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Sample records for differential luteolytic function

  1. Differential gene expression in the bovine corpus luteum during transition from early phase to midphase and its potential role in acquisition of luteolytic sensitivity to prostaglandin F2 alpha.

    PubMed

    Goravanahally, Madhusudan P; Salem, Mohamed; Yao, Jianbo; Inskeep, E Keith; Flores, Jorge A

    2009-05-01

    Prostaglandin F2 alpha (PGF(2alpha)) brings about regression of the bovine corpus luteum (CL). This luteolytic property of PGF(2alpha) is used in beef and dairy cattle to synchronize estrus. A limitation of this protocol is insensitivity of the early CL to luteolytic actions of PGF(2alpha). The mechanisms underlying this differential luteal sensitivity are poorly understood. The developing CL has a maximum number of PGF(2alpha) receptors; therefore, differences in signaling events may be responsible for luteal insensitivity. Hence, differential gene expression at two developmental stages of CL, Day 4 (D-4) and D-10 after estrus, might account for differences in signal transduction pathways associated with luteal sensitivity. This possibility was examined in these studies. Microarray analysis (n = 3 cows per stage) identified 167 genes that were differentially expressed (P < 0.05). These were categorized into genes involved in protein biosynthesis and modification (18.5%), transcription regulation and DNA biosynthesis (18.5%), miscellaneous (17.0%), cell signaling (12.0%), steroidogenesis and metabolism (10.2%), extracellular matrix and cytoskeletal proteins (9.5%), unknown functions (6.0%), protein degradation (5.3%), and antioxidant property (3.0%). Real-time PCR confirmed the differential expression of nine selected genes, including tyrosine 3-monooxygenase/tryptophan 5-monooxygense activation protein zeta polypeptide (YWHAZ) and regulator of G protein signaling 2 24-kDa (RGS2), observed in microarray. Furthermore, the in vivo effect of exogenous PGF(2alpha) (n = 3 cows per stage) on selected genes that were found to be differentially expressed during this developmental transition was examined. PGF(2alpha) increased the expression of a guanine nucleotide-binding protein (G protein) beta polypeptide 1 (GNB1) in D-4 CL and calcium/calmodulin-dependent kinase kinase 2 beta (CAMKK2) in D-10 CL. Therefore, GNB1, CAMKK2, YWHAZ, and RGS2 are candidate genes that may

  2. Differential Person Functioning.

    ERIC Educational Resources Information Center

    Johanson, George; Alsmadi, Abdalla

    In many testing situations, differential item functioning (DIF) is a potentially serious problem. It occurs when a test item appears to be easier for one group of examinees than another even after controlling for overall skill level. Differential person functioning (DPF) can occur when "items" can be considered raters and the persons are the…

  3. Using Differentials to Differentiate Trigonometric and Exponential Functions

    ERIC Educational Resources Information Center

    Dray, Tevian

    2013-01-01

    Starting from geometric definitions, we show how differentials can be used to differentiate trigonometric and exponential functions without limits, numerical estimates, solutions of differential equations, or integration.

  4. Differential dopamine function in fibromyalgia.

    PubMed

    Albrecht, Daniel S; MacKie, Palmer J; Kareken, David A; Hutchins, Gary D; Chumin, Evgeny J; Christian, Bradley T; Yoder, Karmen K

    2016-09-01

    Approximately 30 % of Americans suffer from chronic pain disorders, such as fibromyalgia (FM), which can cause debilitating pain. Many pain-killing drugs prescribed for chronic pain disorders are highly addictive, have limited clinical efficacy, and do not treat the cognitive symptoms reported by many patients. The neurobiological substrates of chronic pain are largely unknown, but evidence points to altered dopaminergic transmission in aberrant pain perception. We sought to characterize the dopamine (DA) system in individuals with FM. Positron emission tomography (PET) with [(18)F]fallypride (FAL) was used to assess changes in DA during a working memory challenge relative to a baseline task, and to test for associations between baseline D2/D3 availability and experimental pain measures. Twelve female subjects with FM and 11 female controls completed study procedures. Subjects received one FAL PET scan while performing a "2-back" task, and one while performing a "0-back" (attentional control, "baseline") task. FM subjects had lower baseline FAL binding potential (BP) in several cortical regions relative to controls, including anterior cingulate cortex. In FM subjects, self-reported spontaneous pain negatively correlated with FAL BP in the left orbitofrontal cortex and parahippocampal gyrus. Baseline BP was significantly negatively correlated with experimental pain sensitivity and tolerance in both FM and CON subjects, although spatial patterns of these associations differed between groups. The data suggest that abnormal DA function may be associated with differential processing of pain perception in FM. Further studies are needed to explore the functional significance of DA in nociception and cognitive processing in chronic pain.

  5. Topologies for neutral functional differential equations.

    NASA Technical Reports Server (NTRS)

    Melvin, W. R.

    1973-01-01

    Bounded topologies are considered for functional differential equations of the neutral type in which present dynamics of the system are influenced by its past behavior. A special bounded topology is generated on a collection of absolutely continuous functions with essentially bounded derivatives, and an application to a class of nonlinear neutral functional differential equations due to Driver (1965) is presented.

  6. Detecting Differential Person Functioning in Emotional Intelligence

    ERIC Educational Resources Information Center

    Alsmadi, Yahia M.; Alsmadi, Abdalla A.

    2009-01-01

    Differential Item Functioning (DIF) is a widely used term in test development literature. It is very important to analyze test's data for DIF because It is a serious threat to validity. If the same data matrix was transposed, similar analysis can be carried for Differential Person Functioning (DPF). The purpose of this paper is to introduce and…

  7. Extracting differential pair distribution functions using MIXSCAT

    SciTech Connect

    Wurden, Caroline; Page, Katharine; Llobet, Anna; White, Claire E.; Proffen, Thomas

    2010-08-27

    Differently weighted experimental scattering data have been used to extract partial or differential structure factors or pair distribution functions in studying many materials. However, this is not done routinely partly because of the lack of user-friendly software. This paper presents MIXSCAT, a new member of the DISCUS program package. MIXSCAT allows one to combine neutron and X-ray pair distribution functions and extract their respective differential functions.

  8. A class of neutral functional differential equations.

    NASA Technical Reports Server (NTRS)

    Melvin, W. R.

    1972-01-01

    Formulation and study of the initial value problem for neutral functional differential equations. The existence, uniqueness, and continuation of solutions to this problem are investigated, and an analysis is made of the dependence of the solutions on the initial conditions and parameters, resulting in the derivation of a continuous dependence theorem in which the fundamental mathematical principles underlying the continuous dependence problem for a very general system of nonlinear neutral functional differential equations are separated out.

  9. Participation of ovarian 20 alpha-hydroxysteroid dehydrogenase in luteotrophic and luteolytic processes during rat pseudopregnancy.

    PubMed

    Matsuda, J; Noda, K; Shiota, K; Takahashi, M

    1990-03-01

    In normal rats, before Day 12 of pseudopregnancy, minimal levels of 20 alpha-HSD activity were detected in functional CL whereas those in the residue were 3-5 times higher. When ovulation was blocked for more than 2 weeks by placing rats in a continuously lit environment before the induction of pseudopregnancy, only minimal levels of 20 alpha-HSD activity were detectable in the functional CL and residue before Day 12. In normal pseudopregnant rats, there was a linear increase in 20 alpha-HSD activity from Day 12 to 15 in the functional CL and residue, but the rate of elevation was much higher in functional CL. This tendency was much more clear-cut in rats in the continuous lighting. In immature rats in which pseudopregnancy was induced by PMSG and hCG treatment, 20 alpha-HSD activity peaked twice. The first small peak was attributed to the early regression of some of the large number of corpora lutea, and the changes in 20 alpha-HSD activity in most of the corpora lutea paralleled those in rats in continuous lighting. Bromocriptine abolished the prolactin surges, and in normal pseudopregnant rats an increase in 20 alpha-HSD activity in functional CL started from 12 h and the rate of the increase was accelerated from 36 h afterwards, while a relatively small increase was observed in the residue at 18 h and later.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Detecting Differential Item Functioning and Differential Step Functioning due to Differences that "Should" Matter

    ERIC Educational Resources Information Center

    Miller, Tess; Chahine, Saad; Childs, Ruth A.

    2010-01-01

    This study illustrates the use of differential item functioning (DIF) and differential step functioning (DSF) analyses to detect differences in item difficulty that are related to experiences of examinees, such as their teachers' instructional practices, that are relevant to the knowledge, skill, or ability the test is intended to measure. This…

  11. The effect of dose and type of cloprostenol on the luteolytic response of dairy cattle during the Ovsynch protocol under different oestrous cycle and physiological characteristics.

    PubMed

    Valldecabres-Torres, X; Larrosa-Morales, P; Cuervo-Arango, J

    2013-10-01

    The objective of this study was to characterize the effect of dose and type of cloprostenol (CLO) on the luteolytic response of dairy cattle during the Ovsynch protocol under different oestrus cycle and physiological characteristics. Twelve non-lactating dairy cows and 111 lactating dairy cows were used in three experiments. In Experiment I, cows were synchronized so that they had only a 5.5- to 6-day-old corpus luteum (CL) at the time of the prostaglandin F2α (PGF2α ) treatment of Ovsynch. In Experiment II, cows were synchronized so that they had at least a CL of approximately 14 days old at the time of PGF2α treatment and an accessory CL if they had responded to the first GnRH of Ovsynch. Furthermore, in each experiment, cows received either a standard or a double dose of d-CLO as the luteolytic treatment. In Experiment III, lactating cows were blocked by parity and assigned to one of three luteolytic treatments during Ovsynch: 500 μg d,l-CLO, 150 or 300 μg of d-CLO. In Experiment I, the dose of d-CLO had an effect (p = 0.08) on the percentage of cows with full luteolysis, but not in Experiment II (p > 0.1). More cows in Experiment II had full luteolysis than did cows of Experiment I (87% vs 58%, respectively; p = 0.007). In Experiment III, 87.1%, 84.4% and 86.2% lactating dairy cows had full luteolysis and 37.8%, 36.8% and 36.1% of cows became pregnant after treatment with 500 μg d,l-CLO, 150 or 300 μg of d-CLO, respectively (p > 0.05).

  12. Real and Artificial Differential Item Functioning

    ERIC Educational Resources Information Center

    Andrich, David; Hagquist, Curt

    2012-01-01

    The literature in modern test theory on procedures for identifying items with differential item functioning (DIF) among two groups of persons includes the Mantel-Haenszel (MH) procedure. Generally, it is not recognized explicitly that if there is real DIF in some items which favor one group, then as an artifact of this procedure, artificial DIF…

  13. Ramsay-Curve Differential Item Functioning

    ERIC Educational Resources Information Center

    Woods, Carol M.

    2011-01-01

    Differential item functioning (DIF) occurs when an item on a test, questionnaire, or interview has different measurement properties for one group of people versus another, irrespective of true group-mean differences on the constructs being measured. This article is focused on item response theory based likelihood ratio testing for DIF (IRT-LR or…

  14. A Multilevel Assessment of Differential Item Functioning.

    ERIC Educational Resources Information Center

    Shen, Linjun

    A multilevel approach was proposed for the assessment of differential item functioning and compared with the traditional logistic regression approach. Data from the Comprehensive Osteopathic Medical Licensing Examination for 2,300 freshman osteopathic medical students were analyzed. The multilevel approach used three-level hierarchical generalized…

  15. Effect of Decreasing Intraluteal Progesterone on Sensitivity of the Early Porcine Corpus Luteum to the Luteolytic Actions of Prostaglandin F2alpha1

    PubMed Central

    Diaz, Francisco J.; Luo, Wenxiang; Wiltbank, Milo C.

    2010-01-01

    Prostaglandin F2alpha (PGF) causes luteolysis of the pig corpus luteum (CL) only after Day 12 of the estrous cycle. Recent evidence indicates that progesterone (P4) may protect the CL from cell death. The present study tested the hypothesis that acute inhibition of P4 by treatment with epostane (EPO; 3betaHSD inhibitor) in CL lacking luteolytic capacity (Day 9 CL) will allow PGF to induce responses associated with luteolysis. Multiple PGF-induced responses were evaluated, including genes involved in production of PGF and estradiol-17beta, apoptosis (caspase 3), and transcription (FOSB). These responses are associated with PGF-induced luteolysis and do not normally occur in CL lacking luteolytic capacity. Animals on Day 7 after estrus were divided into four groups: 1) control (C), 2) PGF, 3) EPO, and 4) PGF plus EPO (PGF+EPO). Treatment with EPO (10 mg/kg) or vehicle was given every 12 h for 36 h. Treatment with PGF (25 mg) or vehicle was given at 38 h, and CL were collected from all animals at 48 h. Some CL from each animal were frozen in liquid nitrogen for mRNA and protein analysis. Remaining CL were incubated in media for 2 h for determination of P4 and PGF production. EPO dramatically decreased production of P4 by luteal tissue (ng/mg tissue) by 90% and 95% in EPO and PGF+EPO groups, respectively, compared to C (P < 0.01). Low production of PGF by luteal tissue was found in C, PGF, and EPO groups; however, treatment with PGF+EPO dramatically increased (782%) luteal PGF production. Similar to intraluteal PGF production, increased mRNA for cyclooxygenase 2 (PTGS2) and phospholipase A2 (group IB; PLA2G1B) was found in the PGF+EPO, but not in the EPO or PGF, group. Aromatase (CYP19A1) mRNA was not induced by PGF or EPO; however, PGF+EPO caused a more than 40-fold increase in CYP19A1 mRNA (P < 0.01). CASP3 mRNA was increased (P < 0.01) by EPO (3.4-fold) and by PGF (2.7-fold) but was most dramatically increased by PGF+EPO (5.3-fold), whereas caspase activity was only

  16. Control of functional differential equations with function space boundary conditions.

    NASA Technical Reports Server (NTRS)

    Banks, H. T.

    1972-01-01

    The results of various authors dealing with problems involving functional differential equations with terminal conditions in function space are reviewed. The review includes not only very recent results, but also some little known results of Soviet mathematicians prior to 1970. Particular attention is given to results concerning controllability, existence of optimal controls, and necessary and sufficient conditions for optimality.

  17. Differential Item Functioning Analysis Using Rasch Item Information Functions

    ERIC Educational Resources Information Center

    Wyse, Adam E.; Mapuranga, Raymond

    2009-01-01

    Differential item functioning (DIF) analysis is a statistical technique used for ensuring the equity and fairness of educational assessments. This study formulates a new DIF analysis method using the information similarity index (ISI). ISI compares item information functions when data fits the Rasch model. Through simulations and an international…

  18. Monotone viable trajectories for functional differential inclusions

    NASA Astrophysics Data System (ADS)

    Haddad, Georges

    This paper is a study on functional differential inclusions with memory which represent the multivalued version of retarded functional differential equations. The main result gives a necessary and sufficient equations. The main result gives a necessary and sufficient condition ensuring the existence of viable trajectories; that means trajectories remaining in a given nonempty closed convex set defined by given constraints the system must satisfy to be viable. Some motivations for this paper can be found in control theory where F( t, φ) = { f( t, φ, u)} uɛU is the set of possible velocities of the system at time t, depending on the past history represented by the function φ and on a control u ranging over a set U of controls. Other motivations can be found in planning procedures in microeconomics and in biological evolutions where problems with memory do effectively appear in a multivalued version. All these models require viability constraints represented by a closed convex set.

  19. Synchronization with propagation - The functional differential equations

    NASA Astrophysics Data System (ADS)

    Rǎsvan, Vladimir

    2016-06-01

    The structure represented by one or several oscillators couple to a one-dimensional transmission environment (e.g. a vibrating string in the mechanical case or a lossless transmission line in the electrical case) turned to be attractive for the research in the field of complex structures and/or complex behavior. This is due to the fact that such a structure represents some generalization of various interconnection modes with lumped parameters for the oscillators. On the other hand the lossless and distortionless propagation along transmission lines has generated several research in electrical, thermal, hydro and control engineering leading to the association of some functional differential equations to the basic initial boundary value problems. The present research is performed at the crossroad of the aforementioned directions. We shall associate to the starting models some functional differential equations - in most cases of neutral type - and make use of the general theorems for existence and stability of forced oscillations for functional differential equations. The challenges introduced by the analyzed problems for the general theory are emphasized, together with the implication of the results for various applications.

  20. Visual determination of differential renal function

    SciTech Connect

    Kipper, M.S.; Witztum, K.F.; Taylor, A. Jr.

    1986-05-01

    Forty patients (43 studies) referred for determination of differential renal function were imaged 24 hours after intravenous administration of Tc-99m-2, 3 DMSA. Visual assessment of relative renal uptake was estimated independently by three observers at three different hospitals from analog images on standard x-ray film. The results were compared with the relative DMSA uptake obtained by summing counts in computer-assisted regions of interest placed over each kidney. There was excellent correlation between the visual estimates of each observer and the computer-generated values (r = 0.98, 0.96, and 0.98, respectively). If a computer is not available, good visual estimates of differential uptake still may be obtained when static imaging agents such as DMSA are administered.

  1. Differential person functioning applied to baseball.

    PubMed

    Johanson, George A; Brooks, Gordon P

    2008-12-01

    The question of whether a baseball player generally hits better against a left-handed or right-handed pitcher is difficult to answer since handedness is only one of many possible attributes of pitchers. The concept of differential functioning from psychometrics is applied, considering both the effect of the handedness of the pitcher and his earned run average (the mean number of runs scored against a pitcher per 9 innings pitched excluding runs due to errors). Two interesting cases are examined, a left-handed batter and a switch-hitter. Suggestions for further research are offered.

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

    ERIC Educational Resources Information Center

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

    2015-01-01

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

  3. Distinguishing Differential Testlet Functioning from Differential Bundle Functioning Using the Multilevel Measurement Model

    ERIC Educational Resources Information Center

    Beretvas, S. Natasha; Walker, Cindy M.

    2012-01-01

    This study extends the multilevel measurement model to handle testlet-based dependencies. A flexible two-level testlet response model (the MMMT-2 model) for dichotomous items is introduced that permits assessment of differential testlet functioning (DTLF). A distinction is made between this study's conceptualization of DTLF and that of…

  4. Legendre-tau approximations for functional differential equations

    NASA Technical Reports Server (NTRS)

    Ito, K.; Teglas, R.

    1986-01-01

    The numerical approximation of solutions to linear retarded functional differential equations are considered using the so-called Legendre-tau method. The functional differential equation is first reformulated as a partial differential equation with a nonlocal boundary condition involving time-differentiation. The approximate solution is then represented as a truncated Legendre series with time-varying coefficients which satisfy a certain system of ordinary differential equations. The method is very easy to code and yields very accurate approximations. Convergence is established, various numerical examples are presented, and comparison between the latter and cubic spline approximation is made.

  5. Computations involving differential operators and their actions on functions

    NASA Technical Reports Server (NTRS)

    Crouch, Peter E.; Grossman, Robert; Larson, Richard

    1991-01-01

    The algorithms derived by Grossmann and Larson (1989) are further developed for rewriting expressions involving differential operators. The differential operators involved arise in the local analysis of nonlinear dynamical systems. These algorithms are extended in two different directions: the algorithms are generalized so that they apply to differential operators on groups and the data structures and algorithms are developed to compute symbolically the action of differential operators on functions. Both of these generalizations are needed for applications.

  6. DIF Trees: Using Classification Trees to Detect Differential Item Functioning

    ERIC Educational Resources Information Center

    Vaughn, Brandon K.; Wang, Qiu

    2010-01-01

    A nonparametric tree classification procedure is used to detect differential item functioning for items that are dichotomously scored. Classification trees are shown to be an alternative procedure to detect differential item functioning other than the use of traditional Mantel-Haenszel and logistic regression analysis. A nonparametric…

  7. Net and Global Differential Item Functioning in PISA Polytomously Scored Science Items: Application of the Differential Step Functioning Framework

    ERIC Educational Resources Information Center

    Akour, Mutasem; Sabah, Saed; Hammouri, Hind

    2015-01-01

    The purpose of this study was to apply two types of Differential Item Functioning (DIF), net and global DIF, as well as the framework of Differential Step Functioning (DSF) to real testing data to investigate measurement invariance related to test language. Data from the Program for International Student Assessment (PISA)-2006 polytomously scored…

  8. Differentials of a State Reading Assessment: Item Functioning, Distractor Functioning, and Omission Frequency for Disability Categories

    ERIC Educational Resources Information Center

    Kato, Kentaro; Moen, Ross E.; Thurlow, Martha L.

    2009-01-01

    Large data sets from a state reading assessment for third and fifth graders were analyzed to examine differential item functioning (DIF), differential distractor functioning (DDF), and differential omission frequency (DOF) between students with particular categories of disabilities (speech/language impairments, learning disabilities, and emotional…

  9. Curriculum, Translation, and Differential Functioning of Measurement and Geometry Items

    ERIC Educational Resources Information Center

    Emenogu, Barnabas C.; Childs, Ruth A.

    2005-01-01

    A test item exhibits differential item functioning (DIF) if students with the same ability find it differentially difficult. When the item is administered in French and English, differences in language difficulty and meaning are the most likely explanations. However, curriculum differences may also contribute to DIF. The responses of Ontario…

  10. Generating functionals and Lagrangian partial differential equations

    SciTech Connect

    Vankerschaver, Joris; Liao, Cuicui; Leok, Melvin

    2013-08-15

    The main goal of this paper is to derive an alternative characterization of the multisymplectic form formula for classical field theories using the geometry of the space of boundary values. We review the concept of Type-I/II generating functionals defined on the space of boundary data of a Lagrangian field theory. On the Lagrangian side, we define an analogue of Jacobi's solution to the Hamilton–Jacobi equation for field theories, and we show that by taking variational derivatives of this functional, we obtain an isotropic submanifold of the space of Cauchy data, described by the so-called multisymplectic form formula. As an example of the latter, we show that Lorentz's reciprocity principle in electromagnetism is a particular instance of the multisymplectic form formula. We also define a Hamiltonian analogue of Jacobi's solution, and we show that this functional is a Type-II generating functional. We finish the paper by defining a similar framework of generating functions for discrete field theories, and we show that for the linear wave equation, we recover the multisymplectic conservation law of Bridges.

  11. Local behavior of autonomous neutral functional differential equations.

    NASA Technical Reports Server (NTRS)

    Hale, J. K.

    1972-01-01

    Basic problems for a special class of neutral functional differential equations (NFDE) are formulated, and some contributions to a general qualitative theory in the neighborhood of an equilibrium point are indicated. The properties of a NFDE (G,f) are examined to determine in what sense these properties are insensitive to small changes in (G,f) in the topology G x F. The special class of equations that is introduced includes retarded functional differential equations and difference equations.

  12. Functional implications of differential chromosome banding.

    PubMed Central

    Hoehn, H

    1975-01-01

    Information on DNA content and banding patterns has been utilized in the construction of a novel ideogram of the human complement. Correspondence between certain features of this ideogram and the clinical record of human autosomal imbalance supports the idea that banding patterns reflect structural as well as functional heterogeneity of chromosomes. PMID:51585

  13. Fuzzy fractional functional differential equations under Caputo gH-differentiability

    NASA Astrophysics Data System (ADS)

    Hoa, Ngo Van

    2015-05-01

    In this paper the fuzzy fractional functional differential equations (FFFDEs) under the Caputo generalized Hukuhara differentiability are introduced. We study the existence and uniqueness results of solutions for FFFDEs under some suitable conditions. Also the solution to fuzzy fractional functional initial value problem under Caputo-type fuzzy fractional derivatives by a modified Adams-Bashforth-Moulton method (MABMM) is presented. The method is illustrated by solving some examples.

  14. Functional differentiability in time-dependent quantum mechanics

    SciTech Connect

    Penz, Markus Ruggenthaler, Michael

    2015-03-28

    In this work, we investigate the functional differentiability of the time-dependent many-body wave function and of derived quantities with respect to time-dependent potentials. For properly chosen Banach spaces of potentials and wave functions, Fréchet differentiability is proven. From this follows an estimate for the difference of two solutions to the time-dependent Schrödinger equation that evolve under the influence of different potentials. Such results can be applied directly to the one-particle density and to bounded operators, and present a rigorous formulation of non-equilibrium linear-response theory where the usual Lehmann representation of the linear-response kernel is not valid. Further, the Fréchet differentiability of the wave function provides a new route towards proving basic properties of time-dependent density-functional theory.

  15. Differential Forms Basis Functions for Better Conditioned Integral Equations

    SciTech Connect

    Fasenfest, B; White, D; Stowell, M; Rieben, R; Sharpe, R; Madsen, N; Rockway, J D; Champagne, N J; Jandhyala, V; Pingenot, J

    2005-01-13

    Differential forms offer a convenient way to classify physical quantities and set up computational problems. By observing the dimensionality and type of derivatives (divergence,curl,gradient) applied to a quantity, an appropriate differential form can be chosen for that quantity. To use these differential forms in a simulation, the forms must be discretized using basis functions. The 0-form through 2-form basis functions are formed for surfaces. Twisted 1-form and 2-form bases will be presented in this paper. Twisted 1-form (1-forms) basis functions ({Lambda}) are divergence-conforming edge basis functions with units m{sup -1}. They are appropriate for representing vector quantities with continuous normal components, and they belong to the same function space as the commonly used RWG bases [1]. They are used here to formulate the frequency-domain EFIE with Galerkin testing. The 2-form basis functions (f) are scalar basis functions with units m{sup -2} and with no enforced continuity between elements. At lowest order, the 2-form basis functions are similar to pulse basis functions. They are used here to formulate an electrostatic integral equation. It should be noted that the derivative of an n-form differential form basis function is an (n+1)-form, i.e. the derivative of a 1-form basis function is a 2-form. Because the basis functions are constructed such that they have spatial units, the spatial units are removed from the degrees of freedom, leading to a better-conditioned system matrix. In this conference paper, we look at the performance of these differential forms and bases by examining the conditioning of matrix systems for electrostatics and the EFIE. The meshes used were refined across the object to consider the behavior of these basis transforms for elements of different sizes.

  16. Regulatory T Cells: Differentiation and Function.

    PubMed

    Plitas, George; Rudensky, Alexander Y

    2016-09-01

    The immune system of vertebrate animals has evolved to mount an effective defense against a diverse set of pathogens while minimizing transient or lasting impairment in tissue function that could result from the inflammation caused by immune responses to infectious agents. In addition, misguided immune responses to "self" and dietary antigens, as well as to commensal microorganisms, can lead to a variety of inflammatory disorders, including autoimmunity, metabolic syndrome, allergies, and cancer. Regulatory T cells expressing the X chromosome-linked transcription factor Foxp3 suppress inflammatory responses in diverse biological settings and serve as a vital mechanism of negative regulation of immune-mediated inflammation. Cancer Immunol Res; 4(9); 721-5. ©2016 AACR. PMID:27590281

  17. Raju's Differential Functioning of Items and Tests (DFIT)

    ERIC Educational Resources Information Center

    Oshima, T. C.; Morris, S. B.

    2008-01-01

    Nambury S. Raju (1937-2005) developed two model-based indices for differential item functioning (DIF) during his prolific career in psychometrics. Both methods, Raju's area measures (Raju, 1988) and Raju's DFIT (Raju, van der Linden, & Fleer, 1995), are based on quantifying the gap between item characteristic functions (ICFs). This approach…

  18. The Differential Diagnosis of Functional Symptoms in Adolescence.

    ERIC Educational Resources Information Center

    Silber, Thomas J.

    1982-01-01

    Functional complaints constitute the major reason why adolescents visit the physician's office. These complaints may coexist with organic illness of minor or major significance. Proposes a definition of functional disorders, sets forth a classification of the differential diagnosis of these disorders and suggests techniques for their management.…

  19. Green's function of the second order differential operator with involution

    NASA Astrophysics Data System (ADS)

    Ashyralyev, Allaberen; Sarsenbi, Abdisalam A.

