injury (SCI) repair. Chitosan scaffolds have therapeutic benefits for spinal cord regeneration. Human dental pulp stem cells (DPSCs) are abundant available stem cells with low immunological incompatibility and can be considered for cell replacement therapy. The purpose of this study is to investigate the role of chitosan scaffolds in the neural differentiation of DPSCs in vitro and to assess the supportive effects of chitosan scaffolds in an animal model of SCI. DPSCs were incubated with chitosan scaffolds. Cell viability and the secretion of neurotrophic factors were analyzed. DPSCs incubated with chitosan scaffolds were treated with neural differentiation medium for 14 days and then neural genes and protein markers were analyzed by Western blot and reverse transcription plus the polymerase chain reaction. Our study revealed a higher cell viability and neural differentiation in the DPSC/chitosan-scaffold group. Compared with the control group, the levels of BDNF, GDNF, b-NGF, and NT-3 were significantly increased in the DPSC/chitosan-scaffold group. The Wnt/β-catenin signaling pathway played a key role in the neural differentiation of DPSCs combined with chitosan scaffolds. Transplantation of DPSCs together with chitosan scaffolds into an SCI rat model resulted in the marked recovery of hind limb locomotor functions. Thus, chitosan scaffolds were non-cytotoxic and provided a conducive and favorable microenvironment for the survival and neural differentiation of DPSCs. Transplantation of DPSCs might therefore be a suitable candidate for treating SCI and other neuronal degenerative diseases. PMID:27147262

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  12. Multiple-factor analysis of the first radioactive iodine therapy in post-operative patients with differentiated thyroid cancer for achieving a disease-free status

    PubMed Central

    Liu, Na; Meng, Zhaowei; Jia, Qiang; Tan, Jian; Zhang, Guizhi; Zheng, Wei; Wang, Renfei; Li, Xue; Hu, Tianpeng; Upadhyaya, Arun; Zhou, Pingping; Wang, Sen

    2016-01-01

    131I treatment is an important management method for patients with differentiated thyroid cancer (DTC). Unsuccessful 131I ablation drastically affects the prognosis of the patients. This study aimed to analyze potential predictive factors influencing the achievement of a disease-free status following the first 131I therapy. This retrospective review included 315 DTC patients, and multiple factors were analyzed. Tumor size, pathological tumor stage, lymph node (LN) metastasis, distant metastasis, American Thyroid Association recommended risks, pre-ablation thyroglobulin (Tg), and thyroid stimulating hormone (TSH) displayed significant differences between unsuccessful and successful group. Cutoff values of Tg and TSH to predict a successful outcome were 3.525 ng/mL and 99.700 uIU/ml by receiver operating characteristic curves analysis. Binary logistic regression analysis showed that tumor stage T3 or T4, LN metastasis to N1b station, intermediate and high risks, pre-ablation Tg ≥ 3.525 ng/ml and TSH <99.700 μIU/mL were significantly associated with unsuccessful outcomes. Logistic regression equation for achieving a disease-free status could be rendered as: y (successful treatment) = −0.270–0.503 X1 (LN metastasis) −0.236 X2 (Tg) + 0.015 X3 (TSH). This study demonstrated LN metastasis, pre-ablation Tg and TSH were the most powerful predictors for achieving a disease-free status by the first 131I therapy. PMID:27721492

  13. Isolation, characterization and the multi-lineage differentiation potential of rabbit bone marrow-derived mesenchymal stem cells

    PubMed Central

    Tan, Sik-Loo; Ahmad, Tunku Sara; Selvaratnam, Lakshmi; Kamarul, Tunku

    2013-01-01

    than that of hMSCs (P < 0.05). There was, however, no difference in the adipogenic (Pparγ) expressions between these cell types (P > 0.05). rbMSCs possess similar morphological characteristics to hMSCs, but have a higher potential for osteogenic and chondrogenic differentiation, despite having a lower cell proliferation rate than hMSCs. The characteristics reported here may be used as a comprehensive set of criteria to define or characterize rbMSCs. PMID:23510053

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

    PubMed

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

    2013-01-15

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

  15. Visualization of the electrostatic potential distribution in both polar ionospheres using multiple satellite measurements

    NASA Technical Reports Server (NTRS)

    Hairston, Marc R.; Heelis, Roderick A.; Rich, Frederick J.

    1995-01-01

    During the time from December 1991 through March 1992, there were four operational DMSP satellites in polar orbit. All four satellites carried the Special Sensor-Ions, Electrons, Scintillation (SSIES) plasma package which included an ion drift meter. Data from the drift meter, combined with the magnetic field data, allowed the calculation of the electrostatic potential in the ionosphere along the satellite's path. Simultaneous polar coverage by four satellites was unprecedented, providing researchers with almost continuous monitoring of the potential distribution in both hemispheres for the four month period. Combining the magnitude and location of the potential data from each of the four satellites in order to examine the varying potential distribution pattern in both hemispheres presented a major challenge in data visualization. The problem was solved by developing a three-dimensional presentation of the data where the potentials are color coded and represented by the vertical dimension. This paper presents examples from a computer animation of several days of data demonstrating evolution of the size and shape of the potential distribution, along with how these changes correspond to variations in other geophysical parameters, such as the IMF orientation and the K(sub p) index.

  16. Visualization of the electrostatic potential distribution in both polar ionospheres using multiple satellite measurements

    SciTech Connect

    Hairston, M.R.; Heelis, R.A.; Rich, F.J.

    1995-01-01

    During the time from December 1991 through March 1992, there were four operational DMSP satellites in polar orbit. All four satellites carried the Special Sensor-Ions, Electrons, Scintillation (SSIES) plasma package which included an ion drift meter. Data from the drift meter, combined with the magnetic field data, allowed the calculation of the electrostatic potential in the ionosphere along the satellite`s path. Simultaneous polar coverage by four satellites was unprecedented, providing researchers with almost continuous monitoring of the potential distribution in both hemispheres for the four month period. Combining the magnitude and location of the potential data from each of the four satellites in order to examine the varying potential distribution pattern in both hemispheres presented a major challenge in data visualization. The problem was solved by developing a three-dimensional presentation of the data where the potentials are color coded and represented by the vertical dimension. This paper presents examples from a computer animation of several days of data demonstrating evolution of the size and shape of the potential distribution, along with how these changes correspond to variations in other geophysical parameters, such as the IMF orientation and the K{sub p} index.

  17. Sexual differentiation in the distribution potential of northern jaguars (Panthera onca)

    USGS Publications Warehouse

    Boydston, Erin E.; Lopez Gonzalez, Carlos A.

    2005-01-01

    We estimated the potential geographic distribution of jaguars in the southwestern United States and northwestern Mexico by modeling the jaguar ecological niche from occurrence records. We modeled separately the distribution of males and females, assuming records of females probably represented established home ranges while male records likely included dispersal movements. The predicted distribution for males was larger than that for females. Eastern Sonora appeared capable for supporting male and female jaguars with potential range expansion into southeastern Arizona. New Mexico and Chihuahua contained environmental characteristics primarily limited to the male niche and thus may be areas into which males occasionally disperse.

  18. Plasmatic microRNA as Potential Biomarkers of Multiple Sclerosis: Literature Review.

    PubMed

    Kacperska, Magdalena J; Walenczak, Jakub; Tomasik, Bartłomiej

    2016-01-01

    There is ongoing research with the goal of finding precise and sensitive biomarkers of multiple sclerosis (MS). Recently, researchers have paid particular attention to small, non-encoding, single stranded endogenous microRNA molecules (miR, miRNA). At first these molecules were thought to be found only within the cell. Today it is known, however, that they can also be found in the extracellular spaces (plasma, serum, saliva, urine, tears, sweat, milk, sperm and amniotic fluid, among others). It has been established that extracellular miRNA perform a wide spectrum of functions, such as transmitting signals between cells, modulating processes involved in angiogenesis, neurogenesis, proliferation or apoptosis. Given the high stability of these small molecules in the extracellular compartment (plasma), their tissue specificity and strong ties with pathological processes underlying multiple sclerosis, miRNA seem to be a good target for researchers trying to discover diseases' new markers. Determining an accurate miRNA expression profile in MS and correlating it with the gene profile may lead to the discovery of new pathophysiological processes. Demonstrating that changes in the composition and concentration of extracellular miRNA may in some cases correlate with certain aspects of the underlying disease (such as its severity) could lead to their use as biomarkers of MS. Further research is needed. PMID:27629854

  19. Exposure to Potentially Traumatic Events in Early Childhood: Differential Links to Emergent Psychopathology

    ERIC Educational Resources Information Center

    Briggs-Gowan, Margaret J.; Carter, Alice S.; Clark, Roseanne; Augustyn, Marilyn; McCarthy, Kimberly J.; Ford, Julian D.

    2010-01-01

    Research NeedsObjective: To examine associations between exposure to potentially traumatic events (PTEs) and clinical patterns of symptoms and disorders in preschool children. Method: Two hundred and thirteen referred and non-referred children, ages 24 to 48 months (MN = 34.9, SD = 6.7 months) were studied. Lifetime exposure to PTEs (family…

  20. Exploring the multiple biotechnological potential of halophilic microorganisms isolated from two Argentinean salterns.

    PubMed

    Nercessian, Débora; Di Meglio, Leonardo; De Castro, Rosana; Paggi, Roberto

    2015-11-01

    The biodiversity and biotechnological potential of microbes from central Argentinean halophilic environments have been poorly explored. Salitral Negro and Colorada Grande salterns are neutral hypersaline basins exploded for NaCl extraction. As part of an ecological analysis of these environments, two bacterial and seven archaeal representatives were isolated, identified and examined for their biotechnological potential. The presence of hydrolases (proteases, amylases, lipases, cellulases and nucleases) and bioactive molecules (surfactants and antimicrobial compounds) was screened. While all the isolates exhibited at least one of the tested activities or biocompounds, the species belonging to Haloarcula genus were the most active, also producing antimicrobial compounds against their counterparts. In general, the biosurfactants were more effective against olive oil and aromatic compounds than detergents (SDS or Triton X-100). Our results demonstrate the broad spectrum of activities with biotechnological potential exhibited by the microorganisms inhabiting the Argentinean salterns and reinforce the importance of screening pristine extreme environments to discover interesting/novel bioactive molecules.

