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Sample records for multiple differentiation potential

  1. 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…

  2. Hertz Potentials and Differential Geometry 

    E-print Network

    Bouas, Jeffrey David

    2011-08-08

    I review the construction of Hertz potentials in vector calculus starting from Maxwell's equations. From here, I lay the minimal foundations of differential geometry to construct Hertz potentials for a general (spatially compact) Lorentzian...

  3. Estimating differential expression from multiple indicators

    PubMed Central

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

    2014-01-01

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

  4. Multiple model simulation: modelling cell division and differentiation in the

    E-print Network

    Stepney, Susan

    Multiple model simulation: modelling cell division and differentiation in the prostate Alastair this approach to building a model of prostate cell division and differentiation, with each model layer can be designed and validated. In this paper we present the modelling and simulation of cell division

  5. Multiple symbol decoding of differential space-time codes 

    E-print Network

    Singhal, Rohit

    2004-09-30

    propose a serial concatenation of the above with a differential space-time code (STDC) and invoke an iterative joint source channel decoding procedure for decoding differentially space-time coded multiple descriptions. Experiments show a gain of up to 5 d...

  6. Asymptotic solvers for ordinary differential equations with multiple frequencies

    NASA Astrophysics Data System (ADS)

    Condon, Marissa; Deańo, Alfredo; Gao, Jing; Iserles, Arieh

    2015-11-01

    We construct asymptotic expansions for ordinary differential equations with highly oscillatory forcing terms, focussing on the case of multiple, non-commensurate frequencies. We derive an asymptotic expansion in inverse powers of the oscillatory parameter and use its truncation as an exceedingly effective means to discretize the differential equation in question. Numerical examples illustrate the effectiveness of the method.

  7. 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…

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

    NASA Technical Reports Server (NTRS)

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

    1989-01-01

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

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

    ERIC Educational Resources Information Center

    Shih, Ching-Lin; Wang, Wen-Chung

    2009-01-01

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

  10. Potential of Urinary Metabolites for Diagnosing Multiple Sclerosis Teklab Gebregiworgis,,

    E-print Network

    Powers, Robert

    Potential of Urinary Metabolites for Diagnosing Multiple Sclerosis Teklab Gebregiworgis ABSTRACT: A definitive diagnostic test for multiple sclerosis (MS) does not exist; instead physicians use healthy and MS drug-treated EAE mice. Multiple sclerosis (MS) is a demyelinating disease of the central

  11. 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.

  12. 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

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

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

    2015-05-01

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

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

    PubMed Central

    2012-01-01

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

  16. 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.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    SciTech Connect

    Koch, Werner Zhang, Dong H.

    2014-07-14

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

  20. Differential Fault Analysis of AES using a Single Multiple-Byte Fault

    E-print Network

    International Association for Cryptologic Research (IACR)

    Differential Fault Analysis of AES using a Single Multiple-Byte Fault Subidh Ali1 , Debdeep. In this paper we present an improved fault attack on the Advanced En- cryption Standard (AES). This paper presents an improvement on a recently pub- lished differential fault analysis of AES that requires one

  1. A study of impulsive multiterm fractional differential equations with single and multiple base points and applications.

    PubMed

    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

  2. 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

  3. 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

  4. Glutathione redox potential in response to differentiation and enzyme inducers.

    PubMed

    Kirlin, W G; Cai, J; Thompson, S A; Diaz, D; Kavanagh, T J; Jones, D P

    1999-12-01

    The reduced glutathione (GSH)/oxidized glutathione (GSSG) redox state is thought to function in signaling of detoxification gene expression, but also appears to be tightly regulated in cells under normal conditions. Thus it is not clear that the magnitude of change in response to physiologic stimuli is sufficient for a role in redox signaling under nontoxicologic conditions. The purpose of this study was to determine the change in 2GSH/GSSG redox during signaling of differentiation and increased detoxification enzyme activity in HT29 cells. We measured GSH, GSSG, cell volume, and cell pH, and we used the Nernst equation to determine the changes in redox potential Eh of the 2GSH/GSSG pool in response to the differentiating agent, sodium butyrate, and the detoxification enzyme inducer, benzyl isothiocyanate. Sodium butyrate caused a 60-mV oxidation (from -260 to -200 mV), an oxidation sufficient for a 100-fold change in protein dithiols:disulfide ratio. Benzyl isothiocyanate caused a 16-mV oxidation in control cells but a 40-mV oxidation (to -160 mV) in differentiated cells. Changes in GSH and mRNA for glutamate:cysteine ligase did not correlate with Eh; however, correlations were seen between Eh and glutathione S-transferase (GST) and nicotinamide adenine dinucleotide phosphate (NADPH):quinone reductase activities (N:QR). These results show that 2GSH/GSSG redox changes in response to physiologic stimuli such as differentiation and enzyme inducers are of a sufficient magnitude to control the activity of redox-sensitive proteins. This suggests that physiologic modulation of the 2GSH/GSSG redox poise could provide a fundamental parameter for the control of cell phenotype. PMID:10641713

  5. 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…

  6. System for measuring multiphase flow using multiple pressure differentials

    DOEpatents

    Fincke, James R. (Idaho Falls, ID)

    2003-01-01

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

  7. 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…

  8. Arachidonic acid-dependent gene regulation during preadipocyte differentiation controls adipocyte potential[S

    PubMed Central

    Nikolopoulou, Evanthia; Papacleovoulou, Georgia; Jean-Alphonse, Frederic; Grimaldi, Giulia; Parker, Malcolm G.; Hanyaloglu, Aylin C.; Christian, Mark

    2014-01-01

    Arachidonic acid (AA) is a major PUFA that has been implicated in the regulation of adipogenesis. We examined the effect of a short exposure to AA at different stages of 3T3-L1 adipocyte differentiation. AA caused the upregulation of fatty acid binding protein 4 (FABP4/aP2) following 24 h of differentiation. This was mediated by the prostaglandin F2? (PGF2?), as inhibition of cyclooxygenases or PGF2? receptor signaling counteracted the AA-mediated aP2 induction. In addition, calcium, protein kinase C, and ERK are all key elements of the pathway through which AA induces the expression of aP2. We also show that treatment with AA during the first 24 h of differentiation upregulates the expression of the transcription factor Fos-related antigen 1 (Fra-1) via the same pathway. Finally, treatment with AA for 24 h at the beginning of the adipocyte differentiation is sufficient to inhibit the late stages of adipogenesis through a Fra-1-dependent pathway, as Fra-1 knockdown rescued adipogenesis. Our data show that AA is able to program the differentiation potential of preadipocytes by regulating gene expression at the early stages of adipogenesis. PMID:25325755

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

    NASA Astrophysics Data System (ADS)

    Eric, L.; Vrugt, J. A.

    2010-12-01

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

  10. Joint analysis of differential gene expression in multiple studies using correlation motifs

    PubMed Central

    Wei, Yingying; Tenzen, Toyoaki; Ji, Hongkai

    2015-01-01

    The standard methods for detecting differential gene expression are mostly designed for analyzing a single gene expression experiment. When data from multiple related gene expression studies are available, separately analyzing each study is not ideal as it may fail to detect important genes with consistent but relatively weak differential signals in multiple studies. Jointly modeling all data allows one to borrow information across studies to improve the analysis. However, a simple concordance model, in which each gene is assumed to be differential in either all studies or none of the studies, is incapable of handling genes with study-specific differential expression. In contrast, a model that naively enumerates and analyzes all possible differential patterns across studies can deal with study-specificity and allow information pooling, but the complexity of its parameter space grows exponentially as the number of studies increases. Here, we propose a correlation motif approach to address this dilemma. This approach searches for a small number of latent probability vectors called correlation motifs to capture the major correlation patterns among multiple studies. The motifs provide the basis for sharing information among studies and genes. The approach has flexibility to handle all possible study-specific differential patterns. It improves detection of differential expression and overcomes the barrier of exponential model complexity. PMID:25143368

  11. A system for simultaneous multiple subject, multiple stimulus modality, and multiple channel collection and analysis of sensory evoked potentials.

    PubMed

    Hamm, C W; Ali, J S; Herr, D W

    2000-10-30

    A system has been developed for collecting sensory evoked potentials simultaneously from multiple channels for multiple subjects at up to 80 kHz sample rate per channel. Sample rates up to 200 kHz are available for four or less chambers and a single channel per chamber. A variety of visual, somatosensory, and auditory stimuli may be presented singly or simultaneously. Collected waveforms are associated with searchable text (metadata) to allow convenient selection from a relational database. Multiple waveforms can then be easily grouped for analysis and processed. Results can be exported to other software for further graphics or statistical processing. Scripting and event logging are available to provide automation and improve data confidence. Sample data are presented from control animals for each of the sensory modalities for comparison with historical data collected from other systems. PMID:11040406

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

    PubMed Central

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

    2011-01-01

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

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

    NASA Technical Reports Server (NTRS)

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

    1983-01-01

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

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    2015-10-01

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

  16. 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…

  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. SELECTIVE OESTROGEN RECEPTOR MODULATORS DIFFERENTIALLY POTENTIATE BRAIN MITOCHONDRIAL FUNCTION

    PubMed Central

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

    2011-01-01

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

  19. 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.

  20. 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, Hélčne; Vignaud, Chloé; Frémaux, Christčle; Jomotte, Thérčse; 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

  1. New immunosuppressants with potential implication in multiple sclerosis.

    PubMed

    Gonsette, R E

    2004-08-15

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

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

    PubMed Central

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

    2015-01-01

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

  3. 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

  4. A multiscale reduced-basis method for parametrized elliptic partial differential equations with multiple scales

    NASA Astrophysics Data System (ADS)

    Nguyen, N. C.

    2008-12-01

    We present a technique for solving parametrized elliptic partial differential equations with multiple scales. The technique is based on the combination of the reduced basis method [C. Prud'homme, D. Rovas, K. Veroy, Y. Maday, A.T. Patera, G. Turinici, Reliable real-time solution of parametrized partial differential equations: reduced-basis output bound methods, Journal of Fluids Engineering 124 (1) (2002) 70-80] and the multiscale finite element method [T.Y. Hou, X.H. Wu, A multiscale finite element method for elliptic problems in composite materials and porous media, Journal of Computational Physics 134 (1) (1997) 169-189] to treat problems in which the differential coefficient is characterized by a large number of independent parameters. For the multiscale finite element method, a large number of cell problems has to be solved at the fine local mesh for each new configuration of the differential coefficient. In order to improve the computational efficiency of this method, we construct reduced basis spaces that are adapted to the local parameter dependence of the differential operator. The approximate solutions of the cell problems are computed accurately and efficiently via performing Galekin projection onto the reduced basis spaces and implementing the offline-online computational procedure. Therefore, a large number of similar computations at the fine local mesh can be carried out with lower computational cost for each new configuration of the differential coefficient. Numerical results are provided to demonstrate the accuracy and efficiency of the proposed approach.

  5. 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.

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

    NASA Technical Reports Server (NTRS)

    Rai, Man Mohan

    2006-01-01

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

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

    PubMed Central

    Deitch, E A

    1992-01-01

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

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

    PubMed

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

    2010-11-01

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

  9. Local field potentials reflect multiple spatial scales in V4

    PubMed Central

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

    2013-01-01

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

  10. 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.

  11. The use of matrix differential calculus in problems of multiple-aquifer flow

    NASA Astrophysics Data System (ADS)

    Maas, C.

    1986-11-01

    The use of matrix functions is well known in several branches of technical sciences and physics but until now the application to geohydrological problems seems to be restricted to certain initial value problems in connection with numerical models. It is the objective of this paper to demonstrate how boundary value problems in the field of multiple-aquifer flow can be formulated in terms of matrix differential equations and subsequently be solved in terms of matrix functions. The technique is applied to several examples of practical interest, thus showing the advantages, which are: conciseness of derivation and presentation of outcome. The resulting matrix formulas can be evaluated numerically by means of commercially available software on eigenvalues and eigenvectors of matrices. Matrix differential calculus is appealing by its close resemblance to plain differential calculus and, in a way, offers the possibility to unify the treatment of single- and multiple-aquifer flow. Multiplicity of aquifers being the rule rather than the exception the technique will proof to be a real benefit in solving many problems of geohydrology.

  12. 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.

  13. 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

  14. 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 28days. MTT results further revealed that fabricated periosteum was cytocompatible and non-toxic to SHEDs. After 21days 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

  15. Linear differential electro-optic conversion of sampled voltage signals using a MSM and multiple quantum well

    E-print Network

    Miller, David A. B.

    Linear differential electro-optic conversion of sampled voltage signals using a MSM and multiple is subsequently annealed for 1 minute at 700 o C. The MSM structure consists of interdigitated titanium

  16. 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 naďve 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

  17. Two-dimensional von Neumann--Wigner potentials with a multiple positive eigenvalue

    E-print Network

    R. G. Novikov; I. A. Taimanov; S. P. Tsarev

    2013-07-19

    By the Moutard transformation method we construct two-dimensional Schrodinger operators with real smooth potential decaying at infinity and with a multiple positive eigenvalue. These potentials are rational functions of spatial variables and their sines and cosines.

  18. 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

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

    NASA Astrophysics Data System (ADS)

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

    2010-01-01

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

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

    PubMed Central

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

    2015-01-01

    The aim of this study was to characterize stem and progenitor cell populations from the equine superficial digital flexor tendon, an energy-storing tendon with similarities to the human Achilles tendon, which is frequently injured. Using published methods for the isolation of tendon-derived stem/progenitor cells by low-density plating we found that isolated cells possessed clonogenicity but were unable to fully differentiate towards mesenchymal lineages using trilineage differentiation assays. In particular, adipogenic differentiation appeared to be restricted, as assessed by Oil Red O staining of stem/progenitor cells cultured in adipogenic medium. We then assessed whether differential adhesion to fibronectin substrates could be used to isolate a population of cells with broader differentiation potential. However we found little difference in the stem and tenogenic gene expression profile of these cells as compared to tenocytes, although the expression of thrombospondin-4 was significantly reduced in hypoxic conditions. Tendon-derived stem/progenitor cells isolated by differential adhesion to fibronectin had a similar differentiation potential to cells isolated by low density plating, and when grown in either normoxic or hypoxic conditions. In summary, we have found a restricted differentiation potential of cells isolated from the equine superficial digital flexor tendon despite evidence for stem/progenitor-like characteristics. © 2015 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 33:849–858, 2015. PMID:25877997

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

    PubMed

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

    2015-08-01

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

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

    PubMed Central

    2014-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  4. 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

  5. The action as a differential n-form and the analytic deduction of the nuclear potentials

    E-print Network

    Enrique Ordaz Romay

    2003-06-17

    All the natural forces act through potential fields. Both, the electromagnetic vector potential and the gravitational potential of the general relativity are usually deduced starting from general analytic considerations. However, the nuclear potentials of the weak and strong forces are calculated experimentally, leading to what is known as phenomenological potentials. That is to say, expressions requiring adjustments according to the experimental results. This fact may change if we consider the action as a differential form. In this case it is possible to deduct some potentials for the nuclear forces departing from general analytic considerations.

  6. 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

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

    PubMed

    Arpa, J; López-Pajares, R; Cruz-Martínez, A; Palomo, F; Ferrer, T; Caminero, A B; Rodríguez-Albarińo, A; Alonso, M; Lacasa, T; Nos, J

    1995-01-01

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

  8. Matched filtering and multiple hypothesis tracking applied to Cfiber action potentials recorded in human nerves

    E-print Network

    Matched filtering and multiple hypothesis tracking applied to C­fiber action potentials recorded, the focus is on the detection and the tracking of the nerve action potentials (APs). The subsequent data recorded in human subjects are presented. Action potentials from C­fibers were recorded

  9. 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

  10. Slaving principle for stochastic differential equations with additive and multiplicative noise and for discrete noisy maps

    NASA Astrophysics Data System (ADS)

    Haken, H.; Wunderlin, A.

    1982-06-01

    We first treat multidimensional nonlinear noisy maps. We assume that the variables can be split into two classes of variables u and s so that the linearized equations would give rise to growth or decay for u and s, respectively. We show how the slaved variables s can be explicitly expressed by the order parameters u by making use of the fully nonlinear equations. By taking the limit of vanishing time steps and using a Wiener process and the Îto calculus we derive the corresponding formulas for stochastic differential equations (including multiplicative noise). In this way a high-dimensional problem can be reduced to a problem of much lower dimensions described again by stochastic equations of the Îto type. A similar procedure holds for the Stratonovich calculus.

  11. 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: [?2; p?=?0.004; OR (95% CI)?=?0.50 (0.31-0.81)] and severity, since CC women presented lower MSSS scores than CT (U-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

  12. Comparative Genomics of Multiple Strains of Pseudomonas cannabina pv. alisalensis, a Potential

    E-print Network

    Dangl, Jeff

    Comparative Genomics of Multiple Strains of Pseudomonas cannabina pv. alisalensis, a Potential. Here we present a comparative analysis of draft genome sequences for four strains of Pseudomonas, Baltrus DA, Bull CT, Wechter WP, et al. (2013) Comparative Genomics of Multiple Strains of Pseudomonas

  13. Discovery of Inhibitors of Soluble Epoxide Hydrolase: A Target with Multiple Potential Therapeutic Indications

    E-print Network

    Hammock, Bruce D.

    Discovery of Inhibitors of Soluble Epoxide Hydrolase: A Target with Multiple Potential Therapeutic been detected in prokaryotes and eukaryotes ranging from plants to mammals.1-3 In mammals these include

  14. Diagnostic potential of plasma carboxymethyllysine and carboxyethyllysine in multiple sclerosis

    PubMed Central

    2010-01-01

    Background This study compared the level of advanced glycation end products (AGEs), N-(Carboxymethyl)lysine (CML) and N-(Carboxyethyl)lysine (CEL), in patients with multiple sclerosis (MS) and healthy controls (HCs), correlating these markers with clinical indicators of MS disease severity. Methods CML and CEL plasma levels were analyzed in 99 MS patients and 43 HCs by tandem mass spectrometry (LC/MS/MS). Patients were stratified based on drug modifying therapies (DMTs) including interferon beta, glatiramer acetate and natalizumab. Results The level of plasma CEL, but not CML, was significantly higher in DMT-naďve MS patients when compared to HCs (P < 0.001). Among MS patients, 91% had higher than mean plasma CEL observed in HCs. DMTs reduced CML and CEL plasma levels by approximately 13% and 40% respectively. CML and CEL plasma levels correlated with the rate of MS clinical relapse. Conclusion Our results suggest that AGEs in general and CEL in particular could be useful biomarkers in MS clinical practice. Longitudinal studies are warranted to determine any causal relationship between changes in plasma level of AGEs and MS disease pathology. These studies will pave the way for use of AGE inhibitors and AGE-breaking agents as new therapeutic modalities in MS. PMID:21034482

  15. RBC micromotors carrying multiple cargos towards potential theranostic applications

    NASA Astrophysics Data System (ADS)

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

    2015-08-01

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

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

    PubMed

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

    2013-01-01

    Human bone marrow mesenchymal stem cells (hBMSCs) are widely used cell source for clinical bone regeneration. Achieving the greatest therapeutic effect is dependent on the osteogenic differentiation potential of the stem cells to be implanted. However, there are still no practical methods to characterize such potential non-invasively or previously. Monitoring cellular morphology is a practical and non-invasive approach for evaluating osteogenic potential. Unfortunately, such image-based approaches had been historically qualitative and requiring experienced interpretation. By combining the non-invasive attributes of microscopy with the latest technology allowing higher throughput and quantitative imaging metrics, we studied the applicability of morphometric features to quantitatively predict cellular osteogenic potential. We applied computational machine learning, combining cell morphology features with their corresponding biochemical osteogenic assay results, to develop prediction model of osteogenic differentiation. Using a dataset of 9,990 images automatically acquired by BioStation CT during osteogenic differentiation culture of hBMSCs, 666 morphometric features were extracted as parameters. Two commonly used osteogenic markers, alkaline phosphatase (ALP) activity and calcium deposition were measured experimentally, and used as the true biological differentiation status to validate the prediction accuracy. Using time-course morphological features throughout differentiation culture, the prediction results highly correlated with the experimentally defined differentiation marker values (R>0.89 for both marker predictions). The clinical applicability of our morphology-based prediction was further examined with two scenarios: one using only historical cell images and the other using both historical images together with the patient's own cell images to predict a new patient's cellular potential. The prediction accuracy was found to be greatly enhanced by incorporation of patients' own cell features in the modeling, indicating the practical strategy for clinical usage. Consequently, our results provide strong evidence for the feasibility of using a quantitative time series of phase-contrast cellular morphology for non-invasive cell quality prediction in regenerative medicine. PMID:23437049

  17. 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.

  18. Rocaglamide-A Potentiates Osteoblast Differentiation by Inhibiting NF-?B Signaling

    PubMed Central

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

    2015-01-01

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

  19. Rocaglamide-A Potentiates Osteoblast Differentiation by Inhibiting NF-?B Signaling.

    PubMed

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

    2015-11-30

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

  20. Individual stem cells are functionally defined by their self-renewal and differentiation potential.

    E-print Network

    Cai, Long

    Individual stem cells are functionally defined by their self-renewal and differentiation potential. Methods for clonal analysis are essential for understanding stem cells, particularly given the increasing evidence for stem-cell heterogeneity. Stem cells reside within complex microenvironments, making single-cell

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    Carré, Gwenn-Aël; Couty, Isabelle; Hennequet-Antier, Christelle; Govoroun, Marina S.

    2011-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2005-04-01

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

  5. 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

  6. 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.

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

    PubMed Central

    Bader, Joel S.; Friedmann, Theodore

    2013-01-01

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

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

    PubMed

    Katikireddy, Kishore Reddy; Jurkunas, Ula V

    2016-01-01

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

  9. Multiplicity of Solutions for Linear Partial Differential Equations Using (Generalized) Energy Operators

    E-print Network

    J. P. Montillet

    2015-09-09

    Families of energy operators and generalized energy operators have recently been introduced in the definition of the solutions of linear Partial Differential Equations (PDEs) with a particular application to the wave equation [Montillet, 2014, doi: 10.1007/s10440-014-9978-9]. To do so, the author has introduced the notion of energy spaces included in the Schwartz space $\\mathbf{S}^-(\\mathbb{R})$. In this model, the key is to look at which ones of these subspaces are reduced to {0} with the help of energy operators (and generalized energy operators). It leads to define additional solutions for a nominated PDE. Beyond that, this work intends to develop the concept of multiplicity of solutions for a linear PDE through the study of these energy spaces (i.e. emptiness). The main concept is that the PDE is viewed as a generator of solutions rather than the classical way of solving the given equation with a known form of the solutions together with boundary conditions. The theory is applied to the wave equation with the special case of the evanescent waves. The work ends with a discussion on another concept, the duplication of solutions. The discussion takes place for the special case of waves trapped in an electromagnetic chamber (i.e. a closed tapered waveguide)

  10. 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

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

    PubMed Central

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

    2014-01-01

    Pluripotency can be induced in somatic cells by overexpressing transcription factors, including POU class 5 homeobox 1 (OCT3/4), sex determining region Y-box 2 (SOX2), 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. PMID:25097266

  12. 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

  13. 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. PMID:25915705

  14. Holographic electrical and thermal conductivity in strongly coupled gauge theory with multiple chemical potentials

    E-print Network

    Sachin Jain

    2010-04-05

    We study transport coefficients of strongly coupled gauge theory in the presence of multiple chemical potential which are dual to rotating D3, M2 and M5 brane. Using the general form of the perturbation equations, we compute DC-electrical conductivity at finite temperature as well as at zero temperature. We also study thermal conductivity for the same class of black holes and show that thermal conductivity and viscosity obeys Wiedemann-Franz like law even in the presence of multiple chemical potential.

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

    PubMed Central

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

    2015-01-01

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

  16. Soft-Output Sphere Decoder for Multiple-Symbol Differential Detection of Impulse-Radio Ultra-Wideband

    E-print Network

    Schenk, Andreas

    2010-01-01

    Power efficiency of noncoherent receivers for impulse-radio ultra-wideband (IR-UWB) transmission systems can significantly be improved, on the one hand, by employing multiple-symbol differential detection (MSDD), and, on the other hand, by providing reliability information to the subsequent channel decoder. In this paper, we combine these two techniques. Incorporating the computation of the soft information into a single-tree-search sphere decoder (SD), the application of this soft-output MSDD in a typical IR-UWB system imposes only a moderate complexity increase at, however, improved performance over hard-output MSDD, and in particular, over conventional symbol-by-symbol noncoherent differential detection.

  17. Characterization of multiple isoforms of protein 4.1R expressed during erythroid terminal differentiation.

    PubMed

    Gascard, P; Lee, G; Coulombel, L; Auffray, I; Lum, M; Parra, M; Conboy, J G; Mohandas, N; Chasis, J A

    1998-12-01

    In erythrocytes, 80-kD protein 4.1R regulates critical membrane properties of deformability and mechanical strength. However, previously obtained data suggest that multiple isoforms of protein 4. 1, generated by alternative pre-mRNA splicing, are expressed during erythroid differentiation. Erythroid precursors use two splice acceptor sites at the 5' end of exon 2, thereby generating two populations of 4.1 RNA: one that includes an upstream AUG-1 in exon 2' and encodes high molecular weight isoforms, and another that skips AUG-1 in exon 2' and encodes 4.1 by initiation at a downstream AUG-2 in exon 4. To begin an analysis of the complex picture of protein 4.1R expression and function during erythropoiesis, we determined the number and primary structure of 4.1R isoforms expressed in erythroblasts. We used reverse-transcription polymerase chain reaction to amplify and clone full-length coding domains from the population of 4.1R cDNA containing AUG-1 and the population excluding AUG-1. We observed an impressive repertoire of 4.1R isoforms that included 7 major and 11 minor splice variants, thus providing the first definitive characterization of 4.1R primary structures in a single-cell lineage. 4.1R isoforms, transfected into COS-7 cells, distributed to the nucleus, cytoplasm, plasma membrane, and apparent centrosome. We confirmed previous studies showing that inclusion of exon 16 was essential for efficient nuclear localization. Unexpectedly, immunochemical analysis of COS-7 cells transfected with an isoform lacking both AUG-1 and AUG-2 documented that a previously unidentified downstream translation initiation codon located in exon 8 can regulate expression of 4.1R. We speculate that the repertoire of primary structure of 4.1R dictates its distinct binding partners and functions during erythropoiesis. PMID:9834247

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

    PubMed

    Glushkov, V N; Assfeld, X

    2012-10-01

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

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

    PubMed

    Wu, Jie; Li, Hong; Li, Ming

    2015-01-01

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

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

    PubMed Central

    Wu, Jie; Li, Hong; Li, Ming

    2015-01-01

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

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

    SciTech Connect

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

    2009-04-01

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

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

    NASA Astrophysics Data System (ADS)

    Sowoidnich, Kay; Kronfeldt, Heinz-Detlef

    2012-09-01

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

  3. Differential expression profiles of microRNAs as potential biomarkers for the early diagnosis of esophageal squamous cell carcinoma.

    PubMed

    Yang, Miao; Liu, Ran; Sheng, Jingyi; Liao, Juan; Wang, Yi; Pan, Enchun; Guo, Wei; Pu, Yuepu; Yin, Lihong

    2013-01-01

    Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies worldwide. To reduce the high morbidity and mortality of the disease, sensitive and specific biomarkers for early detection are urgently needed. Tumor-specific microRNAs (miRNAs) seem to be potential biomarkers for the early diagnosis and treatment of cancer. In this study, differentially expressed miRNAs in tumor tissues and adjacent non-tumor tissues were detected by miRNA microarrays. Stem-loop real-time reverse transcription PCR was conducted to verify the candidate miRNAs discovered by microarray analysis. The data showed that hsa-miR-338-3p, hsa-miR?218 and hsa-miR-139-5p were downregulated in tumor tissues compared with adjacent non-tumor tissues, while hsa-miR?183, hsa-miR-574-5p, hsa-miR-21* and hsa-miR?601 were upregulated in tumor tissues. Multiple regression analysis revealed the aberrant expression of hsa-miR-338-3p, hsa?miR-139-5p, hsa-miR?574-5p and hsa-miR-601 increased the risk of esophageal cancer. Furthermore, we found hsa-miR-21* was significantly increased in heavy drinking patients. Therefore, there is a set of differentially expressed miRNAs in esophageal cancer which may be associated with the incidence and development of ESCC. Differential expression profiles of miRNAs in ESCC may be promising biomarkers for the early screening of high-risk populations and early detection. PMID:23124769

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  6. ABCG2 is a selectable marker for enhanced multilineage differentiation potential in periodontal ligament stem cells.

    PubMed

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

    2015-01-15

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

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

    PubMed Central

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

    2015-01-01

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

  8. Glioblastoma-dependent differentiation and angiogenic potential of human mesenchymal stem cells in vitro.

    PubMed

    Birnbaum, Tobias; Hildebrandt, Jenna; Nuebling, Georg; Sostak, Petra; Straube, Andreas

    2011-10-01

    Tumor angiogenesis is of central importance in the malignancy of glioblastoma multiforme (GBM). As previously shown, human mesenchymal stem cells (hMSC) migrate towards GBM and are incorporated into tumor microvessels. However, phenotype and function of recruited hMSC remain unclear. We evaluated the differentiation and angiogenic potential of hMSC after stimulation with glioblastoma-conditioned medium in vitro. Immunostaining with endothelial, smooth muscle cell and pericyte markers was used to analyze hMSC differentiation in different concentrations of tumor-conditioned medium (CM), and the angiogenic potential was evaluated by matrigel-based tube-formation assay (TFA). Immunofluorescence staining revealed that tumor-conditioned hMSC (CM-hMSC) expressed CD 151, VE-cadherin, desmin, ?-smooth muscle actin, nestin, and nerval/glial antigen 2 (NG2) in a CM concentration-dependent manner, whereas no expression of von-Willebrand factor (vWF) and smooth myosin could be detected. These findings are indicative of GBM-dependent differentiation of hMSC into pericyte-like cells, rather than endothelial or smooth muscle cells. Furthermore, TFA of hMSC and CM-hMSC revealed CM-dependent formation of capillary-like networks, which differed substantially from those formed by human endothelial cells (HUVEC), also implying pericyte-like tube formation. These results are indicative of GBM-derived differentiation of hMSC into pericyte-like mural cells, which might contribute to the neovascularization and stabilization of tumor vessels. PMID:21547397

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

    PubMed Central

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

    2014-01-01

    Background Several studies reported olfactory dysfunction in patients with multiple sclerosis. The estimate of the incidence of olfactory deficits in multiple sclerosis is uncertain; this may arise from different testing methods that may be influenced by patients' response bias and clinical, demographic and cognitive features. Aims To evaluate objectively the olfactory function using Olfactory Event Related Potentials. Materials and Methods We tested the olfactory function of 30 patients with relapsing remitting multiple sclerosis (mean age of 36.03±6.96 years) and of 30 age, sex and smoking–habit matched healthy controls by using olfactory potentials. A selective and controlled stimulation of the olfactory system to elicit the olfactory event related potentials was achieved by a computer-controlled olfactometer linked directly with electroencephalograph. Relationships between olfactory potential results and patients' clinical characteristics, such as gender, disability status score, disease-modifying therapy, and disease duration, were evaluated. Results Seven of 30 patients did not show olfactory event related potentials. Sixteen of remaining 23 patients had a mean value of amplitude significantly lower than control group (p<0.01). The presence/absence of olfactory event related potentials was associated with dichotomous expanded disability status scale (p?=?0.0433), as well as inversely correlated with the disease duration (r?=??0.3641, p?=?0.0479). Conclusion Unbiased olfactory dysfunction of different severity found in multiple sclerosis patients suggests an organic impairment which could be related to neuroinflammatory and/or neurodegenerative processes of olfactory networks, supporting the recent findings on neurophysiopathology of disease. PMID:25047369

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

    NASA Astrophysics Data System (ADS)

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

    2014-09-01

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

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

    SciTech Connect

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

    2013-11-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2016-01-01

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

  13. 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

  14. Differentiation-associated switches in protein 4.1 expression. Synthesis of multiple structural isoforms during normal human erythropoiesis.

    PubMed

    Chasis, J A; Coulombel, L; Conboy, J; McGee, S; Andrews, K; Kan, Y W; Mohandas, N

    1993-01-01

    Erythroid differentiation is accompanied by dramatic alterations in morphology and membrane mechanical properties resulting, in large part, from reorganization of the membrane skeletal protein network. The 80-kD protein 4.1 is an important organizational component of this membrane skeleton. Recently, it has been recognized that multiple structural isoforms of 4.1 are encoded by a single gene via alternative pre-mRNA splicing, and that an upstream ATG can be spliced in and used for translation of high molecular weight 4.1. We are exploring the hypothesis that differentiation-associated switches in protein 4.1 structure play an important role in membrane reorganization. To study changes in 4.1 gene expression during normal human differentiation, we analyzed 4.1 protein and mRNA structure at various developmental stages. Using immunofluorescence microscopy, we observed high molecular weight 4.1 isoforms in preproerythroblasts producing punctate, predominantly cytoplasmic staining with a perinuclear area of intense fluorescence, while mature red cells expressed very little high molecular weight 4.1. Isoforms containing an alternatively expressed 102-nucleotide exon near the COOH terminus were abundant in both preproerythroblasts and mature cells but produced a punctate distribution of fluorescence over the entire preproerythroblast and intense membrane-associated fluorescence in the erythrocyte. Characterization of RNA by polymerase chain reaction and nuclease protection assays revealed a differentiation-associated switch in pre-mRNA splicing in the spectrin-actin binding domain. Since this domain plays a critical role in regulating membrane material properties, we speculate that this switch may be crucial to reorganization of the skeletal network during erythropoiesis. We conclude that 4.1 isoforms are differentially expressed and differentially localized during erythropoiesis, and that this isoform family is likely to have diverse functions during terminal differentiation. PMID:8423229

  15. Differentiation-associated switches in protein 4.1 expression. Synthesis of multiple structural isoforms during normal human erythropoiesis.

    PubMed Central

    Chasis, J A; Coulombel, L; Conboy, J; McGee, S; Andrews, K; Kan, Y W; Mohandas, N

    1993-01-01

    Erythroid differentiation is accompanied by dramatic alterations in morphology and membrane mechanical properties resulting, in large part, from reorganization of the membrane skeletal protein network. The 80-kD protein 4.1 is an important organizational component of this membrane skeleton. Recently, it has been recognized that multiple structural isoforms of 4.1 are encoded by a single gene via alternative pre-mRNA splicing, and that an upstream ATG can be spliced in and used for translation of high molecular weight 4.1. We are exploring the hypothesis that differentiation-associated switches in protein 4.1 structure play an important role in membrane reorganization. To study changes in 4.1 gene expression during normal human differentiation, we analyzed 4.1 protein and mRNA structure at various developmental stages. Using immunofluorescence microscopy, we observed high molecular weight 4.1 isoforms in preproerythroblasts producing punctate, predominantly cytoplasmic staining with a perinuclear area of intense fluorescence, while mature red cells expressed very little high molecular weight 4.1. Isoforms containing an alternatively expressed 102-nucleotide exon near the COOH terminus were abundant in both preproerythroblasts and mature cells but produced a punctate distribution of fluorescence over the entire preproerythroblast and intense membrane-associated fluorescence in the erythrocyte. Characterization of RNA by polymerase chain reaction and nuclease protection assays revealed a differentiation-associated switch in pre-mRNA splicing in the spectrin-actin binding domain. Since this domain plays a critical role in regulating membrane material properties, we speculate that this switch may be crucial to reorganization of the skeletal network during erythropoiesis. We conclude that 4.1 isoforms are differentially expressed and differentially localized during erythropoiesis, and that this isoform family is likely to have diverse functions during terminal differentiation. Images PMID:8423229

  16. Decision-feedback multiple differential detection for space-time coded OFDM systems 

    E-print Network

    Liu, Yan

    2001-01-01

    Differential detection (DD) is an attractive simple technique in flat-fading environments since it is very robust and does not require carrier phase tracking. However, performance of the conventional DD method in flat-fading ...

  17. Inductance Compensation of Multiple Capacitors With Application to Common- and Differential-Mode Filters

    E-print Network

    Pierquet, Brandon J.

    Capacitor parasitic inductance often limits the high-frequency performance of electromagnetic interference (EMI) filters in both common-mode (CM) and differential-mode (DM) filtering domains. However, these limitations can ...

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

    ERIC Educational Resources Information Center

    Gierl, Mark J.; Bolt, Daniel M.

    2001-01-01

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

  19. Identification of a Proximal Progenitor Population from Murine Fetal Lungs with Clonogenic and Multilineage Differentiation Potential

    PubMed Central

    Bilodeau, Mélanie; Shojaie, Sharareh; Ackerley, Cameron; Post, Martin; Rossant, Janet

    2014-01-01

    Summary Lung development-associated diseases are major causes of morbidity and lethality in preterm infants and children. Access to the lung progenitor/stem cell populations controlling pulmonary development during embryogenesis and early postnatal years is essential to understand the molecular basis of such diseases. Using a Nkx2-1mCherry reporter mouse, we have identified and captured Nkx2-1-expressing lung progenitor cells from the proximal lung epithelium during fetal development. These cells formed clonal spheres in semisolid culture that could be maintained in vitro and demonstrated self-renewal and expansion capabilities over multiple passages. In-vitro-derived Nkx2-1-expressing clonal spheres differentiated into a polarized epithelium comprised of multiple cell lineages, including basal and secretory cells, that could repopulate decellularized lung scaffolds. Nkx2-1 expression thus defines a fetal lung epithelial progenitor cell population that can be used as a model system to study pulmonary development and associated pediatric diseases. PMID:25358791

  20. Nuclear Receptor Agonists As Potential Differentiation Therapy Agents for Human Osteosarcoma1

    PubMed Central

    Haydon, Rex C.; Zhou, Lan; Feng, Tao; Breyer, Benjamin; Cheng, Hongwei; Jiang, Wei; Ishikawa, Akira; Peabody, Terrance; Montag, Anthony; Simon, Michael A.; He, Tong-Chuan

    2014-01-01

    Purpose This study was designed to investigate whether nuclear receptor agonists can be used as potential differentiation therapy agents for human osteosarcoma. Experimental Design Four osteosarcoma cell lines (143B, MNNG/HOS, MG-63, and TE-85) were treated with proliferator-activated receptor (PPAR)? agonists, troglitazone and ciglitazone, and a retinoid X receptor (RXR) ligand, 9-cis retinoic acid. The proliferation and induction of apoptosis in the treated cells were assessed, as was the induction of alkaline phosphatase, a differentiation marker of osteoblasts. Results The expression of PPAR? was readily detected in all tested osteosarcoma lines. On treatment with the PPAR? and RXR ligands, all four osteosarcoma lines exhibited a significantly reduced proliferation rate and cell viability. Among the four lines, 143B and MNNG/HOS were shown to be more sensitive to ligand-induced apoptosis, as demonstrated by the Crystal Violet and Hoechst staining assays. Of the three tested ligands, troglitazone was shown to be the most effective in inducing cell death, followed by 9-cis retinoic acid. Moreover, a strong synergistic effect on the induction of cell death was observed when both troglitazone and 9-cis retinoic acid or ciglitazone and 9-cis retinoic acid were administered to osteosarcoma cells. Troglitazone was shown to effectively induce alkaline phosphatase activity, a well-characterized hallmark for osteoblastic differentiation. Conclusions Our findings suggest that PPAR? and/or RXR ligands may be used as efficacious adjuvant therapeutic agents for primary osteosarcoma, as well as potential chemopreventive agents for preventing the recurrence and metastasis of osteosarcoma after the surgical removal of the primary tumors. PMID:12006550

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-09-01

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

  3. Respiratory syncytial virus potentiates ABCA3 mutation-induced loss of lung epithelial cell differentiation.

    PubMed

    Kaltenborn, Eva; Kern, Suncana; Frixel, Sabrina; Fragnet, Laetitia; Conzelmann, Karl-Klaus; Zarbock, Ralf; Griese, Matthias

    2012-06-15

    ATP-binding cassette transporter A3 (ABCA3) is a lipid transporter active in lung alveolar epithelial type II cells (ATII) and is essential for their function as surfactant-producing cells. ABCA3 mutational defects cause respiratory distress in newborns and interstitial lung disease (ILD) in children. The molecular pathomechanisms are largely unknown; however, viral infections may initiate or aggravate ILDs. Here, we investigated the impact of the clinically relevant ABCA3 mutations, p.Q215K and p.E292V, by stable transfection of A549 lung epithelial cells. ABCA3 mutations strongly impaired expression of the ATII differentiation marker SP-C and the key epithelial cell adhesion proteins E-cadherin and zonula occludens-1. Concurrently, cells expressing ABCA3 mutation acquired mesenchymal features as observed by increased expression of SNAI1, MMP-2 and TGF-?1, and elevated phosphorylation of Src. Infection with respiratory syncytial virus (RSV), the most common viral respiratory pathogen in small children, potentiated the observed mutational effects on loss of epithelial and acquisition of mesenchymal characteristics. In addition, RSV infection of cells harboring ABCA3 mutations resulted in a morphologic shift to a mesenchymal phenotype. We conclude that ABCA3 mutations, potentiated by RSV infection, induce loss of epithelial cell differentiation in ATII. Loss of key epithelial features may disturb the integrity of the alveolar epithelium, thereby comprising its functionality. We suggest the impairment of epithelial function as a mechanism by which ABCA3 mutations cause ILD. PMID:22434821

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

    SciTech Connect

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

    2014-05-02

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

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

    PubMed

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

    2015-12-01

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

  6. Differential expression of estrogen receptor ? and ? isoforms in multiple and solitary leiomyomas.

    PubMed

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

    2015-12-01

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

  7. Potential relationship and clinical significance of miRNAs and Th17 cytokines in patients with multiple myeloma.

    PubMed

    Li, Yanjie; Li, Depeng; Yan, Zhiling; Qi, Kunming; Chen, Lili; Zhang, Zhiyao; Fan, Guoqin; Li, Hujun; Xu, Kailin; Li, Zhenyu

    2014-09-01

    We evaluated the potential relationship between miRNAs and Th17 cytokines in multiple myeloma (MM) patients. Twenty-seven newly diagnosed myeloma patients and eight normal donors were studied. We determined that the relative expression levels of miR-15a/16, miR-34a, miR-194 in MM patients were significantly lower than those in the healthy controls with exception for miR-181a/b, which showed significantly higher in MM patients (P<0.05). In contrast, the levels of IL-17, IL-21 and IL-27 were up-regulated in MM patients compared to healthy controls while IL-22 was down-regulated (P<0.05). The expression patterns of them were differentially present in various groups according to the International Staging System (ISS) criteria. Up-regulated IL-17, IL-21 and IL-27 may potentially down-regulate the expression of several miRNAs in MM patients. Establishment of the relationship may be useful for understanding the pathogenesis of MM and for clinical diagnosis of the disease. PMID:25092124

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

    PubMed

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

    2015-11-17

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

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

    PubMed Central

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

    2014-01-01

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

  10. 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.

  11. 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.

  12. 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

  13. 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…

  14. 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.

  15. 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…

  16. Symbolic computation of conservation laws for nonlinear partial differential equations in multiple space dimensions

    E-print Network

    Hereman, Willy A.M.

    1 Symbolic computation of conservation laws for nonlinear partial differential equations been implemented in Mathematica. The software package, ConservationLawsMD.m, can be used evolution equations. The code ConservationLawsMD.m has been applied to multi-dimensional versions

  17. 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…

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

    PubMed Central

    Pipino, Caterina; Pandolfi, Assunta

    2015-01-01

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

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

    PubMed

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

    2015-03-01

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

  20. 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.

  1. Stretchable energy-harvesting tactile electronic skin capable of differentiating multiple mechanical stimuli modes.

    PubMed

    Park, Steve; Kim, Hyunjin; Vosgueritchian, Michael; Cheon, Sangmo; Kim, Hyeok; Koo, Ja Hoon; Kim, Taeho Roy; Lee, Sanghyo; Schwartz, Gregory; Chang, Hyuk; Bao, Zhenan

    2014-11-19

    The first stretchable energy-harvesting electronic-skin device capable of differentiating and generating energy from various mechanical stimuli, such as normal pressure, lateral strain, bending, and vibration, is presented. A pressure sensitivity of 0.7 kPa(-1) is achieved in the pressure region <1 kPa with power generation of tens of ?W cm(-2) from a gentle finger touch. PMID:25256696

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

    ERIC Educational Resources Information Center

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

    2013-01-01

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

  3. Global map of physical interactions among differentially expressed genes in multiple

    E-print Network

    Tuller, Tamir

    ) is an autoimmune inflammatory T-cell-mediated disease, believed to result from a misdirected immune attack against, 2011; Revised and Accepted June 10, 2011 Multiple sclerosis (MS) is a central nervous system autoimmune inflammatory T-cell-mediated disease with a relapsing­remitting course in the majority of patients

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

    ERIC Educational Resources Information Center

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

    2005-01-01

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

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

    ERIC Educational Resources Information Center

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

    2009-01-01

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

  6. 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.

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

    PubMed

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

    2015-01-22

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

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

    PubMed

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

    2012-01-01

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

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

    PubMed Central

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

    2011-01-01

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

  10. Electroosmotic Flow in Rectangular Nanochannels with Variable Wall potential: Generation of Multiple Nano-Vortices

    NASA Astrophysics Data System (ADS)

    Chen, Lei

    2005-11-01

    Electroosmotic flow in nanochannels is characterized by a very small Reynolds number so that mixing is difficult. While several researchers have presented results for the case of periodic wall potential, and for a sudden change in potential there has been no systematic study of the effect of the variation of wall potential on the flow structure. We have calculated the flow and mass transport in a two-dimensional nanochannel having discontinuities in wall potential. Multiple nano-vortices are generated within the bulk flow due to the overpotential at the surface. The distributions of potential, velocity and mole fractions are calculated numerically and the structure of the flow within the ``nano-vortices'' resembles that of the classical Lamb vortex. The parameters that affect the circulation are investigated as well. The long electrode limit (the aspect ratio much less than one ) is investigated for small channels (EDLs are overlapped) and wide (thin EDL) channels as well. It is found that the flow is two-dimensional only near the corners of the electrode and is fully-developed elsewhere. The flow can be thus decomposed into one-dimensional electroosmotic flow and Poiseuille flow. For a wide channel, a singular perturbation analysis is performed for the electroosmotic component. The results are compared with recently generated experimental data. *This work is supported by the Air Force Office of Scientific Research through its Multi-University Research Initiative(MURI) program.

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

    PubMed

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

    2013-07-01

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

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

    PubMed

    Ba?ar, Erol; Tülay, Elif; Güntekin, Bahar

    2015-03-01

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

  13. Can Vestibular-Evoked Myogenic Potentials Help Differentiate Méničre Disease from Vestibular Migraine?

    PubMed Central

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

    2013-01-01

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

  14. 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.

  15. Effect of cooling suit treatment in patients with multiple sclerosis evaluated by evoked potentials.

    PubMed

    Kinnman, J; Andersson, T; Andersson, G

    2000-03-01

    The aim of the present study was to determine whether any significant alterations of evoked potentials could be detected after treatment of patients with multiple sclerosis with a cooling suit. All patients had previously experienced a positive effect of this treatment. Six patients were investigated with visual, sensory and motor evoked potentials and six further patients with only motor evoked potentials. All patients had relevant clinical lesions. The mean values for the group of patients were similar before and after cooling, but a few individuals showed a substantial improvement of motor evoked potentials after cooling, with increased amplitude and/or shortened central motor conduction time. There was also a weak, but significant, correlation between temperature decrements and the reduction of central motor conduction time. However, since the central motor conduction times of most patients were only slightly affected, this effect could explain only a small part of the beneficial effect of cooling. Effects on cognition and executive ability or improvement of spasticity may be of greater importance. PMID:10782936

  16. Multiple chemical sensitivity (MCS)--differential diagnosis in clinical neurotoxicology: a German perspective.

    PubMed

    Altenkirch, H

    2000-08-01

    The multiple chemical sensitivity syndrome (MCS) is a new cluster of environmental symptoms which have been described and commented on for more than 15 years now in the USA. In the meantime it has also been observed in European countries. The main features of this syndrome are: multiple symptoms in multiple organ systems, precipitated by a variety of chemical substances with relapses and exacerbation under certain conditions when exposed to very low levels which do not affect the population at large. There are no lab markers or specific investigative findings. In our view, MCS is not a separate clinical syndrome but a collective term. A very small part of the patients in question may actually exhibit a somatic or psychosomatic response to low levels of a variety of chemicals in the environment. For another part, even if the MCS symptoms are induced by chemical substances in the environment, the basic hypersensitivity is a psychological stress reaction. In the third and largest group, the patients have been misdiagnosed, i.e. a somatic or psychiatric disease has been overlooked. There is a fourth group of patients in whom there is no evidence of any exposure at all but instead a belief system installed by certain physicians, the media and other groups in society. This paper tries to describe the neurological and neurotoxic aspects of MCS problems and to illustrate it with examples of an alleged outbreak of chronic neurotoxic disease caused by pyrethroids in Germany. Research strategy should establish clearly determined diagnostic criteria, agreement on the use of specific questionnaires as well as clinical and technical diagnostic procedures, prospective clinical studies of MCS patients and comparative groups as well as experimental approaches. PMID:11022866

  17. 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

  18. 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.

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

    PubMed

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

    2012-03-01

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

  20. 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

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

    DOEpatents

    Fincke, James R. (Idaho Falls, ID)

    2001-01-01

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

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

    PubMed Central

    Farkas, Attila; Maróti, Gergely; Dürg?, Hajnalka; Györgypál, Zoltán; Lima, Rui M.; Medzihradszky, Katalin F.; Kereszt, Attila; Mergaert, Peter; Kondorosi, Éva

    2014-01-01

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

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

    PubMed

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

    2015-12-20

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

  4. 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

  5. Fine root branch orders contribute differentially to uptake, allocation, and return of potentially toxic metals.

    PubMed

    Guo, Ying-Ying; Wang, Jun-Jian; Kong, De-Liang; Wang, Wei; Guo, Da-Li; Wang, Yan-Bing; Xie, Qing-Long; Liu, Yang-Sheng; Zeng, Hui

    2013-10-15

    Growing evidence has revealed high heterogeneity of fine root networks in both structure and function, with different root orders corporately maintaining trees' physiological activities. However, little information is available on how fine root heterogeneity of trees responds to environmental stresses. We examined concentrations of seven potentially toxic metals (Cr, Ni, Cu, Zn, As, Cd, and Pb) within fine root networks and their correlations with root morphological and macro-elemental traits in six Chinese subtropical trees. The contributions of different orders of roots to fine-root metal storage and return were also estimated. Results showed no consistent pattern for the correlation among different metal concentration against root traits. Unlike root metal concentration that generally decreased with root order, root metal storage was commonly lowest in middle root orders. Root senescence was at least comparable to leaf senescence contributing to metal removal. Although the first-order roots constituted 7.2-22.3% of total fine root biomass, they disproportionately contributed to most of metal return fluxes via root senescence. The two distinct root functional modules contributed differentially to metal uptake, allocation, and return, with defensive (lower-order) roots effectively stabilizing and removing toxic metals and bulk buffering (higher-order) roots possessing a persistent but diluted metal pool. Our results suggest a strong association of physiological functions of metal detoxification and metal homeostasis with the structural heterogeneity in fine root architecture. PMID:24044549

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

    NASA Astrophysics Data System (ADS)

    Chen, Fan; Chen, Jin

    2011-11-01

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

  7. Evaluation of electrospray differential mobility analysis for virus particle analysis: Potential applications for biomanufacturing.

    PubMed

    Guha, Suvajyoti; Pease, Leonard F; Brorson, Kurt A; Tarlov, Michael J; Zachariah, Michael R

    2011-12-01

    The technique of electrospray differential mobility analysis (ES-DMA) was examined as a potential potency assay for routine virus particle analysis in biomanufacturing environments (e.g., evaluation of vaccines and gene delivery products for lot release) in the context of the International Committee of Harmonisation (ICH) Q2 guidelines. ES-DMA is a rapid particle sizing method capable of characterizing certain aspects of the structure (such as capsid proteins) and obtaining complete size distributions of viruses and virus-like particles. It was shown that ES-DMA can distinguish intact virus particles from degraded particles and measure the concentration of virus particles when calibrated with nanoparticles of known concentration. The technique has a measurement uncertainty of ?20%, is linear over nearly 3 orders of magnitude, and has a lower limit of detection of ?10(9)particles/mL. This quantitative assay was demonstrated for non-enveloped viruses. It is expected that ES-DMA will be a useful method for applications involving production and quality control of vaccines and gene therapy vectors for human use. PMID:21963394

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

    PubMed

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

    2014-01-01

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

  9. Schwinger-variational-principle theory of collisions in the presence of multiple potentials

    NASA Astrophysics Data System (ADS)

    Robicheaux, F.; Giannakeas, P.; Greene, Chris H.

    2015-08-01

    A theoretical method for treating collisions in the presence of multiple potentials is developed by employing the Schwinger variational principle. The current treatment agrees with the local (regularized) frame transformation theory and extends its capabilities. Specifically, the Schwinger variational approach gives results without the divergences that need to be regularized in other methods. Furthermore, it provides a framework to identify the origin of these singularities and possibly improve the local frame transformation. We have used the method to obtain the scattering parameters for different confining potentials symmetric in x ,y . The method is also used to treat photodetachment processes in the presence of various confining potentials, thereby highlighting effects of the infinitely many closed channels. Two general features predicted are the vanishing of the total photoabsorption probability at every channel threshold and the occurrence of resonances below the channel thresholds for negative scattering lengths. In addition, the case of negative-ion photodetachment in the presence of uniform magnetic fields is also considered where unique features emerge at large scattering lengths.

  10. 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.

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  13. 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

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

    PubMed

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

    2014-08-01

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

  15. 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.

  16. Potential multiple steady-states in the long-term carbon cycle

    E-print Network

    Tennenbaum, Stephen; Schwartzman, David

    2013-01-01

    Modelers of the long term carbon cycle in Earth history have previously assumed there is only one stable climatic steady state. Here we investigate the possibility of multiple steady states. We find them in Abiotic World, lacking any biotic influence, resulting from possible variations in planetary albedo in different temperature, atmospheric carbon dioxide level regimes, with the same weathering forcing balancing a volcanic source to the atmosphere, ocean pool. In Plant World modeling relevant to the Phanerozoic, we include the additional effects of biotic enhancement of weathering on land, organic carbon burial, oxidation of reduced organic carbon in terrestrial sediments and the variation of biotic productivity with temperature, finding a second stable steady state appearing between twenty and fifty degrees C. The very warm early Triassic climate may be the prime candidate for an upper temperature steady state. Given our results, the anthropogenic driven rise of atmospheric carbon dioxide could potentially...