    2016-08-01

    In the present paper, the Green's function of the second order differential operator L defined by formula L u =α u″ (x ) -u″ (-x ) =λ u (x ) ,-1 function is established.

  20. Decisions that Make a Difference in Detecting Differential Item Functioning

    ERIC Educational Resources Information Center

    Sireci, Stephen G.; Rios, Joseph A.

    2013-01-01

    There are numerous statistical procedures for detecting items that function differently across subgroups of examinees that take a test or survey. However, in endeavouring to detect items that may function differentially, selection of the statistical method is only one of many important decisions. In this article, we discuss the important decisions…

  1. Serum amyloid A inhibits osteoclast differentiation to maintain macrophage function.

    PubMed

    Kim, Jiseon; Yang, Jihyun; Park, Ok-Jin; Kang, Seok-Seong; Yun, Cheol-Heui; Han, Seung Hyun

    2016-04-01

    Serum amyloid A is an acute phase protein that is elevated under inflammatory conditions. Additionally, the serum levels of serum amyloid A are associated with the progression of inflammatory arthritis; thus, serum amyloid A might be involved in the regulation of osteoclast differentiation. In the present study, we examined the effects of serum amyloid A on osteoclast differentiation and function. When bone marrow-derived macrophages, as osteoclast precursors, were stimulated with serum amyloid A in the presence of M-CSF and receptor activator of nuclear factor-κB ligand, osteoclast differentiation and its bone-resorption activity were substantially inhibited. TLR2 was important in the inhibitory effect of serum amyloid A on osteoclast differentiation, because serum amyloid A stimulated TLR2. The inhibitory effect was absent in bone marrow-derived macrophages obtained from TLR2-deficient mice. Furthermore, serum amyloid A inhibited the expression of c-Fos and nuclear factor of activated T cells c1, which are crucial transcription factors for osteoclast differentiation, but prevented downregulation of IFN regulatory factor-8, a negative regulator of osteoclast differentiation. In contrast, serum amyloid A sustained the endocytic capacity of bone marrow-derived macrophages and their ability to induce the proinflammatory cytokines, IL-6, IL-1β, and TNF-α. Taken together, these results suggest that serum amyloid A, when increased by inflammatory conditions, inhibits differentiation of macrophages to osteoclasts, likely to maintain macrophage function for host defense.

  2. The LIM protein LIMD1 influences osteoblast differentiation and function

    SciTech Connect

    Luderer, Hilary F.; Bai Shuting; Longmore, Gregory D.

    2008-09-10

    The balance between bone resorption and bone formation involves the coordinated activities of osteoblasts and osteoclasts. Communication between these two cell types is essential for maintenance of normal bone homeostasis; however, the mechanisms regulating this cross talk are not completely understood. Many factors that mediate differentiation and function of both osteoblasts and osteoclasts have been identified. The LIM protein Limd1 has been implicated in the regulation of stress osteoclastogenesis through an interaction with the p62/sequestosome protein. Here we show that Limd1 also influences osteoblast progenitor numbers, differentiation, and function. Limd1{sup -/-} calvarial osteoblasts display increased mineralization and accelerated differentiation. While no significant differences in osteoblast number or function were detected in vivo, bone marrow stromal cells isolated from Limd1{sup -/-} mice contain significantly more osteoblast progenitors compared to wild type controls when cultured ex vivo. Furthermore, we observed a significant increase in nuclear {beta}-catenin staining in differentiating Limd1{sup -/-} calvarial osteoblasts suggesting that Limd1 is a negative regulator of canonical Wnt signaling in osteoblasts. These results demonstrate that Limd1 influences not only stress osteoclastogenesis but also osteoblast function and osteoblast progenitor commitment. Together, these data identify Limd1 as a novel regulator of both bone osetoclast and bone osteoblast development and function.

  3. HYPERDIRE-HYPERgeometric functions DIfferential REduction: Mathematica-based packages for the differential reduction of generalized hypergeometric functions: Lauricella function FC of three variables

    NASA Astrophysics Data System (ADS)

    Bytev, Vladimir V.; Kniehl, Bernd A.

    2016-09-01

    We present a further extension of the HYPERDIRE project, which is devoted to the creation of a set of Mathematica-based program packages for manipulations with Horn-type hypergeometric functions on the basis of differential equations. Specifically, we present the implementation of the differential reduction for the Lauricella function FC of three variables.

  4. IRT Differential Item Functioning: An Examination of Ability Scale Purifications.

    ERIC Educational Resources Information Center

    Lautenschlager, Gary J.; And Others

    1994-01-01

    Item response theory (IRT) differential item functioning (DIF) methods used to determine the accuracy of item classification as biased or unbiased were studied. Results from simulations show that the iterative linking and ability scale purification method can be more effective than iterative linking alone primarily by reducing false negatives.…

  5. Exploring Crossing Differential Item Functioning by Gender in Mathematics Assessment

    ERIC Educational Resources Information Center

    Ong, Yoke Mooi; Williams, Julian; Lamprianou, Iasonas

    2015-01-01

    The purpose of this article is to explore crossing differential item functioning (DIF) in a test drawn from a national examination of mathematics for 11-year-old pupils in England. An empirical dataset was analyzed to explore DIF by gender in a mathematics assessment. A two-step process involving the logistic regression (LR) procedure for…

  6. 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…

  7. The epigenetic landscape of mammary gland development and functional differentiation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Most of the development and functional differentiation in the mammary gland occur after birth. Epigenetics is defined as the stable alterations in gene expression potential that arise during development and proliferation. Epigenetic changes are mediated at the biochemical level by the chromatin conf...

  8. Three Classes of Nonparametric Differential Step Functioning Effect Estimators

    ERIC Educational Resources Information Center

    Penfield, Randall D.

    2008-01-01

    The examination of measurement invariance in polytomous items is complicated by the possibility that the magnitude and sign of lack of invariance may vary across the steps underlying the set of polytomous response options, a concept referred to as differential step functioning (DSF). This article describes three classes of nonparametric DSF effect…

  9. A Comparison of Methods for Detecting Differential Distractor Functioning

    ERIC Educational Resources Information Center

    Koon, Sharon

    2010-01-01

    This study examined the effectiveness of the odds-ratio method (Penfield, 2008) and the multinomial logistic regression method (Kato, Moen, & Thurlow, 2009) for measuring differential distractor functioning (DDF) effects in comparison to the standardized distractor analysis approach (Schmitt & Bleistein, 1987). Students classified as participating…

  10. Using Mixed Methods to Interpret Differential Item Functioning

    ERIC Educational Resources Information Center

    Benítez, Isabel; Padilla, José-Luis; Hidalgo Montesinos, María Dolores; Sireci, Stephen G.

    2016-01-01

    Analysis of differential item functioning (DIF) is often used to determine if cross-lingual assessments are equivalent across languages. However, evidence on the causes of cross-lingual DIF is still evasive. Expert appraisal is a qualitative method useful for obtaining detailed information about problematic elements in the different linguistic…

  11. Assessing and Explaining Differential Item Functioning Using Logistic Mixed Models

    ERIC Educational Resources Information Center

    Van den Noortgate, Wim; De Boeck, Paul

    2005-01-01

    Although differential item functioning (DIF) theory traditionally focuses on the behavior of individual items in two (or a few) specific groups, in educational measurement contexts, it is often plausible to regard the set of items as a random sample from a broader category. This article presents logistic mixed models that can be used to model…

  12. Differential Item Functioning (DIF): Current Problems and Future Directions

    ERIC Educational Resources Information Center

    Karami, Hossein; Salmani Nodoushan, Mohammad Ali

    2011-01-01

    With the rising concerns over the fairness of language tests, Differential Item Functioning (DIF) has been increasingly applied in bias analysis. Despite its widespread use in psychometric circles, DIF is facing a number of serious problems. This paper is an attempt to shed light on a number of the issues involved in DIF analysis. Specifically,…

  13. Real and Artificial Differential Item Functioning in Polytomous Items

    ERIC Educational Resources Information Center

    Andrich, David; Hagquist, Curt

    2015-01-01

    Differential item functioning (DIF) for an item between two groups is present if, for the same person location on a variable, persons from different groups have different expected values for their responses. Applying only to dichotomously scored items in the popular Mantel-Haenszel (MH) method for detecting DIF in which persons are classified by…

  14. The Effects of Testlets on Reliability and Differential Item Functioning

    ERIC Educational Resources Information Center

    Teker, Gulsen Tasdelen; Dogan, Nuri

    2015-01-01

    Reliability and differential item functioning (DIF) analyses were conducted on testlets displaying local item dependence in this study. The data set employed in the research was obtained from the answers given by 1,500 students to the 20 items included in six testlets given in English Proficiency Exam by the School of Foreign Languages of a state…

  15. Detection of Differential Item Functioning Using the Lasso Approach

    ERIC Educational Resources Information Center

    Magis, David; Tuerlinckx, Francis; De Boeck, Paul

    2015-01-01

    This article proposes a novel approach to detect differential item functioning (DIF) among dichotomously scored items. Unlike standard DIF methods that perform an item-by-item analysis, we propose the "LR lasso DIF method": logistic regression (LR) model is formulated for all item responses. The model contains item-specific intercepts,…

  16. MIMIC Methods for Assessing Differential Item Functioning in Polytomous Items

    ERIC Educational Resources Information Center

    Wang, Wen-Chung; Shih, Ching-Lin

    2010-01-01

    Three multiple indicators-multiple causes (MIMIC) methods, namely, the standard MIMIC method (M-ST), the MIMIC method with scale purification (M-SP), and the MIMIC method with a pure anchor (M-PA), were developed to assess differential item functioning (DIF) in polytomous items. In a series of simulations, it appeared that all three methods…

  17. Master integrals for splitting functions from differential equations in QCD

    NASA Astrophysics Data System (ADS)

    Gituliar, Oleksandr

    2016-02-01

    A method for calculating phase-space master integrals for the decay process 1 → n masslesspartonsinQCDusingintegration-by-partsanddifferentialequationstechniques is discussed. The method is based on the appropriate choice of the basis for master integrals which leads to significant simplification of differential equations. We describe an algorithm how to construct the desirable basis, so that the resulting system of differential equations can be recursively solved in terms of (G) HPLs as a series in the dimensional regulator ɛ to any order. We demonstrate its power by calculating master integrals for the NLO time-like splitting functions and discuss future applications of the proposed method at the NNLO precision.

  18. Almost automorphic solutions for some partial functional differential equations

    NASA Astrophysics Data System (ADS)

    Ezzinbi, Khalil; N'guerekata, Gaston Mandata

    2007-04-01

    In this work, we study the existence of almost automorphic solutions for some partial functional differential equations. We prove that the existence of a bounded solution on implies the existence of an almost automorphic solution. Our results extend the classical known theorem by Bohr and Neugebauer on the existence of almost periodic solutions for inhomegeneous linear almost periodic differential equations. We give some applications to hyperbolic equations and Lotka-Volterra type equations used to describe the evolution of a single diffusive animal species.

  19. [FUNCTIONAL DIFFERENTIATION IN BRYOZOAN COLONY: A PROTEOMIC ANALYSIS].

    PubMed

    Kutyumov, V A; Maltseva, A L; Kotenko, N; Ostrovsky, A N

    2016-01-01

    Bryozoans are typical modular organisms. They consist of repetitive structural units, the zooids. Bryozoan colonies grow by zooidal budding, with the distribution pattern of the budding loci underlying the diversity of colony forms. Budding is usually restricted to the zooids at the periphery of the colony, which form a "growing edge" or local terminal growth zones. Non-budding parts of the colony can be functionally subdivided, too. In many species colonies consists of regular, often repetitive zones of feeding and non-feeding modules, associated with a periodical degeneration and regeneration of the polypide, retractile tentacle crown with a gut and the accompanying musculature. So, there is functional differentiation in bryozoan colonies but its mechanisms are unknown. Presumably, budding and/or polypide recycling in different colony parts are induced or inhibited by certain determinants of functional specialization. An effective tool of their identification is the comparison of proteomes of functionally different zones. Here we report the results of proteomic analysis of three bryozoan species from the White Sea, which have a different colony form: Flustrellidra hispida, Terminoflustra membranaceotruncata and Securiflustra securifrons. Using differential two-dimensional electrophoresis (2D-DIGE), we compared proteomes of the growing edge and the zones consisting of feeding and non-feeding zooids in these species. We estimated the overall proteome variability, revealed proteins whose relative abundance gradually changed along the proximal-distal colony axis and suggested that they might be involved in the functional differentiation of the colony.

  20. [FUNCTIONAL DIFFERENTIATION IN BRYOZOAN COLONY: A PROTEOMIC ANALYSIS].

    PubMed

    Kutyumov, V A; Maltseva, A L; Kotenko, N; Ostrovsky, A N

    2016-01-01

    Bryozoans are typical modular organisms. They consist of repetitive structural units, the zooids. Bryozoan colonies grow by zooidal budding, with the distribution pattern of the budding loci underlying the diversity of colony forms. Budding is usually restricted to the zooids at the periphery of the colony, which form a "growing edge" or local terminal growth zones. Non-budding parts of the colony can be functionally subdivided, too. In many species colonies consists of regular, often repetitive zones of feeding and non-feeding modules, associated with a periodical degeneration and regeneration of the polypide, retractile tentacle crown with a gut and the accompanying musculature. So, there is functional differentiation in bryozoan colonies but its mechanisms are unknown. Presumably, budding and/or polypide recycling in different colony parts are induced or inhibited by certain determinants of functional specialization. An effective tool of their identification is the comparison of proteomes of functionally different zones. Here we report the results of proteomic analysis of three bryozoan species from the White Sea, which have a different colony form: Flustrellidra hispida, Terminoflustra membranaceotruncata and Securiflustra securifrons. Using differential two-dimensional electrophoresis (2D-DIGE), we compared proteomes of the growing edge and the zones consisting of feeding and non-feeding zooids in these species. We estimated the overall proteome variability, revealed proteins whose relative abundance gradually changed along the proximal-distal colony axis and suggested that they might be involved in the functional differentiation of the colony. PMID:27220253

  1. Differential Expression and Network Inferences through Functional Data Modeling

    PubMed Central

    Telesca, Donatello; Inoue, Lurdes Y.T.; Neira, Mauricio; Etzioni, Ruth; Gleave, Martin; Nelson, Colleen

    2010-01-01

    Time–course microarray data consist of mRNA expression from a common set of genes collected at different time points. Such data are thought to reflect underlying biological processes developing over time. In this article we propose a model that allows us to examine differential expression and gene network relationships using time course microarray data. We model each gene expression profile as a random functional transformation of the scale, amplitude and phase of a common curve. Inferences about the gene–specific amplitude parameters allow us to examine differential gene expression. Inferences about measures of functional similarity based on estimated time transformation functions allow us to examine gene networks while accounting for features of the gene expression profiles. We discuss applications to simulated data as well as to microarray data on prostate cancer progression. PMID:19053995

  2. Limited role of functional differentiation in early diversification of animals

    PubMed Central

    Knope, M.L.; Heim, N.A.; Frishkoff, L.O.; Payne, J.L.

    2015-01-01

    The origin of most animal phyla and classes during the Cambrian explosion has been hypothesized to represent an ‘early burst’ of evolutionary exploration of functional ecological possibilities. However, the ecological history of marine animals has yet to be fully quantified, preventing an assessment of the early-burst model for functional ecology. Here we use ecological assignments for 18,621 marine animal genera to assess the relative timing of functional differentiation versus taxonomic diversification from the Cambrian to the present day. We find that functional diversity increased more slowly than would be expected given the history of taxonomic diversity. Contrary to previous inferences of rapid ecological differentiation from the early appearances of all well-fossilized phyla and classes, explicit coding of functional characteristics demonstrates that Cambrian genera occupied comparatively few modes of life. Functional diversity increased in the Ordovician and, especially, during the recoveries from the end-Permian and end-Cretaceous mass extinctions. Permanent shifts in the relationship between functional and taxonomic diversity following the era-bounding extinctions indicates a critical role for these biotic crises in coupling taxonomic and functional diversity. PMID:25737406

  3. Directed Differentiation of Zebrafish Pluripotent Embryonic Cells to Functional Cardiomyocytes.

    PubMed

    Xiao, Yao; Gao, Maomao; Gao, Luna; Zhao, Yu; Hong, Qiang; Li, Zhigang; Yao, Jing; Cheng, Hanhua; Zhou, Rongjia

    2016-09-13

    A cardiomyocyte differentiation in vitro system from zebrafish embryos remains to be established. Here, we have determined pluripotency window of zebrafish embryos by analyzing their gene-expression patterns of pluripotency factors together with markers of three germ layers, and have found that zebrafish undergoes a very narrow period of pluripotency maintenance from zygotic genome activation to a brief moment after oblong stage. Based on the pluripotency and a combination of appropriate conditions, we established a rapid and efficient method for cardiomyocyte generation in vitro from primary embryonic cells. The induced cardiomyocytes differentiated into functional and specific cardiomyocyte subtypes. Notably, these in vitro generated cardiomyocytes exhibited typical contractile kinetics and electrophysiological features. The system provides a new paradigm of cardiomyocyte differentiation from primary embryonic cells in zebrafish. The technology provides a new platform for the study of heart development and regeneration, in addition to drug discovery, disease modeling, and assessment of cardiotoxic agents. PMID:27569061

  4. Sodium-Dependent Phosphate Transporters in Osteoclast Differentiation and Function

    PubMed Central

    Dolder, Silvia; Siegrist, Mark; Wagner, Carsten A.; Biber, Jürg; Hernando, Nati; Hofstetter, Willy

    2015-01-01

    Osteoclasts are multinucleated bone degrading cells. Phosphate is an important constituent of mineralized bone and released in significant quantities during bone resorption. Molecular contributors to phosphate transport during the resorptive activity of osteoclasts have been controversially discussed. This study aimed at deciphering the role of sodium-dependent phosphate transporters during osteoclast differentiation and bone resorption. Our studies reveal RANKL-induced differential expression of sodium-dependent phosphate transport protein IIa (NaPi-IIa) transcript and protein during osteoclast development, but no expression of the closely related NaPi-IIb and NaPi-IIc SLC34 family isoforms. In vitro studies employing NaPi-IIa-deficient osteoclast precursors and mature osteoclasts reveal that NaPi-IIa is dispensable for bone resorption and osteoclast differentiation. These results are supported by the analysis of structural bone parameters by high-resolution microcomputed tomography that yielded no differences between adult NaPi-IIa WT and KO mice. By contrast, both type III sodium-dependent phosphate transporters Pit-1 and Pit-2 were abundantly expressed throughout osteoclast differentiation, indicating that they are the relevant sodium-dependent phosphate transporters in osteoclasts and osteoclast precursors. We conclude that phosphate transporters of the SLC34 family have no role in osteoclast differentiation and function and propose that Pit-dependent phosphate transport could be pivotal for bone resorption and should be addressed in further studies. PMID:25910236

  5. Sodium-dependent phosphate transporters in osteoclast differentiation and function.

    PubMed

    Albano, Giuseppe; Moor, Matthias; Dolder, Silvia; Siegrist, Mark; Wagner, Carsten A; Biber, Jürg; Hernando, Nati; Hofstetter, Willy; Bonny, Olivier; Fuster, Daniel G

    2015-01-01

    Osteoclasts are multinucleated bone degrading cells. Phosphate is an important constituent of mineralized bone and released in significant quantities during bone resorption. Molecular contributors to phosphate transport during the resorptive activity of osteoclasts have been controversially discussed. This study aimed at deciphering the role of sodium-dependent phosphate transporters during osteoclast differentiation and bone resorption. Our studies reveal RANKL-induced differential expression of sodium-dependent phosphate transport protein IIa (NaPi-IIa) transcript and protein during osteoclast development, but no expression of the closely related NaPi-IIb and NaPi-IIc SLC34 family isoforms. In vitro studies employing NaPi-IIa-deficient osteoclast precursors and mature osteoclasts reveal that NaPi-IIa is dispensable for bone resorption and osteoclast differentiation. These results are supported by the analysis of structural bone parameters by high-resolution microcomputed tomography that yielded no differences between adult NaPi-IIa WT and KO mice. By contrast, both type III sodium-dependent phosphate transporters Pit-1 and Pit-2 were abundantly expressed throughout osteoclast differentiation, indicating that they are the relevant sodium-dependent phosphate transporters in osteoclasts and osteoclast precursors. We conclude that phosphate transporters of the SLC34 family have no role in osteoclast differentiation and function and propose that Pit-dependent phosphate transport could be pivotal for bone resorption and should be addressed in further studies.

  6. Optimized higher-order automatic differentiation for the Faddeeva function

    NASA Astrophysics Data System (ADS)

    Charpentier, Isabelle

    2016-08-01

    Considerable research efforts have been directed at implementing the Faddeeva function w(z) and its derivatives with respect to z, but these did not consider the key computing issue of a possible dependence of z on some variable t. The general case is to differentiate the compound function w(z(t)) = w ∘ z(t) with respect to t by applying the chain rule for a first order derivative, or Faà di Bruno's formula for higher-order ones. Higher-order automatic differentiation (HOAD) is an efficient and accurate technique for derivative calculation along scientific computing codes. Although codes are available for w(z) , a special symbolic HOAD is required to compute accurate higher-order derivatives for w ∘ z(t) in an efficient manner. A thorough evaluation is carried out considering a nontrivial case study in optics to support this assertion.

  7. Inorganic arsenic impairs differentiation and functions of human dendritic cells

    SciTech Connect

    Macoch, Mélinda; Morzadec, Claudie; Fardel, Olivier; Vernhet, Laurent

    2013-01-15

    Experimental studies have demonstrated that the antileukemic trivalent inorganic arsenic prevents the development of severe pro-inflammatory diseases mediated by excessive Th1 and Th17 cell responses. Differentiation of Th1 and Th17 subsets is mainly regulated by interleukins (ILs) secreted from dendritic cells (DCs) and the ability of inorganic arsenic to impair interferon-γ and IL-17 secretion by interfering with the physiology of DCs is unknown. In the present study, we demonstrate that high concentrations of sodium arsenite (As(III), 1–2 μM) clinically achievable in plasma of arsenic-treated patients, block differentiation of human peripheral blood monocytes into immature DCs (iDCs) by inducing their necrosis. Differentiation of monocytes in the presence of non-cytotoxic concentrations of As(III) (0.1 to 0.5 μM) only slightly impacts endocytotic activity of iDCs or expression of co-stimulatory molecules in cells activated with lipopolysaccharide. However, this differentiation in the presence of As(III) strongly represses secretion of IL-12p70 and IL-23, two major regulators of Th1 and Th17 activities, from iDCs stimulated with different toll-like receptor (TLR) agonists in metalloid-free medium. Such As(III)-exposed DCs also exhibit reduced mRNA levels of IL12A and/or IL12B genes when activated with TLR agonists. Finally, differentiation of monocytes with non-cytotoxic concentrations of As(III) subsequently reduces the ability of activated DCs to stimulate the release of interferon-γ and IL-17 from Th cells. In conclusion, our results demonstrate that clinically relevant concentrations of inorganic arsenic markedly impair in vitro differentiation and functions of DCs, which may contribute to the putative beneficial effects of the metalloid towards inflammatory autoimmune diseases. Highlights: ► Inorganic arsenic impairs differentiation and functions of human dendritic cells (DCs) ► Arsenite (> 1 μM) blocks differentiation of dendritic cells by

  8. Regulation of T Cell Differentiation and Function by EZH2.

    PubMed

    Karantanos, Theodoros; Chistofides, Anthos; Barhdan, Kankana; Li, Lequn; Boussiotis, Vassiliki A

    2016-01-01

    The enhancer of zeste homolog 2 (EZH2), one of the polycomb-group proteins, is the catalytic subunit of Polycomb-repressive complex 2 (PRC2) and induces the trimethylation of the histone H3 lysine 27 (H3K27me3) promoting epigenetic gene silencing. EZH2 contains a SET domain promoting the methyltransferase activity, while the three other protein components of PRC2, namely EED, SUZ12, and RpAp46/48, induce compaction of the chromatin permitting EZH2 enzymatic activity. Numerous studies highlight the role of this evolutionary conserved protein as a master regulator of differentiation in humans involved in the repression of the homeotic gene and the inactivation of X-chromosome. Through its effects in the epigenetic regulation of critical genes, EZH2 has been strongly linked to cell cycle progression, stem cell pluripotency, and cancer biology, being currently at the cutting edge of research. Most recently, EZH2 has been associated with hematopoietic stem cell proliferation and differentiation, thymopoiesis and lymphopoiesis. Several studies have evaluated the role of EZH2 in the regulation of T cell differentiation and plasticity as well as its implications in the development of autoimmune diseases and graft-versus-host disease (GVHD). The aim of this review is to summarize the current knowledge regarding the role of EZH2 in the regulation of the differentiation and function of T cells focusing on possible applications in various immune-mediated conditions, including autoimmune disorders and GVHD.

  9. Osteoclast differentiation and function in aquaglyceroporin AQP9 null mice

    PubMed Central

    Liu, Yangjian; Song, Linhua; Wang, Yiding; Rojek, Aleksandra; Nielsen, Søren; Agre, Peter; Carbrey, Jennifer M.

    2008-01-01

    Background Information Osteoclasts are cells specialized for bone resorption and play important roles in bone growth and calcium homeostasis. Differentiation of osteoclasts involves fusion of bone marrow macrophage mononuclear precursors in response to extracellular signals. A dramatic increase in osteoclast cell volume occurs during osteoclast biogenesis and is believed to be mediated by Aquaporin 9 (AQP9), a membrane protein that can rapidly transport water and other small neutral solutes across cell membranes. Results Here we report an increase in expression of AQP9 during differentiation of a mouse macrophage cell line into osteoclasts. Bone marrow macrophages from wild type and AQP9 null mice differentiate into osteoclasts that have similar morphology, contain comparable numbers of nuclei, and digest synthetic bone to the same extent. Bones from wild type and AQP9 null mice contain similar numbers of osteoclasts and have comparable density and structure as measured by X-ray absorptiometry and micro-computed tomography. Conclusions Our data confirm that AQP9 expression rises during osteoclast biogenesis but indicate that AQP9 is not essential for osteoclast function or differentiation under normal physiological conditions. PMID:18666888

  10. Control of functional differential equations to target sets in function space

    NASA Technical Reports Server (NTRS)

    Banks, H. T.; Kent, G. A.

    1971-01-01

    Optimal control of systems governed by functional differential equations of retarded and neutral type is considered. Problems with function space initial and terminal manifolds are investigated. Existence of optimal controls, regularity, and bang-bang properties are discussed. Necessary and sufficient conditions are derived, and several solved examples which illustrate the theory are presented.