  1. Detection of multiple potentially pathogenic bacteria in Matang mangrove estuaries, Malaysia.

    PubMed

    Ghaderpour, Aziz; Mohd Nasori, Khairul Nazrin; Chew, Li Lee; Chong, Ving Ching; Thong, Kwai Lin; Chai, Lay Ching

    2014-06-15

    The deltaic estuarine system of the Matang Mangrove Forest Reserve of Malaysia is a site where several human settlements and brackish water aquaculture have been established. Here, we evaluated the level of fecal indicator bacteria (FIB) and the presence of potentially pathogenic bacteria in the surface water and sediments. Higher levels of FIB were detected at downstream sampling sites from the fishing village, indicating it as a possible source of anthropogenic pollution to the estuary. Enterococci levels in the estuarine sediments were higher than in the surface water, while total coliforms and E. coli in the estuarine sediments were not detected in all samples. Also, various types of potentially pathogenic bacteria, including Klebsiella pneumoniae, Serratia marcescens and Enterobacter cloacae were isolated. The results indicate that the Matang estuarine system is contaminated with various types of potential human bacterial pathogens which might pose a health risk to the public.

  2. Increased levels of p21((CIP1/WAF1)) correlate with decreased chondrogenic differentiation potential in synovial membrane progenitor cells.

    PubMed

    Masson, Anand Oliveira; Hess, Ricarda; O'Brien, Kate; Bertram, Karri L; Tailor, Pankaj; Irvine, Edward; Ren, Guomin; Krawetz, Roman J

    2015-07-01

    Cartilage injuries are a major concern in the field of orthopedics. They occur following trauma, as well as from a variety of pathological conditions including Osteoarthritis (OA). Although cartilage does not exhibit robust endogenous repair, it has been demonstrated that modulating the activity of p21 can increase the regenerative abilities of cartilage in vitro and in vivo. Since the synovial membrane is abundant with mesenchymal progenitor cells (MPCs) capable of differentiating into cartilage both in vitro and in vivo, we examined if p21 expression levels varied between MPCs derived from normal vs. OA knee joints. Analysis of p21 at the mRNA and protein levels within normal and OA MPCs demonstrated differential levels of expression between these two groups, with OA MPCs having higher p21 expression levels. The higher levels of p21 in OA MPCs are also correlated with a decreased chondrogenic differentiation capacity and synovial inflammation, however, there was no evidence of senescence in the OA cells. The results of this study suggest that cell cycle regulation in MPCs may be altered in OA and that modulation of this pathway may have therapeutic potential once the mechanism by which this regulates stem/progenitor cells is better understood.

  3. Acrolein detection: potential theranostic utility in multiple sclerosis and spinal cord injury

    PubMed Central

    Tully, Melissa; Zheng, Lingxing; Shi, Riyi

    2015-01-01

    Oxidative stress has been implicated as a major pathological process underlying CNS disease and trauma. More specifically, acrolein, an unsaturated aldehyde, produced by way of lipid peroxidation, has been shown to play a crucial role in initiating and perpetuating detrimental effects associated with multiple sclerosis and spinal cord injury. In light of these findings, quantification of acrolein levels both systemically and locally could allow for the use of acrolein as a biomarker to aid in diagnosis and guide treatment regimens. The three main approaches currently available are acrolein derivatization followed byLC/GC–MS, application of an acrolein antibody and subsequent immunoblotting, and the 3-hydroxypropylmercapturic acid-based method. Of these three strategies, the 3-hydroxypropylmercapturic acid-based method is the least invasive allowing for rapid translation of acrolein detection into a clinical setting. PMID:24831349

  4. Acrolein detection: potential theranostic utility in multiple sclerosis and spinal cord injury.

    PubMed

    Tully, Melissa; Zheng, Lingxing; Shi, Riyi

    2014-06-01

    Oxidative stress has been implicated as a major pathological process underlying CNS disease and trauma. More specifically, acrolein, an unsaturated aldehyde, produced by way of lipid peroxidation, has been shown to play a crucial role in initiating and perpetuating detrimental effects associated with multiple sclerosis and spinal cord injury. In light of these findings, quantification of acrolein levels both systemically and locally could allow for the use of acrolein as a biomarker to aid in diagnosis and guide treatment regimens. The three main approaches currently available are acrolein derivatization followed by LC/GC-MS, application of an acrolein antibody and subsequent immunoblotting, and the 3-hydroxypropylmercapturic acid-based method. Of these three strategies, the 3-hydroxypropylmercapturic acid-based method is the least invasive allowing for rapid translation of acrolein detection into a clinical setting.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  8. Differential protein mapping of ovarian serous adenocarcinomas: identification of potential markers for distinct tumor stage.

    PubMed

    Wang, Yanfei; Wu, Rong; Cho, Kathleen R; Thomas, Dafydd G; Gossner, Gabrielle; Liu, J Rebecca; Giordano, Thomas J; Shedden, Kerby A; Misek, David E; Lubman, David M

    2009-03-01

    Ovarian serous carcinomas (OSCs) comprise over half of all ovarian carcinomas and account for the majority of ovarian cancer-related deaths. We used a 2-dimensional liquid-based protein mapping strategy to characterize global protein expression patterns in 19 OSC tumor samples from 15 different patients to facilitate molecular classification of tumor stage. Protein expression profiles were produced, using pI-based separation in the first dimension and hydrophobicity-based separation in the second dimension, over a pH range of 4.0-7.0. Hierarchical clustering was applied to protein maps to indicate the tumor interrelationships. The 19 tumor samples could be classified into two different groups, one group associated with low stage (Stage 1) tumors and the other group associated with high stage (Stages 3/4) tumors. Proteins that were differentially expressed in different groups were selected for identification by LTQ-ESI-MS/MS. Fourteen of the selected proteins were overexpressed in the low stage tumors; 46 of the proteins were overexpressed in the high stage tumors. These proteins are known to play an important role in cellular functions such as glycolysis, protein biosynthesis, and cytoskeleton rearrangement and may serve as markers associated with different stages of OSCs. To further confirm the stage-dependent protein identifications, Lamin A/C and Vimentin expression in ovarian serous carcinomas was assessed by immunohistochemistry using ovarian tumor tissue microarrays for 66 samples.

  9. Influence of decellularized matrix derived from human mesenchymal stem cells on their proliferation, migration and multi-lineage differentiation potential.

    PubMed

    Lin, Hang; Yang, Guang; Tan, Jian; Tuan, Rocky S

    2012-06-01

    Developing biomaterials to promote stem cell proliferation and differentiation is a critical requirement in tissue engineering and regeneration. Extracellular matrix (ECM) derived from mesenchymal stem cells (MSCs) has recently been shown to be able to maintain the differentiation potential of MSCs during culture expansion and to restore the activities of aging MSCs, suggesting that MSC ECM (MECM) may be a suitable culture substrate to enhance the bioactivity of biomaterial scaffolds for MSCs. This investigation aims to characterize the biological nature and specificity of the influence of the MECM on MSCs. Native ECM produced by human MSC in vitro was extracted in urea, and the residual pellet was further processed with pepsin digestion (denoted as U-MECM and HP-MECM, respectively). The MECM products were then coated as a substrate on standard tissue culture plastic, and the behavior of MSCs seeded on the coated surfaces was studied. Our results showed that U-MECM coating dramatically accelerated MSC proliferation, attachment, spread, migration and multi-lineage differentiation (i.e., osteogenesis and adipogenesis), compared to collagen type I and HP-MECM coating. Non-collagenous proteins are likely the bioactive components in U-MECM, as MSCs cultured on collagen type I and HP-MECM showed similar biological activities, and collagen type I appeared to be the major protein components remaining in HP-MECM based on SDS-PAGE. These findings support the biological utility of MECM in the formulation of biomaterial scaffolds to enhance MSC bioactivities, including proliferation, migration and multi-lineage differentiation, for tissue regeneration applications.

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

    PubMed

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

    2016-03-01

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

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

    PubMed Central

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

    2016-01-01

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

  12. Multiple pipelines in right-of-way: Improved pipe-to-soil potential survey methods. Final report

    SciTech Connect

    Thompson, N.G.; Lawson, K.M.

    1993-10-29

    Pipe-to-soil potential measurements are the primary means for monitoring the effectiveness of cathodic protection systems. All criteria for cathodic protection employ, in one form or another, a potential measurement of the pipe with respect to a reference electrode. With this obvious dependency on pipe-to-soil potential measurements, PRC research program PR-186-807 was undertaken to determine what portion of a pipe is {open_quotes}sampled{close_quotes} by an aboveground potential measurement. One important area which has not yet been investigated is what portion of a pipe is sampled during a potential survey of a pipeline in a right-of-way containing multiple pipelines directly bonded to each other. Previous PRC research conducted under PR-186-807 showed that finite element analysis (FEA) modeling of potential distributions around a pipeline can be used to predict aboveground potentials. Comparison of model data to large scale field site measurements provided a high level of confidence that the model predictions were accurate. For bare pipe, the results showed that the length of pipe sampled depends on depth of burial and does not depend on soil resistivity. For bare pipe, the circumferential area of the pipe sampled depended on the pipe diameter-to-depth of burial ratio. The results further showed that significant shielding of the bottom of the pipe occurs during ground level pipe-to-soil potential measurements. For coated pipelines, the important parameter was the coating resistance-to-soil resistance ratio. The FEA model predicted that small holidays, 3-inch{sup 2}, were not observed in ground level off-potential measurements for coated pipelines with a poor to reasonable coating. In summary, the amount of information on the area of pipe sampled by a potential measurement, though growing, is limited to cases of single pipelines in the right-of-way.