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

    PubMed Central

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

    2015-01-01

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

  18. 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.

  19. 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-1? 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-1? 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.

  20. Radiogenic ingrowth in systems with multiple reservoirs: applications to the differentiation of the mantle-crust system

    NASA Astrophysics Data System (ADS)

    Albarčde, Francis

    2001-06-01

    Mantle isochrons such as those observed for oceanic basalts in the 207Pb/ 204Pb vs. 206Pb/ 204Pb diagram do not date discrete differentiation events but are often suggested to reflect a mean age of differentiation within the mantle-crust system. The present work deals with the isotopic aspects of radioactive decay of long-lived isotopes ( 87Rb, 147Sm, 176Lu) in systems with multiple reservoirs. For these isotopes, the probability of decay is small compared to the frequency of reservoir jumping. Consequently, a state of secular equilibrium exists for which changes in the nuclide abundances in each reservoir balance radioactive decay and ingrowth. Here a theory is presented that predicts the characteristic time to reach secular equilibrium (relaxation time) and the secular equilibrium properties of stable, radioactive, and daughter nuclides in a pair of reservoirs of constant mass. Expressions are derived for parent/daughter ratios, such as 87Rb/ 86Sr, and for isotopic ratios involving a daughter isotope, such as 87Sr/ 86Sr. It is shown that, at secular equilibrium, the reservoirs form linear arrays in isochron diagrams. The isochron slope and intercept reflect the relaxation time and have no significance of a mean age. The derived relationships are extended to an arbitrary number of reservoirs with constant mass. In the case of 87Rb, 147Sm, and 176Lu, the relaxation times of the mantle-crust system agree with each other (1.2±0.1 Gy). It is therefore likely that the Earth is at secular equilibrium for these nuclides and their daughter isotopes and that no memory of the initial differentiation of the Earth is preserved in the isotope composition of Sr, Nd, and Hf of modern basalts. The kappa conundrum is a straightforward consequence of Th and U having different relaxation times in the mantle-crust system. The 207Pb/ 204Pb and 4He/ 3He ratios are not at secular equilibrium, in contrast with 206Pb/ 204Pb and 208Pb/ 204Pb. The properties of oceanic basalts in terms of the last two ratios and the Nd and Hf secular evolution curves of mantle-derived material require the presence of deep hidden reservoirs that interacts with the depleted upper mantle. It is suggested that the most fertile lithospheric oceanic plates, in particular those loaded with plume heads, preferentially sink to the bottom of the mantle. The terrestrial mantle is therefore most likely chemically heterogeneous and models of Earth compositions based on a primitive lower mantle should be abandoned. In contrast, the transient-dominated 207Pb/ 204Pb and 4He/ 3He ratios can be used to model the early differentiation of the planet.

  1. 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.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    Aguilera, Valeria; Briceńo, Luis; Contreras, Hector; Lamperti, Liliana; Sepúlveda, Esperanza; Díaz-Perez, Francisca; León, Marcelo; Veas, Carlos; Maura, Rafael; Toledo, Jorge Roberto; Fernández, Paulina; Covarrubias, Ambart; Zuńiga, Felipe Andrés; Radojkovic, Claudia; Escudero, Carlos; Aguayo, Claudio

    2014-01-01

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

  4. Correlation between in vitro expansion-related cell stiffening and differentiation potential of human mesenchymal stem cells.

    PubMed

    LeBlon, Courtney E; Casey, Meghan E; Fodor, Caitlin R; Zhang, Tony; Zhang, Xiaohui; Jedlicka, Sabrina S

    2015-01-01

    Human mesenchymal stem cells (hMSCs) are an attractive cell source for tissue regeneration, given their self-renewal and multilineage potential. However, they are present in only small percentages in human bone marrow, and are generally propagated in vitro prior to downstream use. Previous work has shown that hMSC propagation can lead to alterations in cell behavior and differentiation potency, yet optimization of differentiation based on starting cell elastic modulus is an area still under investigation. To further advance the knowledge in this field, hMSCs were cultured and routinely passaged on tissue-culture polystyrene to investigate the correlation between cell stiffening and differentiation potency during in vitro aging. Local cell elastic modulus was measured at every passage using atomic force microscopy indentation. At each passage, cells were induced to differentiate down myogenic and osteogenic paths. Cells induced to differentiate, as well as undifferentiated cells were assessed for gene and protein expression using quantitative polymerase chain reaction and immunofluorescent staining, respectively, for osteogenic and myogenic markers. Myogenic and osteogenic cell potential are highly reliant on the elastic modulus of the starting cell population (of undifferentiated cells), and this potential appears to peak when the innate cell elastic modulus is close to that of differentiated tissue. However, the latent expression of the same markers in undifferentiated cells also appears to undergo a correlative relationship with cell elastic modulus, indicating some endogenous effects of cell elastic modulus and gene/protein expression. Overall, this study correlates age-related changes with regards to innate cell stiffening and gene/protein expression in commercial hMSCs, providing some guidance as to maintenance and future use of hMSCs in future tissue engineering applications. PMID:26381795

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  7. Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch

    PubMed Central

    Amsen, Derk; Antov, Andrey; Jankovic, Dragana; Sher, Alan; Radtke, Freddy; Souabni, Abdallah; Busslinger, Meinrad; McCright, Brent; Gridley, Thomas; Flavell, Richard A.

    2007-01-01

    CD4+ T helper cells differentiate into Th1 or Th2 effector lineages, which orchestrate immunity to different types of microbes. Both Th1 and Th2 differentiation can be induced by Notch, but what dictates which of these programs is activated in response to Notch is not known. The requirement for Notch in T helper differentiation is controversial. Using T cell specific gene ablation of the Notch effector RBP-J or the Notch1 and 2 receptors, we show here that Notch is required on CD4+ T cells for physiological Th2 responses to parasite antigens. We find that Gata3 is necessary for Notch induced Th2 differentiation and identify an upstream gata3 promoter as a direct target for Notch signaling. Moreover, we observed that absence of Gata3 turns Notch from a Th2 inducer into a powerful inducer of Th1 differentiation. Therefore, Gata3 is a critical element determining inductive Th2 differentiation and limiting Th1 differentiation by Notch. PMID:17658279

  8. Oscillatory Protein Expression Dynamics Endows Stem Cells with Robust Differentiation Potential

    PubMed Central

    Kaneko, Kunihiko

    2011-01-01

    The lack of understanding of stem cell differentiation and proliferation is a fundamental problem in developmental biology. Although gene regulatory networks (GRNs) for stem cell differentiation have been partially identified, the nature of differentiation dynamics and their regulation leading to robust development remain unclear. Herein, using a dynamical system modeling cell approach, we performed simulations of the developmental process using all possible GRNs with a few genes, and screened GRNs that could generate cell type diversity through cell-cell interactions. We found that model stem cells that both proliferated and differentiated always exhibited oscillatory expression dynamics, and the differentiation frequency of such stem cells was regulated, resulting in a robust number distribution. Moreover, we uncovered the common regulatory motifs for stem cell differentiation, in which a combination of regulatory motifs that generated oscillatory expression dynamics and stabilized distinct cellular states played an essential role. These findings may explain the recently observed heterogeneity and dynamic equilibrium in cellular states of stem cells, and can be used to predict regulatory networks responsible for differentiation in stem cell systems. PMID:22073296

  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. PMID:23666768

  10. A novel differential diagnostic model based on multiple biological parameters for immunoglobulin A nephropathy

    PubMed Central

    2012-01-01

    Background Immunoglobulin A nephropathy (IgAN) is the most common form of glomerulonephritis in China. An accurate diagnosis of IgAN is dependent on renal biopsies, and there is lack of non-invasive and practical classification methods for discriminating IgAN from other primary kidney diseases. The objective of this study was to develop a classification model for the auxiliary diagnosis of IgAN using multiparameter analysis with various biological parameters. Methods To establish an optimal classification model, 121 cases (58 IgAN vs. 63 non-IgAN) were recruited and statistically analyzed. The model was then validated in another 180 cases. Results Of the 57 biological parameters, there were 16 parameters that were significantly different (P?potential clinical applications in distinguishing IgAN from other primary kidney diseases. PMID:22738421

  11. Selected Melanocortin 1 Receptor Single-Nucleotide Polymorphisms Differentially Alter Multiple Signaling Pathways

    PubMed Central

    Doyle, J. R.; Fortin, J. P.; Beinborn, M.

    2012-01-01

    The melanocortin 1 receptor (MC1R) is a highly polymorphic G protein-coupled receptor, which is known to modulate pigmentation and inflammation. In the current study, we investigated the pharmacological effects of select single-nucleotide polymorphisms (SNPs) (V60L, R163Q, and F196L). After transient expression of MC1Rs in human embryonic kidney 293 cells, basal and ligand-induced cAMP signaling and mitogen-activated protein kinase (MAPK) activation were assessed by using luciferase reporter gene assays and Western blot analysis, respectively. All receptor variants showed decreased basal cAMP activity. With the V60L and F196L variants, the decrease in constitutive activity was attributable, at least in part, to a reduction in surface expression. The F196L variant also displayed a significant reduction in potency for both the peptide agonist ?-melanocyte-stimulating hormone (?-MSH) and the small-molecule agonist 1-[1-(3-methyl-l-histidyl-O-methyl-d-tyrosyl)-4-phenyl-4-piperidinyl]-1-butanone (BMS-470539). In MAPK signaling assays, the F196L variant showed decreased phospho-extracellular signal-regulated kinase levels after stimulation with either ?-MSH or BMS-470539. In contrast, the R163Q variant displayed a selective loss of ?-MSH-induced MAPK activation; whereas responsiveness to the small-molecule agonist BMS-470539 was preserved. Further assessment of MC1R variants in A549 cells, an in vitro model of inflammation, revealed an enhanced inflammatory response resulting from expression of the F196L variant (versus the wild-type MC1R). This alteration in function was restored by treatment with BMS-470539. Overall, these studies illustrate novel signaling profiles linked to distinct MC1R SNPs. Furthermore, our investigations highlight the potential for small-molecule drugs to rescue the function of MC1R variants that show reduced basal and/or ?-MSH stimulated activity. PMID:22547573

  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 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

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

    NASA Astrophysics Data System (ADS)

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

    2013-10-01

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

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

    PubMed Central

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

    2014-01-01

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

  16. Identification of genes associated with the differentiation potential of adipose-derived stem cells to osteocytes or myocytes.

    PubMed

    Ren, Yizhong; Han, Changxu; Wang, Jingjuan; Jia, Yanbo; Kong, Lingyue; Eerdun, Tu; Wu, Lishuan; Jiang, Dianming

    2015-02-01

    Adipose-derived stem cells (ADSCs) have been considered as the optimal cells for regenerative medicine because ADSCs have the potential of multi-directional differentiation. To study the mechanisms of ADSCs differentiation, we analyzed microarray of GSE37329. GSE37329 was downloaded from Gene Expression Omnibus including 3 ADSCs, 2 ADSCs-derived osteocytes, and 2 ADSCs-derived myocytes samples. The differentially expressed genes (DEGs) were screened using limma package. Their underlying functions were predicted by gene ontology and pathway enrichment analyses. Besides, the interaction relationships of the proteins encoded by DEGs were obtained from STRING database, and protein-protein interaction (PPI) network was constructed using Cytoscape. Furthermore, modules analysis of PPI network was performed using MCODE in Cytoscape. We screened 662 and 484 DEG separately for the ADSCs-derived osteocytes and myocytes compared with ADSCs. There were 205 common up-regulated and 128 common down-regulated DEGs between the two groups. Function enrichment indicated that these common DEGs, especially, VEGFA, FGF2, and EGR1 may be related to cell differentiation. PPI network for common DEGs also suggested that VEGFA (degree = 29), FGF2 (degree = 17), and EGR1 (degree = 12) might be more important because they had higher connectivity degrees, and they might be involved in cell differentiation by interacting with other genes in module A (e.g., EGR1-NGF and EGR1-LEP), and B (e.g., VEGFA-PDGFD). Additionally, the IGF1 and BTG1 may be, respectively, specific for osteocytes and myocytes differentiation. VEGFA, PDGFD, FGF2, EGR1, NGF, LEP, IGF1, and BTG1 might serve as target genes in regulating ADSCs differentiation. PMID:25385480

  17. 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 3?- 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 bon?s metaphyses of rats flown on board of the space laboratory (Spacelab - 2) It was revealed that population of the perivascular cells is not homogeneous in adaptive zones of the remodeling in both control and test groups (lowering support loading). This population comprises adjacent to endothelium little differentiated forms and isolated cells with differentiation features (specific volume of rough endoplasmic reticulum in cytoplasm is increased). Majority of the perivascular cells in the control group reveals reaction to alkaline phosphatase (marker of the osteogenic differentiation). In little differentiated cells this reaction is registered in nucleolus, nucleous and cytoplasm. In differentiating cells activity of the alkaline phosphatase is also detected on the outer surface of the cellular membrane. Unlike the control group in the bones of animals under microgravitaty reaction to the alkaline phosphatase is registered not for all cells of perivascular population. Part of the differentiating perivascular cells does not contain a product of the reaction. There is also visible trend of individual alkaline phosphatase containing perivascular cells amounts decrease (i.e. osteogenic cells-precursors). Under microgravity some little differentiated perivascular cells reveal destruction signs. Found decrease trend of the alkaline phosphatase containing cells (i.e. osteogenic cells) number in perivascular cells population. It is one of the mechanisms of the osteogenic process intensity decrease in bones due to lowering support loading on the bone skeleton. In particular this is confirmed by the fact that in the zones of adaptive remodeling we found fibroblasts and fibrosis zones - areas filled with non mineralized collagen fibrils on the bones surfaces. Hence it should be considered that lowering (removal) support loading slows down (or blocks) osteogenic differentiation of the perivascular cells part and stimulates differentiation of the fibroblast cells. Obtained data considered as one of the cellular mechanisms of the adaptive reactions development in spongy bone under microgravity which could lead to the bone mass loss.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2007-03-01

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

  20. L1 is a potential marker for poorly-differentiated pancreatic neuroendocrine carcinoma

    PubMed Central

    Kaifi, Jussuf T; Zinnkann, Ulrich; Yekebas, Emre F; Schurr, Paulus G; Reichelt, Uta; Wachowiak, Robin; Fiegel, Henning C; Petri, Susann; Schachner, Melitta; Izbicki, Jakob R

    2006-01-01

    AIM: To determine the expression of L1 in pancreatic neuroendocrine tumor and to correlate it with WHO classification of this tumor. METHODS: We retrospectively analyzed L1 expression in 63 cases of pancreatic neuroendocrine tumor by immunohistochemistry on paraffin sections of primary tumors or metastases. Staining was performed by peroxidase technique with monoclonal antibody UJ127.11 against human L1. All tumors were classified according to WHO classification as well-differentiated neuroendocrine tumors and carcinomas or poorly-differentiated neuroendocrine carcinomas. RESULTS: L1 was detected in 5 (7.9%) of 63 pancreatic neuroendocrine tumors. Four (44.4%) of 9 poorly-differentiated carcinomas expressed L1. In contrast, only 1 (1.9%) of 54 well-differentiated tumors or carcinomas was positive for L1. No expression was found in Langerhans islet cells of normal pancreatic tissue. Cross table analysis showed a significant association between L1 expression and classification of neuroendocrine tumors of the pancreas (P<0.01). CONCLUSION: L1 is specifically expressed in poorly-differentiated pancreatic neuroendocrine carcinomas that are known to have the worst prognosis. L1 might be a marker for risk prediction of patients diagnosed with pancreatic neuroendocrine carcinomas. PMID:16440424

  1. The Effect of the Residual Ion Potential on the Fully Differential Cross Section of Helium for Ionization by Electron Impact

    SciTech Connect

    Toth, A.; Nagy, L.

    2011-10-03

    We have carried out calculations for the fully differential cross section of the ionization of helium by electron projectiles. In order to study the effect of the residual ion potential, we employed three models, and tested them for the coplanar and perpendicular plane geometry. In spite of the simplicity of our models, the results for the coplanar case are in fair agreement with the available experimental data. The results for the perpendicular geometry need more improvement.

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

    NASA Astrophysics Data System (ADS)

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

    2015-09-01

    The physical characterization of potentially hazardous asteroids (PHAs) is important for impact hazard assessment and evaluating mitigation options. Close flybys of PHAs provide an opportunity to study their surface photometric and spectral properties that enable the identification of their source regions in the main asteroid belt. We observed PHA (357439) 2004 BL86 during a close flyby of the Earth at a distance of 1.2 million km (0.0080 AU) on 2015 January 26, with an array of ground-based telescopes to constrain its photometric and spectral properties. Lightcurve observations showed that the asteroid was a binary and subsequent radar observations confirmed the binary nature and gave a primary diameter of 300 m and a secondary diameter of 50-100 m. Our photometric observations were used to derive the phase curve of 2004 BL86 in the V-band. Two different photometric functions were fitted to this phase curve, the IAU H-G model and the Shevchenko model. From the fit of the H-G function we obtained an absolute magnitude of H = 19.51 ± 0.02 and a slope parameter of G = 0.34 ± 0.02. The Shevchenko function yielded an absolute magnitude of H = 19.03 ± 0.07 and a phase coefficient b = 0.0225 ± 0.0006. The phase coefficient was used to calculate the geometric albedo (Ag) using the relationship found by Belskaya & Schevchenko, obtaining a value of Ag = 40% ± 8% in the V-band. With the geometric albedo and the absolute magnitudes derived from the H-G and the Shevchenko functions we calculated the diameter (D) of 2004 BL86, obtaining D = 263 ± 26 and D = 328 ± 35 m, respectively. 2004 BL86 spectral band parameters and pyroxene chemistry are consistent with non-cumulate eucrite meteorites. A majority of these meteorites are derived from Vesta and are analogous with surface lava flows on a differentiated parent body. A non-diagnostic spectral curve match using the Modeling for Asteroids tool yielded a best-match with non-cumulate eucrite Bereba. Three other near-Earth asteroids (1993 VW, 1998 KK17, and 2000 XH44) that were observed by Burbine et al. also have spectral properties similar to 2004 BL86. The presence of eucrites with anomalous oxygen isotope ratios compared to the howardites, eucrites, and diogenites meteorites from Vesta suggests the possible presence of multiple differentiated bodies in the inner main belt or the contamination of Vesta’s surface with exogenic material. The spectral properties of both anomalous and Vestan eucrites are degenerate, making it difficult to identify the parent bodies of anomalous eucrites in the main belt and the NEO population using remote sensing. This makes it difficult to link 2004 BL86 directly to Vesta, although the Vesta family is the largest contributor of V-types to near-Earth space.

  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. PMID:24888892

  4. 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. Stem Cells 2015;33:3291-3303. PMID:26235673

  5. Hypoxia increases Sca-1/CD44 co-expression in murine mesenchymal stem cells and enhances their adipogenic differentiation potential.

    PubMed

    Valorani, M G; Germani, A; Otto, W R; Harper, L; Biddle, A; Khoo, C P; Lin, W R; Hawa, M I; Tropel, P; Patrizi, M P; Pozzilli, P; Alison, M R

    2010-07-01

    Mesenchymal stem cells (MSCs) are usually cultured under normoxic conditions (21% oxygen). However, in vivo, the physiological "niches" for MSCs have a much lower oxygen tension. Because of their plasticity, stem cells are particularly sensitive to their environments, and oxygen tension is one developmentally important stimulus in stem cell biology and plays a role in the intricate balance between cellular proliferation and commitment towards differentiation. Therefore, we investigated here the effect of hypoxia (2% oxygen) on murine adipose tissue (AT) MSC proliferation and adipogenic differentiation. AT cells were obtained from the omental fat and AT-MSCs were selected for their ability to attach to the plastic dishes, and were grown under normoxic and hypoxic conditions. Prior exposure of MSCs to hypoxia led to a significant reduction of ex vivo expansion time, with significantly increased numbers of Sca-1(+) as well as Sca-1(+)/CD44(+)double-positive cells. Under low oxygen culture conditions, the AT-MSC number markedly increased and their adipogenic differentiation potential was reduced. Notably, the hypoxia-mediated inhibition of adipogenic differentiation was reversible: AT-MSCs pre-exposed to hypoxia when switched to normoxic conditions exhibited significantly higher adipogenic differentiation capacity compared to their pre-exposed normoxic-cultured counterparts. Accordingly, the expression of adipocyte-specific genes, peroxisome proliferator activated receptor gamma (Ppargamma), lipoprotein lipase (Lpl) and fatty acid binding protein 4 (Fabp4) were significantly enhanced in hypoxia pre-exposed AT-MSCs. In conclusion, pre-culturing MSCs under hypoxic culture conditions may represent a strategy to enhance MSC production, enrichment and adipogenic differentiation. PMID:20496083

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

    ERIC Educational Resources Information Center

    Elosua, Paula; Lopez-Jauregui, Alicia

    2007-01-01

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

  7. 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…

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

    PubMed

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

    2015-09-01

    In embryos, neural crest cells emerge from the dorsal region of the fusing neural tube and migrate throughout tissues to differentiate into various types of cells including osteoblasts. In adults, subsets of neural crest-derived cells (NCDCs) reside as stem cells and are considered to be useful cell sources for regenerative medicine strategies. Numerous studies have suggested that stem cells with a neural crest origin persist into adulthood, especially those within the mammalian craniofacial compartment. However, their distribution as well as capacity to differentiate into osteoblasts in adults is not fully understood. To analyze the precise distribution and characteristics of NCDCs in adult oral tissues, we utilized an established line of double transgenic (P0-Cre/CAG-CAT-EGFP) mice in which NCDCs express green fluorescent protein (GFP) throughout their life. GFP-positive cells were scattered like islands throughout tissues of the palate, gingiva, tongue, and buccal mucosa in adult mice, with those isolated from the latter shown to form spheres, typical cell clusters composed of stem cells, under low-adherent conditions. Furthermore, GFP-positive cells had markedly increased alkaline phosphatase (a marker enzyme of osteoblast differentiation) activity and mineralization as shown by alizarin red staining, in the presence of bone morphogenetic protein (BMP)-2. These results suggest that NCDCs reside in various adult oral tissues and possess potential to differentiate into osteoblastic cells. NCDCs in adults may be a useful cell source for bone regeneration strategies. PMID:26225748

  9. Potential role of soluble human leukocyte antigen-G molecules in multiple sclerosis.

    PubMed

    Fainardi, Enrico; Rizzo, Roberta; Castellazzi, Massimiliano; Stignani, Marina; Granieri, Enrico; Baricordi, Olavio Roberto

    2009-12-01

    Nonclassical human leukocyte antigen (HLA)-G antigens in soluble form (sHLA-G) have recently been suggested to have a potential role as immunomodulatory factors in multiple sclerosis (MS), a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system of unknown etiology and supposed autoimmune origin. In MS patients, sHLA-G levels were elevated in cerebrospinal fluid (CSF), intrathecally synthesized, predominantly represented by the HLA-G5 isoform and even more elevated in cases of inactive disease, as determined by magnetic resonance imaging. In MS, CSF sHLA-G concentrations were also related to the formation of an intrathecal anti-inflammatory microenvironment based on a positive correlation to CSF interleukin-10 titers and an inverse association to the levels of antiapoptotic sFas molecules in the CSF. Expression of HLA-G antigens was detected in microglia, macrophages, and endothelial cells within and around MS lesions and was enhanced in microglial cells by T-helper-1 proinflammatory cytokines. A novel subpopulation of naturally occurring CD4(+) and CD8(+) regulatory T cells expressing HLA-G1 and secreting HLA-G5 was identified in the CSF of MS patients. Taken together, these findings seem to indicate that sHLA-G antigens may be implicated in the termination of MS autoimmunity and associated with remission of the disease through their function as anti-inflammatory molecules. However, the mechanisms operating in the immunomodulatory circuit mediated by sHLA-G proteins remain to be clarified. PMID:19651179

  10. 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

  11. Potential for pancreatic maturation of differentiating human embryonic stem cells is sensitive to the specific pathway of definitive endoderm commitment.

    PubMed

    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

  12. 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

  13. Measurements of jet multiplicity and differential production cross sections of Z +jets events in proton-proton collisions at ?{s }=7 TeV

    NASA Astrophysics Data System (ADS)

    Khachatryan, V.; Sirunyan, A. M.; Tumasyan, A.; Adam, W.; Bergauer, T.; Dragicevic, M.; Erö, J.; Fabjan, C.; Friedl, M.; Frühwirth, R.; Ghete, V. M.; Hartl, C.; Hörmann, N.; Hrubec, J.; Jeitler, M.; Kiesenhofer, W.; Knünz, V.; Krammer, M.; Krätschmer, I.; Liko, D.; Mikulec, I.; Rabady, D.; Rahbaran, B.; Rohringer, H.; Schöfbeck, R.; Strauss, J.; Taurok, A.; Treberer-Treberspurg, W.; Waltenberger, W.; Wulz, C.-E.; Mossolov, V.; Shumeiko, N.; Suarez Gonzalez, J.; Alderweireldt, S.; Bansal, M.; Bansal, S.; Cornelis, T.; De Wolf, E. A.; Janssen, X.; Knutsson, A.; Luyckx, S.; Ochesanu, S.; Roland, B.; Rougny, R.; Van De Klundert, M.; Van Haevermaet, H.; Van Mechelen, P.; Van Remortel, N.; Van Spilbeeck, A.; Blekman, F.; Blyweert, S.; D'Hondt, J.; Daci, N.; Heracleous, N.; Keaveney, J.; Lowette, S.; Maes, M.; Olbrechts, A.; Python, Q.; Strom, D.; Tavernier, S.; Van Doninck, W.; Van Mulders, P.; Van Onsem, G. P.; Villella, I.; Caillol, C.; Clerbaux, B.; De Lentdecker, G.; Dobur, D.; Favart, L.; Gay, A. P. R.; Grebenyuk, A.; Léonard, A.; Mohammadi, A.; Pernič, L.; Reis, T.; Seva, T.; Thomas, L.; Vander Velde, C.; Vanlaer, P.; Wang, J.; Adler, V.; Beernaert, K.; Benucci, L.; Cimmino, A.; Costantini, S.; Crucy, S.; Dildick, S.; Fagot, A.; Garcia, G.; Mccartin, J.; Ocampo Rios, A. A.; Ryckbosch, D.; Salva Diblen, S.; Sigamani, M.; Strobbe, N.; Thyssen, F.; Tytgat, M.; Yazgan, E.; Zaganidis, N.; Basegmez, S.; Beluffi, C.; Bruno, G.; Castello, R.; Caudron, A.; Ceard, L.; Da Silveira, G. G.; Delaere, C.; du Pree, T.; Favart, D.; Forthomme, L.; Giammanco, A.; Hollar, J.; Jez, P.; Komm, M.; Lemaitre, V.; Nuttens, C.; Pagano, D.; Perrini, L.; Pin, A.; Piotrzkowski, K.; Popov, A.; Quertenmont, L.; Selvaggi, M.; Vidal Marono, M.; Vizan Garcia, J. M.; Beliy, N.; Caebergs, T.; Daubie, E.; Hammad, G. H.; Aldá Júnior, W. L.; Alves, G. A.; Brito, L.; Correa Martins Junior, M.; Dos Reis Martins, T.; Mora Herrera, C.; Pol, M. E.; Carvalho, W.; Chinellato, J.; Custódio, A.; Da Costa, E. M.; De Jesus Damiao, D.; De Oliveira Martins, C.; Fonseca De Souza, S.; Malbouisson, H.; Matos Figueiredo, D.; Mundim, L.; Nogima, H.; Prado Da Silva, W. L.; Santaolalla, J.; Santoro, A.; Sznajder, A.; Tonelli Manganote, E. J.; Vilela Pereira, A.; Bernardes, C. A.; Dogra, S.; Fernandez Perez Tomei, T. R.; Gregores, E. M.; Mercadante, P. G.; Novaes, S. F.; Padula, Sandra S.; Aleksandrov, A.; Genchev, V.; Iaydjiev, P.; Marinov, A.; Piperov, S.; Rodozov, M.; Stoykova, S.; Sultanov, G.; Tcholakov, V.; Vutova, M.; Dimitrov, A.; Glushkov, I.; Hadjiiska, R.; Kozhuharov, V.; Litov, L.; Pavlov, B.; Petkov, P.; Bian, J. G.; Chen, G. M.; Chen, H. S.; Chen, M.; Du, R.; Jiang, C. H.; Liang, S.; Plestina, R.; Tao, J.; Wang, X.; Wang, Z.; Asawatangtrakuldee, C.; Ban, Y.; Guo, Y.; Li, Q.; Li, W.; Liu, S.; Mao, Y.; Qian, S. J.; Wang, D.; Zhang, L.; Zou, W.; Avila, C.; Chaparro Sierra, L. F.; Florez, C.; Gomez, J. P.; Gomez Moreno, B.; Sanabria, J. C.; Godinovic, N.; Lelas, D.; Polic, D.; Puljak, I.; Antunovic, Z.; Kovac, M.; Brigljevic, V.; Kadija, K.; Luetic, J.; Mekterovic, D.; Sudic, L.; Attikis, A.; Mavromanolakis, G.; Mousa, J.; Nicolaou, C.; Ptochos, F.; Razis, P. A.; Bodlak, M.; Finger, M.; Finger, M.; Assran, Y.; Ellithi Kamel, A.; Mahmoud, M. A.; Radi, A.; Kadastik, M.; Murumaa, M.; Raidal, M.; Tiko, A.; Eerola, P.; Fedi, G.; Voutilainen, M.; Härkönen, J.; Karimäki, V.; Kinnunen, R.; Kortelainen, M. J.; Lampén, T.; Lassila-Perini, K.; Lehti, S.; Lindén, T.; Luukka, P.; Mäenpää, T.; Peltola, T.; Tuominen, E.; Tuominiemi, J.; Tuovinen, E.; Wendland, L.; Tuuva, T.; Besancon, M.; Couderc, F.; Dejardin, M.; Denegri, D.; Fabbro, B.; Faure, J. L.; Favaro, C.; Ferri, F.; Ganjour, S.; Givernaud, A.; Gras, P.; Hamel de Monchenault, G.; Jarry, P.; Locci, E.; Malcles, J.; Rander, J.; Rosowsky, A.; Titov, M.; Baffioni, S.; Beaudette, F.; Busson, P.; Charlot, C.; Dahms, T.; Dalchenko, M.; Dobrzynski, L.; Filipovic, N.; Florent, A.; Granier de Cassagnac, R.; Mastrolorenzo, L.; Miné, P.; Mironov, C.; Naranjo, I. N.; Nguyen, M.; Ochando, C.; Paganini, P.; Regnard, S.; Salerno, R.; Sauvan, J. B.; Sirois, Y.; Veelken, C.; Yilmaz, Y.; Zabi, A.; Agram, J.-L.; Andrea, J.; Aubin, A.; Bloch, D.; Brom, J.-M.; Chabert, E. C.; Collard, C.; Conte, E.; Fontaine, J.-C.; Gelé, D.; Goerlach, U.; Goetzmann, C.; Le Bihan, A.-C.; Van Hove, P.; Gadrat, S.; Beauceron, S.; Beaupere, N.; Boudoul, G.; Bouvier, E.; Brochet, S.; Carrillo Montoya, C. A.; Chasserat, J.; Chierici, R.; Contardo, D.; Depasse, P.; El Mamouni, H.; Fan, J.; Fay, J.; Gascon, S.; Gouzevitch, M.; Ille, B.; Kurca, T.; Lethuillier, M.; Mirabito, L.; Perries, S.; Ruiz Alvarez, J. D.; Sabes, D.; Sgandurra, L.; Sordini, V.; Vander Donckt, M.; Verdier, P.; Viret, S.; Xiao, H.

    2015-03-01

    Measurements of differential cross sections are presented for the production of a Z boson and at least one hadronic jet in proton-proton collisions at ?{s }=7 TeV , recorded by the CMS detector, using a data sample corresponding to an integrated luminosity of 4.9 fb-1 . The jet multiplicity distribution is measured for up to six jets. The differential cross sections are measured as a function of jet transverse momentum and pseudorapidity for the four highest transverse momentum jets. The distribution of the scalar sum of jet transverse momenta is also measured as a function of the jet multiplicity. The measurements are compared with theoretical predictions at leading and next-to-leading order in perturbative QCD.

  14. Differential regulation by organic compounds and heavy metals of multiple laccase genes in the aquatic hyphomycete Clavariopsis aquatica.

    PubMed

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

    2012-07-01

    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 ?M, in favor of a fungal adaptation to low copper concentrations of aquatic habitats. PMID:22544244

  15. 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 ?M, in favor of a fungal adaptation to low copper concentrations of aquatic habitats. PMID:22544244

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

    E-print Network

    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...

  17. 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 ?-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 information on the efficacy and safety of daclizumab and to determine its place in the fast-growing armamentarium of MS therapies. PMID:24409199

  18. Irradiation alters the differentiation potential of bone marrow mesenchymal stem cells

    PubMed Central

    WANG, YU; ZHU, GUOYING; WANG, JIANPING; CHEN, JUNXIANG

    2016-01-01

    Bone injury following radiotherapy has been confirmed by epidemiological and animal studies. However, the underlying mechanism remains to be elucidated and no preventive or curative solution has been identified for this bone loss. The present study aimed to investigate the irradiation-altered osteogenesis and adipogenesis of bone marrow mesenchymal stem cells (BMSCs). BMSCs were derived and exposed to ?-irradiation at doses of 0, 0.25, 0.5, 1, 2, 5 and 10 Gy. Cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay, and clonal expansion in vitro was detected by colony forming unit assessment. The osteogenic differentiation ability was demonstrated by alkaline phosphatase (ALP) activity, ALP staining and mineralization alizarin red staining, and the adipogenic differentiation ability was determined using Oil O red staining. The osteogenesis-associated genes, RUNX2, ALP, osteocalcin (OCN) and adipogenesis-associated genes, PPAR-? and C/EBP?, were detected using reverse transcription-quantitative polymerase chain reaction analyses. The protein expression levels of RUNX2, ALP and PPAR-? were detected using western blotting. Compared with the control, significant decreases in the proliferation, ALP activity and mineralization ability of the BMSCs were observed in the ?-irradiation group, with a high level of correlation with the exposure dose. However, no significant changes were observed in the area of Oil red O positive staining. The mRNA levels of RUNX2, ALP and OCN were decreased (P<0.05), however, no significant changes were observed in the levels of C/EBP? and PPAR-?. The protein expression levels of RUNX2 and ALP were decreased in the irradiated BMSCs, however, no significant difference was observed in the protein expression of PPAR-?. Irradiation inhibited the osteogenic and adipogenic ability of the BMSCs, and the osteogenic differentiation was decreased. The results of the present study provided evidence to assist in further elucidating radiotherapy-associated side effects on the skeleton. PMID:26572960

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

    PubMed

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

    2012-06-01

    Embryonic stem cells (ESCs) derived from inner cell mass (ICM) of mammalian blastocyst are having indefinite proliferation and differentiation capability for any type of cell lineages. In the present study, ICMs of in vitro-derived buffalo blastocysts were cultured into two different culture systems using buffalo fetal fibroblast as somatic cell support and Matrigel as synthetic support to obtain pluripotent buffalo embryonic stem cell (buESC) colonies. Pluripotency of the ESCs were characterised through pluripotency markers whereas, their differentiation capability was assessed by teratoma assay using immuno-compromised mice. Cumulus ooccyte complexes from slaughter house-derived ovaries were subjected to in vitro maturation, in vitro fertilization and in vitro culture to generate blastocysts. Total 262 blastocysts were derived through IVEP with 11.83 % (31/262) hatching rate. To generate buESCs, 15 ICMs from hatched blastocysts were cultured on mitomycin-C-treated homologous fetal fibroblast feeder layer, whereas the leftover 16 ICMs were cultured on extra-cellular matrix (Matrigel). No significant differences were observed for primary ESCs colony formation between two culture systems. Primary colonies as well as passaged ESCs were characterised by alkaline phosphatase staining, karyotyping and expression of transcription-based stem cell markers, OCT-4 and cell surface antigens SSEA-4 and TRA-1-60. Batch of ESCs found positive for pluripotency markers and showing normal karyotype after fifteenth passage were inoculated into eight immuno-compromised mice through subcutaneous and intramuscular route. Subcutaneous route of inoculation was found to be better than intramuscular route. Developed teratomas were excised surgically and subjected to histological analysis. Histological findings revealed presence of all the three germinal layer derivatives in teratoma sections. Presence of germinal layer derivatives were further confirmed by reverse transcriptase-polymerase chain reaction for the presence of differentiation markers like nerve cell adhesion molecule, fetal liver kinase-1 and alpha-feto protein for ectoderm, mesoderm and endoderm, respectively. PMID:22678753

  20. 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.

  1. RNA sequencing reveals differentially expressed genes as potential diagnostic and prognostic indicators of gallbladder carcinoma

    PubMed Central

    Jiang, Mingming; Fang, Meng; Ji, Jun; Wang, Aihua; Wang, Mengmeng; Jiang, Xiaoqing; Gao, Chunfang

    2015-01-01

    Gallbladder carcinoma (GBC) is a rare tumor with a dismal survival rate overall. Hence, there is an urgent need for exploring more specific and sensitive biomarkers for the diagnosis and treatment of GBC. At first, amplified total RNAs from two paired GBC tumors and adjacent non-tumorous tissues (ANTTs) were subjected to RNA sequencing. 161 genes were identified differentially expressed between tumors and ANTTs. Functional enrichment analysis indicated that the up-regulated genes in tumor were primarily associated with signaling molecules and enzyme modulators, and mainly involved in cell cycles and pathways in cancer. Twelve differentially expressed genes (DEGs) were further confirmed in another independent cohort of 35 GBC patients. Expression levels of BIRC5, TK1, TNNT1 and MMP9 were found to be positively related to postoperative relapse. There was also a significant correlation between BIRC5 expression and tumor-node-metastasis (TNM) stage. Besides, we observed a positive correlation between serum CA19–9 concentration and the expression levels of TNNT1, MMP9 and CLIC3. Survival analysis revealed that GBC patients with high TK1 and MMP9 expression levels had worse prognosis. These identified DEGs might not only be promising biomarkers for GBC diagnosis and prognosis, but also expedite the discovery of novel therapeutic strategies. PMID:25970782

  2. Cellular mechanical properties reflect the differentiation potential of adipose-derived mesenchymal stem cells.

    PubMed

    González-Cruz, Rafael D; Fonseca, Vera C; Darling, Eric M

    2012-06-12

    The mechanical properties of adipose-derived stem cell (ASC) clones correlate with their ability to produce tissue-specific metabolites, a finding that has dramatic implications for cell-based regenerative therapies. Autologous ASCs are an attractive cell source due to their immunogenicity and multipotent characteristics. However, for practical applications ASCs must first be purified from other cell types, a critical step which has proven difficult using surface-marker approaches. Alternative enrichment strategies identifying broad categories of tissue-specific cells are necessary for translational applications. One possibility developed in our lab uses single-cell mechanical properties as predictive biomarkers of ASC clonal differentiation capability. Elastic and viscoelastic properties of undifferentiated ASCs were tested via atomic force microscopy and correlated with lineage-specific metabolite production. Cell sorting simulations based on these "mechanical biomarkers" indicated they were predictive of differentiation capability and could be used to enrich for tissue-specific cells, which if implemented could dramatically improve the quality of regenerated tissues. PMID:22615348

  3. Personality traits as potential susceptibility markers: differential susceptibility to support among parents.

    PubMed

    Slagt, Meike; Dubas, Judith Semon; Denissen, Jaap J A; Dekovi?, Maja; van Aken, Marcel A G

    2015-04-01

    In this study, we examined whether parents are differentially susceptible to support from their spouse and adolescent child depending on their personality traits, and whether differences in susceptibility to support among parents, in turn, are linked to the quality of support parents give to their children. Participants in this three-wave longitudinal study were 288 two-parent Dutch families with an adolescent child. Fathers were on average 43.9 years old (SD?=?3.7 years), mothers were 41.7 years old (SD?=?3.3 years), and adolescents (50% girls) were 14.5 years old (SD?=?0.8 years). We found that the association between support from children toward their parents and subsequent support from parents toward their children was more pronounced for parents high on Openness, for better and for worse. Extraversion, Agreeableness, Conscientiousness, and Emotional Stability did not emerge as markers of differences in susceptibility. Also, parents did not differ in their susceptibility to support from their spouse, nor were differences in susceptibility found a year later when using data from a third wave. We found very modest support for differential susceptibility, only for Openness, and depending on the source of perceived support and on the timing of measurement. PMID:24471708

  4. 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 ?-glycerophosphate (?-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 ?1 (TGF-?1), 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-?1, 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.

  5. Minimization of self-potential survey mis-ties acquired with multiple reference locations

    E-print Network

    Minsley, Burke J.

    Self-potential (SP) surveys often involve many interconnected lines of data along available roads or trails, with the ultimate goal of producing a unique map of electric potentials at each station relative to a single ...

  6. Please cite this article in press as: M. Schiavon, et al., Transcriptome profiling of genes differentially modulated by sulfur and chromium identifies potential targets for phytoremediation and reveals a complex SCr interplay on sulfate transport regulati

    E-print Network

    differentially modulated by sulfur and chromium identifies potential targets for phytoremediation and reveals differentially modulated by sulfur and chromium identifies potential targets for phytoremediation and reveals 2012 Accepted 25 August 2012 Available online xxx Keywords: Chromium Sulfur Brassica juncea

  7. 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)

  8. p16 Expression in Fat Necrosis: A Potential Diagnostic Pitfall in the Evaluation of Differentiated Adipocytic Neoplasms.

    PubMed

    Ng, Wen; Messiou, Christina; Smith, Myles; Thway, Khin

    2015-10-01

    Distinguishing well-differentiated liposarcoma (WDL) from lipoma is of clinical and prognostic importance, but can be difficult on imaging and histology alone. WDL characteristically harbor amplifications of the MDM2 and CDK4 cell cycle oncogenes and overexpress the cell cycle regulator p16. Fluorescence in situ hybridization (FISH) to assess for MDM2 and CDK4 gene amplification is the diagnostic gold standard, and immunohistochemistry for the overexpressed MDM2 and CDK4 proteins is also useful but may not be routinely offered by pathology laboratories. p16 immunohistochemistry is a sensitive marker for WDL and is in the repertoire of most laboratories, and it has been suggested as a useful method of distinguishing WDL from lipomas when other ancillary modalities are not readily available. We describe a case of a large retroperitoneal adipocytic mass occurring in a 27-year-old male, which was clinically and radiologically in keeping with WDL. Histologically this was a differentiated adipocytic neoplasm with prominent fibrous septa and fat necrosis, more suggestive of retroperitoneal lipoma. Immunohistochemistry showed diffuse, strong nuclear expression of p16 in the areas of fat necrosis. However, CDK4 was negative and the lesion lacked evidence of MDM2 amplification with FISH. Diffuse expression of p16 in areas of fat necrosis in large or deep lipomas highlights the potential for diagnostic misinterpretation as well differentiated liposarcoma, and we therefore emphasize that p16 immunohistochemistry should always be interpreted as part of a panel with CDK4 +/- MDM2 in the differential diagnosis of WDL and lipoma. PMID:26173427

  9. Comparative analysis of neural differentiation potential in human mesenchymal stem cells derived from chorion and adult bone marrow.

    PubMed

    Ziadlou, Reihane; Shahhoseini, Maryam; Safari, Fatemeh; Sayahpour, Forugh-Azam; Nemati, Shiva; Eslaminejad, Mohamadreza Baghaban

    2015-11-01

    The finding of a reliable and abundant source of stem cells for the replacement of missing neurons in nervous system diseases requires extensive characterization of neural-differentiation-associated markers in stem cells from various sources. Chorion-derived stem cells from the human placenta have recently been described as an abundant, ethically acceptable, and easily accessible source of cells that are not limited in the same way as bone marrow (BM) mesenchymal stem cells (MSCs). We have isolated and cultured chorion MSCs (C-MSCs) and compared their proliferative capacity, multipotency, and neural differentiation ability with BM-MSCs. C-MSCs showed a higher proliferative capacity compared with BM-MSCs. The expression and histone modification of Nestin, as a marker for neural stem/progenitor cells, was evaluated quantitatively between the two groups. The Nestin expression level in C-MSCs was significantly higher than that in BM-MSCs. Notably, modifications of lys9, lys4, and lys27 of histone H3 agreed with the remarkable higher expression of Nestin in C-MSCs than in BM-MSCs. Furthermore, after neural differentiation of MSCs upon retinoic acid induction, both immunocytochemical and flow cytometry analyses demonstrated that the expression of neural marker genes was significantly higher in neural-induced C-MSCs compared with BM-MSCs. Mature neuron marker genes were also expressed at a significantly higher level in C-MSCs than in BM-MSCs. Thus, C-MSCs have a greater potential than BM-MSCs for differentiation to neural cell lineages and can be regarded as a promising source of stem cells for the cell therapy of neurological disorders. PMID:26022335

  10. 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.

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

    NASA Astrophysics Data System (ADS)

    Mar?dziak, Monika; ?mieszek, Agnieszka; Tomaszewski, Krzysztof A.; Lewandowski, Daniel; Marycz, Krzysztof

    2016-01-01

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

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

    SciTech Connect

    Kawasaki, Haruhisa; Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210 ; Guan, Jianjun; Tamama, Kenichi; Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210; Center for Stem Cell and Regenerative Medicine, The Ohio State University, Columbus, OH 43210

    2010-07-02

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

  13. Potential misinterpretation of data on differential gene expression in normal and malignant cells in vitro.

    PubMed

    Ye, Xiaofeng; Lotan, Reuben

    2008-07-01

    High throughput genomic and proteomic methods are often used for comparisons between expression of genes and proteins, respectively in normal cells and malignant counterparts for the identification of potential tumor markers for diagnosis and prognosis. Some experiments use normal and malignant cells cultured in vitro as a source of the mRNA or proteins for analysis. The conditions used for cell culture can exert major effects on the expression of genes and proteins. The interpretation of results of some such studies can be erroneous if normal cells and cancer cells are cultured in serum-free medium (SFM) and serum-supplemented media, respectively as recommended for their optimal growth. The reason for potential complications in the data interpretation is that serum contains different factors that affect gene expression. Likewise, SFM is usually supplemented with specific growth factors as well as bovine pituitary extract. Experimental examples demonstrating the issue include the stimulatory effects of serum on the expression of retinoic acid-inducible genes (e.g. GPRC5A) leading to the potentially erroneous conclusion that such genes are overexpressed in cancer cells. Potential remedy for this problem is to grow the normal and malignant cells in the same medium (serum-free or serum-containing) before analysis. PMID:18467351

  14. Multiple liquid-liquid critical points and density anomaly in core-softened potentials

    E-print Network

    Barbosa, Marcia C. B.

    REV IEW CO PY N O T FO R D ISTRIBU TIO N Multiple liquid-liquid critical points and density anomaly Abstract The relation between liquid-liquid phase transitions and waterlike density anomalies in core shown to present three liquid phases, two liquid-liquid phase transitions closely connected to two

  15. 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...

  16. A Combination of Culture Conditions and Gene Expression Analysis Can Be Used to Investigate and Predict hES Cell Differentiation Potential towards Male Gonadal Cells

    PubMed Central

    Kjartansdóttir, Kristín Rós; Reda, Ahmed; Panula, Sarita; Day, Kelly; Hultenby, Kjell; Söder, Olle; Hovatta, Outi; Stukenborg, Jan-Bernd

    2015-01-01

    Human embryonic stem cell differentiation towards various cell types belonging to ecto-, endo- and mesodermal cell lineages has been demonstrated, with high efficiency rates using standardized differentiation protocols. However, germ cell differentiation from human embryonic stem cells has been very inefficient so far. Even though the influence of various growth factors has been evaluated, the gene expression of different cell lines in relation to their differentiation potential has not yet been extensively examined. In this study, the potential of three male human embryonic stem cell lines to differentiate towards male gonadal cells was explored by analysing their gene expression profiles. The human embryonic stem cell lines were cultured for 14 days as monolayers on supporting human foreskin fibroblasts or as spheres in suspension, and were differentiated using BMP7, or spontaneous differentiation by omitting exogenous FGF2. TLDA analysis revealed that in the undifferentiated state, these cell lines have diverse mRNA profiles and exhibit significantly different potentials for differentiation towards the cell types present in the male gonads. This potential was associated with important factors directing the fate of the male primordial germ cells in vivo to form gonocytes, such as SOX17 or genes involved in the NODAL/ACTIVIN pathway, for example. Stimulation with BMP7 in suspension culture resulted in up-regulation of cytoplasmic SOX9 protein expression in all three lines. The observation that human embryonic stem cells differentiate towards germ and somatic cells after spontaneous and BMP7-induced stimulation in suspension emphasizes the important role of somatic cells in germ cell differentiation in vitro. PMID:26630562

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

    PubMed Central

    2014-01-01

    Introduction Studies with mesenchymal stem cells (MSCs) are increasing due to their immunomodulatory, anti-inflammatory and tissue regenerative properties. However, there is still no agreement about the best source of equine MSCs for a bank for allogeneic therapy. The aim of this study was to evaluate the cell culture and immunophenotypic characteristics and differentiation potential of equine MSCs from bone marrow (BM-MSCs), adipose tissue (AT-MSCs) and umbilical cord (UC-MSCs) under identical in vitro conditions, to compare these sources for research or an allogeneic therapy cell bank. Methods The BM-MSCs, AT-MSCs and UC-MSCs were cultured and evaluated in vitro for their osteogenic, adipogenic and chondrogenic differentiation potential. Additionally, MSCs were assessed for CD105, CD44, CD34, CD90 and MHC-II markers by flow cytometry, and MHC-II was also assessed by immunocytochemistry. To interpret the flow cytometry results, statistical analysis was performed using ANOVA. Results The harvesting and culturing procedures of BM-MSCs, AT-MSCs and UC-MSCs were feasible, with an average cell growth until the third passage of 25 days for BM-MSCs, 15 days for AT-MSCs and 26 days for UC-MSCs. MSCs from all sources were able to differentiate into osteogenic (after 10 days for BM-MSCs and AT-MSCs and 15 days for UC-MSCs), adipogenic (after 8 days for BM-MSCs and AT-MSCs and 15 days for UC-MSCs) and chondrogenic (after 21 days for BM-MSCs, AT-MSCs and UC-MSCs) lineages. MSCs showed high expression of CD105, CD44 and CD90 and low or negative expression of CD34 and MHC-II. The MHC-II was not detected by immunocytochemistry techniques in any of the MSCs studied. Conclusions The BM, AT and UC are feasible sources for harvesting equine MSCs, and their immunophenotypic and multipotency characteristics attained minimal criteria for defining MSCs. Due to the low expression of MHC-II by MSCs, all of the sources could be used in clinical trials involving allogeneic therapy in horses. However, the BM-MSCs and AT-MSCs showed fastest ‘‘in vitro’’ differentiation and AT-MSCs showed highest cell growth until third passage. These findings suggest that BM and AT may be preferable for cell banking purposes. PMID:24559797

  18. A multiple scattering theory approach to solving the time-dependent Schrödinger equation with an asymmetric rectangular potential

    E-print Network

    Victor F. Los; Nicholas V. Los

    2015-06-29

    An exact time-dependent solution for the wave function $\\psi(r,t)$ of a particle moving in the presence of an asymmetric rectangular well/barrier potential varying in one dimension is obtained by applying a novel for this problem approach using multiple scattering theory (MST) for the calculation of the space-time propagator. This approach, based on the localized at the potential jumps effective potentials responsible for transmission through and reflection from the considered rectangular potential, enables considering these processes from a particle (rather than a wave) point of view. The solution describes these quantum phenomena as a function of time and is related to the fundamental issues (such as measuring time) of quantum mechanics. It is presented in terms of integrals of elementary functions and is a sum of the forward- and backward-moving components of the wave packet. The relative contribution of these components and their interference as well as of the potential asymmetry to the probability density $|\\psi(x,t)|^2$ and particle dwell time is considered and numerically visualized for narrow and broad energy (momentum) distributions of the initial Gaussian wave packet. The obtained solution is also related to the kinetic theory of nanostructures due to the fact that the considered potential can model the spin-dependent potential profile of the magnetic multilayers used in spintronics devices.

  19. The potential of panobinostat as a treatment option in patients with relapsed and refractory multiple myeloma.

    PubMed

    Andreu-Vieyra, Claudia V; Berenson, James R

    2014-12-01

    Panobinostat is an investigational and potent histone deacetylase inhibitor (HDACi) that has shown promise as an antimultiple myeloma agent in the preclinical setting. In this review, we discuss the rationale for the use of panobinostat as a combination therapy for multiple myeloma and provide an overview of recent and ongoing clinical trials testing the safety and efficacy of panobinostat for the treatment of the disease. PMID:25469210

  20. Placebo controlled pilot trial to study the remyelinating potential of intravenous immunoglobulins in multiple sclerosis

    PubMed Central

    Stangel, M.; Boegner, F.; Klatt, C.; Hofmeister, C.; Seyfert, S.

    2000-01-01

    Currently there is no treatment available to improve a stable deficit in multiple sclerosis. It was shown in animal models that intravenous immunoglobulins (IVIg) can enhance central nervous remyelination, and the first open trials were promising. We therefore conducted a double blind, placebo controlled pilot study to evaluate the effect of IVIg treatment in patients with multiple sclerosis with a stable clinical deficit. The primary outcome parameter was the change in central motor conduction time as an indirect measure of central myelination. Secondary outcome parameters were neurological examinations including the expanded disability status scale (EDSS), neurological rating scale (NRS), and manual muscle testing (MMT). Ten patients were treated first with placebo and then with IVIg (0.4 g/kg body weight on 5 consecutive days), the two treatments being separated by an interval of 6 weeks. There was no difference in the central motor conduction times measured before and 6 weeks after each treatment. Clinically there was a small improvement after IVIg treatment, but there was no significant difference when compared with placebo. In conclusion, our data do not support a role for IVIg in the remyelination of stable multiple sclerosis lesions as measured by central conduction time. The importance of the small clinical benefit is currently not clear.?? PMID:10601410

  1. Osteogenic Differentiation Evaluation of an Engineered Extracellular Matrix Based Tissue Sheet for Potential Periosteum Replacement.