  11. Sirt6 regulates dendritic cell differentiation, maturation, and function

    PubMed Central

    Lasigliè, Denise; Boero, Silvia; Bauer, Inga; Morando, Sara; Damonte, Patrizia; Cea, Michele; Monacelli, Fiammetta; Odetti, Paizio; Ballestrero, Alberto; Uccelli, Antonio; Mostoslavsky, Raul; Poggi, Alessandro; Nencioni, Alessio

    2016-01-01

    Dendritic cells (DCs) are antigen-presenting cells that critically influence decisions about immune activation or tolerance. Impaired DC function is at the core of common chronic disorders and contributes to reduce immunocompetence during aging. Knowledge on the mechanisms regulating DC generation and function is necessary to understand the immune system and to prevent disease and immunosenescence. Here we show that the sirtuin Sirt6, which was previously linked to healthspan promotion, stimulates the development of myeloid, conventional DCs (cDCs). Sirt6-knockout (Sirt6KO) mice exhibit low frequencies of bone marrow cDC precursors and low yields of bone marrow-derived cDCs compared to wild-type (WT) animals. Sirt6KO cDCs express lower levels of class II MHC, of costimulatory molecules, and of the chemokine receptor CCR7, and are less immunostimulatory compared to WT cDCs. Similar effects in terms of differentiation and immunostimulatory capacity were observed in human monocyte-derived DCs in response to SIRT6 inhibition. Finally, while Sirt6KO cDCs show an overall reduction in their ability to produce IL-12, TNF-α and IL-6 secretion varies dependent on the stimulus, being reduced in response to CpG, but increased in response to other Toll-like receptor ligands. In conclusion, Sirt6 plays a crucial role in cDC differentiation and function and reduced Sirt6 activity may contribute to immunosenescence. PMID:26761436

  12. Role of PPARγ in the Differentiation and Function of Neurons

    PubMed Central

    Quintanilla, Rodrigo A.; Utreras, Elias; Cabezas-Opazo, Fabián A.

    2014-01-01

    Neuronal processes (neurites and axons) have an important role in brain cells communication and, generally, they are damaged in neurodegenerative diseases. Recent evidence has showed that the activation of PPARγ pathway promoted neuronal differentiation and axon polarity. In addition, activation of PPARγ using thiazolidinediones (TZDs) prevented neurodegeneration by reducing neuronal death, improving mitochondrial function, and decreasing neuroinflammation in neuropathic pain. In this review, we will discuss important evidence that supports a possible role of PPARγ in neuronal development, improvement of neuronal health, and pain signaling. Therefore, activation of PPARγ is a potential target with therapeutic applications against neurodegenerative disorders, brain injury, and pain regulation. PMID:25246934

  13. Finding first order differential invariants through the S-function

    NASA Astrophysics Data System (ADS)

    Duarte, L. G. S.; da Mota, L. A. C. P.; Nunez, E.

    2016-10-01

    The method presented in Duarte and da Mota (2009) and Avellar et al. (2014) to search for first order invariants of second order ordinary differential equation (2ODEs) makes use of the so called Darboux polynomials. The main difficulty involved in this process is the determination of the Darboux polynomials, which is computationally very expensive. Here, we introduce an optional argument in the main routine that enables a shortcut in the calculations through the use of the S-function associated with the 2ODE.

  14. Silibinin Regulates Lipid Metabolism and Differentiation in Functional Human Adipocytes

    PubMed Central

    Barbagallo, Ignazio; Vanella, Luca; Cambria, Maria T.; Tibullo, Daniele; Godos, Justyna; Guarnaccia, Laura; Zappalà, Agata; Galvano, Fabio; Li Volti, Giovanni

    2016-01-01

    Silibinin, a natural plant flavonolignan is the main active constituent found in milk thistle (Silybum marianum). It is known to have hepatoprotective, anti-neoplastic effect, and suppresses lipid accumulation in adipocytes. Objective of this study was to investigate the effect of silibinin on adipogenic differentiation and thermogenic capacity of human adipose tissue derived mesenchymal stem cells. Silibinin (10 μM) treatment, either at the beginning or at the end of adipogenic differentiation, resulted in an increase of SIRT-1, PPARα, Pgc-1α, and UCPs gene expression. Moreover, silibinin administration resulted in a decrease of PPARγ, FABP4, FAS, and MEST/PEG1 gene expression during the differentiation, confirming that this compound is able to reduce fatty acid accumulation and adipocyte size. Our data showed that silibinin regulated adipocyte lipid metabolism, inducing thermogenesis and promoting a brown remodeling in adipocyte. Taken together, our findings suggest that silibinin increases UCPs expression by stimulation of SIRT1, PPARα, and Pgc-1α, improved metabolic parameters, decreased lipid mass leading to the formation of functional adipocytes. PMID:26834634

  15. Nodal centrality of functional network in the differentiation of schizophrenia.

    PubMed

    Cheng, Hu; Newman, Sharlene; Goñi, Joaquín; Kent, Jerillyn S; Howell, Josselyn; Bolbecker, Amanda; Puce, Aina; O'Donnell, Brian F; Hetrick, William P

    2015-10-01

    A disturbance in the integration of information during mental processing has been implicated in schizophrenia, possibly due to faulty communication within and between brain regions. Graph theoretic measures allow quantification of functional brain networks. Functional networks are derived from correlations between time courses of brain regions. Group differences between SZ and control groups have been reported for functional network properties, but the potential of such measures to classify individual cases has been little explored. We tested whether the network measure of betweenness centrality could classify persons with schizophrenia and normal controls. Functional networks were constructed for 19 schizophrenic patients and 29 non-psychiatric controls based on resting state functional MRI scans. The betweenness centrality of each node, or fraction of shortest-paths that pass through it, was calculated in order to characterize the centrality of the different regions. The nodes with high betweenness centrality agreed well with hub nodes reported in previous studies of structural and functional networks. Using a linear support vector machine algorithm, the schizophrenia group was differentiated from non-psychiatric controls using the ten nodes with the highest betweenness centrality. The classification accuracy was around 80%, and stable against connectivity thresholding. Better performance was achieved when using the ranks as feature space as opposed to the actual values of betweenness centrality. Overall, our findings suggest that changes in functional hubs are associated with schizophrenia, reflecting a variation of the underlying functional network and neuronal communications. In addition, a specific network property, betweenness centrality, can classify persons with SZ with a high level of accuracy. PMID:26299706

  16. An Effect Size Measure for Raju's Differential Functioning for Items and Tests

    ERIC Educational Resources Information Center

    Wright, Keith D.; Oshima, T. C.

    2015-01-01

    This study established an effect size measure for differential functioning for items and tests' noncompensatory differential item functioning (NCDIF). The Mantel-Haenszel parameter served as the benchmark for developing NCDIF's effect size measure for reporting moderate and large differential item functioning in test items. The effect size of…

  17. Exploration of the Validity of Gender Differences in Mathematics Assessment Using Differential Bundle Functioning

    ERIC Educational Resources Information Center

    Ong, Yoke Mooi; Williams, Julian Scott; Lamprianou, Iasonas

    2011-01-01

    The aims of this study are (a) to examine the sources of differential functioning by gender via differential bundle functioning (DBF) in mathematics assessment and (b) to use DBF to explore whether the differential functioning displayed is construct-relevant or construct-irrelevant. Three qualitatively different areas, namely curriculum domains,…

  18. Redundancy of myostatin and growth/differentiation factor 11 function

    PubMed Central

    McPherron, Alexandra C; Huynh, Thanh V; Lee, Se-Jin

    2009-01-01

    Background Myostatin (Mstn) and growth/differentiation factor 11 (Gdf11) are highly related transforming growth factor β (TGFβ) family members that play important roles in regulating embryonic development and adult tissue homeostasis. Despite their high degree of sequence identity, targeted mutations in these genes result in non-overlapping phenotypes affecting distinct biological processes. Loss of Mstn in mice causes a doubling of skeletal muscle mass while loss of Gdf11 in mice causes dramatic anterior homeotic transformations of the axial skeleton, kidney agenesis, and an increase in progenitor cell number in several tissues. In order to investigate the possible functional redundancy of myostatin and Gdf11, we analyzed the effect of eliminating the functions of both of these signaling molecules. Results We show that Mstn-/- Gdf11-/- mice have more extensive homeotic transformations of the axial skeleton than Gdf11-/- mice in addition to skeletal defects not seen in single mutants such as extra forelimbs. We also show that deletion of Gdf11 specifically in skeletal muscle in either Mstn+/+ or Mstn-/- mice does not affect muscle size, fiber number, or fiber type. Conclusion These results provide evidence that myostatin and Gdf11 have redundant functions in regulating skeletal patterning in mice but most likely not in regulating muscle size. PMID:19298661

  19. Expression of factors associated with apoptosis in the porcine corpus luteum throughout the luteal phase of the estrous cycle and early pregnancy: their possible involvement in acquisition of luteolytic sensitivity.

    PubMed

    Przygrodzka, E; Witek, K J; Kaczmarek, M M; Andronowska, A; Ziecik, A J

    2015-03-01

    The studies on the acquisition of luteolytic sensitivity have been focused mainly on molecular changes induced in the luteal tissue after treatment with exogenous PGF2α or on physiological changes occurring during the estrous cycle. The comparison of changes leading to the acquisition of luteolytic sensitivity after Day 12 of the estrous cycle and corresponding days of pregnancy has not been investigated in the pig. The present study was undertaken to evaluate (1) apoptosis measured as the proportions of early apoptotic, late apoptotic, and viable cells; (2) expression of factors involved in the extrinsic (TNFA/TNFα, TNFRSF1A/TNFR1, TNFRSF1B/TNFR2, FAS/Fas, and FASLG/FasL) and intrinsic (CASP3/Casp3, TP53/p-53, BAX/Bax, and BCL2/Bcl-2) apoptotic pathways, with two components of the activating protein-1 complex, i.e., FOS/Fos and JUN/Jun and IFNG/IFNγ; and (3) concentrations of luteal and blood plasma progesterone (P4) throughout the luteal phase of the estrous cycle and early pregnancy. Corpora lutea (CL) were collected postmortem on Days 8, 10, 12, and 14 of the estrous cycle and the corresponding days of pregnancy. The luteal tissue was subjected to RNA and/or protein isolation and disaggregation of CL cells followed by flow cytometry analysis aimed to determine apoptotic changes. Luteal and blood plasma P4 concentrations decreased on Day 14 of the estrous cycle versus pregnancy (P < 0.05 and P < 0.001, respectively). A significant increase in the number of early apoptotic cells and a decrease in the number of viable cells were observed on Day 14 of the estrous cycle (P < 0.001 and P < 0.05, respectively). Increase (P < 0.05) of TNFA messenger RNA (mRNA) level coincided with that of IFNG on Day 12 of the estrous cycle but not on the corresponding day of pregnancy. The content of FAS mRNA and protein increased on Day 14 of the estrous cycle versus pregnancy (P < 0.05). The mRNA expression of CASP3, BCL-2 and BAX was unchanged in cyclic and pregnant

  20. Differential Assemblage of Functional Units in Paddy Soil Microbiomes

    PubMed Central

    Kim, Yongkyu; Liesack, Werner

    2015-01-01

    Flooded rice fields are not only a global food source but also a major biogenic source of atmospheric methane. Using metatranscriptomics, we comparatively explored structural and functional succession of paddy soil microbiomes in the oxic surface layer and anoxic bulk soil. Cyanobacteria, Fungi, Xanthomonadales, Myxococcales, and Methylococcales were the most abundant and metabolically active groups in the oxic zone, while Clostridia, Actinobacteria, Geobacter, Anaeromyxobacter, Anaerolineae, and methanogenic archaea dominated the anoxic zone. The protein synthesis potential of these groups was about 75% and 50% of the entire community capacity, respectively. Their structure-function relationships in microbiome succession were revealed by classifying the protein-coding transcripts into core, non-core, and taxon-specific transcripts based on homologous gene distribution. The differential expression of core transcripts between the two microbiomes indicated that structural succession is primarily governed by the cellular ability to adapt to the given oxygen condition, involving oxidative stress, nitrogen/phosphorus metabolism, and fermentation. By contrast, the non-core transcripts were expressed from genes involved in the metabolism of various carbon sources. Among those, taxon-specific transcripts revealed highly specialized roles of the dominant groups in community-wide functioning. For instance, taxon-specific transcripts involved in photosynthesis and methane oxidation were a characteristic of the oxic zone, while those related to methane production and aromatic compound degradation were specific to the anoxic zone. Degradation of organic matters, antibiotics resistance, and secondary metabolite production were detected to be expressed in both the oxic and anoxic zones, but by different taxonomic groups. Cross-feeding of methanol between members of the Methylococcales and Xanthomonadales was suggested by the observation that in the oxic zone, they both

  1. Multiscale functions, scale dynamics, and applications to partial differential equations

    NASA Astrophysics Data System (ADS)

    Cresson, Jacky; Pierret, Frédéric

    2016-05-01

    Modeling phenomena from experimental data always begins with a choice of hypothesis on the observed dynamics such as determinism, randomness, and differentiability. Depending on these choices, different behaviors can be observed. The natural question associated to the modeling problem is the following: "With a finite set of data concerning a phenomenon, can we recover its underlying nature? From this problem, we introduce in this paper the definition of multi-scale functions, scale calculus, and scale dynamics based on the time scale calculus [see Bohner, M. and Peterson, A., Dynamic Equations on Time Scales: An Introduction with Applications (Springer Science & Business Media, 2001)] which is used to introduce the notion of scale equations. These definitions will be illustrated on the multi-scale Okamoto's functions. Scale equations are analysed using scale regimes and the notion of asymptotic model for a scale equation under a particular scale regime. The introduced formalism explains why a single scale equation can produce distinct continuous models even if the equation is scale invariant. Typical examples of such equations are given by the scale Euler-Lagrange equation. We illustrate our results using the scale Newton's equation which gives rise to a non-linear diffusion equation or a non-linear Schrödinger equation as asymptotic continuous models depending on the particular fractional scale regime which is considered.

  2. Defining a Model for Mitochondrial Function in mESC Differentiation

    EPA Science Inventory

    Defining a Model for Mitochondrial Function in mESC DifferentiationDefining a Model for Mitochondrial Function in mESC Differentiation Differentiating embryonic stem cells (ESCs) undergo mitochondrial maturation leading to a switch from a system dependent upon glycolysis to a re...

  3. Dystroglycan depletion inhibits the functions of differentiated HL-60 cells.

    PubMed

    Martínez-Zárate, Alma Delia; Martínez-Vieyra, Ivette; Alonso-Rangel, Lea; Cisneros, Bulmaro; Winder, Steve J; Cerecedo, Doris

    2014-06-01

    Dystroglycan has recently been characterized in blood tissue cells, as part of the dystrophin glycoprotein complex but to date nothing is known of its role in the differentiation process of neutrophils. We have investigated the role of dystroglycan in the human promyelocytic leukemic cell line HL-60 differentiated to neutrophils. Depletion of dystroglycan by RNAi resulted in altered morphology and reduced properties of differentiated HL-60 cells, including chemotaxis, respiratory burst, phagocytic activities and expression of markers of differentiation. These findings strongly implicate dystroglycan as a key membrane adhesion protein involved in the differentiation process in HL-60 cells.

  4. Building the blocks of executive functioning: Differentiating early developing processes contributing to executive functioning skills

    PubMed Central

    Mandell, Dorothy J.; Ward, Sarah E.

    2011-01-01

    The neural processes that underlie executive function begin to develop in infancy. However, it is unclear how the behavior manifested by these processes are related or if they can be differentiated early in development. This study seeks to examine early emerging executive functioning skills in monkeys (M. fascicularis) by using an error analysis approach where traditional measures of the tasks, as well as identification of major error patterns are related. Results show that during the infancy and early juvenile period, two processes that help support set-maintenance could be differentiated: modulation of responses to novelty and persistence despite negative feedback. The results suggest that these two aspects of set-maintenance were largely independent. Modulation of responses to novelty was most prominent in the infancy and early juvenile period. The ability to persist with a response set despite negative feedback emerged in the early juvenile period and was related to task performance until the end of the study. PMID:21563178

  5. Functional differentiation of cytotoxic cancer drugs and targeted cancer therapeutics.

    PubMed

    Winkler, Gian C; Barle, Ester Lovsin; Galati, Giuseppe; Kluwe, William M

    2014-10-01

    There is no nationally or internationally binding definition of the term "cytotoxic drug" although this term is used in a variety of regulations for pharmaceutical development and manufacturing of drugs as well as in regulations for protecting medical personnel from occupational exposure in pharmacy, hospital, and other healthcare settings. The term "cytotoxic drug" is frequently used as a synonym for any and all oncology or antineoplastic drugs. Pharmaceutical companies generate and receive requests for assessments of the potential hazards of drugs regularly - including cytotoxicity. This publication is intended to provide functional definitions that help to differentiate between generically-cytotoxic cancer drugs of significant risk to normal human tissues, and targeted cancer therapeutics that pose much lesser risks. Together with specific assessments, it provides comprehensible guidance on how to assess the relevant properties of cancer drugs, and how targeted therapeutics discriminate between cancer and normal cells. The position of several regulatory agencies in the long-term is clearly to regulate all drugs regardless of classification, according to scientific risk based data. Despite ongoing discussions on how to replace the term "cytotoxic drugs" in current regulations, it is expected that its use will continue for the near future.

  6. Phosphoinositides differentially regulate alpha-actinin flexibility and function.

    PubMed

    Corgan, Anne Marie; Singleton, CoreyAyne; Santoso, Cynthia B; Greenwood, Jeffrey A

    2004-03-15

    Alpha-actinin is a cell-adhesion and cytoskeletal protein that bundles actin microfilaments and links these filaments directly to integrin-adhesion receptors. Phosphoinositides bind to and regulate the interaction of a-actinin with actin filaments and integrin receptors. In the present study, we demonstrate that PtdIns(3,4,5)P3 inhibits and disrupts a-actinin-bundling activity, whereas PtdIns(4,5)P2 can only inhibit activity. In addition, a protease-sensitivity assay was developed to examine the flexibility of the linker region between the actin-binding domain and the spectrin repeats of a-actinin. Both phosphoinositides influenced the extent of proteolysis and the cleavage sites. PtdIns(4,5)P2 binding decreased the proteolysis of a-actinin, suggesting a role in stabilizing the structure of the protein. In contrast, PtdIns(3,4,5)P3 binding enhanced a-actinin proteolysis, indicating an increase in the flexibility of the protein. Furthermore, phosphoinositide binding influenced the proteolysis of the N- and C-terminal domains of a-actinin, indicating regulation of structure within both domains. These results support the hypothesis that PtdIns(4,5)P2 and PtdIns(3,4,5)P3 differentially regulate a-actinin function by modulating the structure and flexibility of the protein.

  7. Phosphoinositides differentially regulate alpha-actinin flexibility and function.

    PubMed Central

    Corgan, Anne Marie; Singleton, CoreyAyne; Santoso, Cynthia B; Greenwood, Jeffrey A

    2004-01-01

    Alpha-actinin is a cell-adhesion and cytoskeletal protein that bundles actin microfilaments and links these filaments directly to integrin-adhesion receptors. Phosphoinositides bind to and regulate the interaction of a-actinin with actin filaments and integrin receptors. In the present study, we demonstrate that PtdIns(3,4,5)P3 inhibits and disrupts a-actinin-bundling activity, whereas PtdIns(4,5)P2 can only inhibit activity. In addition, a protease-sensitivity assay was developed to examine the flexibility of the linker region between the actin-binding domain and the spectrin repeats of a-actinin. Both phosphoinositides influenced the extent of proteolysis and the cleavage sites. PtdIns(4,5)P2 binding decreased the proteolysis of a-actinin, suggesting a role in stabilizing the structure of the protein. In contrast, PtdIns(3,4,5)P3 binding enhanced a-actinin proteolysis, indicating an increase in the flexibility of the protein. Furthermore, phosphoinositide binding influenced the proteolysis of the N- and C-terminal domains of a-actinin, indicating regulation of structure within both domains. These results support the hypothesis that PtdIns(4,5)P2 and PtdIns(3,4,5)P3 differentially regulate a-actinin function by modulating the structure and flexibility of the protein. PMID:14670080

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

    PubMed

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

    2012-01-01

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

  9. Carcinoma origin dictates differential skewing of monocyte function

    PubMed Central

    Bögels, Marijn; Braster, Rens; Nijland, Philip G.; Gül, Nuray; van de Luijtgaarden, Wendy; Fijneman, Remond J.A.; Meijer, Gerrit A.; Jimenez, Connie R.; Beelen, Robert H.J.; van Egmond, Marjolein

    2012-01-01

    Macrophages are versatile cells, which phenotype is profoundly influenced by their environment. Pro-inflammatory classically activated or M1 macrophages, and anti-inflammatory alternatively-activated or M2 macrophages represent two extremes of a continuum of functional states. Consequently, macrophages that are present in tumors can exert tumor-promoting and tumor-suppressing activity, depending on the tumor milieu. In this study we investigated how human monocytes—the precursors of macrophages—are influenced by carcinoma cells of different origin. We demonstrate that monocytes, stimulated with breast cancer supernatant, showed increased expression of interleukin (IL)-10, IL-8 and chemokines CCL17 and CCL22, which are associated with an alternatively-activated phenotype. By contrast, monocytes that were cultured in supernatants of colon cancer cells produced more pro-inflammatory cytokines (e.g., IL-12 and TNFα) and reactive oxygen species. Secretome analysis revealed differential secretion of proteins by colon and breast cancer cell lines, of which the proteoglycan versican was exclusively secreted by colon carcinoma cell lines. Reducing active versican by blocking with monoclonal antibodies or shRNA diminished pro-inflammatory cytokine production by monocytes. Thus, colon carcinoma cells polarize monocytes toward a more classically-activated anti-tumorigenic phenotype, whereas breast carcinomas predispose monocytes toward an alternatively activated phenotype. Interestingly, presence of macrophages in breast or colon carcinomas correlates with poor or good prognosis in patients, respectively. The observed discrepancy in macrophage activation by either colon or breast carcinoma cells may therefore explain the dichotomy between patient prognosis and macrophage presence in these different tumors. Designing new therapies, directing development of monocytes toward M1 activated tumor macrophages in cancer patients, may have great clinical benefits. PMID:23162747

  10. Quasi-Newton methods for parameter estimation in functional differential equations

    NASA Technical Reports Server (NTRS)

    Brewer, Dennis W.

    1988-01-01

    A state-space approach to parameter estimation in linear functional differential equations is developed using the theory of linear evolution equations. A locally convergent quasi-Newton type algorithm is applied to distributed systems with particular emphasis on parameters that induce unbounded perturbations of the state. The algorithm is computationally implemented on several functional differential equations, including coefficient and delay estimation in linear delay-differential equations.

  11. The Item Parameter Replication Method for Detecting Differential Functioning in the Polytomous DFIT Framework

    ERIC Educational Resources Information Center

    Raju, Nambury S.; Fortmann-Johnson, Kristen A.; Kim, Wonsuk; Morris, Scott B.; Nering, Michael L.; Oshima, T. C.

    2009-01-01

    The recent study of Oshima, Raju, and Nanda proposes the item parameter replication (IPR) method for assessing statistical significance of the noncompensatory differential item functioning (NCDIF) index within the differential functioning of items and tests (DFIT) framework. Previous Monte Carlo simulations have found that the appropriate cutoff…

  12. A Generalized DIF Effect Variance Estimator for Measuring Unsigned Differential Test Functioning in Mixed Format Tests

    ERIC Educational Resources Information Center

    Penfield, Randall D.; Algina, James

    2006-01-01

    One approach to measuring unsigned differential test functioning is to estimate the variance of the differential item functioning (DIF) effect across the items of the test. This article proposes two estimators of the DIF effect variance for tests containing dichotomous and polytomous items. The proposed estimators are direct extensions of the…

  13. A Comparison of Function-Based Differential Reinforcement Interventions for Children Engaging in Disruptive Classroom Behavior

    ERIC Educational Resources Information Center

    LeGray, Matthew W.; Dufrene, Brad A.; Sterling-Turner, Heather; Olmi, D. Joe; Bellone, Katherine

    2010-01-01

    This study provides a direct comparison of differential reinforcement of other behavior (DRO) and differential reinforcement of alternative behavior (DRA). Participants included three children in center-based classrooms referred for functional assessments due to disruptive classroom behavior. Functional assessments included interviews and brief…

  14. The Impact of Multidimensionality on the Detection of Differential Bundle Functioning Using Simultaneous Item Bias Test

    ERIC Educational Resources Information Center

    Furlow, Carolyn F.; Ross, Terris Raiford; Gagne, Phill

    2009-01-01

    Douglas, Roussos, and Stout introduced the concept of differential bundle functioning (DBF) for identifying the underlying causes of differential item functioning (DIF). In this study, reference group was simulated to have higher mean ability than the focal group on a nuisance dimension, resulting in DIF for each of the multidimensional items…

  15. Establishing Effect Size Guidelines for Interpreting the Results of Differential Bundle Functioning Analyses Using SIBTEST

    ERIC Educational Resources Information Center

    Walker, Cindy M.; Zhang, Bo; Banks, Kathleen; Cappaert, Kevin

    2012-01-01

    The purpose of this simulation study was to establish general effect size guidelines for interpreting the results of differential bundle functioning (DBF) analyses using simultaneous item bias test (SIBTEST). Three factors were manipulated: number of items in a bundle, test length, and magnitude of uniform differential item functioning (DIF)…

  16. Differentiation mechanism and function of the cereal aleurone cells and hormone effects on them.

    PubMed

    Zheng, Yankun; Wang, Zhong

    2014-11-01

    The cereal aleurone cells differentiate from the endosperm epidermis with the exception of endosperm transfer cells. Aleurone cells contain proteins, lipids, and minerals, and are important for digesting the endosperm storage products to nurse the embryo under effects of several hormones during the seed germination. The differentiation of aleurone cells is related to location effect and special gene expression. Moreover, the differentiation of aleurone cells is probably affected by the cues from maternal tissues. In the paper, differentiation mechanism and function of aleurone cells and hormone effects on them are reviewed. Some speculations about the differentiation mechanism of aleurone cells are given here.

  17. Differential inequalities imposed by the extended hypergeometric function.

    PubMed

    Ibrahim, Rabha W; Ahmad, M Z; Al-Janaby, Hiba F

    2016-01-01

    Recently, the generalized hypergeometric function is extended by utilizing the Beta function. Based on this type of function, we introduce a new operator in the open unit disk. The present article investigates some subordination and superordination results for certain normalized analytic functions in the open unit disk, which are acted upon by the generalized Noor integral operator. Some of outcomes improve and generalize previously known outcomes.

  18. Metabolic regulation of T cell differentiation and function

    PubMed Central

    Park, Benjamin V.; Pan, Fan

    2016-01-01

    Upon encountering pathogens, T cells mount immune responses by proliferating, increasing cellular mass and differentiating. These cellular changes impose significant energetic challenges on T cells. It was believed that TCR and cytokine-mediated signaling are dominant dictators of T cell-mediated immune responses. Recently, it was recognized that T cells utilize metabolic transporters and metabolic sensors that allow them to rapidly respond to nutrient-limiting inflammatory environments. Metabolic sensors allow T cells to find a balance between energy consumption (anabolic metabolism) and production (catabolic metabolism) in order to mount effective immune responses. Also, metabolic regulators interact with cytokine-dependent transcriptional regulators, suggesting a more integrative and advanced model of T cell activation and differentiation. In this review, we will discuss recent discoveries regarding the roles of metabolic regulators in effector and memory T cell development and their interaction with canonical transcription factors. PMID:26277275

  19. Human dermal stem cells differentiate into functional epidermal melanocytes.

    PubMed

    Li, Ling; Fukunaga-Kalabis, Mizuho; Yu, Hong; Xu, Xiaowei; Kong, Jun; Lee, John T; Herlyn, Meenhard

    2010-03-15

    Melanocytes sustain a lifelong proliferative potential, but a stem cell reservoir in glabrous skin has not yet been found. Here, we show that multipotent dermal stem cells isolated from human foreskins lacking hair follicles are able to home to the epidermis to differentiate into melanocytes. These dermal stem cells, grown as three-dimensional spheres, displayed a capacity for self-renewal and expressed NGFRp75, nestin and OCT4, but not melanocyte markers. In addition, cells derived from single-cell clones were able to differentiate into multiple lineages including melanocytes. In a three-dimensional skin equivalent model, sphere-forming cells differentiated into HMB45-positive melanocytes, which migrated from the dermis to the epidermis and aligned singly among the basal layer keratinocytes in a similar fashion to pigmented melanocytes isolated from the epidermis. The dermal stem cells were negative for E-cadherin and N-cadherin, whereas they acquired E-cadherin expression and lost NGFRp75 expression upon contact with epidermal keratinocytes. These results demonstrate that stem cells in the dermis of human skin with neural-crest-like characteristics can become mature epidermal melanocytes. This finding could significantly change our understanding of the etiological factors in melanocyte transformation and pigmentation disorders; specifically, that early epigenetic or genetic alterations leading to transformation may take place in the dermis rather than in the epidermis.