  13. Differential action potentials and firing patterns in injured and uninjured small dorsal root ganglion neurons after nerve injury.

    PubMed

    Zhang, Xu-Feng; Zhu, Chang Z; Thimmapaya, Rama; Choi, Won S; Honore, Prisca; Scott, Victoria E; Kroeger, Paul E; Sullivan, James P; Faltynek, Connie R; Gopalakrishnan, Murali; Shieh, Char-Chang

    2004-05-29

    The profile of tetrodotoxin sensitive (TTX-S) and resistant (TTX-R) Na(+) channels and their contribution to action potentials and firing patterns were studied in isolated small dorsal root ganglion (DRG) neurons after L5/L6 spinal nerve ligation (SNL). Total TTX-R Na(+) currents and Na(v) 1.8 mRNA were reduced in injured L5 DRG neurons 14 days after SNL. In contrast, TTX-R Na(+)currents and Na(v) 1.8 mRNA were upregulated in uninjured L4 DRG neurons after SNL. Voltage-dependent inactivation of TTX-R Na(+) channels in these neurons was shifted to hyperpolarized potentials by 4 mV. Two types of neurons were identified in injured L5 DRG neurons after SNL. Type I neurons (57%) had significantly lower threshold but exhibited normal resting membrane potential (RMP) and action potential amplitude. Type II neurons (43%) had significantly smaller action potential amplitude but retained similar RMP and threshold to those from sham rats. None of the injured neurons could generate repetitive firing. In the presence of TTX, only 26% of injured neurons could generate action potentials that had smaller amplitude, higher threshold, and higher rheobase compared with sham rats. In contrast, action potentials and firing patterns in uninjured L4 DRG neurons after SNL, in the presence or absence of TTX, were not affected. These results suggest that TTX-R Na(+) channels play important roles in regulating action potentials and firing patterns in small DRG neurons and that downregulation in injured neurons and upregulation in uninjured neurons confer differential roles in shaping electrogenesis, and perhaps pain transmission, in these neurons. PMID:15120592

  14. Differentiation of the action potential in the smooth muscle of canine gastric antrum using calcium-inhibitory drugs.

    PubMed

    Hohnsbein, J; Golenhofen, K

    1985-03-01

    Electrical and mechanical activity were recorded simultaneously in smooth muscle preparations from the antrum region of canine stomach by means of a single sucrose gap technique (SGT). The SGT was optimized to permit stable recording from multicellular smooth muscle preparations over several hours of electrical and mechanical activity with little disturbance of their normal properties. Acetylcholine (ACh, 10(-8) to 10(-6) M) induced or augmented dose-dependently the electrical and mechanical activity. The plateau of the action potential complex was elevated by ACh, while the contraction was increased in linear correlation to the magnitude of the plateau component. In spontaneously active (or in ACh-stimulated) preparations TEA (5 to 20 mM) magnified the plateau component, induced or strengthened spikes on the plateau ('secondary spikes'), and induced or strengthened phasic contractions. Nifedipine (10(-6) M) abolished secondary spikes, part of the plateau component of the action potential, and suppressed mechanical activity. The complex action potential of canine gastric antrum can be differentiated into (a) a basic action potential, consisting of an initial, primary spike and a plateau depolarization; this basic action potential is resistant to nifedipine and does not trigger any mechanical activity; and (b) a nifedipine-sensitive component (calcium component), which consists of an augmentation of the plateau depolarization and of secondary spikes, and which is responsible for the initiation of mechanical activity.

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

    PubMed

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

    2016-05-01

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

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

    SciTech Connect

    Kawasaki, Haruhisa; Guan, Jianjun; Tamama, Kenichi

    2010-07-02

    Cell therapy with bone marrow multipotential stromal cells/mesenchymal stem cells (MSCs) represents a promising approach in the field of regenerative medicine. Low frequency of MSCs in adult bone marrow necessitates ex vivo expansion of MSCs after harvest; however, such a manipulation causes cellular senescence with loss of differentiation, proliferative, and therapeutic potentials of MSCs. Hydrogen molecules have been shown to exert organ protective effects through selective reduction of hydroxyl radicals. As oxidative stress is one of the key insults promoting cell senescence in vivo as well as in vitro, we hypothesized that hydrogen molecules prevent senescent process during MSC expansion. Addition of 3% hydrogen gas enhanced preservation of colony forming early progenitor cells within MSC preparation and prolonged the in vitro replicative lifespan of MSCs without losing differentiation potentials and paracrine capabilities. Interestingly, 3% hydrogen gas treatment did not decrease hydroxyl radical, protein carbonyl, and 8-hydroxydeoxyguanosine, suggesting that scavenging hydroxyl radical might not be responsible for these effects of hydrogen gas in this study.

  17. The effect of low static magnetic field on osteogenic and adipogenic differentiation potential of human adipose stromal/stem cells

    NASA Astrophysics Data System (ADS)

    Marędziak, Monika; Śmieszek, Agnieszka; Tomaszewski, Krzysztof A.; Lewandowski, Daniel; Marycz, Krzysztof

    2016-01-01

    The aim of this work was to investigate the effects of static magnetic field (SMF) on the osteogenic properties of human adipose derived mesenchymal stem cells (hASCs). In this study in seven days viability assay we examined the impact of SMF on cells proliferation rate, population doubling time, and ability to form single-cell derived colonies. We have also examined cells' morphology, ultrastructure and osteogenic properties on the protein as well as mRNA level. We established a complex approach, which enabled us to obtain information about SMF and hASCs potential in the context of differentiation into osteogenic and adipogenic lineages. We demonstrated that SMF enhances both viability and osteogenic properties of hASCs through higher proliferation factor and shorter population doubling time. We have also observed asymmetrically positioned nuclei and organelles after SMF exposition. With regards to osteogenic properties we observed increased levels of osteogenic markers i.e. osteopontin, osteocalcin and increased ability to form osteonodules with positive reaction to Alizarin Red dye. We have also shown that SMF besides enhancing osteogenic properties of hASCs, simultaneously decreases their ability to differentiate into adipogenic lineage. Our results clearly show a direct influence of SMF on the osteogenic potential of hASCs. These results provide key insights into the role of SMF on their cellular fate and properties.

  18. Utilization of PET imaging in differential diagnostics between a tumefactive multiple sclerosis lesion and low-grade glioma.

    PubMed

    Tarkkonen, Aleksi; Rissanen, Eero; Tuokkola, Terhi; Airas, Laura

    2016-09-01

    We present a case where a 30-year-old man with a history of combined MS and Charcot-Marie-Tooth (CMT I) disease was additionally diagnosed and treated for grade II glioma (astrocytoma). Tumefactive MS and gliomas are sometimes difficult to distinguish from one another based on conventional magnetic resonance imaging (MRI). In our case, positron emission tomography (PET) scans with(11)C-methionine ((11)C-MET) and (11)C-PK11195 radioligands were performed to aid in differential diagnostics. The diagnosis was confirmed finally by brain biopsy. The usefulness of PET imaging in differential diagnostics between tumefactive MS and glioma is discussed. PMID:27645363

  19. Differentiation and migration properties of human foetal umbilical cord perivascular cells: potential for lung repair

    PubMed Central

    Montemurro, Tiziana; Andriolo, Gabriella; Montelatici, Elisa; Weissmann, Gaia; Crisan, Mihaela; Colnaghi, Maria Rosa; Rebulla, Paolo; Mosca, Fabio; Péault, Bruno; Lazzari, Lorenza

    2011-01-01

    Abstract Mesenchymal stem cells (MSC) have been derived from different cultured human tissues, including bone marrow, adipose tissue, amniotic fluid and umbilical cord blood. Only recently it was suggested that MSC descended from perivascular cells, the latter being defined as CD146+ neuro-glial proteoglycan (NG)2+ platelet-derived growth factor-Rβ+ ALP+ CD34– CD45– von Willebrand factor (vWF)– CD144–. Herein we studied the properties of perivascular cells from a novel source, the foetal human umbilical cord (HUC) collected from pre-term newborns. By immunohistochemistry and flow cytometry we show that pre-term/foetal HUCs contain more perivascular cells than their full-term counterparts (2.5%versus 0.15%). Moreover, foetal HUC perivascular cells (HUCPC) express the embryonic cell markers specific embryonic antigen-4, Runx1 and Oct-4 and can be cultured over the long term. To further confirm the MSC identity of these cultured perivascular cells, we also showed their expression at different passages of antigens that typify MSC. The multilineage differentiative capacity of HUCPC into osteogenic, adipogenic and myogenic cell lineages was demonstrated in culture. In the perspective of a therapeutic application in chronic lung disease of pre-term newborns, we demonstrated the in vitro ability of HUCPC to migrate towards an alveolar type II cell line damaged with bleomycin, an anti-cancer agent with known pulmonary toxicity. The secretory profile exhibited by foetal HUCPC in the migration assay suggested a paracrine effect that could be exploited in various clinical conditions including lung disorders. PMID:20219017

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

    PubMed

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

    2012-12-01

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

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

    PubMed

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

    2012-12-01

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

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

    PubMed Central

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

    2012-01-01

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

  3. Quantifying the dispersal potential of seagrass vegetative fragments: A comparison of multiple subtropical species

    NASA Astrophysics Data System (ADS)

    Weatherall, E. J.; Jackson, E. L.; Hendry, R. A.; Campbell, M. L.