    PubMed

    Xing, Qi; Qian, Zichen; Kannan, Baratwaaj; Tahtinen, Mitchell; Zhao, Feng

    2015-10-21

    Due to the indispensable role of periosteum in bone defect healing and regeneration, a promising method to enhance osteogenesis of bone grafts by using an engineered biomimetic periosteum would be highly beneficial. The stromal microenvironment of periosteum is composed of various highly organized extracellular matrix (ECM) fibers, so an aligned natural ECM sheet, derived from the human dermal fibroblast cell sheet, may be advantageous when applied for artificial periosteum fabrication. Human mesenchymal stem cells (hMSCs) have been used to replace the osteoprogenitor cell population in native periosteum due to hMSCs' great osteogenic potential and fast in vitro expansion capacity. The objective of this work is to investigate if the natural ECM sheet and the substrate alignment can promote in vitro osteogenesis of hMSCs. The conventional cell culture substrates collagen I-coated polydimethylsiloxane (PDMS) and tissue culture plastic (TCP) were used as controls. It was found that the ECM sheet significantly increased alkaline phosphatase activity and calcium deposition. The enhanced osteogenic potential was further confirmed by increased bone-specific gene expression. The ECM sheet can bind significantly higher amounts of growth factors including ANG-1, TGF-?1, bFGF, and VEGF, as well as calcium phosphate nanoparticles, which contributed to high osteogenesis of the hMSCs on ECM sheet. However, the alignment of the substrates did not show significant influence on osteogenic activity and growth factor binding. These results demonstrated the great potential of hMSC-seeded ECM sheet as a biomimetic periosteum to improve critical sized bone regeneration. PMID:26419888

  2. The normal matrix model with a monomial potential, a vector equilibrium problem, and multiple orthogonal polynomials on a star

    NASA Astrophysics Data System (ADS)

    Kuijlaars, Arno B. J.; López-García, Abey

    2015-02-01

    We investigate the asymptotic behaviour of a family of multiple orthogonal polynomials that is naturally linked with the normal matrix model with a monomial potential of arbitrary degree d + 1. The polynomials that we investigate are multiple orthogonal with respect to a system of d analytic weights defined on a symmetric (d + 1)-star centred at the origin. In the first part we analyse in detail a vector equilibrium problem involving a system of d interacting measures (?1, …, ?d) supported on star-like sets in the plane. We show that in the subcritical regime, the first component ?1* of the solution to this problem is the asymptotic zero distribution of the multiple orthogonal polynomials. It also characterizes the domain where the eigenvalues in the normal matrix model accumulate, in the sense that the Schwarz function associated with the boundary of this domain can be expressed explicitly in terms of ?1* . The second part of the paper is devoted to the asymptotic analysis of the multiple orthogonal polynomials. The asymptotic results are obtained again in the subcritical regime, and they follow from the Deift/Zhou steepest descent analysis of a Riemann-Hilbert problem of size (d + 1) × (d + 1). The vector equilibrium problem and the Riemann-Hilbert problem that we investigate are generalizations of those studied recently by Bleher-Kuijlaars in the case d = 2.

  3. MiRNAs with Apoptosis Regulating Potential Are Differentially Expressed in Chronic Exercise-Induced Physiologically Hypertrophied Hearts

    PubMed Central

    Ramprasath, Tharmarajan; Kalpana, Krishnan

    2015-01-01

    Physiological cardiac hypertrophy is an adaptive mechanism, induced during chronic exercise. As it is reversible and not associated with cardiomyocyte death, it is considered as a natural tactic to prevent cardiac dysfunction and failure. Though, different studies revealed the importance of microRNAs (miRNAs) in pathological hypertrophy, their role during physiological hypertrophy is largely unexplored. Hence, this study is aimed at revealing the global expression profile of miRNAs during physiological cardiac hypertrophy. Chronic swimming protocol continuously for eight weeks resulted in induction of physiological hypertrophy in rats and histopathology revealed the absence of tissue damage, apoptosis or fibrosis. Subsequently, the total RNA was isolated and small RNA sequencing was executed. Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during physiological hypertrophy. The expression profile of the significantly differentially expressed miRNAs was validated by qPCR. In silico prediction of target genes by miRanda, miRdB and TargetScan and subsequent qPCR analysis unraveled that miRNAs including miR-99b, miR-100, miR-19b, miR-10, miR-208a, miR-133, miR-191a, miR-22, miR-30e and miR-181a are targeting the genes that primarily regulate cell proliferation and cell death. Gene ontology and pathway mapping showed that the differentially expressed miRNAs and their target genes were mapped to apoptosis and cell death pathways principally via PI3K/Akt/mTOR and MAPK signaling. In summary, our data indicates that regulation of these miRNAs with apoptosis regulating potential can be one of the major key factors in determining pathological or physiological hypertrophy by controlling fibrosis, apoptosis and cell death mechanisms. PMID:25793527

  4. The AP-1 transcription factor component Fosl2 potentiates the rate of myocardial differentiation from the zebrafish second heart field.

    PubMed

    Jahangiri, Leila; Sharpe, Michka; Novikov, Natasha; González-Rosa, Juan Manuel; Borikova, Asya; Nevis, Kathleen; Paffett-Lugassy, Noelle; Zhao, Long; Adams, Meghan; Guner-Ataman, Burcu; Burns, Caroline E; Burns, C Geoffrey

    2016-01-01

    The vertebrate heart forms through successive phases of cardiomyocyte differentiation. Initially, cardiomyocytes derived from first heart field (FHF) progenitors assemble the linear heart tube. Thereafter, second heart field (SHF) progenitors differentiate into cardiomyocytes that are accreted to the poles of the heart tube over a well-defined developmental window. Although heart tube elongation deficiencies lead to life-threatening congenital heart defects, the variables controlling the initiation, rate and duration of myocardial accretion remain obscure. Here, we demonstrate that the AP-1 transcription factor, Fos-like antigen 2 (Fosl2), potentiates the rate of myocardial accretion from the zebrafish SHF. fosl2 mutants initiate accretion appropriately, but cardiomyocyte production is sluggish, resulting in a ventricular deficit coupled with an accumulation of SHF progenitors. Surprisingly, mutant embryos eventually correct the myocardial deficit by extending the accretion window. Overexpression of Fosl2 also compromises production of SHF-derived ventricular cardiomyocytes, a phenotype that is consistent with precocious depletion of the progenitor pool. Our data implicate Fosl2 in promoting the progenitor to cardiomyocyte transition and uncover the existence of regulatory mechanisms to ensure appropriate SHF-mediated cardiomyocyte contribution irrespective of embryonic stage. PMID:26732840

  5. Embryonic Stem Cells Derived from In Vivo or In Vitro-Generated Murine Blastocysts Display Similar Transcriptome and Differentiation Potential

    PubMed Central

    Simbulan, Rhodel K.; Di Santo, Marlea; Liu, Xiaowei; Lin, Wingka; Donjacour, Annemarie; Maltepe, Emin; Shenoy, Archana; Borini, Andrea; Rinaudo, Paolo

    2015-01-01

    The use of assisted reproductive technologies (ART) such as in vitro fertilization (IVF) has resulted in the birth of more than 5 million children. While children conceived by these technologies are generally healthy, there is conflicting evidence suggesting an increase in adult-onset complications like glucose intolerance and high blood pressure in IVF children. Animal models indicate similar potential risks. It remains unclear what molecular mechanisms may be operating during in vitro culture to predispose the embryo to these diseases. One of the limitations faced by investigators is the paucity of the material in the preimplantation embryo to test for molecular analysis. To address this problem, we generated mouse embryonic stem cells (mESC) from blastocysts conceived after natural mating (mESCFB) or after IVF, using optimal (KSOM + 5% O2; mESCKAA) and suboptimal (Whitten’s Medium, + 20% O2, mESCWM) conditions. All three groups of embryos showed similar behavior during both derivation and differentiation into their respective mESC lines. Unsupervised hierarchical clustering of microarray data showed that blastocyst culture does not affect the transcriptome of derived mESCs. Transcriptomic changes previously observed in the inner cell mass (ICM) of embryos derived in the same conditions were not present in mESCs, regardless of method of conception or culture medium, suggesting that mESC do not fully maintain a memory of the events occurring prior to their derivation. We conclude that the fertilization method or culture media used to generate blastocysts does not affect differentiation potential, morphology and transcriptome of mESCs. PMID:25723476

  6. Embryonic stem cells derived from in vivo or in vitro-generated murine blastocysts display similar transcriptome and differentiation potential.

    PubMed

    Simbulan, Rhodel K; Di Santo, Marlea; Liu, Xiaowei; Lin, Wingka; Donjacour, Annemarie; Maltepe, Emin; Shenoy, Archana; Borini, Andrea; Rinaudo, Paolo

    2015-01-01

    The use of assisted reproductive technologies (ART) such as in vitro fertilization (IVF) has resulted in the birth of more than 5 million children. While children conceived by these technologies are generally healthy, there is conflicting evidence suggesting an increase in adult-onset complications like glucose intolerance and high blood pressure in IVF children. Animal models indicate similar potential risks. It remains unclear what molecular mechanisms may be operating during in vitro culture to predispose the embryo to these diseases. One of the limitations faced by investigators is the paucity of the material in the preimplantation embryo to test for molecular analysis. To address this problem, we generated mouse embryonic stem cells (mESC) from blastocysts conceived after natural mating (mESCFB) or after IVF, using optimal (KSOM + 5% O2; mESCKAA) and suboptimal (Whitten's Medium, + 20% O2, mESCWM) conditions. All three groups of embryos showed similar behavior during both derivation and differentiation into their respective mESC lines. Unsupervised hierarchical clustering of microarray data showed that blastocyst culture does not affect the transcriptome of derived mESCs. Transcriptomic changes previously observed in the inner cell mass (ICM) of embryos derived in the same conditions were not present in mESCs, regardless of method of conception or culture medium, suggesting that mESC do not fully maintain a memory of the events occurring prior to their derivation. We conclude that the fertilization method or culture media used to generate blastocysts does not affect differentiation potential, morphology and transcriptome of mESCs. PMID:25723476

  7. SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway.

    PubMed

    Wu, Ching-Shyi; Ouyang, Jian; Mori, Eiichiro; Nguyen, Hai Dang; Maréchal, Alexandre; Hallet, Alexander; Chen, David J; Zou, Lee

    2014-07-01

    The ATR (ATM [ataxia telangiectasia-mutated]- and Rad3-related) checkpoint is a crucial DNA damage signaling pathway. While the ATR pathway is known to transmit DNA damage signals through the ATR-Chk1 kinase cascade, whether post-translational modifications other than phosphorylation are important for this pathway remains largely unknown. Here, we show that protein SUMOylation plays a key role in the ATR pathway. ATRIP, the regulatory partner of ATR, is modified by SUMO2/3 at K234 and K289. An ATRIP mutant lacking the SUMOylation sites fails to localize to DNA damage and support ATR activation efficiently. Surprisingly, the ATRIP SUMOylation mutant is compromised in the interaction with a protein group, rather than a single protein, in the ATR pathway. Multiple ATRIP-interacting proteins, including ATR, RPA70, TopBP1, and the MRE11-RAD50-NBS1 complex, exhibit reduced binding to the ATRIP SUMOylation mutant in cells and display affinity for SUMO2 chains in vitro, suggesting that they bind not only ATRIP but also SUMO. Fusion of a SUMO2 chain to the ATRIP SUMOylation mutant enhances its interaction with the protein group and partially suppresses its localization and functional defects, revealing that ATRIP SUMOylation promotes ATR activation by providing a unique type of protein glue that boosts multiple protein interactions along the ATR pathway. PMID:24990965

  8. SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway

    PubMed Central

    Wu, Ching-Shyi; Ouyang, Jian; Mori, Eiichiro; Nguyen, Hai Dang; Maréchal, Alexandre; Hallet, Alexander; Chen, David J.; Zou, Lee

    2014-01-01

    The ATR (ATM [ataxia telangiectasia-mutated]- and Rad3-related) checkpoint is a crucial DNA damage signaling pathway. While the ATR pathway is known to transmit DNA damage signals through the ATR–Chk1 kinase cascade, whether post-translational modifications other than phosphorylation are important for this pathway remains largely unknown. Here, we show that protein SUMOylation plays a key role in the ATR pathway. ATRIP, the regulatory partner of ATR, is modified by SUMO2/3 at K234 and K289. An ATRIP mutant lacking the SUMOylation sites fails to localize to DNA damage and support ATR activation efficiently. Surprisingly, the ATRIP SUMOylation mutant is compromised in the interaction with a protein group, rather than a single protein, in the ATR pathway. Multiple ATRIP-interacting proteins, including ATR, RPA70, TopBP1, and the MRE11–RAD50–NBS1 complex, exhibit reduced binding to the ATRIP SUMOylation mutant in cells and display affinity for SUMO2 chains in vitro, suggesting that they bind not only ATRIP but also SUMO. Fusion of a SUMO2 chain to the ATRIP SUMOylation mutant enhances its interaction with the protein group and partially suppresses its localization and functional defects, revealing that ATRIP SUMOylation promotes ATR activation by providing a unique type of protein glue that boosts multiple protein interactions along the ATR pathway. PMID:24990965

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

    PubMed

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

    2015-11-01

    The biodiversity and biotechnological potential of microbes from central Argentinean halophilic environments have been poorly explored. Salitral Negro and Colorada Grande salterns are neutral hypersaline basins exploded for NaCl extraction. As part of an ecological analysis of these environments, two bacterial and seven archaeal representatives were isolated, identified and examined for their biotechnological potential. The presence of hydrolases (proteases, amylases, lipases, cellulases and nucleases) and bioactive molecules (surfactants and antimicrobial compounds) was screened. While all the isolates exhibited at least one of the tested activities or biocompounds, the species belonging to Haloarcula genus were the most active, also producing antimicrobial compounds against their counterparts. In general, the biosurfactants were more effective against olive oil and aromatic compounds than detergents (SDS or Triton X-100). Our results demonstrate the broad spectrum of activities with biotechnological potential exhibited by the microorganisms inhabiting the Argentinean salterns and reinforce the importance of screening pristine extreme environments to discover interesting/novel bioactive molecules. PMID:26369649

  10. Multiple liquid-liquid critical points and anomalies in core-softened potentials

    E-print Network

    Marco Aurélio A. Barbosa; Evy Salcedo; Marcia Barbosa

    2012-06-19

    The relation between liquid-liquid phase transitions and waterlike density anomalies in core-softened potentials of fluids was investigated in an exactly solvable one dimensional lattice model and a in a three dimensional fluid with fermi-like potential, the latter by molecular dynamics. Both systems were shown to present three liquid phases, two liquid-liquid phase transitions closely connected to two distinct regions of anomalous density increase. We propose that an oscillatory behavior observed on the thermal expansion coefficient as a function of pressure can be used as a signature of the connection between liquid-liquid phase and density.

  11. Differentially charged isoforms of apolipoprotein E from human blood are potential biomarkers of Alzheimer’s disease

    PubMed Central

    2014-01-01

    Introduction Alzheimer’s disease (AD) is the major cause of dementia among the elderly. Finding blood-based biomarkers for disease diagnosis and prognosis is urgently needed. Methods We studied protein distributions in brain tissues, cerebrospinal fluid (CSF), and blood of AD patients by using proteomics and a new proteomic method that we call “2D multiplexed Western blot” (2D mxWd). This method allows us to determine in multiple samples the electrophoretic patterns of protein isoforms with different isoelectric points. Results Apolipoprotein E (ApoE) displays a unique distribution of electrophoretic isoforms in the presence of AD and also a unique pattern specific to the APOE genotype. Conclusions The isoelectric distribution of differentially charged ApoE isoforms was used to determine the presence of AD in a small group of samples. Further studies are needed to validate their use as predictors of disease onset and progression, and as biomarkers for determining the efficacy of therapeutic treatments. PMID:25478016

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

    PubMed

    Sándor, Nikolett; Schilling-Tóth, Boglárka; Kis, Enik?; 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-? superfamily) in low and high dose radiation-induced cellular responses. A telomerase immortalized human fibroblast cell line (F11hT) was used in the experiments. A lentiviral system encoding small hairpin RNAs (shRNA) was used to establish GDF-15 silenced cells. Secreted GDF-15 levels were measured in culture medium by ELISA. Cell cycle analysis was performed by flow cytometry. The experiments demonstrated that in irradiated human fibroblasts GDF-15 expression increased with dose starting from 100mGy. Elevated GDF-15 expression was not detected in bystander cells. The potential role of GDF-15 in radiation response was investigated by silencing GDF-15 in immortalized human fibroblasts with five different shRNA encoded in lentiviral vectors. Cell lines with considerably reduced GDF-15 levels presented increased radiation sensitivity, while a cell line with elevated GDF-15 was more radiation resistant than wild type cells. We have investigated how the reduced GDF-15 levels alter the response of several known radiation inducible genes. In F11hT-shGDF-15 cells the basal expression level of CDKN1A was unaltered relative to F11hT cells, while GADD45A and TGF-?1 mRNA levels were slightly higher, and TP53INP1 was considerably reduced. The radiation-induced expression of TP53INP1 was lower in the silenced than in wild type fibroblast cells. Cell cycle analysis indicated that radiation-induced early G2/M arrest was abrogated in GDF-15 silenced cells. Moreover, radiation-induced bystander effect was less pronounced in GDF-15 silenced fibroblasts. In conclusion, the results suggest that GDF-15 works as a radiation inducible radiation resistance increasing factor in normal human fibroblast cells, acts by regulating the radiation-induced transcription of several genes and might serve as a radiation-induced early biomarker in exposed cells. PMID:26520384

  13. 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.

  14. 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.

  15. 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…

  16. Lipidome analysis in multiple sclerosis reveals protein lipoxidative damage as a potential pathogenic mechanism.

    PubMed

    Gonzalo, Hugo; Brieva, Luis; Tatzber, Franz; Jové, Mariona; Cacabelos, Daniel; Cassanyé, Anna; Lanau-Angulo, Lucia; Boada, Jordi; Serrano, José C E; González, Cristina; Hernández, Lourdes; Peralta, Sílvia; Pamplona, Reinald; Portero-Otin, Manuel

    2012-11-01

    Metabolomic and lipidomic analyses have been used for the profiling of neurodegenerative processes, both in targeted and untargeted approaches. In this work we have applied these techniques to the study of CSF samples of multiple sclerosis (MS) patients (n = 9), compared with samples of non-MS individuals (n = 9) using mass-spectrometry. We have used western-blot and analyzed cell culture to confirm pathogenic pathways suggested by mass-spectrometric measurements. The results of the untargeted approach of metabolomics and lipidomics suggest the existence of several metabolites and lipids discriminating both populations. Applying targeted lipidomic analyses focused to a pathogenic pathway in MS, oxidative stress, reveal that the lipid peroxidation marker 8-iso-prostaglandin F2? is increased in CSF from MS patients. Furthermore, as lipid peroxidation exerts its pathogenical effects through protein modification, we studied the incidence of protein lipoxidation, revealing specific increases in carboxymethylated, neuroketal and malondialdehyde-mediated protein modifications in proteins of CSF from MS patients, despite the absence of their precursors glyoxal and methylglyoxal. Finally, we report that the level of neuroketal-modified proteins correlated with a hitherto unknown increased amount of autoantibodies against lipid peroxidation-modified proteins in CSF, without compensation by signaling induced by lipid peroxidation via peroxisome proliferator-activated receptor ? (PPAR?). The results, despite the limitation of being obtained in a small population, strongly suggest that autoimmunity against in situ produced epitopes derived from lipid peroxidation can be a relevant pathogenic factor in MS. PMID:22924648

  17. Potential role of FLT3-ligand in the angiogenic process of multiple myeloma.

    PubMed

    Kokonozaki, M; Tsirakis, G; Devetzoglou, M; Kyriakaki, S; Antonakis, A; Vyzoukaki, R; Pappa, C A; Tzardi, M; Alexandrakis, M G

    2015-12-01

    The aim of the study was to evaluate serum levels of FLT3-ligand (FLT3-L), a soluble molecule in bone marrow (BM), participating actively in hematopoiesis, in relation with angiogenic factors in multiple myeloma (MM) patients. We measured, in 70 patients with active MM and in 38 of them who responded to conventional therapy, serum levels of FLT3-L, along with known angiogenic factors, such as VEGF, endoglin, TNF-alpha and HGF (with ELISA) and BM microvascular density (MVD), estimating the immunohistochemical expression of CD31. All pre-treatment values were higher in active MM patients compared to controls (p<0.001 for all cases), in parallel with both International Staging System and Durie-Salmon stages (p<0.001 for all cases). Moreover, levels of FLT3-L correlated positively with all soluble angiogenic factors, as well with MVD (p<0.0001 for all cases). Post-treatment values of FLT3-L decreased significantly in responders to therapy (p<0.001). The underlying relation of MM angiogenesis with FLT3-L may result from the fact that BM microvasculature is a major source of FLT3-L, both in BM niche and probably in peripheral blood. Our results suggest that serum levels of FLT3-L may be used as angiogenic marker in MM patients. PMID:26521986

  18. Knockdown of Human TCF4 Affects Multiple Signaling Pathways Involved in Cell Survival, Epithelial to Mesenchymal Transition and Neuronal Differentiation

    PubMed Central

    Forrest, Marc P.; Waite, Adrian J.; Martin-Rendon, Enca; Blake, Derek J.

    2013-01-01

    Haploinsufficiency of TCF4 causes Pitt-Hopkins syndrome (PTHS): a severe form of mental retardation with phenotypic similarities to Angelman, Mowat-Wilson and Rett syndromes. Genome-wide association studies have also found that common variants in TCF4 are associated with an increased risk of schizophrenia. Although TCF4 is transcription factor, little is known about TCF4-regulated processes in the brain. In this study we used genome-wide expression profiling to determine the effects of acute TCF4 knockdown on gene expression in SH-SY5Y neuroblastoma cells. We identified 1204 gene expression changes (494 upregulated, 710 downregulated) in TCF4 knockdown cells. Pathway and enrichment analysis on the differentially expressed genes in TCF4-knockdown cells identified an over-representation of genes involved in TGF-? signaling, epithelial to mesenchymal transition (EMT) and apoptosis. Among the most significantly differentially expressed genes were the EMT regulators, SNAI2 and DEC1 and the proneural genes, NEUROG2 and ASCL1. Altered expression of several mental retardation genes such as UBE3A (Angelman Syndrome), ZEB2 (Mowat-Wilson Syndrome) and MEF2C was also found in TCF4-depleted cells. These data suggest that TCF4 regulates a number of convergent signaling pathways involved in cell differentiation and survival in addition to a subset of clinically important mental retardation genes. PMID:24058414

  19. Differential metabolomic analysis of the potential antiproliferative mechanism of olive leaf extract on the JIMT-1 breast cancer cell line.

    PubMed

    Barrajón-Catalán, Enrique; Taamalli, Amani; Quirantes-Piné, Rosa; Roldan-Segura, Cristina; Arráez-Román, David; Segura-Carretero, Antonio; Micol, Vicente; Zarrouk, Mokhtar

    2015-02-01

    A new differential metabolomic approach has been developed to identify the phenolic cellular metabolites derived from breast cancer cells treated with a supercritical fluid extracted (SFE) olive leaf extract. The SFE extract was previously shown to have significant antiproliferative activity relative to several other olive leaf extracts examined in the same model. Upon SFE extract incubation of JIMT-1 human breast cancer cells, major metabolites were identified by using HPLC coupled to electrospray ionization quadrupole-time-of-flight mass spectrometry (ESI-Q-TOF-MS). After treatment, diosmetin was the most abundant intracellular metabolite, and it was accompanied by minor quantities of apigenin and luteolin. To identify the putative antiproliferative mechanism, the major metabolites and the complete extract were assayed for cell cycle, MAPK and PI3K proliferation pathways modulation. Incubation with only luteolin showed a significant effect in cell survival. Luteolin induced apoptosis, whereas the whole olive leaf extract incubation led to a significant cell cycle arrest at the G1 phase. The antiproliferative activity of both pure luteolin and olive leaf extract was mediated by the inactivation of the MAPK-proliferation pathway at the extracellular signal-related kinase (ERK1/2). However, the flavone concentration of the olive leaf extract did not fully explain the strong antiproliferative activity of the extract. Therefore, the effects of other compounds in the extract, probably at the membrane level, must be considered. The potential synergistic effects of the extract also deserve further attention. Our differential metabolomics approach identified the putative intracellular metabolites from a botanical extract that have antiproliferative effects, and this metabolomics approach can be expanded to other herbal extracts or pharmacological complex mixtures. PMID:25560707

  20. Immunomodulatory Effects of Four Leishmania infantum Potentially Excreted/Secreted Proteins on Human Dendritic Cells Differentiation and Maturation

    PubMed Central

    Markikou-Ouni, Wafa; Drini, Sima; Bahi-Jaber, Narges; Chenik, Mehdi; Meddeb-Garnaoui, Amel

    2015-01-01

    Leishmania parasites and some molecules they secrete are known to modulate innate immune responses through effects on dendritic cells (DCs) and macrophages. Here, we characterized four Leishmania infantum potentially excreted/secreted recombinant proteins (LipESP) identified in our laboratory: Elongation Factor 1 alpha (LiEF-1?), a proteasome regulatory ATPase (LiAAA-ATPase) and two novel proteins with unknown functions, which we termed LiP15 and LiP23, by investigating their effect on in vitro differentiation and maturation of human DCs and on cytokine production by DCs and monocytes. During DCs differentiation, LipESP led to a significant decrease in CD1a. LiP23 and LiEF-1?, induced a decrease of HLA-DR and an increase of CD86 surface expression, respectively. During maturation, an up-regulation of HLA-DR and CD80 was found in response to LiP15, LiP23 and LiAAA-ATPase, while an increase of CD40 expression was only observed in response to LiP15. All LipESP induced an over-expression of CD86 with significant differences between proteins. These proteins also induced significant IL-12p70 levels in immature DCs but not in monocytes. The LipESP-induced IL-12p70 production was significantly enhanced by a co-treatment with IFN-? in both cell populations. TNF-? and IL-10 were induced in DCs and monocytes with higher levels observed for LiP15 and LiAAA-ATPase. However, LPS-induced cytokine production during DC maturation or in monocyte cultures was significantly down regulated by LipESP co-treatment. Our findings suggest that LipESP strongly interfere with DCs differentiation suggesting a possible involvement in mechanisms established by the parasite for its survival. These proteins also induce DCs maturation by up-regulating several costimulatory molecules and by inducing the production of proinflammatory cytokines, which is a prerequisite for T cell activation. However, the reduced ability of LipESP-stimulated DCs and monocytes to respond to lipopolysaccharide (LPS) that can be observed during human leishmaniasis, suggests that under certain circumstances LipESP may play a role in disease progression. PMID:26581100

  1. Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy

    PubMed Central

    Pender, Michael P; Burrows, Scott R

    2014-01-01

    Multiple sclerosis (MS) is a common chronic inflammatory demyelinating disease of the central nervous system (CNS) causing progressive disability. Many observations implicate Epstein–Barr virus (EBV) in the pathogenesis of MS, namely universal EBV seropositivity, high anti-EBV antibody levels, alterations in EBV-specific CD8+ T-cell immunity, increased spontaneous EBV-induced transformation of peripheral blood B cells, increased shedding of EBV from saliva and accumulation of EBV-infected B cells and plasma cells in the brain. Several mechanisms have been postulated to explain the role of EBV in the development of MS including cross-reactivity between EBV and CNS antigens, bystander damage to the CNS by EBV-specific CD8+ T cells, activation of innate immunity by EBV-encoded small RNA molecules in the CNS, expression of ?B-crystallin in EBV-infected B cells leading to a CD4+ T-cell response against oligodendrocyte-derived ?B-crystallin and EBV infection of autoreactive B cells, which produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells in the CNS. The rapidly accumulating evidence for a pathogenic role of EBV in MS provides ground for optimism that it might be possible to prevent and cure MS by effectively controlling EBV infection through vaccination, antiviral drugs or treatment with EBV-specific cytotoxic CD8+ T cells. Adoptive immunotherapy with in vitro-expanded autologous EBV-specific CD8+ T cells directed against viral latent proteins was recently used to treat a patient with secondary progressive MS. Following the therapy, there was clinical improvement, decreased disease activity on magnetic resonance imaging and reduced intrathecal immunoglobulin production. PMID:25505955

  2. Potential role of multiple carbon fixation pathways during lipid accumulation in Phaeodactylum tricornutum

    PubMed Central

    2012-01-01

    Background Phaeodactylum tricornutum is a unicellular diatom in the class Bacillariophyceae. The full genome has been sequenced (<30?Mb), and approximately 20 to 30% triacylglyceride (TAG) accumulation on a dry cell basis has been reported under different growth conditions. To elucidate P. tricornutum gene expression profiles during nutrient-deprivation and lipid-accumulation, cell cultures were grown with a nitrate to phosphate ratio of 20:1 (N:P) and whole-genome transcripts were monitored over time via RNA-sequence determination. Results The specific Nile Red (NR) fluorescence (NR fluorescence per cell) increased over time; however, the increase in NR fluorescence was initiated before external nitrate was completely exhausted. Exogenous phosphate was depleted before nitrate, and these results indicated that the depletion of exogenous phosphate might be an early trigger for lipid accumulation that is magnified upon nitrate depletion. As expected, many of the genes associated with nitrate and phosphate utilization were up-expressed. The diatom-specific cyclins cyc7 and cyc10 were down-expressed during the nutrient-deplete state, and cyclin B1 was up-expressed during lipid-accumulation after growth cessation. While many of the genes associated with the C3 pathway for photosynthetic carbon reduction were not significantly altered, genes involved in a putative C4 pathway for photosynthetic carbon assimilation were up-expressed as the cells depleted nitrate, phosphate, and exogenous dissolved inorganic carbon (DIC) levels. P. tricornutum has multiple, putative carbonic anhydrases, but only two were significantly up-expressed (2-fold and 4-fold) at the last time point when exogenous DIC levels had increased after the cessation of growth. Alternative pathways that could utilize HCO3- were also suggested by the gene expression profiles (e.g., putative propionyl-CoA and methylmalonyl-CoA decarboxylases). Conclusions The results indicate that P. tricornutum continued carbon dioxide reduction when population growth was arrested and different carbon-concentrating mechanisms were used dependent upon exogenous DIC levels. Based upon overall low gene expression levels for fatty acid synthesis, the results also suggest that the build-up of precursors to the acetyl-CoA carboxylases may play a more significant role in TAG synthesis rather than the actual enzyme levels of acetyl-CoA carboxylases per se. The presented insights into the types and timing of cellular responses to inorganic carbon will help maximize photoautotrophic carbon flow to lipid accumulation. PMID:22672912

  3. Proteases Potentiate Fibrocyte Differentiation 

    E-print Network

    Galvis Carvajal, Elkin David

    2013-09-27

    . Thrombin plays a role in the formation of the fibrous matrix of blood clots; this is accomplished by converting fibrinogen to fibrin. Also, thrombin contributes to platelet formation by triggering shape changes in platelets and releasing platelet...=10), or (C) thrombin (n=7) for 5 days. Fibrocyte counts were normalized for each donor to the no-protease control. The no-protease controls developed 187 ± 22 fibrocytes per 10 5 PBMC. Values in A through C are mean ± SEM; the absence of error...

  4. Identification of differentially-expressed genes potentially implicated in drought response in pitaya (Hylocereus undatus) by suppression subtractive hybridization and cDNA microarray analysis.

    PubMed

    Fan, Qing-Jie; Yan, Feng-Xia; Qiao, Guang; Zhang, Bing-Xue; Wen, Xiao-Peng

    2014-01-01

    Drought is one of the most severe threats to the growth, development and yield of plant. In order to unravel the molecular basis underlying the high tolerance of pitaya (Hylocereus undatus) to drought stress, suppression subtractive hybridization (SSH) and cDNA microarray approaches were firstly combined to identify the potential important or novel genes involved in the plant responses to drought stress. The forward (drought over drought-free) and reverse (drought-free over drought) suppression subtractive cDNA libraries were constructed using in vitro shoots of cultivar 'Zihonglong' exposed to drought stress and drought-free (control). A total of 2112 clones, among which half were from either forward or reverse SSH library, were randomly picked up to construct a pitaya cDNA microarray. Microarray analysis was carried out to verify the expression fluctuations of this set of clones upon drought treatment compared with the controls. A total of 309 expressed sequence tags (ESTs), 153 from forward library and 156 from reverse library, were obtained, and 138 unique ESTs were identified after sequencing by clustering and blast analyses, which included genes that had been previously reported as responsive to water stress as well as some functionally unknown genes. Thirty six genes were mapped to 47 KEGG pathways, including carbohydrate metabolism, lipid metabolism, energy metabolism, nucleotide metabolism, and amino acid metabolism of pitaya. Expression analysis of the selected ESTs by reverse transcriptase polymerase chain reaction (RT-PCR) corroborated the results of differential screening. Moreover, time-course expression patterns of these selected ESTs further confirmed that they were closely responsive to drought treatment. Among the differentially expressed genes (DEGs), many are related to stress tolerances including drought tolerance. Thereby, the mechanism of drought tolerance of this pitaya genotype is a very complex physiological and biochemical process, in which multiple metabolism pathways and many genes were implicated. The data gained herein provide an insight into the mechanism underlying the drought stress tolerance of pitaya, as well as may facilitate the screening of candidate genes for drought tolerance. PMID:24076355

  5. Carboxyl-terminal domain of transient receptor potential vanilloid 1 contains distinct segments differentially involved in capsaicin- and heat-induced desensitization.

    PubMed

    Joseph, John; Wang, Sen; Lee, Jongseok; Ro, Jin Y; Chung, Man-Kyo

    2013-12-13

    Multiple Ca(2+)-dependent processes are involved in capsaicin-induced desensitization of transient receptor potential vanilloid 1 (TRPV1), but desensitization of TRPV1 by heat occurs even in the absence of extracellular Ca(2+), although the mechanisms are unknown. In this study, we tested the hypothesis that capsaicin and heat desensitize TRPV1 through distinct mechanisms involving distinct structural segments of TRPV1. In HEK293 cells that heterologously express TRPV1, we found that heat-induced desensitization was not affected by the inclusion of intracellular ATP or alanine mutation of Lys(155), both of which attenuate capsaicin-induced desensitization, suggesting that heat-induced desensitization occurs through mechanisms distinct from capsaicin-induced desensitization. To determine protein domains involved in heat-induced desensitization, we generated chimeric proteins between TRPV1 and TRPV3, a heat-gated channel lacking heat-induced desensitization. We found that TRPV1 with the carboxyl-terminal domain (CTD) of TRPV3 retained heat activation but was impaired in heat-induced desensitization. Further experiments using chimeric or deletion mutants within TRPV1 CTD indicated that the distal half of CTD regulates the activation and desensitization of TRPV1 in modality-specific manners. Within the distal CTD, we identified two segments that distinctly regulated capsaicin- and heat-induced desensitization. The results suggest that the activation and desensitization of TRPV1 by capsaicin and heat can be modulated differentially and disproportionally through different regions of TRPV1 CTD. Identifying the domains involved in thermal regulation of TRPV1 may facilitate the development of novel anti-hyperalgesic approaches aimed at attenuating activation and enhancing desensitization of TRPV1 by thermal stimuli. PMID:24174527

  6. Carboxyl-terminal Domain of Transient Receptor Potential Vanilloid 1 Contains Distinct Segments Differentially Involved in Capsaicin- and Heat-induced Desensitization*

    PubMed Central

    Joseph, John; Wang, Sen; Lee, Jongseok; Ro, Jin Y.; Chung, Man-Kyo

    2013-01-01

    Multiple Ca2+-dependent processes are involved in capsaicin-induced desensitization of transient receptor potential vanilloid 1 (TRPV1), but desensitization of TRPV1 by heat occurs even in the absence of extracellular Ca2+, although the mechanisms are unknown. In this study, we tested the hypothesis that capsaicin and heat desensitize TRPV1 through distinct mechanisms involving distinct structural segments of TRPV1. In HEK293 cells that heterologously express TRPV1, we found that heat-induced desensitization was not affected by the inclusion of intracellular ATP or alanine mutation of Lys155, both of which attenuate capsaicin-induced desensitization, suggesting that heat-induced desensitization occurs through mechanisms distinct from capsaicin-induced desensitization. To determine protein domains involved in heat-induced desensitization, we generated chimeric proteins between TRPV1 and TRPV3, a heat-gated channel lacking heat-induced desensitization. We found that TRPV1 with the carboxyl-terminal domain (CTD) of TRPV3 retained heat activation but was impaired in heat-induced desensitization. Further experiments using chimeric or deletion mutants within TRPV1 CTD indicated that the distal half of CTD regulates the activation and desensitization of TRPV1 in modality-specific manners. Within the distal CTD, we identified two segments that distinctly regulated capsaicin- and heat-induced desensitization. The results suggest that the activation and desensitization of TRPV1 by capsaicin and heat can be modulated differentially and disproportionally through different regions of TRPV1 CTD. Identifying the domains involved in thermal regulation of TRPV1 may facilitate the development of novel anti-hyperalgesic approaches aimed at attenuating activation and enhancing desensitization of TRPV1 by thermal stimuli. PMID:24174527

  7. Differential sensitivity of osteoblasts and bacterial pathogens to 405-nm light highlighting potential for decontamination applications in orthopedic surgery

    NASA Astrophysics Data System (ADS)

    Ramakrishnan, Praveen; Maclean, Michelle; MacGregor, Scott J.; Anderson, John G.; Grant, M. Helen

    2014-10-01

    Healthcare associated infections pose a major threat to patients admitted to hospitals and infection rates following orthopedic arthroplasty surgery are as high as 4%. A 405-nm high-intensity narrow spectrum light has been proven to reduce environmental contamination in hospital isolation rooms, and there is potential to develop this technology for application in arthroplasty surgery. Cultured rat osteoblasts were exposed to varying light intensities and it was found that exposures of up to a dose of 36 J/cm2 had no significant effect on cell viability [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay], function (alkaline phosphatase activity), and proliferation rate (BrdU cell proliferation assay). High irradiance exposures (54 J/cm2) significantly affected the cell viability indicating that the effects of 405-nm light on osteoblasts are dose dependent. Additionally, exposure of a variety of clinically related bacteria to a dose of 36 J/cm2 resulted in up to 100% kill. These results demonstrating the differential sensitivity of osteoblasts and bacteria to 405-nm light are an essential step toward developing the technique for decontamination in orthopedic surgery.

  8. Modeling the Potential Effects of New Tobacco Products and Policies: A Dynamic Population Model for Multiple Product Use and Harm

    PubMed Central

    Vugrin, Eric D.; Rostron, Brian L.; Verzi, Stephen J.; Brodsky, Nancy S.; Brown, Theresa J.; Choiniere, Conrad J.; Coleman, Blair N.; Paredes, Antonio; Apelberg, Benjamin J.

    2015-01-01

    Background Recent declines in US cigarette smoking prevalence have coincided with increases in use of other tobacco products. Multiple product tobacco models can help assess the population health impacts associated with use of a wide range of tobacco products. Methods and Findings We present a multi-state, dynamical systems population structure model that can be used to assess the effects of tobacco product use behaviors on population health. The model incorporates transition behaviors, such as initiation, cessation, switching, and dual use, related to the use of multiple products. The model tracks product use prevalence and mortality attributable to tobacco use for the overall population and by sex and age group. The model can also be used to estimate differences in these outcomes between scenarios by varying input parameter values. We demonstrate model capabilities by projecting future cigarette smoking prevalence and smoking-attributable mortality and then simulating the effects of introduction of a hypothetical new lower-risk tobacco product under a variety of assumptions about product use. Sensitivity analyses were conducted to examine the range of population impacts that could occur due to differences in input values for product use and risk. We demonstrate that potential benefits from cigarette smokers switching to the lower-risk product can be offset over time through increased initiation of this product. Model results show that population health benefits are particularly sensitive to product risks and initiation, switching, and dual use behaviors. Conclusion Our model incorporates the variety of tobacco use behaviors and risks that occur with multiple products. As such, it can evaluate the population health impacts associated with the introduction of new tobacco products or policies that may result in product switching or dual use. Further model development will include refinement of data inputs for non-cigarette tobacco products and inclusion of health outcomes such as morbidity and disability. PMID:25815840

  9. Modeling the Potential Effects of New Tobacco Products and Policies: A Dynamic Population Model for Multiple Product Use and Harm

    DOE PAGESBeta

    Vugrin, Eric D.; Rostron, Brian L.; Verzi, Stephen J.; Brodsky, Nancy S.; Brown, Theresa J.; Choiniere, Conrad J.; Coleman, Blair N.; Paredes, Antonio; Apelberg, Benjamin J.

    2015-03-27

    Background Recent declines in US cigarette smoking prevalence have coincided with increases in use of other tobacco products. Multiple product tobacco models can help assess the population health impacts associated with use of a wide range of tobacco products. Methods and Findings We present a multi-state, dynamical systems population structure model that can be used to assess the effects of tobacco product use behaviors on population health. The model incorporates transition behaviors, such as initiation, cessation, switching, and dual use, related to the use of multiple products. The model tracks product use prevalence and mortality attributable to tobacco use formore »the overall population and by sex and age group. The model can also be used to estimate differences in these outcomes between scenarios by varying input parameter values. We demonstrate model capabilities by projecting future cigarette smoking prevalence and smoking-attributable mortality and then simulating the effects of introduction of a hypothetical new lower-risk tobacco product under a variety of assumptions about product use. Sensitivity analyses were conducted to examine the range of population impacts that could occur due to differences in input values for product use and risk. We demonstrate that potential benefits from cigarette smokers switching to the lower-risk product can be offset over time through increased initiation of this product. Model results show that population health benefits are particularly sensitive to product risks and initiation, switching, and dual use behaviors. Conclusion Our model incorporates the variety of tobacco use behaviors and risks that occur with multiple products. As such, it can evaluate the population health impacts associated with the introduction of new tobacco products or policies that may result in product switching or dual use. Further model development will include refinement of data inputs for non-cigarette tobacco products and inclusion of health outcomes such as morbidity and disability.« less

  10. Modeling the Potential Effects of New Tobacco Products and Policies: A Dynamic Population Model for Multiple Product Use and Harm

    SciTech Connect

    Vugrin, Eric D.; Rostron, Brian L.; Verzi, Stephen J.; Brodsky, Nancy S.; Brown, Theresa J.; Choiniere, Conrad J.; Coleman, Blair N.; Paredes, Antonio; Apelberg, Benjamin J.

    2015-03-27

    Background Recent declines in US cigarette smoking prevalence have coincided with increases in use of other tobacco products. Multiple product tobacco models can help assess the population health impacts associated with use of a wide range of tobacco products. Methods and Findings We present a multi-state, dynamical systems population structure model that can be used to assess the effects of tobacco product use behaviors on population health. The model incorporates transition behaviors, such as initiation, cessation, switching, and dual use, related to the use of multiple products. The model tracks product use prevalence and mortality attributable to tobacco use for the overall population and by sex and age group. The model can also be used to estimate differences in these outcomes between scenarios by varying input parameter values. We demonstrate model capabilities by projecting future cigarette smoking prevalence and smoking-attributable mortality and then simulating the effects of introduction of a hypothetical new lower-risk tobacco product under a variety of assumptions about product use. Sensitivity analyses were conducted to examine the range of population impacts that could occur due to differences in input values for product use and risk. We demonstrate that potential benefits from cigarette smokers switching to the lower-risk product can be offset over time through increased initiation of this product. Model results show that population health benefits are particularly sensitive to product risks and initiation, switching, and dual use behaviors. Conclusion Our model incorporates the variety of tobacco use behaviors and risks that occur with multiple products. As such, it can evaluate the population health impacts associated with the introduction of new tobacco products or policies that may result in product switching or dual use. Further model development will include refinement of data inputs for non-cigarette tobacco products and inclusion of health outcomes such as morbidity and disability.

  11. 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 perform sample-to-answer testing with cell sample concentrations between SO to 400 cells. In addition, the commercial systems were evaluated for initial flight safety and readiness, sample concentration needs were reviewed, and a competitive procurement of commercially available platforms was initiated.

  12. Differentiation of Rubidiated Methyl-d-Glycoside Stereoisomers by Infrared Multiple-Photon Dissociation Spectroscopy in the O-H and C-H Stretching Regions.

    PubMed

    Pearson, Wright L; Contreras, Cesar; Powell, David; Berden, Giel; Oomens, Jos; Bendiak, Brad; Eyler, John R

    2015-10-15

    Four isomeric sugar methylglycosides (?- and ?-d-gluco- and galactopyranosides) were evaluated as rubidium cation coordination adducts in the gas phase using variable-wavelength multiple-photon dissociation in the range from 2750 to 3750 cm(-1). The adducts dissociated following photon absorption to yield neutral sugars and the rubidium cation, resulting in infrared "action" spectra. Well-resolved hydroxyl stretching bands clearly differentiate stereoisomers that vary solely in their asymmetry at single carbons. Density functional theory calculations of the lowest-energy gas-phase complexes indicate that rubidium coordinates with lone pairs of oxygen atoms as either bi- or tridentate complexes and that more than one positional coordination isomer could adequately account for most of the O-H stretch frequencies observed for each methylglycoside. PMID:26393375

  13. Determination of total Pu content in a Spent Fuel Assembly by Measuring Passive Neutron Count rate and Multiplication with the Differential Die-Away Instrument

    SciTech Connect

    Henzl, Vladimir; Croft, Stephen; Swinhoe, Martyn T.; Tobin, Stephen J.

    2012-07-18

    A key objective of the Next Generation Safeguards Initiative (NGSI) is to evaluate and develop non-destructive assay (NDA) techniques to determine the elemental plutonium content in a commercial-grade nuclear spent fuel assembly (SFA) [1]. Within this framework, we investigate by simulation a novel analytical approach based on combined information from passive measurement of the total neutron count rate of a SFA and its multiplication determined by the active interrogation using an instrument based on a Differential Die-Away technique (DDA). We use detailed MCNPX simulations across an extensive set of SFA characteristics to establish the approach and demonstrate its robustness. It is predicted that Pu content can be determined by the proposed method to a few %.

  14. Gas and Gas Hydrate Potential Offshore Amasra,Bartin and Zonguldak and Possible Agent for Multiple BSR Occurrence

    NASA Astrophysics Data System (ADS)

    Mert Küçük, Hilmi; Dondurur, Derman; Özel, Özkan; S?nayuç, Ça?lar; Merey, ?ükrü; Parlaktuna, Mahmut; Çifçi, Günay

    2015-04-01

    Gas hydrates, shallow gases and mud volcanoes have been studied intensively in the Black Sea in recent years. Researches have shown that the Black Sea region has an important potential about hydrocarbon. BSR reflections in the seismic sections and seabed sampling studies also have proven the formations of hydrates clearly. In this respect, total of 2400 km multichannel seismic reflection, chirp and multibeam bathymetry data were collected along shelf to abyssal plain in 2010 and 2012 offshore Amasra, Bart?n, Zonguldak-Kozlu in the central Black Sea.. Collected data represent BSRs, bright spots and transparent zones. It has been clearly observed that possible gas chimneys cross the base of gas hydrate stability zones as a result of possible weak zones in the gas hydrate bearing sediments. Seabed samples were collected closely to possible gas chimneys due to shallow gas anomalies in the data. Head space gas cromatography was applied to seabed samples to observe gas composition and the gas cromatography results represented hydrocarbon gases such as Methane, Ethane, Propane, i-Butane, n-Butane, i-Pentane, n-Pentane and Hexane. Thermogenic gas production by Turkish Petroleum Corp. from Akçakoca-1 and Ayazl?-1 well is just located at the southwest of the study area and the observations of the study area point out there is also thermogenic gas potential at the eastern side of the Akçakoca. In addition, multiple-BSRs were observed in the study area and it is thought the key point of the multiple-BSRs are different gas compositions. This suggests that hydrate formations can be formed by gas mixtures. Changing of the thermobaric conditions can trigger dissociation of the gas hydrates in the marine sediments due to sedimentary load and changing of the water temperature around seabed. Our gas hydrate modelling study suggest that gas hydrates are behaving while their dissociation process if the gas hydrates are generated by gas mixture. Monitoring of our gas hydrate modelling study based on depressurization at constant temperature have shown that some of the gases start to dissociate while the other gases are stable in the gas hydrate formation. This respective dissociation of the gases from gas hydrates suggest that each multiple-BSR can be related with hydrate formations including different gas composition.

  15. Urinary Metabolite Profiling Offers Potential for Differentiation of Liver-Kidney Yin Deficiency and Dampness-Heat Internal Smoldering Syndromes in Posthepatitis B Cirrhosis Patients

    PubMed Central

    Wang, Xiaoyan; Zhou, Mingmei; Yu, Huan; Lin, Yan; Du, Guangli; Luo, Guoan

    2015-01-01

    Zheng is the basic theory and essence of traditional Chinese medicine (TCM) in diagnosing diseases. However, there are no biological evidences to support TCM Zheng differentiation. In this study we elucidated the biological alteration of cirrhosis with TCM “Liver-Kidney Yin Deficiency (YX)” or “Dampness-Heat Internal Smoldering (SR)” Zheng and the potential of urine metabonomics in TCM Zheng differentiation. Differential metabolites contributing to the intergroup variation between healthy controls and liver cirrhosis patients were investigated, respectively, and mainly participated in energy metabolism, gut microbiota metabolism, oxidative stress, and bile acid metabolism. Three metabolites, aconitate, citrate, and 2-pentendioate, altered significantly in YX Zheng only, representing the abnormal energy metabolism. Contrarily, hippurate and 4-pyridinecarboxylate altered significantly in SR Zheng only, representing the abnormalities of gut microbiota metabolism. Moreover, there were significant differences between two TCM Zhengs in three metabolites, glycoursodeoxycholate, cortolone-3-glucuronide, and L-aspartyl-4-phosphate, among all differential metabolites. Metabonomic profiling, as a powerful approach, provides support to the understanding of biological mechanisms of TCM Zheng stratification. The altered urinary metabolites constitute a panel of reliable biological evidence for TCM Zheng differentiation in patients with posthepatitis B cirrhosis and may be used for the potential biomarkers of TCM Zheng stratification. PMID:25667596

  16. The Potential of Gait Analysis to Contribute to Differential Diagnosis of Early Stage Dementia: Current Research and Future Directions

    ERIC Educational Resources Information Center

    Morgan, Debra; Funk, Melanie; Crossley, Margaret; Basran, Jenny; Kirk, Andrew; Bello-Haas, Vanina Dal

    2007-01-01

    Early differential diagnosis of dementia is becoming increasingly important as new pharmacologic therapies are developed, as these treatments are not equally effective for all types of dementia. Early detection and differential diagnosis also facilitates informed family decision making and timely access to appropriate services. Information about…

  17. Seed dimorphism, nutrients and salinity differentially affect seed traits of the desert halophyte Suaeda aralocaspica via multiple maternal effects

    PubMed Central

    2012-01-01

    Background Maternal effects may influence a range of seed traits simultaneously and are likely to be context-dependent. Disentangling the interactions of plant phenotype and growth environment on various seed traits is important for understanding regeneration and establishment of species in natural environments. Here, we used the seed-dimorphic plant Suaeda aralocaspica to test the hypothesis that seed traits are regulated by multiple maternal effects. Results Plants grown from brown seeds had a higher brown:black seed ratio than plants from black seeds, and germination percentage of brown seeds was higher than that of black seeds under all conditions tested. However, the coefficient of variation (CV) for size of black seeds was higher than that of brown seeds. Seeds had the smallest CV at low nutrient and high salinity for plants from brown seeds and at low nutrient and low salinity for plants from black seeds. Low levels of nutrients increased size and germinability of black seeds but did not change the seed morph ratio or size and germinability of brown seeds. High levels of salinity decreased seed size but did not change the seed morph ratio. Seeds from high-salinity maternal plants had a higher germination percentage regardless of level of germination salinity. Conclusions Our study supports the multiple maternal effects hypothesis. Seed dimorphism, nutrient and salinity interacted in determining a range of seed traits of S. aralocaspica via bet-hedging and anticipatory maternal effects. This study highlights the importance of examining different maternal factors and various offspring traits in studies that estimate maternal effects on regeneration. PMID:23006315

  18. Using Multiple Approaches, including ?18O Signatures of Phosphate to Investigate Potential Phosphorus Limitation and Cycling under Changing Climate Conditions

    NASA Astrophysics Data System (ADS)

    Roberts, K.; Paytan, A.; Field, C. B.; Honn, E.; Edwards, E.; Gottlieb, R.

    2012-12-01

    Phosphorus (P) is often a limiting or co-limiting nutrient in terrestrial systems. It has been proposed that it will play an even greater role in ecosystems experiencing some of the many predicted effects of climate change, in particular release from nitrogen limitation. Recent work in 2007 by Menge et al. suggests that this is indeed a possibility. To investigate the potential for P limitation, and P cycling under multiple controlled conditions we collected samples from the Jasper Ridge Global Change Experiment (JRGCE) in May 2011. For over a decade the JRGCE has been manipulating four key parameters predicted to change in the future in a native Californian grassland system. Elevated Nitrogen deposition, increased precipitation, increased pCO2, and increased temperature are applied and monitored in a split plot design at the Jasper Ridge Biological Preserve in the eastern foothills of the Santa Cruz Mountains, California. Work done previously at the site using a suite of indicators of the potential P limitation suggest P limitation in some of the manipulated plots in the JRGCE. In this study we replicate a subset of the prior analyses to compare inter-annual signals of P limitation, and further attempt to utilize the oxygen isotopes of phosphate to investigate P cycling in soils at JRGCE. A fractional soil extraction process for phosphate enables separation of several operationally defined P pools, and provides auxiliary information regarding the relative concentrations of bio-available P, and relevant minerals in this grassland system under the varied conditions.

  19. Lake hydrogeophysics; Estimating areas of potential groundwater seepage using reflection seismic, ground penetrating radar and multiple electrode profiling

    NASA Astrophysics Data System (ADS)

    Looms, M. C.; Boldreel, L. O.; Kidmose, J.; Engesgaard, P.; Rasmussen, R.; Nilsson, B.

    2008-12-01

    Lake Hampen, a groundwater seepage lake located on sandy deposits, is one of the cleanest lakes in Denmark. The lake is mainly surrounded by areas with forestry. A small agricultural area has been shown to potentially discharge high concentrations of nitrate to the lake. In order to minimize future nutrient loading to Lake Hampen it is essential that the water balance components and the areas of groundwater in- and outflow are estimated correctly. Groundwater/lake water interaction estimated using seepage meters, hydraulic gradients, and stable isotope measurements give reliable point estimates of groundwater in- and out flow rates. These rates are affected by the heterogeneity in the geological sediments beneath the lake and the lake bed properties. In order to construct a hydrological model covering the entire lake, having an approx. surface area of 760.000 m2, an improved spatial coverage of the geology beneath the lake is necessary. In this study three geophysical techniques; reflection seismic, ground penetrating radar and multiple electrode profiling, are used to map the sediment types and thicknesses at the lake bottom. Areas with thick layers of gyttja or peat are expected to reduce groundwater seepage, while a sandy lake bottom will enable high rates of in- and outflow. The geophysical measurements thereby help identifying areas of potential groundwater seepage that later can be verified using more traditional point measurements.