  20. Dynamic Network-Based Relevance Score Reveals Essential Proteins and Functional Modules in Directed Differentiation

    PubMed Central

    Wu, Chia-Chou; Lin, Che

    2015-01-01

    The induction of stem cells toward a desired differentiation direction is required for the advancement of stem cell-based therapies. Despite successful demonstrations of the control of differentiation direction, the effective use of stem cell-based therapies suffers from a lack of systematic knowledge regarding the mechanisms underlying directed differentiation. Using dynamic modeling and the temporal microarray data of three differentiation stages, three dynamic protein-protein interaction networks were constructed. The interaction difference networks derived from the constructed networks systematically delineated the evolution of interaction variations and the underlying mechanisms. A proposed relevance score identified the essential components in the directed differentiation. Inspection of well-known proteins and functional modules in the directed differentiation showed the plausibility of the proposed relevance score, with the higher scores of several proteins and function modules indicating their essential roles in the directed differentiation. During the differentiation process, the proteins and functional modules with higher relevance scores also became more specific to the neuronal identity. Ultimately, the essential components revealed by the relevance scores may play a role in controlling the direction of differentiation. In addition, these components may serve as a starting point for understanding the systematic mechanisms of directed differentiation and for increasing the efficiency of stem cell-based therapies. PMID:25977693

  1. T Cell Receptor Signaling in the Control of Regulatory T Cell Differentiation and Function

    PubMed Central

    Li, Ming O.; Rudensky, Alexander Y.

    2016-01-01

    Regulatory T cells (TReg cells), a specialized T cell lineage, have a pivotal function in the control of self-tolerance and inflammatory responses. Recent studies have revealed a discrete mode of TCR signaling that regulates Treg cell differentiation, maintenance and function and that impacts on gene expression, metabolism, cell adhesion and migration of these cells. Here, we discuss the emerging understanding of TCR-guided differentiation of Treg cells in the context of their function in health and disease. PMID:27026074

  2. JAKEF: a portable symbolic differentiator of functions given by algorithms

    SciTech Connect

    Hillstrom, K.E.

    1982-08-01

    JAKEF is a compiler that accepts as data a single or double precision FORTRAN subroutine program defining an objective function F(x) or a vector function f(x) and produces as output a single or double precision FORTRAN program defining the gradient of F(x) or the jacobian of f(x).

  3. Exploring Differential Bundle Functioning in Mathematics by Gender: The Effect of Hierarchical Modelling

    ERIC Educational Resources Information Center

    Ong, Yoke Mooi; Williams, Julian; Lamprianou, Iasonas

    2013-01-01

    Researchers interested in exploring substantive group differences are increasingly attending to bundles of items (or testlets): the aim is to understand how gender differences, for instance, are explained by differential performances on different types or bundles of items, hence differential bundle functioning (DBF). Some previous work has…

  4. Clonogenic multipotent stem cells in human adipose tissue differentiate into functional smooth muscle cells

    PubMed Central

    Rodríguez, Larissa V.; Alfonso, Zeni; Zhang, Rong; Leung, Joanne; Wu, Benjamin; Ignarro, Louis J.

    2006-01-01

    Smooth muscle is a major component of human tissues and is essential for the normal function of a multitude of organs including the intestine, urinary tract and the vascular system. The use of stem cells for cell-based tissue engineering and regeneration strategies represents a promising alternative for smooth muscle repair. For such strategies to succeed, a reliable source of smooth muscle precursor cells must be identified. Adipose tissue provides an abundant source of multipotent cells. In this study, the capacity of processed lipoaspirate (PLA) and adipose-derived stem cells to differentiate into phenotypic and functional smooth muscle cells was evaluated. To induce differentiation, PLA cells were cultured in smooth muscle differentiation medium. Smooth muscle differentiation of PLA cells induced genetic expression of all smooth muscle markers and further confirmed by increased protein expression of smooth muscle cell-specific α actin (ASMA), calponin, caldesmon, SM22, myosin heavy chain (MHC), and smoothelin. Clonal studies of adipose derived multipotent cells demonstrated differentiation of these cells into smooth muscle cells in addition to trilineage differentiation capacity. Importantly, smooth muscle-differentiated cells, but not their precursors, exhibit the functional ability to contract and relax in direct response to pharmacologic agents. In conclusion, adipose-derived cells have the potential to differentiate into functional smooth muscle cells and, thus, adipose tissue can be a useful source of cells for treatment of injured tissues where smooth muscle plays an important role. PMID:16880387

  5. Collective Dynamics Differentiates Functional Divergence in Protein Evolution

    PubMed Central

    Glembo, Tyler J.; Farrell, Daniel W.; Gerek, Z. Nevin; Thorpe, M. F.; Ozkan, S. Banu

    2012-01-01

    Protein evolution is most commonly studied by analyzing related protein sequences and generating ancestral sequences through Bayesian and Maximum Likelihood methods, and/or by resurrecting ancestral proteins in the lab and performing ligand binding studies to determine function. Structural and dynamic evolution have largely been left out of molecular evolution studies. Here we incorporate both structure and dynamics to elucidate the molecular principles behind the divergence in the evolutionary path of the steroid receptor proteins. We determine the likely structure of three evolutionarily diverged ancestral steroid receptor proteins using the Zipping and Assembly Method with FRODA (ZAMF). Our predictions are within ∼2.7 Å all-atom RMSD of the respective crystal structures of the ancestral steroid receptors. Beyond static structure prediction, a particular feature of ZAMF is that it generates protein dynamics information. We investigate the differences in conformational dynamics of diverged proteins by obtaining the most collective motion through essential dynamics. Strikingly, our analysis shows that evolutionarily diverged proteins of the same family do not share the same dynamic subspace, while those sharing the same function are simultaneously clustered together and distant from those, that have functionally diverged. Dynamic analysis also enables those mutations that most affect dynamics to be identified. It correctly predicts all mutations (functional and permissive) necessary to evolve new function and ∼60% of permissive mutations necessary to recover ancestral function. PMID:22479170

  6. On the Relationship between Differential Item Functioning and Item Difficulty: An Issue of Methods? Item Response Theory Approach to Differential Item Functioning

    ERIC Educational Resources Information Center

    Santelices, Maria Veronica; Wilson, Mark

    2012-01-01

    The relationship between differential item functioning (DIF) and item difficulty on the SAT is such that more difficult items tended to exhibit DIF in favor of the focal group (usually minority groups). These results were reported by Kulick and Hu, and Freedle and have been enthusiastically discussed by more recent literature. Examining the…

  7. Regulation of ES cell differentiation by functional and conformational modulation of p53.

    PubMed Central

    Sabapathy, K; Klemm, M; Jaenisch, R; Wagner, E F

    1997-01-01

    Embryonic stem (ES) cell lines were used to examine the role of p53 during in vitro differentiation. Undifferentiated ES cells express high levels of p53 exclusively in the wild-type conformation, immunoprecipitable by monoclonal antibody PAb246, and p53 was found to be functionally active as determined by its ability to bind DNA specifically and to activate transcription of target genes. Differentiation in vitro resulted in a decrease in the levels of p53 and in a shift in its conformational status to the mutant form, detectable by monoclonal antibody PAb240, with a concomitant loss of functional activity. The presence of functional p53 in the undifferentiated ES cells renders them hypersensitive to UV irradiation, whereas the differentiated cells were resistant to UV treatment. ES cells lacking p53 exhibit enhanced proliferation in both the undifferentiated and differentiated state, and apoptosis accompanying differentiation was found to be reduced. Furthermore, wild-type ES cells undergoing apoptosis expressed functional p53. Expression of the temperature-sensitive p53val135 mutant in wild-type ES cells resulted in a reduction of apoptosis accompanying differentiation when it adopted a mutant conformation at 39 degrees C. These data demonstrate that functional inactivation of p53 allows differentiating cells to escape from apoptosis, and suggest that the conformational switch could regulate the inactivation process. PMID:9321401

  8. Mental Functioning, Perceptual Differentiation, Personality, and Achievement among Art and Non-Art Majors.

    ERIC Educational Resources Information Center

    Dorethy, Rex; Reeves, Dan

    1979-01-01

    College art majors, art education majors, and nonart majors were compared on measures of brain hemisphere dominance, general intelligence, brain functioning, visual perceptual differentiation, grade point average, flexibility-rigidity, and personal-social adjustment. (SJL)

  9. Differentiating High-Functioning Autism and Social Phobia

    ERIC Educational Resources Information Center

    Tyson, Katherine E.; Cruess, Dean G.

    2012-01-01

    Both high-functioning autism (HFA) and social phobia (SP) involve profound social interaction deficits. Although these disorders share some similar symptoms, they are conceptualized as distinct. Because both HFA and SP are defined behaviorally, the degree of overlap between the two disorders may result in misinterpretation of symptoms. However,…

  10. Differential function of Themis CABIT domains during T cell development.

    PubMed

    Okada, Toshiyuki; Nitta, Takeshi; Kaji, Kentaro; Takashima, Akiko; Oda, Hiroyo; Tamehiro, Norimasa; Goto, Motohito; Okamura, Tadashi; Patrick, Michael S; Suzuki, Harumi

    2014-01-01

    Themis (also named Gasp) is a newly identified Grb2-binding protein that is essential for thymocyte positive selection. Despite the possible involvement of Themis in TCR-mediated signal transduction, its function remains unresolved and controversial. Themis contains two functionally uncharacterized regions called CABIT (cysteine-containing, all-β in Themis) domains, a nuclear localization signal (NLS), and a proline-rich sequence (PRS). To elucidate the role of these motifs in Themis's function in vivo, we established a series of mutant Themis transgenic mice on a Themis(-/-) background. Deletion of the highly conserved Core motif of CABIT1 or CABIT2 (Core1 or Core2, respectively), the NLS, or the PRS abolished Grb2-association, as well as TCR-dependent tyrosine-phosphorylation and the ability to induce positive selection in the thymus. The NLS and Core1 motifs were required for the nuclear localization of Themis, whereas Core2 and PRS were not. Furthermore, expression of ΔCore1- but not ΔCore2-Themis conferred dominant negative-type inhibition on T cell development. Collectively, our current results indicate that PRS, NLS, CABIT1, and CABIT2 are all required for positive selection, and that each of the CABIT domains exerts distinct functions during positive selection. PMID:24586531

  11. Role of CrkII Signaling in RANKL-Induced Osteoclast Differentiation and Function.

    PubMed

    Kim, Jung Ha; Kim, Kabsun; Kim, Inyoung; Seong, Semun; Nam, Kwang-Il; Lee, Seoung Hoon; Kim, Kyung Keun; Kim, Nacksung

    2016-02-01

    Rac1, a member of small GTPases, is a key regulator of osteoclast differentiation and function. The Crk family adaptor proteins, consisting of Src homology (SH) 2 and SH3 protein-binding domains, regulate cell proliferation, migration, and invasion through Rac1 activation. In this study, we examined the role of CrkII in osteoclast differentiation and function. Retroviral overexpression of CrkII in osteoclast precursors enhanced osteoclast differentiation and resorptive function through Rac1 activation. The knockdown of CrkII in osteoclast precursors using small interfering RNA inhibited osteoclast differentiation and its resorption activity. Unlike wild-type CrkII, overexpression of the three SH domains in mutant forms of CrkII did not enhance either osteoclast differentiation or function. Phosphorylation of p130 Crk-associated substrate (p130Cas) by osteoclastogenic cytokines in preosteoclasts increased the interaction between p130Cas and CrkII, which is known to be involved in Rac1 activation. Furthermore, transgenic mice overexpressing CrkII under control of a tartrate-resistant acid phosphatase promoter exhibited a low bone mass phenotype, associated with increased resorptive function of osteoclasts in vivo. Taken together, our data suggest that the p130Cas/CrkII/Rac1 signaling pathway plays an important role in osteoclast differentiation and function, both in vitro and in vivo.

  12. Decellularized Tracheal Extracellular Matrix Supports Epithelial Migration, Differentiation, and Function

    PubMed Central

    Kutten, Johannes C.; McGovern, David; Hobson, Christopher M.; Luffy, Sarah A.; Nieponice, Alejandro; Tobita, Kimimasa; Francis, Richard J.; Reynolds, Susan D.

    2015-01-01

    Tracheal loss is a source of significant morbidity for affected patients with no acceptable solution. Interest in engineering tracheal transplants has created a demand for small animal models of orthotopic tracheal transplantation. Here, we examine the use of a decellularized graft in a murine model of tracheal replacement. Fresh or decellularized tracheas harvested from age-matched female donor C57BL/6 mice were transplanted into syngeneic recipients. Tracheas were decellularized using repeated washes of water, 3% Triton X-100, and 3 M NaCl under cyclic pressure changes, followed by disinfection with 0.1% peracetic acid/4% ethanol, and terminal sterilization by gamma irradiation. Tracheas were explanted for immunolabeling at 1, 4, and 8 weeks following surgery. Video microscopy and computed tomography were performed to assess function and structure. Decellularized grafts supported complete reepithelialization by 8 weeks and motile cilia were observed. Cartilaginous portions of the trachea were maintained in mice receiving fresh transplants, but repopulation of the cartilage was not seen in mice receiving decellularized transplants. We observed superior postsurgical survival, weight gain, and ciliary function in mice receiving fresh transplants compared with those receiving decellularized transplants. The murine orthotopic tracheal transplant provides an appropriate model to assess the repopulation and functional regeneration of decellularized tracheal grafts. PMID:24980864

  13. Decellularized tracheal extracellular matrix supports epithelial migration, differentiation, and function.

    PubMed

    Kutten, Johannes C; McGovern, David; Hobson, Christopher M; Luffy, Sarah A; Nieponice, Alejandro; Tobita, Kimimasa; Francis, Richard J; Reynolds, Susan D; Isenberg, Jeffrey S; Gilbert, Thomas W

    2015-01-01

    Tracheal loss is a source of significant morbidity for affected patients with no acceptable solution. Interest in engineering tracheal transplants has created a demand for small animal models of orthotopic tracheal transplantation. Here, we examine the use of a decellularized graft in a murine model of tracheal replacement. Fresh or decellularized tracheas harvested from age-matched female donor C57BL/6 mice were transplanted into syngeneic recipients. Tracheas were decellularized using repeated washes of water, 3% Triton X-100, and 3 M NaCl under cyclic pressure changes, followed by disinfection with 0.1% peracetic acid/4% ethanol, and terminal sterilization by gamma irradiation. Tracheas were explanted for immunolabeling at 1, 4, and 8 weeks following surgery. Video microscopy and computed tomography were performed to assess function and structure. Decellularized grafts supported complete reepithelialization by 8 weeks and motile cilia were observed. Cartilaginous portions of the trachea were maintained in mice receiving fresh transplants, but repopulation of the cartilage was not seen in mice receiving decellularized transplants. We observed superior postsurgical survival, weight gain, and ciliary function in mice receiving fresh transplants compared with those receiving decellularized transplants. The murine orthotopic tracheal transplant provides an appropriate model to assess the repopulation and functional regeneration of decellularized tracheal grafts. PMID:24980864

  14. Differential geometry of the Fermat quartic and theta functions

    NASA Astrophysics Data System (ADS)

    Hadnot, Jason

    2012-02-01

    The universal curve over a finite cover of the moduli space of elliptic curves with level four structure is embedded in C as the Fermat quartic and is parametrized via the four Jacobi theta functions. Constructions from completely integrable systems have shown the importance of looking at the curvature of certain spaces and here we compute sectional curvatures. For our computations, we choose the ambient Fubini-Study metric of C. We also derive several theta identities which arise from the quartic's holomorphic two-form.

  15. [Function and expression of transcription factors implicated in gonadal differentiation].

    PubMed

    Morohashi, K

    1998-07-01

    Several transcription factors such as SRY, DAX-1, Ad4BP/SF-1, WT-1 and SOX -9, have been revealed to be implicated in gonadal development by analyzing the genetic disorders of human and the gene disrupted mice. All of these transcription factors are expressed in the early stage of the gonadal development and the expression profiles during the gonadal development are clearly different between the two sexes. Functions of the transcription factors are discussed by referring genes under the control of these factors. Effects of endocrine disruptants on the expression of Ad4BP/SF-1 in the fetal gonads was also discussed. PMID:9702047

  16. Vibration of plates using plate characteristic functions obtained by reduction of partial differential equation

    NASA Astrophysics Data System (ADS)

    Bhat, R. B.; Mundkur, G.

    1993-02-01

    Vibration of rectangular plates is studied using a set of plate characteristic functions generated by reduction of the plate partial differential equation, and exactly solving the resulting ordinary differential equation. The plate characteristic functions are used as deflection shape functions in the Rayleigh-Ritz method to obtain the natural frequencies. Because the solution is exact in one direction, the results fall in between the exact values and those obtained with the straight forward Rayleigh-Ritz method, where the complete deflection shape is assumed initially. Results are provided for rectangular plates with combinations of clamped, simply supported and free edge conditions.

  17. Detection of Gender-Based Differential Item Functioning in a Mathematics Performance Assessment.

    ERIC Educational Resources Information Center

    Wang, Ning; Lane, Suzanne

    This study used three different differential item functioning (DIF) procedures to examine the extent to which items in a mathematics performance assessment functioned differently for matched gender groups. In addition to examining the appropriateness of individual items in terms of DIF with respect to gender, an attempt was made to identify…

  18. Analysis of Sources of Latent Class Differential Item Functioning in International Assessments

    ERIC Educational Resources Information Center

    Oliveri, Maria Elena; Ercikan, Kadriye; Zumbo, Bruno

    2013-01-01

    In this study, we investigated differential item functioning (DIF) and its sources using a latent class (LC) modeling approach. Potential sources of LC DIF related to instruction and teacher-related variables were investigated using substantive and three statistical approaches: descriptive discriminant function, multinomial logistic regression,…

  19. Building Mathematical Maturity in Calculus: Teaching Implicit Differentiation through a Review of Functions

    ERIC Educational Resources Information Center

    Hare, Angela; Phillippy, Doug

    2004-01-01

    A program on calculus is conducted, which helps students learn about inherent differentiation through a study of mathematical functions, while simultaneously reinforcing their understanding of functional concepts. This process develops their mathematical experience in the field of calculus and in other advanced quantitative programs.

  20. Children with High-Functioning Autism and Asperger's Syndrome: Can We Differentiate Their Cognitive Profiles?

    ERIC Educational Resources Information Center

    Planche, Pascale; Lemonnier, Eric

    2012-01-01

    The aim of this study was to investigate whether children with high-functioning autism (HFA) and Asperger's syndrome (AS) can be differentiated from each other and from typically developing children on their cognitive profiles. The present study included a total of 45 participants: children with autism (high-functioning autism or Asperger's…

  1. Parental Divorce and Family Functioning: Effects on Differentiation Levels of Young Adults.

    ERIC Educational Resources Information Center

    Johnson, Patrick; Throngren, Jill M.; Smith, Adina J.

    2001-01-01

    Study examines the effect of parental divorce and various dimensions of functioning in the family of origin on young adult development. Results indicate that parental divorce and family functioning significantly affect differentiation levels of young adults. Implications of the results for counselors and future researchers are provided. (Contains…

  2. Differential Item Functioning Analysis of the Mental, Emotional, and Bodily Toughness Inventory

    ERIC Educational Resources Information Center

    Gao, Yong; Mack, Mick G.; Ragan, Moira A.; Ragan, Brian

    2012-01-01

    In this study the authors used differential item functioning analysis to examine if there were items in the Mental, Emotional, and Bodily Toughness Inventory functioning differently across gender and athletic membership. A total of 444 male (56.3%) and female (43.7%) participants (30.9% athletes and 69.1% non-athletes) responded to the Mental,…

  3. 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…

  4. Starches of varied digestibilities differentially modify intestinal function in rats.

    PubMed

    Lajvardi, A; Mazarin, G I; Gillespie, M B; Satchithanandam, S; Calvert, R J

    1993-12-01

    Starches of different digestibilities may enter the colon to different extents and alter colonic function. Male Fischer 344 rats were fed diets containing 25% cooked potato starch, arrowroot starch, high amylose cornstarch or raw potato starch for 6 wk. Fecal weight, transit time, colonic thymidine kinase activity (a marker for cell proliferation), and weight, starch content and pH of the cecum and proximal and distal colon were measured. Raw potato starch was much less completely digested than high amylose cornstarch, resulting in a 32-fold greater amount of undigested starch entering the cecum in the raw potato starch group. Both the high amylose cornstarch and raw potato starch diets significantly enhanced fecal weight and produced large intestinal hypertrophy, effects that were greatest in the raw potato starch group. Raw potato starch feeding was associated with the highest level of thymidine kinase activity, although the differences in thymidine kinase activity among the four groups were not significant. This diet also produced a 50% longer transit time. Entry of a large amount of raw potato starch into the colon resulted in greater luminal acidity, greater luminal bulk and slower transit. A much smaller amount of starch entered the colon in the high amylose cornstarch group and resulted in fecal bulking but no alteration in transit. PMID:8263598

  5. Differential regional effects of octreotide on human gastrointestinal motor function.

    PubMed Central

    von der Ohe, M R; Camilleri, M; Thomforde, G M; Klee, G G

    1995-01-01

    The effects of octreotide on regional motor function in the human gut are unclear. In a randomised, blinded study the effects of octreotide (50 micrograms, subcutaneously, three times daily) and placebo on gastric, small bowel, and colonic transit, and colonic motility and tone were assessed in 12 healthy volunteers whose colon had been cleansed. Octreotide accelerated initial gastric emptying (p = 0.05), inhibited small bowel transit (p < 0.01), and reduced ileocolonic bolus transfers (p < 0.05). Colonic transit was unaltered by octreotide; the postprandial colonic tonic response was inhibited (p < 0.05 v placebo), whereas colonic phasic pressure activity was increased by octreotide (p < 0.05 v placebo). These data support the use of octreotide in diarrhoeal states but not in diseases that cause small bowel stasis and bacterial overgrowth. Simultaneous measurements of colonic transit, tone, and phasic contractility are valid in studying the effects of pharmacological changes and may be applicable to the study of the human colon in health and disease. PMID:7797125

  6. Starches of varied digestibilities differentially modify intestinal function in rats.

    PubMed

    Lajvardi, A; Mazarin, G I; Gillespie, M B; Satchithanandam, S; Calvert, R J

    1993-12-01

    Starches of different digestibilities may enter the colon to different extents and alter colonic function. Male Fischer 344 rats were fed diets containing 25% cooked potato starch, arrowroot starch, high amylose cornstarch or raw potato starch for 6 wk. Fecal weight, transit time, colonic thymidine kinase activity (a marker for cell proliferation), and weight, starch content and pH of the cecum and proximal and distal colon were measured. Raw potato starch was much less completely digested than high amylose cornstarch, resulting in a 32-fold greater amount of undigested starch entering the cecum in the raw potato starch group. Both the high amylose cornstarch and raw potato starch diets significantly enhanced fecal weight and produced large intestinal hypertrophy, effects that were greatest in the raw potato starch group. Raw potato starch feeding was associated with the highest level of thymidine kinase activity, although the differences in thymidine kinase activity among the four groups were not significant. This diet also produced a 50% longer transit time. Entry of a large amount of raw potato starch into the colon resulted in greater luminal acidity, greater luminal bulk and slower transit. A much smaller amount of starch entered the colon in the high amylose cornstarch group and resulted in fecal bulking but no alteration in transit.

  7. Differential Light Chain Assembly Influences Outer Arm Dynein Motor Function

    PubMed Central

    DiBella, Linda M.; Gorbatyuk, Oksana; Sakato, Miho; Wakabayashi, Ken-ichi; Patel-King, Ramila S.; Pazour, Gregory J.; Witman, George B.; King, Stephen M.

    2005-01-01

    Tctex1 and Tctex2 were originally described as potential distorters/sterility factors in the non-Mendelian transmission of t-haplotypes in mice. These proteins have since been identified as subunits of cytoplasmic and/or axonemal dyneins. Within the Chlamydomonas flagellum, Tctex1 is a subunit of inner arm I1. We have now identified a second Tctex1-related protein (here termed LC9) in Chlamydomonas. LC9 copurifies with outer arm dynein in sucrose density gradients and is missing only in those strains completely lacking this motor. Zero-length cross-linking of purified outer arm dynein indicates that LC9 interacts directly with both the IC1 and IC2 intermediate chains. Immunoblot analysis revealed that LC2, LC6, and LC9 are missing in an IC2 mutant strain (oda6-r88) that can assemble outer arms but exhibits significantly reduced flagellar beat frequency. This defect is unlikely to be due to lack of LC6, because an LC6 null mutant (oda13) exhibits only a minor swimming abnormality. Using an LC2 null mutant (oda12-1), we find that although some outer arm dynein components assemble in the absence of LC2, they are nonfunctional. In contrast, dyneins from oda6-r88, which also lack LC2, retain some activity. Furthermore, we observed a synthetic assembly defect in an oda6-r88 oda12-1 double mutant. These data suggest that LC2, LC6, and LC9 have different roles in outer arm assembly and are required for wild-type motor function in the Chlamydomonas flagellum. PMID:16195342

  8. Polarization of an electroactive functional film on titanium for inducing osteogenic differentiation

    PubMed Central

    Zhou, Zhengnan; Li, Weiping; He, Tianrui; Qian, Lei; Tan, Guoxin; Ning, Chengyun

    2016-01-01

    To enhance the surface bioactivity of titanium (Ti) prostheses, an electroactive polyvinylidene fluoride (PVDF) film was prepared on a Ti substrate to provide a mimetic of the electrical microenvironment, which facilitated the performance of cell functions. The results of cell proliferation and differentiation assays indicated that polarization of the PVDF-Ti (PTi) altered its surface charge, thus inducing adhesion, proliferation and osteogenic differentiation of cells. The polarized PVDF-Ti (PPTi) may therefore find applications in bone regeneration. PMID:27762318

  9. Fisher information of special functions and second-order differential equations

    NASA Astrophysics Data System (ADS)

    Yáñez, R. J.; Sánchez-Moreno, P.; Zarzo, A.; Dehesa, J. S.

    2008-08-01

    We investigate a basic question of analytic information theory, namely, the evaluation of the Fisher information and the relative Fisher information with respect to a non-negative function, for the probability distributions obtained by squaring the special functions of mathematical physics which are solutions of second-order differential equations. We obtain explicit expressions for these information-theoretic properties via the expectation values of the coefficients of the differential equation. We illustrate our approach for various nonrelativistic D-dimensional wavefunctions and some special functions of physicomathematical interest. Emphasis is made in the Nikiforov-Uvarov hypergeometric-type functions, which include and generalize the Hermite functions and the Gauss and Kummer hypergeometric functions, among others.