    2016-02-01

    Seagrass meadows are threatened by anthropogenic and natural disturbances on both a local and global scale. Understanding the potential for seagrasses to disperse, connecting populations separated by unsuitable habitat is important to assess the resilience of regional populations. This study investigated the relative dispersal potential of vegetative fragments of seagrass from five subtropical species (Zostera muelleri, Halodule uninervis, Halophila ovalis, Halophila spinulosa, Halophila decipiens). Five questions were examined: 1) do vegetative fragments of different species settle at different velocities; 2) does a species morphometric variables influence settling velocities; 3) is a species settling velocity related to the species local distribution; 4) does temperature stress affect settling velocity; and 5) what is the composition and potential viability of seagrass fragments floating in the bay. A proportional distribution index for each species was determined using data from a habitat prediction model. It was found that H. spinulosa settled significantly faster than the remaining species and Z. muelleri settled the slowest. Variables influencing settling velocity included rhizome length, weight and surface area. In both Z. muelleri and H. ovalis settling velocities were significantly greater at higher temperatures (although there was no significant difference between approximately 5 and 10 °C above ambient temperature). H. uninervis was not significantly influenced by temperature. There was a significant negative correlation between species settling velocities and their distribution.

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

    PubMed Central

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

    2014-01-01

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

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

    NASA Astrophysics Data System (ADS)

    Hastings, Mardi C.

    2003-04-01

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

  6. p205, a potential tumor suppressor, inhibits cell proliferation via multiple pathways of cell cycle regulation.

    PubMed

    Asefa, Benyam; Dermott, Jonathan M; Kaldis, Philipp; Stefanisko, Karen; Garfinkel, David J; Keller, Jonathan R

    2006-02-20

    p205 is a member of the interferon-inducible p200 family of proteins that regulate cell proliferation. Over-expression of p205 inhibits cell growth, although its mechanism of action is currently unknown. Therefore, we evaluated the effect of p205 on the p53 and Rb-dependent pathways of cell cycle regulation. p205 expression results in elevated levels of p21, and activates the p21 promoter in vitro in a p53-dependent manner. In addition, p205 induces increased expression of Rb, and binds directly to Rb and p53. Interestingly, p205 also induces growth inhibition independent of p53 and Rb by delaying G2/M progression in proliferating cells, and is a substrate for Cdk2 kinase activity. Finally, we have identified other binding partners of p205 by a yeast two-hybrid screen, including the paired homeodomain protein HoxB2. Taken together, our results indicate that p205 induces growth arrest by interaction with multiple transcription factors that regulate the cell cycle, including but not entirely dependent on the Rb- and p53-mediated pathways of growth inhibition. PMID:16458891

  7. Ellipticine derivative NSC 338258 represents a potential new antineoplastic agent for the treatment of multiple myeloma.

    PubMed

    Tian, Erming; Landowski, Terry H; Stephens, Owen W; Yaccoby, Shmuel; Barlogie, Bart; Shaughnessy, John D

    2008-03-01

    High-risk multiple myeloma can be correlated with amplification and overexpression of the cell cycle regulator CKS1B. Herein, we used the COMPARE algorithm to correlate high expression of CKS1B mRNA in the NCI-60 cell line panel with the concentration causing 50% growth inhibition (GI(50)) of >40,000 synthetic compounds. This led to the identification of NSC 338258 (EPED3), a highly stable, hydrophilic derivative of the plant alkaloid ellipticine. In vitro, this synthetic anticancer compound exhibits dramatic cytotoxic activity against myeloma cells grown in suspension or in coculture with stromal cells. EPED3-induced cell cycle arrest and an apoptotic progression that appear to be a consequence of the instantaneous effect of the drug on cytoplasmic organelles, particularly mitochondria. Disruption of mitochondria and cytoplasmic distribution of cytochrome c initiated the intracellular proteolytic cascade through the intrinsic apoptotic pathway. EPED3 is able to induce apoptosis in myeloma cells with de novo or acquired resistance to commonly administered antimyeloma agents. Collectively, our data suggest that EPED3 targets mitochondrial function to rapidly deplete chemical energy and initiate apoptosis in myeloma cells at nanomolar concentrations while leaving stromal cells unharmed.

  8. Differential repair of potentially lethal damage in exponentially growing and quiescent 9L cells

    SciTech Connect

    Mendonca, M.S.; Rodriguez, A.; Alpen, E.L. )

    1990-04-01

    The alteration of potentially lethal damage repair by postirradiation treatment with hypertonic saline (0.5 M PBS) was investigated in exponentially growing and quiescent 9L cells in vitro. A single dose of X rays (8.5 Gy) immediately followed by a 30-min treatment with hypertonic PBS at 37 degrees C reduced the survival of exponentially growing 9L cells by a factor of 13-18 compared to survival of irradiated immediately and delayed-plated cells, while the survival of quiescent cells was reduced by only a factor of 5-8. Survival curves confirmed the relative resistance of the quiescent 9L cells versus exponentially growing 9L cells to X rays plus hypertonic treatment. Both the slope and the shoulder of the survival curve were reduced to a greater extent in exponentially growing cells than in the quiescent cells by hypertonic treatment. The response of quiescent cells cannot be explained by either the duration of hypertonic treatment or the redistribution of the cells into G1 phase. We show that quiescent 9L cells can recover from hypertonically induced potentially lethal damage when incubated under conditions which have been found to delay progression through the cell cycle, and postulate that an altered chromatin structure or an enhanced repair capacity of quiescent 9L cells may be responsible for their resistance.

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

    NASA Astrophysics Data System (ADS)

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

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

  10. Equine mesenchymal stem cells from bone marrow, adipose tissue and umbilical cord: immunophenotypic characterization and differentiation potential

    PubMed Central

    2014-01-01

    Introduction Studies with mesenchymal stem cells (MSCs) are increasing due to their immunomodulatory, anti-inflammatory and tissue regenerative properties. However, there is still no agreement about the best source of equine MSCs for a bank for allogeneic therapy. The aim of this study was to evaluate the cell culture and immunophenotypic characteristics and differentiation potential of equine MSCs from bone marrow (BM-MSCs), adipose tissue (AT-MSCs) and umbilical cord (UC-MSCs) under identical in vitro conditions, to compare these sources for research or an allogeneic therapy cell bank. Methods The BM-MSCs, AT-MSCs and UC-MSCs were cultured and evaluated in vitro for their osteogenic, adipogenic and chondrogenic differentiation potential. Additionally, MSCs were assessed for CD105, CD44, CD34, CD90 and MHC-II markers by flow cytometry, and MHC-II was also assessed by immunocytochemistry. To interpret the flow cytometry results, statistical analysis was performed using ANOVA. Results The harvesting and culturing procedures of BM-MSCs, AT-MSCs and UC-MSCs were feasible, with an average cell growth until the third passage of 25 days for BM-MSCs, 15 days for AT-MSCs and 26 days for UC-MSCs. MSCs from all sources were able to differentiate into osteogenic (after 10 days for BM-MSCs and AT-MSCs and 15 days for UC-MSCs), adipogenic (after 8 days for BM-MSCs and AT-MSCs and 15 days for UC-MSCs) and chondrogenic (after 21 days for BM-MSCs, AT-MSCs and UC-MSCs) lineages. MSCs showed high expression of CD105, CD44 and CD90 and low or negative expression of CD34 and MHC-II. The MHC-II was not detected by immunocytochemistry techniques in any of the MSCs studied. Conclusions The BM, AT and UC are feasible sources for harvesting equine MSCs, and their immunophenotypic and multipotency characteristics attained minimal criteria for defining MSCs. Due to the low expression of MHC-II by MSCs, all of the sources could be used in clinical trials involving allogeneic therapy

  11. An information potential approach for tracking and surveilling multiple moving targets using mobile sensor agents

    NASA Astrophysics Data System (ADS)

    Lu, W.; Zhang, G.; Ferrari, S.; Fierro, R.; Palunko, I.

    2011-05-01

    The problem of surveilling moving targets using mobile sensor agents (MSAs) is applicable to a variety of fields, including environmental monitoring, security, and manufacturing. Several authors have shown that the performance of a mobile sensor can be greatly improved by planning its motion and control strategies based on its sensing objectives. This paper presents an information potential approach for computing the MSAs' motion plans and control inputs based on the feedback from a modified particle filter used for tracking moving targets. The modified particle filter, as presented in this paper implements a new sampling method (based on supporting intervals of density functions), which accounts for the latest sensor measurements and adapts, accordingly, a mixture representation of the probability density functions (PDFs) for the target motion. It is assumed that the target motion can be modeled as a semi-Markov jump process, and that the PDFs of the Markov parameters can be updated based on real-time sensor measurements by a centralized processing unit or MSAs supervisor. Subsequently, the MSAs supervisor computes an information potential function that is communicated to the sensors, and used to determine their individual feedback control inputs, such that sensors with bounded field-of-view (FOV) can follow and surveil the target over time.

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

    PubMed

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

    2013-10-01

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

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

    PubMed

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

    2013-10-01

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

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

    PubMed

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

    2016-08-01

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

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

    PubMed

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

    2016-09-01

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

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

    PubMed

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

    2016-09-01

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

  17. Identifying Multiple Potential Metabolic Cycles in Time-Series from Biolog Experiments

    PubMed Central

    Schaufler, Katharina; Tedin, Karsten; Vehkala, Minna; Corander, Jukka

    2016-01-01

    Biolog Phenotype Microarray (PM) is a technology allowing simultaneous screening of the metabolic behaviour of bacteria under a large number of different conditions. Bacteria may often undergo several cycles of metabolic activity during a Biolog experiment. We introduce a novel algorithm to identify these metabolic cycles in PM experimental data, thus increasing the potential of PM technology in microbiology. Our method is based on a statistical decomposition of the time-series measurements into a set of growth models. We show that the method is robust to measurement noise and captures accurately the biologically relevant signals from the data. Our implementation is made freely available as a part of an R package for PM data analysis and can be found at www.helsinki.fi/bsg/software/Biolog_Decomposition. PMID:27676629

  18. The heterodimeric sweet taste receptor has multiple potential ligand binding sites.

    PubMed

    Cui, Meng; Jiang, Peihua; Maillet, Emeline; Max, Marianna; Margolskee, Robert F; Osman, Roman