  20. A composite enhancer regulates p63 gene expression in epidermal morphogenesis and in keratinocyte differentiation by multiple mechanisms

    PubMed Central

    Antonini, Dario; Sirico, Anna; Aberdam, Edith; Ambrosio, Raffaele; Campanile, Carmen; Fagoonee, Sharmila; Altruda, Fiorella; Aberdam, Daniel; Brissette, Janice L.; Missero, Caterina

    2015-01-01

    p63 is a crucial regulator of epidermal development, but its transcriptional control has remained elusive. Here, we report the identification of a long-range enhancer (p63LRE) that is composed of two evolutionary conserved modules (C38 and C40), acting in concert to control tissue- and layer-specific expression of the p63 gene. Both modules are in an open and active chromatin state in human and mouse keratinocytes and in embryonic epidermis, and are strongly bound by p63. p63LRE activity is dependent on p63 expression in embryonic skin, and also in the commitment of human induced pluripotent stem cells toward an epithelial cell fate. A search for other transcription factors involved in p63LRE regulation revealed that the CAAT enhancer binding proteins Cebpa and Cebpb and the POU domain-containing protein Pou3f1 repress p63 expression during keratinocyte differentiation by binding the p63LRE enhancer. Collectively, our data indicate that p63LRE is composed of additive and partly redundant enhancer modules that act to direct robust p63 expression selectively in the basal layer of the epidermis. PMID:25567987

  1. NDR1 interaction with RIN4 mediates the differential activation of multiple disease resistance pathways in Arabidopsis.

    PubMed

    Day, Brad; Dahlbeck, Douglas; Staskawicz, Brian J

    2006-10-01

    Recognition of pathogens by plants involves the coordinated efforts of molecular chaperones, disease resistance (R) proteins, and components of disease resistance signaling pathways. Characterization of events associated with pathogen perception in Arabidopsis thaliana has advanced understanding of molecular genetic mechanisms associated with disease resistance and protein interactions critical for the activation of resistance signaling. Regulation of R protein-mediated signaling in response to the bacterial pathogen Pseudomonas syringae in Arabidopsis involves the physical association of at least two R proteins with the negative regulator RPM1 INTERACTING PROTEIN4 (RIN4). While the RIN4-RPS2 (for RESISTANCE TO P. SYRINGAE2) and RIN4-RPM1 (for RESISTANCE TO P. SYRINGAE PV MACULICOLA1) signaling pathways exhibit differential mechanisms of activation in terms of effector action, the requirement for NON-RACE-SPECIFIC DISEASE RESISTANCE1 (NDR1) is shared. Using a yeast two-hybrid screen, followed by a series of coimmunoprecipitation experiments, we demonstrate that the RIN4-NDR1 interaction occurs on the cytoplasmically localized N-terminal portion of NDR1 and that this interaction is required for the activation of resistance signaling following infection by P. syringae expressing the Cys protease Type III effector protein AvrRpt2. We demonstrate that like RPS2 and RPM1, NDR1 also associates with RIN4 in planta. We suggest that this interaction serves to further regulate activation of disease resistance signaling following recognition of P. syringae DC3000-AvrRpt2 by Arabidopsis. PMID:17012600

  2. Differential Potential of Pharmacological PARP Inhibitors for Inhibiting Cell Proliferation and Inducing Apoptosis in Human Breast Cancer Cells.

    PubMed

    W?sierska-G?dek, Józefa; Mauritz, Matthias; Mitulovic, Goran; Cupo, Maria

    2015-12-01

    BRCA1/2-mutant cells are hypersensitive to inactivation of poly(ADP-ribose) polymerase 1 (PARP-1). We recently showed that inhibition of PARP-1 by NU1025 is strongly cytotoxic for BRCA1-positive BT-20 cells, but not BRCA1-deficient SKBr-3 cells. These results raised the possibility that other PARP-1 inhibitors, particularly those tested in clinical trials, may be more efficacious against BRCA1-deficient SKBr-3 breast cancer cells than NU1025. Thus, in the presented study the cytotoxicity of four PARP inhibitors under clinical evaluation (olaparib, rucaparib, iniparib and AZD2461) was examined and compared to that of NU1025. The sensitivity of breast cancer cells to the PARP-1 inhibition strongly varied. Remarkably, BRCA-1-deficient SKBr-3 cells were almost completely insensitive to NU1025, olaparib and rucaparib, whereas BRCA1-expressing BT-20 cells were strongly affected by NU1025 even at low doses. In contrast, iniparib and AZD2461 were cytotoxic for both BT-20 and SKBr-3 cells. Of the four tested PARP-1 inhibitors only AZD2461 strongly affected cell cycle progression. Interestingly, the anti-proliferative and pro-apoptotic potential of the tested PARP-1 inhibitors clearly correlated with their capacity to damage DNA. Further analyses revealed that proteomic signatures of the two studied breast cancer cell lines strongly differ, and a set of 197 proteins was differentially expressed in NU1025-treated BT-20 cancer cells. These results indicate that BT-20 cells may harbor an unknown defect in DNA repair pathway(s) rendering them sensitive to PARP-1 inhibition. They also imply that therapeutic applicability of PARP-1 inhibitors is not limited to BRCA mutation carriers but can be extended to patients harboring deficiencies in other components of the pathway(s). J. Cell. Biochem. 116: 2824-2839, 2015. © 2015 Wiley Periodicals, Inc. PMID:25981734

  3. Inflammatory MAPK and NF-?B signaling pathways differentiated hepatitis potential of two agglomerated titanium dioxide particles.

    PubMed

    Chen, Jin; Zhang, Jianying; Cao, Junmei; Xia, Zongping; Gan, Jay

    2016-03-01

    TiO2 nanoparticles (TiO2NPs) consumption and deposit in liver have possible implications for hepatitis risks. Specific signal dysregulation at early inflammatory responses needs to be characterized in TiO2NP-induced hepatopathy. MAPK and NF-?B signaling pathways are known to participate in inflammation and respond sensitively to chemical agents, making them preferable biomarkers for hepatitis. In the present study, dynamic activation of MAPK and NF-?B pathways were explored by immunoblotting and NF-?B luciferase reporter assay depending on characterization of TiO2NP agglomeration in human HepG2 cells. Inflammatory and cytotoxic potential of TiO2NPs were determined by qRT-PCR and WST-1 assay. AFM and TEM analyses uncovered ultrastructure damages underlying hepatotoxicity of TiO2NPs. Rod-like rutile agglomerated smaller and induced more pronounced cytotoxicity and immunogenicity than anatase. Correspondingly, though both rutile and anatase significantly activated p38, ERK1/2 and NF-?B pathways, rutile accelerated the maximum phosphorylation of ERK1/2 and elevated the potency of I?B? phosphorylation to its bell curve shape in comparison with a lower and sigmoid type of I?B? phosphorylation for anatase. Furthermore, cell elasticity indicated by Young's modulus and adhesion force increased accompanied with mitochondria damage, contributing to signal dysregulation and hepatotoxicity. The results suggested that differential activation of MAPK and NF-?B pathways could be early predictors for distinct hepatitis risks of two agglomerated TiO2NPs. PMID:26590873

  4. Differential Effects of Acute Alcohol on Prepulse Inhibition and Event-Related Potentials in Adolescent and Adult Wistar Rats

    PubMed Central

    Pian, Jerry P.; Criado, Jose R.; Ehlers, Cindy L.

    2009-01-01

    Background Previous studies have demonstrated that adolescent and adult rats show differential sensitivity to many of the acute effects of alcohol. We recently reported evidence of developmental differences in the effects of acute alcohol on the cortical electroencephalogram (EEG). However, it is unclear whether developmental differences are also observed in other neurophysiological and neurobehavioral measurements known to be sensitive to alcohol exposure. The present study determined the age-related effects of acute alcohol on behavioral and event-related potential (ERP) responses to acoustic startle (AS) and prepulse inhibition (PPI). Methods Male adolescent and adult Wistar rats were implanted with cortical recording electrodes. The effects of acute alcohol (0.0, 0.75, and 1.5 g/kg) on behavioral and ERP responses to AS and PPI were assessed. Results Acute alcohol (0.75 and 1.5 g/kg) significantly reduced the behavioral and electrophysiological response to AS in adolescent and adult rats. Both 0.75 and 1.5 g/kg alcohol significantly enhanced the behavioral response to PPI in adolescent, but not in adult rats. During prepulse+pulse trials, 1.5 g/kg alcohol significantly increased the N10 pulse response in the adolescent frontal cortex. Acute alcohol (0.75 and 1.5 g/kg) also increased the N1 ERP pulse response to prepulse stimuli in frontal and parietal cortices in adult rats, but not in adolescent rats. Conclusions These data suggest that alcohol’s effect on behavioral and electrophysiological indices of AS do not differ between adults and adolescents whereas developmental stage does appear to significantly modify alcohol influenced response to PPI. PMID:18828807

  5. Poly(Epsilon-lysine) dendrons tethered with phosphoserine increase mesenchymal stem cell differentiation potential of calcium phosphate gels.

    PubMed

    Raucci, Maria Grazia; Alvarez-Perez, Marco Antonio; Meikle, Steven; Ambrosio, Luigi; Santin, Matteo

    2014-02-01

    Calcium phosphates (CaP) are considered as biomaterials of choice for the treatment of critical-sized bone defects. Novel injectable CaP materials integrating poly(epsilon-lysine) generation 3 dendrons tethered with phosphoserine were obtained by sol-gel synthesis. This type of dendron was integrated to mimic the biochemical structure of noncollagenous proteins present in the forming osteoids during bone repair. Sol-gel synthesis was coupled with a dialysis process able to equilibrate the materials at a physiological pH value. Fourier transform infrared spectroscopy (FTIR) showed the successful retention of the dendrons after gel dialysis, whereas X-ray diffraction analysis demonstrated both the pH-tuned formation of a hydroxyapatite crystalline phase within the gel and the complete removal of ammonium nitrate deriving from the sol-gel reaction solvent. Scanning electron microscopy images confirmed the presence of crystalline domains in gels synthesized at pH 9.0. Injectability tests showed that the optimized formulations fulfilled the rheological properties required to minimally invasive surgical procedures. Cytotoxicity tests on osteoblast-like MG-63 cells as well as morphology and viability studies showed that the dendrons induced a significantly higher level of cell proliferation at early incubation time. Differentiation of the cell was also clearly enhanced at longer incubation time as demonstrated by both alkaline phosphatase activity and expression of typical markers. Altogether, the data from this work indicate the clinical potential of the osteoid-mimicking CaP cements in minimally invasive bone surgery. PMID:24229073

  6. Positive impact of IGF-1-coupled nanoparticles on the differentiation potential of human chondrocytes cultured on collagen scaffolds

    PubMed Central

    Pasold, Juliane; Zander, Kathleen; Heskamp, Benjamin; Grüttner, Cordula; Lüthen, Frank; Tischer, Thomas; Jonitz-Heincke, Anika; Bader, Rainer

    2015-01-01

    Purpose In the present study, silica nanoparticles (sNP) coupled with insulin-like growth factor 1 (IGF-1) were loaded on a collagen-based scaffold intended for cartilage repair, and the influence on the viability, proliferation, and differentiation potential of human primary articular chondrocytes was examined. Methods Human chondrocytes were isolated from the hyaline cartilage of patients (n=4, female, mean age: 73±5.1 years) undergoing primary total knee joint replacement. Cells were dedifferentiated and then cultivated on a bioresorbable collagen matrix supplemented with fluorescent sNP coupled with IGF-1 (sNP–IGF-1). After 3, 7, and 14 days of cultivation, cell viability and integrity into the collagen scaffold as well as metabolic cell activity and synthesis rate of matrix proteins (collagen type I and II) were analyzed. Results The number of vital cells increased over 14 days of cultivation, and the cells were able to infiltrate the collagen matrix (up to 120 ?m by day 7). Chondrocytes cultured on the collagen scaffold supplemented with sNP–IGF-1 showed an increase in metabolic activity (5.98-fold), and reduced collagen type I (1.58-fold), but significantly increased collagen type II expression levels (1.53-fold; P=0.02) after 7 days of cultivation compared to 3 days. In contrast, chondrocytes grown in a monolayer on plastic supplemented with sNP-IGF-1 had significantly lower metabolic activity (1.32-fold; P=0.007), a consistent amount of collagen type I, and significantly reduced collagen type II protein expression (1.86-fold; P=0.001) after 7 days compared to 3 days. Conclusion Collagen-based scaffolds enriched with growth factors, such as IGF-1 coupled to nanoparticles, represent an improved therapeutic intervention for the targeted and controlled treatment of articular cartilage lesions. PMID:25709437

  7. Differential Entrainment and Learning-Related Dynamics of Spike and Local Field Potential Activity in the Sensorimotor and Associative Striatum

    PubMed Central

    Thorn, Catherine A.

    2014-01-01

    Parallel cortico-basal ganglia loops are thought to have distinct but interacting functions in motor learning and habit formation. In rats, the striatal projection neuron populations (MSNs) in the dorsolateral and dorsomedial striatum, respectively corresponding to sensorimotor and associative regions of the striatum, exhibit contrasting dynamics as rats acquire T-maze tasks (Thorn et al., 2010). Here, we asked whether these patterns could be related to the activity of local interneuron populations in the striatum and to the local field potential activity recorded simultaneously in the corresponding regions. We found that dorsolateral and dorsomedial striatal fast-spiking interneurons exhibited task-specific and training-related dynamics consistent with those of corresponding MSN populations. Moreover, both MSNs and interneuron populations in both regions became entrained to theta-band (5–12 Hz) frequencies during task acquisition. However, the predominant entrainment frequencies were different for the sensorimotor and associative zones. Dorsolateral striatal neurons became entrained mid-task to oscillations centered ?5 Hz, whereas simultaneously recorded neurons in the dorsomedial region became entrained to higher frequency (?10 Hz) rhythms. These region-specific patterns of entrainment evolved dynamically with the development of region-specific patterns of interneuron and MSN activity, indicating that, with learning, these two striatal regions can develop different frequency-modulated circuit activities in parallel. We suggest that such differential entrainment of sensorimotor and associative neuronal populations, acquired through learning, could be critical for coordinating information flow throughout each trans-striatal network while simultaneously enabling nearby components of the separate networks to operate independently. PMID:24553926

  8. Differential entrainment and learning-related dynamics of spike and local field potential activity in the sensorimotor and associative striatum.

    PubMed

    Thorn, Catherine A; Graybiel, Ann M

    2014-02-19

    Parallel cortico-basal ganglia loops are thought to have distinct but interacting functions in motor learning and habit formation. In rats, the striatal projection neuron populations (MSNs) in the dorsolateral and dorsomedial striatum, respectively corresponding to sensorimotor and associative regions of the striatum, exhibit contrasting dynamics as rats acquire T-maze tasks (Thorn et al., 2010). Here, we asked whether these patterns could be related to the activity of local interneuron populations in the striatum and to the local field potential activity recorded simultaneously in the corresponding regions. We found that dorsolateral and dorsomedial striatal fast-spiking interneurons exhibited task-specific and training-related dynamics consistent with those of corresponding MSN populations. Moreover, both MSNs and interneuron populations in both regions became entrained to theta-band (5-12 Hz) frequencies during task acquisition. However, the predominant entrainment frequencies were different for the sensorimotor and associative zones. Dorsolateral striatal neurons became entrained mid-task to oscillations centered ? 5 Hz, whereas simultaneously recorded neurons in the dorsomedial region became entrained to higher frequency (? 10 Hz) rhythms. These region-specific patterns of entrainment evolved dynamically with the development of region-specific patterns of interneuron and MSN activity, indicating that, with learning, these two striatal regions can develop different frequency-modulated circuit activities in parallel. We suggest that such differential entrainment of sensorimotor and associative neuronal populations, acquired through learning, could be critical for coordinating information flow throughout each trans-striatal network while simultaneously enabling nearby components of the separate networks to operate independently. PMID:24553926

  9. Role of PI3K, MAPK/ERK1/2, and p38 in implementation of the proliferative and differentiation potential of erythroid progenitors after blood loss.

    PubMed

    Dygai, A M; Zhdanov, V V; Miroshnichenko, L A; Udut, E V; Zyuz'kov, G N; Simanina, E V; Sherstoboev, E Yu; Chaikovskii, A V; Stavrova, L A; Burmina, Ya V; Khrichkova, T Yu; Reichart, D V; Goldberg, V E

    2015-02-01

    The involvement of PI3K, ERK and p38-dependent signaling system in the regulation of functional activity of erythroid precursors after blood loss (30% of circulating volume) was studied. We demonstrated the important role of PI3K and p38 in the suppression of differentiation of erythroid precursors the contribution of p38 to stimulation of mitotic activity of erythroid CFU, which maintains the growth potential of the precursors at the optimal physiological level. The classical MAPK/ERK-kinase pathway does not determine the proliferative and differentiation status of erythroid CFU. PMID:25711660

  10. Functional connectivity indicates differential roles for the intraparietal sulcus and the superior parietal lobule in multiple object tracking.

    PubMed

    Alnćs, Dag; Sneve, Markus H; Richard, Genevičve; Skĺtun, Kristina C; Kaufmann, Tobias; Nordvik, Jan Egil; Andreassen, Ole A; Endestad, Tor; Laeng, Bruno; Westlye, Lars T

    2015-12-01

    Attentive tracking requires sustained object-based attention, rather than passive vigilance or rapid attentional shifts to brief events. Several theories of tracking suggest a mechanism of indexing objects that allows for attentional resources to be directed toward the moving targets. Imaging studies have shown that cortical areas belonging to the dorsal frontoparietal attention network increase BOLD-signal during multiple object tracking (MOT). Among these areas, some studies have assigned IPS a particular role in object indexing, but the neuroimaging evidence has been sparse. In the present study, we tested participants on a continuous version of the MOT task in order to investigate how cortical areas engage in functional networks during attentional tracking. Specifically, we analyzed the data using eigenvector centrality mapping (ECM) analysis, which provides estimates of individual voxels' connectedness with hub-like parts of the functional network. The results obtained using permutation based voxel-wise statistics support the proposed role for the IPS in object indexing as this region displayed increased centrality during tracking as well as increased functional connectivity with both prefrontal and visual perceptual cortices. In contrast, the opposite pattern was observed for the SPL, with decreasing centrality, as well as reduced functional connectivity with the visual and frontal cortices, in agreement with a hypothesized role for SPL in attentional shifts. These findings provide novel evidence that IPS and SPL serve different functional roles during MOT, while at the same time being highly engaged during tracking as measured by BOLD-signal changes. PMID:26299796

  11. Monoclonal antibody therapies for the treatment of relapsing-remitting multiple sclerosis: differentiating mechanisms and clinical outcomes.

    PubMed

    Lycke, Jan

    2015-11-01

    Monoclonal antibody (mAb) therapies for relapsing-remitting multiple sclerosis (MS) target immune cells or other molecules involved in pathogenic pathways with extraordinary specificity. Natalizumab and alemtuzumab are the only two currently approved mAbs for the treatment of MS, having demonstrated significant reduction in clinical and magnetic resonance imaging disease activity and disability in clinical studies. Ocrelizumab and daclizumab are in the late stages of phase III trials, and several other mAbs are in the early stages of clinical evaluation. mAbs have distinct structural characteristics (e.g. chimeric, humanized, fully human) and unique targets (e.g. blocking interactions, induction of signal transduction by receptor binding, complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity) conferring different mechanisms of action in MS. Because of these differences, mAbs for MS do not constitute a single treatment class; each must be considered individually when selecting appropriate therapy. Furthermore, in reviewing the data from clinical studies of mAbs, attention should be drawn to use of different comparators (e.g. placebo or interferon ?-1a) and study designs. Each mAb treatment has a unique administration schedule. In the decision to select the appropriate treatment for each individual MS patient, careful review of the benefits relative to risks of mAbs is balanced against the risk of development of MS-associated disability. PMID:26600872

  12. Differential effects of TR ligands on hormone dissociation rates: evidence for multiple ligand entry/exit pathways.

    PubMed

    Cunha Lima, Suzana T; Nguyen, Ngoc-Ha; Togashi, Marie; Apriletti, James W; Nguyen, Phuong; Polikarpov, Igor; Scanlan, Thomas S; Baxter, John D; Webb, Paul

    2009-11-01

    Some nuclear receptor (NR) ligands promote dissociation of radiolabeled bound hormone from the buried ligand binding cavity (LBC) more rapidly than excess unlabeled hormone itself. This result was interpreted to mean that challenger ligands bind allosteric sites on the LBD to induce hormone dissociation, and recent findings indicate that ligands bind weakly to multiple sites on the LBD surface. Here, we show that a large fraction of thyroid hormone receptor (TR) ligands promote rapid dissociation (T(1/2)<2h) of radiolabeled T(3) vs. T(3) (T(1/2) approximately 5-7h). We cannot discern relationships between this effect and ligand size, activity or affinity for TRbeta. One ligand, GC-24, binds the TR LBC and (weakly) to the TRbeta-LBD surface that mediates dimer/heterodimer interaction, but we cannot link this interaction to rapid T(3) dissociation. Instead, several lines of evidence suggest that the challenger ligand must interact with the buried LBC to promote rapid T(3) release. Since previous molecular dynamics simulations suggest that TR ligands leave the LBC by several routes, we propose that a subset of challenger ligands binds and stabilizes a partially unfolded intermediate state of TR that arises during T(3) release and that this effect enhances hormone dissociation. PMID:19729063

  13. Worldwide patterns of genetic differentiation imply multiple ‘domestications’ of Aedes aegypti, a major vector of human diseases

    PubMed Central

    Brown, Julia E.; McBride, Carolyn S.; Johnson, Petrina; Ritchie, Scott; Paupy, Christophe; Bossin, Hervé; Lutomiah, Joel; Fernandez-Salas, Ildefonso; Ponlawat, Alongkot; Cornel, Anthony J.; Black, William C.; Gorrochotegui-Escalante, Norma; Urdaneta-Marquez, Ludmel; Sylla, Massamba; Slotman, Michel; Murray, Kristy O.; Walker, Christopher; Powell, Jeffrey R.

    2011-01-01

    Understanding the processes by which species colonize and adapt to human habitats is particularly important in the case of disease-vectoring arthropods. The mosquito species Aedes aegypti, a major vector of dengue and yellow fever viruses, probably originated as a wild, zoophilic species in sub-Saharan Africa, where some populations still breed in tree holes in forested habitats. Many populations of the species, however, have evolved to thrive in human habitats and to bite humans. This includes some populations within Africa as well as almost all those outside Africa. It is not clear whether all domestic populations are genetically related and represent a single ‘domestication’ event, or whether association with human habitats has developed multiple times independently within the species. To test the hypotheses above, we screened 24 worldwide population samples of Ae. aegypti at 12 polymorphic microsatellite loci. We identified two distinct genetic clusters: one included all domestic populations outside of Africa and the other included both domestic and forest populations within Africa. This suggests that human association in Africa occurred independently from that in domestic populations across the rest of the world. Additionally, measures of genetic diversity support Ae. aegypti in Africa as the ancestral form of the species. Individuals from domestic populations outside Africa can reliably be assigned back to their population of origin, which will help determine the origins of new introductions of Ae. aegypti. PMID:21227970

  14. Monoclonal antibody therapies for the treatment of relapsing-remitting multiple sclerosis: differentiating mechanisms and clinical outcomes

    PubMed Central

    Lycke, Jan

    2015-01-01

    Monoclonal antibody (mAb) therapies for relapsing-remitting multiple sclerosis (MS) target immune cells or other molecules involved in pathogenic pathways with extraordinary specificity. Natalizumab and alemtuzumab are the only two currently approved mAbs for the treatment of MS, having demonstrated significant reduction in clinical and magnetic resonance imaging disease activity and disability in clinical studies. Ocrelizumab and daclizumab are in the late stages of phase III trials, and several other mAbs are in the early stages of clinical evaluation. mAbs have distinct structural characteristics (e.g. chimeric, humanized, fully human) and unique targets (e.g. blocking interactions, induction of signal transduction by receptor binding, complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity) conferring different mechanisms of action in MS. Because of these differences, mAbs for MS do not constitute a single treatment class; each must be considered individually when selecting appropriate therapy. Furthermore, in reviewing the data from clinical studies of mAbs, attention should be drawn to use of different comparators (e.g. placebo or interferon ?-1a) and study designs. Each mAb treatment has a unique administration schedule. In the decision to select the appropriate treatment for each individual MS patient, careful review of the benefits relative to risks of mAbs is balanced against the risk of development of MS-associated disability. PMID:26600872

  15. Comparison of Sewage and Animal Fecal Microbiomes by Using Oligotyping Reveals Potential Human Fecal Indicators in Multiple Taxonomic Groups.

    PubMed

    Fisher, Jenny C; Eren, A Murat; Green, Hyatt C; Shanks, Orin C; Morrison, Hilary G; Vineis, Joseph H; Sogin, Mitchell L; McLellan, Sandra L

    2015-10-15

    Most DNA-based microbial source tracking (MST) approaches target host-associated organisms within the order Bacteroidales, but the gut microbiota of humans and other animals contain organisms from an array of other taxonomic groups that might provide indicators of fecal pollution sources. To discern between human and nonhuman fecal sources, we compared the V6 regions of the 16S rRNA genes detected in fecal samples from six animal hosts to those found in sewage (as a proxy for humans). We focused on 10 abundant genera and used oligotyping, which can detect subtle differences between rRNA gene sequences from ecologically distinct organisms. Our analysis showed clear patterns of differential oligotype distributions between sewage and animal samples. Over 100 oligotypes of human origin occurred preferentially in sewage samples, and 99 human oligotypes were sewage specific. Sequences represented by the sewage-specific oligotypes can be used individually for development of PCR-based assays or together with the oligotypes preferentially associated with sewage to implement a signature-based approach. Analysis of sewage from Spain and Brazil showed that the sewage-specific oligotypes identified in U.S. sewage have the potential to be used as global alternative indicators of human fecal pollution. Environmental samples with evidence of prior human fecal contamination had consistent ratios of sewage signature oligotypes that corresponded to the trends observed for sewage. Our methodology represents a promising approach to identifying new bacterial taxa for MST applications and further highlights the potential of the family Lachnospiraceae to provide human-specific markers. In addition to source tracking applications, the patterns of the fine-scale population structure within fecal taxa suggest a fundamental relationship between bacteria and their hosts. PMID:26231648

  16. Multiple techniques for mineral identification on Mars:. a study of hydrothermal rocks as potential analogues for astrobiology sites on Mars

    NASA Astrophysics Data System (ADS)

    Bishop, Janice L.; Murad, Enver; Lane, Melissa D.; Mancinelli, Rocco L.

    2004-06-01

    Spectroscopic studies of Mars analog materials combining multiple spectral ranges and techniques are necessary in order to obtain ground truth information for interpretation of rocks and soils on Mars. Two hydrothermal rocks from Yellowstone National Park, Wyoming, were characterized here because they contain minerals requiring water for formation and they provide a possible niche for some of the earliest organisms on Earth. If related rocks formed in hydrothermal sites on Mars, identification of these would be important for understanding the geology of the planet and potential habitability for life. XRD, thermal properties, VNIR, mid-IR, and Raman spectroscopy were employed to identify the mineralogy of the samples in this study. The rocks studied here include a travertine from Mammoth Formation that contains primarily calcite with some aragonite and gypsum and a siliceous sinter from Octopus Spring that contains a variety of poorly crystalline to amorphous silicate minerals. Calcite was detected readily in the travertine rock using any one of the techniques studied. The small amount of gypsum was uniquely identified using XRD, VNIR, and mid-IR, while the aragonite was uniquely identified using XRD and Raman. The siliceous sinter sample was more difficult to characterize using each of these techniques and a combination of all techniques was more useful than any single technique. Although XRD is the historical standard for mineral identification, it presents some challenges for remote investigations. Thermal properties are most useful for minerals with discrete thermal transitions. Raman spectroscopy is most effective for detecting polarized species such as CO 3, OH, and CH, and exhibits sharp bands for most highly crystalline minerals when abundant. Mid-IR spectroscopy is most useful in characterizing Si-O (and metal-O) bonds and also has the advantage that remote information about sample texture (e.g., particle size) can be determined. Mid-IR spectroscopy is also sensitive to structural OH, CO 3, and SO 4 bonds when abundant. VNIR spectroscopy is best for characterizing metal excitational bands and water, and is also a good technique for identification of structural OH, CO 3, SO 4, or CH bonds. Combining multiple techniques provides the most comprehensive information about mineralogy because of the different selection rules and particle size sensitivities, in addition to maximum coverage of excitational and vibrational bands at all wavelengths. This study of hydrothermal rocks from Yellowstone provides insights on how to combine information from multiple instruments to identify mineralogy and hence evidence of water on Mars.

  17. Mitochondrial analysis of a Byzantine population reveals the differential impact of multiple historical events in South Anatolia

    PubMed Central

    Ottoni, Claudio; Ricaut, François-X; Vanderheyden, Nancy; Brucato, Nicolas; Waelkens, Marc; Decorte, Ronny

    2011-01-01

    The archaeological site of Sagalassos is located in Southwest Turkey, in the western part of the Taurus mountain range. Human occupation of its territory is attested from the late 12th millennium BP up to the 13th century AD. By analysing the mtDNA variation in 85 skeletons from Sagalassos dated to the 11th–13th century AD, this study attempts to reconstruct the genetic signature potentially left in this region of Anatolia by the many civilizations, which succeeded one another over the centuries until the mid-Byzantine period (13th century BC). Authentic ancient DNA data were determined from the control region and some SNPs in the coding region of the mtDNA in 53 individuals. Comparative analyses with up to 157 modern populations allowed us to reconstruct the origin of the mid-Byzantine people still dwelling in dispersed hamlets in Sagalassos, and to detect the maternal contribution of their potential ancestors. By integrating the genetic data with historical and archaeological information, we were able to attest in Sagalassos a significant maternal genetic signature of Balkan/Greek populations, as well as ancient Persians and populations from the Italian peninsula. Some contribution from the Levant has been also detected, whereas no contribution from Central Asian population could be ascertained. PMID:21224890

  18. Mitochondrial analysis of a Byzantine population reveals the differential impact of multiple historical events in South Anatolia.

    PubMed

    Ottoni, Claudio; Ricaut, François-X; Vanderheyden, Nancy; Brucato, Nicolas; Waelkens, Marc; Decorte, Ronny

    2011-05-01

    The archaeological site of Sagalassos is located in Southwest Turkey, in the western part of the Taurus mountain range. Human occupation of its territory is attested from the late 12th millennium BP up to the 13th century AD. By analysing the mtDNA variation in 85 skeletons from Sagalassos dated to the 11th-13th century AD, this study attempts to reconstruct the genetic signature potentially left in this region of Anatolia by the many civilizations, which succeeded one another over the centuries until the mid-Byzantine period (13th century BC). Authentic ancient DNA data were determined from the control region and some SNPs in the coding region of the mtDNA in 53 individuals. Comparative analyses with up to 157 modern populations allowed us to reconstruct the origin of the mid-Byzantine people still dwelling in dispersed hamlets in Sagalassos, and to detect the maternal contribution of their potential ancestors. By integrating the genetic data with historical and archaeological information, we were able to attest in Sagalassos a significant maternal genetic signature of Balkan/Greek populations, as well as ancient Persians and populations from the Italian peninsula. Some contribution from the Levant has been also detected, whereas no contribution from Central Asian population could be ascertained. PMID:21224890

  19. HLA class I alleles tag HLA-DRB1*1501 haplotypes for differential risk in multiple sclerosis susceptibility.

    PubMed

    Chao, Michael J; Barnardo, Martin C N M; Lincoln, Matthew R; Ramagopalan, Sreeram V; Herrera, Blanca M; Dyment, David A; Montpetit, Alexandre; Sadovnick, A Dessa; Knight, Julian C; Ebers, George C

    2008-09-01

    The major locus for multiple sclerosis (MS) susceptibility is located within the class II region of the Major Histocompatibility Complex (MHC). HLA-DRB1 alleles, constituting the strongest MS susceptibility factors, have been widely exploited in research including construction of transgenic animal models of MS. Many studies have concluded that HLA-DRB1*15 allele itself determines MS-associated susceptibility. If this were true, haplotypes bearing this allele would confer equal risk. If HLA-DRB1*15 bearing haplotypes differed for risk, roles for other loci in this region would be implied and further study of the fine structure of this locus would be compelling. We have tested the hypothesis comparing haplotypes stratified by HLA class I tagging. We show here that HLA-DRB1*15-bearing-haplotypes in 1970 individuals from 494 MS families are indeed heterogeneous. Some HLA-DRB1*15 haplotypes determine susceptibility while others do not. Three groups of class I tagged HLA-DRB1*15 haplotypes were not over-transmitted: (i) HLA-DRB1*15-HLA-B*08 (TR = 25, NT = 23, Odds Ratio = 1.09), (ii) -HLA-B*27 (TR = 18, NT = 17, Odds Ratio = 1.06), and (iii) rare HLA-DRB1*15 haplotypes (frequency <0.02). Rare haplotypes were significantly different from common haplotypes, and transmissions were remarkably similar to those for class-I-matched non-HLA-DRB1*15 haplotypes. These results unambiguously indicate that HLA-DRB1*15 is part of a susceptibility haplotype but cannot be the susceptibility allele itself, requiring either epistatic interactions, epigenetic modifications on some haplotypes, or nearby structural variation. These findings strongly imply that differences among HLA-DRB1*15 haplotypes will furnish the basis for MHC-associated susceptibility in MS and raise the possibility that the MHC haplotype is the fundamental unit of genetic control of immune response. PMID:18765817

  20. Queuine, a tRNA anticodon wobble base, maintains the proliferative and pluripotent potential of HL-60 cells in the presence of the differentiating agent 6-thioguanine.

    PubMed Central

    French, B T; Patrick, D E; Grever, M R; Trewyn, R W

    1991-01-01

    6-Thioguanine (6-TG)-induced differentiation of hypoxanthine phosphoribosyltransferase (IMP: pyrophosphate phosphoribosyltransferase, EC 2.4.2.8)-deficient HL-60 cells is characterized by 2 days of growth, after which morphological differentiation proceeds. Addition of the tRNA wobble base queuine, in the presence of 6-TG, maintains the proliferative capability of the cells. The ability of 6-TG to induce differentiation correlates with c-myc mRNA down-regulation, but queuine has no effect on this parameter. Treatment with 6-TG for 2-3 days commits HL-60 cells to granulocytic differentiation, and, once committed, these cells do not respond to the monocytic inducer phorbol 12-myristate 13-acetate. Nonetheless, when cells are treated with queuine and 6-TG, they maintain the promyelocytic morphology and are capable of being induced down the monocytic pathway by phorbol 12-myristate 13-acetate as indicated by stabilization of c-fms mRNA and cell adherence. In the absence of queuine, phorbol 12-myristate 13-acetate is incapable of inducing monocytic markers in the 6-TG-treated cells. The data presented indicate that 6-TG-induced differentiation of HL-60 cells is a tRNA-facilitated event and that the tRNA wobble base queuine is capable of maintaining both the proliferative and pluripotent potential of the cells. Images PMID:1988936

  1. Differential neuroprotective potential of CRMP2 peptide aptamers conjugated to cationic, hydrophobic, and amphipathic cell penetrating peptides.

    PubMed

    Moutal, Aubin; François-Moutal, Liberty; Brittain, Joel M; Khanna, May; Khanna, Rajesh

    2014-01-01

    The microtubule-associated axonal specification collapsin response mediator protein 2 (CRMP2) is a novel target for neuroprotection. A CRMP2 peptide (TAT-CBD3) conjugated to the HIV transactivator of transcription (TAT) protein's cationic cell penetrating peptide (CPP) motif protected neurons in the face of toxic levels of Ca(2+) influx leaked in via N-methyl-D-aspartate receptor (NMDAR) hyperactivation. Here we tested whether replacing the hydrophilic TAT motif with alternative cationic (nona-arginine (R9)), hydrophobic (membrane transport sequence (MTS) of k-fibroblast growth factor) or amphipathic (model amphipathic peptide (MAP)) CPPs could be superior to the neuroprotection bestowed by TAT-CBD3. In giant plasma membrane vesicles (GPMVs) derived from cortical neurons, the peptides translocated across plasma membranes with similar efficiencies. Cortical neurons, acutely treated with peptides prior to a toxic glutamate challenge, demonstrated enhanced efflux of R9-CBD3 compared to others. R9-CBD3 inhibited N-methyl-D-aspartate (NMDA)-evoked Ca(2+) influx to a similar extent as TAT-CBD3 while MTS-CBD3 was ineffective which correlated with the ability of R9- and TAT-CBD3, but not MTS-CBD3, to block NMDAR interaction with CRMP2. Unrestricted Ca(2+) influx through NMDARs leading to delayed calcium dysregulation and neuronal cell death was blocked by all peptides but MAP-CBD3. When applied acutely for 10 min, R9-CBD3 was more effective than TAT-CBD3 at neuroprotection while MTS- and MAP-CBD3 were ineffective. In contrast, long-term (>24 h) treatment with MTS-CBD3 conferred neuroprotection where TAT-CBD3 failed. Neither peptide altered surface trafficking of NMDARs. Neuroprotection conferred by MTS-CBD3 peptide is likely due to its increased uptake coupled with decreased efflux when compared to TAT-CBD3. Overall, our results demonstrate that altering CPPs can bestow differential neuroprotective potential onto the CBD3 cargo. PMID:25674050

  2. Common gamma chain (?c) cytokines differentially potentiate TNFR family signaling in antigen-activated CD8+ T cells

    PubMed Central

    2014-01-01

    Background Several members of the common gamma chain (gc) cytokine family are already approved (IL-2) or actively being developed as vaccine adjuvants and cancer immunotherapies. Studies have indicated that co-administration of gc cytokines may enhance the efficacy of immunotherapies that function via direct activation of co-stimulatory T cell receptors. To define the specific influence of gc cytokines on the co-stimulatory capacity of CD8+ T cells and identify combinations with synergistic potential, we investigated the direct impact of gc cytokines on the differentiation and transcriptional profile of recently antigen-primed CD8+ T cells. Methods Naďve CD8+ T cells were activated with peptide-pulsed APCs. After 48 hours, CD8+ T cells were harvested and re-cultured in media supplemented with IL-2, IL-4, IL-7, IL-15 or IL-21. After 24 hours, cells were analyzed by cytokine bead array, flow cytometry, and mRNA micro-array. Gene networks responsible for specific CD8+ T cell functions were constructed through literature-meta review and publicly available annotation databases. Gene expression data from the experimental groups was imported into this network to visualize the impact of each gc cytokine on the functional polarization of recently-activated CD8+ T cells. Results Among the gc cytokines, IL-2 induced the greatest increase in the expression of co-stimulatory receptors in recently-activated CD8+ T cells. IL-2 increased significantly expression of 4-1BB, GITR, ICOS and OX40, at both the transcriptional and protein level. IL-2 also drove the greatest increase in cellular proliferation and the most robust shift towards a pro-survival phenotype, compared with the other gc cytokines. Both IL-4 and IL-21 enhanced expression of cytotoxic effector proteins, but drove distinct phenotypic polarizations, Th2/Tc2 and NK-like, respectively. Conclusions Overall, these observations suggest that among gc cytokines, IL-2 may be uniquely capable of synergizing with therapeutic strategies that combine immunization with agonists of co-stimulatory T cell receptors. Previous studies have shown that the timing of IL-2 treatment relative to immunization plays a key role in defining the CD8+ T cell response, and the findings from this study indicate that administration of exogenous IL-2 shortly after the initial antigen-priming event has concluded may augment the receptivity of these cells to subsequent TNFR co-stimulation. PMID:25411639

  3. Lateral ventricular cerebrospinal fluid diffusivity as a potential neuroimaging marker of brain temperature in multiple sclerosis: a hypothesis and implications.

    PubMed

    Hasan, Khader M; Lincoln, John A; Nelson, Flavia M; Wolinsky, Jerry S; Narayana, Ponnada A

    2015-04-01

    In this retrospective study we tested the hypothesis that the net effect of impaired electrical conduction and therefore increased heat dissipation in multiple sclerosis (MS) results in elevated lateral ventricular (LV) cerebrospinal fluid (CSF) diffusivity as a measure of brain temperature estimated in vivo using diffusion tensor imaging (DTI). We used validated DTI-based segmentation methods to obtain normalized LV-CSF volume and its corresponding CSF diffusivity in 108 MS patients and 103 healthy controls in the age range of 21-63 years. The LV CSF diffusivity was ~2% higher in MS compared to controls that correspond to a temperature rise of ~1°C that could not be explained by changes in the CSF viscosity due to altered CSF protein content in MS. The LV diffusivity decreased with age in healthy controls (r=-0.29; p=0.003), but not in MS (r=0.15; p=0.11), possibly related to MS pathology. Age-adjusted LV diffusivity increased with lesion load (r=0.518; p=1×10(-8)). Our data suggest that the total brain lesion load is the primary contributor to the increase in LV CSF diffusivity in MS. These findings suggest that LV diffusivity is a potential in vivo biomarker of the mismatch between heat generation and dissipation in MS. We also discuss limitations and possible confounders. PMID:25485790

  4. Evaluation of Antioxidant Potential of “Maltese Mushroom” (Cynomorium coccineum) by Means of Multiple Chemical and Biological Assays

    PubMed Central

    Zucca, Paolo; Rosa, Antonella; Tuberoso, Carlo I. G.; Piras, Alessandra; Rinaldi, Andrea C.; Sanjust, Enrico; Dessě, Maria A.; Rescigno, Antonio

    2013-01-01

    Cynomorium coccineum is an edible, non-photosynthetic plant widespread along the coasts of the Mediterranean Sea. The medicinal properties of Maltese mushroom—one of the oldest vernacular names used to identify this species—have been kept in high regard since ancient times to the present day. We evaluated the antioxidant potential of fresh specimens of C. coccineum picked in Sardinia, Italy. Both aqueous and methanolic extracts were tested by using multiple assay systems (DPPH, FRAP, TEAC, ORAC-PYR). Total phenolics and flavonoids were also determined. Gallic acid and cyanidin 3-O-glucoside were identified as the main constituents and measured. Both extracts showed antioxidant capacities; ORAC-PYR assay gave the highest antioxidant value in both cases. The methanolic extract was further investigated with in vitro biological models of lipid oxidation; it showed a significant activity in preventing cholesterol degradation and exerted protection against Cu2+-mediated degradation of the liposomal unsaturated fatty acids. Results of the present study demonstrate that the extracts of C. coccineum show a significant total antioxidant power and also exert an in vitro protective effect in different bio-assays of oxidative stress. Therefore, Maltese mushroom can be considered a valuable source of antioxidants and phytochemicals useful in the preparation of nutraceuticals and functional foods. PMID:23344249

  5. In Silico Repositioning-Chemogenomics Strategy Identifies New Drugs with Potential Activity against Multiple Life Stages of Schistosoma mansoni

    PubMed Central

    Neves, Bruno J.; Braga, Rodolpho C.; Bezerra, José C. B.; Cravo, Pedro V. L.; Andrade, Carolina H.

    2015-01-01

    Morbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD), DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes. PMID:25569258

  6. Molecular dynamics simulations with many-body potentials on multiple GPUs—The implementation, package and performance

    NASA Astrophysics Data System (ADS)

    Hou, Qing; Li, Min; Zhou, Yulu; Cui, Jiechao; Cui, Zhenguo; Wang, Jun

    2013-09-01

    Molecular dynamics (MD) is an important research tool extensively applied in materials science. Running MD on a graphics processing unit (GPU) is an attractive new approach for accelerating MD simulations. Currently, GPU implementations of MD usually run in a one-host-process-one-GPU (OHPOG) scheme. This scheme may pose a limitation on the system size that an implementation can handle due to the small device memory relative to the host memory. In this paper, we present a one-host-process-multiple-GPU (OHPMG) implementation of MD with embedded-atom-model or semi-empirical tight-binding many-body potentials. Because more device memory is available in an OHPMG process, the system size that can be handled is increased to a few million or more atoms. In comparison with the serial CPU implementation, in which Newton's third law is applied to improve the computational efficiency, our OHPMG implementation has achieved a 28.9x-86.0x speedup in double precision, depending on the system size, the cut-off ranges and the number of GPUs. The implementation can also handle a group of small simulation boxes in one run by combining the small boxes into a large box. This approach greatly improves the GPU computing efficiency when a large number of MD simulations for small boxes are needed for statistical purposes.

  7. Predators with multiple ontogenetic niche shifts have limited potential for population growth and top-down control of their prey.

    PubMed

    van Leeuwen, Anieke; Huss, Magnus; Gĺrdmark, Anna; Casini, Michele; Vitale, Francesca; Hjelm, Joakim; Persson, Lennart; de Roos, André M

    2013-07-01

    Catastrophic collapses of top predators have revealed trophic cascades and community structuring by top-down control. When populations fail to recover after a collapse, this may indicate alternative stable states in the system. Overfishing has caused several of the most compelling cases of these dynamics, and in particular Atlantic cod stocks exemplify such lack of recovery. Often, competition between prey species and juvenile predators is hypothesized to explain the lack of recovery of predator populations. The predator is then considered to compete with its prey for one resource when small and to subsequently shift to piscivory. Yet predator life history is often more complex than that, including multiple ontogenetic diet shifts. Here we show that no alternative stable states occur when predators in an intermediate life stage feed on an additional resource (exclusive to the predator) before switching to piscivory, because predation and competition between prey and predator do not simultaneously structure community dynamics. We find top-down control by the predator only when there is no feedback from predator foraging on the additional resource. Otherwise, the predator population dynamics are governed by a bottleneck in individual growth occurring in the intermediate life stage. Therefore, additional resources for predators may be beneficial or detrimental for predator population growth and strongly influence the potential for top-down community control. PMID:23778226

  8. Demonstration of differential quantitative requirements for NSF among multiple vesicle fusion pathways of GLUT4 using a dominant-negative ATPase-deficient NSF

    SciTech Connect

    Chen Xiaoli; Matsumoto, Hideko; Hinck, Cynthia S.; Al-Hasani, Hadi; St-Denis, Jean-Francois; Whiteheart, Sidney W.; Cushman, Samuel W. . E-mail: sam_cushman@nih.gov

    2005-07-22

    In this study, we investigated the relative participation of N-ethylmaleimide-sensitive factor (NSF) in vivo in a complex multistep vesicle trafficking system, the translocation response of GLUT4 to insulin in rat adipose cells. Transfections of rat adipose cells demonstrate that over-expression of wild-type NSF has no effect on total, or basal and insulin-stimulated cell-surface expression of HA-tagged GLUT4. In contrast, a dominant-negative NSF (NSF-D1EQ) can be expressed at a low enough level that it has little effect on total HA-GLUT4, but does reduce both basal and insulin-stimulated cell-surface HA-GLUT4 by {approx}50% without affecting the GLUT4 fold-translocation response to insulin. However, high expression levels of NSF-D1EQ decrease total HA-GLUT4. The inhibitory effect of NSF-D1EQ on cell-surface HA-GLUT4 is reversed when endocytosis is inhibited by co-expression of a dominant-negative dynamin (dynamin-K44A). Moreover, NSF-D1EQ does not affect cell-surface levels of constitutively recycling GLUT1 and TfR, suggesting a predominant effect of low-level NSF-D1EQ on the trafficking of GLUT4 from the endocytic recycling compared to the intracellular GLUT4-specific compartment. Thus, our data demonstrate that the multiple fusion steps in GLUT4 trafficking have differential quantitative requirements for NSF activity. This indicates that the rates of plasma and intracellular membrane fusion reactions vary, leading to differential needs for the turnover of the SNARE proteins.

  9. ERK2 protein regulates the proliferation of human mesenchymal stem cells without affecting their mobilization and differentiation potential

    SciTech Connect

    Carcamo-Orive, Ivan; Tejados, Naiara; Delgado, Jesus; Gaztelumendi, Ainhoa; Otaegui, David; Lang, Valerie; Trigueros, Cesar

    2008-05-01

    Human Mesenchymal Stem Cells (hMSC), derived mainly from adult bone marrow, are valuable models for the study of processes involved in stem cell self-renewal and differentiation. As the Extracellular signal-Regulated Kinase (ERK) signalling pathway is a major contributor to cellular growth, differentiation and survival, we have studied the functions of this kinase in hMSC activity. Ablation of ERK2 gene expression (but not ERK1) by RNA interference significantly reduced proliferation of hMSC. This reduction was due to a defect in Cyclin D1 expression and subsequent arrest in the G0/G1 phase of the cell cycle. hMSC growth is enhanced through culture medium supplementation with growth factors (GFs) such as Platelet-Derived Growth Factor (PDGF), basic Fibroblast Growth Factor (bFGF) or Epidermal Growth Factor (EGF). However, these supplements could not rescue the defect observed after ERK2 knockdown, suggesting a common signalling pathway used by these GFs for proliferation. In contrast, ERK1/2 may be dissociated from chemotactic signalling induced by the same GFs. Additionally, hMSCs were capable of differentiating into adipocytes even in the absence of either ERK1 or ERK2 proteins. Our data show that hMSCs do not require cell division to enter the adipogenic differentiation process, indicating that clonal amplification of these cells is not a critical step. However, cell-cell contact seems to be an essential requirement to be able to differentiate into mature adipocytes.

  10. Partial Least Squares Regression Can Aid in Detecting Differential Abundance of Multiple Features in Sets of Metagenomic Samples

    PubMed Central

    Libiger, Ondrej; Schork, Nicholas J.

    2015-01-01

    It is now feasible to examine the composition and diversity of microbial communities (i.e., “microbiomes”) that populate different human organs and orifices using DNA sequencing and related technologies. To explore the potential links between changes in microbial communities and various diseases in the human body, it is essential to test associations involving different species within and across microbiomes, environmental settings and disease states. Although a number of statistical techniques exist for carrying out relevant analyses, it is unclear which of these techniques exhibit the greatest statistical power to detect associations given the complexity of most microbiome datasets. We compared the statistical power of principal component regression, partial least squares regression, regularized regression, distance-based regression, Hill's diversity measures, and a modified test implemented in the popular and widely used microbiome analysis methodology “Metastats” across a wide range of simulated scenarios involving changes in feature abundance between two sets of metagenomic samples. For this purpose, simulation studies were used to change the abundance of microbial species in a real dataset from a published study examining human hands. Each technique was applied to the same data, and its ability to detect the simulated change in abundance was assessed. We hypothesized that a small subset of methods would outperform the rest in terms of the statistical power. Indeed, we found that the Metastats technique modified to accommodate multivariate analysis and partial least squares regression yielded high power under the models and data sets we studied. The statistical power of diversity measure-based tests, distance-based regression and regularized regression was significantly lower. Our results provide insight into powerful analysis strategies that utilize information on species counts from large microbiome data sets exhibiting skewed frequency distributions obtained on a small to moderate number of samples.

  11. Differential analysis of N-glycoproteome between hepatocellular carcinoma and normal human liver tissues by combination of multiple protease digestion and solid phase based labeling

    PubMed Central

    2014-01-01

    Background Dysregulation of glycoproteins is closely related with many diseases. Quantitative proteomics methods are powerful tools for the detection of glycoprotein alterations. However, in almost all quantitative glycoproteomics studies, trypsin is used as the only protease to digest proteins. This conventional method is unable to quantify N-glycosites in very short or long tryptic peptides and so comprehensive glycoproteomics analysis cannot be achieved. Methods In this study, a comprehensive analysis of the difference of N-glycoproteome between hepatocellular carcinoma (HCC) and normal human liver tissues was performed by an integrated workflow combining the multiple protease digestion and solid phase based labeling. The quantified N-glycoproteins were analyzed by GoMiner to obtain a comparative view of cellular component, biological process and molecular function. Results/conclusions An integrated workflow was developed which enabled the processes of glycoprotein coupling, protease digestion and stable isotope labeling to be performed in one reaction vessel. This workflow was firstly evaluated by analyzing two aliquots of the same protein extract from normal human liver tissue. It was demonstrated that the multiple protease digestion improved the glycoproteome coverage and the quantification accuracy. This workflow was further applied to the differential analysis of N-glycoproteome of normal human liver tissue and that with hepatocellular carcinoma. A total of 2,329 N-glycosites on 1,052 N-glycoproteins were quantified. Among them, 858 N-glycosites were quantified from more than one digestion strategy with over 99% confidence and 1,104 N-glycosites were quantified from only one digestion strategy with over 95% confidence. By comparing the GoMiner results of the N-glycoproteins with and without significant changes, the percentage of membrane and secreted proteins and their featured biological processes were found to be significant different revealing that protein glycosylation may play the vital role in the development of HCC. PMID:25097464

  12. Regulation of miR-24, miR-30b, and miR-142-3p during macrophage and dendritic cell differentiation potentiates innate immunity.

    PubMed

    Fordham, Jezrom B; Naqvi, Afsar R; Nares, Salvador

    2015-08-01

    miRNAs are ubiquitous regulators of human biology. Parallel profiling of in vitro monocyte-to-M? and monocyte-to-DC differentiation revealed static, convergent, and divergent expression of miRNA. Bioinformatic and network analysis of differentially expressed miRNAs implicated miR-24, miR-30b, and miR-142-3p as negative regulators of intracellular signaling pathways, triggered not only by differentiation factors (M-CSF/GM-CSF/IL-4) but also from PRRs. Manipulation of miR-24, miR-30b, and miR-142-3p expression during the differentiation of mD-M? and mD-DC differentiation had minimal impact on the acquisition of phenotype but significantly abrogated the ability of these cells to mount inflammatory responses to pathogen-associated stimuli. Forced expression of these miRNAs, which are down-regulated during differentiation, inhibited release of inflammatory cytokines [TNF-?, IL-12(p40), IL-6] upon stimulation with LPS. Functional analysis revealed overlapping mechanisms of inhibition, including surface expression of TLR4/CD14/MD-1 and intracellular PKC?/NF-?B activation. Potential intermediary targets of the TLR4-NF-?B axis included members of the PI3K and MAPK families and PKC isoforms. These results demonstrate the requirement of miR-24, miR-30b, and miR-142-3p down-regulation for the generation of fully functional M?s and DCs. PMID:25990241

  13. Differentiated evolutionary relationships among chordates from comparative alignments of multiple sequences of MyoD and MyoG myogenic regulatory factors.