  10. Glycogen synthase kinase 3β inhibition promotes human iTreg differentiation and suppressive function.

    PubMed

    Xia, Yongxiang; Zhuo, Han; Lu, Yunjie; Deng, Lei; Jiang, Runqiu; Zhang, Long; Zhu, Qin; Pu, Liyong; Wang, Xuehao; Lu, Ling

    2015-05-01

    Induced regulatory T cells (iTregs) are essential to maintain immunological tolerance, immune homeostasis and prevention of autoimmunity. Some studies suggest that glycogen synthase kinase 3β (GSK3β) is involved in the mouse iTreg differentiation; however, whether GSK3β inhibits or enhances iTreg differentiation is still a matter of controversy. To address this issue, we have utilized human naïve CD4(+) T cells and investigated whether GSK3 activity changes during iTreg differentiation and whether altering GSK3 activity influences the development of iTregs and its suppressive function. As a constitutively activated kinase, during iTreg differentiation GSK3β became quickly deactivated (phosphorylated at serine 9), which is dependent on MAPK pathway rather than PI3-kinase/Akt pathway. Our results indicated that inhibition of GSK3β by specific inhibitors, SB216763 or TDZD-8, promoted the differentiation of iTreg and increased their suppressive activity. In contrast, overexpression of GSK3β significantly inhibited iTreg differentiation. Furthermore, GSK3β inhibition enhanced iTreg differentiation through the TGF-β/Smad3 pathway. Taken together, this study demonstrates that inhibition of GSK3β enhances human iTreg differentiation and its suppressive activity, and provides a rationale to target GSK3β as a novel immunotherapeutic strategy.

  11. A novel crosstalk between Alk7 and cGMP signaling differentially regulates brown adipocyte function

    PubMed Central

    Balkow, Aileen; Jagow, Johanna; Haas, Bodo; Siegel, Franziska; Kilić, Ana; Pfeifer, Alexander

    2015-01-01

    Objective Obesity is an enormous burden for patients and health systems world-wide. Brown adipose tissue dissipates energy in response to cold and has been shown to be metabolically active in human adults. The type I transforming growth factor β (TGFβ) receptor Activin receptor-like kinase 7 (Alk7) is highly expressed in adipose tissues and is down-regulated in obese patients. Here, we studied the function of Alk7 in brown adipocytes. Methods Using pharmacological and genetic tools, Alk7 signaling pathway and its effects were studied in murine brown adipocytes. Brown adipocyte differentiation and activation was analyzed. Results Alk7 is highly upregulated during differentiation of brown adipocytes. Interestingly, Alk7 expression is increased by cGMP/protein kinase G (PKG) signaling, which enhances brown adipocyte differentiation. Activin AB effectively activates Alk7 and SMAD3 signaling. Activation of Alk7 in brown preadipocytes suppresses the master adipogenic transcription factor PPARγ and differentiation. Stimulation of Alk7 during late differentiation of brown adipocytes reduces lipid content and adipogenic marker expression but enhances UCP1 expression. Conclusions We found a so far unknown crosstalk between cGMP and Alk7 signaling pathways. Tight regulation of Alk7 is required for efficient differentiation of brown adipocytes. Alk7 has differential effects on adipogenic differentiation and the development of the thermogenic program in brown adipocytes. PMID:26266090

  12. Rectifying and negative differential resistance behaviors of a functionalized Tour wire: The position effects of functional groups

    NASA Astrophysics Data System (ADS)

    Kwong, Gordon; Zhang, Zhenhua; Pan, Jinbo

    2011-09-01

    Based on Tour wire, we construct four D-π-A molecular devices with different positional functional groups, in an attempt to explore the position effects of functional groups on their electronic transport properties and to show that some interesting physical phenomena can emerge by only varying the position of functional groups. The first-principles calculations demonstrate that the position of functional groups can affect the rectifying behaviors (rectification direction and ratio) significantly and determines whether or not the negative differential resistance (NDR) can be observed as well as the physical origin of the NDR phenomenon.

  13. DiffNet: automatic differential functional summarization of dE-MAP networks.

    PubMed

    Seah, Boon-Siew; Bhowmick, Sourav S; Dewey, C Forbes

    2014-10-01

    The study of genetic interaction networks that respond to changing conditions is an emerging research problem. Recently, Bandyopadhyay et al. (2010) proposed a technique to construct a differential network (dE-MAPnetwork) from two static gene interaction networks in order to map the interaction differences between them under environment or condition change (e.g., DNA-damaging agent). This differential network is then manually analyzed to conclude that DNA repair is differentially effected by the condition change. Unfortunately, manual construction of differential functional summary from a dE-MAP network that summarizes all pertinent functional responses is time-consuming, laborious and error-prone, impeding large-scale analysis on it. To this end, we propose DiffNet, a novel data-driven algorithm that leverages Gene Ontology (go) annotations to automatically summarize a dE-MAP network to obtain a high-level map of functional responses due to condition change. We tested DiffNet on the dynamic interaction networks following MMS treatment and demonstrated the superiority of our approach in generating differential functional summaries compared to state-of-the-art graph clustering methods. We studied the effects of parameters in DiffNet in controlling the quality of the summary. We also performed a case study that illustrates its utility.

  14. Normal Form of Saddle-Node-Hopf Bifurcation in Retarded Functional Differential Equations and Applications

    NASA Astrophysics Data System (ADS)

    Jiang, Heping; Jiang, Jiao; Song, Yongli

    In this paper, we firstly employ the normal form theory of delayed differential equations according to Faria and Magalhães to derive the normal form of saddle-node-Hopf bifurcation for the general retarded functional differential equations. Then, the dynamical behaviors of a Leslie-Gower predator-prey model with time delay and nonmonotonic functional response are considered. Specially, the dynamical classification near the saddle-node-Hopf bifurcation point is investigated by using the normal form and the center manifold approaches. Finally, the numerical simulations are employed to support the theoretical results.

  15. Human embryonic stem cells differentiate into functional renal proximal tubular-like cells.

    PubMed

    Narayanan, Karthikeyan; Schumacher, Karl M; Tasnim, Farah; Kandasamy, Karthikeyan; Schumacher, Annegret; Ni, Ming; Gao, Shujun; Gopalan, Began; Zink, Daniele; Ying, Jackie Y

    2013-04-01

    Renal cells are used in basic research, disease models, tissue engineering, drug screening, and in vitro toxicology. In order to provide a reliable source of human renal cells, we developed a protocol for the differentiation of human embryonic stem cells into renal epithelial cells. The differentiated stem cells expressed markers characteristic of renal proximal tubular cells and their precursors, whereas markers of other renal cell types were not expressed or expressed at low levels. Marker expression patterns of these differentiated stem cells and in vitro cultivated primary human renal proximal tubular cells were comparable. The differentiated stem cells showed morphological and functional characteristics of renal proximal tubular cells, and generated tubular structures in vitro and in vivo. In addition, the differentiated stem cells contributed in organ cultures for the formation of simple epithelia in the kidney cortex. Bioreactor experiments showed that these cells retained their functional characteristics under conditions as applied in bioartificial kidneys. Thus, our results show that human embryonic stem cells can differentiate into renal proximal tubular-like cells. Our approach would provide a source for human renal proximal tubular cells that are not affected by problems associated with immortalized cell lines or primary cells.

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

    PubMed

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

    2009-03-01

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

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

    PubMed Central

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

    2009-01-01

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

  18. /sup 99m/Tc-glucoheptonate for quantitation of differential renal function

    SciTech Connect

    Ziessman, H.A.; Balseiro, J.; Fahey, F.H.; Le, T.V.; Dubiansky, V.

    1987-05-01

    Differential renal function was calculated by using /sup 99m/Tc-glucoheptonate (Tc-GH) in 51 patients. Computer-acquired background-corrected individual renal function was calculated by using both the 1-3-min uptake counts and the 2-4-hr delayed static counts. The degree of correlation between the two was high (r = .96). An equally high correlation was noted in 16 children who were 12 years old or younger, in 15 patients with renal size disparity greater than 60/40%, and in six patients with abnormal creatinine clearances. Ten patients had a 30-min dynamic /sup 99m/Tc-DTPA study followed immediately by the injection of Tc-GH and acquisition of delayed static images 2-4 hr later. A high degree of correlation (r = .99) was seen between the 1-3-min differential function obtained by using Tc-DTPA and the 2-4-hr delayed differential function obtained by using Tc-GH. This study shows that Tc-GH is a clinically useful and valid tool for calculation of differential renal function and that Tc-GH combines many of the best aspects of Tc-DTPA and Tc-DMSA.

  19. Water extract of Acer tegmentosum reduces bone destruction by inhibiting osteoclast differentiation and function.

    PubMed

    Ha, Hyunil; Shim, Ki-Shuk; Kim, Taesoo; An, Hyosun; Lee, Chung-Jo; Lee, Kwang Jin; Ma, Jin Yeul

    2014-04-01

    The stem of Acer tegmentosum has been widely used in Korea for the treatment of hepatic disorders. In this study, we investigated the bone protective effect of water extract of the stem of Acer tegmentosum (WEAT). We found that WEAT inhibits osteoclast differentiation induced by receptor activator of nuclear factor-κB ligand (RANKL), an essential cytokine for osteoclast differentiation. In osteoclast precursor cells, WEAT inhibited RANKL-induced activation of JNK, NF-κB, and cAMP response element-binding protein, leading to suppression of the induction of c-Fos and nuclear factor of activated T cells cytoplasmic 1, key transcription factors for osteoclast differentiation. In addition, WEAT inhibited bone resorbing activity of mature osteoclasts. Furthermore, the oral administration of WEAT reduced RANKL-induced bone resorption and trabecular bone loss in mice. Taken together, our study demonstrates that WEAT possesses a protective effect on bone destruction by inhibiting osteoclast differentiation and function.

  20. Differential Editosome Protein Function between Life Cycle Stages of Trypanosoma brucei *

    PubMed Central

    McDermott, Suzanne M.; Guo, Xuemin; Carnes, Jason; Stuart, Kenneth

    2015-01-01

    Uridine insertion and deletion RNA editing generates functional mitochondrial mRNAs in Trypanosoma brucei. The mRNAs are differentially edited in bloodstream form (BF) and procyclic form (PF) life cycle stages, and this correlates with the differential utilization of glycolysis and oxidative phosphorylation between the stages. The mechanism that controls this differential editing is unknown. Editing is catalyzed by multiprotein ∼20S editosomes that contain endonuclease, 3′-terminal uridylyltransferase, exonuclease, and ligase activities. These editosomes also contain KREPB5 and KREPA3 proteins, which have no functional catalytic motifs, but they are essential for parasite viability, editing, and editosome integrity in BF cells. We show here that repression of KREPB5 or KREPA3 is also lethal in PF, but the effects on editosome structure differ from those in BF. In addition, we found that point mutations in KREPB5 or KREPA3 differentially affect cell growth, editosome integrity, and RNA editing between BF and PF stages. These results indicate that the functions of KREPB5 and KREPA3 editosome proteins are adjusted between the life cycle stages. This implies that these proteins are involved in the processes that control differential editing and that the 20S editosomes differ between the life cycle stages. PMID:26304125

  1. Osteogenic Differentiation of MSC through Calcium Signaling Activation: Transcriptomics and Functional Analysis

    PubMed Central

    Viti, Federica; Landini, Martina; Mezzelani, Alessandra; Petecchia, Loredana; Milanesi, Luciano; Scaglione, Silvia

    2016-01-01

    The culture of progenitor mesenchymal stem cells (MSC) onto osteoconductive materials to induce a proper osteogenic differentiation and mineralized matrix regeneration represents a promising and widely diffused experimental approach for tissue-engineering (TE) applications in orthopaedics. Among modern biomaterials, calcium phosphates represent the best bone substitutes, due to their chemical features emulating the mineral phase of bone tissue. Although many studies on stem cells differentiation mechanisms have been performed involving calcium-based scaffolds, results often focus on highlighting production of in vitro bone matrix markers and in vivo tissue ingrowth, while information related to the biomolecular mechanisms involved in the early cellular calcium-mediated differentiation is not well elucidated yet. Genetic programs for osteogenesis have been just partially deciphered, and the description of the different molecules and pathways operative in these differentiations is far from complete, as well as the activity of calcium in this process. The present work aims to shed light on the involvement of extracellular calcium in MSC differentiation: a better understanding of the early stage osteogenic differentiation program of MSC seeded on calcium-based biomaterials is required in order to develop optimal strategies to promote osteogenesis through the use of new generation osteoconductive scaffolds. A wide spectrum of analysis has been performed on time-dependent series: gene expression profiles are obtained from samples (MSC seeded on calcium-based scaffolds), together with related microRNAs expression and in vivo functional validation. On this basis, and relying on literature knowledge, hypotheses are made on the biomolecular players activated by the biomaterial calcium-phosphate component. Interestingly, a key role of miR-138 was highlighted, whose inhibition markedly increases osteogenic differentiation in vitro and enhance ectopic bone formation in vivo

  2. Low-shear modelled microgravity environment maintains morphology and differentiated functionality of primary porcine hepatocyte cultures.

    PubMed

    Nelson, Leonard J; Walker, Simon W; Hayes, Peter C; Plevris, John N

    2010-01-01

    Hepatocytes cultured in conventional static culture rapidly lose polarity and differentiated function. This could be explained by gravity-induced sedimentation, which prevents formation of complete three-dimensional (3D) cell-cell/cell-matrix interactions and disrupts integrin-mediated signals (including the most abundant hepatic integrin alpha(5)beta(1)), important for cellular polarity and differentiation. Cell culture in a low fluid shear modelled microgravity (about 10(-2) g) environment promotes spatial colocation/self-aggregation of dissociated cells and induction of 3D differentiated liver morphology. Previously, we demonstrated the utility of a NASA rotary bioreactor in maintaining key metabolic functions and 3D aggregate formation of high-density primary porcine hepatocyte cultures over 21 days. Using serum-free chemically defined medium, without confounding interactions of exogenous bioscaffolding or bioenhancing surface materials, we investigated features of hepatic cellular polarity and differentiated functionality, including expression of hepatic integrin alpha(5), as markers of functional morphology. We report here that in the absence of exogenous biomatrix scaffolding, hepatocytes cultured in serum-free chemically defined medium in a microgravity environment rapidly (<24 h) form macroscopic (2-5 mm), compacted 3D hepatospheroid structures consisting of a shell of glycogen-positive viable cells circumscribing a core of eosinophilic cells. The spheroid shell layers exhibited ultrastructural, morphological and functional features of differentiated, polarized hepatic tissue including strong expression of the integrin alpha(5) subunit, functional bile canaliculi, albumin synthesis, and fine ultrastructure reminiscent of in vivo hepatic tissue. The low fluid shear microgravity environment may promote tissue-like self-organization of dissociated cells, and offer advantages over spheroids cultured in conventional formats to delineate optimal conditions for

  3. Global series solutions of nonlinear differential equations with shocks using Walsh functions

    NASA Astrophysics Data System (ADS)

    Gnoffo, Peter A.

    2014-02-01

    An orthonormal basis set composed of Walsh functions is used for deriving global solutions (valid over the entire domain) to nonlinear differential equations that include discontinuities. Function gn(x) of the set, a scaled Walsh function in sequency order, is comprised of n piecewise constant values (square waves) across the domain xa⩽x⩽xb. Only two square wave lengths are allowed in any function and a new derivation of the basis functions applies a fractal-like algorithm (infinitely self-similar) focused on the distribution of wave lengths. This distribution is determined by a recursive folding algorithm that propagates fundamental symmetries to successive values of n. Functions, including those with discontinuities, may be represented on the domain as a series in gn(x) with no occurrence of a Gibbs phenomenon (ringing) across the discontinuity. A much more powerful, self-mapping characteristic of the series is closure under multiplication - the product of any two Walsh functions is also a Walsh function. This self-mapping characteristic transforms the solution of nonlinear differential equations to the solution of systems of polynomial equations if the original nonlinearities can be represented as products of the dependent variables and the convergence of the series for n→∞ can be demonstrated. Fundamental operations (reciprocal, integral, derivative) on Walsh function series representations of functions with discontinuities are defined. Examples are presented for solution of the time dependent Burger's equation and for quasi-one-dimensional nozzle flow including a shock.

  4. Detecting Differential Item Functioning of Polytomous Items for an Ideal Point Response Process

    ERIC Educational Resources Information Center

    Wang, Wei; Tay, Louis; Drasgow, Fritz

    2013-01-01

    There has been growing use of ideal point models to develop scales measuring important psychological constructs. For meaningful comparisons across groups, it is important to identify items on such scales that exhibit differential item functioning (DIF). In this study, the authors examined several methods for assessing DIF on polytomous items…

  5. Identifying Differential Item Functioning in Multi-Stage Computer Adaptive Testing

    ERIC Educational Resources Information Center

    Gierl, Mark J.; Lai, Hollis; Li, Johnson

    2013-01-01

    The purpose of this study is to evaluate the performance of CATSIB (Computer Adaptive Testing-Simultaneous Item Bias Test) for detecting differential item functioning (DIF) when items in the matching and studied subtest are administered adaptively in the context of a realistic multi-stage adaptive test (MST). MST was simulated using a 4-item…

  6. Assessment of Differential Item Functioning in Testlet-Based Items Using the Rasch Testlet Model

    ERIC Educational Resources Information Center

    Wang, Wen-Chung; Wilson, Mark

    2005-01-01

    This study presents a procedure for detecting differential item functioning (DIF) for dichotomous and polytomous items in testlet-based tests, whereby DIF is taken into account by adding DIF parameters into the Rasch testlet model. Simulations were conducted to assess recovery of the DIF and other parameters. Two independent variables, test type…

  7. Detecting Differential Rater Functioning over Time (DRIFT) Using a Rasch Multi-faceted Rating Scale Model.

    ERIC Educational Resources Information Center

    Wolfe, Edward W.; Moulder, Bradley C.; Myford, Carol M.

    2001-01-01

    Describes a class of rater effects, differential rater functioning over time (DRIFT), that depicts rater-by-time interactions. Also describes Rasch measurement procedures designed to identify these types of DRIFT in rating data. Applied these procedures to simulated data to show their usefulness in classifying raters as aberrant or non-aberrant…

  8. Gender-Related Differential Item Functioning on a Middle-School Mathematics Performance Assessment.

    ERIC Educational Resources Information Center

    Lane, Suzanne; And Others

    This study examined gender-related differential item functioning (DIF) using a mathematics performance assessment, the QUASAR Cognitive Assessment Instrument (QCAI), administered to middle school students. The QCAI was developed for the Quantitative Understanding: Amplifying Student Achievement and Reading (QUASAR) project, which focuses on…

  9. Parent Ratings of ADHD Symptoms: Generalized Partial Credit Model Analysis of Differential Item Functioning across Gender

    ERIC Educational Resources Information Center

    Gomez, Rapson

    2012-01-01

    Objective: Generalized partial credit model, which is based on item response theory (IRT), was used to test differential item functioning (DIF) for the "Diagnostic and Statistical Manual of Mental Disorders" (4th ed.), inattention (IA), and hyperactivity/impulsivity (HI) symptoms across boys and girls. Method: To accomplish this, parents completed…

  10. Detecting Differential Item Functioning of a Course Satisfaction Instrument in the Presence of Multilevel Data

    ERIC Educational Resources Information Center

    Finch, Holmes; French, Brian

    2010-01-01

    The purposes of this study were to test for uniform differential item functioning (DIF) between male and female students on end-of-semester class evaluations in an introductory university science course and to demonstrate DIF detection methods that take into account the complex sampling mechanism that often underlies data used in such assessments.…

  11. Differential Item Functioning By Sex and Race in The Hogan Personality Inventory

    ERIC Educational Resources Information Center

    Sheppard, Richard; Han, Kyunghee; Colarelli, Stephen M.; Dai, Guangdong; King, Daniel W.

    2006-01-01

    The authors examined measurement bias in the Hogan Personality Inventory by investigating differential item functioning (DIF) across sex and two racial groups (Caucasian and Black). The sample consisted of 1,579 Caucasians (1,023 men, 556 women) and 523 Blacks (321 men, 202 women) who were applying for entry-level, unskilled jobs in factories.…

  12. Numerical approximation of a nonlinear delay-advance functional differential equation by a finite element method

    NASA Astrophysics Data System (ADS)

    Teodoro, M. F.

    2012-09-01

    We are particularly interested in the numerical solution of the functional differential equations with symmetric delay and advance. In this work, we consider a nonlinear forward-backward equation, the Fitz Hugh-Nagumo equation. It is presented a scheme which extends the algorithm introduced in [1]. A computational method using Newton's method, finite element method and method of steps is developped.

  13. Comparing Methods of Assessing Differential Item Functioning in a Computerized Adaptive Testing Environment

    ERIC Educational Resources Information Center

    Lei, Pui-Wa; Chen, Shu-Ying; Yu, Lan

    2006-01-01

    Mantel-Haenszel and SIBTEST, which have known difficulty in detecting non-unidirectional differential item functioning (DIF), have been adapted with some success for computerized adaptive testing (CAT). This study adapts logistic regression (LR) and the item-response-theory-likelihood-ratio test (IRT-LRT), capable of detecting both unidirectional…

  14. Assessment of Differential Item Functioning under Cognitive Diagnosis Models: The DINA Model Example

    ERIC Educational Resources Information Center

    Li, Xiaomin; Wang, Wen-Chung

    2015-01-01

    The assessment of differential item functioning (DIF) is routinely conducted to ensure test fairness and validity. Although many DIF assessment methods have been developed in the context of classical test theory and item response theory, they are not applicable for cognitive diagnosis models (CDMs), as the underlying latent attributes of CDMs are…

  15. Explaining Crossing DIF in Polytomous Items Using Differential Step Functioning Effects

    ERIC Educational Resources Information Center

    Penfield, Randall D.

    2010-01-01

    Crossing, or intersecting, differential item functioning (DIF) is a form of nonuniform DIF that exists when the sign of the between-group difference in expected item performance changes across the latent trait continuum. The presence of crossing DIF presents a problem for many statistics developed for evaluating DIF because positive and negative…

  16. The Usefulness of Differential Item Functioning Methodology in Longitudinal Intervention Studies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Perceived self-efficacy (SE) for engaging in physical activity (PA) is a key variable mediating PA change in interventions. The purpose of this study is to demonstrate the usefulness of item response modeling-based (IRM) differential item functioning (DIF) in the investigation of group differences ...

  17. Detecting Native Language Group Differences at the Subskills Level of Reading: A Differential Skill Functioning Approach

    ERIC Educational Resources Information Center

    Li, Hongli; Suen, Hoi K.

    2013-01-01

    Differential skill functioning (DSF) exists when examinees from different groups have different probabilities of successful performance in a certain subskill underlying the measured construct, given that they have the same ability on the overall construct. Using a DSF approach, this study examined the differences between two native language…

  18. Cauchy problem and Green's functions for first order differential operators and algebraic quantization

    SciTech Connect

    Muehlhoff, Rainer

    2011-02-15

    Existence and uniqueness of advanced and retarded fundamental solutions (Green's functions) and of global solutions to the Cauchy problem is proved for a general class of first order linear differential operators on vector bundles over globally hyperbolic Lorentzian manifolds. This is a core ingredient to CAR-/CCR-algebraic constructions of quantum field theories on curved spacetimes, particularly for higher spin field equations.

  19. Evaluation of Model Selection Strategies for Cross-Level Two-Way Differential Item Functioning Analysis

    ERIC Educational Resources Information Center

    Patarapichayatham, Chalie; Kamata, Akihito; Kanjanawasee, Sirichai

    2012-01-01

    Model specification issues on the cross-level two-way differential item functioning model were previously investigated by Patarapichayatham et al. (2009). Their study clarified that an incorrect model specification can easily lead to biased estimates of key parameters. The objective of this article is to provide further insights on the issue by…

  20. Group-Specific Effects of Matching Subtest Contamination on the Identification of Differential Item Functioning

    ERIC Educational Resources Information Center

    Keiffer, Elizabeth Ann

    2011-01-01

    A differential item functioning (DIF) simulation study was conducted to explore the type and level of impact that contamination had on type I error and power rates in DIF analyses when the suspect item favored the same or opposite group as the DIF items in the matching subtest. Type I error and power rates were displayed separately for the…

  1. A Comparison of Four Differential Item Functioning Procedures in the Presence of Multidimensionality

    ERIC Educational Resources Information Center

    Bastug, Özlem Yesim Özbek

    2016-01-01

    Differential item functioning (DIF), or item bias, is a relatively new concept. It has been one of the most controversial and the most studied subject in measurement theory. DIF occurs when people who have the same ability level but from different groups have a different probability of a correct response. According to Item Response Theory (IRT),…

  2. Detecting and Analyzing Differential Item Functioning in an Essay Test Using the Partial Credit Model.

    ERIC Educational Resources Information Center

    Ferrara, Steven; Walker-Bartnick, Leslie

    A procedure was developed to detect differential item functioning (DIF) in a standardized essay test using the Partial Credit Model, the general polychotomous form of the Rasch model. Using a panel of experts in the writing process, hypothesized explanations for DIF at some score points were developed. Data for the study included averaged…

  3. Analysis of Differential Item Functioning (DIF) Using Hierarchical Logistic Regression Models.

    ERIC Educational Resources Information Center

    Swanson, David B.; Clauser, Brian E.; Case, Susan M.; Nungester, Ronald J.; Featherman, Carol

    2002-01-01

    Outlines an approach to differential item functioning (DIF) analysis using hierarchical linear regression that makes it possible to combine results of logistic regression analyses across items to identify consistent sources of DIF, to quantify the proportion of explained variation in DIF coefficients, and to compare the predictive accuracy of…

  4. Parent Ratings of ADHD Symptoms: Differential Symptom Functioning across Malaysian Malay and Chinese Children

    ERIC Educational Resources Information Center

    Gomez, Rapson; Vance, Alasdair

    2008-01-01

    This study examined differential symptom functioning (DSF) in ADHD symptoms across Malay and Chinese children in Malaysia. Malay (N = 571) and Chinese (N = 254) parents completed the Disruptive Behavior Rating Scale, which lists the DSM-IV ADHD symptoms. DSF was examined using the multiple indicators multiple causes (MIMIC) structural equation…

  5. RIM: A Random Item Mixture Model to Detect Differential Item Functioning

    ERIC Educational Resources Information Center

    Frederickx, Sofie; Tuerlinckx, Francis; De Boeck, Paul; Magis, David

    2010-01-01

    In this paper we present a new methodology for detecting differential item functioning (DIF). We introduce a DIF model, called the random item mixture (RIM), that is based on a Rasch model with random item difficulties (besides the common random person abilities). In addition, a mixture model is assumed for the item difficulties such that the…

  6. Differential Item Functioning Analysis of Math Performance of Hispanic, Asian, and White NAEP Respondents.

    ERIC Educational Resources Information Center

    Rock, Donald; Chan, Kaling

    The differential item functioning of mathematics performance of Hispanic, Asian, and White students on the National Assessment of Educational Progress (NAEP) was studied, using a modification of the Mantel-Haenszel Procedure. The sample for grades 3, 7, and 11, respectively, included: (1) 1,367, 1,570, and 1,580 Whites; (2) 265, 613, and 760…

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

    ERIC Educational Resources Information Center

    Wu, Amery D.; Ercikan, Kadriye

    2006-01-01

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

  8. A Monte Carlo Study Investigating Missing Data, Differential Item Functioning, and Effect Size

    ERIC Educational Resources Information Center

    Garrett, Phyllis

    2009-01-01

    The use of polytomous items in assessments has increased over the years, and as a result, the validity of these assessments has been a concern. Differential item functioning (DIF) and missing data are two factors that may adversely affect assessment validity. Both factors have been studied separately, but DIF and missing data are likely to occur…

  9. Myogenic Differentiation of Mouse Embryonic Stem Cells That Lack a Functional Pax7 Gene

    PubMed Central

    Czerwinska, Areta M.; Grabowska, Iwona; Archacka, Karolina; Bem, Joanna; Swierczek, Barbara; Helinska, Anita; Streminska, Wladyslawa; Fogtman, Anna; Iwanicka-Nowicka, Roksana; Koblowska, Marta