    2006-01-01

    The sweet taste receptor is a heterodimer of two G protein coupled receptors, T1R2 and T1R3. This discovery has increased our understanding at the molecular level of the mechanisms underlying sweet taste. Previous experimental studies using sweet receptor chimeras and mutants show that there are at least three potential binding sites in this heterodimeric receptor. Receptor activity toward the artificial sweeteners aspartame and neotame depends on residues in the amino terminal domain of human T1R2. In contrast, receptor activity toward the sweetener cyclamate and the sweet taste inhibitor lactisole depends on residues within the transmembrane domain of human T1R3. Furthermore, receptor activity toward the sweet protein brazzein depends on the cysteine rich domain of human T1R3. Although crystal structures are not available for the sweet taste receptor, useful homology models can be developed based on appropriate templates. The amino terminal domain, cysteine rich domain and transmembrane helix domain of T1R2 and T1R3 have been modeled based on the crystal structures of metabotropic glutamate receptor type 1, tumor necrosis factor receptor, and bovine rhodopsin, respectively. We have used homology models of the sweet taste receptors, molecular docking of sweet ligands to the receptors, and site-directed mutagenesis of the receptors to identify potential ligand binding sites of the sweet taste receptor. These studies have led to a better understanding of the structure and function of this heterodimeric receptor, and can act as a guide for rational structure-based design of novel non-caloric sweeteners, which can be used in the fighting against obesity and diabetes. PMID:17168764

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

    PubMed

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

    2016-10-01

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

  20. Multiple Pathogens Including Potential New Species in Tick Vectors in Côte d’Ivoire

    PubMed Central

    Ehounoud, Cyrille Bilé; Yao, Kouassi Patrick; Dahmani, Mustapha; Achi, Yaba Louise; Amanzougaghene, Nadia; Kacou N’Douba, Adèle; N’Guessan, Jean David; Raoult, Didier; Fenollar, Florence; Mediannikov, Oleg

    2016-01-01

    Background Our study aimed to assess the presence of different pathogens in ticks collected in two regions in Côte d’Ivoire. Methodology/Principal Findings Real-time PCR and standard PCR assays coupled to sequencing were used. Three hundred and seventy eight (378) ticks (170 Amblyomma variegatum, 161 Rhipicepalus microplus, 3 Rhipicephalus senegalensis, 27 Hyalomma truncatum, 16 Hyalomma marginatum rufipes, and 1 Hyalomma impressum) were identified and analyzed. We identified as pathogenic bacteria, Rickettsia africae in Am. variegatum (90%), Rh. microplus (10%) and Hyalomma spp. (9%), Rickettsia aeschlimannii in Hyalomma spp. (23%), Rickettsia massiliae in Rh. senegalensis (33%) as well as Coxiella burnetii in 0.2%, Borrelia sp. in 0.2%, Anaplasma centrale in 0.2%, Anaplasma marginale in 0.5%, and Ehrlichia ruminantium in 0.5% of all ticks. Potential new species of Borrelia, Anaplasma, and Wolbachia were detected. Candidatus Borrelia africana and Candidatus Borrelia ivorensis (detected in three ticks) are phylogenetically distant from both the relapsing fever group and Lyme disease group borreliae; both were detected in Am. variegatum. Four new genotypes of bacteria from the Anaplasmataceae family were identified, namely Candidatus Anaplasma ivorensis (detected in three ticks), Candidatus Ehrlichia urmitei (in nine ticks), Candidatus Ehrlichia rustica (in four ticks), and Candidatus Wolbachia ivorensis (in one tick). Conclusions/Significance For the first time, we demonstrate the presence of different pathogens such as R. aeschlimannii, C. burnetii, Borrelia sp., A. centrale, A. marginale, and E. ruminantium in ticks in Côte d’Ivoire as well as potential new species of unknown pathogenicity. PMID:26771308

  1. The heterodimeric sweet taste receptor has multiple potential ligand binding sites.

    PubMed

    Cui, Meng; Jiang, Peihua; Maillet, Emeline; Max, Marianna; Margolskee, Robert F; Osman, Roman

    2006-01-01

    The sweet taste receptor is a heterodimer of two G protein coupled receptors, T1R2 and T1R3. This discovery has increased our understanding at the molecular level of the mechanisms underlying sweet taste. Previous experimental studies using sweet receptor chimeras and mutants show that there are at least three potential binding sites in this heterodimeric receptor. Receptor activity toward the artificial sweeteners aspartame and neotame depends on residues in the amino terminal domain of human T1R2. In contrast, receptor activity toward the sweetener cyclamate and the sweet taste inhibitor lactisole depends on residues within the transmembrane domain of human T1R3. Furthermore, receptor activity toward the sweet protein brazzein depends on the cysteine rich domain of human T1R3. Although crystal structures are not available for the sweet taste receptor, useful homology models can be developed based on appropriate templates. The amino terminal domain, cysteine rich domain and transmembrane helix domain of T1R2 and T1R3 have been modeled based on the crystal structures of metabotropic glutamate receptor type 1, tumor necrosis factor receptor, and bovine rhodopsin, respectively. We have used homology models of the sweet taste receptors, molecular docking of sweet ligands to the receptors, and site-directed mutagenesis of the receptors to identify potential ligand binding sites of the sweet taste receptor. These studies have led to a better understanding of the structure and function of this heterodimeric receptor, and can act as a guide for rational structure-based design of novel non-caloric sweeteners, which can be used in the fighting against obesity and diabetes.

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

    PubMed

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

    2016-10-01

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

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

    USGS Publications Warehouse

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

    2013-01-01

    he Grubbs-Beck test is recommended by the federal guidelines for detection of low outliers in flood flow frequency computation in the United States. This paper presents a generalization of the Grubbs-Beck test for normal data (similar to the Rosner (1983) test; see also Spencer and McCuen (1996)) that can provide a consistent standard for identifying multiple potentially influential low flows. In cases where low outliers have been identified, they can be represented as “less-than” values, and a frequency distribution can be developed using censored-data statistical techniques, such as the Expected Moments Algorithm. This approach can improve the fit of the right-hand tail of a frequency distribution and provide protection from lack-of-fit due to unimportant but potentially influential low flows (PILFs) in a flood series, thus making the flood frequency analysis procedure more robust.

  4. DIFFERENTIATION AND FUNCTIONAL EXPRESSION OF POTENTIAL ANTIBODY-PRODUCING CELLS IN THE PRESENCE OF CHLORAMPHENICOL

    PubMed Central

    Schoenberg, Melvin D.; Moore, Richard D.; Weisberger, Austin S.

    1967-01-01

    Rabbits were immunized with diphtheria toxoid combined with complete Freund's adjuvant. Half of the animals were started on intramuscular injections of chloramphenicol 24 hr before the injection of the antigens. There was a general depression of protein synthesis in the immune system in the presence of chloramphenicol, but a greater effect on the synthesis of antibody than on the synthesis of proteins necessary for reproduction and maturation. In contrast to the finding of antibody in cells of the spleen and in the circulation of the control animals, those animals receiving chloramphenicol did not have measurable circulating antibody, and their spleens contained only a few cells with intracytoplasmic antibody late in the course of the experiment. Cytologically there was maturation of potential antibody-producing cells in the red pulp and nonfollicular white pulp of the spleen while the animals were receiving chloramphenicol. These cells developed more slowly, and were fewer and smaller than those of the control animals. They had numerous small, electron-opaque particles in their cytoplasm early in development. Ribosomes were synthesized, though fewer in number. The endoplasmic reticulum formed more slowly. PMID:10976231

  5. Redox potential tuning through differential quinone binding in the photosynthetic reaction center of Rhodobacter sphaeroides.

    PubMed

    Vermaas, Josh V; Taguchi, Alexander T; Dikanov, Sergei A; Wraight, Colin A; Tajkhorshid, Emad

    2015-03-31

    Ubiquinone forms an integral part of the electron transport chain in cellular respiration and photosynthesis across a vast number of organisms. Prior experimental results have shown that the photosynthetic reaction center (RC) from Rhodobacter sphaeroides is only fully functional with a limited set of methoxy-bearing quinones, suggesting that specific interactions with this substituent are required to drive electron transport and the formation of quinol. The nature of these interactions has yet to be determined. Through parameterization of a CHARMM-compatible quinone force field and subsequent molecular dynamics simulations of the quinone-bound RC, we have investigated and characterized the interactions of the protein with the quinones in the Q(A) and Q(B) sites using both equilibrium simulation and thermodynamic integration. In particular, we identify a specific interaction between the 2-methoxy group of ubiquinone in the Q(B) site and the amide nitrogen of GlyL225 that we implicate in locking the orientation of the 2-methoxy group, thereby tuning the redox potential difference between the quinones occupying the Q(A) and Q(B) sites. Disruption of this interaction leads to weaker binding in a ubiquinone analogue that lacks a 2-methoxy group, a finding supported by reverse electron transfer electron paramagnetic resonance experiments of the Q(A)⁻Q(B)⁻ biradical and competitive binding assays. PMID:25734689

  6. Differential Vocational Rehabilitation Service Patterns Related to the Job Retention and Job-Seeking Needs of Individuals with Multiple Sclerosis

    ERIC Educational Resources Information Center

    Tansey, Timothy N.; Strauser, David; Frain, Michael P.; Bishop, Malachy; Chiu, Chung-Yi; Kaya, Cahit; Chan, Fong

    2015-01-01

    The experience of living with multiple sclerosis (MS) can have a profound effect on employment. The impact of MS is a complex interaction of personal, medical, functional, financial, and psychosocial variables that ultimately results in up to 80% of persons with MS leaving their jobs within 10 years of their diagnosis. The aim of this study was to…

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

    PubMed

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

    2016-08-01

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

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

    PubMed

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

    2016-08-01

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

  9. Multiple doses of diacylglycerol and calcium ionophore are necessary to activate AP-1 enhancer activity and induce markers of macrophage differentiation.