    PubMed

    Oliani, L C; Lidani, K C F; Gabriel, J E

    2015-01-01

    MyoD and MyoG are transcription factors that have essential roles in myogenic lineage determination and muscle differentiation. The purpose of this study was to compare multiple amino acid sequences of myogenic regulatory proteins to infer evolutionary relationships among chordates. Protein sequences from Mus musculus (P10085 and P12979), human Homo sapiens (P15172 and P15173), bovine Bos taurus (Q7YS82 and Q7YS81), wild pig Sus scrofa (P49811 and P49812), quail Coturnix coturnix (P21572 and P34060), chicken Gallus gallus (P16075 and P17920), rat Rattus norvegicus (Q02346 and P20428), domestic water buffalo Bubalus bubalis (D2SP11 and A7L034), and sheep Ovis aries (Q90477 and D3YKV7) were searched from a non-redundant protein sequence database UniProtKB/Swiss-Prot, and subsequently analyzed using the Mega6.0 software. MyoD evolutionary analyses revealed the presence of three main clusters with all mammals branched in one cluster, members of the order Rodentia (mouse and rat) in a second branch linked to the first, and birds of the order Galliformes (chicken and quail) remaining isolated in a third. MyoG evolutionary analyses aligned sequences in two main clusters, all mammalian specimens grouped in different sub-branches, and birds clustered in a second branch. These analyses suggest that the evolution of MyoD and MyoG was driven by different pathways. PMID:26505406

  14. Differential Relationships between WISC-IV and WIAT-II Scales: An Evaluation of Potentially Moderating Child Demographics

    ERIC Educational Resources Information Center

    Konold, Timothy R.; Canivez, Gary L.

    2010-01-01

    Considerable debate exists regarding the accuracy of intelligence tests with members of different groups. This study investigated differential predictive validity of the "Wechsler Intelligence Scale for Children-Fourth Edition". Participants from the WISC-IV--WIAT-II standardization linking sample (N = 550) ranged in age from 6 through 16 years (M…

  15. Potentiation of Acute Promyelocytic Leukemia Cell Differentiation and Prevention of Leukemia Development in Mice by Oleanolic Acid.

    PubMed

    Rawendra, Reynetha D S; Lin, Ping-Yuan; Chang, Ching-Dong; Hsu, Jue-Liang; Huang, Tzou-Chi; Shih, Wen-Ling

    2015-12-01

    Although differentiation therapy with all-trans retinoic acid (ATRA) induces complete remission in most acute promyelocytic leukemia (APL) patients, it is associated with organ toxicity. The present study focused on investigating the effects of the natural compounds oleanolic acid (OA) and ursolic acid (UA) on proliferation and differentiation of human APL HL-60 cells in vitro and murine APL WEHI-3 cells in vivo. Results demonstrated that OA and UA significantly inhibited cellular proliferation of HL-60 in a concentration- and time-dependent manner. Non-cytotoxic concentration of OA exhibited a marked differentiation-inducing effect on HL-60 and enhanced ATRA-induced HL-60 differentiation. In contrast, UA showed only a moderate effect. Activation of MAPK/NF-?B signaling pathway was likely found to be involved in the mechanism. Moreover, OA increased survival duration of WEHI-3 transplanted BALB/c mice, and decreased leukemia cells infiltration in the liver and spleen. Thus, these results may provide new insight for developing alternative therapy in APL patients. PMID:26637873

  16. Actin-associated protein palladin is required for migration behavior and differentiation potential of C2C12 myoblast cells

    SciTech Connect

    Nguyen, Ngoc Uyen Nhi; Liang, Vincent Roderick; Wang, Hao-Ven

    2014-09-26

    Highlights: • Palladin is involved in myogenesis in vitro. • Palladin knockdown by siRNA increases myoblast proliferation, viability and differentiation. • Palladin knockdown decreases C2C12 myoblast migration ability. - Abstract: The actin-associated protein palladin has been shown to be involved in differentiation processes in non-muscle tissues. However, but its function in skeletal muscle has rarely been studied. Palladin plays important roles in the regulation of diverse actin-related signaling in a number of cell types. Since intact actin-cytoskeletal remodeling is necessary for myogenesis, in the present study, we pursue to investigate the role of actin-associated palladin in skeletal muscle differentiation. Palladin in C2C12 myoblasts is knocked-down using specific small interfering RNA (siRNA). The results show that down-regulation of palladin decreased migratory activity of mouse skeletal muscle C2C12 myoblasts. Furthermore, the depletion of palladin enhances C2C12 vitality and proliferation. Of note, the loss of palladin promotes C2C12 to express the myosin heavy chain, suggesting that palladin has a role in the modulation of C2C12 differentiation. It is thus proposed that palladin is required for normal C2C12 myogenesis in vitro.

  17. Isolation of Two Unknown Genes Potentially Involved in Differentiation of the Hematopoietic Pathway, and Studies of Spermidine/Spermine Acetyltransferase Regulation

    SciTech Connect

    Kubera, C.; Gavin, I.; Huberman, E.

    2002-01-01

    Differential display identified a number of candidate genes involved with growth and differentiation in the human leukemia cell lines HL-60 and HL-525. Two of these genes were previously unknown, and one is the gene for the enzyme spermidine/spermine acetyltransferase (SSAT). One of our objectives is to isolate and sequence the unknown genes, 631A1 and 510C1, in order to characterize them and determine their functions. The other is to determine how SSAT is regulated, and look at how the polyamines that SSAT regulates effect macrophage differentiation. By screening the CEM T-cell DNA library and the fetal brain library, we were able to identify clones that had inserts with homology to the 631A1 cDNA probe sequence. The insert was amplified using the polymerase chain reaction (PCR) and is currently being sent to the University of Chicago for automated sequencing. The library screens for 510C1 are currently underway, but hybridization of the 510C1 cDNA probe with nylon membranes containing CEM library phage DNA produced strong signal, indicating the gene is there. SSAT experiments identified that the rate-limiting enzyme that marks the polyamines spermidine and spermine for degradation is regulated by PKC and a transcription factor called Nrf2. The knowledge of regulation and function of these genes involved in macrophage differentiation will provide new insight into this cellular process, potentially making it possible to discover the roots of the problems that cause cancerous diseases.

  18. Coordinate-Independent Computations on Differential Equations

    E-print Network

    Lin, Kevin K.

    1998-03-01

    This project investigates the computational representation of differentiable manifolds, with the primary goal of solving partial differential equations using multiple coordinate systems on general n- dimensional spaces. ...

  19. Constructing multiple prolongation structures from homotopic maps

    NASA Astrophysics Data System (ADS)

    Ifidon, E. O.

    2011-02-01

    In this paper, we show how multiple prolongation structures developed out of homotopy theory, can be constructed from a differential ideal corresponding to an exterior differential system. We use this method to construct multiple prolongation structures for the Robinson-Trautman equations of Petrov type III. It is found that the introduction of two arbitrary pseudo-potentials in the carrier space of the vector fields of this equation imposes nontrivial constraints on the prolongation structures which prevents the algebra from growing rapidly. Specific choices of the newly introduced pseudo-potentials result a coupled Kac-Moody A?A and Virasoro algebra as prolongation structure. Other choices of the potentials reproduce previously established results, namely the contragradient algebra K of infinite groiwth. The Lax pair and Riccati equations for pseudo-potentials can be formulated respectively from linear and nonlinear realizations of the prolongation structure.

  20. Effects of pyrite bioleaching solution of Acidithiobacillus ferrooxidans on viability, differentiation and mineralization potentials of rat osteoblasts.

    PubMed

    Zhou, Jian; Chen, Ke-Ming; Zhi, De-Juan; Xie, Qin-Jian; Xian, Cory J; Li, Hong-Yu

    2015-12-01

    Iron pyrite, an important component of traditional Chinese medicine, has a poor solubility, bioavailability, and patient compliance due to a high dose required and associated side effects, all of which have limited its clinical applications and experimental studies on its action mechanisms in improving fracture healing. This study investigated Acidithiobacillus ferrooxidans (A.f)-bioleaching of two kinds of pyrites and examined bioactivities of the derived solutions in viability and osteogenic differentiation in rat calvarial osteoblasts. A.f bioleaching improved element contents (Fe, Mn, Zn, Cu, and Se) in the derived solutions and the solutions concentration-dependently affected osteoblast viability and differentiation. While the solutions had no effects at low concentrations and inhibited the osteoblast alkaline phosphatase (ALP) activity at high concentrations, they improved ALP activity at their optimal concentrations. The improved osteoblast differentiation and osteogenic function at optimal concentrations were also revealed by levels of ALP cytochemical staining, calcium deposition, numbers and areas of mineralized nodules formed, mRNA and protein expression levels of osteogenesis-related genes (osteocalcin, Bmp-2, Runx-2, and IGF-1), and Runx-2 nuclear translocation. Data from this study will be useful in offering new strategies for improving pyrite bioavailability and providing a mechanistic explanation for the beneficial effects of pyrite in improving bone healing. PMID:26283321

  1. Unilateral Acute Closed-Angle Glaucoma After Elective Lumbar Surgery Reveals Multiple Intracranial Aneurysms. A Case Report and Discussion on Workup of Differential Diagnoses.

    PubMed

    Storey, Christopher; Menger, Richard; Hefner, Matthew; Keating, Patrick; Ahmed, Osama; Guthikonda, Bharat

    2015-11-01

    The purpose of our paper is to present a case of a rare complication of posterior lumbar surgery. Our patient presented for elective lumbar decompression, which was complicated by durotomy. She then developed sudden headache and right eye pain once upright on postoperative day 2. Then on postoperative day 3, she developed a dilated nonreactive pupil with extraocular movements intact. A computed tomography scan of the head was negative for subarachnoid hemorrhage. Magnetic resonance angiography showed a possible right posterior communicating artery aneurysm. She was transferred to a tertiary center with a severe headache and a nonreactive pupil, raising concern for evolving third nerve palsy due to aneurysm. A cerebral angiogram was performed and showed multiple aneurysms. Aneurysm location did not explain the patient's symptoms, and ophthalmology was consulted. Elevated intraocular pressure was noted, and the patient was diagnosed with acute angle-closure glaucoma (AACG). Our patient was medically treated and subsequently underwent laser peripheral iridotomy. She has had improved vision and pupillary function at 1 month follow-up. The diagnosis is complicated by a durotomy, which led to cascade in the differential diagnosis to rule out intracranial pathology. Her age and home medications, which had sympathomimetic effects, placed her at increased risk, but lying prone in the dark under the drapes was likely the lead causative factor. In conclusion, a postoperative posterior spine patient with eye pain and changes in vision and pupils should be evaluated with AACG in mind due to the devastating consequences if left untreated or treatment is delayed. PMID:25959248

  2. Multiple Structurally Distinct ER? mRNA Variants in Zebrafish are Differentially Expressed by Tissue Type, Stage of Development and Estrogen Exposure

    PubMed Central

    Cotter, Kellie A.; Yershov, Anya; Novillo, Apolonia; Callard, Gloria V.

    2013-01-01

    It is well established that estrogen-like environmental chemicals interact with the ligand-binding site of estrogen receptors (ER) to disrupt transcriptional control of estrogen responsive targets. Here we investigate the possibility that estrogens also impact splicing decisions on estrogen responsive genes, such as that encoding ER? itself. Targeted PCR cloning was applied to identify six ER? mRNA variants in zebrafish. Sequencing revealed alternate use of transcription and translation start sites, multiple exon deletions, intron retention and alternate polyadenylation. As determined by quantitative (q)PCR, N-terminal mRNA variants predicting long (ER?L) and short (ER?S) isoforms were differentially expressed by tissue-type, sex, stage of development and estrogen exposure. Whereas ER?L mRNA was diffusely distributed in liver, brain, heart, eye, and gonads, ER?S mRNA was preferentially expressed in liver (female > male) and ovary. Neither ER?L nor ER?S transcripts varied significantly during development, but 17?-estradiol selectively increased accumulation of ER?S mRNA (~170-fold by 120 hpf), an effect mimicked by bisphenol-A and diethylstilbestrol. Significantly, a C-truncated variant (ER?S-Cx) lacking most of the ligand binding and AF-2 domains was transcribed exclusively from the short isoform promoter and was similar to ER?S in its tissue-, stage- and estrogen inducible expression. These results support the idea that promoter choice and alternative splicing of the esr1 gene of zebrafish are part of the autoregulatory mechanism by which estrogen modulates subsequent ER? expression, and further suggest that environmental estrogens could exert some of their toxic effects by altering the relative abundance of structurally and functionally distinct ER? isoforms. PMID:24090614

  3. Identification of differentially expressed genes potentially involved in the tolerance of Lotus tenuis to long-term alkaline stress.

    PubMed

    Paz, Rosalía Cristina; Rocco, Rubén Anibal; Jiménez-Bremont, Juan Francisco; Rodríguez-Kessler, Margarita; Becerra-Flora, Alicia; Menéndez, Ana Bernardina; Ruíz, Oscar Adolfo

    2014-09-01

    Soil alkalinity is one of the most serious agricultural problems limiting crop yields. The legume Lotus tenuis is an important forage acknowledged by its ability to naturally grow in alkaline soils. To gain insight into the molecular responses that are activated by alkalinity in L. tenuis plants, subtractive cDNA libraries were generated from leaves and roots of these plants. Total RNAs of non-stressed plants (pH 5.8; E.C. 1.2), and plants stressed by the addition of 10 mM of NaHCO3 (pH 9.0; E.C. 1.9), were used as source of the driver and the tester samples, respectively. RNA samples were collected after 14 and 28 days of treatment. A total of 158 unigenes from leaves and 92 unigenes from roots were obtained and classified into 11 functional categories. Unigenes from these categories (4 for leaves and 8 for roots), that were related with nutrient metabolism and oxidative stress relief were selected, and their differential expression analyzed by qRT-PCR. These genes were found to be differentially expressed in a time dependent manner in L. tenuis during the alkaline stress application. Data generated from this study will contribute to the understanding of the general molecular mechanisms associated to plant tolerance under long-term alkaline stress in plants. PMID:25025825

  4. X-ray fluorescence-based differentiation of neck tissues in a bovine model: implications for potential intraoperative use.

    PubMed

    Lahav, G; Shilstein, S; Shchemelinin, S; Ikher, S; Halperin, D; Chechik, R; Breskin, A

    2015-05-01

    This study explores the possibility of using X-ray fluorescence (XRF)-based trace-element analysis for differentiation of various bovine neck tissues. It is motivated by the requirement for an intra-operative in-vivo method for identifying parathyroid glands, particularly beneficial in surgery in the central neck-compartment. Using a dedicated X-ray spectral analysis, we examined ex-vivo XRF spectra from various histologically verified fresh neck tissues from cow, which was chosen as the animal model; these tissues included fat, muscle, thyroid, parathyroid, lymph nodes, thymus and salivary gland. The data for six trace elements K, Fe, Zn, Br, Rb and I, provided the basis for tissue identification by using multi-parameter analysis of the recorded XRF spectra. It is shown that the combination of XRF signals from these elements is sufficient for a reliable tissue differentiation. The average total abundance of these trace elements was evaluated in each tissue type, including parathyroid and salivary gland for the first time. It is shown that some tissues can unequivocally be identified on the basis of the abundance of a single element, for example, iodine and zinc for the identification of thyroid gland and muscle, respectively. PMID:25677045

  5. Toxin detection based on action potential shape analysis using a realistic mathematical model of differentiated NG108-15 cells.

    PubMed

    Mohan, Dinesh K; Molnar, Peter; Hickman, James J

    2006-03-15

    The NG108-15 neuroblastoma/glioma hybrid cell line has been frequently used for toxin detection, pharmaceutical screening and as a whole-cell biosensor. However, detailed analysis of its action potentials during toxin or drug administration has not been accomplished previously using patch clamp electrophysiology. In order to explore the possibility of identifying toxins based on their effect on the shape of intracellularly or extracellularly detected action potentials, we created a computer model of the action potential generation of this cell type. To generate the experimental data to validate the model, voltage dependent sodium, potassium and high-threshold calcium currents, as well as action potentials, were recorded from NG108-15 cells with conventional whole-cell patch-clamp methods. Based on the classic Hodgkin-Huxley formalism and the linear thermodynamic description of the rate constants, ion-channel parameters were estimated using an automatic fitting method. Utilizing the established parameters, action potentials were generated in the model and were optimized to represent the actual recorded action potentials to establish baseline conditions. To demonstrate the applicability of the method for toxin detection and discrimination, the effect of tetrodotoxin (a sodium channel blocker) and tefluthrin (a pyrethroid that is a sodium channel opener) were studied. The two toxins affected the shape of the action potentials differently and their respective effects were identified based on the changes in the fitted parameters. Our results represent one of the first steps to establish a complex model of NG108-15 cells for quantitative toxin detection based on action potential shape analysis of the experimental results. PMID:16460924

  6. Investigation of low-level laser therapy potentiality on proliferation and differentiation of human osteoblast-like cells in the absence/presence of osteogenic factors

    NASA Astrophysics Data System (ADS)

    Bloise, Nora; Ceccarelli, Gabriele; Minzioni, Paolo; Vercellino, Marco; Benedetti, Laura; De Angelis, Maria Gabriella Cusella; Imbriani, Marcello; Visai, Livia

    2013-12-01

    Several studies have shown that low-level laser irradiation (LLLI) has beneficial effects on bone regeneration. The objective of this study was to examine the in vitro effects of LLLI on proliferation and differentiation of a human osteoblast-like cell line (Saos-2 cell line). Cultured cells were exposed to different doses of LLLI with a semiconductor diode laser (659 nm 10 mW power output). The effects of laser on proliferation were assessed daily up to seven days of culture in cells irradiated once or for three consecutive days with laser doses of 1 or 3 J/cm2. The obtained results showed that laser stimulation enhances the proliferation potential of Saos-2 cells without changing their telomerase pattern or morphological characteristics. The effects on cell differentiation were assessed after three consecutive laser irradiation treatments in the presence or absence of osteo-inductive factors on day 14. Enhanced secretion of proteins specific for differentiation toward bone as well as calcium deposition and alkaline phosphatase activity were observed in irradiated cells cultured in a medium not supplemented with osteogenic factors. Taken together these findings indicate that laser treatment enhances the in vitro proliferation of Saos-2 cells, and also influences their osteogenic maturation, which suggest it is a helpful application for bone tissue regeneration.

  7. Expression patterns of CD200 and CD148 in leukemic B-cell chronic lymphoproliferative disorders and their potential value in differential diagnosis.

    PubMed

    Fan, Lei; Miao, Yi; Wu, Yu-Jie; Wang, Yan; Guo, Rui; Wang, Li; Shen, An-Li; Chen, Yao-Yu; Xu, Wei; Li, Jian-Yong

    2015-12-01

    Different combinations of biomarkers analyzed by flow cytometry are critical for the accurate diagnosis of leukemic B-cell chronic lymphoproliferative disorders (B-CLPDs). We investigated CD200 and CD148 expression patterns of blood or bone marrow from 374 cases of B-CLPD by multicolor flow cytometry. Our results showed that CD200 and CD148 expression patterns distinguished different types of B-CLPD. CD200 mean fluorescence intensity (MFI) or CD148 MFI had a high sensitivity and specificity to differentiate mantle cell lymphoma (MCL) from chronic lymphocytic leukemia (CLL). Furthermore, CD148 MFI/CD200 MFI ratio > 4.79 produced a specificity of 94.46% (95% confidence interval [CI]: 91.04-96.87%) and a sensitivity of 100% (95% CI: 88.78-100.0%) in establishing the diagnosis of MCL in differential diagnosis between MCL and CLL. We therefore conclude that the combination of CD200 and CD148 may have a potential differential diagnostic value in leukemic B-CLPDs, especially between CLL and MCL. PMID:25791119

  8. The DNA glycosylases OGG1 and NEIL3 influence differentiation potential, proliferation, and senescence-associated signs in neural stem cells

    SciTech Connect

    Reis, Amilcar; Hermanson, Ola

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer DNA glycosylases OGG1 and NEIL3 are required for neural stem cell state. Black-Right-Pointing-Pointer No effect on cell viability by OGG1 or NEIL3 knockdown in neural stem cells. Black-Right-Pointing-Pointer OGG1 or NEIL3 RNA knockdown result in decreased proliferation and differentiation. Black-Right-Pointing-Pointer Increased HP1{gamma} immunoreactivity after NEIL3 knockdown suggests premature senescence. -- Abstract: Embryonic neural stem cells (NSCs) exhibit self-renewal and multipotency as intrinsic characteristics that are key parameters for proper brain development. When cells are challenged by oxidative stress agents the resulting DNA lesions are repaired by DNA glycosylases through the base excision repair (BER) pathway as a means to maintain the fidelity of the genome, and thus, proper cellular characteristics. The functional roles for DNA glycosylases in NSCs have however remained largely unexplored. Here we demonstrate that RNA knockdown of the DNA glycosylases OGG1 and NEIL3 decreased NSC differentiation ability and resulted in decreased expression of both neuronal and astrocytic genes after mitogen withdrawal, as well as the stem cell marker Musashi-1. Furthermore, while cell survival remained unaffected, NEIL3 deficient cells displayed decreased cell proliferation rates along with an increase in HP1{gamma} immunoreactivity, a sign of premature senescence. Our results suggest that DNA glycosylases play multiple roles in governing essential neural stem cell characteristics.

  9. Identification of three microsatellites at the human myelin oligodendrocyte glycoprotein (MOG) locus, a gene potentially involved in multiple sclerosis

    SciTech Connect

    Borot, N.; Dolbois, L.; Coppin, H.

    1994-09-01

    The gene encoding MOG is located on the short arm of chromosome 6, less than 120 kb telomeric to HLA-F. We have cloned the MOG gene from a cosmid library. Using tandemly repeated dinucleotides, we probed the genomic region containing the human MOG gene in order to identify and localize polymorphic markers: three microsatellites were characterized in that region. Using a polymerase chain reaction-based technique, we studied length variability for these three markers among 173 healthy individuals and 167 multiple sclerosis patients. Heterozygosity varied from 50% to 60% according to the marker. Pairwise studies showed significant linkage disequilibrium between some alleles. Multiple sclerosis patients and controls were not shown to have statistically significant differences in the MOG region. Further studies on the coding regions are in progress in order to exclude any involvement of the MOG gene in multiple sclerosis.

  10. The potential of differential mobility analysis coupled to MS for the study of very large singly and multiply charged proteins and protein complexes in the gas phase.

    PubMed

    de la Mora, Juan Fernández; Ude, Sven; Thomson, Bruce A

    2006-09-01

    As previously demonstrated by the technique of gas-phase electrophoretic mobility molecular analyzer (GEMMA) introduced by Kaufman and colleagues, differential mobility analysis (DMA) of charge-reduced electrospray ions in the gas phase is a useful complement to MS for studying large proteins and their weakly bound complexes. Several limitations of GEMMA, the solutions for which have the potential to greatly improve its performance, are discussed here, including DMA resolution and transmission. A quantitative theory of charge reduction kinetics for dried multiply charged globular proteins at atmospheric pressures is also presented, showing that the charge reduction time must be carefully chosen to maximize a singly charged ion signal, while avoiding survival of contaminating multiply charged species. Because charge reduction limits the range of masses analyzable by MS, we also consider the potential of a parallel-plate DMA coupled in series to an MS for DMA-MS studies without charge reduction. PMID:16941442

  11. Genetic expression of adipose derived stem cell and smooth muscle cell markers to monitor differentiation potential following low intensity laser irradiation

    NASA Astrophysics Data System (ADS)

    Abrahamse, Heidi

    2014-02-01

    Mesenchymal stem cells (MSCs) have the capacity to differentiate into a variety of cell types that could potentially be used in tissue engineering and regenerative medicine. Low intensity laser irradiation (LILI) has been shown to induce a significant increase in cell viability and proliferation. Growth factors such as retinoic acid (RA) and transforming growth factor ?1 (TGF-?1) play important roles in the differentiation of cells. The aim of this study was to investigate whether LILI in combination with growth factors could induce the differentiation of adipose derived stem cells (ADSCs) cocultured with smooth muscle cells (SMCs). The study used primary and continuous ADSC cell lines and a SMC line (SKUT-1) as control. Cells were co-cultured directly at a ratio of 1:1 using established methods, with and without growth factors and then exposed to LILI at 5 J/cm2 using a 636 nm diode laser. The cellular morphology, viability and proliferation of the co-cultures were assessed over a period of one week. The study also monitored the expression of cell specific markers over the same period of time. Genetic expression of the markers for both adipose derived stem cells (?1 Integrin and Thymidine 1) and smooth muscle cells (Heavy Myosin Chain) was monitored using flow cytometry. Cell viability and proliferation increased significantly in the co-cultured groups that were exposed to laser alone, as well as in combination with growth factors. Furthermore, there was a significant decrease in the expression of stem cell markers in the ADSCs over time. The results indicate that LILI in combination with growth factors not only increases the viability and proliferation of co-cultured cells but also decreases the expression of ADSC stem cell markers. This could indicate the possible differentiation of ADSCs into SMCs.

  12. TeratoScore: Assessing the Differentiation Potential of Human Pluripotent Stem Cells by Quantitative Expression Analysis of Teratomas.

    PubMed

    Avior, Yishai; Biancotti, Juan Carlos; Benvenisty, Nissim

    2015-06-01

    Teratoma formation is the gold standard assay for testing the capacity of human pluripotent stem cells to differentiate into all embryonic germ layers. Although widely used, little effort has been made to transform this qualitative assay into a quantitative one. Using gene expression data from a wide variety of cells, we created a scorecard representing tissues from all germ layers and extraembryonic tissues. TeratoScore, an online, open-source platform based on this scorecard, distinguishes pluripotent stem cell-derived teratomas from malignant tumors, translating cell potency into a quantitative measure (http://benvenisty.huji.ac.il/teratoscore.php). The teratomas used for the algorithm also allowed us to examine gene expression differences between tumors with a diploid karyotype and those initiated by aneuploid cells. Chromosomally aberrant teratomas show a significantly different gene expression signature from that of teratomas originating from diploid cells, particularly in central nervous system-specific genes, congruent with human chromosomal syndromes. PMID:26070610

  13. TeratoScore: Assessing the Differentiation Potential of Human Pluripotent Stem Cells by Quantitative Expression Analysis of Teratomas

    PubMed Central

    Avior, Yishai; Biancotti, Juan Carlos; Benvenisty, Nissim

    2015-01-01

    Summary Teratoma formation is the gold standard assay for testing the capacity of human pluripotent stem cells to differentiate into all embryonic germ layers. Although widely used, little effort has been made to transform this qualitative assay into a quantitative one. Using gene expression data from a wide variety of cells, we created a scorecard representing tissues from all germ layers and extraembryonic tissues. TeratoScore, an online, open-source platform based on this scorecard, distinguishes pluripotent stem cell-derived teratomas from malignant tumors, translating cell potency into a quantitative measure (http://benvenisty.huji.ac.il/teratoscore.php). The teratomas used for the algorithm also allowed us to examine gene expression differences between tumors with a diploid karyotype and those initiated by aneuploid cells. Chromosomally aberrant teratomas show a significantly different gene expression signature from that of teratomas originating from diploid cells, particularly in central nervous system-specific genes, congruent with human chromosomal syndromes. PMID:26070610

  14. Serum Unsaturated Free Fatty Acids: A Potential Biomarker Panel for Differentiating Benign Thyroid Diseases from Thyroid Cancer

    PubMed Central

    Zhang, Yaping; Qiu, Ling; He, Chengyan; Wang, Yanmin; liu, Yujie; Zhang, Dan; Li, Zhili

    2015-01-01

    Background: Serum free fatty acids (FFAs) are correlated with pathological status, and change in serum FFA levels may be associated with thyroid diseases. Materials and Methods: In this study, 664 serum samples from 322 healthy controls, 129 patients with benign thyroid disease (BTD), and 213 patients with thyroid cancer (TC) were collected. Chip-based direct-infusion nanoelectrospray-mass spectrometry was performed to simultaneously quantify six serum FFAs (i.e., C16:1, C18:1, C18:2, C18:3, C20:4, and C22:6.), with the excellent correlation coefficients of > 0.99 and relative standard deviation of <18% for all analysts. The Mann-Whitney U test was used to compare the differences in serum FFA levels between three above-mentioned groups. Results: Significant increase in the levels of C16:1, C18:1, C18:2, C18:3, C20:4, and C22:6 in healthy controls relative to TC patients and BTD patients was observed, and the levels of C16:1, C18:2, C20:4, and C22:6 in BTD patients were significantly decreased relative to TC patients. Receiver operating characteristic (ROC) analysis indicated that a combination of C16:1, C18:2, C20:4, and C22:6 has excellent diagnostic performance to differentiate BTD patients from TC patients, with an area under the ROC curve of 0.857, a sensitivity of 76.8%, and a specificity of 83.7%. Conclusions: Change in serum levels of FFAs is closely correlated with thyroid diseases, and a biomarker panel (C16:1, C18:2, C20:4, and C22:6) should be of benefit to differentiate BTD patients from TC patients. PMID:26640588

  15. Comparative genomics of multiple strains of Pseudomonas cannabina pv. alisalensis, a potential model pathogen of both Monocots and Dicots

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Comparative genomics of closely related pathogens that differ in host range can provide insights into mechanisms of host-pathogen interactions and host adaptation. Sequencing multiple strains of the same pathogen further reveals information concerning pathogen diversity and the molecular basis of vi...

  16. Non-differentiability of the effective potential and the replica symmetry breaking in the random energy model

    NASA Astrophysics Data System (ADS)

    Mukaida, Hisamitsu

    2016-01-01

    The effective potential for the two-replica system of the random energy model is exactly derived. It is an analytic function of the magnetizations of two replicas, {\\varphi }1 and {\\varphi }2 in the high-temperature phase. In the low-temperature phase, where the replica symmetry breaking takes place, the effective potential becomes non-analytic when {\\varphi }1={\\varphi }2. The non-analyticity is considered as a consequence of the condensation of the Boltzmann measure, which is a typical property of a glass phase.

  17. Differentiation among Multiple Sources of Anthropogenic Nitrate in a Complex Groundwater System using Dual Isotope Systematics: A case study from Mortandad Canyon, New Mexico

    NASA Astrophysics Data System (ADS)

    Larson, T. E.; Perkins, G.; Longmire, P.; Heikoop, J. M.; Fessenden, J. E.; Rearick, M.; Fabyrka-Martin, J.; Chrystal, A. E.; Dale, M.; Simmons, A. M.

    2009-12-01

    The groundwater system beneath Los Alamos National Laboratory has been affected by multiple sources of anthropogenic nitrate contamination. Average NO3-N concentrations of up to 18.2±1.7 mg/L have been found in wells in the perched intermediate aquifer beneath one of the more affected sites within Mortandad Canyon. Sources of nitrate potentially reaching the alluvial and intermediate aquifers include: (1) sewage effluent, (2) neutralized nitric acid, (3) neutralized 15N-depleted nitric acid (treated waste from an experiment enriching nitric acid in 15N), and (4) natural background nitrate. Each of these sources is unique in ?18O and ?15N space. Using nitrate stable isotope ratios, a mixing model for the three anthropogenic sources of nitrate was established, after applying a linear subtraction of the background component. The spatial and temporal variability in nitrate contaminant sources through Mortandad Canyon is clearly shown in ternary plots. While microbial denitrification has been shown to change groundwater nitrate stable isotope ratios in other settings, the redox potential, relatively high dissolved oxygen content, increasing nitrate concentrations over time, and lack of observed NO2 in these wells suggest minimal changes to the stable isotope ratios have occurred. Temporal trends indicate that the earliest form of anthropogenic nitrate in this watershed was neutralized nitric acid. Alluvial wells preserve a trend of decreasing nitrate concentrations and mixing models show decreasing contributions of 15N-depleted nitric acid. Nearby intermediate wells show increasing nitrate concentrations and mixing models indicate a larger component derived from 15N-depleted nitric acid. These data indicate that the pulse of neutralized 15N-depleted nitric acid that was released into Mortandad Canyon between 1986 and 1989 has infiltrated through the alluvial aquifer and is currently affecting two intermediate wells. This hypothesis is consistent with previous research suggesting that the perched intermediate aquifers in the Mortandad Canyon watershed are recharged locally from the overlying alluvial aquifers.

  18. The Effect of Age on Osteogenic and Adipogenic Differentiation Potential of Human Adipose Derived Stromal Stem Cells (hASCs) and the Impact of Stress Factors in the Course of the Differentiation Process.

    PubMed

    Kornicka, Katarzyna; Marycz, Krzysztof; Tomaszewski, Krzysztof Andrzej; Mar?dziak, Monika; ?mieszek, Agnieszka

    2015-01-01

    Human adipose tissue is a great source of autologous mesenchymal stem cells (hASCs), which are recognized for their vast therapeutic applications. Their ability to self-renew and differentiate into several lineages makes them a promising tool for cell-based therapies in different types of degenerative diseases. Thus it is crucial to evaluate age-related changes in hASCs, as the elderly are a group that will benefit most from their considerable potential. In this study we investigated the effect of donor age on growth kinetics, cellular senescence marker levels, and osteogenic and adipogenic potential of hASCs. It also has been known that, during life, organisms accumulate oxidative damage that negatively affects cell metabolism. Taking this into consideration, we evaluated the levels of nitric oxide, reactive oxygen species, and superoxide dismutase activity. We observed that ROS and NO increase with aging, while SOD activity is significantly reduced. Moreover cells obtained from older patients displayed senescence associated features, for example, ?-galactosidase activity, enlarged morphology, and p53 protein upregulation. All of those characteristics seem to contribute to decreased proliferation potential of those cells. Our results suggest that due to aging some cellular modification may be required before applying aged cells efficiently in therapies such as tissue engineering and regenerative medicine. PMID:26246868

  19. The Effect of Age on Osteogenic and Adipogenic Differentiation Potential of Human Adipose Derived Stromal Stem Cells (hASCs) and the Impact of Stress Factors in the Course of the Differentiation Process

    PubMed Central

    Kornicka, Katarzyna; Marycz, Krzysztof; Tomaszewski, Krzysztof Andrzej; Mar?dziak, Monika; ?mieszek, Agnieszka

    2015-01-01

    Human adipose tissue is a great source of autologous mesenchymal stem cells (hASCs), which are recognized for their vast therapeutic applications. Their ability to self-renew and differentiate into several lineages makes them a promising tool for cell-based therapies in different types of degenerative diseases. Thus it is crucial to evaluate age-related changes in hASCs, as the elderly are a group that will benefit most from their considerable potential. In this study we investigated the effect of donor age on growth kinetics, cellular senescence marker levels, and osteogenic and adipogenic potential of hASCs. It also has been known that, during life, organisms accumulate oxidative damage that negatively affects cell metabolism. Taking this into consideration, we evaluated the levels of nitric oxide, reactive oxygen species, and superoxide dismutase activity. We observed that ROS and NO increase with aging, while SOD activity is significantly reduced. Moreover cells obtained from older patients displayed senescence associated features, for example, ?-galactosidase activity, enlarged morphology, and p53 protein upregulation. All of those characteristics seem to contribute to decreased proliferation potential of those cells. Our results suggest that due to aging some cellular modification may be required before applying aged cells efficiently in therapies such as tissue engineering and regenerative medicine. PMID:26246868

  20. The calculus of the electric potential and field intensity in multiple electrodes lateral tunneling transistors with double gate

    E-print Network

    Sever Spanulescu

    2009-12-15

    The paper presents an adaptive over-relaxation method for calculating the electric potential and field intensity, for a complex tunnel transistor structure involving a split gate and a shielding boundary. The accuracy and speed of the method has been numerically tested and found satisfactory for the study of such devices by calculating the tunneling currents for the obtained potential distribution.

  1. Isolation and characterization of beta-glucan synthase: A potential biochemical regulator of gravistimulated differential cell wall loosening

    NASA Technical Reports Server (NTRS)

    Kuzmanoff, K. M.

    1984-01-01

    In plants, gravity stimulates differential growth in the upper and lower halves of horizontally oriented organs. Auxin regulation of cell wall loosening and elongation is the basis for most models of this phenomenon. Auxin treatment of pea stem tissue rapidly increases the activity of Golgi-localized Beta-1,4-glucan synthase, an enzyme involved in biosynthesis of wall xyloglucan which apparently constitutes the substrate for the wall loosening process. The primary objective is to determine if auxin induces de novo formation of Golgi glucan synthase and increases the level of this glucan synthase mRNA. This shall be accomplished by (a) preparation of a monoclonal antibody to the synthase, (b) isolation, and characterization of the glucan synthase, and (c) examination for cross reactivity between the antibody and translation products of auxin induced mRNAs in pea tissue. The antibody will also be used to localize the glucan synthase in upper and lower halves of pea stem tissue before, during and after the response to gravity.

  2. Differential expression of proteoglycans on the surface of human melanoma cells characterized by altered experimental metastatic potential.

    PubMed Central

    Timar, J.; Ladanyi, A.; Lapis, K.; Moczar, M.

    1992-01-01

    Heparan sulphate (HS) and chondroitin sulphate (CS) proteoglycans (PGs) frequently have opposite biologic functions in cell-matrix adhesion as well as in the regulation of cell proliferation. Data revealed that sulphated glycosaminoglycans (sGAGs) (sugar chains of PGs) are differently expressed in tumor cells characterized by different metastatic potential; the more metastatic cells contain a higher HS/CS ratio. As the proliferative capacity of tumor cells is also frequently altered in parallel with their metastatic potential, it was not clear whether observed PG alterations reflect changes in cell proliferation or metastatic potential. The cell-associated PG expression and sGAG biosynthesis was studied in tumor cells of human melanoma lines characterized by different experimental metastatic potential to the mouse liver but similar in vitro/in vivo proliferation rates. Using antibodies against PGs we found different expression of PG epitopes in melanoma lines, except from the melanoma antigen. Unlike the low CSPG (melCSPG) metastatic melanoma cells, the cell line with high metastatic capacity contained a higher proportion of positive cells for surface-HSPG without the coexpression of certain cartilage-type CSPG epitopes (recognized by MAb HSFPG 529) as well as by an increased pericellular HS/CS ratio due to intracellular accumulation/retention of CS. Immunocytochemistry of adherent cells revealed HSPGs at substrate-attached membrane areas only in cases of highly metastatic melanoma cells. These data further support our view that the absolute or relative dominance of HSPGs over CSPGs at the cell surface of metastatic tumor cells can be considered a marker of a more metastatic phenotype. Images Figure 1 to 2 Figure 3 to 4 Figure 5 PMID:1379782

  3. Unmasking the effects of masking on performance: The potential of multiple-voice masking in the office environment.

    PubMed

    Keus van de Poll, Marijke; Carlsson, Johannes; Marsh, John E; Ljung, Robert; Odelius, Johan; Schlittmeier, Sabine J; Sundin, Gunilla; Sörqvist, Patrik

    2015-08-01

    Broadband noise is often used as a masking sound to combat the negative consequences of background speech on performance in open-plan offices. As office workers generally dislike broadband noise, it is important to find alternatives that are more appreciated while being at least not less effective. The purpose of experiment 1 was to compare broadband noise with two alternatives-multiple voices and water waves-in the context of a serial short-term memory task. A single voice impaired memory in comparison with silence, but when the single voice was masked with multiple voices, performance was on level with silence. Experiment 2 explored the benefits of multiple-voice masking in more detail (by comparing one voice, three voices, five voices, and seven voices) in the context of word processed writing (arguably a more office-relevant task). Performance (i.e., writing fluency) increased linearly from worst performance in the one-voice condition to best performance in the seven-voice condition. Psychological mechanisms underpinning these effects are discussed. PMID:26328697

  4. Between-Lesion Discrepancies in Terms of Dysplasia, Cell Turnover and Diagnosis in Patients with Multiple Potentially Malignant Oral Lesions

    PubMed Central

    Lucio, Montebugnoli; Andrea, Gabusi; Bartolomeo, Gissi Davide; Fabio, Cervellati; Dora, Servidio

    2013-01-01

    Objective: The present study assessed patients with multiple oral lesions to evaluate the mis-estimation rate in terms of diagnosis and risk of malignant transformation when only one biopsy is performed. Study Design: Thirty-five patients presenting at least two white and/or red lesions in different oral mucosa sites with a final diagnosis of leuko/erythroplakias or lichenoid lesions were included, for a total of 70 biopsies. Results: Nineteen patients (54%) had at least one between-lesion discrepancy considering the presence/absence of dysplasia (10 patients), normal/high cell turnover (13 patients) or diagnosis (5 patients). Discrepancies were not related to clinical aspect or within-patient similarity of lesions. Conclusions: Multiple oral lesions in the same patient can significantly differ in terms of dysplasia, high cell turnover and, even diagnosis. Multiple biopsies are imperative and diagnosis as well as risk of malignant transformation should be formulated for each single lesion rather than for each individual patient. PMID:24363787

  5. Potential for Measurement of Trace Volatile Organic Compounds in Closed Environments Using Gas Chromatograph/Differential Mobility Spectrometer

    NASA Technical Reports Server (NTRS)

    Limero, Thomas; Cheng, Patti

    2007-01-01

    For nearly 3.5 years, the Volatile Organic Analyzer (VOA) has routinely analyzed the International Space Station (ISS) atmosphere for a target list of approximately 20 volatile organic compounds (VOCs). Additionally, an early prototype of the VOA collected data aboard submarines in two separate trials. Comparison of the data collected on ISS and submarines showed a surprising similarity in the atmospheres of the two environments. Furthermore, in both cases it was demonstrated that the VOA data can detect hardware issues unrelated to crew health. Finally, it was also clear in both operations that the VOA s size and resource consumption were major disadvantages that would restrict its use in the future. The VOA showed the value of measuring VOCs in closed environments, but it had to be shrunk if it was to be considered for future operations in these environments that are characterized by cramped spaces and limited resources. The Sionex Microanalyzer is a fraction of the VOA s size and this instrument seems capable of maintaining or improving upon the analytical performance of the VOA. The two design improvements that led to a smaller, less complex instrument are the Microanalyzer s use of recirculated air as the gas chromatograph s carrier gas and a micromachined detector. Although the VOA s ion mobility spectrometer and the Microanalyzer s differential mobility spectrometer (DMS) are related detector technologies, the DMS was more amenable to micromachining. This paper will present data from the initial assessment of the Microanalyzer. The instrument was challenged with mixtures that simulated the VOCs typically detected in closed-environment atmospheres.

  6. Evaluation of a Gas Chromatograph-Differential Mobility Spectrometer for Potential Water Monitoring on the International Space Station

    NASA Technical Reports Server (NTRS)

    Wallace, William T.; Limero, Thomas F.; Gazda, Daniel B.; Macatangay, Ariel V.; Dwivedi, Prabha; Fernandez, Facundo M.

    2015-01-01

    Environmental monitoring for manned spaceflight has long depended on archival sampling, which was sufficient for short missions. However, the longer mission durations aboard the International Space Station (ISS) have shown that enhanced, real-time monitoring capabilities are necessary in order to protect both the crewmembers and the spacecraft systems. Over the past several years, a number of real-time environmental monitors have been deployed on the ISS. Currently, volatile organic compounds (VOCs) in the station air are monitored by the Air Quality Monitor (AQM), a small, lightweight gas chromatograph-differential mobility spectrometer. For water monitoring, real-time monitors are used for total organic carbon (TOC) and biocide analysis. No information on the actual makeup of the TOC is provided presently, however. An improvement to the current state of environmental monitoring could be realized by modifying a single instrument to analyze both air and water. As the AQM currently provides quantitative, compound-specific information for VOCs in air samples, this instrument provides a logical starting point to evaluate the feasibility of this approach. The major hurdle for this effort lies in the liberation of the target analytes from the water matrix. In this presentation, we will discuss our recent studies, in which an electro-thermal vaporization unit has been interfaced with the AQM to analyze target VOCs at the concentrations at which they are routinely detected in archival water samples from the ISS. We will compare the results of these studies with those obtained from the instrumentation routinely used to analyze archival water samples.

  7. Multiple fruit-flavored alcoholic drinks in a can (MFAC): an overlooked class of potentially harmful alcohol products.

    PubMed

    Rossheim, Matthew E; Thombs, Dennis L

    2013-09-01

    This article examines an overlooked class of alcohol products, described herein as multiple fruit-flavored alcoholic drinks in a can (MFAC). The article describes how characteristics of these products likely contribute to hazardous alcohol consumption among youth. Government regulation of these products may be needed to protect adolescent and young adult populations. National substance abuse surveillance systems should consider immediate adoption of MFAC use indicators to determine use and harm associated with these products, and to assess the effectiveness of future regulatory actions. PMID:23968170

  8. Differentially Expressed Androgen-Regulated Genes in Androgen-Sensitive Tissues Reveal Potential Biomarkers of Early Prostate Cancer

    PubMed Central

    Altintas, Dogus Murat; Allioli, Nathalie; Decaussin, Myriam; de Bernard, Simon; Ruffion, Alain; Samarut, Jacques; Vlaeminck-Guillem, Virginie

    2013-01-01

    Background Several data favor androgen receptor implication in prostate cancer initiation through the induction of several gene activation programs. The aim of the study is to identify potential biomarkers for early diagnosis of prostate cancer (PCa) among androgen-regulated genes (ARG) and to evaluate comparative expression of these genes in normal prostate and normal prostate-related androgen-sensitive tissues that do not (or rarely) give rise to cancer. Methods ARG were selected in non-neoplastic adult human prostatic epithelial RWPE-1 cells stably expressing an exogenous human androgen receptor, using RNA-microarrays and validation by qRT-PCR. Expression of 48 preselected genes was quantified in tissue samples (seminal vesicles, prostate transitional zones and prostate cancers, benign prostatic hypertrophy obtained from surgical specimens) using TaqMan® low-density arrays. The diagnostic performances of these potential biomarkers were compared to that of genes known to be associated with PCa (i.e. PCA3 and DLX1). Results and Discussion By crossing expression studies in 26 matched PCa and normal prostate transitional zone samples, and 35 matched seminal vesicle and PCa samples, 14 genes were identified. Similarly, 9 genes were overexpressed in 15 benign prostatic hypertrophy samples, as compared to PCa samples. Overall, we selected 8 genes of interest to evaluate their diagnostic performances in comparison with that of PCA3 and DLX1. Among them, 3 genes: CRYAB, KCNMA1 and SDPR, were overexpressed in all 3 reference non-cancerous tissues. The areas under ROC curves of these genes reached those of PCA3 (0.91) and DLX1 (0.94). Conclusions We identified ARG with reduced expression in PCa and with significant diagnostic values for discriminating between cancerous and non-cancerous prostatic tissues, similar that of PCA3. Given their expression pattern, they could be considered as potentially protective against prostate cancer. Moreover, they could be complementary to known genes overexpressed in PCa and included along with them in multiplex diagnostic tools. PMID:23840433

  9. Detection of Differentially Expressed MicroRNAs in Rheumatic Heart Disease: miR-1183 and miR-1299 as Potential Diagnostic Biomarkers

    PubMed Central

    Li, Ni; Lian, Jiangfang; Zhao, Sheng; Zheng, Dawei; Yang, Xi; Huang, Xiaoyan; Shi, Xinbao; Sun, Lebo; Zhou, Qingyun; Shi, Huoshun; Xu, Guodong; Incoom, Enchill KoJo; Zhou, Jianqing; Shao, Guofeng

    2015-01-01

    This study compared microRNA (miRNA) expression profiles between rheumatic heart disease (RHD) patients and healthy controls to investigate their differential expression and help elucidate their mechanisms of action. Microarray analysis was used to measure miRNA expression, and a total of 133 miRNAs were shown to be significantly upregulated in RHD patients compared with controls, including miR-1183 and miR-1299. A total of 137 miRNAs, including miR-4423-3p and miR-218-1-3p, were significantly downregulated in RHD patients. Quantitative real-time-PCR confirmed microarray findings for miR-1183 and miR-1299 in both tissue and plasma. Bioinformatic predictions were also made of differentially expressed miRNAs as biomarkers in RHD by databases and GO/pathway analysis. Furthermore, we investigated miR-1183 and miR-1299 expression in RHD patients with secondary pulmonary hypertension (PAH). Our findings identified an important role for miR-1299 as a direct regulator of RHD, while the observed difference in expression of miR-1183 between RHD-PAH patients with high or low pulmonary artery pressure suggests that miR-1183 overexpression may reflect pulmonary artery remodeling. miR-1183 and miR-1299 appear to play distinct roles in RHD pathogenesis accompanied by secondary PAH and could be used as potential biological markers for disease development. PMID:26539505

  10. Characteristics of Evoked Potential Multiple EEG Recordings in Patients with Chronic Pain by Means of Parallel Factor Analysis

    PubMed Central

    Wang, Juan; Li, Xiaoli; Lu, Chengbiao; Voss, Logan J.; Barnard, John P. M.; Sleigh, Jamie W.

    2012-01-01

    This paper presents an alternative method, called as parallel factor analysis (PARAFAC) with a continuous wavelet transform, to analyze of brain activity in patients with chronic pain in the time-frequency-channel domain and quantifies differences between chronic pain patients and controls in these domains. The event related multiple EEG recordings of the chronic pain patients and non-pain controls with somatosensory stimuli (pain, random pain, touch, random touch) are analyzed. Multiple linear regression (MLR) is applied to describe the effects of aging on the frequency response differences between patients and controls. The results show that the somatosensory cortical responses occurred around 250?ms in both groups. In the frequency domain, the neural response frequency in the pain group (around 4?Hz) was less than that in the control group (around 5.5?Hz) under the somatosensory stimuli. In the channel domain, cortical activation was predominant in the frontal region for the chronic pain group and in the central region for controls. The indices of active ratios were statistical significant between the two groups in the frontal and central regions. These findings demonstrate that the PARAFAC is an interesting method to understanding the pathophysiological characteristics of chronic pain. PMID:22400048

  11. Multiple Case Studies of Teachers and Classrooms Successful in Supporting Academic Success of High Potential Low Economic Students of Color

    ERIC Educational Resources Information Center

    Tomlinson, Carol Ann; Gould, Holly; Schroth, Stephen; Jarvis, Jane

    2006-01-01

    The National Research Center on the Gifted and Talented at the University of Virginia conducted a 4-year qualitative case study in three very different school sites to explore how teachers contribute to the academic success of high potential, low economic students of color. Typically, the ethnicity, race, and/or economic status of these…

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

    E-print Network

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

    2015-01-01

    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 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 January 26, 2015, 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 meters and a secondary diameter of 50-100 meters. 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 (Bowell et al. 1989) and the Shevchenko model (Shevchenko 1996). From the fi...

  13. Differential gene expression profiling of Listeria monocytogenes in Cacciatore and Felino salami to reveal potential stress resistance biomarkers.

    PubMed

    Mataragas, M; Rovetto, F; Bellio, A; Alessandria, V; Rantsiou, K; Decastelli, L; Cocolin, L

    2015-04-01

    The current study reports a) the in situ transcriptional profiles of Listeria monocytogenes in response to fermented sausage stress and b) an approach in which in situ RT-qPCR data have been combined with advanced statistical techniques to discover potential stress resistance or cell viability biomarkers. Gene expression profiling of the pathogen has been investigated using RT-qPCR to understand how L. monocytogenes responds to the conditions encountered during the fermentation and ripening of sausages. A cocktail of five L. monocytogenes strains was inoculated into the batter of Cacciatore and Felino sausages. The RT-qPCR data showed that the acidic and osmotic stress-related genes were up-regulated. The transcripts of the lmo0669 gene increased during the fermentation and ripening of Cacciatore, whereas gbuA and lmo1421 were up-regulated during the ripening of Felino and Cacciatore, respectively. sigB expression was induced in both sausages throughout the whole process. Finally, the virulence-related gene prfA was down-regulated during the fermentation of Cacciatore. The multivariate gene expression profiling analysis suggested that sigB and lmo1421 or sigB and gbuA could be used as different types of stress resistance biomarkers to track, for example, stress resistance or cell viability in fermented sausages with short (Cacciatore) or long (Felino) maturation times, respectively. PMID:25475310

  14. Differential expression of transforming growth factor-beta in benign vs. papillary thyroid cancer nodules; a potential diagnostic tool?

    PubMed Central

    2014-01-01

    Background Thyroid nodules are common, but only 5% of nodules are found to be malignant. In North America, the incidence of thyroid cancer is increasing. Fine needle aspirate (FNA) biopsy is the diagnostic test of choice. Unfortunately, up to 20% of FNAs are non-diagnostic. A specific molecular marker for thyroid cancer is desirable. Evidence suggests that cell signaling through transforming growth factor beta (TGF- ?) is important in the development of thyroid cancer. We sought to compare the expression of TGF- ? in malignant and benign thyroid nodules. Methods From 2008-present, thyroid nodule tissue from thyroidectomy specimens was prospectively collected and stored at ?80°C. RNA extraction and reverse transcription was performed on 47 samples (24 papillary thyroid cancer and 23 benign nodules). Quantitative PCR using SYBR green was performed to detect TGF-?-1 and ?2. Resulting CT values were normalized against ?-actin. Gene expression was calculated using the 2-?CT method. Results A significantly greater expression of TGF- ?1 (p?potential diagnostic marker for papillary thyroid cancer. PMID:25927212

  15. Mesenchymal Stem Cells Obtained from Synovial Fluid Mesenchymal Stem Cell-Derived Induced Pluripotent Stem Cells on a Matrigel Coating Exhibited Enhanced Proliferation and Differentiation Potential

    PubMed Central

    Zhang, Hong; Liu, Wen-Jing; Jiang, Rui; Li, Wen-Yu; Zheng, You-Hua; Zhang, Zhi-Guang

    2015-01-01

    Induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) serve as a promising source for cell-based therapies in regenerative medicine. However, optimal methods for transforming iPSCs into MSCs and the characteristics of iPSC-MSCs obtained from different methods remain poorly understood. In this study, we developed a one-step method for obtaining iPSC-MSCs (CD146+STRO-1+ MSCs) from human synovial fluid MSC-derived induced iPSCs (SFMSC-iPSCs). CD146-STRO-1-SFMSCs were reprogrammed into iPSCs by transduction with lentivirus-mediated Sox2, Oct-3/4, klf4, and c-Myc. SFMSC-iPSCs were maintained with mTeSR1 medium in Matrigel-coated culture plates. Single dissociated cells were obtained by digesting the SFMSC-iPSCs with trypsin. The dissociated cells were then plated into Matrigel-coated culture plate with alpha minimum essential medium supplemented with 10% fetal bovine serum, 1× Glutamax, and the ROCK inhibitor Y-27632. Cells were then passaged in standard cell culture plates with alpha minimum essential medium supplemented with 10% fetal bovine serum and 1× Glutamax. After passaging in vitro, the cells showed a homogenous spindle-shape similar to their ancestor cells (SFMSCs), but with more robust proliferative activity. Flow cytometric analysis revealed typical MSC surface markers, including expression of CD73, CD90, CD105, and CD44 and lack of CD45, CD34, CD11b, CD19, and HLA-DR. However, these cells were positive for CD146 and stro-1, which the ancestor cells were not. Moreover, the cells could also be induced to differentiate in osteogenic, chondrogenic, and adipogenic lineages in vitro. The differentiation potential was improved compared with the ancestor cells in vitro. The cells were not found to exhibit oncogenicity in vivo. Therefore, the method presented herein facilitated the generation of STRO-1+CD146+ MSCs from SFMSC-iPSCs exhibiting enhanced proliferation and differentiation potential. PMID:26649753

  16. PHYS 301 --Introduction to Mathematical Physics Chapter 4 Partial Differentiation (Section 11-12), Chapter 5 Multiple Integrals (Section 1-4)

    E-print Network

    Ng, Chung-Sang

    is needed. (ii) In doing a calculation with a multiple integral, it is important to consider carefully, it is essential to consider carefully how integration limits can be expressed in terms of new variables. (iii) We

  17. [Prognosis and therapy of multiple myeloma].