    2016-01-01

    The transcription factor Pax7 plays a key role during embryonic myogenesis and sustains the proper function of satellite cells, which serve as adult skeletal muscle stem cells. Overexpression of Pax7 has been shown to promote the myogenic differentiation of pluripotent stem cells. However, the effects of the absence of functional Pax7 in differentiating embryonic stem cells (ESCs) have not yet been directly tested. Herein, we studied mouse stem cells that lacked a functional Pax7 gene and characterized the differentiation of these stem cells under conditions that promoted the derivation of myoblasts in vitro. We analyzed the expression of myogenic factors, such as myogenic regulatory factors and muscle-specific microRNAs, in wild-type and mutant cells. Finally, we compared the transcriptome of both types of cells and did not find substantial differences in the expression of genes related to the regulation of myogenesis. As a result, we showed that the absence of functional Pax7 does not prevent the in vitro myogenic differentiation of ESCs. PMID:26649785

  10. The MIMIC Method with Scale Purification for Detecting Differential Item Functioning

    ERIC Educational Resources Information Center

    Wang, Wen-Chung; Shih, Ching-Lin; Yang, Chih-Chien

    2009-01-01

    This study implements a scale purification procedure onto the standard MIMIC method for differential item functioning (DIF) detection and assesses its performance through a series of simulations. It is found that the MIMIC method with scale purification (denoted as M-SP) outperforms the standard MIMIC method (denoted as M-ST) in controlling…

  11. Examining Type I Error and Power for Detection of Differential Item and Testlet Functioning

    ERIC Educational Resources Information Center

    Lee, Young-Sun; Cohen, Allan; Toro, Maritsa

    2009-01-01

    In this study, the effectiveness of detection of differential item functioning (DIF) and testlet DIF using SIBTEST and Poly-SIBTEST were examined in tests composed of testlets. An example using data from a reading comprehension test showed that results from SIBTEST and Poly-SIBTEST were not completely consistent in the detection of DIF and testlet…

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

    ERIC Educational Resources Information Center

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

    2016-01-01

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

  13. An Examination of Differential Item Functioning on the Vanderbilt Assessment of Leadership in Education

    ERIC Educational Resources Information Center

    Polikoff, Morgan S.; May, Henry; Porter, Andrew C.; Elliott, Stephen N.; Goldring, Ellen; Murphy, Joseph

    2009-01-01

    The Vanderbilt Assessment of Leadership in Education is a 360-degree assessment of the effectiveness of principals' learning-centered leadership behaviors. In this report, we present results from a differential item functioning (DIF) study of the assessment. Using data from a national field trial, we searched for evidence of DIF on school level,…

  14. Examining Differential Item Functions of Different Item Ordered Test Forms According to Item Difficulty Levels

    ERIC Educational Resources Information Center

    Çokluk, Ömay; Gül, Emrah; Dogan-Gül, Çilem

    2016-01-01

    The study aims to examine whether differential item function is displayed in three different test forms that have item orders of random and sequential versions (easy-to-hard and hard-to-easy), based on Classical Test Theory (CTT) and Item Response Theory (IRT) methods and bearing item difficulty levels in mind. In the correlational research, the…

  15. Evaluation of Two Types of Differential Item Functioning in Factor Mixture Models with Binary Outcomes

    ERIC Educational Resources Information Center

    Lee, HwaYoung; Beretvas, S. Natasha

    2014-01-01

    Conventional differential item functioning (DIF) detection methods (e.g., the Mantel-Haenszel test) can be used to detect DIF only across observed groups, such as gender or ethnicity. However, research has found that DIF is not typically fully explained by an observed variable. True sources of DIF may include unobserved, latent variables, such as…

  16. Differential Item Functioning Analysis of the 2003-04 NHANES Physical Activity Questionnaire

    ERIC Educational Resources Information Center

    Gao, Yong; Zhu, Weimo

    2011-01-01

    Using differential item functioning (DIF) analyses, this study examined whether there were any DIF items in the National Health and Nutrition Examination Survey (NHANES) physical activity (PA) questionnaire. A subset of adult data from the 2003-04 NHANES study (n = 3,083) was used. PA items related to respondents' occupational, transportation,…

  17. 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…

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

    ERIC Educational Resources Information Center

    Woods, Carol M.; Grimm, Kevin J.

    2011-01-01

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

  19. A Comparison of Adjacent Categories and Cumulative Differential Step Functioning Effect Estimators

    ERIC Educational Resources Information Center

    Gattamorta, Karina A.; Penfield, Randall D.

    2012-01-01

    The study of measurement invariance in polytomous items that targets individual score levels is known as differential step functioning (DSF). The analysis of DSF requires the creation of a set of dichotomizations of the item response variable. There are two primary approaches for creating the set of dichotomizations to conduct a DSF analysis: the…

  20. The Effect of Differential Item Functioning in Anchor Items on Population Invariance of Equating

    ERIC Educational Resources Information Center

    Huggins, Anne Corinne

    2014-01-01

    Invariant relationships in the internal mechanisms of estimating achievement scores on educational tests serve as the basis for concluding that a particular test is fair with respect to statistical bias concerns. Equating invariance and differential item functioning are both concerned with invariant relationships yet are treated separately in the…

  1. A Synthesis of the Peer-Reviewed Differential Bundle Functioning Research

    ERIC Educational Resources Information Center

    Banks, Kathleen

    2013-01-01

    The purpose of this article was to present a synthesis of the peer-reviewed differential bundle functioning (DBF) research that has been conducted to date. A total of 16 studies were synthesized according to the following characteristics: tests used and learner groups, organizing principles used for developing bundles, DBF detection methods used,…

  2. Does Gender-Specific Differential Item Functioning Affect the Structure in Vocational Interest Inventories?

    ERIC Educational Resources Information Center

    Beinicke, Andrea; Pässler, Katja; Hell, Benedikt

    2014-01-01

    The study investigates consequences of eliminating items showing gender-specific differential item functioning (DIF) on the psychometric structure of a standard RIASEC interest inventory. Holland's hexagonal model was tested for structural invariance using a confirmatory methodological approach (confirmatory factor analysis and randomization…

  3. Correlates of Communalities as Matching Variables in Differential Item Functioning Analyses

    ERIC Educational Resources Information Center

    Yildirim, Huseyin H.; Yildirim, Selda

    2011-01-01

    Multivariate matching in Differential Item Functioning (DIF) analyses may contribute to understand the sources of DIF. In this context, detecting appropriate additional matching variables is a crucial issue. This present article argues that the variables which are correlated with communalities in item difficulties can be used as an additional…

  4. Assessing the Item Response Theory with Covariate (IRT-C) Procedure for Ascertaining Differential Item Functioning

    ERIC Educational Resources Information Center

    Tay, Louis; Vermunt, Jeroen K.; Wang, Chun

    2013-01-01

    We evaluate the item response theory with covariates (IRT-C) procedure for assessing differential item functioning (DIF) without preknowledge of anchor items (Tay, Newman, & Vermunt, 2011). This procedure begins with a fully constrained baseline model, and candidate items are tested for uniform and/or nonuniform DIF using the Wald statistic.…

  5. Differentiation of Cognitive Abilities as a Function of Neuroticism Level: A Measurement Equivalence/Invariance Analysis

    ERIC Educational Resources Information Center

    Bonaccio, Silvia; Reeve, Charlie L.

    2006-01-01

    This paper investigates the differentiation of cognitive abilities as a function of neuroticism. Specifically, we examine Eysenck and White's [Eysenck, H. J., and White, P. O. (1964). Personality and the measurement of intelligence. British Journal of Educational Psychology, 24, 197-201.] hypothesis that cognitive abilities are less differentiated…

  6. Differential Effects of a Tier Two Behavior Intervention Based on Function of Problem Behavior

    ERIC Educational Resources Information Center

    McIntosh, Kent; Campbell, Amy L.; Carter, Deborah Russell; Dickey, Celeste Rossetto

    2009-01-01

    The purpose of this study was to investigate the effectiveness of a tier two daily behavior card intervention and differential effects based on function of problem behavior. The participants were 36 elementary school students nominated for additional intervention beyond universal School-Wide Positive Behavior Support. Measures included…

  7. The differentiation and protective function of cytolytic CD4 T cells in influenza infection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    CD4 T cells that recognize peptide antigen in the context of Class II MHC can differentiate into various subsets that are characterized by their helper functions. However, increasing evidence indicates that CD4 cells with direct cytolytic activity play a role in chronic, as well as, acute infections...

  8. Item Purification in Differential Item Functioning Using Generalized Linear Mixed Models

    ERIC Educational Resources Information Center

    Liu, Qian

    2011-01-01

    For this dissertation, four item purification procedures were implemented onto the generalized linear mixed model for differential item functioning (DIF) analysis, and the performance of these item purification procedures was investigated through a series of simulations. Among the four procedures, forward and generalized linear mixed model (GLMM)…

  9. The Matching Criterion Purification for Differential Item Functioning Analyses in a Large-Scale Assessment

    ERIC Educational Resources Information Center

    Lee, HyeSun; Geisinger, Kurt F.

    2016-01-01

    The current study investigated the impact of matching criterion purification on the accuracy of differential item functioning (DIF) detection in large-scale assessments. The three matching approaches for DIF analyses (block-level matching, pooled booklet matching, and equated pooled booklet matching) were employed with the Mantel-Haenszel…

  10. Iterative Purification and Effect Size Use with Logistic Regression for Differential Item Functioning Detection

    ERIC Educational Resources Information Center

    French, Brian F.; Maller, Susan J.

    2007-01-01

    Two unresolved implementation issues with logistic regression (LR) for differential item functioning (DIF) detection include ability purification and effect size use. Purification is suggested to control inaccuracies in DIF detection as a result of DIF items in the ability estimate. Additionally, effect size use may be beneficial in controlling…

  11. Differential Item Functioning Detection across Two Methods of Defining Group Comparisons: Pairwise and Composite Group Comparisons

    ERIC Educational Resources Information Center

    Sari, Halil Ibrahim; Huggins, Anne Corinne

    2015-01-01

    This study compares two methods of defining groups for the detection of differential item functioning (DIF): (a) pairwise comparisons and (b) composite group comparisons. We aim to emphasize and empirically support the notion that the choice of pairwise versus composite group definitions in DIF is a reflection of how one defines fairness in DIF…

  12. Accommodations and Item-Level Analyses Using Mixture Differential Item Functioning Models

    ERIC Educational Resources Information Center

    Scarpati, Stanley E.; Wells, Craig S.; Lewis, Christine; Jirka, Stephen

    2011-01-01

    The purpose of this study was to use differential item functioning (DIF) and latent mixture model analyses to explore factors that explain performance differences on a large-scale mathematics assessment between examinees allowed to use a calculator or who were afforded item presentation accommodations versus those who did not receive the same…

  13. Power and Sample Size Calculations for Logistic Regression Tests for Differential Item Functioning

    ERIC Educational Resources Information Center

    Li, Zhushan

    2014-01-01

    Logistic regression is a popular method for detecting uniform and nonuniform differential item functioning (DIF) effects. Theoretical formulas for the power and sample size calculations are derived for likelihood ratio tests and Wald tests based on the asymptotic distribution of the maximum likelihood estimators for the logistic regression model.…

  14. A Robust Outlier Approach to Prevent Type I Error Inflation in Differential Item Functioning

    ERIC Educational Resources Information Center

    Magis, David; De Boeck, Paul

    2012-01-01

    The identification of differential item functioning (DIF) is often performed by means of statistical approaches that consider the raw scores as proxies for the ability trait level. One of the most popular approaches, the Mantel-Haenszel (MH) method, belongs to this category. However, replacing the ability level by the simple raw score is a source…

  15. Disruption of endogenous perlecan function improves differentiation of rat articular chondrocytes in vitro.

    PubMed

    Nakamura, Ryosuke; Nakamura, Fumio; Fukunaga, Shigeharu

    2015-04-01

    Heparan sulfate (HS) and heparan sulfate proteoglycans (HSPG) are necessary for normal cartilage development and chondrocyte differentiation. However, recent studies demonstrated that HSPG accelerate dedifferentiation and catabolism in chondrocytes from degenerative cartilage. In this study, we investigated the inhibitory effect of HSPG on chondrocyte differentiation in vitro. Rat articular chondrocytes were cultured at low (0.3 × 10(4) cells/cm(2) ) and high (1.5 × 10(5) cells/cm(2) ) density in the presence or absence of heparitinase I, an HS degrading enzyme. Cells cultured at low density dedifferentiated and exhibited an elongated morphology, and treatment with heparitinase I precluded cell elongation. Conversely, populations of chondrocytes cultured at high density exhibited either a dedifferentiated or differentiated phenotype. Glycosaminoglycan accumulation increased in heparitinase I-treated cells. To determine the function of perlecan, an important HSPG for cartilage development, in chondrocyte differentiation, rat chondrocyte cultures were exposed to an anti-perlecan antiserum to inhibit perlecan function. Western blotting analysis indicated that preventing perlecan activity increased type II collagen synthesis. Our results suggest that HSPG are negative regulators of chondrocyte differentiation in vitro and that perlecan contributes to chondrocyte dedifferentiation in vitro.

  16. Identification of the microRNA networks contributing to macrophage differentiation and function

    PubMed Central

    Zhou, Hong; Zhang, Jie; Eyers, Fiona; Xiang, Yang; Herbert, Cristan; Tay, Hock L.

    2016-01-01

    Limited evidence is available about the specific miRNA networks that regulate differentiation of specific immune cells. In this study, we characterized miRNA expression and associated alterations in expression with putative mRNA targets that are critical during differentiation of macrophages. In an effort to map the dynamic changes in the bone marrow (BM), we profiled whole BM cultures during differentiation into macrophages. We identified 112 miRNAs with expression patterns that were differentially regulated 5-fold or more during BMDM development. With TargetScan and MeSH databases, we identified 1267 transcripts involved in 30 canonical pathways linked to macrophage biology as potentially regulated by these specific 112 miRNAs. Furthermore, by employing miRanda and Ingenuity Pathways Analysis (IPA) analysis systems, we identified 18 miRNAs that are temporally linked to the expression of CSF1R, CD36, MSR1 and SCARB1; 7 miRNAs linked to the regulation of the transcription factors RUNX1 and PU.1, and 14 miRNAs target the nuclear receptor PPARα and PPARγ. This novel information provides an important reference resource for further study of the functional links between miRNAs and their target mRNAs for the regulation of differentiation and function of macrophages. PMID:27119502

  17. Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin.

    PubMed

    Zhang, Haiying; Pasolli, H Amalia; Fuchs, Elaine

    2011-02-01

    In mammals, skin begins as a single-layered epithelium, which, through a series of signals, either stratifies and differentiates to become epidermis or invaginates downward to make hair follicles (HFs). To achieve and maintain proper tissue architecture, keratinocytes must intricately balance growth and differentiation. Here, we uncover a critical and hitherto unappreciated role for Yes-associated protein (YAP), an evolutionarily conserved transcriptional coactivator with potent oncogenic potential. We show that YAP is highly expressed and nuclear in single-layered basal epidermal progenitors. Notably, nuclear YAP progressively declines with age and correlates with proliferative potential of epidermal progenitors. Shortly after initiation of HF morphogenesis, YAP translocates to the cytoplasm of differentiating cells. Through genetic analysis, we demonstrate a role for YAP in maintaining basal epidermal progenitors and regulating HF morphogenesis. YAP overexpression causes hair placodes to evaginate into epidermis rather than invaginate into dermis. YAP also expands basal epidermal progenitors, promotes proliferation, and inhibits terminal differentiation. In vitro gain-and-loss of function studies show that primary mouse keratinocytes (MKs) accelerate proliferation, suppress differentiation, and inhibit apoptosis when YAP is activated and reverse these features when YAP is inhibited. Finally, we identify Cyr61 as a target of YAP in MKs and demonstrate a requirement for TEA domain (TEAD) transcriptional factors to comediate YAP functions in MKs.

  18. Integrin-Linked Kinase Is Indispensable for Keratinocyte Differentiation and Epidermal Barrier Function.

    PubMed

    Sayedyahossein, Samar; Rudkouskaya, Alena; Leclerc, Valerie; Dagnino, Lina

    2016-02-01

    A functional permeability barrier is essential to prevent the passage of water and electrolytes, macromolecules, and pathogens through the epidermis. This is accomplished in terminally differentiated keratinocytes through formation of a cornified envelope and the assembly of tight intercellular junctions. Integrin-linked kinase (ILK) is a scaffold protein essential for hair follicle morphogenesis and epidermal attachment to the basement membrane. However, the biological functions of ILK in differentiated keratinocytes remain poorly understood. Furthermore, whether ILK is implicated in keratinocyte differentiation and intercellular junction formation has remained an unresolved issue. Here we describe a pivotal role for ILK in keratinocyte differentiation responses to increased extracellular Ca(2+), regulation of adherens and tight junction assembly, and the formation of an outside-in permeability barrier toward macromolecules. In the absence of ILK, the calcium sensing receptor, E-cadherin, and ZO-1 fail to translocate to the cell membrane, through mechanisms that involve abnormalities in microtubules and in RhoA activation. In situ, ILK-deficient epidermis exhibits reduced tight junction formation and increased outside-in permeability to a dextran tracer, indicating reduced barrier properties toward macromolecules. Therefore, ILK is an essential component of keratinocyte differentiation programs that contribute to epidermal integrity and the establishment of its barrier properties. PMID:26967476

  19. Identification of the microRNA networks contributing to macrophage differentiation and function.

    PubMed

    Zhou, Hong; Zhang, Jie; Eyers, Fiona; Xiang, Yang; Herbert, Cristan; Tay, Hock L; Foster, Paul S; Yang, Ming

    2016-05-17

    Limited evidence is available about the specific miRNA networks that regulate differentiation of specific immune cells. In this study, we characterized miRNA expression and associated alterations in expression with putative mRNA targets that are critical during differentiation of macrophages. In an effort to map the dynamic changes in the bone marrow (BM), we profiled whole BM cultures during differentiation into macrophages. We identified 112 miRNAs with expression patterns that were differentially regulated 5-fold or more during BMDM development. With TargetScan and MeSH databases, we identified 1267 transcripts involved in 30 canonical pathways linked to macrophage biology as potentially regulated by these specific 112 miRNAs. Furthermore, by employing miRanda and Ingenuity Pathways Analysis (IPA) analysis systems, we identified 18 miRNAs that are temporally linked to the expression of CSF1R, CD36, MSR1 and SCARB1; 7 miRNAs linked to the regulation of the transcription factors RUNX1 and PU.1, and 14 miRNAs target the nuclear receptor PPARα and PPARγ. This novel information provides an important reference resource for further study of the functional links between miRNAs and their target mRNAs for the regulation of differentiation and function of macrophages. PMID:27119502

  20. Surviving Endoplasmic Reticulum Stress Is Coupled to Altered Chondrocyte Differentiation and Function

    PubMed Central

    Cheslett, Deborah; Chan, Wilson C. W; So, Chi Leong; Melhado, Ian G; Chan, Tori W. Y; Kwan, Kin Ming; Hunziker, Ernst B; Yamada, Yoshihiko; Bateman, John F; Cheung, Kenneth M. C; Cheah, Kathryn S. E

    2007-01-01

    In protein folding and secretion disorders, activation of endoplasmic reticulum (ER) stress signaling (ERSS) protects cells, alleviating stress that would otherwise trigger apoptosis. Whether the stress-surviving cells resume normal function is not known. We studied the in vivo impact of ER stress in terminally differentiating hypertrophic chondrocytes (HCs) during endochondral bone formation. In transgenic mice expressing mutant collagen X as a consequence of a 13-base pair deletion in Col10a1 (13del), misfolded α1(X) chains accumulate in HCs and elicit ERSS. Histological and gene expression analyses showed that these chondrocytes survived ER stress, but terminal differentiation is interrupted, and endochondral bone formation is delayed, producing a chondrodysplasia phenotype. This altered differentiation involves cell-cycle re-entry, the re-expression of genes characteristic of a prehypertrophic-like state, and is cell-autonomous. Concomitantly, expression of Col10a1 and 13del mRNAs are reduced, and ER stress is alleviated. ERSS, abnormal chondrocyte differentiation, and altered growth plate architecture also occur in mice expressing mutant collagen II and aggrecan. Alteration of the differentiation program in chondrocytes expressing unfolded or misfolded proteins may be part of an adaptive response that facilitates survival and recovery from the ensuing ER stress. However, the altered differentiation disrupts the highly coordinated events of endochondral ossification culminating in chondrodysplasia. PMID:17298185

  1. Tracking the Spatial and Functional Gradient of Monocyte-To-Macrophage Differentiation in Inflamed Lung

    PubMed Central

    Sen, Debasish; Jones, Stephen M.; Oswald, Erin M.; Pinkard, Henry; Corbin, Kaitlin

    2016-01-01

    Myeloid-derived cells such as monocytes, dendritic cells (DCs), and macrophages are at the heart of the immune effector function in an inflammatory response. But because of the lack of an efficient imaging system to trace these cells live during their migration and maturation in their native environment at sub-cellular resolution, our knowledge is limited to data available from specific time-points analyzed by flow cytometry, histology, genomics and other immunological methods. Here, we have developed a ratiometric imaging method for measuring monocyte maturation in inflamed mouse lungs in situ using real-time using 2-photon imaging and complementary methods. We visualized that while undifferentiated monocytes were predominantly found only in the vasculature, a semi-differentiated monocyte/macrophage population could enter the tissue and resembled more mature and differentiated populations by morphology and surface phenotype. As these cells entered and differentiated, they were already selectively localized near inflamed airways and their entry was associated with changes in motility and morphology. We were able to visualize these during the act of differentiation, a process that can be demonstrated in this way to be faster on a per-cell basis under inflammatory conditions. Finally, our in situ analyses demonstrated increases, in the differentiating cells, for both antigen uptake and the ability to mediate interactions with T cells. This work, while largely confirming proposed models for in situ differentiation, provides important in situ data on the coordinated site-specific recruitment and differentiation of these cells and helps elaborate the predominance of immune pathology at the airways. Our novel imaging technology to trace immunogenic cell maturation in situ will complement existing information available on in situ differentiation deduced from other immunological methods, and assist better understanding of the spatio-temporal cellular behavior during an

  2. Exponential rational function method for space-time fractional differential equations

    NASA Astrophysics Data System (ADS)

    Aksoy, Esin; Kaplan, Melike; Bekir, Ahmet

    2016-04-01

    In this paper, exponential rational function method is applied to obtain analytical solutions of the space-time fractional Fokas equation, the space-time fractional Zakharov Kuznetsov Benjamin Bona Mahony, and the space-time fractional coupled Burgers' equations. As a result, some exact solutions for them are successfully established. These solutions are constructed in fractional complex transform to convert fractional differential equations into ordinary differential equations. The fractional derivatives are described in Jumarie's modified Riemann-Liouville sense. The exact solutions obtained by the proposed method indicate that the approach is easy to implement and effective.

  3. Viscoelastic Properties of Differentiating Blood Cells Are Fate- and Function-Dependent

    PubMed Central

    Ekpenyong, Andrew E.; Whyte, Graeme; Chalut, Kevin; Pagliara, Stefano; Lautenschläger, Franziska; Fiddler, Christine; Paschke, Stephan; Keyser, Ulrich F.; Chilvers, Edwin R.; Guck, Jochen

    2012-01-01

    Although cellular mechanical properties are known to alter during stem cell differentiation, understanding of the functional relevance of such alterations is incomplete. Here, we show that during the course of differentiation of human myeloid precursor cells into three different lineages, the cells alter their viscoelastic properties, measured using an optical stretcher, to suit their ultimate fate and function. Myeloid cells circulating in blood have to be advected through constrictions in blood vessels, engendering the need for compliance at short time-scales (differentiated cell types reduce their steady-state viscosity by more than 50% and show over 140% relative increase in their ability to migrate through tissue-like pores at long time-scales (>minutes), compared to undifferentiated cells. These findings suggest that reduction in steady-state viscosity is a physiological adaptation for enhanced migration through tissues. Our results indicate that the material properties of cells define their function, can be used as a cell differentiation marker and could serve as target for novel therapies. PMID:23028868

  4. Fractional Order Digital Differentiator Design Based on Power Function and Least squares

    NASA Astrophysics Data System (ADS)

    Kumar, Manjeet; Rawat, Tarun Kumar

    2016-10-01

    In this article, we propose the use of power function and least squares method for designing of a fractional order digital differentiator. The input signal is transformed into a power function by using Taylor series expansion, and its fractional derivative is computed using the Grunwald-Letnikov (G-L) definition. Next, the fractional order digital differentiator is modelled as a finite impulse response (FIR) system that yields fractional order derivative of the G-L type for a power function. The FIR system coefficients are obtained by using the least squares method. Two examples are used to demonstrate that the fractional derivative of the digital signals is computed by using the proposed technique. The results of the third and fourth examples reveal that the proposed technique gives superior performance in comparison with the existing techniques.

  5. Lhx1 Controls Terminal Differentiation and Circadian Function of the Suprachiasmatic Nucleus

    PubMed Central

    Bedont, Joseph L.; LeGates, Tara A.; Slat, Emily A.; Byerly, Mardi S.; Wang, Hong; Hu, Jianfei; Rupp, Alan C.; Qian, Jiang; Wong, G. William; Herzog, Erik D.; Hattar, Samer; Blackshaw, Seth

    2014-01-01

    SUMMARY Vertebrate circadian rhythms are organized by the hypothalamic suprachiasmatic nucleus (SCN). Despite its physiological importance, SCN development is poorly understood. Here, we show that Lim homeodomain transcription factor 1 (Lhx1) is essential for terminal differentiation and function of the SCN. Deletion of Lhx1 in the developing SCN results in loss of SCN-enriched neuropeptides involved in synchronization and coupling to downstream oscillators, among other aspects of circadian function. Intact, albeit damped, clock gene expression rhythms persist in Lhx1-deficient SCN; however, circadian activity rhythms are highly disorganized and susceptible to surprising changes in period, phase, and consolidation following neuropeptide infusion. Our results identify a factor required for SCN terminal differentiation. In addition, our in vivo study of combinatorial SCN neuropeptide disruption uncovered synergies among SCN-enriched neuropeptides in regulating normal circadian function. These animals provide a platform for studying the central oscillator's role in physiology and cognition. PMID:24767996

  6. Functional Maintenance of Differentiated Embryoid Bodies in Microfluidic Systems: A Platform for Personalized Medicine

    PubMed Central

    Guven, Sinan; Lindsey, Jennifer S.; Poudel, Ishwari; Chinthala, Sireesha; Nickerson, Michael D.; Gerami-Naini, Behzad; Gurkan, Umut A.

    2015-01-01

    Hormone replacement therapies have become important for treating diseases such as premature ovarian failure or menopausal complications. The clinical use of bioidentical hormones might significantly reduce some of the potential risks reportedly associated with the use of synthetic hormones. In the present study, we demonstrate the utility and advantage of a microfluidic chip culture system to enhance the development of personalized, on-demand, treatment modules using embryoid bodies (EBs). Functional EBs cultured on microfluidic chips represent a platform for personalized, patient-specific treatment cassettes that can be cryopreserved until required for treatment. We assessed the viability, differentiation, and functionality of EBs cultured and cryopreserved in this system. During extended microfluidic culture, estradiol, progesterone, testosterone, and anti-müllerian hormone levels were measured, and the expression of differentiated steroidogenic cells was confirmed by immunocytochemistry assay for the ovarian tissue markers anti-müllerian hormone receptor type II, follicle-stimulating hormone receptor, and inhibin β-A and the estrogen biosynthesis enzyme aromatase. Our studies showed that under microfluidic conditions, differentiated steroidogenic EBs continued to secrete estradiol and progesterone at physiologically relevant concentrations (30–120 pg/ml and 150–450 pg/ml, respectively) for up to 21 days. Collectively, we have demonstrated for the first time the feasibility of using a microfluidic chip system with continuous flow for the differentiation and extended culture of functional steroidogenic stem cell-derived EBs, the differentiation of EBs into cells expressing ovarian antigens in a microfluidic system, and the ability to cryopreserve this system with restoration of growth and functionality on thawing. These results present a platform for the development of a new therapeutic system for personalized medicine. PMID:25666845

  7. Functional maintenance of differentiated embryoid bodies in microfluidic systems: a platform for personalized medicine.