    PubMed

    William, F; Wagner, F; Karin, M; Kraft, A S

    1990-10-25

    In contrast to phorbol esters, multiple doses of diacylgycerols are needed to differentiate U937 human monoblastic leukemic cells to a macrophage-like phenotype. Although both of these agents similarly activate protein kinase C in vitro, it is not known why these agents appear to have differing biologic effects. One possibility is that they regulate gene transcription in slightly different ways. Regulation of gene transcription by phorbol esters is complex and involves the stimulation of the transactivating proteins Jun and Fos which form dimers and bind to the AP-1 enhancer elements (5'-TGAGTCA-3'). To understand whether diacylglycerols regulate gene transcription similarly to phorbol esters and to examine whether activation of AP-1 enhancer activity is correlated with differentiation, we have treated U937 human monoblastic leukemic cells with these agents and examined activation of transcription from AP-1 enhancer elements. We find that, although a single dose of diacylglycerol, like phorbol esters, is sufficient to elevate mRNA levels of both the c-jun and c-fos protooncogenes, in contrast to phorbol esters there is no increase in either Jun protein or activation of AP-1 enhancer activity. However, multiple doses of this agent given over 24 h stimulate repeated elevations in c-jun and c-fos mRNA, increases in Jun protein, and enhancer activation. Treatment of U937 cells with ionomycin, a calcium ionophore, also stimulates an increase in c-jun mRNA, but neither activates AP-1 enhancer activity nor stimulates differentiation of these cells. However ionomycin functions to enhance the effects of diacylglycerols both on transcriptional activation and U937 differentiation. These results suggest a complex regulation of AP-1 enhancer activity in U937 cells by diacylglycerols involving both transcriptional and post-transcriptional regulatory mechanisms. Maximal activation of AP-1 enhancer elements, and not changes in jun and fos mRNA, is correlated with increases in

  10. A Combination of Culture Conditions and Gene Expression Analysis Can Be Used to Investigate and Predict hES Cell Differentiation Potential towards Male Gonadal Cells.

    PubMed

    Kjartansdóttir, Kristín Rós; Reda, Ahmed; Panula, Sarita; Day, Kelly; Hultenby, Kjell; Söder, Olle; Hovatta, Outi; Stukenborg, Jan-Bernd

    2015-01-01

    Human embryonic stem cell differentiation towards various cell types belonging to ecto-, endo- and mesodermal cell lineages has been demonstrated, with high efficiency rates using standardized differentiation protocols. However, germ cell differentiation from human embryonic stem cells has been very inefficient so far. Even though the influence of various growth factors has been evaluated, the gene expression of different cell lines in relation to their differentiation potential has not yet been extensively examined. In this study, the potential of three male human embryonic stem cell lines to differentiate towards male gonadal cells was explored by analysing their gene expression profiles. The human embryonic stem cell lines were cultured for 14 days as monolayers on supporting human foreskin fibroblasts or as spheres in suspension, and were differentiated using BMP7, or spontaneous differentiation by omitting exogenous FGF2. TLDA analysis revealed that in the undifferentiated state, these cell lines have diverse mRNA profiles and exhibit significantly different potentials for differentiation towards the cell types present in the male gonads. This potential was associated with important factors directing the fate of the male primordial germ cells in vivo to form gonocytes, such as SOX17 or genes involved in the NODAL/ACTIVIN pathway, for example. Stimulation with BMP7 in suspension culture resulted in up-regulation of cytoplasmic SOX9 protein expression in all three lines. The observation that human embryonic stem cells differentiate towards germ and somatic cells after spontaneous and BMP7-induced stimulation in suspension emphasizes the important role of somatic cells in germ cell differentiation in vitro.

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

    NASA Astrophysics Data System (ADS)

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

    2010-12-01

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

  12. Profiling and Characterization of Influenza Virus N1 Strains Potentially Resistant to Multiple Neuraminidase Inhibitors

    PubMed Central

    Baek, Yun Hee; Song, Min-Suk; Lee, Eun-Young; Kim, Young-il; Kim, Eun-Ha; Park, Su-Jin; Park, Kuk Jin; Kwon, Hyeok-il; Pascua, Philippe Noriel Q.; Lim, Gyo-Jin; Kim, Semi; Yoon, Sun-Woo; Kim, Myung Hee; Webby, Richard J.

    2014-01-01

    ABSTRACT Neuraminidase inhibitors (NAIs) have been widely used to control influenza virus infection, but their increased use could promote the global emergence of resistant variants. Although various mutations associated with NAI resistance have been identified, the amino acid substitutions that confer multidrug resistance with undiminished viral fitness remain poorly understood. We therefore screened a known mutation(s) that could confer multidrug resistance to the currently approved NAIs oseltamivir, zanamivir, and peramivir by assessing recombinant viruses with mutant NA-encoding genes (catalytic residues R152K and R292K, framework residues E119A/D/G, D198N, H274Y, and N294S) in the backbones of the 2009 pandemic H1N1 (pH1N1) and highly pathogenic avian influenza (HPAI) H5N1 viruses. Of the 14 single and double mutant viruses recovered in the backbone of pH1N1, four variants (E119D, E119A/D/G-H274Y) exhibited reduced inhibition by all of the NAIs and two variants (E119D and E119D-H274Y) retained the overall properties of gene stability, replicative efficiency, pathogenicity, and transmissibility in vitro and in vivo. Of the nine recombinant H5N1 viruses, four variants (E119D, E119A/D/G-H274Y) also showed reduced inhibition by all of the NAIs, though their overall viral fitness was impaired in vitro and/or in vivo. Thus, single mutations or certain combination of the established mutations could confer potential multidrug resistance on pH1N1 or HPAI H5N1 viruses. Our findings emphasize the urgency of developing alternative drugs against influenza virus infection. IMPORTANCE There has been a widespread emergence of influenza virus strains with reduced susceptibility to neuraminidase inhibitors (NAIs). We screened multidrug-resistant viruses by studying the viral fitness of neuraminidase mutants in vitro and in vivo. We found that recombinant E119D and E119A/D/G/-H274Y mutant viruses demonstrated reduced inhibition by all of the NAIs tested in both the backbone of

  13. Differential Radiosensitizing Potential of Temozolomide in MGMT Promoter Methylated Glioblastoma Multiforme Cell Lines

    SciTech Connect

    Nifterik, Krista A. van; Berg, Jaap van den; Stalpers, Lukas J.A.; Lafleur, M. Vincent M.; Leenstra, Sieger; Slotman, Ben J.; Hulsebos, Theo J.M.; Sminia, Peter

    2007-11-15

    Purpose: To investigate the radiosensitizing potential of temozolomide (TMZ) for human glioblastoma multiforme (GBM) cell lines using single-dose and fractionated {gamma}-irradiation. Methods and Materials: Three genetically characterized human GBM cell lines (AMC-3046, VU-109, and VU-122) were exposed to various single (0-6 Gy) and daily fractionated doses (2 Gy per fraction) of {gamma}-irradiation. Repeated TMZ doses were given before and concurrent with irradiation treatment. Immediately plated clonogenic cell-survival curves were determined for both the single-dose and the fractionated irradiation experiments. To establish the net effect of clonogenic cell survival and cell proliferation, growth curves were determined, expressed as the number of surviving cells. Results: All three cell lines showed MGMT promoter methylation, lacked MGMT protein expression, and were sensitive to TMZ. The isotoxic TMZ concentrations used were in a clinically feasible range of 10 {mu}mol/L (AMC-3046), 3 {mu}mol/L (VU-109), and 2.5 {mu}mol/L (VU-122). Temozolomide was able to radiosensitize two cell lines (AMC 3046 and VU-122) using single-dose irradiation. A reduction in the number of surviving cells after treatment with the combination of TMZ and fractionated irradiation was seen in all three cell lines, but only AMC 3046 showed a radiosensitizing effect. Conclusions: This study on TMZ-sensitive GBM cell lines shows that TMZ can act as a radiosensitizer and is at least additive to {gamma}-irradiation. Enhancement of the radiation response by TMZ seems to be independent of the epigenetically silenced MGMT gen000.

  14. Protective effects of bioactive phytochemicals from Mentha piperita with multiple health potentials.

    PubMed

    Sharafi, Seyedeh Maryam; Rasooli, Iraj; Owlia, Parviz; Taghizadeh, Massoud; Astaneh, Shakiba Darvish Alipoor

    2010-07-01

    Mentha piperita essential oil was bactericidal in order of E. coli> S. aureus > Pseudomonas aeruginosa > S. faecalis > Klebsiella pneumoniae. The oil with total phenolics of 89.43 ± 0.58 µg GAE/mg had 63.82 ± 0.05% DPPH inhibition activity with an IC (50) = 3.9 µg/ml. Lipid peroxidation inhibition was comparable to BHT and BHA. A 127% hike was noted in serum ferric-reducing antioxidant power. There was 38.3% decrease in WBCs count, while platelet count showed increased levels of 214.12%. Significant decrease in uric acid level and cholesterol/HDL and LDL/HDL ratios were recorded. The volatile oil displayed high cytotoxic action toward the human tumor cell line. The results of this study deserve attention with regard to antioxidative and possible anti-neoplastic chemotherapy that form a basis for future research. The essential oil of mint may be exploited as a natural source of bioactive phytopchemicals bearing antimicrobial and antioxidant potentials that could be supplemented for both nutritional purposes and preservation of foods.