    TOXLINE Toxicology Bibliographic Information

    Sonntag RW

    1978-08-12

    Criteria for the diagnosis of multiple myeloma and differential diagnostic considerations are presented. The indications for treatment are discussed. Combination of melphalan or cyclophosphamide with prednisone may be considered standard therapy today. This produces objective tumor regression in 50-70% of patients. The parameters for determining remission and their significance with regard to survival and tumor cell mass are discussed. The importance of supportive measures is stressed. Persistent problems and potential for improving present therapy are discussed.

  18. X-ray absorption spectra of graphene and graphene oxide by full-potential multiple scattering calculations with self-consistent charge density

    NASA Astrophysics Data System (ADS)

    Xu, Junqing; Krüger, Peter; Natoli, Calogero R.; Hayakawa, Kuniko; Wu, Ziyu; Hatada, Keisuke

    2015-09-01

    The x-ray absorption near-edge structure of graphene, graphene oxide, and diamond is studied by the recently developed real-space full potential multiple scattering (FPMS) theory with space-filling cells. It is shown how accurate potentials for FPMS can be generated from self-consistent charge densities obtained with other schemes, especially the projector augmented wave method. Compared to standard multiple scattering calculations in the muffin-tin approximation, FPMS gives much better agreement with experiment. The effects of various structural modifications on the graphene spectra are well reproduced. (1) Stacking of graphene layers increases the peak intensity in the higher energy region. (2) The spectrum of the C atom located at the edge of a graphene sheet shows a prominent pre-edge structure. (3) Adsorption of oxygen gives rise to the so-called interlayer-state peak. Moreover, O K-edge spectra of graphene oxide are calculated for three types of bonding, C-OH, C-O-C, and C-O, and the proportions of these bondings at 800 ?C are deduced by fitting them to the experimental spectrum.

  19. Feasibility and potential effectiveness of a non-pharmacological multidisciplinary care programme for persons with generalised osteoarthritis: a randomised, multiple-baseline single-case study

    PubMed Central

    Kwakkenbos, Linda; Rietveld, Leonie; den Broeder, Alfons A; de Bie, Rob A; van den Ende, Cornelia H M

    2012-01-01

    Objectives To evaluate the feasibility and potential effectiveness of a 12-week, non-pharmacological multidisciplinary intervention in patients with generalised osteoarthritis (GOA). Design A randomised, concurrent, multiple-baseline single-case design. During the baseline period, the intervention period and the postintervention period, all participants completed several health outcomes twice a week on Visual Analogue Scales. Setting Rheumatology outpatient department of a specialised hospital in the Netherlands. Participants 1 man and four women (aged 51–76?years) diagnosed with GOA. Primary outcome measures To assess feasibility, the authors assessed the number of dropouts and adverse events, adherence rates and patients' satisfaction. Secondary outcome measures To assess the potential effectiveness, the authors assessed pain and self-efficacy using visual data inspection and randomisation tests. Results The intervention was feasible in terms of adverse events (none) and adherence rate but not in terms of participants' satisfaction with the intervention. Visual inspection of the data and randomisation testing demonstrated no effects on pain (p=0.93) or self-efficacy (p=0.85). Conclusions The results of the present study indicate that the proposed intervention for patients with GOA was insufficiently feasible and effective. The data obtained through this multiple-baseline study have highlighted several areas in which the therapy programme can be optimised. PMID:22815466

  20. Potential of the reversed-inject differential flow modulator for comprehensive two-dimensional gas chromatography in the quantitative profiling and fingerprinting of essential oils of different complexity.

    PubMed

    Cordero, Chiara; Rubiolo, Patrizia; Cobelli, Luigi; Stani, Gianluca; Miliazza, Armando; Giardina, Matthew; Firor, Roger; Bicchi, Carlo

    2015-10-23

    In this study, the first capillary flow technology reverse-inject differential flow modulator was implemented with different column configurations (lengths, diameters and stationary phase coupling) and detector combinations (mass spectrometry--MS and flame ionization detection--FID) to evaluate its potential in the quantitative profiling and fingerprinting of medium-to-highly complex essential oils. In particular, a parallel dual-secondary column dual-detection configuration that has shown to improve the information potential also with thermally modulated GC × GC platforms (MS identification reliability and accurate FID quantitation), was tested. Several system performance parameters (separation measure SGC × GC, modulation ratio MR, separation space used and peak symmetry) were evaluated by analyzing a mixture of volatiles of interest in the flavor and fragrance field. The systems demonstrating the best chromatographic performance were selected for quantitative profiling of lavender and mint essential oils and fingerprinting of vetiver essential oil. Experimental results demonstrate that careful tuning of column dimensions and system configurations yields improved: (a) selectivity; (b) operable carrier gas linear velocities at close-to-optimal values; (c) (2)D separation power by extending the modulation period and (d) handling of overloaded peaks without dramatic losses in resolution and quantitative accuracy. PMID:26387790

  1. Myeloid differentiation primary response gene 88-leukotriene B4 receptor 2 cascade mediates lipopolysaccharide-potentiated invasiveness of breast cancer cells

    PubMed Central

    Park, Geun-Soo; Kim, Jae-Hong

    2015-01-01

    Inflammation and local inflammatory mediators are inextricably linked to tumor progression through complex pathways in the tumor microenvironment. Lipopolysaccharide (LPS) exposure to tumor cells has been suggested to promote tumor invasiveness and metastasis. However, the detailed signaling mechanism involved has not been elucidated. In this study, we showed that LPS upregulated the expression of leukotriene B4 receptor-2 (BLT2) and the synthesis of BLT2 ligands in MDA-MB-231 and MDA-MB-435 breast cancer cells, thereby promoting invasiveness. BLT2 depletion with siRNA clearly attenuated LPS-induced invasiveness. In addition, we demonstrated that myeloid differentiation primary response gene 88 (MyD88) lies upstream of BLT2 in LPS-potentiated invasiveness and that this ‘MyD88-BLT2’ cascade mediates activation of NF-?B and the synthesis of IL-6 and IL-8, which are critical for the invasiveness and aggression of breast cancer cells. LPS-driven metastasis of MDA-MB-231 cells was also markedly suppressed by the inhibition of BLT2. Together, our results demonstrate, for the first time, that LPS potentiates the invasiveness and metastasis of breast cancer cells via a ‘MyD88-BLT2’-linked signaling cascade. PMID:25691060

  2. Central nervous system multiple myeloma--potential roles for intrathecal therapy and measurement of cerebrospinal fluid light chains.

    PubMed

    Lee, Denise; Kalff, Anna; Low, Michael; Gangatharan, Shane; Ho, Prahlad; Bajel, Ashish; Ritchie, David; Grigg, Andrew; Spencer, Andrew

    2013-08-01

    Central nervous system (CNS) multiple myeloma (MM) is exceedingly rare and portends a dismal prognosis. While immunomodulators have contributed to the improvement in survival in MM, they appear to have limited activity against CNS MM and, paradoxically, may contribute to the evolution of resistant MM clones capable of surviving within the CNS. We undertook a retrospective analysis to characterize the features of CNS MM and outcome in 17 patients from four institutions identified between 2000 and 2011. The median age was 58 years. Patients had received a median of three prior therapies and all had been exposed to at least one of the so-called novel anti-MM agents before the diagnosis of CNS MM. The median time to CNS disease from initial diagnosis was 36 months. Cerebrospinal fluid (CSF) light chain measurements produced discrepant results to serum light chain measurements in some patients. Treatments included systemic pharmacotherapy, intrathecal (IT) chemotherapy and/or radiotherapy (RT). The median overall survival (OS) from diagnosis of CNS MM was only 4 months. OS was significantly better in patients who received IT chemotherapy (20 months vs. 2 months, respectively; P < 0.02). We conclude that the systematic evaluation of IT therapy and diagnostic utility of CSF light chain measurements in CNS MM are warranted. PMID:23718539

  3. Multiple Sources of Infection and Potential Endemic Characteristics of the Large Outbreak of Dengue in Guangdong in 2014

    PubMed Central

    Shen, Shu-Qun; Wei, Hai-Xia; Fu, Yong-Hang; Zhang, Hao; Mo, Qing-Yi; Wang, Xiao-Jun; Deng, Sheng-Qun; Zhao, Wei; Liu, Yu; Feng, Xiao-Shuang; Chen, Wei; Peng, Hong-Juan

    2015-01-01

    A large outbreak of dengue, with the most documented cases, occurred in Guangdong China in 2014. Epidemiological studies and phylogenetic analysis of the isolated dengue virus (DENV) showed this outbreak was attributed to multiple sources and caused by at least two genotypes of DENV-1 (Genotypes I and III) and two genotypes of DENV-2 (Cosmopolitan and Asian I Genotypes). A retrospective review and phylogenetic analysis of DENV isolated in Guangdong showed that DENV-1 Genotype I strains were reported continuously during 2004–2014, Genotype III strains were reported during 2009–2014 ; DENV-2 Cosmopolitan and Asian I Genotype strains were reported continuously during 2012–2014. At least 45,171 cases were reported in this outbreak, with 65.9% of the patients in the 21–55-year-old group. A trend toward a decrease in the daily newly emerged cases lagged by approximately 20 days compared with the mosquito density curve. Several epidemiological characteristics of this outbreak and the stably sustained serotypes and genotypes of DENV isolated in Guangdong suggest that Guangdong has been facing a threat of transforming from a dengue epidemic area to an endemic area. The high temperature, drenching rain, rapid urbanization, and pandemic of dengue in Southeast Asia may have contributed to this large outbreak of dengue. PMID:26593240

  4. Anti-inflammatory mechanisms of IFN-? studied in experimental autoimmune encephalomyelitis reveal neutrophils as a potential target in multiple sclerosis

    PubMed Central

    Miller, Nichole M.; Wang, Jun; Tan, Yanping; Dittel, Bonnie N.

    2015-01-01

    Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) mediated by T helper (h)1 and/or Th17 CD4 T cells that drive inflammatory lesion development along with demyelination and neuronal damage. Defects in immune regulatory mechanisms are thought to play a role in the pathogenesis of MS. While an early clinical trial indicated that IFN-? administration was detrimental to MS, studies in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), indicated that IFN-? exhibits a number of anti-inflammatory properties within the CNS. These mechanisms include inhibition of IL-17 production, induction of regulatory T cells, T cell apoptosis and regulation of chemokine production. Mice deficient in IFN-? or its receptor were instrumental in deciphering the anti-inflammatory properties of IFN-? in the CNS. In particular, they revealed that IFN-? is a major regulator of neutrophil recruitment into the CNS, which by a variety of mechanisms including disruption of the blood-brain-barrier (BBB) and production of reactive oxygen species are thought to contribute to the onset and progression of EAE. Neutrophils were also shown to be instrumental in EAE relapses. To date neutrophils have not been appreciated as a driver of MS, but more recently based largely on strong EAE data this view is being reevaluated by some investigators in the field. PMID:26347600

  5. A Fresh Look at the Potential Mechanisms of Progressive Muscle Relaxation Therapy on Depression in Female Patients With Multiple Sclerosis

    PubMed Central

    Safi, Seyyedeh Zahra

    2015-01-01

    Background: According to the World Health Organization (WHO) report released in 2000, about 121 million people worldwide suffer from depression. The major depressive disorder (MDD) among multiple sclerosis (MS) patients is one of the most common mood disorders experienced during life. MS patients who simultaneously suffer from depression have reported more severe symptoms of disease and slower adaptation to new conditions, which ultimately increase the cost of treatment. Objectives: The aim of this study was to assess the effectiveness of progressive muscle relaxation therapy (PMRT) as an adjunctive therapy for reducing level of depression for MS patients. Materials and Methods: This research had the randomized controlled trial design with pre and posttest. Thirty female patients based on criteria of MS and MDD disease, were selected from the MS Society of Shiraz, Iran. Beck Depression Inventory (BDI-II) was administered at pre and posttest. The participants were randomly allocated to two groups (experimental and control). Twelve sessions of PMRT using Bernstein and Borkovec’s method were held for the experimental group. Levin’s test, covariance and ANOVA with repeated measures were used for data analysis. Results: Experimental and control groups were compared before and after treatment. Analysis of covariance showed that seven levels of depression decreased in the experimental group and analysis of repeated measure showed that 49% of the changes were related to PMRT. Conclusion: According to the results, PMRT is effective in reducing depression. This therapy enables patients to reach relaxation quickly, and thus can cope with depression reactions effectively. PMID:26251663

  6. Multiple Sources of Infection and Potential Endemic Characteristics of the Large Outbreak of Dengue in Guangdong in 2014.

    PubMed

    Shen, Shu-Qun; Wei, Hai-Xia; Fu, Yong-Hang; Zhang, Hao; Mo, Qing-Yi; Wang, Xiao-Jun; Deng, Sheng-Qun; Zhao, Wei; Liu, Yu; Feng, Xiao-Shuang; Chen, Wei; Peng, Hong-Juan

    2015-01-01

    A large outbreak of dengue, with the most documented cases, occurred in Guangdong China in 2014. Epidemiological studies and phylogenetic analysis of the isolated dengue virus (DENV) showed this outbreak was attributed to multiple sources and caused by at least two genotypes of DENV-1 (Genotypes I and III) and two genotypes of DENV-2 (Cosmopolitan and Asian I Genotypes). A retrospective review and phylogenetic analysis of DENV isolated in Guangdong showed that DENV-1 Genotype I strains were reported continuously during 2004-2014, Genotype III strains were reported during 2009-2014 ; DENV-2 Cosmopolitan and Asian I Genotype strains were reported continuously during 2012-2014. At least 45,171 cases were reported in this outbreak, with 65.9% of the patients in the 21-55-year-old group. A trend toward a decrease in the daily newly emerged cases lagged by approximately 20 days compared with the mosquito density curve. Several epidemiological characteristics of this outbreak and the stably sustained serotypes and genotypes of DENV isolated in Guangdong suggest that Guangdong has been facing a threat of transforming from a dengue epidemic area to an endemic area. The high temperature, drenching rain, rapid urbanization, and pandemic of dengue in Southeast Asia may have contributed to this large outbreak of dengue. PMID:26593240

  7. Genotypic Distribution and Phylogenetic Characterization of Enterocytozoon bieneusi in Diarrheic Chickens and Pigs in Multiple Cities, China: Potential Zoonotic Transmission

    PubMed Central

    Li, Wei; Tao, Wei; Jiang, Yanxue; Diao, Ruinan; Yang, Jinping; Xiao, Lihua

    2014-01-01

    This study investigated diarrheic broiler and layer chickens (<50 days; n?=?14) and pigs of three age groups (preweaned <30 days, weaned ?30 to 60 days, and growing >60 days; n?=?64) for E. bieneusi genotypes in northeast China and evaluated the potential roles of chickens and pigs in zoonotic transmission of microsporidiosis. Two 45-day-old layer chickens in city Jixi, Heilongjiang province and one 23-day-old broiler chicken in city Songyuan, Jilin province were identified to harbor a human-pathogenic E. bieneusi genotype Henan-IV and a new genotype named CC-1, respectively, by nested PCR and sequence analysis of the ribosomal internal transcribed spacer (ITS). Eleven of 64 (17.2%) duodenal mucosal specimens from pigs in city Tianjin, city Tongliao of Inner Mongolia, cities Jilin and Songyuan of Jilin province, and cities Daqing, Harbin, and Suihua of Heilongjiang province, were positive for E. bieneusi, with the infection rates of weaned pigs (35%, 7/20) significantly higher than preweaned ones (3.6%, 1/28; P<0.05). Nucleotide sequences of the ITS were obtained from 6 pig specimens, belonging to 3 known genotypes CHN7, EbpC, and Henan-IV. That the previous reports have described the occurrence of genotypes EbpC and Henan-IV in humans and EbpC in wastewater in central China and the clustering of genotypes CC-1 and CHN7 into a major phylogenetic group of E. bieneusi genotypes with zoonotic potential indicated that chickens and pigs could be potential sources of human micorsporidiosis. To our knowledge, this is the first report describing the existence of zoonotic E. bieneusi genotypes in diarrheic chickens. PMID:25255117

  8. Long-distance potentials: An approach to the multiple-minima problem in ligand-receptor interaction

    E-print Network

    Vakser, Ilya A.

    1996-01-01

    ligand's atoms are represented by unity values. The potentials for all atoms of the receptor are projected, one by one, onto a 3-D grid with a grid step of R. At the beginning of the projection procedure all values on the grid are zero. During... of intermolecular energy at a given ligand's orientation. The 3- D grids for the receptor and the ligand are identical (the same interval of the grid and the same number of grid points). At each step of the correlation procedure, the values in the equivalent points...

  9. Detection of Differential Item Functioning on the Kirton Adaption-Innovation Inventory Using Multiple-Group Mean and Covariance Structure Analyses.

    ERIC Educational Resources Information Center

    Chan, David

    2000-01-01

    Demonstrates how the mean and covariance structure analysis model of D. Sorbom (1974) can be used to detect uniform and nonuniform differential item functioning (DIF) on polytomous ordered response items assumed to approximate a continuous scale. Uses results from 773 civil service employees administered the Kirton Adaption-Innovation Inventory…

  10. Brucella melitensis 16M?TcfSR as a potential live vaccine allows for the differentiation between natural and vaccinated infection

    PubMed Central

    LI, ZHIQIANG; ZHANG, JUNBO; ZHANG, KE; FU, QIANG; WANG, ZHEN; LI, TIANSEN; ZHANG, HUI; GUO, FEI; CHEN, CHUANGFU

    2015-01-01

    Brucellosis is a zoonotic disease that poses a serious threat to public health and safety. Although the live attenuated vaccines targeting brucellosis, such as M5-90, are effective, there are a number of drawbacks to their use. For example, the vaccines are unable to differentiate between the natural and vaccinated forms of the infection, and these vaccines have also been shown to cause abortion in pregnant animals. Therefore, a safer and more potent vaccine is required. In the present study, a B. melitensis 16M TcfSR promoter mutant (16M?TcfSR) was constructed in an attempt to overcome these drawbacks. A TcfSR mutant was derived from B. melitensis 16M and tested for virulence and protection efficiency. Levels of immuoglobulin G (IgG), and cytokine production were determined. In addition, TcfS was assessed as a diagnostic marker for brucellosis. The survival capacity of the 16M?TcfSR mutant was shown to be attenuated in the RAW 264.7 murine macrophage cell line and BALB/c mice, and the vaccination was shown to induce a high level of protective immunity in BALB/c mice. In addition, the 16M?TcfSR vaccination elicited an anti-Brucella-specific IgG response and induced the secretion of interferon-?. Thus, the TcfS antigen allowed for the serological differentiation between the natural and vaccinated infection in animals. In conclusion, the results demonstrated that the 16M?TcfSR mutant was attenuated in murine macrophage cells and BALB/c mice; therefore, 16M?TcfSR is a potential candidate for a live attenuated vaccine against B. melitensis infection. PMID:26622461

  11. Alloreactive CD154-expressing T-cell subsets with differential sensitivity to the immunosuppressant, belatacept: potential targets of novel belatacept-based regimens

    PubMed Central

    Ashokkumar, Chethan; Ganguly, Bishu; Townsend, Robert; White, Jaimie; Levy, Samantha; Moritz, Michael; Mazariegos, George; Sun, Qing; Sindhi, Rakesh

    2015-01-01

    Belatacept blocks CD28-mediated T-cell costimulation and prevents renal transplant rejection. Understanding T-cell subset sensitivity to belatacept may identify cellular markers for immunosuppression failure to better guide treatment selection. Here, we evaluate the belatacept sensitivity of allo-antigen-specific CD154-expressing-T-cells, whose T-cytotoxic memory (TcM) subset predicts rejection with high sensitivity after non-renal transplantation. The belatacept concentration associated with half-maximal reduction (EC50) of CD154 expression was calculated for 36 T-cell subsets defined by combinations of T-helper (Th), Tc, T-memory and CD28 receptors, following allostimulation of peripheral blood leukocytes from 20 normal healthy subjects. Subsets were ranked by median EC50, and by whether subset EC50 was correlated with and therefore could be represented by the frequency of other subsets. No single subset frequency emerged as the significant correlate of EC50 for a given subset. Most (n?=?25) T-cell subsets were sensitive to belatacept. Less sensitive subsets demonstrated a memory phenotype and absence of CD28 receptor. Potential drug-resistance markers for future validation include the low frequency highly differentiated, Th-memory-CD28-negative T-cells with the highest median EC50, and the least differentiated, high-frequency Tc subset, with the most CD28-negative T-cells, the third highest median EC50, and significant correlations with frequencies of the highest number of CD28-negative and memory subsets. PMID:26472085

  12. ?-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve

    PubMed Central

    Wilson, Michael J.; Yoshikami, Doju; Azam, Layla; Gajewiak, Joanna; Olivera, Baldomero M.; Bulaj, Grzegorz; Zhang, Min-Min

    2011-01-01

    Voltage-gated sodium channels (VGSCs) are important for action potentials. There are seven major isoforms of the pore-forming and gate-bearing ?-subunit (NaV1) of VGSCs in mammalian neurons, and a given neuron can express more than one isoform. Five of the neuronal isoforms, NaV1.1, 1.2, 1.3, 1.6, and 1.7, are exquisitely sensitive to tetrodotoxin (TTX), and a functional differentiation of these presents a serious challenge. Here, we examined a panel of 11 ?-conopeptides for their ability to block rodent NaV1.1 through 1.8 expressed in Xenopus oocytes. Although none blocked NaV1.8, a TTX-resistant isoform, the resulting “activity matrix” revealed that the panel could readily discriminate between the members of all pair-wise combinations of the tested isoforms. To examine the identities of endogenous VGSCs, a subset of the panel was tested on A- and C-compound action potentials recorded from isolated preparations of rat sciatic nerve. The results show that the major subtypes in the corresponding A- and C-fibers were NaV1.6 and 1.7, respectively. Ruled out as major players in both fiber types were NaV1.1, 1.2, and 1.3. These results are consistent with immunohistochemical findings of others. To our awareness this is the first report describing a qualitative pharmacological survey of TTX-sensitive NaV1 isoforms responsible for propagating action potentials in peripheral nerve. The panel of ?-conopeptides should be useful in identifying the functional contributions of NaV1 isoforms in other preparations. PMID:21652775

  13. Multiple metabolomics of uropathogenic E. coli reveal different information content in terms of metabolic potential compared to virulence factors.

    PubMed

    AlRabiah, Haitham; Xu, Yun; Rattray, Nicholas J W; Vaughan, Andrew A; Gibreel, Tarek; Sayqal, Ali; Upton, Mathew; Allwood, J William; Goodacre, Royston

    2014-09-01

    No single analytical method can cover the whole metabolome and the choice of which platform to use may inadvertently introduce chemical selectivity. In order to investigate this we analysed a collection of uropathogenic Escherichia coli. The selected strains had previously undergone extensive characterisation using classical microbiological methods for a variety of metabolic tests and virulence factors. These bacteria were analysed using Fourier transform infrared (FT-IR) spectroscopy; gas chromatography mass spectrometry (GC-MS) after derivatisation of polar non-volatile analytes; as well as reversed-phase liquid chromatography mass spectrometry in both positive (LC-MS(+ve)) and negative (LC-MS(-ve)) electrospray ionisation modes. A comparison of the discriminatory ability of these four methods with the metabolic test and virulence factors was made using Procrustes transformations to ascertain which methods produce congruent results. We found that FT-IR and LC-MS(-ve), but not LC-MS(+ve), were comparable with each other and gave highly similar clustering compared with the virulence factors tests. By contrast, FT-IR and LC-MS(-ve) were not comparable to the metabolic tests, and we found that the GC-MS profiles were significantly more congruent with the metabolic tests than the virulence determinants. We conclude that metabolomics investigations may be biased to the analytical platform that is used and reflects the chemistry employed by the methods. We therefore consider that multiple platforms should be employed where possible and that the analyst should consider that there is a danger of false correlations between the analytical data and the biological characteristics of interest if the full metabolome has not been measured. PMID:24841677

  14. Multiple Stressors in a Top Predator Seabird: Potential Ecological Consequences of Environmental Contaminants, Population Health and Breeding Conditions

    PubMed Central

    Bustnes, Jan O.; Bourgeon, Sophie; Leat, Eliza H. K.; Magnusdóttir, Ellen; Strřm, Hallvard; Hanssen, Sveinn A.; Petersen, Aevar; Olafsdóttir, Kristin; Borgĺ, Katrine; Gabrielsen, Geir W.; Furness, Robert W.

    2015-01-01

    Environmental contaminants may have impacts on reproduction and survival in wildlife populations suffering from multiple stressors. This study examined whether adverse effects of persistent organic pollutants (POPs) increased with poor population health and breeding conditions in three colonies (60–74°N) of great skua (Stercorarius skua) in the north-eastern Atlantic (Shetland, Iceland and Bjřrnřya [Bear Island]). POPs (organochlorines [OCs] and polybrominated diphenyl ethers [BDEs]) were measured in plasma of incubating birds (n = 222), concentrations differing nearly tenfold among colonies: Bjřrnřya (2009) > Bjřrnřya (2010) > Iceland (2009) > Shetland (2009). Reproductive success (hatching success and chick survival) showed that breeding conditions were favourable in Shetland and at Bjřrnřya (2010), but were very poor in Iceland and at Bjřrnřya (2009). Biomarkers indicated that health was poor in the Shetland population compared to the other populations. Females whose chicks hatched late had high POP concentrations in all colonies except at Bjřrnřya (2010), and females losing their eggs at Bjřrnřya (2009) tended to have higher concentrations than those hatching. Moreover, there was a negative relationship between female POP concentrations and chick body condition at hatching in Iceland and at Bjřrnřya (2010). Supplementary feeding experiments were conducted, and in Iceland where feeding conditions were poor, significant negative relationships were found between female POP concentrations and daily growth-rate in first-hatched chicks of control nests, but not in food supplemented nests. This suggests that negative impacts of POPs were mitigated by improved feeding conditions. For second-chicks, there was a strong negative relationship between the female POP concentrations and growth-rate, but no effects of supplementary feeding. Lowered adult return-rate between breeding seasons with increasing POP loads were found both at Bjřrnřya (2009) and in Shetland, especially related to BDEs. This indicates stronger fitness consequences of POPs following seasons with very poor breeding conditions and/or high reproductive effort. This study suggests that the impacts of POPs may differ depending on population health and breeding conditions, and that even low concentrations of POPs could have ecological consequences during adverse circumstances. This is important with regard to risk assessment of biomagnifying contaminants in marine ecosystems. PMID:26172383

  15. Multiple Stressors in a Top Predator Seabird: Potential Ecological Consequences of Environmental Contaminants, Population Health and Breeding Conditions.

    PubMed

    Bustnes, Jan O; Bourgeon, Sophie; Leat, Eliza H K; Magnusdóttir, Ellen; Strřm, Hallvard; Hanssen, Sveinn A; Petersen, Aevar; Olafsdóttir, Kristin; Borgĺ, Katrine; Gabrielsen, Geir W; Furness, Robert W

    2015-01-01

    Environmental contaminants may have impacts on reproduction and survival in wildlife populations suffering from multiple stressors. This study examined whether adverse effects of persistent organic pollutants (POPs) increased with poor population health and breeding conditions in three colonies (60-74°N) of great skua (Stercorarius skua) in the north-eastern Atlantic (Shetland, Iceland and Bjřrnřya [Bear Island]). POPs (organochlorines [OCs] and polybrominated diphenyl ethers [BDEs]) were measured in plasma of incubating birds (n = 222), concentrations differing nearly tenfold among colonies: Bjřrnřya (2009) > Bjřrnřya (2010) > Iceland (2009) > Shetland (2009). Reproductive success (hatching success and chick survival) showed that breeding conditions were favourable in Shetland and at Bjřrnřya (2010), but were very poor in Iceland and at Bjřrnřya (2009). Biomarkers indicated that health was poor in the Shetland population compared to the other populations. Females whose chicks hatched late had high POP concentrations in all colonies except at Bjřrnřya (2010), and females losing their eggs at Bjřrnřya (2009) tended to have higher concentrations than those hatching. Moreover, there was a negative relationship between female POP concentrations and chick body condition at hatching in Iceland and at Bjřrnřya (2010). Supplementary feeding experiments were conducted, and in Iceland where feeding conditions were poor, significant negative relationships were found between female POP concentrations and daily growth-rate in first-hatched chicks of control nests, but not in food supplemented nests. This suggests that negative impacts of POPs were mitigated by improved feeding conditions. For second-chicks, there was a strong negative relationship between the female POP concentrations and growth-rate, but no effects of supplementary feeding. Lowered adult return-rate between breeding seasons with increasing POP loads were found both at Bjřrnřya (2009) and in Shetland, especially related to BDEs. This indicates stronger fitness consequences of POPs following seasons with very poor breeding conditions and/or high reproductive effort. This study suggests that the impacts of POPs may differ depending on population health and breeding conditions, and that even low concentrations of POPs could have ecological consequences during adverse circumstances. This is important with regard to risk assessment of biomagnifying contaminants in marine ecosystems. PMID:26172383

  16. Climate impact of beef: an analysis considering multiple time scales and production methods without use of global warming potentials

    NASA Astrophysics Data System (ADS)

    Pierrehumbert, R. T.; Eshel, G.

    2015-08-01

    An analysis of the climate impact of various forms of beef production is carried out, with a particular eye to the comparison between systems relying primarily on grasses grown in pasture (‘grass-fed’ or ‘pastured’ beef) and systems involving substantial use of manufactured feed requiring significant external inputs in the form of synthetic fertilizer and mechanized agriculture (‘feedlot’ beef). The climate impact is evaluated without employing metrics such as {{CO}}2{{e}} or global warming potentials. The analysis evaluates the impact at all time scales out to 1000 years. It is concluded that certain forms of pastured beef production have substantially lower climate impact than feedlot systems. However, pastured systems that require significant synthetic fertilization, inputs from supplemental feed, or deforestation to create pasture, have substantially greater climate impact at all time scales than the feedlot and dairy-associated systems analyzed. Even the best pastured system analyzed has enough climate impact to justify efforts to limit future growth of beef production, which in any event would be necessary if climate and other ecological concerns were met by a transition to primarily pasture-based systems. Alternate mitigation options are discussed, but barring unforseen technological breakthroughs worldwide consumption at current North American per capita rates appears incompatible with a 2 °C warming target.

  17. Tissue loss (white syndrome) in the coral Montipora capitata is a dynamic disease with multiple host responses and potential causes

    PubMed Central

    Work, Thierry M.; Russell, Robin; Aeby, Greta S.

    2012-01-01

    Tissue loss diseases or white syndromes (WS) are some of the most important coral diseases because they result in significant colony mortality and morbidity, threatening dominant Acroporidae in the Caribbean and Pacific. The causes of WS remain elusive in part because few have examined affected corals at the cellular level. We studied the cellular changes associated with WS over time in a dominant Hawaiian coral, Montipora capitata, and showed that: (i) WS has rapidly progressing (acute) phases mainly associated with ciliates or slowly progressing (chronic) phases mainly associated with helminths or chimeric parasites; (ii) these phases interchanged and waxed and waned; (iii) WS could be a systemic disease associated with chimeric parasitism or a localized disease associated with helminths or ciliates; (iv) corals responded to ciliates mainly with necrosis and to helminths or chimeric parasites with wound repair; (v) mixed infections were uncommon; and (vi) other than cyanobacteria, prokaryotes associated with cell death were not seen. Recognizing potential agents associated with disease at the cellular level and the host response to those agents offers a logical deductive rationale to further explore the role of such agents in the pathogenesis of WS in M. capitata and helps explain manifestation of gross lesions. This approach has broad applicability to the study of the pathogenesis of coral diseases in the field and under experimental settings. PMID:22951746

  18. Multiple personality: diagnostic considerations.

    PubMed

    Coons, P M

    1980-10-01

    Multiple personality is a syndrome characterized by 2 or more alternating personality states and amnesia. Multiple personality must be differentiated from fugue, possession syndromes, mediumships, hysterical personality, schizophrenia, hypnotic states, organic brain syndrome and simulation. A review of the literature, discussion of diagnosis, and 4 illustrative cases are presented. PMID:7430076

  19. Endogenously released ACh and exogenous nicotine differentially facilitate long-term potentiation induction in the hippocampal CA1 region of mice.

    PubMed

    Nakauchi, Sakura; Sumikawa, Katumi

    2012-05-01

    We examined the role of ?7- and ?2-containing nicotinic acetylcholine receptors (nAChRs) in the induction of long-term potentiation (LTP). Theta-burst stimulation (TBS), mimicking the brain's naturally occurring theta rhythm, induced robust LTP in hippocampal slices from ?7 and ?2 knockout mice. This suggests TBS is capable of inducing LTP without activation of ?7- or ?2-containing nAChRs. However, when weak TBS was applied, the modulatory effects of nicotinic receptors on LTP induction became visible. We showed that during weak TBS, activation of ?7 nAChRs occurs by the release of ACh, contributing to LTP induction. Additionally, bath-application of nicotine activated ?2-containing nAChRs to promote LTP induction. Despite predicted nicotine-induced desensitization, synaptically mediated activation of ?7 nAChRs still occurs in the presence of nicotine and contributed to LTP induction. Optical recording of single-stimulation-evoked excitatory activity with a voltage-sensitive dye revealed enhanced excitatory activity in the presence of nicotine. This effect of nicotine was robust during high-frequency stimulation, and was accompanied by enhanced burst excitatory postsynaptic potentials. Nicotine-induced enhancement of excitatory activity was observed in slices from ?7 knockout mice, but was absent in ?2 knockout mice. These results suggest that the nicotine-induced enhancement of excitatory activity is mediated by ?2-containing nAChRs, and is related to the nicotine-induced facilitation of LTP induction. Thus, our study demonstrates that the activation of ?7- and ?2-containing nAChRs differentially facilitates LTP induction via endogenously released ACh and exogenous nicotine, respectively, in the hippocampal CA1 region of mice. PMID:22462479

  20. Rational Design of a Structural Framework with Potential Use to Develop Chemical Reagents That Target and Modulate Multiple Facets of Alzheimer’s Disease

    PubMed Central

    Lee, Sanghyun; Zheng, Xueyun; Krishnamoorthy, Janarthanan; Savelieff, Masha G.; Park, Hyun Min; Brender, Jeffrey R.; Kim, Jin Hoon; Derrick, Jeffrey S.; Kochi, Akiko; Lee, Hyuck Jin; Kim, Cheal; Ramamoorthy, Ayyalusamy; Bowers, Michael T.; Lim, Mi Hee

    2014-01-01

    Alzheimer’s disease (AD) is characterized by multiple, intertwined pathological features, including amyloid-? (A?) aggregation, metal ion dyshomeostasis, and oxidative stress. We report a novel compound (ML) prototype of a rationally designed molecule obtained by integrating structural elements for A? aggregation control, metal chelation, reactive oxygen species (ROS) regulation, and antioxidant activity within a single molecule. Chemical, biochemical, ion mobility mass spectrometric, and NMR studies indicate that the compound ML targets metal-free and metal-bound A? (metal–A?) species, suppresses A? aggregation in vitro, and diminishes toxicity induced by A? and metal-treated A? in living cells. Comparison of ML to its structural moieties (i.e., 4-(dimethylamino)phenol (DAP) and (8-aminoquinolin-2-yl)methanol (1)) for reactivity with A? and metal–A? suggests the synergy of incorporating structural components for both metal chelation and A? interaction. Moreover, ML is water-soluble and potentially brain permeable, as well as regulates the formation and presence of free radicals. Overall, we demonstrate that a rational structure-based design strategy can generate a small molecule that can target and modulate multiple factors, providing a new tool to uncover and address AD complexity. PMID:24397771

  1. Doxorubicin Differentially Induces Apoptosis, Expression of Mitochondrial Apoptosis-Related Genes, and Mitochondrial Potential in BCR-ABL1-Expressing Cells Sensitive and Resistant to Imatinib

    PubMed Central

    Synowiec, Ewelina; Hoser, Grazyna; Bialkowska-Warzecha, Jolanta; Pawlowska, Elzbieta; Skorski, Tomasz; Blasiak, Janusz

    2015-01-01

    Imatinib resistance is an emerging problem in the therapy of chronic myeloid leukemia (CML). Because imatinib induces apoptosis, which may be coupled with mitochondria and DNA damage is a prototype apoptosis-inducing factor, we hypothesized that imatinib-sensitive and -resistant CML cells might differentially express apoptosis-related mitochondrially encoded genes in response to genotoxic stress. We investigated the effect of doxorubicin (DOX), a DNA-damaging anticancer drug, on apoptosis and the expression of the mitochondrial NADH dehydrogenase 3 (MT-ND3) and cytochrome b (MT-CYB) in model CML cells showing imatinib resistance caused by Y253H mutation in the BCR-ABL1 gene (253) or culturing imatinib-sensitive (S) cells in increasing concentrations of imatinib (AR). The imatinib-resistant 253 cells displayed higher sensitivity to apoptosis induced by 1??M DOX and this was confirmed by an increased activity of executioner caspases 3 and 7 in those cells. Native mitochondrial potential was lower in imatinib-resistant cells than in their sensitive counterparts and DOX lowered it. MT-CYB mRNA expression in 253 cells was lower than that in S cells and 0.1??M DOX kept this relationship. In conclusion, imatinib resistance may be associated with altered mitochondrial response to genotoxic stress, which may be further exploited in CML therapy in patients with imatinib resistance. PMID:26618175

  2. Rapid differentiation and identification of potential severe strains of Citrus tristeza virus by real-time reverse transcription-polymerase chain reaction assays.

    PubMed

    Yokomi, R K; Saponari, M; Sieburth, P J

    2010-04-01

    A multiplex Taqman-based real-time reverse transcription (RT) polymerase chain reaction (PCR) assay was developed to identify potential severe strains of Citrus tristeza virus (CTV) and separate genotypes that react with the monoclonal antibody MCA13. Three strain-specific probes were developed using intergene sequences between the major and minor coat protein genes (CPi) in a multiplex reaction. Probe CPi-VT3 was designed for VT and T3 genotypes; probe CPi-T36 for T36 genotypes; and probe CPi-T36-NS to identify isolates in an outgroup clade of T36-like genotypes mild in California. Total nucleic acids extracted by chromatography on silica particles, sodium dodecyl sulfate-potassium acetate, and CTV virion immunocapture all yielded high quality templates for real-time PCR detection of CTV. These assays successfully differentiated CTV isolates from California, Florida, and a large panel of CTV isolates from an international collection maintained in Beltsville, MD. The utility of the assay was validated using field isolates collected in California and Florida. PMID:20205535

  3. Sub-250 nm room-temperature optical gain from AlGaN/AlN multiple quantum wells with strong band-structure potential fluctuations

    SciTech Connect

    Francesco Pecora, Emanuele; Zhang Wei; Nikiforov, A.Yu.; Yin Jian; Paiella, Roberto; Dal Negro, Luca; Moustakas, T. D.; Zhou Lin; Smith, David J.

    2012-02-06

    Deep-UV optical gain has been demonstrated in Al{sub 0.7}Ga{sub 0.3}N/AlN multiple quantum wells under femtosecond optical pumping. Samples were grown by molecular beam epitaxy under a growth mode that introduces band structure potential fluctuations and high-density nanocluster-like features within the AlGaN wells. A maximum net modal gain value of 118 {+-} 9 cm{sup -1} has been measured and the transparency threshold of 5 {+-} 1 {mu}J/cm{sup 2} was experimentally determined, corresponding to 1.4 x 10{sup 17} cm{sup -3} excited carriers. These findings pave the way for the demonstration of solid-state lasers with sub-250 nm emission at room temperature.

  4. Multiple signatures of a disease in potential biomarker space: Getting the signatures consensus and identification of novel biomarkers

    PubMed Central

    2015-01-01

    Background The lack of consensus among reported gene signature subsets (GSSs) in multi-gene biomarker discovery studies is often a concern for researchers and clinicians. Subsequently, it discourages larger scale prospective studies, prevents the translation of such knowledge into a practical clinical setting and ultimately hinders the progress of the field of biomarker-based disease classification, prognosis and prediction. Methods We define all "gene identificators" (gIDs) as constituents of the entire potential disease biomarker space. For each gID in a GSS of interest ("tested GSS"/tGSS), our method counts the empirical frequency of gID co-occurrences/overlaps in other reference GSSs (rGSSs) and compares it with the expected frequency generated via implementation of a randomized sampling procedure. Comparison of the empirical frequency distribution (EFD) with the expected background frequency distribution (BFD) allows dichotomization of statistically novel (SN) and common (SC) gIDs within the tGSS. Results We identify SN or SC biomarkers for tGSSs obtained from previous studies of high-grade serous ovarian cancer (HG-SOC) and breast cancer (BC). For each tGSS, the EFD of gID co-occurrences/overlaps with other rGSSs is characterized by scale and context-dependent Pareto-like frequency distribution function. Our results indicate that while independently there is little overlap between our tGSS with individual rGSSs, comparison of the EFD with BFD suggests that beyond a confidence threshold, tested gIDs become more common in rGSSs than expected. This validates the use of our tGSS as individual or combined prognostic factors. Our method identifies SN and SC genes of a 36-gene prognostic signature that stratify HG-SOC patients into subgroups with low, intermediate or high-risk of the disease outcome. Using 70 BC rGSSs, the method also predicted SN and SC BC prognostic genes from the tested obesity and IGF1 pathway GSSs. Conclusions Our method provides a strategy that identify/predict within a tGSS of interest, gID subsets that are either SN or SC when compared to other rGSSs. Practically, our results suggest that there is a stronger association of the IGF1 signature genes with the 70 BC rGSSs, than for the obesity-associated signature. Furthermore, both SC and SN genes, in both signatures could be considered as perspective prognostic biomarkers of BCs that stratify the patients onto low or high risks of cancer development. PMID:26100469

  5. A multi-level differential item functioning analysis of trends in international mathematics and science study: Potential sources of gender and minority difference among U.S. eighth graders' science achievement

    NASA Astrophysics Data System (ADS)

    Qian, Xiaoyu

    Science is an area where a large achievement gap has been observed between White and minority, and between male and female students. The science minority gap has continued as indicated by the National Assessment of Educational Progress and the Trends in International Mathematics and Science Studies (TIMSS). TIMSS also shows a gender gap favoring males emerging at the eighth grade. Both gaps continue to be wider in the number of doctoral degrees and full professorships awarded (NSF, 2008). The current study investigated both minority and gender achievement gaps in science utilizing a multi-level differential item functioning (DIF) methodology (Kamata, 2001) within fully Bayesian framework. All dichotomously coded items from TIMSS 2007 science assessment at eighth grade were analyzed. Both gender DIF and minority DIF were studied. Multi-level models were employed to identify DIF items and sources of DIF at both student and teacher levels. The study found that several student variables were potential sources of achievement gaps. It was also found that gender DIF favoring male students was more noticeable in the content areas of physics and earth science than biology and chemistry. In terms of item type, the majority of these gender DIF items were multiple choice than constructed response items. Female students also performed less well on items requiring visual-spatial ability. Minority students performed significantly worse on physics and earth science items as well. A higher percentage of minority DIF items in earth science and biology were constructed response than multiple choice items, indicating that literacy may be the cause of minority DIF. Three-level model results suggested that some teacher variables may be the cause of DIF variations from teacher to teacher. It is essential for both middle school science teachers and science educators to find instructional methods that work more effectively to improve science achievement of both female and minority students. Physics and earth science are two areas to be improved for both groups. Curriculum and instruction need to enhance female students' learning interests and give them opportunities to improve their visual perception skills. Science instruction should address improving minority students' literacy skills while teaching science.

  6. Extensive sampling of polar bears (Ursus maritimus) in the Northwest Passage (Canadian Arctic Archipelago) reveals population differentiation across multiple spatial and temporal scales

    PubMed Central

    Campagna, Leonardo; Van Coeverden de Groot, Peter J; Saunders, Brenda L; Atkinson, Stephen N; Weber, Diana S; Dyck, Markus G; Boag, Peter T; Lougheed, Stephen C

    2013-01-01

    As global warming accelerates the melting of Arctic sea ice, polar bears (Ursus maritimus) must adapt to a rapidly changing landscape. This process will necessarily alter the species distribution together with population dynamics and structure. Detailed knowledge of these changes is crucial to delineating conservation priorities. Here, we sampled 361 polar bears from across the center of the Canadian Arctic Archipelago spanning the Gulf of Boothia (GB) and M'Clintock Channel (MC). We use DNA microsatellites and mitochondrial control region sequences to quantify genetic differentiation, estimate gene flow, and infer population history. Two populations, roughly coincident with GB and MC, are significantly differentiated at both nuclear (FST = 0.01) and mitochondrial (?ST = 0.47; FST = 0.29) loci, allowing Bayesian clustering analyses to assign individuals to either group. Our data imply that the causes of the mitochondrial and nuclear genetic patterns differ. Analysis of mtDNA reveals the matrilineal structure dates at least to the Holocene, and is common to individuals throughout the species’ range. These mtDNA differences probably reflect both genetic drift and historical colonization dynamics. In contrast, the differentiation inferred from microsatellites is only on the scale of hundreds of years, possibly reflecting contemporary impediments to gene flow. Taken together, our data suggest that gene flow is insufficient to homogenize the GB and MC populations and support the designation of GB and MC as separate polar bear conservation units. Our study also provide a striking example of how nuclear DNA and mtDNA capture different aspects of a species demographic history. PMID:24102001

  7. Extensive sampling of polar bears (Ursus maritimus) in the Northwest Passage (Canadian Arctic Archipelago) reveals population differentiation across multiple spatial and temporal scales.

    PubMed

    Campagna, Leonardo; Van Coeverden de Groot, Peter J; Saunders, Brenda L; Atkinson, Stephen N; Weber, Diana S; Dyck, Markus G; Boag, Peter T; Lougheed, Stephen C

    2013-09-01

    As global warming accelerates the melting of Arctic sea ice, polar bears (Ursus maritimus) must adapt to a rapidly changing landscape. This process will necessarily alter the species distribution together with population dynamics and structure. Detailed knowledge of these changes is crucial to delineating conservation priorities. Here, we sampled 361 polar bears from across the center of the Canadian Arctic Archipelago spanning the Gulf of Boothia (GB) and M'Clintock Channel (MC). We use DNA microsatellites and mitochondrial control region sequences to quantify genetic differentiation, estimate gene flow, and infer population history. Two populations, roughly coincident with GB and MC, are significantly differentiated at both nuclear (F ST = 0.01) and mitochondrial (?ST = 0.47; F ST = 0.29) loci, allowing Bayesian clustering analyses to assign individuals to either group. Our data imply that the causes of the mitochondrial and nuclear genetic patterns differ. Analysis of mtDNA reveals the matrilineal structure dates at least to the Holocene, and is common to individuals throughout the species' range. These mtDNA differences probably reflect both genetic drift and historical colonization dynamics. In contrast, the differentiation inferred from microsatellites is only on the scale of hundreds of years, possibly reflecting contemporary impediments to gene flow. Taken together, our data suggest that gene flow is insufficient to homogenize the GB and MC populations and support the designation of GB and MC as separate polar bear conservation units. Our study also provide a striking example of how nuclear DNA and mtDNA capture different aspects of a species demographic history. PMID:24102001

  8. The effects of cannabidiol and its synergism with bortezomib in multiple myeloma cell lines. A role for transient receptor potential vanilloid type-2.

    PubMed

    Morelli, Maria Beatrice; Offidani, Massimo; Alesiani, Francesco; Discepoli, Giancarlo; Liberati, Sonia; Olivieri, Attilio; Santoni, Matteo; Santoni, Giorgio; Leoni, Pietro; Nabissi, Massimo

    2014-06-01

    Multiple myeloma (MM) is a plasma cell (PC) malignancy characterised by the accumulation of a monoclonal PC population in the bone marrow (BM). Cannabidiol (CBD) is a non-psychoactive cannabinoid with antitumoural activities, and the transient receptor potential vanilloid type-2 (TRPV2) channel has been reported as a potential CBD receptor. TRPV2 activation by CBD decreases proliferation and increases susceptibility to drug-induced cell death in human cancer cells. However, no functional role has been ascribed to CBD and TRPV2 in MM. In this study, we identified the presence of heterogeneous CD138+TRPV2+ and CD138+TRPV2- PC populations in MM patients, whereas only the CD138+ TRPV2- population was present in RPMI8226 and U266 MM cell lines. Because bortezomib (BORT) is commonly used in MM treatment, we investigated the effects of CBD and BORT in CD138+TRPV2- MM cells and in MM cell lines transfected with TRPV2 (CD138+TRPV2+). These results showed that CBD by itself or in synergy with BORT strongly inhibited growth, arrested cell cycle progression and induced MM cells death by regulating the ERK, AKT and NF-?B pathways with major effects in TRPV2+ cells. These data provide a rationale for using CBD to increase the activity of proteasome inhibitors in MM. PMID:24293211

  9. Multiple antidepressant potential modes of action of curcumin: a review of its anti-inflammatory, monoaminergic, antioxidant, immune-modulating and neuroprotective effects.

    PubMed

    Lopresti, Adrian L; Hood, Sean D; Drummond, Peter D

    2012-12-01

    Curcumin is the principal curcuminoid of the popular Indian spice turmeric and has attracted increasing attention for the treatment of a range of conditions. Research into its potential as a treatment for depression is still in its infancy, although several potential antidepressant mechanisms of action have been identified. Research completed to date on the multiple effects of curcumin is reviewed in this paper, with a specific emphasis on the biological systems that are compromised in depression. The antidepressant effects of curcumin in animal models of depression are summarised, and its influence on neurotransmitters such as serotonin and dopamine is detailed. The effects of curcumin in moderating hypothalamus-pituitary-adrenal disturbances, lowering inflammation and protecting against oxidative stress, mitochondrial damage, neuroprogression and intestinal hyperpermeability, all of which are compromised in major depressive disorder, are also summarised. With increasing interest in natural treatments for depression, and efforts to enhance current treatment outcomes, curcumin is presented as a promising novel, adjunctive or stand-alone natural antidepressant. PMID:23035031

  10. Disruption of Src function potentiates Chk1-inhibitor–induced apoptosis in human multiple myeloma cells in vitro and in vivo

    PubMed Central

    Dai, Yun; Chen, Shuang; Shah, Rena; Pei, Xin-Yan; Wang, Li; Almenara, Jorge A.; Kramer, Lora B.; Dent, Paul

    2011-01-01

    Ras/MEK/ERK pathway activation represents an important compensatory response of human multiple myeloma (MM) cells to checkpoint kinase 1 (Chk1) inhibitors. To investigate the functional roles of Src in this event and potential therapeutic significance, interactions between Src and Chk1 inhibitors (eg, UCN-01 or Chk1i) were examined in vitro and in vivo. The dual Src/Abl inhibitors BMS354825 and SKI-606 blocked Chk1-inhibitor–induced extracellular signal-regulated kinase 1/2 (ERK1/2) activation, markedly increasing apoptosis in association with BimEL up-regulation, p34cdc2 activation, and DNA damage in MM cell lines and primary CD138+ MM samples. Loss-of-function Src mutants (K297R, K296R/Y528F) or shRNA knock-down of Src prevented the ERK1/2 activation induced by Chk1 inhibitors and increased apoptosis. Conversely, constitutively active Ras or mitogen-activated protein kinase/ERK kinase 1 (MEK1) significantly diminished the ability of Src inhibitors to potentiate Chk1-inhibitor lethality. Moreover, Src/Chk1-inhibitor cotreatment attenuated MM-cell production of vascular endothelial growth factor and other angiogenic factors (eg, ANG [angiogenin], TIMP1/2 [tissue inhibitor of metalloproteinases 1/2], and RANTES [regulated on activation normal T-cell expressed and secreted]), and inhibited in vitro angiogenesis. Finally, coadministration of BMS354825 and UCN-01 suppressed human MM tumor growth in a murine xenograft model, increased apoptosis, and diminished angiogenesis. These findings suggest that Src kinase is required for Chk1-inhibitor–mediated Ras ? ERK1/2 signaling activation, and that disruption of this event sharply potentiates the anti-MM activity of Chk1 inhi-bitors in vitro and in vivo. PMID:21148814

  11. Chronic thromboembolic pulmonary hypertension (CTEPH) - potential role of multidetector-row CT (MD-CT) and MR imaging in the diagnosis and differential diagnosis of the disease.

    PubMed

    Wirth, G; Brüggemann, K; Bostel, T; Mayer, E; Düber, C; Kreitner, K F

    2014-08-01

    Chronic thromboembolic pulmonary hypertension (CTEPH) can be defined as pulmonary hypertension (resting mean pulmonary arterial pressure of 25 mm Hg or more determined at right heart catheterization) with persistent pulmonary perfusion defects. It is a rare, but underdiagnosed disease with estimated incidences ranging from 0.5% to 3.8% of patients after an acute pulmonary embolism (PE), and in up to 10% of those with a history of recurrent PE. CTEPH is the only form of pulmonary hypertension that can be surgically treated leading to normalization of pulmonary hemodynamics and exercise capacity in the vast majority of patients. The challenges for imaging in patients with suspected CTEPH are fourfold: the imaging modality should have a high diagnostic accuracy with regard to the presence of CTEPH and allow for differential diagnosis. It should enable detection of patients suitable for PEA with great certainty, and allow for quantification of PH by measuring pulmonary hemodynamics (mPAP and PVR), and finally, it can be used for therapy monitoring. This overview tries to elucidate the potential role of ECG-gated multidetector CT pulmonary angiography (MD-CTPA) and MR imaging, and summarizes the most important results that have been achieved so far. Generally speaking, ECG-gated MD-CTPA is superior to MR in the assessment of parenchymal and vascular pathologies of the lung, and allows for the assessment of cardiac structures. The implementation of iodine maps as a surrogate for lung perfusion enables functional assessment of lung perfusion by CT. MR imaging is the reference standard for the assessment of right heart function and lung perfusion, the latter delineating typical wedge-shaped perfusion defects in patients with CTEPH. New developments show that with MR techniques, an estimation of hemodynamic parameters like mean pulmonary arterial pressure and pulmonary vascular resistance will be possible. CT and MR imaging should be considered as complementary investigations providing comprehensive information in patients with CTEPH. PMID:24756429

  12. Early in-flight detection of SO2 via Differential Optical Absorption Spectroscopy: A feasible aviation safety measure to prevent potential encounters with volcanic plumes

    USGS Publications Warehouse

    Vogel, L.; Galle, B.; Kern, C.; Delgado, Granados H.; Conde, V.; Norman, P.; Arellano, S.; Landgren, O.; Lubcke, P.; Alvarez, Nieves J.M.; Cardenas, Gonzales L.; Platt, U.