    PubMed

    Guven, Sinan; Lindsey, Jennifer S; Poudel, Ishwari; Chinthala, Sireesha; Nickerson, Michael D; Gerami-Naini, Behzad; Gurkan, Umut A; Anchan, Raymond M; Demirci, Utkan

    2015-03-01

    Hormone replacement therapies have become important for treating diseases such as premature ovarian failure or menopausal complications. The clinical use of bioidentical hormones might significantly reduce some of the potential risks reportedly associated with the use of synthetic hormones. In the present study, we demonstrate the utility and advantage of a microfluidic chip culture system to enhance the development of personalized, on-demand, treatment modules using embryoid bodies (EBs). Functional EBs cultured on microfluidic chips represent a platform for personalized, patient-specific treatment cassettes that can be cryopreserved until required for treatment. We assessed the viability, differentiation, and functionality of EBs cultured and cryopreserved in this system. During extended microfluidic culture, estradiol, progesterone, testosterone, and anti-müllerian hormone levels were measured, and the expression of differentiated steroidogenic cells was confirmed by immunocytochemistry assay for the ovarian tissue markers anti-müllerian hormone receptor type II, follicle-stimulating hormone receptor, and inhibin β-A and the estrogen biosynthesis enzyme aromatase. Our studies showed that under microfluidic conditions, differentiated steroidogenic EBs continued to secrete estradiol and progesterone at physiologically relevant concentrations (30-120 pg/ml and 150-450 pg/ml, respectively) for up to 21 days. Collectively, we have demonstrated for the first time the feasibility of using a microfluidic chip system with continuous flow for the differentiation and extended culture of functional steroidogenic stem cell-derived EBs, the differentiation of EBs into cells expressing ovarian antigens in a microfluidic system, and the ability to cryopreserve this system with restoration of growth and functionality on thawing. These results present a platform for the development of a new therapeutic system for personalized medicine. PMID:25666845

  8. Detecting differential rater functioning over time (DRIFT) using a Rasch multi-faceted rating scale model.

    PubMed

    Wolfe, E W; Moulder, B C; Myford, C M

    2001-01-01

    This paper describes a class of rater effects that depict rater-by-time interactions. We refer to this class of rater effects as DRIFT differential rater functioning over time. This article describes several types of DRIFT (primacy/recency, differential centrality/extremism, and practice/fatigue) and Rasch measurement procedures designed to identify these types of DRIFT in rating data. These procedures are applied to simulated data and are shown to be useful in classifying raters as being aberrant or non-aberrant for primacy, recency, and differential centrality and extremism, particularly for moderate or larger effect sizes. Rates of correct classification for practice and fatigue were lower and statistical power exceeded.50 only with very large effect sizes. Type I error rates (i.e., incorrect nomination) were near expected levels in all cases.

  9. Estimation of time- and state-dependent delays and other parameters in functional differential equations

    NASA Technical Reports Server (NTRS)

    Murphy, K. A.

    1988-01-01

    A parameter estimation algorithm is developed which can be used to estimate unknown time- or state-dependent delays and other parameters (e.g., initial condition) appearing within a nonlinear nonautonomous functional differential equation. The original infinite dimensional differential equation is approximated using linear splines, which are allowed to move with the variable delay. The variable delays are approximated using linear splines as well. The approximation scheme produces a system of ordinary differential equations with nice computational properties. The unknown parameters are estimated within the approximating systems by minimizing a least-squares fit-to-data criterion. Convergence theorems are proved for time-dependent delays and state-dependent delays within two classes, which say essentially that fitting the data by using approximations will, in the limit, provide a fit to the data using the original system. Numerical test examples are presented which illustrate the method for all types of delay.

  10. Estimation of time- and state-dependent delays and other parameters in functional differential equations

    NASA Technical Reports Server (NTRS)

    Murphy, K. A.

    1990-01-01

    A parameter estimation algorithm is developed which can be used to estimate unknown time- or state-dependent delays and other parameters (e.g., initial condition) appearing within a nonlinear nonautonomous functional differential equation. The original infinite dimensional differential equation is approximated using linear splines, which are allowed to move with the variable delay. The variable delays are approximated using linear splines as well. The approximation scheme produces a system of ordinary differential equations with nice computational properties. The unknown parameters are estimated within the approximating systems by minimizing a least-squares fit-to-data criterion. Convergence theorems are proved for time-dependent delays and state-dependent delays within two classes, which say essentially that fitting the data by using approximations will, in the limit, provide a fit to the data using the original system. Numerical test examples are presented which illustrate the method for all types of delay.

  11. Butyrate affects differentiation, maturation and function of human monocyte-derived dendritic cells and macrophages

    PubMed Central

    Millard, A L; Mertes, P M; Ittelet, D; Villard, F; Jeannesson, P; Bernard, J

    2002-01-01

    We studied the in vitro effects of butyric acid on differentiation, maturation and function of dendritic cells (DC) and macrophages (MΦ) generated from human monocytes. A non-toxic dose of butyrate was shown to alter the phenotypic differentiation process of DC as assessed by a persistence of CD14, and a decreased CD54, CD86 and HLA class II expression. The more immature differentiation stage of treated cells was confirmed further by their increased phagocytic capability, their altered capacity to produce IL-10 and IL-12, and their weak allostimulatory abilities. Butyrate also altered DC terminal maturation, regardless of the maturation inducer, as demonstrated by a strong down-regulation of CD83, a decreased expression of CD40, CD86 and HLA class II. Similarly, butyrate altered MΦ differentiation, down-regulating the expression of the restricted membrane antigens and reducing the phagocytic capacity of treated cells. To investigate further the mechanism by which butyrate hampers the monocyte dual differentiation pathway, we studied the effects of 1,25(OH)2D3 alone or in combination with butyrate on the phenotypic features of DC. Unlike 1,25(OH)2D3, butyrate inhibited DC differentiation without redirecting it towards MΦ. Combined treatment gave rise to a new cell subset (CD14high, CD86 and HLA-DRlow) phenotypically distinct from monocytes. These results reveal an alternative mechanism of inhibition of DC and MΦ differentiation. Altogether, our data demonstrate a novel immune suppression property of butyrate that may modulate both inflammatory and immune responses and support further the interest for butyrate and its derivatives as new immunotherapeutic agents. PMID:12390312

  12. H19 activates Wnt signaling and promotes osteoblast differentiation by functioning as a competing endogenous RNA

    PubMed Central

    Liang, Wei-Cheng; Fu, Wei-Ming; Wang, Yu-Bing; Sun, Yu-Xin; Xu, Liang-Liang; Wong, Cheuk-Wa; Chan, Kai-Ming; Li, Gang; Waye, Mary Miu-Yee; Zhang, Jin-Fang

    2016-01-01

    Bone homeostasis is tightly orchestrated and maintained by the balance between osteoblasts and osteoclasts. Recent studies have greatly expanded our understanding of the molecular mechanisms of cellular differentiation. However, the functional roles of non-coding RNAs particularly lncRNAs in remodeling bone architecture remain elusive. In our study, lncRNA H19 was found to be upregulated during osteogenesis in hMSCs. Stable expression of H19 significantly accelerated in vivo and in vitro osteoblast differentiation. Meanwhile, by using bioinformatic investigations and RIP assays combined with luciferase reporter assays, we demonstrated that H19 functioned as an miRNA sponge for miR-141 and miR-22, both of which were negative regulators of osteogenesis and Wnt/β-catenin pathway. Further investigations revealed that H19 antagonized the functions of these two miRNAs and led to de-repression of their shared target gene β-catenin, which eventually activated Wnt/β-catenin pathway and hence potentiated osteogenesis. In addition, we also identified a novel regulatory feedback loop between H19 and its encoded miR-675-5p. And miR-675-5p was found to directly target H19 and counteracted osteoblast differentiation. To sum up, these observations indicate that the lncRNA H19 modulates Wnt/β-catenin pathway by acting as a competing endogenous RNA, which may shed light on the functional role of lncRNAs in coordinating osteogenesis. PMID:26853553

  13. Fetal dexamethasone exposure accelerates development of renal function: relationship to dose, cell differentiation and growth inhibition.

    PubMed

    Slotkin, T A; Seidler, F J; Kavlock, R J; Gray, J A

    1992-02-01

    Fetal exposure to high doses of glucocorticoids slows cellular development and impairs organ performance, in association with growth retardation. Nevertheless, low doses of glucocorticoids may enhance cell differentiation and accelerate specific functions. The current study examined this apparent paradox in the developing rat kidney, using doses of dexamethasone that span the threshold for growth impairment: 0.05 or 0.2 mg/kg given on gestational days 17, 18 and 19. At the lower dose, which did not significantly retard body growth, the postnatal development of tubular reabsorptive capabilities for sodium, potassium, osmotic particles, water and urea was accelerated. These effects were less notable at the higher dose, which caused initial body growth impairment. The selectivity toward promotion of tubular function was evidenced by the absence of effect of either dose of dexamethasone on development of glomerular filtration rate. Because of the wide spectrum of dexamethasone's effects on tubular function, we also assessed fetal kidney adenylate cyclase as a means of detecting altered cell differentiation in the prenatal period during which dexamethasone was given. Either glucocorticoid dose increased the total adenylate cyclase catalytic activity (assessed with forskolin). Thus, the net effect of fetal dexamethasone exposure on development of renal excretory capabilities probably represents the summation of promoted cell differentiation and slowed development consequent to growth retardation. At low dose levels, the former effect predominates, leading to enhanced functional development, whereas higher doses that interfere with general growth and development can offset the direct promotional effect.

  14. Functional network analysis of genes differentially expressed during xylogenesis in soc1ful woody Arabidopsis plants.

    PubMed

    Davin, Nicolas; Edger, Patrick P; Hefer, Charles A; Mizrachi, Eshchar; Schuetz, Mathias; Smets, Erik; Myburg, Alexander A; Douglas, Carl J; Schranz, Michael E; Lens, Frederic

    2016-06-01

    Many plant genes are known to be involved in the development of cambium and wood, but how the expression and functional interaction of these genes determine the unique biology of wood remains largely unknown. We used the soc1ful loss of function mutant - the woodiest genotype known in the otherwise herbaceous model plant Arabidopsis - to investigate the expression and interactions of genes involved in secondary growth (wood formation). Detailed anatomical observations of the stem in combination with mRNA sequencing were used to assess transcriptome remodeling during xylogenesis in wild-type and woody soc1ful plants. To interpret the transcriptome changes, we constructed functional gene association networks of differentially expressed genes using the STRING database. This analysis revealed functionally enriched gene association hubs that are differentially expressed in herbaceous and woody tissues. In particular, we observed the differential expression of genes related to mechanical stress and jasmonate biosynthesis/signaling during wood formation in soc1ful plants that may be an effect of greater tension within woody tissues. Our results suggest that habit shifts from herbaceous to woody life forms observed in many angiosperm lineages could have evolved convergently by genetic changes that modulate the gene expression and interaction network, and thereby redeploy the conserved wood developmental program. PMID:26952251

  15. Divergent regulation of functionally distinct γ-tubulin complexes during differentiation.

    PubMed

    Muroyama, Andrew; Seldin, Lindsey; Lechler, Terry

    2016-06-20

    Differentiation induces the formation of noncentrosomal microtubule arrays in diverse tissues. The formation of these arrays requires loss of microtubule-organizing activity (MTOC) at the centrosome, but the mechanisms regulating this transition remain largely unexplored. Here, we use the robust loss of centrosomal MTOC activity in the epidermis to identify two pools of γ-tubulin that are biochemically and functionally distinct and differentially regulated. Nucleation-competent CDK5RAP2-γ-tubulin complexes were maintained at centrosomes upon initial epidermal differentiation. In contrast, Nedd1-γ-tubulin complexes did not promote nucleation but were required for anchoring of microtubules, a previously uncharacterized activity for this complex. Cell cycle exit specifically triggered loss of Nedd1-γ-tubulin complexes, providing a mechanistic link connecting MTOC activity and differentiation. Collectively, our studies demonstrate that distinct γ-tubulin complexes regulate different microtubule behaviors at the centrosome and show that differential regulation of these complexes drives loss of centrosomal MTOC activity. PMID:27298324

  16. A parsimonious statistical method to detect groupwise differentially expressed functional connectivity networks.

    PubMed

    Chen, Shuo; Kang, Jian; Xing, Yishi; Wang, Guoqing

    2015-12-01

    Group-level functional connectivity analyses often aim to detect the altered connectivity patterns between subgroups with different clinical or psychological experimental conditions, for example, comparing cases and healthy controls. We present a new statistical method to detect differentially expressed connectivity networks with significantly improved power and lower false-positive rates. The goal of our method was to capture most differentially expressed connections within networks of constrained numbers of brain regions (by the rule of parsimony). By virtue of parsimony, the false-positive individual connectivity edges within a network are effectively reduced, whereas the informative (differentially expressed) edges are allowed to borrow strength from each other to increase the overall power of the network. We develop a test statistic for each network in light of combinatorics graph theory, and provide p-values for the networks (in the weak sense) by using permutation test with multiple-testing adjustment. We validate and compare this new approach with existing methods, including false discovery rate and network-based statistic, via simulation studies and a resting-state functional magnetic resonance imaging case-control study. The results indicate that our method can identify differentially expressed connectivity networks, whereas existing methods are limited.

  17. A Parsimonious Statistical Method to Detect Groupwise Differentially Expressed Functional Connectivity Networks

    PubMed Central

    Chen, Shuo; Kang, Jian; Xing, Yishi; Wang, Guoqing

    2016-01-01

    Group-level functional connectivity analyses often aim to detect the altered connectivity patterns between subgroups with different clinical or psychological experimental conditions, for example, comparing cases and healthy controls. We present a new statistical method to detect differentially expressed connectivity networks with significantly improved power and lower false-positive rates. The goal of our method was to capture most differentially expressed connections within networks of constrained numbers of brain regions (by the rule of parsimony). By virtue of parsimony, the false-positive individual connectivity edges within a network are effectively reduced, whereas the informative (differentially expressed) edges are allowed to borrow strength from each other to increase the overall power of the network. We develop a test statistic for each network in light of combinatorics graph theory, and provide p-values for the networks (in the weak sense) by using permutation test with multiple-testing adjustment. We validate and compare this new approach with existing methods, including false discovery rate and network-based statistic, via simulation studies and a resting-state functional magnetic resonance imaging case–control study. The results indicate that our method can identify differentially expressed connectivity networks, whereas existing methods are limited. PMID:26416398

  18. An Efficient Spectral Method for Ordinary Differential Equations with Rational Function Coefficients

    NASA Technical Reports Server (NTRS)

    Coutsias, Evangelos A.; Torres, David; Hagstrom, Thomas

    1994-01-01

    We present some relations that allow the efficient approximate inversion of linear differential operators with rational function coefficients. We employ expansions in terms of a large class of orthogonal polynomial families, including all the classical orthogonal polynomials. These families obey a simple three-term recurrence relation for differentiation, which implies that on an appropriately restricted domain the differentiation operator has a unique banded inverse. The inverse is an integration operator for the family, and it is simply the tridiagonal coefficient matrix for the recurrence. Since in these families convolution operators (i.e. matrix representations of multiplication by a function) are banded for polynomials, we are able to obtain a banded representation for linear differential operators with rational coefficients. This leads to a method of solution of initial or boundary value problems that, besides having an operation count that scales linearly with the order of truncation N, is computationally well conditioned. Among the applications considered is the use of rational maps for the resolution of sharp interior layers.

  19. A parsimonious statistical method to detect groupwise differentially expressed functional connectivity networks.

    PubMed

    Chen, Shuo; Kang, Jian; Xing, Yishi; Wang, Guoqing

    2015-12-01

    Group-level functional connectivity analyses often aim to detect the altered connectivity patterns between subgroups with different clinical or psychological experimental conditions, for example, comparing cases and healthy controls. We present a new statistical method to detect differentially expressed connectivity networks with significantly improved power and lower false-positive rates. The goal of our method was to capture most differentially expressed connections within networks of constrained numbers of brain regions (by the rule of parsimony). By virtue of parsimony, the false-positive individual connectivity edges within a network are effectively reduced, whereas the informative (differentially expressed) edges are allowed to borrow strength from each other to increase the overall power of the network. We develop a test statistic for each network in light of combinatorics graph theory, and provide p-values for the networks (in the weak sense) by using permutation test with multiple-testing adjustment. We validate and compare this new approach with existing methods, including false discovery rate and network-based statistic, via simulation studies and a resting-state functional magnetic resonance imaging case-control study. The results indicate that our method can identify differentially expressed connectivity networks, whereas existing methods are limited. PMID:26416398

  20. On the generalization of statistical thermodynamic functions by a Riccati differential equation.

    NASA Astrophysics Data System (ADS)

    Peña, J. J.; Rubio-Ponce, A.; Morales, J.

    2016-08-01

    In this work, we propose a non-linear differential equation of Riccati-type, where the standard partition function Z(T) is taken as its particular solution leading to their generalization Zg(T); from there, other related statistical thermodynamic functions are generalized. As an useful application of our proposal, other thermodynamic functions, namely, the internal energy, heat capacity, Helmholtz free energy and entropy, associated to the model of the ideal monatomic gas in D-dimensions are generalized. According to our results, thermodynamic properties derived from the standard partition functions by means of ordinary statistical mechanics are incomplete. In fact, although asymptotically with the increasing of temperature the generalized statistical thermodynamic functions reduce to the standard ones, these contain an extra term which is dominant at very low temperature indicating that standard findings should be corrected.

  1. Using Item Response Theory and Model-Data Fit to Conceptualize Differential Item and Person Functioning for Students with Disabilities

    ERIC Educational Resources Information Center

    Engelhard, George, Jr.

    2009-01-01

    The major purpose of this study is to describe a conceptual framework for examining differential item functioning (DIF) and differential person functioning (DPF) as types of model-data misfit within the context of assessing students with disabilities. Specifically, DIF and DPF can be viewed through the lens of residual analyses. Residual analyses…

  2. It Might Not Make a Big DIF: Improved Differential Test Functioning Statistics That Account for Sampling Variability

    ERIC Educational Resources Information Center

    Chalmers, R. Philip; Counsell, Alyssa; Flora, David B.

    2016-01-01

    Differential test functioning, or DTF, occurs when one or more items in a test demonstrate differential item functioning (DIF) and the aggregate of these effects are witnessed at the test level. In many applications, DTF can be more important than DIF when the overall effects of DIF at the test level can be quantified. However, optimal statistical…

  3. A New Method for Assessing the Statistical Significance in the Differential Functioning of Items and Tests (DFIT) Framework

    ERIC Educational Resources Information Center

    Oshima, T. C.; Raju, Nambury S.; Nanda, Alice O.

    2006-01-01

    A new item parameter replication method is proposed for assessing the statistical significance of the noncompensatory differential item functioning (NCDIF) index associated with the differential functioning of items and tests framework. In this new method, a cutoff score for each item is determined by obtaining a (1-alpha ) percentile rank score…

  4. Neurons Differentiated from Transplanted Stem Cells Respond Functionally to Acoustic Stimuli in the Awake Monkey Brain.

    PubMed

    Wei, Jing-Kuan; Wang, Wen-Chao; Zhai, Rong-Wei; Zhang, Yu-Hua; Yang, Shang-Chuan; Rizak, Joshua; Li, Ling; Xu, Li-Qi; Liu, Li; Pan, Ming-Ke; Hu, Ying-Zhou; Ghanemi, Abdelaziz; Wu, Jing; Yang, Li-Chuan; Li, Hao; Lv, Long-Bao; Li, Jia-Li; Yao, Yong-Gang; Xu, Lin; Feng, Xiao-Li; Yin, Yong; Qin, Dong-Dong; Hu, Xin-Tian; Wang, Zheng-Bo

    2016-07-26

    Here, we examine whether neurons differentiated from transplanted stem cells can integrate into the host neural network and function in awake animals, a goal of transplanted stem cell therapy in the brain. We have developed a technique in which a small "hole" is created in the inferior colliculus (IC) of rhesus monkeys, then stem cells are transplanted in situ to allow for investigation of their integration into the auditory neural network. We found that some transplanted cells differentiated into mature neurons and formed synaptic input/output connections with the host neurons. In addition, c-Fos expression increased significantly in the cells after acoustic stimulation, and multichannel recordings indicated IC specific tuning activities in response to auditory stimulation. These results suggest that the transplanted cells have the potential to functionally integrate into the host neural network.

  5. Recovery of partial differential operators on classes of periodic functions with mixed smoothness

    NASA Astrophysics Data System (ADS)

    Balgimbayeva, Sholpan

    2016-08-01

    We consider the problem of optimal linear recovery for mixed partial differential operator A on the unit ball SBpθ r(Tn) of the Nikol'skii-Besov space of periodic functions with mixed smoothness. We find error bounds sharp in order for optimal linear recovery of operator A on class SBpθ r(Tn) . As information IMδ(f ) about the functions f from class SBpθ r(Tn) we shall use Fourier coefficients with numbers from step "hyperbolic" cross. As the linear method using the information about Fourier coefficients, we shall consider action of the mixed partial differential operator A on the special "private" sum of decomposition on system (type as wavelets) trigonometric polynomials.

  6. Neurons Differentiated from Transplanted Stem Cells Respond Functionally to Acoustic Stimuli in the Awake Monkey Brain.

    PubMed

    Wei, Jing-Kuan; Wang, Wen-Chao; Zhai, Rong-Wei; Zhang, Yu-Hua; Yang, Shang-Chuan; Rizak, Joshua; Li, Ling; Xu, Li-Qi; Liu, Li; Pan, Ming-Ke; Hu, Ying-Zhou; Ghanemi, Abdelaziz; Wu, Jing; Yang, Li-Chuan; Li, Hao; Lv, Long-Bao; Li, Jia-Li; Yao, Yong-Gang; Xu, Lin; Feng, Xiao-Li; Yin, Yong; Qin, Dong-Dong; Hu, Xin-Tian; Wang, Zheng-Bo

    2016-07-26

    Here, we examine whether neurons differentiated from transplanted stem cells can integrate into the host neural network and function in awake animals, a goal of transplanted stem cell therapy in the brain. We have developed a technique in which a small "hole" is created in the inferior colliculus (IC) of rhesus monkeys, then stem cells are transplanted in situ to allow for investigation of their integration into the auditory neural network. We found that some transplanted cells differentiated into mature neurons and formed synaptic input/output connections with the host neurons. In addition, c-Fos expression increased significantly in the cells after acoustic stimulation, and multichannel recordings indicated IC specific tuning activities in response to auditory stimulation. These results suggest that the transplanted cells have the potential to functionally integrate into the host neural network. PMID:27425612

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

    PubMed Central

    Zhang, Chuan

    2015-01-01

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

  8. Regeneration of Thyroid Function by Transplantation of Differentiated Pluripotent Stem Cells.

    PubMed

    Kurmann, Anita A; Serra, Maria; Hawkins, Finn; Rankin, Scott A; Mori, Munemasa; Astapova, Inna; Ullas, Soumya; Lin, Sui; Bilodeau, Melanie; Rossant, Janet; Jean, Jyh C; Ikonomou, Laertis; Deterding, Robin R; Shannon, John M; Zorn, Aaron M; Hollenberg, Anthony N; Kotton, Darrell N

    2015-11-01

    Differentiation of functional thyroid epithelia from pluripotent stem cells (PSCs) holds the potential for application in regenerative medicine. However, progress toward this goal is hampered by incomplete understanding of the signaling pathways needed for directed differentiation without forced overexpression of exogenous transgenes. Here we use mouse PSCs to identify key conserved roles for BMP and FGF signaling in regulating thyroid lineage specification from foregut endoderm in mouse and Xenopus. Thyroid progenitors derived from mouse PSCs can be matured into thyroid follicular organoids that provide functional secretion of thyroid hormones in vivo and rescue hypothyroid mice after transplantation. Moreover, by stimulating the same pathways, we were also able to derive human thyroid progenitors from normal and disease-specific iPSCs generated from patients with hypothyroidism resulting from NKX2-1 haploinsufficiency. Our studies have therefore uncovered the regulatory mechanisms that underlie early thyroid organogenesis and provide a significant step toward cell-based regenerative therapy for hypothyroidism. PMID:26593959

  9. Differential relationships between personal and community stressors and children's neurocognitive functioning.

    PubMed

    Fishbein, Diana; Warner, Tara; Krebs, Christopher; Trevarthen, Nancy; Flannery, Barbara; Hammond, Jane

    2009-11-01

    Early adversity can alter development of neurocognition, including executive cognitive and emotional regulatory functions. This is the first study to explore differential relationships between personal (physical and emotional abuse and neglect, school and parental stressors) and community (neighborhood problems and witnessing neighborhood violence) stressors and neurocognition. Predominantly Latino children (n = 553) aged 10 to 12 years completed tasks measuring intelligence, impulsivity, problem solving, cognitive flexibility, decision making, and emotion attributions. Adjusting for age and parent education, bivariate regression analyses found exposure to personal stressors to be associated with relative deficits in at least one neurocognitive function. Community stressors were related to relative deficits in emotion attributions and problem solving. In multivariate analyses, neglect was related to misattributions of emotion and IQ deficits, and physical abuse was related to problem solving. Community stressors were not correlated with neurocognition when viewed relative to personal stressors. Stressor types were differentially associated with performance on specific neurocognitive tasks.

  10. Unsteady Solution of Non-Linear Differential Equations Using Walsh Function Series

    NASA Technical Reports Server (NTRS)

    Gnoffo, Peter A.

    2015-01-01

    Walsh functions form an orthonormal basis set consisting of square waves. The discontinuous nature of square waves make the system well suited for representing functions with discontinuities. The product of any two Walsh functions is another Walsh function - a feature that can radically change an algorithm for solving non-linear partial differential equations (PDEs). The solution algorithm of non-linear differential equations using Walsh function series is unique in that integrals and derivatives may be computed using simple matrix multiplication of series representations of functions. Solutions to PDEs are derived as functions of wave component amplitude. Three sample problems are presented to illustrate the Walsh function series approach to solving unsteady PDEs. These include an advection equation, a Burgers equation, and a Riemann problem. The sample problems demonstrate the use of the Walsh function solution algorithms, exploiting Fast Walsh Transforms in multi-dimensions (O(Nlog(N))). Details of a Fast Walsh Reciprocal, defined here for the first time, enable inversion of aWalsh Symmetric Matrix in O(Nlog(N)) operations. Walsh functions have been derived using a fractal recursion algorithm and these fractal patterns are observed in the progression of pairs of wave number amplitudes in the solutions. These patterns are most easily observed in a remapping defined as a fractal fingerprint (FFP). A prolongation of existing solutions to the next highest order exploits these patterns. The algorithms presented here are considered a work in progress that provide new alternatives and new insights into the solution of non-linear PDEs.