  15. Protective effects of bioactive phytochemicals from Mentha piperita with multiple health potentials

    PubMed Central

    Sharafi, Seyedeh Maryam; Rasooli, Iraj; Owlia, Parviz; Taghizadeh, Massoud; Astaneh, Shakiba Darvish Alipoor

    2010-01-01

    Mentha piperita essential oil was bactericidal in order of E. coli> S. aureus > Pseudomonas aeruginosa > S. faecalis > Klebsiella pneumoniae. The oil with total phenolics of 89.43 ± 0.58 µg GAE/mg had 63.82 ± 0.05% DPPH inhibition activity with an IC 50 = 3.9 µg/ml. Lipid peroxidation inhibition was comparable to BHT and BHA. A 127% hike was noted in serum ferric-reducing antioxidant power. There was 38.3% decrease in WBCs count, while platelet count showed increased levels of 214.12%. Significant decrease in uric acid level and cholesterol/HDL and LDL/HDL ratios were recorded. The volatile oil displayed high cytotoxic action toward the human tumor cell line. The results of this study deserve attention with regard to antioxidative and possible anti-neoplastic chemotherapy that form a basis for future research. The essential oil of mint may be exploited as a natural source of bioactive phytopchemicals bearing antimicrobial and antioxidant potentials that could be supplemented for both nutritional purposes and preservation of foods. PMID:20931070

  16. Loss of the Osteogenic Differentiation Potential during Senescence Is Limited to Bone Progenitor Cells and Is Dependent on p53

    PubMed Central

    Despars, Geneviève; Carbonneau, Cynthia L.; Bardeau, Pascal; Coutu, Daniel L.; Beauséjour, Christian M.

    2013-01-01

    DNA damage can lead to the induction of cellular senescence. In particular, we showed that exposure to ionizing radiation (IR) leads to the senescence of bone marrow-derived multipotent stromal cells (MSC) and osteoblast-like stromal cells (OB–SC), a phenotype associated with bone loss. The mechanism by which IR leads to bone dysfunction is not fully understood. One possibility involves that DNA damage-induced senescence limits the regeneration of bone progenitor cells. Another possibility entails that bone dysfunction arises from the inability of accumulating senescent cells to fulfill their physiological function. Indeed, we show here that exposure to IR prevented the differentiation and mineralization functions of MSC, an effect we found was limited to this population as more differentiated OB–SC could still form mineralize nodules. This is in contrast to adipogenesis, which was inhibited in both IR-induced senescent MSC and 3T3-L1 pre-adipocytes. Furthermore, we demonstrate that IR-induced loss of osteogenic potential in MSC was p53-dependent, a phenotype that correlates with the inability to upregulate key osteogenic transcription factors. These results are the first to demonstrate that senescence impacts osteogenesis in a cell type dependent manner and suggest that the accumulation of senescent osteoblasts is unlikely to significantly contribute to bone dysfunction in a cell autonomous manner. PMID:24009740

  17. An interneuron progenitor maintains neurogenic potential in vivo and differentiates into GABAergic interneurons after transplantation in the postnatal rat brain

    PubMed Central

    Wang, Qi; Hong, Peiwei; Gao, Hui; Chen, Yuntian; Yang, Qi; Jiang, Mei; Li, Hedong

    2016-01-01

    Dysfunction of cortical GABAergic interneurons are involved in numerous neurological disorders including epilepsy, schizophrenia and autism; and replenishment of these cells by transplantation strategy has proven to be a feasible and effective method to help revert the symptoms in several animal models. To develop methodology of generating transplantable GABAergic interneurons for therapy, we previously reported the isolation of a v-myc-induced GABAergic interneuron progenitor clone GE6 from embryonic ganglionic eminence (GE). These cells can proliferate and form functional inhibitory synapses in culture. Here, we tested their differentiation behavior in vivo by transplanting them into the postnatal rat forebrain. We found that GE6 cells migrate extensively in the neonatal forebrain and differentiate into both neurons and glia, but preferentially into neurons when compared with a sister progenitor clone CTX8. The neurogenic potential of GE6 cells is also maintained after transplantation into a non-permissive environment such as adult cortex or when treated with inflammatory cytokine in culture. The GE6-derived neurons were able to mature in vivo as GABAergic interneurons expressing GABAergic, not glutamatergic, presynaptic puncta. Finally, we propose that v-myc-induced human interneuron progenitor clones could be an alternative cell source of transplantable GABAergic interneurons for treating related neurological diseases in future clinic. PMID:26750620

  18. The AP-1 transcription factor component Fosl2 potentiates the rate of myocardial differentiation from the zebrafish second heart field.

    PubMed

    Jahangiri, Leila; Sharpe, Michka; Novikov, Natasha; González-Rosa, Juan Manuel; Borikova, Asya; Nevis, Kathleen; Paffett-Lugassy, Noelle; Zhao, Long; Adams, Meghan; Guner-Ataman, Burcu; Burns, Caroline E; Burns, C Geoffrey

    2016-01-01

    The vertebrate heart forms through successive phases of cardiomyocyte differentiation. Initially, cardiomyocytes derived from first heart field (FHF) progenitors assemble the linear heart tube. Thereafter, second heart field (SHF) progenitors differentiate into cardiomyocytes that are accreted to the poles of the heart tube over a well-defined developmental window. Although heart tube elongation deficiencies lead to life-threatening congenital heart defects, the variables controlling the initiation, rate and duration of myocardial accretion remain obscure. Here, we demonstrate that the AP-1 transcription factor, Fos-like antigen 2 (Fosl2), potentiates the rate of myocardial accretion from the zebrafish SHF. fosl2 mutants initiate accretion appropriately, but cardiomyocyte production is sluggish, resulting in a ventricular deficit coupled with an accumulation of SHF progenitors. Surprisingly, mutant embryos eventually correct the myocardial deficit by extending the accretion window. Overexpression of Fosl2 also compromises production of SHF-derived ventricular cardiomyocytes, a phenotype that is consistent with precocious depletion of the progenitor pool. Our data implicate Fosl2 in promoting the progenitor to cardiomyocyte transition and uncover the existence of regulatory mechanisms to ensure appropriate SHF-mediated cardiomyocyte contribution irrespective of embryonic stage.

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

    PubMed

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

    2015-11-01

    We have investigated the importance of GDF-15 (secreted cytokine belonging to the TGF-β superfamily) in low and high dose radiation-induced cellular responses. A telomerase immortalized human fibroblast cell line (F11hT) was used in the experiments. A lentiviral system encoding small hairpin RNAs (shRNA) was used to establish GDF-15 silenced cells. Secreted GDF-15 levels were measured in culture medium by ELISA. Cell cycle analysis was performed by flow cytometry. The experiments demonstrated that in irradiated human fibroblasts GDF-15 expression increased with dose starting from 100mGy. Elevated GDF-15 expression was not detected in bystander cells. The potential role of GDF-15 in radiation response was investigated by silencing GDF-15 in immortalized human fibroblasts with five different shRNA encoded in lentiviral vectors. Cell lines with considerably reduced GDF-15 levels presented increased radiation sensitivity, while a cell line with elevated GDF-15 was more radiation resistant than wild type cells. We have investigated how the reduced GDF-15 levels alter the response of several known radiation inducible genes. In F11hT-shGDF-15 cells the basal expression level of CDKN1A was unaltered relative to F11hT cells, while GADD45A and TGF-β1 mRNA levels were slightly higher, and TP53INP1 was considerably reduced. The radiation-induced expression of TP53INP1 was lower in the silenced than in wild type fibroblast cells. Cell cycle analysis indicated that radiation-induced early G2/M arrest was abrogated in GDF-15 silenced cells. Moreover, radiation-induced bystander effect was less pronounced in GDF-15 silenced fibroblasts. In conclusion, the results suggest that GDF-15 works as a radiation inducible radiation resistance increasing factor in normal human fibroblast cells, acts by regulating the radiation-induced transcription of several genes and might serve as a radiation-induced early biomarker in exposed cells. PMID:26520384

  20. Phase Locking of Multiple Single Neurons to the Local Field Potential in Cat V1.

    PubMed

    Martin, Kevan A C; Schröder, Sylvia

    2016-02-24

    The local field potential (LFP) is thought to reflect a temporal reference for neuronal spiking, which may facilitate information coding and orchestrate the communication between neural populations. To explore this proposed role, we recorded the LFP and simultaneously the spike activity of one to three nearby neurons in V1 of anesthetized cats during the presentation of drifting sinusoidal gratings, binary dense noise stimuli, and natural movies. In all stimulus conditions and during spontaneous activity, the average LFP power at frequencies >20 Hz was higher when neurons were spiking versus not spiking. The spikes were weakly but significantly phase locked to all frequencies of the LFP. The average spike phase of the LFP was stable across high and low levels of LFP power, but the strength of phase locking at low frequencies (≤10 Hz) increased with increasing LFP power. In a next step, we studied how strong stimulus responses of single neurons are reflected in the LFP and the LFP-spike relationship. We found that LFP power was slightly increased and phase locking was slightly stronger during strong compared with weak stimulus-locked responses. In summary, the coupling strength between high frequencies of the LFP and spikes was not strongly modulated by LFP power, which is thought to reflect spiking synchrony, nor was it strongly influenced by how strongly the neuron was driven by the stimulus. Furthermore, a comparison between neighboring neurons showed no clustering of preferred LFP phase. We argue that hypotheses on the relevance of phase locking in their current form are inconsistent with our findings.