    2011-01-01

    Volcanic ash constitutes a risk to aviation, mainly due to its ability tocause jet engines to fail. Other risks include the possibility of abrasion ofwindshields and potentially serious damage to avionic systems. These hazardshave been widely recognized since the early 1980s, when volcanic ash provokedseveral incidents of engine failure in commercial aircraft. In addition tovolcanic ash, volcanic gases also pose a threat. Prolonged and/or cumulativeexposure to sulphur dioxide (SO2) or sulphuric acid (H2SO4)aerosols potentially affects e.g. windows, air frame and may cause permanentdamage to engines. SO2 receives most attention among the gas speciescommonly found in volcanic plumes because its presence above the lowertroposphere is a clear proxy for a volcanic cloud and indicates that fine ashcould also be present. Up to now, remote sensing of SO2 via Differential Optical AbsorptionSpectroscopy (DOAS) in the ultraviolet spectral region has been used tomeasure volcanic clouds from ground based, airborne and satellite platforms.Attention has been given to volcanic emission strength, chemistry insidevolcanic clouds and measurement procedures were adapted accordingly. Here wepresent a set of experimental and model results, highlighting the feasibilityof DOAS to be used as an airborne early detection system of SO2 intwo spatial dimensions. In order to prove our new concept, simultaneousairborne and ground-based measurements of the plume of Popocat??petlvolcano, Mexico, were conducted in April 2010. The plume extended at analtitude around 5250 m above sea level and was approached and traversed at thesame altitude with several forward looking DOAS systems aboard an airplane.These DOAS systems measured SO2 in the flight direction and at?? 40 mrad (2.3??) angles relative to it in both, horizontal andvertical directions. The approaches started at up to 25 km distance to theplume and SO2 was measured at all times well above the detectionlimit. In combination with radiative transfer studies, this study indicatesthat an extended volcanic cloud with a concentration of 1012 molecules cm-3 at typical flight levels of 10 km can be detectedunambiguously at distances of up to 80 km away. This range provides enoughtime (approx. 5 min) for pilots to take action to avoid entering avolcanic cloud in the flight path, suggesting that this technique can be usedas an effective aid to prevent dangerous aircraft encounters with potentiallyash rich volcanic clouds. ?? Author(s) 2011.

  13. A Bayesian Approach to Estimating Coupling Between Neural Components: Evaluation of the Multiple Component, Event-Related Potential (mcERP) Algorithm

    NASA Technical Reports Server (NTRS)

    Shah, Ankoor S.; Knuth, Kevin H.; Truccolo, Wilson A.; Ding, Ming-Zhou; Bressler, Steven L.; Schroeder, Charles E.; Clancy, Daniel (Technical Monitor)

    2002-01-01

    Accurate measurement of single-trial responses is key to a definitive use of complex electromagnetic and hemodynamic measurements in the investigation of brain dynamics. We developed the multiple component, Event-Related Potential (mcERP) approach to single-trial response estimation. To improve our resolution of dynamic interactions between neuronal ensembles located in different layers within a cortical region and/or in different cortical regions. The mcERP model assets that multiple components defined as stereotypic waveforms comprise the stimulus-evoked response and that these components may vary in amplitude and latency from trial to trial. Maximum a posteriori (MAP) solutions for the model are obtained by iterating a set of equations derived from the posterior probability. Our first goal was to use the ANTWERP algorithm to analyze interactions (specifically latency and amplitude correlation) between responses in different layers within a cortical region. Thus, we evaluated the model by applying the algorithm to synthetic data containing two correlated local components and one independent far-field component. Three cases were considered: the local components were correlated by an interaction in their single-trial amplitudes, by an interaction in their single-trial latencies, or by an interaction in both amplitude and latency. We then analyzed the accuracy with which the algorithm estimated the component waveshapes and the single-trial parameters as a function of the linearity of each of these relationships. Extensions of these analyses to real data are discussed as well as ongoing work to incorporate more detailed prior information.

  14. Habitat choice of multiple pollinators in almond trees and its potential effect on pollen movement and productivity: A theoretical approach using the Shigesada-Kawasaki-Teramoto model.

    PubMed

    Yong, Kamuela E; Li, Yi; Hendrix, Stephen D

    2012-07-21

    California's almond industry, valued at $2.3 billion per year, depends on the pollinator services of honey bees, although pollination by other insects, mainly solitary wild bees, is being investigated as an alternative because of recent declines in the number of honey bee colonies. Our objective is to model the movements of honey bees and determine the conditions under which they will forage in less favorable areas of a tree and its surroundings when other pollinators are present. We hypothesize that foraging in less favorable areas leads to increased movement between trees and increased cross pollination between varieties which is required for successful nut production. We use the Shigesada-Kawasaki-Teramoto model (1979) which describes the density of two species in a two-dimensional environment of variable favorableness with respect to intrinsic diffusions and intra and interspecific interactions of species. The model is applied to almond pollination by honey bees and other pollinators with environmental favorableness based on the distribution of flowers in trees. Using the spectral-Galerkin method in a rectangular domain, we numerically approximated the two-dimensional nonlinear parabolic partial differential system arising in the model. When cross-diffusion or interspecific effects of other pollinators was high, honey bees foraged in less favorable areas of the tree. In the model, high cross-diffusion also resulted in increased activity in honey bees which manifested itself in the field in terms of accelerations, decelerations, and changes in direction, indicating rapid redistribution of densities to an equilibrium state. Empirical analysis of the number of honey bees and other visitors in 2-min intervals to almond trees shows a negative relationship, indicating cross-diffusion effects in nature with the potential to increase movement to a different tree with a more favorable environment, potentially increasing nut production. PMID:22575553

  15. Induction of autophagy is a key component of all-trans-retinoic acid-induced differentiation in leukemia cells and a potential target for pharmacologic modulation.

    PubMed

    Orfali, Nina; O'Donovan, Tracey R; Nyhan, Michelle J; Britschgi, Adrian; Tschan, Mario P; Cahill, Mary R; Mongan, Nigel P; Gudas, Lorraine J; McKenna, Sharon L

    2015-09-01

    Acute myeloid leukemia (AML) is characterized by the accumulation of immature blood cell precursors in the bone marrow. Pharmacologically overcoming the differentiation block in this condition is an attractive therapeutic avenue, which has achieved success only in a subtype of AML, acute promyelocytic leukemia (APL). Attempts to emulate this success in other AML subtypes have thus far been unsuccessful. Autophagy is a conserved protein degradation pathway with important roles in mammalian cell differentiation, particularly within the hematopoietic system. In the study described here, we investigated the functional importance of autophagy in APL cell differentiation. We found that autophagy is increased during all-trans-retinoic acid (ATRA)-induced granulocytic differentiation of the APL cell line NB4 and that this is associated with increased expression of LC3II and GATE-16 proteins involved in autophagosome formation. Autophagy inhibition, using either drugs (chloroquine/3-methyladenine) or short-hairpin RNA targeting the essential autophagy gene ATG7, attenuates myeloid differentiation. Importantly, we found that enhancing autophagy promotes ATRA-induced granulocytic differentiation of an ATRA-resistant derivative of the non-APL AML HL60 cell line (HL60-Diff-R). These data support the development of strategies to stimulate autophagy as a novel approach to promote differentiation in AML. PMID:25986473

  16. Murine embryonic stem cell line CGR8 expresses all subtypes of muscarinic receptors and multiple nicotinic receptor subunits: Down-regulation of ?4- and ?4-subunits during early differentiation.

    PubMed

    Kaltwasser, Susanne; Schmitz, Luise; Michel-Schmidt, Rosmarie; Anspach, Laura; Kirkpatrick, Charles James; Wessler, Ignaz

    2015-11-01

    Non-neuronal acetylcholine mediates its cellular effects via stimulation of the G-protein-coupled muscarinic receptors and the ligand-gated ion channel nicotinic receptors. The murine embryonic stem cell line CGR8 synthesizes and releases non-neuronal acetylcholine. In the present study a systematic investigation of the expression of nicotinic receptor subunits and muscarinic receptors was performed, when the stem cells were grown in the presence or absence of LIF, as the latter condition induces early differentiation. CGR8 cells expressed multiple nicotinic receptor subtypes (?3, ?4, ?7, ?9, ?10, ?1, ?2, ?3, ?4, ?, ?, ?) and muscarinic receptors (M1, M3, M4, M5); M2 was detected only in 2 out of 8 cultures. LIF removal caused a down-regulation only of the ?4- and ?4-subunit. In conclusion, more or less the whole repertoire of cholinergic receptors is expressed on the murine embryonic stem cell line CGR8 for mediating cellular signaling of non-neuronal acetylcholine which acts via auto- and paracrine pathways. During early differentiation of the murine CGR8 stem cell signaling via nicotinic receptors containing ?4- or ?4 subunits is reduced. Thus, the so-called neuronal ?4 nicotine receptor composed of these subunits may be involved in the regulation of pluripotency in this murine stem cell line. PMID:26299974

  17. Numerical Implementation of a Multiple-ISV Thermodynamically-Based Work Potential Theory for Modeling Progressive Damage and Failure in Fiber-Reinforced Laminates

    NASA Technical Reports Server (NTRS)

    Pineda, Evan J.; Waas, Anthony M.

    2011-01-01

    A thermodynamically-based work potential theory for modeling progressive damage and failure in fiber-reinforced laminates is presented. The current, multiple-internal state variable (ISV) formulation, enhanced Schapery theory (EST), utilizes separate ISVs for modeling the effects of damage and failure. Damage is considered to be the effect of any structural changes in a material that manifest as pre-peak non-linearity in the stress versus strain response. Conversely, failure is taken to be the effect of the evolution of any mechanisms that results in post-peak strain softening. It is assumed that matrix microdamage is the dominant damage mechanism in continuous fiber-reinforced polymer matrix laminates, and its evolution is controlled with a single ISV. Three additional ISVs are introduced to account for failure due to mode I transverse cracking, mode II transverse cracking, and mode I axial failure. Typically, failure evolution (i.e., post-peak strain softening) results in pathologically mesh dependent solutions within a finite element method (FEM) setting. Therefore, consistent character element lengths are introduced into the formulation of the evolution of the three failure ISVs. Using the stationarity of the total work potential with respect to each ISV, a set of thermodynamically consistent evolution equations for the ISVs is derived. The theory is implemented into commercial FEM software. Objectivity of total energy dissipated during the failure process, with regards to refinements in the FEM mesh, is demonstrated. The model is also verified against experimental results from two laminated, T800/3900-2 panels containing a central notch and different fiber-orientation stacking sequences. Global load versus displacement, global load versus local strain gage data, and macroscopic failure paths obtained from the models are compared to the experiments.

  18. Inhibition deficit in the spatial tendency of the response in multiple-domain amnestic mild cognitive impairment. An event-related potential study

    PubMed Central

    Cespón, Jesús; Galdo-Álvarez, Santiago; Díaz, Fernando

    2015-01-01

    Longitudinal studies have shown that a high percentage of people with amnestic mild cognitive impairment (MCI) develop Alzheimer’s disease (AD). Prodromal AD is known to involve deficits in executive control processes. In the present study, we examined such deficits by recording EEG in 13 single-domain amnestic MCI (sdaMCI), 12 multiple-domain amnestic MCI (mdaMCI) and 18 healthy elderly (control group, CG) participants while they performed a Simon task. The Simon task demands deployment of executive processes because participants have to respond to non-spatial features of a lateralized stimulus and inhibit the more automatic spatial tendency of the response. We specifically focused on the negativity central contralateral (N2cc), an event-related potential (ERP) component related to brain activity that prevents the cross-talk between direction of spatial attention and manual response preparation. The reaction time (RT) was not significantly different among the three groups of participants. The percentage of errors (PE) was higher in mdaMCI than in CG and sdaMCI participants. In addition, N2cc latency was delayed in mdaMCI (i.e., delayed implementation of mechanisms for controlling the spatial tendency of the response). The N2cc latency clearly distinguished among mdaMCI and CG/sdaMCI participants (area under curve: 0.91). Longer N2cc was therefore associated with executive control deficits, which suggests that N2cc latency is a correlate of mdaMCI. PMID:25999853

  19. Erythropoietin-Stimulating Agents and Survival in End-Stage Renal Disease: Comparison of Payment Policy Analysis, Instrumental Variables, and Multiple Imputation of Potential Outcomes

    PubMed Central

    Dore, David D.; Swaminathan, Shailender; Gutman, Roee; Trivedi, Amal N.; Mor, Vincent

    2013-01-01

    Objective To compare the assumptions and estimands across three approaches to estimating the effect of erythropoietin-stimulating agents (ESAs) on mortality. Study Design and Setting Using data from the Renal Management Information System, we conducted two analyses utilizing a change to bundled payment that we hypothesized mimicked random assignment to ESA (pre-post, difference-in-difference, and instrumental variable analyses). A third analysis was based on multiply imputing potential outcomes using propensity scores. Results There were 311,087 recipients of ESAs and 13,095 non-recipients. In the pre-post comparison, we identified no clear relationship between bundled payment (measured by calendar time) and the incidence of death within six months (risk difference -1.5%; 95% CI - 7.0% to 4.0%). In the instrumental variable analysis, the risk of mortality was similar among ESA recipients (risk difference -0.9%; 95% CI -2.1 to 0.3). In the multiple imputation analysis, we observed a 4.2% (95% CI 3.4% to 4.9%) absolute reduction in mortality risk with use of ESAs, but closer to the null for patients with baseline hematocrit >36%. Conclusion Methods emanating from different disciplines often rely on different assumptions, but can be informative about a similar causal contrast. The implications of these distinct approaches are discussed. PMID:23849152

  20. Molecular characterization of the ?-subunit of Na?/K? ATPase from the euryhaline barnacle Balanus improvisus reveals multiple genes and differential expression of alternative splice variants.

    PubMed

    Lind, Ulrika; Alm Rosenblad, Magnus; Wrange, Anna-Lisa; Sundell, Kristina S; Jonsson, Per R; André, Carl; Havenhand, Jonathan; Blomberg, Anders

    2013-01-01

    The euryhaline bay barnacle Balanus improvisus has one of the broadest salinity tolerances of any barnacle species. It is able to complete its life cycle in salinities close to freshwater (3 PSU) up to fully marine conditions (35 PSU) and is regarded as one of few truly brackish-water species. Na?/K? ATPase (NAK) has been shown to be important for osmoregulation when marine organisms are challenged by changing salinities, and we therefore cloned and examined the expression of different NAKs from B. improvisus. We found two main gene variants, NAK1 and NAK2, which were approximately 70% identical at the protein level. The NAK1 mRNA existed in a long and short variant with the encoded proteins differing only by 27 N-terminal amino acids. This N-terminal stretch was coded for by a separate exon, and the two variants of NAK1 mRNAs appeared to be created by alternative splicing. We furthermore showed that the two NAK1 isoforms were differentially expressed in different life stages and in various tissues of adult barnacle, i.e the long isoform was predominant in cyprids and in adult cirri. In barnacle cyprid larvae that were exposed to a combination of different salinities and pCO2 levels, the expression of the long NAK1 mRNA increased relative to the short in low salinities. We suggest that the alternatively spliced long variant of the Nak1 protein might be of importance for osmoregulation in B. improvisus in low salinity conditions. PMID:24130836

  1. Molecular Characterization of the ?-Subunit of Na+/K+ ATPase from the Euryhaline Barnacle Balanus improvisus Reveals Multiple Genes and Differential Expression of Alternative Splice Variants

    PubMed Central

    Lind, Ulrika; Alm Rosenblad, Magnus; Wrange, Anna-Lisa; Sundell, Kristina S.; Jonsson, Per R.; André, Carl; Havenhand, Jonathan; Blomberg, Anders

    2013-01-01

    The euryhaline bay barnacle Balanus improvisus has one of the broadest salinity tolerances of any barnacle species. It is able to complete its life cycle in salinities close to freshwater (3 PSU) up to fully marine conditions (35 PSU) and is regarded as one of few truly brackish-water species. Na+/K+ ATPase (NAK) has been shown to be important for osmoregulation when marine organisms are challenged by changing salinities, and we therefore cloned and examined the expression of different NAKs from B. improvisus. We found two main gene variants, NAK1 and NAK2, which were approximately 70% identical at the protein level. The NAK1 mRNA existed in a long and short variant with the encoded proteins differing only by 27 N-terminal amino acids. This N-terminal stretch was coded for by a separate exon, and the two variants of NAK1 mRNAs appeared to be created by alternative splicing. We furthermore showed that the two NAK1 isoforms were differentially expressed in different life stages and in various tissues of adult barnacle, i.e the long isoform was predominant in cyprids and in adult cirri. In barnacle cyprid larvae that were exposed to a combination of different salinities and pCO2 levels, the expression of the long NAK1 mRNA increased relative to the short in low salinities. We suggest that the alternatively spliced long variant of the Nak1 protein might be of importance for osmoregulation in B. improvisus in low salinity conditions. PMID:24130836

  2. Differential gene expression in Neurospora crassa cell types: heterogeneity and multiple copies of rRNA genes. Annual progress report, July 1981-June 1982

    SciTech Connect

    Dutta, S.K.

    1982-01-01

    The significant results obtained were as follows: (I) Multiple copies of isolated rRNA genes from N. crassa were tested for heterogeneity by rRNA: rDNA reassociation kinetics. More than 90% of rDNA copies were identical. The possible heterogeneity of a small fraction of rDNAs could not be attributed to inclusion of any tDNA sequences. (II) Two approaches to study gross differences between rRNA genes from N. crassa cell types-conidia, germinated conidia, and mycelia were undertaken. No difference was seen in either the restriction patterns nor the autoradiographs. Either gross differences between rDNAS of N. crassa cell types were not present or they were not detected by these two approaches. (III) Using similar DNA restriction analysis procedures, differences between closely related heterothallic and homothallic species of Neurospora were detected. (IV) Successful sequencing of 317 bases of the N. crassa slime mutant pMF2 clone which includes the 5.8S rDNA and it's flanking internal spacer regions was achieved. (ERB)

  3. The Novel Multiple Inner Primers-Loop-Mediated Isothermal Amplification (MIP-LAMP) for Rapid Detection and Differentiation of Listeria monocytogenes.

    PubMed

    Wang, Yi; Wang, Yan; Ma, Aijing; Li, Dongxun; Luo, Lijuan; Liu, Dongxin; Hu, Shoukui; Jin, Dong; Liu, Kai; Ye, Changyun

    2015-01-01

    Here, a novel model of loop-mediated isothermal amplification (LAMP), termed multiple inner primers-LAMP (MIP-LAMP), was devised and successfully applied to detect Listeria monocytogenes. A set of 10 specific MIP-LAMP primers, which recognized 14 different regions of target gene, was designed to target a sequence in the hlyA gene. The MIP-LAMP assay efficiently amplified the target element within 35 min at 63 °C and was evaluated for sensitivity and specificity. The templates were specially amplified in the presence of the genomic DNA from L. monocytogenes. The limit of detection (LoD) of MIP-LAMP assay was 62.5 fg/reaction using purified L. monocytogenes DNA. The LoD for DNA isolated from serial dilutions of L. monocytogenes cells in buffer and in milk corresponded to 2.4 CFU and 24 CFU, respectively. The amplified products were analyzed by real-time monitoring of changes in turbidity, and visualized by adding Loop Fluorescent Detection Reagent (FD), or as a ladder-like banding pattern on gel electrophoresis. A total of 48 pork samples were investigated for L. monocytogenes by the novel MIP-LAMP method, and the diagnostic accuracy was shown to be 100% when compared to the culture-biotechnical method. In conclusion, the MIP-LAMP methodology was demonstrated to be a reliable, sensitive and specific tool for rapid detection of L. monocytogenes strains. PMID:26633345

  4. Use of near-surface channel conductance and differential capacitance versus potential measurements to correlate inversion layer formation with low effective surface recombination velocities at n-Si/liquid contacts

    NASA Astrophysics Data System (ADS)

    Michalak, David J.; Lewis, Nathan S.

    2002-06-01

    Near-surface channel conductance measurements, differential capacitance versus potential measurements, and surface recombination velocity measurements have been performed on (111)- and (100)-oriented n-type Si samples in contact with nitrogen and/or liquid electrolyte solutions containing I2, I2/I-, ferrocene+/0, or decamethylferrocene+/0 in either methanol or tetrahydrofuran. Si/liquid contacts that displayed a low effective surface recombination velocity S corresponded to those that formed an inversion layer at the solid/liquid contact as indicated by channel conductance measurements or by differential capacitance versus potential measurements. Contacts that did not produce an inversion layer at the Si surface did not produce low effective S values. The observed behavior is consistent with the known energetics of Si/liquid contacts and provides an explanation for the low effective S values observed in these systems.

  5. Evaluation of the zoonotic potential of a novel reassortant H1N2 swine influenza virus with gene constellation derived from multiple viral sources.

    PubMed

    Lee, Jee Hoon; Pascua, Philippe Noriel Q; Decano, Arun G; Kim, Se Mi; Park, Su-Jin; Kwon, Hyeok-Il; Kim, Eun-Ha; Kim, Young-Il; Kim, HyongKyu; Kim, Seok-Yong; Song, Min-Suk; Jang, Hyung-Kwan; Park, Bong Kyun; Choi, Young Ki

    2015-08-01

    In 2011-2012, contemporary North American-like H3N2 swine influenza viruses (SIVs) possessing the 2009 pandemic H1N1 matrix gene (H3N2pM-like virus) were detected in domestic pigs of South Korea where H1N2 SIV strains are endemic. More recently, we isolated novel reassortant H1N2 SIVs bearing the Eurasian avian-like swine H1-like hemagglutinin and Korean swine H1N2-like neuraminidase in the internal gene backbone of the H3N2pM-like virus. In the present study, we clearly provide evidence on the genetic origins of the novel H1N2 SIVs virus through genetic and phylogenetic analyses. In vitro studies demonstrated that, in comparison with a pre-existing 2012 Korean H1N2 SIV [A/swine/Korea/CY03-11/2012 (CY03-11/2012)], the 2013 novel reassortant H1N2 isolate [A/swine/Korea/CY0423/2013 (CY0423-12/2013)] replicated more efficiently in differentiated primary human bronchial epithelial cells. The CY0423-12/2013 virus induced higher viral titers than the CY03-11/2012 virus in the lungs and nasal turbinates of infected mice and nasal wash samples of ferrets. Moreover, the 2013 H1N2 reassortant, but not the intact 2012 H1N2 virus, was transmissible to naďve contact ferrets via respiratory-droplets. Noting that the viral precursors have the ability to infect humans, our findings highlight the potential threat of a novel reassortant H1N2 SIV to public health and underscore the need to further strengthen influenza surveillance strategies worldwide, including swine populations. PMID:26051886

  6. Differential effects of three interferon betas on neutralising antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory

    PubMed Central

    Bertolotto, A; Malucchi, S; Sala, A; Orefice, G; Carrieri, P; Capobianco, M; Milano, E; Melis, F; Giordana, M

    2002-01-01

    Objective: To evaluate the incidence and the prevalence of neutralising antibodies (NABs) to three interferon beta (IFNß) products in patients with multiple sclerosis (MS). Methods: Sera were tested from 125 patients with relapsing-remitting MS. Patients were treated with IFNß-1b (Betaferon, n = 29) 8 MIU subcutaneously every other day, IFNß-1a (Avonex, n = 44) 30 µg intramuscularly once weekly, or IFNß-1a (Rebif, n = 36) 22 µg subcutaneously three times weekly for 6 to 18 months. An additional 16 patients were treated with Rebif 22 µg intramuscularly once or twice weekly. NABs were assessed using the cytopathic effect assay before treatment and every three months during treatment. Patients with two or more consecutive positive samples were considered to be persistent NAB positive (NAB+). Results: At baseline, no patients were NAB+. NABs developed during the first three months of treatment and continued to develop until month 18. Over 18 months of treatment, the risk of being persistent NAB+ was 31% for Betaferon, 15% for Rebif, and 2% for Avonex (Betaferon versus Avonex, p = 0.001; Betaferon versus Rebif, p = 0.19; Rebif versus Avonex, p = 0.04). In all patients with one or more NAB+ samples, the risk of becoming NAB+ was 38% for Betaferon, 18% for Rebif, and 7% for Avonex (Betaferon versus Avonex, p = 0.0007; Betaferon versus Rebif, p = 0.10; Rebif versus Avonex, p = 0.07). At month 18, the prevalence of persistent NAB+ patients was 31.6% for Betaferon, 18.7% for Rebif, and 4% for Avonex. Numbers of NAB+ patients observed were similar with intramuscular Rebif and with subcutaneous Rebif. Conclusion: The three IFNß preparations have different degrees of immunogenicity, with Betaferon producing the highest incidence of NABs and Avonex the lowest. These differences should be considered by neurologists when selecting treatment for their patients with MS because NABs can reduce both bioavailability and clinical efficacy of IFNß. PMID:12122172

  7. Molecular mechanism of anticancer effect of Sclerotium rolfsii lectin in HT29 cells involves differential expression of genes associated with multiple signaling pathways: A microarray analysis.

    PubMed

    Barkeer, Srikanth; Guha, Nilanjan; Hothpet, Vishwanathreddy; Saligrama Adavigowda, Deepak; Hegde, Prajna; Padmanaban, Arunkumar; Yu, Lu-Gang; Swamy, Bale M; Inamdar, Shashikala R

    2015-12-01

    Sclerotium rolfsii lectin (SRL) is a lectin isolated from fungus S. rolfsii and has high binding specificity toward the oncofetal Thomsen-Friedenreich carbohydrate antigen (Gal?1-3GalNAc-?-O-Ser/Thr, T or TF), which is expressed in more than 90% of human cancers. Our previous studies have shown that binding of SRL to human colon, breast and ovarian cancer cells induces cell apoptosis in vitro and suppresses tumor growth in vivo. This study investigated the SRL-mediated cell signaling in human colon cancer HT29 cells by mRNA and miRNA microarrays. It was found that SRL treatment results in altered expression of several hundred molecules including mitogen-activated protein kinase (MAPK) and c-JUN-associated, apoptosis-associated and cell cycle and DNA replication-associated signaling molecules. Pathway analysis using GeneSpring 12.6.1 revealed that SRL treatment induces changes of MAPK and c-JUN-associated signaling pathways as early as 2 h while changes of cell cycle, DNA replication and apoptosis pathways were significantly affected only after 24 h. A significant change of cell miRNA expression was also observed after 12 h treatment of the cells with SRL. These changes were further validated by quantitative real time polymerase chain reaction and immunoblotting. This study thus suggests that the presence of SRL affects multiple signaling pathways in cancer cells with early effects on cell proliferation pathways associated with MAPK and c-JUN, followed by miRNA-associated cell activity and apoptosis. This provides insight information into the molecular mechanism of the anticancer activity of this fungal lectin. PMID:26347523

  8. Differential regulation of ER Ca2+ uptake and release rates accounts for multiple modes of Ca2+-induced Ca2+ release.

    PubMed

    Albrecht, Meredith A; Colegrove, Stephen L; Friel, David D

    2002-03-01

    The ER is a central element in Ca(2+) signaling, both as a modulator of cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) and as a locus of Ca(2+)-regulated events. During surface membrane depolarization in excitable cells, the ER may either accumulate or release net Ca(2+), but the conditions of stimulation that determine which form of net Ca(2+) transport occurs are not well understood. The direction of net ER Ca(2+) transport depends on the relative rates of Ca(2+) uptake and release via distinct pathways that are differentially regulated by Ca(2+), so we investigated these rates and their sensitivity to Ca(2+) using sympathetic neurons as model cells. The rate of Ca(2+) uptake by SERCAs (J(SERCA)), measured as the t-BuBHQ-sensitive component of the total cytoplasmic Ca(2+) flux, increased monotonically with [Ca(2+)](i). Measurement of the rate of Ca(2+) release (J(Release)) during t-BuBHQ-induced [Ca(2+)](i) transients made it possible to characterize the Ca(2+) permeability of the ER ((~)P(ER)), describing the activity of all Ca(2+)-permeable channels that contribute to passive ER Ca(2+) release, including ryanodine-sensitive Ca(2+) release channels (RyRs) that are responsible for CICR. Simulations based on experimentally determined descriptions of J(SERCA), and of Ca(2+) extrusion across the plasma membrane (J(pm)) accounted for our previous finding that during weak depolarization, the ER accumulates Ca(2+), but at a rate that is attenuated by activation of a CICR pathway operating in parallel with SERCAs to regulate net ER Ca(2+) transport. Caffeine greatly increased the [Ca(2+)] sensitivity of ((~)P(ER)), accounting for the effects of caffeine on depolarization-evoked [Ca(2+)](i) elevations and caffeine-induced [Ca(2+)](i) oscillations. Extending the rate descriptions of J(SERCA), ((~)P(ER)), and J(pm) to higher [Ca(2+)](i) levels shows how the interplay between Ca(2+) transport systems with different Ca(2+) sensitivities accounts for the different modes of CICR over different ranges of [Ca(2+)](i) during stimulation. PMID:11865019

  9. Expressions of miR-181a and miR-20a in RPMI8226 cell line and their potential as biomarkers for multiple myeloma.

    PubMed

    Peng, Jing; Thakur, Asmitananda; Zhang, Shuo; Dong, Yuanfeng; Wang, Xiaoqin; Yuan, Ruili; Zhang, Kaige; Guo, Xuan

    2015-11-01

    Multiple myeloma (MM) is characterized by clonal proliferation of malignant plasma cells in the bone marrow. The anti-tumor activity of bortezomib (a proteosome inhibitor) in MM is challenged by emergence of drug resistance. MicroRNAs (miR) regulate and orchestrate multiple cellular pathways. We investigate the contribution miR-181a and miR-20a expressions' on cell proliferation and apoptosis in RPMI8226 cell line and their influence on bortezomib treatment. RNA isolation, quantitative real-time PCR (qRT-PCR), cell proliferation assay, cell cycle analysis, and cell apoptosis assay were done. Statistical analysis was performed using SPSS 17.0 software (SPSS, Chicago, IL, USA). P values of less than 0.05 were considered statistically significant. RPMI8226 cells seeded in 96-well plates and treated for 24 h with different concentrations of bortezomib showed dose-dependent growth inhibition; expression of both miR-181a and miR-20a were inhibited by bortezomib. We found decrease of miR-181a (60 %) and miR-20a (30 %) in cells transfected with 20-nM inhibitor. A relative increase of 14-fold in miR-181a and 11-fold in miR-20a was observed in cells transfected with mimics of the same concentration. Transient low expression of miR-181a/20a inhibited proliferation at day 4, and overexpression of miR-181a promoted proliferation. Cells transfected with miR-181a/20a inhibitor within day 4 showed lower survival rate, and low expression of miR-181a on the fourth day after transfection promoted apoptosis. Our findings suggest that miR-181a/20a has a higher expression in MM. miR-181-a expression is proportional to MM tumor burden and could be a biomaker for monitoring treatment. miR-20a shows the potential of a diagnostic biomarker. PMID:26032093

  10. Dietary protection against free radicals: a case for multiple testing to establish structure-activity relationships for antioxidant potential of anthocyanic plant species.

    PubMed

    Philpott, Martin; Lim, Chiara Cheng; Ferguson, Lynnette R

    2009-03-01

    DNA damage by reactive species is associated with susceptibility to chronic human degenerative disorders. Anthocyanins are naturally occurring antioxidants, that may prevent or reverse such damage. There is considerable interest in anthocyanic food plants as good dietary sources, with the potential for reducing susceptibility to chronic disease. While structure-activity relationships have provided guidelines on molecular structure in relation to free hydroxyl-radical scavenging, this may not cover the situation in food plants where the anthocyanins are part of a complex mixture, and may be part of complex structures, including anthocyanic vacuolar inclusions (AVIs). Additionally, new analytical methods have revealed new structures in previously-studied materials. We have compared the antioxidant activities of extracts from six anthocyanin-rich edible plants (red cabbage, red lettuce, blueberries, pansies, purple sweetpotato skin, purple sweetpotato flesh and Maori potato flesh) using three chemical assays (DPPH, TRAP and ORAC), and the in vitro Comet assay. Extracts from the flowering plant, lisianthus, were used for comparison. The extracts showed differential effects in the chemical assays, suggesting that closely related structures have different affinities to scavenge different reactive species. Integration of anthocyanins to an AVI led to more sustained radical scavenging activity as compared with the free anthocyanin. All but the red lettuce extract could reduce endogenous DNA damage in HT-29 colon cancer cells. However, while extracts from purple sweetpotato skin and flesh, Maori potato and pansies, protected cells against subsequent challenge by hydrogen peroxide at 0 degrees C, red cabbage extracts were pro-oxidant, while other extracts had no effect. When the peroxide challenge was at 37 degrees C, all of the extracts appeared pro-oxidant. Maori potato extract, consistently the weakest antioxidant in all the chemical assays, was more effective in the Comet assays. These results highlight the dangers of generalising to potential health benefits, based solely on identification of high anthocyanic content in plants, results of a single antioxidant assay and traditional approaches to structure activity relationships. Subsequent studies might usefully consider complex mixtures and a battery of assays. PMID:19399239

  11. Dietary Protection Against Free Radicals: A Case for Multiple Testing to Establish Structure-activity Relationships for Antioxidant Potential of Anthocyanic Plant Species

    PubMed Central

    Philpott, Martin; Lim, Chiara Cheng; Ferguson, Lynnette R.

    2009-01-01

    DNA damage by reactive species is associated with susceptibility to chronic human degenerative disorders. Anthocyanins are naturally occurring antioxidants, that may prevent or reverse such damage. There is considerable interest in anthocyanic food plants as good dietary sources, with the potential for reducing susceptibility to chronic disease. While structure-activity relationships have provided guidelines on molecular structure in relation to free hydroxyl-radical scavenging, this may not cover the situation in food plants where the anthocyanins are part of a complex mixture, and may be part of complex structures, including anthocyanic vacuolar inclusions (AVIs). Additionally, new analytical methods have revealed new structures in previously-studied materials. We have compared the antioxidant activities of extracts from six anthocyanin-rich edible plants (red cabbage, red lettuce, blueberries, pansies, purple sweetpotato skin, purple sweetpotato flesh and Maori potato flesh) using three chemical assays (DPPH, TRAP and ORAC), and the in vitro Comet assay. Extracts from the flowering plant, lisianthus, were used for comparison. The extracts showed differential effects in the chemical assays, suggesting that closely related structures have different affinities to scavenge different reactive species. Integration of anthocyanins to an AVI led to more sustained radical scavenging activity as compared with the free anthocyanin. All but the red lettuce extract could reduce endogenous DNA damage in HT-29 colon cancer cells. However, while extracts from purple sweetpotato skin and flesh, Maori potato and pansies, protected cells against subsequent challenge by hydrogen peroxide at 0°C, red cabbage extracts were pro-oxidant, while other extracts had no effect. When the peroxide challenge was at 37°C, all of the extracts appeared pro-oxidant. Maori potato extract, consistently the weakest antioxidant in all the chemical assays, was more effective in the Comet assays. These results highlight the dangers of generalising to potential health benefits, based solely on identification of high anthocyanic content in plants, results of a single antioxidant assay and traditional approaches to structure activity relationships. Subsequent studies might usefully consider complex mixtures and a battery of assays. PMID:19399239

  12. Bone-marrow-derived mesenchymal stem cells as a target for cytomegalovirus infection: Implications for hematopoiesis, self-renewal and differentiation potential

    SciTech Connect

    Smirnov, Sergey V.; Harbacheuski, Ryhor; Lewis-Antes, Anita; Zhu Hua; Rameshwar, Pranela; Kotenko, Sergei V. . E-mail: kotenkse@umdnj.edu

    2007-03-30

    Mesenchymal stem cells (MSCs) in bone marrow (BM) regulate the differentiation and proliferation of adjacent hematopoietic precursor cells and contribute to the regeneration of mesenchymal tissues, including bone, cartilage, fat and connective tissue. BM is an important site for the pathogenesis of human cytomegalovirus (HCMV) where the virus establishes latency in hematopoietic progenitors and can transmit after reactivation to neighboring cells. Here we demonstrate that BM-MSCs are permissive to productive HCMV infection, and that HCMV alters the function of MSCs: (i) by changing the repertoire of cell surface molecules in BM-MSCs, HCMV modifies the pattern of interaction between BM-MSCs and hematopoietic cells; (ii) HCMV infection of BM-MSCs undergoing adipogenic or osteogenic differentiation impaired the process of differentiation. Our results suggest that by altering BM-MSC biology, HCMV may contribute to the development of various diseases.

  13. Multiple Sclerosis

    MedlinePLUS

    MENU Return to Web version Multiple Sclerosis Overview What is multiple sclerosis (MS)? Multiple sclerosis is an autoimmune disease that affects the nervous system. Normally, antibodies produced by ...

  14. Women with Multiple Chemical Sensitivity Have Increased Harm Avoidance and Reduced 5-HT1A Receptor Binding Potential in the Anterior Cingulate and Amygdala

    PubMed Central

    Ĺhs, Fredrik; Savic, Ivanka

    2013-01-01

    Multiple chemical sensitivity (MCS) is a common condition, characterized by somatic distress upon exposure to odors. As in other idiopathic environmental intolerances, the underlying mechanisms are unknown. Contrary to the expectations it was recently found that persons with MCS activate the odor-processing brain regions less than controls, while their activation of the anterior cingulate cortex (ACC) is increased. The present follow-up study was designed to test the hypotheses that MCS subjects have increased harm avoidance and deviations in the serotonin system, which could render them intolerant to environmental odors. Twelve MCS and 11 control subjects, age 22–44, all working or studying females, were included in a PET study where 5-HT1A receptor binding potential (BP) was assessed after bolus injection of [11C]WAY100635. Psychological profiles were assessed by the Temperament and Character Inventory and the Swedish universities Scales of Personality. All MCS and 12 control subjects were also tested for emotional startle modulation in an acoustic startle test. MCS subjects exhibited significantly increased harm avoidance, and anxiety compared to controls. They also had a reduced 5-HT1A receptor BP in amygdala (p?=?0.029), ACC (p?=?0.005) (planned comparisons, significance level 0.05), and insular cortex (p?=?0.003; significance level p<0.005 with Bonferroni correction), and showed an inverse correlation between degree of anxiety and the BP in the amygdala (planned comparison). No group by emotional category difference was found in the startle test. Increased harm avoidance and the observed changes in the 5-HT1A receptor BP in the regions processing harm avoidance provides a plausible pathophysiological ground for the symptoms described in MCS, and yields valuable information for our general understanding of idiopathic environmental intolerances. PMID:23349968

  15. Potential artifacts in interpretation of differential breakthrough of colloids and dissolved tracers in the context of transport in a zero-valent iron permeable reactive barrier

    USGS Publications Warehouse

    Zhang, P.; Johnson, W.P.; Piana, M.J.; Fuller, C.C.; Naftz, D.L.

    2001-01-01

    Many published studies have used visual comparison of the timing of peak breakthrough of colloids versus conservative dissolved tracers (hereafter referred to as dissolved tracers or tracers) in subsurface media to determine whether they are advected differently, and to elucidate the mechanisms of differential advection. This purely visual approach of determining differential advection may have artifacts, however, due to the attachment of colloids to subsurface media. The attachment of colloids to subsurface media may shift the colloidal peak breakthrough to earlier times, causing an apparent "faster" peak breakthrough of colloids relative to dissolve tracers even though the transport velocities for the colloids and the dissolved tracers may actually be equivalent. In this paper, a peak shift analysis was presented to illustrate the artifacts associated with the purely visual approach in determining differential advection, and to quantify the peak shift due to colloid attachment. This peak shift analysis was described within the context of microsphere and bromide transport within a zero-valent iron (ZVI) permeable reactive barrier (PRB) located in Fry Canyon, Utah. Application of the peak shift analysis to the field microsphere and bromide breakthrough data indicated that differential advection of the microspheres relative to the bromide occurred in the monitoring wells closest to the injection well in the PRB. It was hypothesized that the physical heterogeneity at the grain scale, presumably arising from differences in inter- versus intra-particle porosity, contributed to the differential advection of the microspheres versus the bromide in the PRB. The relative breakthrough (RB) of microspheres at different wells was inversely related to the ionic strength of ground water at these wells, in agreement with numerous studies showing that colloid attachment is directly related to solution ionic strength.

  16. Connective tissue growth factor differentially binds to members of the cystine knot superfamily and potentiates platelet-derived growth factor-B signaling in rabbit corneal fibroblast cells

    PubMed Central

    Pi, Liya; Chung, Pei-Yu; Sriram, Sriniwas; Rahman, Masmudur M; Song, Wen-Yuan; Scott, Edward W; Petersen, Bryon E; Schultz, Gregory S

    2015-01-01

    AIM: To study the binding of connective tissue growth factor (CTGF) to cystine knot-containing ligands and how this impacts platelet-derived growth factor (PDGF)-B signaling. METHODS: The binding strengths of CTGF to cystine knot-containing growth factors including vascular endothelial growth factor (VEGF)-A, PDGF-B, bone morphogenetic protein (BMP)-4, and transforming growth factor (TGF)-?1 were compared using the LexA-based yeast two-hybrid system. EYG48 reporter strain that carried a wild-type LEU2 gene under the control of LexA operators and a lacZ reporter plasmid (p80p-lacZ) containing eight high affinity LexA binding sites were used in the yeast two-hybrid analysis. Interactions between CTGF and the tested growth factors were evaluated based on growth of transformed yeast cells on selective media and colorimetric detection in a liquid ?-galactosidase activity assay. Dissociation constants of CTGF to VEGF-A isoform 165 or PDGF-BB homo-dimer were measured in surface plasma resonance (SPR) analysis. CTGF regulation in PDGF-B presentation to the PDGF receptor ? (PDGFR?) was also quantitatively assessed by the SPR analysis. Combinational effects of CTGF protein and PDGF-BB on activation of PDGFR? and downstream signaling molecules ERK1/2 and AKT were assessed in rabbit corneal fibroblast cells by Western analysis. RESULTS: In the LexA-based yeast two-hybrid system, cystine knot motifs of tested growth factors were fused to the activation domain of the transcriptional factor GAL4 while CTGF was fused to the DNA binding domain of the bacterial repressor protein LexA. Yeast co-transformants containing corresponding fusion proteins for CTGF and all four tested cystine knot motifs survived on selective medium containing galactose and raffinose but lacking histidine, tryptophan, and uracil. In liquid ?-galactosidase assays, CTGF expressing cells that were co-transformed with the cystine knot of VEGF-A had the highest activity, at 29.88 ± 0.91 fold above controls (P < 0.01). Cells containing the cystine knot of BMP-4 expressed the second most activity, with a 24.77 ± 0.47 fold increase (P < 0.01). Cells that contained the cystine knot of TGF-?1 had a 3.80 ± 0.66 fold increase (P < 0.05) and the ones with the cystine knot of PDGF-B had a 2.64 ± 0.33 fold increase of ?-galactosidase activity (P < 0.01). Further SPR analysis showed that the association rate between VEGF-A 165 and CTGF was faster than PDGF-BB and CTGF. The calculated dissociation constant (KD) of CTGF to VEGF165 and PDGF-BB was 1.8 and 43 nmol/L respectively. PDGF-BB ligand and PDGFR? receptor formed a stable complex with a low dissociation constant 1.4 nmol/L. Increasing the concentration of CTGF up to 263.2 nmol/L significantly the ligand/receptor binding. In addition, CTGF potentiated phosphorylation of PDGFR? and AKT in rabbit corneal fibroblast cells stimulated by PDGF-BB in tissue culture condition. In contrast, CTGF did not affect PDGF-B induced phosphorylation of ERK1/2. CONCLUSION: CTGF has a differential binding affinity to VEGF-A, PDGF-B, BMP-4, and TGF-?. Its weak association with PDGF-B may represent a novel mechanism to enhance PDGF-B signaling. PMID:26629321

  17. Early in-flight detection of SO2 via Differential Optical Absorption Spectroscopy: A feasible aviation safety measure to prevent potential encounters with volcanic plumes

    NASA Astrophysics Data System (ADS)

    Vogel, L.; Galle, B.; Kern, C.; Delgado Granados, H.; Conde, V.; Norman, P.; Arellano, S.; Landgren, O.; Luebcke, P.; Alvarez Nieves, J.; Cárdenas Gonzáles, L.; Platt, U.

    2010-12-01

    Volcanic ash is a hazard to aviation mainly due to its threat to jet engines with the risk of total engine failure. Other hazards consist of abrasion of windshields and damage to avionic systems. These hazards have been widely recognized since the early 1980s, when volcanic ashes provoked severe incidents of engine failure of jet aircrafts (e.g. Mt. St. Helens, USA, 1980; Mt. Galunggung, Indonesia, 1982 and Redoubt volcano, USA, 1989). In addition to volcanic ash, also volcanic gases pose a threat. Prolonged and/or cumulative exposure of sulfur dioxide (SO2) or sulfuric acid (H2SO4) aerosols potentially affects e.g. windows, air frame and provokes damage to engines. SO2 receives most attention because its presence above the lower troposphere atmosphere is a clear proxy for a volcanic plume and indicates that fine ash could also be present. One of the most recent examples of volcanic ash impairing aviation is the eruption of Eyjafjallajoküll, Iceland, between March and May 2010, which lead to temporal closure of the European air space. Although no severe incidents were reported, it affected an unprecedented number of people and had a considerable negative economic impact on carriers. Up to now, remote sensing of SO2 via Differential Optical Spectroscopy (DOAS) in the ultraviolet spectral region has primarily been used to measure volcanic clouds from satellites and ground-based platforms. Here we present a set of experimental and model data, highlighting the feasibility of DOAS to be used as an airborne early detection system of SO2 distributions in two spatial dimensions. In order to prove the concept, simultaneous airborne and ground-based measurements were conducted at Popocatépetl volcano, Mexico, in April 2010. These observations were combined with radiative transfer studies modelling the conditions at hand. The ground based measurements were made by two stationary instruments, a further, mobile instrument was used to perform vehicle traverses below the plume. From these data, plume height and wind direction relative to the source were retrieved. The plume of Popocatépetl extended at an altitude around 5000m a.s.l. and was approached and passed through at the same flight level with forward looking DOAS systems aboard an airplane. These DOAS systems measured SO2 in the flight direction and at ±40mrad angles in both horizontal and vertical directions relative to it. The approaches were started at up to 25km distance to the plume and SO2 was measured at all times well above the detection limit. The experimental data validate the radiative transfer modelling results. They indicate that a volcanic plume with a slant column density of 1018 molecules/cm2 as viewed from the outside can be detected unambiguously at distances up to 80km away.

  18. Multiple sclerosis.

    PubMed

    Files, Daniel Kane; Jausurawong, Tani; Katrajian, Ruba; Danoff, Robert

    2015-06-01

    Multiple sclerosis (MS) is a chronic, debilitating disease that can have devastating effects. Presentation varies widely in symptoms, pace, and progression. In addition to a thorough history and physical examination, diagnostic tools required to diagnose MS and exclude other diagnoses include MRI, evoked potential testing, and cerebrospinal fluid analysis. Although the disease is not curable presently, quality of life can be improved by minimizing the frequency and severity of disease burden. Disease modification, symptom management, preservation of function, and treatment of psychosocial issues are paramount to enhance the quality of life for the patient affected with MS. PMID:25979578

  19. DQB1*06:02-Associated Pathogenic Anti-Myelin Autoimmunity in Multiple Sclerosis-Like Disease: Potential Function of DQB1*06:02 as a Disease-Predisposing Allele

    PubMed Central

    Kaushansky, Nathali; Ben-Nun, Avraham

    2014-01-01

    Susceptibility to multiple sclerosis (MS) has been linked mainly to the HLA-DRB1 locus, with the HLA-DR15 haplotype (DRB1*1501-DQA1*0102-DQB1*0602-DRB5*0101) dominating MS risk in Caucasians. Although genes in the HLA-II region, particularly DRB1*1501, DQA1*0102-DQB1*0602, are in tight linkage disequilibrium, genome-wide-association, and gene candidate studies identified the DRB1*15:01 allele as the primary risk factor in MS. Many genetic and immune-functional studies have indicated DRB1*15:01 as a primary risk factor in MS, while only some functional studies suggested a disease-modifying role for the DRB5*01 or DQB1*06 alleles. In this respect, the susceptibility of DRB1*15:01-transgenic (Tg) mice to myelin basic protein- or myelin oligodendrocyte glycoprotein-induced MS-like disease is consistent with primary contribution of DRB1*15:01 to HLA-DR15+ MS. The studies summarized here show that susceptibility to MS-like disease, induced in HLA-“humanized” mice by myelin oligodendrocytic basic protein or by the proteolipid protein, one of the most prominent encephalitogenic target antigens implicated in human MS, is determined by DQB1*06:02, rather than by the DRB1*15:01 allele. These findings not only offer a rationale for a potential role for DQB1*06:02 in predisposing susceptibility to MS, but also suggest a more complex and differential functional role for HLA-DR15 alleles, depending on the primary target myelin antigen. However, the conflict between these findings in HLA-Tg mice and the extensive genome-wide-association studies, which could not detect any significant effect from the DQB1*06:02 allele on MS risk, is rather puzzling. Functional analysis of MS PBLs for DQB1*06:02-associated anti-myelin autoimmunity may indicate whether or not DQB1*06:02 is associated with MS pathogenesis. PMID:25360418

  20. Influence of self-assembling peptide nanofibre scaffolds on retinal differentiation potential of stem/progenitor cells derived from ciliary pigment epithelial cells.

    PubMed

    Jasty, Srilatha; Suriyanarayanan, Saranya; Krishnakumar, Subramanian

    2014-07-28

    Aim of the study was to investigate the influence of the self-assembling peptide nanofibre scaffolds (SAPNs) on the growth, proliferation and retinal neuronal differentiation of the stem/progenitor cells (SCs) derived from the ciliary pigment epithelium (CPE) of human cadaveric eye. Here SAPNs (RADA16-I, PM), which is well described in previous studies, commercially available and xeno-free. The CPE cells isolated were cultured in DMEM/F12 supplemented with N2 and growth factors such as basic fibroblast growth factor and epidermal growth factor, encapsulated in the scaffolds. The entrapped SCs actively expanded and formed clone-like clusters in the scaffolds. Many cells in the cluster were proliferating, as revealed by 5-bromo-2-deoxyuridine uptake and could be maintained for up to 6?days and expressed neural progenitor markers such as ?-III tubulin, Nestin, Pax6 and Musashi1. Upon differentiation of these cells in conditioned medium, the cells exhibited retinal neuronal markers such as s-Opsin, rhodopsin and Recoverin. The RT(2) profiler polymerase chain reaction array experiments showed selective gene expression, possibly involved in neural stem/progenitor cell adhesion and differentiation. These findings suggest the suitability of the three-dimensional culture system for the proliferation and maintenance of CPE stem/progenitor cells (CPE-NS) and for possible use in ex vivo studies of small molecules, drug deliveries for retinal diseases and for use in combination with directed stem/progenitor cell differentiation. and ultimately for tissue replacement therapies. Copyright © 2014 John Wiley & Sons, Ltd. PMID:25066608

  1. Deregulation of MUC4 in gastric adenocarcinoma: potential pathobiological implication in poorly differentiated non-signet ring cell type gastric cancer

    PubMed Central

    Senapati, S; Chaturvedi, P; Sharma, P; Venkatraman, G; Meza, J L; El-Rifai, W; Roy, H K; Batra, S K

    2008-01-01

    MUC4 is a large, heavily glycosylated transmembrane mucin, that is implicated in the pathogenesis of various types of cancers. To date, no extensive study has been done to check the expression and functional significance of MUC4 in different types of gastric adenocarcinomas. Here, we report the expression profile of MUC4 in gastric adenocarcinomas and its function in poorly differentiated gastric non-signet ring cell carcinoma (non-SRCC) type cells. Immunohistochemical analysis using tissue microarray (TMA) showed a significant difference in MUC4 expression between normal adjacent (n=45) and gastric adenocarcinoma (n=83; P<0.001). MUC4 expression was not associated with tumour type, stage or with the degree of differentiation. To gain further insight into the significance of MUC4 expression in gastric non-SRCC cells, MUC4 was ectopically expressed in AGS, a poorly differentiated gastric non-signet ring cell line. The MUC4 overexpressing cells (AGS-MUC4) showed a significant increase (P<0.005) in cell motility and a decrease in cellular aggregation as compared with the vector-transfected cells. Furthermore, in vivo tumorigenicity analysis revealed that animals transplanted with the MUC4 overexpressing cells (AGS-MUC4) had a greater incidence of tumours (83%) in comparison to empty vector control (17%). In addition, the expression of MUC4 resulted in enhanced expression of total cellular ErbB2 and phosphorylated ErbB2. In conclusion, our results showed that MUC4 is overexpressed in gastric adenocarcinoma tissues, and that it has a role in promoting aggressive properties in poorly differentiated gastric non-SRCC cells through the activation of the ErbB2 oncoprotein. PMID:18781152

  2. [Current immunotherapy of multiple sclerosis].

    PubMed

    Paul, F; Ruprecht, K

    2015-08-01

    Following the introduction of interferon beta 1b as the first immunomodulatory therapy for multiple sclerosis (MS) in 1993, there are currently nine substances or substance classes approved for the treatment of MS (i.e. alemtuzumab, azathioprine, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta, mitoxantrone, natalizumab and teriflunomide). Major developments during the last 5 years include the approval of orally administered medications (i.e. fingolimod, teriflunomide and dimethyl fumarate), a monoclonal antibody (alemtuzumab), as well as glatiramer acetate with an administration frequency three times a week and a pegylated formulation of interferon beta 1a. The broadened therapeutic options enable a more differentiated and individualized therapy of MS; however, evidence-based data for therapeutic decision-making relevant in clinical practice are not always available. Rare but potentially severe and even life-threatening side effects of immunotherapies for MS require continuous pharmacovigilance and adherence to risk management plans. PMID:26253589

  3. The marine sponge-derived inorganic polymers, biosilica and polyphosphate, as morphogenetically active matrices/scaffolds for the differentiation of human multipotent stromal cells: potential application in 3D printing and distraction osteogenesis.