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

    PubMed

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

    2016-07-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

    2016-01-01

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

  5. Expression profiling of the RPE in zebrafish smarca4 mutant revealed altered signals that potentially affect RPE and retinal differentiation

    PubMed Central

    Ma, Ping; Collery, Ross; Trowbridge, Sara; Zhong, Wenxuan; Leung, Yuk Fai

    2014-01-01

    Purpose The purpose of this study was to develop a framework for analyzing retinal pigment epithelium (RPE) expression profiles from zebrafish eye mutants. Methods The fish model we used was SWI/SNF-related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (smarca4), a retinal dystrophic mutant with a previously described retinal phenotype and expression profiles. Histological and Affymetrix GeneChip analyses were conducted to characterize the RPE defects and underlying differential expression, respectively. Results Histological analysis revealed that smarca4 RPE was formed, but its differentiation was abnormal. In particular, ultrastructural analysis of smarca4 RPE by transmission electron microscopy demonstrated several defects in melanogenesis. The nature of these defects also suggests that the cytoskeletal dynamics, which are tightly linked with melanogenesis, were impaired in smarca4 RPE. To compare the expression profile of normal wild-type (WT) and smarca4 RPE, the gene expression profiles of microdissected retinas and RPE-attached retinas were measured with Affymetrix GeneChip analysis. The RPE expression values were then estimated from these samples by subtracting the retinal expression values from the expression values of the RPE-attached retinas. A factorial analysis was conducted using the expression values of the RPE, retinal, and whole-embryo samples. Specific rules (contrasts) were built using the coefficients of the resulting fitted models to select for three groups of genes: 1) smarca4-regulated RPE genes, 2) smarca4-regulated retinal genes, and 3) smarca4-regulated RPE genes that are not differentially expressed in the retina. Interestingly, the third group consists of 39 genes that are highly related to cytoskeletal dynamics, melanogenesis, and paracrine and intracellular signal transduction. Conclusions Our analytical framework provides an experimental approach to identify differentially-regulated genes in the

  6. Microbial Monitoring of Pathogens by Comparing Multiple Real-Time PCR Platforms for Potential Space Applications

    NASA Technical Reports Server (NTRS)

    Birmele, Michele

    2012-01-01

    The International Space Station (ISS) is a closed environment wih rotations of crew and equipment each introducing their own microbial flora making it necessary to monitor the air, surfaces, and water for microbial contamination. Current microbial monitoring includes labor and time intensive methods to enumerate total bacterial and fungal cells with limited characterization during in-flight testing. Although this culture-based method has been sufficient for monitoring the ISS, future long duration missions will need to perform more comprehensive characterization in-flight, since sample return and ground characterization may not be available. A workshop was held in 2011 at the Johnson Space Center to discuss alternative methodologies and technologies suitable for microbial monitoring for these longterm exploration missions where molecular-based methodologies, such as polymerase chain reaction (PCR), were recommended. In response, a multi-center (Marshall Space Flight Center, Johnson Space Center, Jet Propulsion Laboratory, and Kennedy Space Center) collaborative research effort was initiated to explore novel commercial-off-the-shelf hardware options for spaceflight environmental monitoring. The goal was to evaluate quantitative/semi-quantitative PCR approaches to space applications for low cost in-flight rapid identification of microorganisms affecting crew safety. The initial phase of this project identified commercially available platforms that could be minimally modified to perform nominally in microgravity followed by proof-of-concept testing on the highest qualifying candidates with a universally available test organism, Salmonella enterica. The platforms evaluated during proof-of-concept testing included the iCubate 2.0(TradeMark) (iCubate, Huntsville, AL), RAZOR EX (BioFire Diagnostics; Salt Lake City, Utah) and SmartCycler(TradeMark) (Cepheid; Sunnyvale, CA). The analysis identified two potential technologies (iCubate 2.0 and RAZOR EX) that were able to

  7. Determination of Pu content in a Spent Fuel Assembly by Measuring Passive Total Neutron count rate and Multiplication with the Differential Die-Away Instrument

    SciTech Connect

    Henzl, Vladimir; Croft, Stephen; Swinhoe, Martyn T.; Tobin, Stephen J.

    2012-07-13

    Inspired by approach of Bignan and Martin-Didier (ESARDA 1991) we introduce novel (instrument independent) approach based on multiplication and passive neutron. Based on simulations of SFL-1 the accuracy of determination of {sup tot}Pu content with new approach is {approx}1.3-1.5%. Method applicable for DDA instrument, since it can measure both multiplication and passive neutron count rate. Comparison of pro's & con's of measuring/determining of {sup 239}Pu{sub eff} and {sup tot}Pu suggests a potential for enhanced diversion detection sensitivity.

  8. Beat-to-beat variability of repolarization differentiates the extent of torsadogenic potential of multi ion channel-blockers bepridil and amiodarone.

    PubMed

    Takahara, Akira; Nakamura, Yuji; Sugiyama, Atsushi

    2008-10-31

    Bepridil and amiodarone are known to have a multiple ion channel-blocking property in the heart. In this study, we compared the effects of bepridil on beat-to-beat variability of repolarization, a new predictive marker of torsades de pointes arrhythmia, with those of amiodarone. Bepridil (30 mg/kg, n=4) or amiodarone (200 mg/day for initial 7 days and 100 mg/day for following 21 days, n=4) was orally administered to chronic atrioventricular block dogs under the Holter ECG monitoring. The QT interval was prolonged after the administration of bepridil and amiodarone, and torsades de pointes arrhythmia was induced in 3 out of 4 dogs after the bepridil administration, which was not observed during the chronic administration of amiodarone. Beat-to-beat variability of repolarization, quantified as the short-term variability of the QT interval, increased after the administration of bepridil by +3.0 ms, whereas no significant change was detected in this parameter after the administration of amiodarone. These results suggest that the beat-to-beat variability of repolarization is a useful marker for differentiating the extent of torsadogenic potential of multi ion channel-blockers bepridil and amiodarone.

  9. The Differentiation of Giant Right Atrial Myxoma from Metastatic Cancer with the Use of Multiple Imaging Modalities.

    PubMed

    Nakabayashi, Keisuke; Murata, Satoru; Kato, Hiroko; Oka, Toshiaki

    2016-01-01

    Whether a cardiac tumor is primary or metastatic strongly influences the therapeutic strategy. We herein present a case of a cardiac tumor that occupied most of the right atrium which required immediate treatment in a patient with breast cancer. Multiple imaging modalities, especially computed tomography and cardiac magnetic resonance imaging, provided a precise preoperative diagnosis. We performed cardiac surgery prior to breast cancer surgery because the cardiac tumor was thought to be a myxoma rather than a metastatic cancer. PMID:27086806

  10. Differential gene expression in the siphonophore Nanomia bijuga (Cnidaria) assessed with multiple next-generation sequencing workflows.

    PubMed

    Siebert, Stefan; Robinson, Mark D; Tintori, Sophia C; Goetz, Freya; Helm, Rebecca R; Smith, Stephen A; Shaner, Nathan; Haddock, Steven H D; Dunn, Casey W

    2011-01-01

    We investigated differential gene expression between functionally specialized feeding polyps and swimming medusae in the siphonophore Nanomia bijuga (Cnidaria) with a hybrid long-read/short-read sequencing strategy. We assembled a set of partial gene reference sequences from long-read data (Roche 454), and generated short-read sequences from replicated tissue samples that were mapped to the references to quantify expression. We collected and compared expression data with three short-read expression workflows that differ in sample preparation, sequencing technology, and mapping tools. These workflows were Illumina mRNA-Seq, which generates sequence reads from random locations along each transcript, and two tag-based approaches, SOLiD SAGE and Helicos DGE, which generate reads from particular tag sites. Differences in expression results across workflows were mostly due to the differential impact of missing data in the partial reference sequences. When all 454-derived gene reference sequences were considered, Illumina mRNA-Seq detected more than twice as many differentially expressed (DE) reference sequences as the tag-based workflows. This discrepancy was largely due to missing tag sites in the partial reference that led to false negatives in the tag-based workflows. When only the subset of reference sequences that unambiguously have tag sites was considered, we found broad congruence across workflows, and they all identified a similar set of DE sequences. Our results are promising in several regards for gene expression studies in non-model organisms. First, we demonstrate that a hybrid long-read/short-read sequencing strategy is an effective way to collect gene expression data when an annotated genome sequence is not available. Second, our replicated sampling indicates that expression profiles are highly consistent across field-collected animals in this case. Third, the impacts of partial reference sequences on the ability to detect DE can be mitigated through

  11. Identification of Differentially Expressed Genes in Kawasaki Disease Patients as Potential Biomarkers for IVIG Sensitivity by Bioinformatics Analysis.

    PubMed

    He, Lan; Sheng, Youyu; Huang, Chunyun; Huang, Guoying

    2016-08-01

    Kawasaki disease (KD) is a leading cause of acquired heart disease predominantly affecting infants and young children. Intravenous immunoglobulin (IVIG) is applied as the most favorable treatment against KD, but IVIG resistant remains exist. Although several clinical scoring systems have been developed to identify children at highest risk of IVIG resistance, there is a need to identify sufficiently sensitive biomarkers for IVIG treatment. Some differentially expressed genes (DEGs) could be the promising potential biomarkers for IVIG-related sensitivity diagnosis. We employed a systematic and integrative bioinformatics framework to identify such kind of genes. The performance of the candidate genes was evaluated by hierarchical clustering, ROC analysis and literature mining. By analyzing three datasets of KD patients, 34 DEGs of the three groups have been found to be associated with IVIG-related sensitivity. A module of 12 genes could predict resistant group patients with high accuracy, and a module of ten genes could predict responsive group patients effectively with accuracy of 96 %. And three of them are most likely to serve as drug targets or diagnostic biomarkers in the future. Compared with unsupervised hierarchical clustering analysis, our modules could distinct IVIG-resistant patients efficiently. Two groups of DEGs could predict IVIG-related sensitivity with high accuracy, which are potential biomarkers for the clinical diagnosis and prediction of IVIG treatment response in KD patients, improving the prognosis of patients.

  12. Labeling Adipose-Derived Stem Cells with Hoechst 33342: Usability and Effects on Differentiation Potential and DNA Damage

    PubMed Central

    Schendzielorz, P.; Froelich, K.; Rak, K.; Gehrke, T.; Scherzad, A.; Hagen, R.; Radeloff, A.

    2016-01-01

    Adipose-derived stem cells (ASCs) have been extensively studied in the field of stem cell research and possess numerous clinical applications. Cell labeling is an essential component of various experimental protocols and Hoechst 33342 (H33342) represents a cost-effective and easy methodology for live staining. The purpose of this study was to evaluate the labeling of rat ASCs with two different concentrations of H33342 (0.5 μg/mL and 5 μg/mL), with particular regard to usability, interference with cell properties, and potential DNA damage. Hoechst 33342 used at a low concentration of 0.5 μg/mL did not significantly affect cell proliferation, viability, or differentiation potential of the ASCs, nor did it cause any significant DNA damage as measured by the olive tail moment. High concentrations of 5 μg/mL H33342, however, impaired the prolife