    PubMed

    Wang, Xiaohong; Schröder, Heinz C; Grebenjuk, Vladislav; Diehl-Seifert, Bärbel; Mailänder, Volker; Steffen, Renate; Schloßmacher, Ute; Müller, Werner E G

    2014-02-01

    The two marine inorganic polymers, biosilica (BS), enzymatically synthesized from ortho-silicate, and polyphosphate (polyP), a likewise enzymatically synthesized polymer consisting of 10 to >100 phosphate residues linked by high-energy phosphoanhydride bonds, have previously been shown to display a morphogenetic effect on osteoblasts. In the present study, the effect of these polymers on the differential differentiation of human multipotent stromal cells (hMSC), mesenchymal stem cells, that had been encapsulated into beads of the biocompatible plant polymer alginate, was studied. The differentiation of the hMSCs in the alginate beads was directed either to the osteogenic cell lineage by exposure to an osteogenic medium (mineralization activation cocktail; differentiation into osteoblasts) or to the chondrogenic cell lineage by incubating in chondrocyte differentiation medium (triggering chondrocyte maturation). Both biosilica and polyP, applied as Ca˛? salts, were found to induce an increased mineralization in osteogenic cells; these inorganic polymers display also morphogenetic potential. The effects were substantiated by gene expression studies, which revealed that biosilica and polyP strongly and significantly increase the expression of bone morphogenetic protein 2 (BMP-2) and alkaline phosphatase (ALP) in osteogenic cells, which was significantly more pronounced in osteogenic versus chondrogenic cells. A differential effect of the two polymers was seen on the expression of the two collagen types, I and II. While collagen Type I is highly expressed in osteogenic cells, but not in chondrogenic cells after exposure to biosilica or polyP, the upregulation of the steady-state level of collagen Type II transcripts in chondrogenic cells is comparably stronger than in osteogenic cells. It is concluded that the two polymers, biosilica and polyP, are morphogenetically active additives for the otherwise biologically inert alginate polymer. It is proposed that alginate, supplemented with polyP and/or biosilica, is a suitable biomaterial that promotes the growth and differentiation of hMSCs and might be beneficial for application in 3D tissue printing of hMSCs and for the delivery of hMSCs in fractures, surgically created during distraction osteogenesis. PMID:24566262

  4. The Marine Sponge-Derived Inorganic Polymers, Biosilica and Polyphosphate, as Morphogenetically Active Matrices/Scaffolds for the Differentiation of Human Multipotent Stromal Cells: Potential Application in 3D Printing and Distraction Osteogenesis

    PubMed Central

    Wang, Xiaohong; Schröder, Heinz C.; Grebenjuk, Vladislav; Diehl-Seifert, Bärbel; Mailänder, Volker; Steffen, Renate; Schloßmacher, Ute; Müller, Werner E. G.

    2014-01-01

    The two marine inorganic polymers, biosilica (BS), enzymatically synthesized from ortho-silicate, and polyphosphate (polyP), a likewise enzymatically synthesized polymer consisting of 10 to >100 phosphate residues linked by high-energy phosphoanhydride bonds, have previously been shown to display a morphogenetic effect on osteoblasts. In the present study, the effect of these polymers on the differential differentiation of human multipotent stromal cells (hMSC), mesenchymal stem cells, that had been encapsulated into beads of the biocompatible plant polymer alginate, was studied. The differentiation of the hMSCs in the alginate beads was directed either to the osteogenic cell lineage by exposure to an osteogenic medium (mineralization activation cocktail; differentiation into osteoblasts) or to the chondrogenic cell lineage by incubating in chondrocyte differentiation medium (triggering chondrocyte maturation). Both biosilica and polyP, applied as Ca2+ salts, were found to induce an increased mineralization in osteogenic cells; these inorganic polymers display also morphogenetic potential. The effects were substantiated by gene expression studies, which revealed that biosilica and polyP strongly and significantly increase the expression of bone morphogenetic protein 2 (BMP-2) and alkaline phosphatase (ALP) in osteogenic cells, which was significantly more pronounced in osteogenic versus chondrogenic cells. A differential effect of the two polymers was seen on the expression of the two collagen types, I and II. While collagen Type I is highly expressed in osteogenic cells, but not in chondrogenic cells after exposure to biosilica or polyP, the upregulation of the steady-state level of collagen Type II transcripts in chondrogenic cells is comparably stronger than in osteogenic cells. It is concluded that the two polymers, biosilica and polyP, are morphogenetically active additives for the otherwise biologically inert alginate polymer. It is proposed that alginate, supplemented with polyP and/or biosilica, is a suitable biomaterial that promotes the growth and differentiation of hMSCs and might be beneficial for application in 3D tissue printing of hMSCs and for the delivery of hMSCs in fractures, surgically created during distraction osteogenesis. PMID:24566262

  5. Deguelin, a selective silencer of the NPM1 mutant, potentiates apoptosis and induces differentiation in AML cells carrying the NPM1 mutation.

    PubMed

    Yi, Sha; Wen, Lu; He, Jing; Wang, Youping; Zhao, Fei; Zhao, Jie; Zhao, Zichu; Cui, Guohui; Chen, Yan

    2015-02-01

    Nucleophosmin (NPM1) is a multifunctional protein that functions as a molecular chaperone, shuttling between the nucleolus and the cytoplasm. In up to one third of patients with acute myeloid leukemia, mutation of NPM1 results in the aberrant cytoplasmic accumulation of mutant protein and is thought to be responsible for leukemogenesis. Deguelin, a rotenoid isolated from several plant species, has been shown to be a strong anti-tumor agent. Human leukemia cell lines were used for in vitro studies. Drug efficacy was evaluated by apoptosis and differentiation assays, and associated molecular events were assessed by Western blot. Gene silencing was performed using small interfering RNA (siRNA). Deguelin exhibited strong cytotoxic activity in the cell line of OCI-AML3 and selectively down-regulated the NPM1 mutant protein, which was accompanied by up-regulation of the activity of caspase-6 and caspase-8 in high concentrations. Deguelin induced differentiation of OCI-AML3 cells at a nontoxic concentration which was associated with a decrease in expression of activated caspase-8, p53, p21, and the 30-kD form of CCAAT/enhancer binding protein ? (C/EBP?), whereas no effects were found in OCIM2 cells expressing NPM-wt. Moreover, treatment with siRNA in the NPM mutant cell line OCI-AML3 decreased expression of p53, p21, pro-caspase-8, and the 30-kD form of C/EBP?, and it inhibited proliferation and induced differentiation of the OCI-AML3 cells. In conclusion, deguelin is a potent in vitro inhibitor of the mutant form of NPM1, which provides the molecular basis for its anti-leukemia activities in NPM1 mutant acute myeloid leukemia cells. PMID:25242579

  6. Enhanced expression of extracellular calcium sensing receptor in monocyte-differentiated versus undifferentiated HL-60 cells: potential role in regulation of a nonselective cation channel

    NASA Technical Reports Server (NTRS)

    Yamaguchi, T.; Ye, C.; Chattopadhyay, N.; Sanders, J. L.; Vassilev, P. M.; Brown, E. M.; O'Malley, B. W. (Principal Investigator)

    2000-01-01

    Human promyelocytic leukemia cells (HL-60) have been used widely as a model for studying the differentiation of hematopoietic progenitor cells in vitro. After treatment with phorbol-12-myristate-13-acetate (PMA) or 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], HL-60 cells differentiate into cells with the phenotype of monocytes/macrophages. We previously showed that peripheral blood monocytes and the murine J774 monocytic cell line express the CaR, and myeloid progenitors in the bone marrow and myeloid cells in peripheral blood other than monocytes express lower levels of the CaR. Therefore, we investigated whether undifferentiated HL-60 cells express a functional G protein-coupled, extracellular calcium (Ca(2+)(o))-sensing receptor (CaR) and if the expression of the CaR increases as these cells differentiate along the monocytic lineage. The use of reverse transcription-polymerase chain reaction (RT-PCR) with CaR-specific primers, followed by sequencing of the amplified products, identified an authentic CaR transcript in undifferentiated HL-60 cells. Both immunocytochemistry and Western blot analysis using a CaR-specific antiserum detected low levels of CaR protein expression in undifferentiated HL-60 cells. The levels of CaR protein increased considerably following treatment of the cells with PMA (50 nM) or 1,25(OH)(2)D(3) (100 nM) for 5 days. Northern analysis using a CaR-specific riboprobe identified CaR transcripts in undifferentiated HL-60 cells, but CaR mRNA levels did not change appreciably after treatment with either agent, suggesting that upregulation of CaR protein occurs at a translational level. PMA-treated HL-60 cells expressed a nonselective cation channel (NCC), and the calcimimetic CaR activator, NPS R-467, but not its less active stereoisomer, NPS S-467, as well as the polycationic CaR agonist, neomycin, activated this NCC, demonstrating that the CaR expressed in these cells is functionally active. Therefore, HL-60 cells exhibit an increase in CaR protein expression, occurring at a translational level during their differentiation into cells with a monocyte/macrophage phenotype in response to treatment with PMA or 1, 25(OH)(2)D(3), which is functionally linked to activation of a nonselective cation channel.

  7. Cell-type specific photoreceptors and light signaling pathways in the multicellular green alga volvox carteri and their potential role in cellular differentiation

    PubMed Central

    Kianianmomeni, Arash

    2015-01-01

    The formation of multicellular organisms requires genetically predefined signaling pathways in various cell types. Besides differences in size, energy balance and life time, cell types should be enable to modulate appropriate developmental and adaptive responses in ever-changing surrounding environment. One of the most important environmental cues is light which regulates a variety of physiological and cellular processes. During evolution, diverse light-sensitive proteins, so-called photoreceptors, and corresponding signaling pathways have evolved, in almost all kingdoms of life, to monitor light continuously and adjust their growth and development accordingly. However, considering the fact that different cell types should be enable to trigger distinct light signaling pathways according to their needs, cell-type specific light signaling pathways are required to guarantee cell type-matched modulation of cellular and developmental processes in response to different light signals. The multicellular green alga Volvox carteri, which has only 2 cell types with clear division of labor, possesses cell-type specific photoreceptors and light signaling pathways which allow differential regulation of genes involved in various cellular and metabolic pathways in response to environmental light. The existence of cell-type specific light signaling pathways in muticellular organism like Volvox reflects an early development of cell-type specific signaling mechanisms during evolution to ensure maintenance of differentiation. PMID:25874475

  8. Investigating the Potential Influence of Cause of Death and Cocaine Levels on the Differential Expression of Genes Associated with Cocaine Abuse

    PubMed Central

    Bannon, Michael J.; Savonen, Candace L.; Hartley, Zachary J.; Johnson, Magen M.; Schmidt, Carl J.

    2015-01-01

    The development of new therapeutic strategies for the treatment of complex brain disorders such as drug addiction is likely to be advanced by a more complete understanding of the underlying molecular pathophysiology. Although the study of postmortem human brain represents a unique resource in this regard, it can be challenging to disentangle the relative contribution of chronic pathological processes versus perimortem events to the observed changes in gene expression. To begin to unravel this issue, we analyzed by quantitative PCR the midbrain expression of numerous candidate genes previously associated with cocaine abuse. Data obtained from chronic cocaine abusers (and matched control subjects) dying of gunshot wounds were compared with a prior study of subjects with deaths directly attributable to cocaine abuse. Most of the genes studied (i.e., tyrosine hydroxylase, dopamine transporter, forkhead box A2, histone variant H3 family 3B, nuclear factor kappa B inhibitor alpha, growth arrest and DNA damage-inducible beta) were found to be differentially expressed in chronic cocaine abusers irrespective of immediate cause of death or perimortem levels of cocaine, suggesting that these may represent core pathophysiological changes arising with chronic drug abuse. On the other hand, chemokine C-C motif ligand 2 and jun proto-oncogene expression were unaffected in cocaine-abusing subjects dying of gunshot wounds, in contrast to the differential expression previously reported in cocaine-related fatalities. The possible influence of cause of death and other factors on the cocaine-responsiveness of these genes is discussed. PMID:25658879

  9. Multiple Sclerosis

    MedlinePLUS

    ... Awards Enhancing Diversity Find People About NINDS NINDS Multiple Sclerosis Information Page Condensed from Multiple Sclerosis: Hope Through ... en Espańol Additional resources from MedlinePlus What is Multiple Sclerosis? An unpredictable disease of the central nervous system, ...

  10. Highly interactive nature of flower-specific enhancers and promoters, and its potential impact on tissue-specific expression and engineering of multiple genes or agronomic traits

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Molecular stacking via a single transgene enables multiple traits being engineered efficiently in crops. However, whether distinct plant promoters co-existed in the same transgene could, like their mammalian counterparts, mutually interact or interfere remains unknown. In this study, researchers d...

  11. Differential games.

    NASA Technical Reports Server (NTRS)

    Varaiya, P. P.

    1972-01-01

    General discussion of the theory of differential games with two players and zero sum. Games starting at a fixed initial state and ending at a fixed final time are analyzed. Strategies for the games are defined. The existence of saddle values and saddle points is considered. A stochastic version of a differential game is used to examine the synthesis problem.

  12. Bile acids induce hepatic differentiation of mesenchymal stem cells

    PubMed Central

    Sawitza, Iris; Kordes, Claus; Götze, Silke; Herebian, Diran; Häussinger, Dieter

    2015-01-01

    Mesenchymal stem cells (MSC) have the potential to differentiate into multiple cell lineages and their therapeutic potential has become obvious. In the liver, MSC are represented by stellate cells which have the potential to differentiate into hepatocytes after stimulation with growth factors. Since bile acids can promote liver regeneration, their influence on liver-resident and bone marrow-derived MSC was investigated. Physiological concentrations of bile acids such as tauroursodeoxycholic acid were able to initiate hepatic differentiation of MSC via the farnesoid X receptor and transmembrane G-protein-coupled bile acid receptor 5 as investigated with knockout mice. Notch, hedgehog, transforming growth factor-?/bone morphogenic protein family and non-canonical Wnt signalling were also essential for bile acid-mediated differentiation, whereas ?-catenin-dependent Wnt signalling was able to attenuate this process. Our findings reveal bile acid-mediated signalling as an alternative way to induce hepatic differentiaion of stem cells and highlight bile acids as important signalling molecules during liver regeneration. PMID:26304833

  13. Bile acids induce hepatic differentiation of mesenchymal stem cells.

    PubMed

    Sawitza, Iris; Kordes, Claus; Götze, Silke; Herebian, Diran; Häussinger, Dieter

    2015-01-01

    Mesenchymal stem cells (MSC) have the potential to differentiate into multiple cell lineages and their therapeutic potential has become obvious. In the liver, MSC are represented by stellate cells which have the potential to differentiate into hepatocytes after stimulation with growth factors. Since bile acids can promote liver regeneration, their influence on liver-resident and bone marrow-derived MSC was investigated. Physiological concentrations of bile acids such as tauroursodeoxycholic acid were able to initiate hepatic differentiation of MSC via the farnesoid X receptor and transmembrane G-protein-coupled bile acid receptor 5 as investigated with knockout mice. Notch, hedgehog, transforming growth factor-?/bone morphogenic protein family and non-canonical Wnt signalling were also essential for bile acid-mediated differentiation, whereas ?-catenin-dependent Wnt signalling was able to attenuate this process. Our findings reveal bile acid-mediated signalling as an alternative way to induce hepatic differentiaion of stem cells and highlight bile acids as important signalling molecules during liver regeneration. PMID:26304833

  14. Mechanical stimuli differentially control stem cell behavior: morphology, proliferation, and differentiation

    PubMed Central

    Maul, Timothy M.; Chew, Douglas W.; Nieponice, Alejandro

    2011-01-01

    Mesenchymal stem cell (MSC) therapy has demonstrated applications in vascular regenerative medicine. Although blood vessels exist in a mechanically dynamic environment, there has been no rigorous, systematic analysis of mechanical stimulation on stem cell differentiation. We hypothesize that mechanical stimuli, relevant to the vasculature, can differentiate MSCs toward smooth muscle (SMCs) and endothelial cells (ECs). This was tested using a unique experimental platform to differentially apply various mechanical stimuli in parallel. Three forces, cyclic stretch, cyclic pressure, and laminar shear stress, were applied independently to mimic several vascular physiologic conditions. Experiments were conducted using subconfluent MSCs for 5 days and demonstrated significant effects on morphology and proliferation depending upon the type, magnitude, frequency, and duration of applied stimulation. We have defined thresholds of cyclic stretch that potentiate SMC protein expression, but did not find EC protein expression under any condition tested. However, a second set of experiments performed at confluence and aimed to elicit the temporal gene expression response of a select magnitude of each stimulus revealed that EC gene expression can be increased with cyclic pressure and shear stress in a cell-contact-dependent manner. Further, these MSCs also appear to express genes from multiple lineages simultaneously which may warrant further investigation into post-transcriptional mechanisms for controlling protein expression. To our knowledge, this is the first systematic examination of the effects of mechanical stimulation on MSCs and has implications for the understanding of stem cell biology, as well as potential bioreactor designs for tissue engineering and cell therapy applications. PMID:21253809

  15. Potential for Differentiation of Pseudoprogression From True Tumor Progression With Dynamic Susceptibility-Weighted Contrast-Enhanced Magnetic Resonance Imaging Using Ferumoxytol vs. Gadoteridol: A Pilot Study

    SciTech Connect

    Gahramanov, Seymur; Raslan, Ahmed M.; Muldoon, Leslie L.; Hamilton, Bronwyn E.; Rooney, William D.; Varallyay, Csanad G.; Njus, Jeffrey M.; Haluska, Marianne; Neuwelt, Edward A.

    2011-02-01

    Purpose: We evaluated dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging (DSC-MRI) using gadoteridol in comparison to the iron oxide nanoparticle blood pool agent, ferumoxytol, in patients with glioblastoma multiforme (GBM) who received standard radiochemotherapy (RCT). Methods and Materials: Fourteen patients with GBM received standard RCT and underwent 19 MRI sessions that included DSC-MRI acquisitions with gadoteridol on Day 1 and ferumoxytol on Day 2. Relative cerebral blood volume (rCBV) values were calculated from DSC data obtained from each contrast agent. T1-weighted acquisition post-gadoteridol administration was used to identify enhancing regions. Results: In seven MRI sessions of clinically presumptive active tumor, gadoteridol-DSC showed low rCBV in three and high rCBV in four, whereas ferumoxytol-DSC showed high rCBV in all seven sessions (p = 0.002). After RCT, seven MRI sessions showed increased gadoteridol contrast enhancement on T1-weighted scans coupled with low rCBV without significant differences between contrast agents (p = 0.9). Based on post-gadoteridol T1-weighted scans, DSC-MRI, and clinical presentation, four patterns of response to RCT were observed: regression, pseudoprogression, true progression, and mixed response. Conclusion: We conclude that DSC-MRI with a blood pool agent such as ferumoxytol may provide a better monitor of tumor rCBV than DSC-MRI with gadoteridol. Lesions demonstrating increased enhancement on T1-weighted MRI coupled with low ferumoxytol rCBV are likely exhibiting pseudoprogression, whereas high rCBV with ferumoxytol is a better marker than gadoteridol for determining active tumor. These interesting pilot observations suggest that ferumoxytol may differentiate tumor progression from pseudoprogression and warrant further investigation.

  16. Improving the Classification of Multiple Disorders with Problem Decomposition

    E-print Network

    Abdel-Aal, Radwan E.

    Improving the Classification of Multiple Disorders with Problem Decomposition Radwan E. Abdel-Aal1@kfupm.edu.sa Phone: +966 3 860 4320 Fax: +966 3 860 4281 #12;Abstract Differential diagnosis of multiple disorders, Multiple Disorders, Dermatology. 2 #12;1. Introduction Differential diagnosis among a group of disorders

  17. Isorhamnetin, A Flavonol Aglycone from Ginkgo biloba L., Induces Neuronal Differentiation of Cultured PC12 Cells: Potentiating the Effect of Nerve Growth Factor

    PubMed Central

    Xu, Sherry L.; Choi, Roy C. Y.; Zhu, Kevin Y.; Leung, Ka-Wing; Guo, Ava J. Y.; Bi, Dan; Xu, Hong; Lau, David T. W.; Dong, Tina T. X.; Tsim, Karl W. K.

    2012-01-01

    Flavonoids, a group of compounds mainly derived from vegetables and herbal medicines, share a chemical resemblance to estrogen, and indeed some of which have been used as estrogen substitutes. In searching for possible functions of flavonoids, the neuroprotective effect in brain could lead to novel treatment, or prevention, for neurodegenerative diseases. Here, different subclasses of flavonoids were analyzed for its inductive role in neurite outgrowth of cultured PC12 cells. Amongst the tested flavonoids, a flavonol aglycone, isorhamnetin that was isolated mainly from the leaves of Ginkgo biloba L. showed robust induction in the expression of neurofilament, a protein marker for neurite outgrowth, of cultured PC12 cells. Although isorhamnetin by itself did not show significant inductive effect on neurite outgrowth of cultured PC12 cells, the application of isorhamnetin potentiated the nerve growth factor- (NGF-)induced neurite outgrowth. In parallel, the expression of neurofilaments was markedly increased in the cotreatment of NGF and isorhamnetin in the cultures. The identification of these neurite-promoting flavonoids could be very useful in finding potential drugs, or food supplements, for treating various neurodegenerative diseases, including Alzheimer's disease and depression. PMID:22761636

  18. Germline BAP1 mutation in a family with high incidence of multiple primary cancers and a potential gene-environment interaction.

    PubMed

    Cheung, Mitchell; Kadariya, Yuwaraj; Talarchek, Jacqueline; Pei, Jianming; Ohar, Jill A; Kayaleh, Omar R; Testa, Joseph R

    2015-12-28

    We report a high-risk cancer family with multiple mesotheliomas, cutaneous melanomas, basal cell carcinomas, and meningiomas segregating with a germline nonsense mutation in BAP1 (c.1938T>A; p.Y646X). Notably, most (four of five) mesotheliomas were peritoneal rather than the usually more common pleural form of the disease, and all five mesothelioma patients also developed second or third primary cancers, including two with meningiomas. Another family member developed both cutaneous melanoma and breast cancer. Two family members had basal cell carcinomas, and six others had melanocytic tumors, including four cutaneous melanomas, one uveal melanoma, and one benign melanocytic tumor. The family resides in a subtropical area, and several members had suspected exposure to asbestos either occupationally or in the home. We hypothesize that the concurrence of a genetic predisposing factor and environmental exposure to asbestos and UV irradiation contributed to the high incidence of multiple cancers seen in this family, specifically mesothelioma and various uveal/skin tumors, respectively. PMID:26409435

  19. The AP-1 transcription factor homolog Pf-AP-1 activates transcription of multiple biomineral proteins and potentially participates in Pinctada fucata biomineralization

    PubMed Central

    Zheng, Xiangnan; Cheng, Minzhang; Xiang, Liang; Liang, Jian; Xie, Liping; Zhang, Rongqing

    2015-01-01

    Activator protein-1 (AP-1) is an important bZIP transcription factor that regulates a series of physiological processes by specifically activating transcription of several genes, and one of its well-chartered functions in mammals is participating in bone mineralization. We isolated and cloned the complete cDNA of a Jun/AP-1 homolog from Pinctada fucata and called it Pf-AP-1. Pf-AP-1 had a highly conserved bZIP region and phosphorylation sites compared with those from mammals. A tissue distribution analysis showed that Pf-AP-1 was ubiquitously expressed in P. fucata and the mRNA level of Pf-AP-1 is extremely high in mantle. Pf-AP-1 expression was positively associated with multiple biomineral proteins in the mantle. The luciferase reporter assay in a mammalian cell line showed that Pf-AP-1 significantly up-regulates the transcriptional activity of the promoters of KRMP, Pearlin, and Prisilkin39. Inhibiting the activity of Pf-AP-1 depressed the expression of multiple matrix proteins. Pf-AP-1 showed a unique expression pattern during shell regeneration and pearl sac development, which was similar to the pattern observed for biomineral proteins. These results suggest that the Pf-AP-1 AP-1 homolog is an important transcription factor that regulates transcription of several biomineral proteins simultaneously and plays a role in P. fucata biomineralization, particularly during pearl and shell formation. PMID:26404494

  20. Stochastic partial differential equations driven by colored noise

    E-print Network

    Huang, Jingyu

    2015-05-31

    This dissertation studies some problems for stochastic partial differential equations, in particular, (nonlinear) stochastic heat and stochastic wave equations, driven by (multiplicative) colored Gaussian noises. These problems considered...

  1. A Simple Method for Decreasing the Liquid Junction Potential in a Flow-through-Type Differential pH Sensor Probe Consisting of pH-FETs by Exerting Spatiotemporal Control of the Liquid Junction

    PubMed Central

    Yamada, Akira; Mohri, Satoshi; Nakamura, Michihiro; Naruse, Keiji

    2015-01-01

    The liquid junction potential (LJP), the phenomenon that occurs when two electrolyte solutions of different composition come into contact, prevents accurate measurements in potentiometry. The effect of the LJP is usually remarkable in measurements of diluted solutions with low buffering capacities or low ion concentrations. Our group has constructed a simple method to eliminate the LJP by exerting spatiotemporal control of a liquid junction (LJ) formed between two solutions, a sample solution and a baseline solution (BLS), in a flow-through-type differential pH sensor probe. The method was contrived based on microfluidics. The sensor probe is a differential measurement system composed of two ion-sensitive field-effect transistors (ISFETs) and one Ag/AgCl electrode. With our new method, the border region of the sample solution and BLS is vibrated in order to mix solutions and suppress the overshoot after the sample solution is suctioned into the sensor probe. Compared to the conventional method without vibration, our method shortened the settling time from over two min to 15 s and reduced the measurement error by 86% to within 0.060 pH. This new method will be useful for improving the response characteristics and decreasing the measurement error of many apparatuses that use LJs. PMID:25835300

  2. Differential modulation by the GABAB receptor allosteric potentiator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)-phenol (CGP7930) of synaptic transmission in the rat hippocampal CA1 area.

    PubMed

    Chen, Ying; Menendez-Roche, Nicole; Sher, Emanuele

    2006-06-01

    The recently discovered GABAB receptor-positive allosteric modulators enhanced the potency and efficacy of GABAB receptor agonists in in vitro experiments. These GABAB modulators also attenuated reward and anxiety in behavioral experiments without causing the untoward side effects associated with GABAB receptor activation by agonist administration and hence exhibited potential therapeutic utility. However, the underlying molecular mechanisms enabling the GABAB allosteric modulators to dissociate from the GABAB agonistic side effects remain elusive. To address this question, we have examined the effects of a typical GABAB modulator, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)-phenol (CGP7930), on GABAB receptor-mediated modulations of both the excitatory and the delayed inhibitory components of hippocampal CA1 synaptic transmission. Using baclofen as an agonist and a multielectrode recording system, we recorded GABAB receptor-mediated modulations of both the field excitatory postsynaptic potentials and the population spikes simultaneously, as well as the paired-pulse inhibition of the population spike. We found that CGP7930 selectively enhanced the baclofen-induced modulation of synaptic inhibition without having any significant effects on the synaptic excitation. Our experiments have therefore revealed a pathway-selective differential modulation of synaptic transmission by CGP7930. This finding provides a synaptic mechanism to support the hypothesis that GABAB potentiators may be a better therapeutic alternative than GABAB agonists for central nervous system disorders. PMID:16507713

  3. Multiple Sclerosis

    MedlinePLUS

    Multiple sclerosis (MS) is a nervous system disease that affects your brain and spinal cord. It damages the ... attacks healthy cells in your body by mistake. Multiple sclerosis affects women more than men. It often begins ...

  4. Gamma Rossi-alpha, Feynman-alpha and Gamma Differential Die-Away concepts as a potential alternative/complement to the traditional thermal neutron based analysis in Safeguards

    E-print Network

    Dina Chernikova; Syed F. Naeem; Nermin Trnjanin; Kĺre Axell; Anders Nordlund

    2015-07-20

    A new concept for thermal neutron based correlation and multiplicity measurements is proposed in this paper. The main idea of the concept consists of using 2.223 MeV gammas (or 1.201 MeV, DE) originating in the 1H(n,gamma)2D-reaction instead of using traditional thermal neutron counting. Results of investigations presented in this paper indicate that gammas from thermal neutron capture reaction preserve the information about the correlation characteristics of thermal (fast) neutrons in the same time scale. Therefore, instead of thermal neutron detectors (or as a complement) one may use traditional and inexpensive gamma detectors, such NaI, BGO, CdZnTe or any other gamma detectors. In this work we used D8x8 cm2 NaI scintillator to test the concept. Thus, the new approach helps to address the problem of replacement of 3He-counters and problems related to the specific measurements of spent nuclear fuel directly in the spent fuel pool. It has a particular importance for nuclear safeguards and security. Overall, this work represents the proof of concept study and reports on the experimental and numerical evidence that thermal neutron capture gammas may be used in the context of correlation and multiplicity measurements. Investigations were performed for a 252Cf-correlated neutron source and an 241Am-Be-random neutron source. The related idea of Gamma Differential Die-Away approach is investigated numerically in this paper as well, and will be tested experimentally in a future work.

  5. Finger Multiplication

    ERIC Educational Resources Information Center

    Simanihuruk, Mudin

    2011-01-01

    Multiplication facts are difficult to teach. Therefore many researchers have put a great deal of effort into finding multiplication strategies. Sherin and Fuson (2005) provided a good survey paper on the multiplication strategies research area. Kolpas (2002), Rendtorff (1908), Dabell (2001), Musser (1966) and Markarian (2009) proposed the finger…

  6. MicroRNA and mRNA expression profile screening in multiple sclerosis patients to unravel novel pathogenic steps and identify potential biomarkers.

    PubMed

    Martinelli-Boneschi, Filippo; Fenoglio, Chiara; Brambilla, Paola; Sorosina, Melissa; Giacalone, Giacomo; Esposito, Federica; Serpente, Maria; Cantoni, Claudia; Ridolfi, Elisa; Rodegher, Mariaemma; Moiola, Lucia; Colombo, Bruno; De Riz, Milena; Martinelli, Vittorio; Scarpini, Elio; Comi, Giancarlo; Galimberti, Daniela

    2012-02-01

    Identification of novel targets and biomarkers, such as microRNAs, is extremely helpful to understand the pathogenetic mechanisms in a disease like multiple sclerosis (MS). We tested the expression profile of 1145 microRNAs in peripheral blood mononuclear cells (PBMCs) of 19 MS patients and 14 controls, and we further explored their function by performing a whole-genome mRNA profiling in same subjects and using bioinformatic prediction tool. A total of 104 miRNAs have been identified as deregulated in MS patients; 2/10 which ranked highest (let-7g and miR-150) have been validated in a replication sample, leading to the identification of putative target genes. PMID:22108567

  7. Tumor necrosis factor-? impairs oligodendroglial differentiation through a mitochondria-dependent process

    PubMed Central

    Bonora, M; De Marchi, E; Patergnani, S; Suski, J M; Celsi, F; Bononi, A; Giorgi, C; Marchi, S; Rimessi, A; Duszy?ski, J; Pozzan, T; Wieckowski, M R; Pinton, P

    2014-01-01

    Mitochondrial defects, affecting parameters such as mitochondrial number and shape, levels of respiratory chain complex components and markers of oxidative stress, have been associated with the appearance and progression of multiple sclerosis. Nevertheless, mitochondrial physiology has never been monitored during oligodendrocyte progenitor cell (OPC) differentiation, especially in OPCs challenged with proinflammatory cytokines. Here, we show that tumor necrosis factor alpha (TNF-?) inhibits OPC differentiation, accompanied by altered mitochondrial calcium uptake, mitochondrial membrane potential, and respiratory complex I activity as well as increased reactive oxygen species production. Treatment with a mitochondrial uncoupler (FCCP) to mimic mitochondrial impairment also causes cells to accumulate at the progenitor stage. Interestingly, AMP-activated protein kinase (AMPK) levels increase during TNF-? exposure and inhibit OPC differentiation. Overall, our data indicate that TNF-? induces metabolic changes, driven by mitochondrial impairment and AMPK activation, leading to the inhibition of OPC differentiation. PMID:24658399

  8. Cognitive event-related potentials differentiate schizophrenia with obsessive-compulsive disorder (schizo-OCD) from OCD and schizophrenia without OC symptoms.

    PubMed

    Pallanti, Stefano; Castellini, Giovanni; Chamberlain, Samuel R; Quercioli, Leonardo; Zaccara, Gaetano; Fineberg, Naomi A

    2009-11-30

    Clinical and neurobiological evidence suggests that concurrent presentation of schizophrenia and obsessive-compulsive (schizo-OCD) symptoms represents a distinct clinical entity. Given that obsessive-compulsive disorder (OCD) and schizophrenia have been modeled as having different neurofunctional profiles, the overlap between them represents a heuristic challenge for cognitive and endophenotype research. Event-related potentials (ERPs) may be used to probe neurophysiological correlates of the cognitive, emotional and behavioral disturbances found in neuropsychiatric entities such as schizo-OCD. Here we measure ERPs during a discriminative response task (DRT) in patients presenting with the DSM-IV criteria for both schizophrenia and OCD. We also performed these measurements in patients with OCD without psychotic features, as well as in patients with schizophrenia without OC symptoms. Schizo-OCD patients showed a distinct ERP pattern, with abnormally increased target activation (akin to OCD patients, but unlike the pattern observed in schizophrenic patients) and reduced P300 amplitudes (akin to schizophrenic patients, but unlike OCD patients). Similar to the control subjects, schizo-OCD patients showed larger amplitudes in the non-target condition than in the target condition. These results suggest that schizo-OCD may not only be a distinct clinical entity from pure OCD and schizophrenia, but it may also be characterized by a distinguishable neurophysiologic pattern. Neurobiological underpinnings deserve further considerations and might drive to a definition of a distinctive endophenotype for schizo-OCD in the de-construction of the schizophrenia endophenotype. PMID:19800695

  9. The Differential Proteome of the Probiotic Lactobacillus acidophilus NCFM Grown on the Potential Prebiotic Cellobiose Shows Upregulation of Two ?-Glycoside Hydrolases

    PubMed Central

    van Zanten, Gabriella C.; Sparding, Nadja; Majumder, Avishek; Lahtinen, Sampo J.; Svensson, Birte; Jacobsen, Susanne

    2015-01-01

    Probiotics, prebiotics, and combinations thereof, that is, synbiotics, are known to exert beneficial health effects in humans; however interactions between pro- and prebiotics remain poorly understood at the molecular level. The present study describes changes in abundance of different proteins of the probiotic bacterium Lactobacillus acidophilus NCFM (NCFM) when grown on the potential prebiotic cellobiose as compared to glucose. Cytosolic cell extract proteomes after harvest at late exponential phase of NCFM grown on cellobiose or glucose were analyzed by two dimensional difference gel electrophoresis (2D-DIGE) in the acidic (pH 4–7) and the alkaline (pH 6–11) regions showing a total of 136 spots to change in abundance. Proteins were identified by MS or MS/MS from 81 of these spots representing 49 unique proteins and either increasing 1.5–13.9-fold or decreasing 1.5–7.8-fold in relative abundance. Many of these proteins were associated with energy metabolism, including the cellobiose related glycoside hydrolases phospho-?-glucosidase (LBA0881) and phospho-?-galactosidase II (LBA0726). The data provide insight into the utilization of the candidate prebiotic cellobiose by the probiotic bacterium NCFM. Several of the upregulated or downregulated identified proteins associated with utilization of cellobiose indicate the presence of carbon catabolite repression and regulation of enzymes involved in carbohydrate metabolism. PMID:25961012

  10. Differential expression of id genes and their potential regulator znf238 in zebrafish adult neural progenitor cells and neurons suggests distinct functions in adult neurogenesis.

    PubMed

    Diotel, Nicolas; Beil, Tanja; Strähle, Uwe; Rastegar, Sepand

    2015-01-01

    Teleost fish display a remarkable ability to generate new neurons and to repair brain lesions during adulthood. They are, therefore, a very popular model to investigate the molecular mechanisms of constitutive and induced neurogenesis in adult vertebrates. In this study, we investigated the expression patterns of inhibitor of DNA binding (id) genes and of their potential transcriptional repressor, znf238, in the whole brain of adult zebrafish. We show that while id1 is exclusively expressed in ventricular cells in the whole brain, id2a, id3 and id4 genes are expressed in broader areas. Interestingly, znf238 was also detected in these regions, its expression overlapping with id2a, id3 and id4 expression. Further detailed characterization of the id-expressing cells demonstrated that (a) id1 is expressed in type 1 and type 2 neural progenitors as previously published, (b) id2a in type 1, 2 and 3 neural progenitors, (c) id3 in type 3 neural progenitors and (d) id4 in postmitotic neurons. Our data provide a detailed map of id and znf238 expression in the brain of adult zebrafish, supplying a framework for studies of id genes function during adult neurogenesis and brain regeneration in the zebrafish. PMID:26107416

  11. Differential contribution of extracellular and intracellular calcium sources to basal transmission and long-term potentiation in the sympathetic ganglion of the rat.

    PubMed

    Vargas, R; Cifuentes, F; Morales, M A

    2007-04-01

    Calcium involved in basal ganglionic transmission and long-term potentiation (LTP) can arise either by influx from the extracellular medium or release from intracellular stores. No attempts have yet been made to concurrently explore the contributions of extracellular and intracellular Ca2+ to basal ganglionic transmission or LTP. Here, we investigate this subject using the superior cervical ganglion of the rat. To explore the extracellular Ca2+ contribution, we evaluated basal transmission and LTP at different extracellular Ca2+ concentrations. To assess intracellular Ca2+ release, we explored the contribution of the calcium-induced calcium release process by overactivation or blockade of ryanodine-sensitive Ca2+ receptor channel with caffeine, and also by blocking either IP3R with Xestospongin C or the sarco(endo)plasmic reticulum Ca2+-ATPase pump with thapsigargin. Extracellular Ca2+ affected ganglionic basal transmission and LTP to different extents. While 25% of the physiological Ca2+ concentration supported 80% of basal transmission, 50% of normal Ca2+ was required to achieve 80% of LTP. Notably, disruption of intracellular Ca2+ release by all the drugs tested apparently did not affect basal ganglionic transmission but impaired LTP. We conclude that basal transmission requires only a small level of Ca2+ entry, while LTP expression not only requires more Ca2+ entry but is also dependent on Ca2+ release from intracellular stores. PMID:17443810

  12. Differential effects of climate and species interactions on range limits at a hybrid zone: potential direct and indirect impacts of climate change.

    PubMed

    McQuillan, Michael A; Rice, Amber M

    2015-11-01

    The relative contributions of climate versus interspecific interactions in shaping species distributions have important implications for closely related species at contact zones. When hybridization occurs within a contact zone, these factors regulate hybrid zone location and movement. While a hybrid zone's position may depend on both climate and interactions between the hybridizing species, little is known about how these factors interact to affect hybrid zone dynamics. Here, we utilize SDM (species distribution modeling) both to characterize the factors affecting the current location of a moving North American avian hybrid zone and to predict potential direct and indirect effects of climate change on future distributions. We focus on two passerine species that hybridize where their ranges meet, the Black-capped (Poecile atricapillus) and Carolina (P. carolinensis) chickadee. Our contemporary climate models predict the occurrence of climatically suitable habitat extending beyond the hybrid zone for P. atricapillus only, suggesting that interspecific interactions primarily regulate this range boundary in P. atricapillus, while climatic factors regulate P. carolinensis. Year 2050 climate models predict a drastic northward shift in suitable habitat for P. carolinensis. Because of the greater importance of interspecific interactions for regulating the southern range limit of P. atricapillus, these climate-mediated shifts in the distribution of P. carolinensis may indirectly lead to a range retraction in P. atricapillus. Together, our results highlight the ways climate change can both directly and indirectly affect species distributions and hybrid zone location. In addition, our study lends support to the longstanding hypothesis that abiotic factors regulate species' poleward range limits, while biotic factors shape equatorial range limits. PMID:26640687

  13. Long-Duration Spaceflight During the Bion-M1 Spaceflight Experiment Resulted in Significant Bone Loss in the Femoral Head and Alterations in Stem Cell Differentiation Potential in Male Mice

    NASA Astrophysics Data System (ADS)

    Blaber, Elizabeth; Almeida, Eduardo; Grigoryan, Eleonora; Globus, Ruth

    Scientific understanding of the effects of microgravity on mammalian physiology has been limited to short duration spaceflight experiments (10-15 days). As long duration and inter-planetary missions are being initiated, there is a great need to understand the long-term effects of spaceflight on various physiological processes, including stem cell-based tissue regeneration. Bion-M1, for the first time, enabled the possibility of studying the effects of 30-days of microgravity exposure on a mouse model with sufficient sample size to enable statistical analysis. In this experiment, we hypothesized that microgravity negatively impacts stem cell based tissue regeneration, such as bone remodeling and regeneration from hematopoietic and mesenchymal precursors, thereby resulting in tissue degeneration in mice exposed to spaceflight. To test this hypothesis we collected the pelvis and proximal femur from space-flown mice and asynchronous ground controls and analyzed bone and bone marrow using techniques including Microcomputed Tomography (MicroCT), and in-vitro differentiation and differentiating cell motility assays. To determine the effects of 30-days spaceflight on bone tissue mass, we used MicroCT to analyze the trabecular bone of the femoral head and the cortical bone of the femoral neck and mid-shaft. We found that spaceflight caused a 45% decrease in bone volume ratio, a 17% decrease in trabecular thickness, a 25% decrease in trabecular number, and a 17% increase in trabecular spacing of trabecular bone. Furthermore, structural model index and trabecular pattern factor were increased by 32% and 82% respectively indicating that 30-days spaceflight resulted not only in a large loss of trabecular bone but also in a decrease of bone strength indicators. Analysis of the femoral neck cortical bone showed an increase in marrow area and cortical porosity indicating an overall widening of the femoral neck. Interestingly, no significant alterations were found in the cortical bone of the femoral mid-shaft. To determine the regenerative potential of osteoblasts derived from mesenchymal stem cells flown in microgravity we conducted post-flight in-vitro osteoblastogenesis and mineralized nodule formation assays. We found an increase in post-flight differentiation and mineralization of microgravity-flown osteogenic cells, suggesting an accumulation of precursor cells that fail to fully differentiate in space, and then resume vigorous osteogenesis upon reloading at 1g. Overall, these preliminary results indicate that exposure to 30-days spaceflight causes significant trabecular bone loss in the femoral head, a decrease in trabecular bone strength indicators, and compensatory widening of the femoral neck. These results, coupled with diminished regenerative potential of bone marrow stem cells during mechanical unloading in microgravity, have potentially serious implications for bone health and fracture risk during long-duration spaceflight.

  14. Valuing the Advanced Learner: Differentiating up

    ERIC Educational Resources Information Center

    Manning, Sandra; Stanford, Barbara; Reeves, Stacy

    2010-01-01

    In today's educational climate, differentiated instruction is a common practice for students who need remediation; what is less common is to Differentiate Instruction for the advanced learner. Contrary to popular perceptions, advanced learners do not automatically differentiate instruction on their own. Students who have the potential to excel…

  15. Rapid Exercise-Induced Mobilization of Dendritic Cells Is Potentially Mediated by a Flt3L- and MMP-9-Dependent Process in Multiple Sclerosis

    PubMed Central

    Deckx, Nathalie; Wens, Inez; Nuyts, Amber H.; Lee, Wai-Ping; Hens, Niel; Koppen, Gudrun; Goossens, Herman; Van Damme, Pierre; Berneman, Zwi N.; Eijnde, Bert O.; Cools, Nathalie

    2015-01-01

    In healthy individuals, one exercise bout induces a substantial increase in the number of circulating leukocytes, while their function is transiently suppressed. The effect of one exercise bout in multiple sclerosis (MS) is less studied. Since recent evidence suggests a role of dendritic cells (DC) in the pathogenesis of MS, we investigated the effect of one combined endurance/resistance exercise bout on the number and function of DC in MS patients and healthy controls. Our results show a rapid increase in the number of DC in response to physical exercise in both MS patients and controls. Further investigation revealed that in particular DC expressing the migratory molecules CCR5 and CD62L were increased upon acute physical activity. This may be mediated by Flt3L- and MMP-9-dependent mobilization of DC, as demonstrated by increased circulating levels of Flt3L and MMP-9 following one exercise bout. Circulating DC display reduced TLR responsiveness after acute exercise, as evidenced by a less pronounced upregulation of activation markers, HLA-DR and CD86, on plasmacytoid DC and conventional DC, respectively. Our results indicate mobilization of DC, which may be less prone to drive inflammatory processes, following exercise. This may present a negative feedback mechanism for exercise-induced tissue damage and inflammation. PMID:26604429

  16. Mass Spectrometric Immunoassay and Multiple Reaction Monitoring as Targeted MS-based Quantitative Approaches in Biomarker Development: Potential Applications to Cardiovascular Disease and Diabetes

    PubMed Central

    Yassine, Hussein; Borges, Chad R.; Schaab, Matthew R.; Billheimer, Dean; Stump, Craig; Reaven, Peter; Lau, Serrine S.; Nelson, Randall

    2014-01-01

    Type 2 diabetes (T2DM) is an important risk factor for cardiovascular disease (CVD)—the leading cause of death in the US. Yet not all subjects with T2DM are at equal risk for CVD complications; the challenge lies in identifying those at greatest risk. Therapies directed towards treating conventional risk factors have failed to significantly reduce this residual risk in T2DM patients. Thus newer targets and markers are needed for the development and testing of novel therapies. Herein we review two complementary mass spectrometry-based approaches—Mass Spectrometric Immunoassay (MSIA) and tandem mass spectrometry as multiple reaction monitoring (MRM)—for the analysis of plasma proteins and post translational modifications (PTMs) of relevance to T2DM and CVD. Together, these complementary approaches allow for high-throughput monitoring of many PTMs and the absolute quantification of proteins near the low picomolar range. In this review article, we discuss the clinical relevance of the HDL proteome and Apolipoprotein A-I PTMs to T2DM and CVD as well as provide illustrative MSIA and MRM data on high density lipoprotein (HDL) proteins from T2DM patients to provide examples of how these mass spectrometry approaches can be applied to gain new insight regarding cardiovascular risk factors. Also discussed are the reproducibility, interpretation and limitations of each technique with an emphasis on their capacities to facilitate the translation of new biomarkers into clinical practice. PMID:23696124

  17. The histone deacetylase inhibitor, PXD101, potentiates bortezomib-induced anti-multiple myeloma effect by induction of oxidative stress and DNA damage.

    PubMed

    Feng, Rentian; Oton, Ana; Mapara, Markus Y; Anderson, Gülsüm; Belani, Chandra; Lentzsch, Suzanne

    2007-11-01

    Clinical trials have shown the high anti-myeloma activity of the proteasome inhibitor bortezomib. The present study examined the activity of bortezomib combined with PXD101, a histone deacetylase inhibitor, against multiple myeloma (MM) and osteoclastogenesis. Treatment of myeloma cell lines with combinations of bortezomib and PXD101 led to synergistic inhibition of proliferation and induction of cell death. The combination significantly decreased the viability of primary human CD138(+) myeloma cells but not of bone marrow mononuclear cells. Further studies showed a dose-dependent activation of caspases-3, -8 and -9 and nuclear fragmentation in myeloma cells. Bortezomib/PXD101 treatment markedly triggered reactive oxygen species (ROS) generation that was accompanied by p53, H2A.X and p38-mitogen-activated protein kinase phosphorylation. ROS generation could be blocked by the free radical scavenger N-acetyl-L-cysteine. The combination of bortezomib and PXD101 also resulted in synergistic inhibition of osteoclast formation. In conclusion, bortezomib and PXD101 have different molecular targets. The combination induces cell death in myeloma cells via ROS-mediated DNA damage and also inhibits osteoclastogenesis. Therefore, this study provides the rationale for the clinical evaluation of bortezomib combined with PXD101 in patients with MM. PMID:17910628

  18. Lect 13: Quantitative genetics II Evolution at multiple loci

    E-print Network

    Lect 13: Quantitative genetics II · Evolution at multiple loci · Quantitative genetics ­ Selection gradients ­ 3 generalization · Constraints on evolutionary responses ­ Genetic variation ­ Genetic Multiple loci: quantitative genetics Fig. 8.1 Xb Measuring Directional Selection Xa Selection differential

  19. Targeting the integrated networks of aggresome formation, proteasome, and autophagy potentiates ER stress-mediated cell death in multiple myeloma cells

    PubMed Central

    MORIYA, SHOTA; KOMATSU, SEIICHIRO; YAMASAKI, KAHO; KAWAI, YUSUKE; KOKUBA, HIROKO; HIROTA, AYAKO; CHE, XIAO-FANG; INAZU, MASATO; GOTOH, AKIHIKO; HIRAMOTO, MASAKI; MIYAZAWA, KEISUKE

    2015-01-01

    The inhibitory effects of macrolide antibiotics including clarithromycin (CAM) on autophagy flux have been reported. Although a macrolide antibiotic exhibits no cytotoxicity, its combination with bortezomib (BZ), a proteasome inhibitor, for the simultaneous blocking of the ubiquitin (Ub)-proteasome and autophagy-lysosome pathways leads to enhanced multiple myeloma (MM) cell apoptosis induction via stress overloading of the endoplasmic reticulum (ER). As misfolded protein cargo is recruited by histone deacetylase 6 (HDAC6) to dynein motors for aggresome transport, serving to sequester misfolded proteins, we further investigated the cellular effects of targeting proteolytic pathways and aggresome formation concomitantly in MM cells. Pronounced apoptosis was induced by the combination of vorinostat [suberoylanilide hydroxamic acid (SAHA); potently inhibits HDAC6] with CAM and BZ compared with each reagent or a 2-reagent combination. CAM/BZ treatment induced vimentin positive-aggresome formation along with the accumulation of autolysosomes in the perinuclear region, whereas they were inhibited in the presence of SAHA. The SAHA/CAM/BZ combination treatment maximally upregulated genes related to ER stress including C/EBP homologous protein (CHOP). Similarly to MM cell lines, enhanced cytotoxicity with CHOP upregulation following SAHA/CAM/BZ treatment was shown by a wild-type murine embryonic fibroblast (MEF) cell line; however, a CHOP-deficient MEF cell line almost completely canceled this pronounced cytotoxicity. Knockdown of HDAC6 with siRNA exhibited further enhanced CAM/BZ-induced cytotoxicity and CHOP induction along with the cancellation of aggresome formation. Targeting the integrated networks of aggresome, proteasome, and autophagy is suggested to induce efficient ER stress-mediated apoptosis in MM cells. PMID:25422130

  20. Targeting the integrated networks of aggresome formation, proteasome, and autophagy potentiates ER stress?mediated cell death in multiple myeloma cells.

    PubMed

    Moriya, Shota; Komatsu, Seiichiro; Yamasaki, Kaho; Kawai, Yusuke; Kokuba, Hiroko; Hirota, Ayako; Che, Xiao-Fang; Inazu, Masato; Gotoh, Akihiko; Hiramoto, Masaki; Miyazawa, Keisuke

    2015-02-01

    The inhibitory effects of macrolide antibiotics including clarithromycin (CAM) on autophagy flux have been reported. Although a macrolide antibiotic exhibits no cytotoxicity, its combination with bortezomib (BZ), a proteasome inhibitor, for the simultaneous blocking of the ubiquitin (Ub)?proteasome and autophagy?lysosome pathways leads to enhanced multiple myeloma (MM) cell apoptosis induction via stress overloading of the endoplasmic reticulum (ER). As misfolded protein cargo is recruited by histone deacetylase 6 (HDAC6) to dynein motors for aggresome transport, serving to sequester misfolded proteins, we further investigated the cellular effects of targeting proteolytic pathways and aggresome formation concomitantly in MM cells. Pronounced apoptosis was induced by the combination of vorinostat [suberoylanilide hydroxamic acid (SAHA); potently inhibits HDAC6] with CAM and BZ compared with each reagent or a 2?reagent combination. CAM/BZ treatment induced vimentin positive?aggresome formation along with the accumulation of autolysosomes in the perinuclear region, whereas they were inhibited in the presence of SAHA. The SAHA/CAM/BZ combination treatment maximally upregulated genes related to ER stress including C/EBP homologous protein (CHOP). Similarly to MM cell lines, enhanced cytotoxicity with CHOP upregulation following SAHA/CAM/BZ treatment was shown by a wild?type murine embryonic fibroblast (MEF) cell line; however, a CHOP?deficient MEF cell line almost completely canceled this pronounced cytotoxicity. Knockdown of HDAC6 with siRNA exhibited further enhanced CAM/BZ?induced cytotoxicity and CHOP induction along with the cancellation of aggresome formation. Targeting the integrated networks of aggresome, proteasome, and autophagy is suggested to induce efficient ER stress?mediated apoptosis in MM cells. PMID:25422130

  1. Assembly of near infra-red emitting upconverting nanoparticles and multiple Gd(III)-chelates as a potential bimodal contrast agent for MRI and optical imaging.

    PubMed

    Carron, Sophie; Li, Qiang Ying; Vander Elst, Luce; Muller, Robert N; Parac-Vogt, Tatjana N; Capobianco, John A

    2015-07-01

    Linking multiple paramagnetic gadolinium(III)-chelates based on the 2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetate (DOTA) ligand to the surface of NaGdF4:Yb(3+),Tm(3+) upconverting nanoparticles with an average particle size of 20 nm resulted in an assembly that has favorable properties for bimodal Magnetic Resonance Imaging (MRI) and Optical Imaging (OI). An improved synthetic pathway was used to couple the paramagnetic precursor to the nanoparticles. The nanoparticles were rendered water dispersible via citrate capping, leaving one acid group free for amide coupling with the mono-amino precursor of the DOTA ligand. Luminescence spectroscopy measurements have shown that the excitation of the nanoconstruct at 980 nm resulted in intense upconverted emission of thulium(III) at 800 nm. The assembly of several paramagnetic centers on the nanoparticle scaffold reduces the overall tumbling rate, resulting in enhanced longitudinal relaxation times and improved relaxivity. The proton NMRD profiles show a characteristic hump at higher frequencies, which is caused by the slow rotation of the nanoconstruct, resulting in r1 values of 25 mM(-1) s(-1) per gadolinium(III)-ion at 60 MHz and 310 K. This is a significant improvement compared to the Gd-DO3A-ethylamine precursor (4) for which a value of