  11. The DIF-Free-Then-DIF Strategy for the Assessment of Differential Item Functioning

    ERIC Educational Resources Information Center

    Wang, Wen-Chung; Shih, Ching-Lin; Sun, Guo-Wei

    2012-01-01

    The DIF-free-then-DIF (DFTD) strategy consists of two steps: (a) select a set of items that are the most likely to be DIF-free and (b) assess the other items for DIF (differential item functioning) using the designated items as anchors. The rank-based method together with the computer software IRTLRDIF can select a set of DIF-free polytomous items…

  12. Finite-difference models of ordinary differential equations - Influence of denominator functions

    NASA Technical Reports Server (NTRS)

    Mickens, Ronald E.; Smith, Arthur

    1990-01-01

    This paper discusses the influence on the solutions of finite-difference schemes of using a variety of denominator functions in the discrete modeling of the derivative for any ordinary differential equation. The results obtained are a consequence of using a generalized definition of the first derivative. A particular example of the linear decay equation is used to illustrate in detail the various solution possibilities that can occur.

  13. Spatial congregation of STAT binding directs selective nuclear architecture during T-cell functional differentiation

    PubMed Central

    Hakim, Ofir; Sung, Myong-Hee; Nakayamada, Shingo; Voss, Ty C.; Baek, Songjoon; Hager, Gordon L.

    2013-01-01

    Higher-order genome organization shows tissue-specific patterns. However, functional relevance and the mechanisms shaping the genome architecture are poorly understood. Here we report a profound shift from promiscuous to highly selective genome organization that accompanies the effector lineage choice of differentiating T cells. As multipotent naive cells receive antigenic signals and commit to a T helper (Th) pathway, the genome-wide contacts of a lineage-specific cytokine locus are preferentially enriched for functionally relevant genes. Despite the establishment of divergent interactomes and global reprogramming of transcription in Th1 versus Th2, the overall expression status of the contact genes is surprisingly similar between the two lineages. Importantly, during differentiation, the genomic contacts are retained and strengthened precisely at DNA binding sites of the specific lineage-determining STAT transcription factor. In cells from the specific STAT knock-out mouse, the signature cytokine locus is unable to shed the promiscuous contacts established in the naive T cells, indicating the importance of genomic STAT binding. Altogether, the global aggregation of STAT binding loci from genic and nongenic regions highlights a new role for differentiation-promoting transcription factors in direct specification of higher-order nuclear architecture through interacting with regulatory regions. Such subnuclear environments have significant implications for efficient functioning of the mature effector lymphocytes. PMID:23212947

  14. Isotonic Modeling with Non-Differentiable Loss Functions with Application to Lasso Regularization.

    PubMed

    Painsky, Amichai; Rosset, Saharon

    2016-02-01

    In this paper we present an algorithmic approach for fitting isotonic models under convex, yet non-differentiable, loss functions. It is a generalization of the greedy non-regret approach proposed by Luss and Rosset (2014) for differentiable loss functions, taking into account the sub-gradiental extensions required. We prove that our suggested algorithm solves the isotonic modeling problem while maintaining favorable computational and statistical properties. As our suggested algorithm may be used for any non-differentiable loss function, we focus our interest on isotonic modeling for either regression or two-class classification with appropriate log-likelihood loss and lasso penalty on the fitted values. This combination allows us to maintain the non-parametric nature of isotonic modeling, while controlling model complexity through regularization. We demonstrate the efficiency and usefulness of this approach on both synthetic and real world data. An implementation of our suggested solution is publicly available from the first author's website (https://sites.google.com/site/amichaipainsky/software).

  15. Assessing impact of differential symptom functioning on post-traumatic stress disorder (PTSD) diagnosis.

    PubMed

    He, Qiwei; Glas, Cees A W; Veldkamp, Bernard P

    2014-06-01

    This article explores the generalizability of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria for post-traumatic stress disorder (PTSD) to various subpopulations. Besides identifying the differential symptom functioning (also referred to as differential item functioning [DIF]) related to various background variables such as gender, marital status and educational level, this study emphasizes the importance of evaluating the impact of DIF on population inferences as made in health surveys and clinical trials, and on the diagnosis of individual patients. Using a sample from the National Comorbidity Study-Replication (NCS-R), four symptoms for gender, one symptom for marital status, and three symptoms for educational level were significantly flagged as DIF, but their impact on diagnosis was fairly small. We conclude that the DSM-IV diagnostic criteria for PTSD do not produce substantially biased results in the investigated subpopulations, and there should be few reservations regarding their use. Further, although the impact of DIF (i.e. the influence of differential symptom functioning on diagnostic results) was found to be quite small in the current study, we recommend that diagnosticians always perform a DIF analysis of various subpopulations using the methodology presented here to ensure the diagnostic criteria is valid in their own studies.

  16. Use of multilevel logistic regression to identify the causes of differential item functioning.

    PubMed

    Balluerka, Nekane; Gorostiaga, Arantxa; Gómez-Benito, Juana; Hidalgo, María Dolores

    2010-11-01

    Given that a key function of tests is to serve as evaluation instruments and for decision making in the fields of psychology and education, the possibility that some of their items may show differential behaviour is a major concern for psychometricians. In recent decades, important progress has been made as regards the efficacy of techniques designed to detect this differential item functioning (DIF). However, the findings are scant when it comes to explaining its causes. The present study addresses this problem from the perspective of multilevel analysis. Starting from a case study in the area of transcultural comparisons, multilevel logistic regression is used: 1) to identify the item characteristics associated with the presence of DIF; 2) to estimate the proportion of variation in the DIF coefficients that is explained by these characteristics; and 3) to evaluate alternative explanations of the DIF by comparing the explanatory power or fit of different sequential models. The comparison of these models confirmed one of the two alternatives (familiarity with the stimulus) and rejected the other (the topic area) as being a cause of differential functioning with respect to the compared groups.

  17. New results for global exponential synchronization in neural networks via functional differential inclusions.

    PubMed

    Wang, Dongshu; Huang, Lihong; Tang, Longkun

    2015-08-01

    This paper is concerned with the synchronization dynamical behaviors for a class of delayed neural networks with discontinuous neuron activations. Continuous and discontinuous state feedback controller are designed such that the neural networks model can realize exponential complete synchronization in view of functional differential inclusions theory, Lyapunov functional method and inequality technique. The new proposed results here are very easy to verify and also applicable to neural networks with continuous activations. Finally, some numerical examples show the applicability and effectiveness of our main results. PMID:26328554

  18. Pointwise estimates of the Green's function of a second order differential operator with the variable coefficient

    NASA Astrophysics Data System (ADS)

    Ashyralyev, Allaberen; Tetikoglu, Fatih Sabahattin

    2015-09-01

    In this study, the Green's function of the second order differential operator Ax defined by the formula Axu =-a (x )ux x(x )+δ u (x ), δ ≥0 , a (x )=a (x +2 π ), x ∈ℝ1 with domain D (Ax)={ u (x ):u (x ),u '(x ),u″(x )∈C (ℝ1),u (x )=u (x +2 π ), x ∈ℝ1,∫0 2 π u (x )d x =0 } is presented. The estimates for the Green's function and it's derivative are obtained. The positivity of the operator Ax is proved.

  19. Cellular Trafficking of Phospholamban and Formation of Functional Sarcoplasmic Reticulum During Myocyte DIfferentiation

    SciTech Connect

    Stenoien, David L.; Knyushko, Tatyana V.; Londono, Monica P.; Opresko, Lee; Mayer, M. Uljana; Brady, Scott T.; Squier, Thomas C.; Bigelow, Diana J.

    2007-06-01

    The sarco/endoplasmic reticulum Ca-ATPase (SERCA) family members are transmembrane proteins that play an essential role in regulating intracellular calcium levels. Phospholamban (PLB), a 52 amino acid phosphoprotein, regulates SERCA activity in adult heart and skeletal muscle. Using the C2C12 myocyte cell line, we find endogenous PLB constitutively expressed in both myoblasts and myotubes, whereas SERCA expression coincides with activation of the differentiation program. PLB has a punctuate distribution in myoblasts changing to a reticular distribution in myotubes where it colocalizes with SERCAs. To examine the distribution and dynamics of PLB and SERCA, we expressed fluorescent fusion proteins (GFP, CFP, and YFP) of PLB and SERCA in myoblasts. Coexpressed PLB and SERCA localize to distinct cellular compartments in myoblasts but begin to colocalize as cells differentiate. Fluorescence Recovery After Photobleaching (FRAP) studies show different recovery patterns for each protein in myoblasts confirming their localization to distinct compartments. To extend these studies, we created stable cell lines expressing O6-alkylguanine-DNA alkyltransferase (AGT) fusions with PLB or SERCA to track their localization as myocytes differentiate. These experiments demonstrate that PLB localizes to punctate vesicles in myoblasts and adopts a reticular distribution that coincides with SERCA distribution after differentiation. Colocalization experiments indicate that a subset of PLB in myoblasts colocalizes with endosomes, Golgi, and the plasma membrane however PLB also localizes to other, as yet unidentified vesicles. Our results indicate that differentiation plays a critical role in regulating PLB distribution to ensure its colocalization within the same cellular compartment as SERCA in differentiated cells. The presence and altered distribution of PLB in undifferentiated myoblasts raises the possibility that this protein has additional functions distinct from SERCA regulation.

  20. Age-related Differential Item Functioning for the Patient-Reported Outcomes Information System (PROMIS®) Physical Functioning Items

    PubMed Central

    Paz, Sylvia H; Spritzer, Karen L; Morales, Leo S; Hays, Ron D

    2013-01-01

    Purpose To evaluate the equivalence of the PROMIS® wave 1 physical functioning item bank, by age (50 years or older versus 18-49). Materials and methods A total of 114 physical functioning items with 5 response choices were administered to English- (n=1504) and Spanish-language (n=640) adults. Item frequencies, means and standard deviations, item-scale correlations, and internal consistency reliability were estimated. Differential Item Functioning (DIF) by age was evaluated. Results Thirty of the 114 items were fagged for DIF based on an R-squared of 0.02 or above criterion. The expected total score was higher for those respondents who were 18-49 than those who were 50 or older. Conclusions Those who were 50 years or older versus 18-49 years old with the same level of physical functioning responded differently to 30 of the 114 items in the PROMIS® physical functioning item bank. This study yields essential information about the equivalence of the physical functioning items in older versus younger individuals. PMID:24052925

  1. Stimulus set meaningfulness and neurophysiological differentiation: a functional magnetic resonance imaging study.

    PubMed

    Boly, Melanie; Sasai, Shuntaro; Gosseries, Olivia; Oizumi, Masafumi; Casali, Adenauer; Massimini, Marcello; Tononi, Giulio

    2015-01-01

    A meaningful set of stimuli, such as a sequence of frames from a movie, triggers a set of different experiences. By contrast, a meaningless set of stimuli, such as a sequence of 'TV noise' frames, triggers always the same experience--of seeing 'TV noise'--even though the stimuli themselves are as different from each other as the movie frames. We reasoned that the differentiation of cortical responses underlying the subject's experiences, as measured by Lempel-Ziv complexity (incompressibility) of functional MRI images, should reflect the overall meaningfulness of a set of stimuli for the subject, rather than differences among the stimuli. We tested this hypothesis by quantifying the differentiation of brain activity patterns in response to a movie sequence, to the same movie scrambled in time, and to 'TV noise', where the pixels from each movie frame were scrambled in space. While overall cortical activation was strong and widespread in all conditions, the differentiation (Lempel-Ziv complexity) of brain activation patterns was correlated with the meaningfulness of the stimulus set, being highest in the movie condition, intermediate in the scrambled movie condition, and minimal for 'TV noise'. Stimulus set meaningfulness was also associated with higher information integration among cortical regions. These results suggest that the differentiation of neural responses can be used to assess the meaningfulness of a given set of stimuli for a given subject, without the need to identify the features and categories that are relevant to the subject, nor the precise location of selective neural responses.

  2. Olig1 function is required for oligodendrocyte differentiation in the mouse brain.

    PubMed

    Dai, Jinxiang; Bercury, Kathryn K; Ahrendsen, Jared T; Macklin, Wendy B

    2015-03-11

    Oligodendrocyte differentiation and myelination are tightly regulated processes orchestrated by a complex transcriptional network. Two bHLH transcription factors in this network, Olig1 and Olig2, are expressed exclusively by oligodendrocytes after late embryonic development. Although the role of Olig2 in the lineage is well established, the role of Olig1 is still unclear. The current studies analyzed the function of Olig1 in oligodendrocyte differentiation and developmental myelination in brain. Both oligodendrocyte progenitor cell commitment and oligodendrocyte differentiation were impaired in the corpus callosum of Olig1-null mice, resulting in hypomyelination throughout adulthood in the brain. As seen in previous studies with this mouse line, although there was an early myelination deficit in the spinal cord, essentially full recovery with normal spinal cord myelination was seen. Intriguingly, this regional difference may be partially attributed to compensatory upregulation of Olig2 protein expression in the spinal cord after Olig1 deletion, which is not seen in brain. The current study demonstrates a unique role for Olig1 in promoting oligodendrocyte progenitor cell commitment, differentiation, and subsequent myelination primarily in brain, but not spinal cord.

  3. Functions of Heterogeneous Nuclear Ribonucleoproteins in Stem Cell Potency and Differentiation

    PubMed Central

    Chen, Qishan; Jin, Min; Zhu, Jianhua; Zhang, Li

    2013-01-01

    Stem cells possess huge importance in developmental biology, disease modelling, cell replacement therapy, and tissue engineering in regenerative medicine because they have the remarkable potential for self-renewal and to differentiate into almost all the cell types in the human body. Elucidation of molecular mechanisms regulating stem cell potency and differentiation is essential and critical for extensive application. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are modular proteins consisting of RNA-binding motifs and auxiliary domains characterized by extensive and divergent functions in nucleic acid metabolism. Multiple roles of hnRNPs in transcriptional and posttranscriptional regulation enable them to be effective gene expression regulators. More recent findings show that hnRNP proteins are crucial factors implicated in maintenance of stem cell self-renewal and pluripotency and cell differentiation. The hnRNPs interact with certain sequences in target gene promoter regions to initiate transcription. In addition, they recognize 3′UTR or 5′UTR of specific gene mRNA forming mRNP complex to regulate mRNA stability and translation. Both of these regulatory pathways lead to modulation of gene expression that is associated with stem cell proliferation, cell cycle control, pluripotency, and committed differentiation. PMID:23984388

  4. The characterisation and functional β-cell differentiation of duck pancreas-derived mesenchymal cells.

    PubMed

    Zhang, S; Bai, C Y; Ma, Y H; Li, X C; Gao, Y H; Fan, Y N; Guan, W J; Zheng, D

    2016-04-01

    The generation of insulin-producing pancreatic β-cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation therapy in diabetes research. The fractionation, expansion and conversion of primary duck pancreas-derived mesenchymal stem cells (PSCs) into functional β-cells are described in this study. The cell surface antigens of PSCs, FOXA2, SOX9, NKX6.1 and INS were detected by immunofluorescent stain and flow cytometry for determining the biological characteristics of PSCs. The genes CD44, Ki67, Vimentin, C-myc, glucagon, PDX1 and insulin were detected by reverse-transcription polymerase chain reaction techniques. The growth curves of different passages were all typically sigmoidal. Karyotype analysis was conducted to estimate the stability of PSCs. A simple protocol was developed to assess functional differentiation by assessing the expression of pancreas β-cell markers, the staining of dithizone and confirmation of insulin secretion. Insulin and PDX1 were all increased in differentiated cells compared to controls. Differentiated cells secreted insulin in a glucose-responsive manner. PMID:26727993

  5. Pax3 functions at a nodal point in melanocyte stem cell differentiation.

    PubMed

    Lang, Deborah; Lu, Min Min; Huang, Li; Engleka, Kurt A; Zhang, Maozhen; Chu, Emily Y; Lipner, Shari; Skoultchi, Arthur; Millar, Sarah E; Epstein, Jonathan A

    2005-02-24

    Most stem cells are not totipotent. Instead, they are partially committed but remain undifferentiated. Upon appropriate stimulation they are capable of regenerating mature cell types. Little is known about the genetic programmes that maintain the undifferentiated phenotype of lineage-restricted stem cells. Here we describe the molecular details of a nodal point in adult melanocyte stem cell differentiation in which Pax3 simultaneously functions to initiate a melanogenic cascade while acting downstream to prevent terminal differentiation. Pax3 activates expression of Mitf, a transcription factor critical for melanogenesis, while at the same time it competes with Mitf for occupancy of an enhancer required for expression of dopachrome tautomerase, an enzyme that functions in melanin synthesis. Pax3-expressing melanoblasts are thus committed but undifferentiated until Pax3-mediated repression is relieved by activated beta-catenin. Thus, a stem cell transcription factor can both determine cell fate and simultaneously maintain an undifferentiated state, leaving a cell poised to differentiate in response to external stimuli. PMID:15729346

  6. Dynamic competition between large-scale functional networks differentiates fear conditioning and extinction in humans.

    PubMed

    Marstaller, Lars; Burianová, Hana; Reutens, David C

    2016-07-01

    The high evolutionary value of learning when to respond to threats or when to inhibit previously learned associations after changing threat contingencies is reflected in dedicated networks in the animal and human brain. Recent evidence further suggests that adaptive learning may be dependent on the dynamic interaction of meta-stable functional brain networks. However, it is still unclear which functional brain networks compete with each other to facilitate associative learning and how changes in threat contingencies affect this competition. The aim of this study was to assess the dynamic competition between large-scale networks related to associative learning in the human brain by combining a repeated differential conditioning and extinction paradigm with independent component analysis of functional magnetic resonance imaging data. The results (i) identify three task-related networks involved in initial and sustained conditioning as well as extinction, and demonstrate that (ii) the two main networks that underlie sustained conditioning and extinction are anti-correlated with each other and (iii) the dynamic competition between these two networks is modulated in response to changes in associative contingencies. These findings provide novel evidence for the view that dynamic competition between large-scale functional networks differentiates fear conditioning from extinction learning in the healthy brain and suggest that dysfunctional network dynamics might contribute to learning-related neuropsychiatric disorders.

  7. Dynamic competition between large-scale functional networks differentiates fear conditioning and extinction in humans.

    PubMed

    Marstaller, Lars; Burianová, Hana; Reutens, David C

    2016-07-01

    The high evolutionary value of learning when to respond to threats or when to inhibit previously learned associations after changing threat contingencies is reflected in dedicated networks in the animal and human brain. Recent evidence further suggests that adaptive learning may be dependent on the dynamic interaction of meta-stable functional brain networks. However, it is still unclear which functional brain networks compete with each other to facilitate associative learning and how changes in threat contingencies affect this competition. The aim of this study was to assess the dynamic competition between large-scale networks related to associative learning in the human brain by combining a repeated differential conditioning and extinction paradigm with independent component analysis of functional magnetic resonance imaging data. The results (i) identify three task-related networks involved in initial and sustained conditioning as well as extinction, and demonstrate that (ii) the two main networks that underlie sustained conditioning and extinction are anti-correlated with each other and (iii) the dynamic competition between these two networks is modulated in response to changes in associative contingencies. These findings provide novel evidence for the view that dynamic competition between large-scale functional networks differentiates fear conditioning from extinction learning in the healthy brain and suggest that dysfunctional network dynamics might contribute to learning-related neuropsychiatric disorders. PMID:27079532

  8. Multi-voxel Patterns Reveal Functionally Differentiated Networks Underlying Auditory Feedback Processing of Speech

    PubMed Central

    Zheng, Zane Z.; Vicente-Grabovetsky, Alejandro; MacDonald, Ewen N.; Munhall, Kevin G.; Cusack, Rhodri; Johnsrude, Ingrid S.

    2013-01-01

    The everyday act of speaking involves the complex processes of speech motor control. An important component of control is monitoring, detection and processing of errors when auditory feedback does not correspond to the intended motor gesture. Here we show, using fMRI and converging operations within a multi-voxel pattern analysis framework, that this sensorimotor process is supported by functionally differentiated brain networks. During scanning, a real-time speech-tracking system was employed to deliver two acoustically different types of distorted auditory feedback or unaltered feedback while human participants were vocalizing monosyllabic words, and to present the same auditory stimuli while participants were passively listening. Whole-brain analysis of neural-pattern similarity revealed three functional networks that were differentially sensitive to distorted auditory feedback during vocalization, compared to during passive listening. One network of regions appears to encode an ‘error signal’ irrespective of acoustic features of the error: this network, including right angular gyrus, right supplementary motor area, and bilateral cerebellum, yielded consistent neural patterns across acoustically different, distorted feedback types, only during articulation (not during passive listening). In contrast, a fronto-temporal network appears sensitive to the speech features of auditory stimuli during passive listening; this preference for speech features was diminished when the same stimuli were presented as auditory concomitants of vocalization. A third network, showing a distinct functional pattern from the other two, appears to capture aspects of both neural response profiles. Taken together, our findings suggest that auditory feedback processing during speech motor control may rely on multiple, interactive, functionally differentiated neural systems. PMID:23467350

  9. Electrical double layers and differential capacitance in molten salts from density functional theory

    DOE PAGESBeta

    Frischknecht, Amalie L.; Halligan, Deaglan O.; Parks, Michael L.

    2014-08-05

    Classical density functional theory (DFT) is used to calculate the structure of the electrical double layer and the differential capacitance of model molten salts. The DFT is shown to give good qualitative agreement with Monte Carlo simulations in the molten salt regime. The DFT is then applied to three common molten salts, KCl, LiCl, and LiKCl, modeled as charged hard spheres near a planar charged surface. The DFT predicts strong layering of the ions near the surface, with the oscillatory density profiles extending to larger distances for larger electrostatic interactions resulting from either lower temperature or lower dielectric constant. Inmore » conclusion, overall the differential capacitance is found to be bell-shaped, in agreement with recent theories and simulations for ionic liquids and molten salts, but contrary to the results of the classical Gouy-Chapman theory.« less

  10. Human amnion epithelial cells can be induced to differentiate into functional insulin-producing cells.

    PubMed

    Hou, Yanan; Huang, Qin; Liu, Tianjin; Guo, Lihe

    2008-09-01

    Pancreatic islet transplantation has demonstrated that long-term insulin independence may be achieved in patients suffering from diabetes mellitus type 1. However, limited availability of islet tissue means that new sources of insulin-producing cells that are responsive to glucose are required. Here, we show that human amnion epithelial cells (HAEC) can be induced to differentiate into functional insulin-producing cells in vitro. After induction of differentiation, HAEC expressed multiple pancreatic beta-cell genes, including insulin, pancreas duodenum homeobox-1, paired box gene 6, NK2 transcription factor-related locus 2, Islet 1, glucokinase, and glucose transporter-2, and released C-peptide in a glucose-regulated manner in response to other extracellular stimulations. The transplantation of induced HAEC into streptozotocin-induced diabetic C57 mice reversed hyperglycemia, restored body weight, and maintained euglycemia for 30 d. These findings indicated that HAEC may be a new source for cell replacement therapy in type 1 diabetes.

  11. Usefulness of acoustic studies on the differential diagnostics of organic and functional dysphonia.

    PubMed

    Pruszewicz, A; Obrebowski, A; Swidziński, P; Demeńko, G; Wika, T; Wojciechowska, A

    1991-01-01

    Phoniatric and acoustic examinations were carried out in a group of 30 patients with dysphonia, including 15 with organic type and 15 with functional type. A complex phoniatric assessment offered the possibility to differentiate between these two groups of pathological voices. This was achieved also on the basis of acoustic analysis of the voice by extracting characteristics such as: formant frequency, Fo and its range, percentage of noise in the analysed verbal text, mean and maximum values of jitter. The possibility of differential diagnosis of these two different types of dysphonia in acoustic studies was confirmed by clinical examinations. The acoustic studies presented can be regarded as a new approach to a fast and sufficiently precise method in the screening diagnostics of dysphonia conditioned by growth of the vocal fold mass.

  12. Electrical double layers and differential capacitance in molten salts from density functional theory

    SciTech Connect

    Frischknecht, Amalie L.; Halligan, Deaglan O.; Parks, Michael L.

    2014-08-05

    Classical density functional theory (DFT) is used to calculate the structure of the electrical double layer and the differential capacitance of model molten salts. The DFT is shown to give good qualitative agreement with Monte Carlo simulations in the molten salt regime. The DFT is then applied to three common molten salts, KCl, LiCl, and LiKCl, modeled as charged hard spheres near a planar charged surface. The DFT predicts strong layering of the ions near the surface, with the oscillatory density profiles extending to larger distances for larger electrostatic interactions resulting from either lower temperature or lower dielectric constant. In conclusion, overall the differential capacitance is found to be bell-shaped, in agreement with recent theories and simulations for ionic liquids and molten salts, but contrary to the results of the classical Gouy-Chapman theory.

  13. Electrical double layers and differential capacitance in molten salts from density functional theory.

    PubMed

    Frischknecht, Amalie L; Halligan, Deaglan O; Parks, Michael L

    2014-08-01

    Classical density functional theory (DFT) is used to calculate the structure of the electrical double layer and the differential capacitance of model molten salts. The DFT is shown to give good qualitative agreement with Monte Carlo simulations in the molten salt regime. The DFT is then applied to three common molten salts, KCl, LiCl, and LiKCl, modeled as charged hard spheres near a planar charged surface. The DFT predicts strong layering of the ions near the surface, with the oscillatory density profiles extending to larger distances for larger electrostatic interactions resulting from either lower temperature or lower dielectric constant. Overall the differential capacitance is found to be bell-shaped, in agreement with recent theories and simulations for ionic liquids and molten salts, but contrary to the results of the classical Gouy-Chapman theory.

  14. Physical mapping of a functional cluster of epidermal differentiation genes on chromosome 1q21

    SciTech Connect

    Volz, A.; Ziegler, A.; Mischke, D. ); Korge, B.P.; Compton, J.G.; Steinert, P.M. )

    1993-10-01

    Genes of three protein families, which are in part specifically expressed in the course of terminal differentiation of human epidermis, have previously been mapped to chromosome 1q21. Here, the authors show that these genes are physically linked within 2.05 Mb of DNA. The order is calpactin I light chain, trichohyalin, profilaggrin, involucrin/small proline-rich protein, loricrin, and calcyclin. The colocalization in the 1q21 region together with their functional interdependence during epidermal differentiation raises the question whether these genes share regulatory elements which control their transcriptional activities. As several of them are potential candidate genes for dyskeratotic skin diseases, this physical map should be of great value for genetic linkage analyses. 55 refs., 3 figs., 1 tab.

  15. Effect of RGD-functionalization and stiffness modulation of polyelectrolyte multilayer films on muscle cell differentiation

    PubMed Central

    Gribova, Varvara; Gauthier-Rouvière, Cécile; Albigès-Rizo, Corinne; Auzely-Velty, Rachel; Picart, Catherine

    2014-01-01

    Skeletal muscle tissue engineering holds promise for the replacement of muscle due to an injury and for the treatment of muscle diseases. Although RGD substrates have been widely explored in tissue engineering, there is no study aimed at investigating the combined effects of RGD nanoscale presentation and matrix stiffness on myogenesis. In the present work, we use polyelectrolyte multilayer films made of poly(L-lysine) (PLL) and poly(L-glutamic) acid (PGA) as substrates of tunable stiffness that can be functionalized by a RGD adhesive peptide to investigate important events in myogenesis, including adhesion, migration, proliferation and differentiation. C2C12 myoblasts were used as cellular models. RGD presentation on soft films and increased film stiffness could both induce cell adhesion, but integrins involved in adhesion were different in case of soft and stiff films. Moreover, soft films with RGD peptide appeared to be the most appropriate substrate for myogenic differentiation while the stiff PLL/PGA films significantly induced cell migration, proliferation and inhibited myogenic differentiation. The ROCK kinase was found to be involved in myoblast response to the different films. Indeed, its inhibition was sufficient to rescue the differentiation on stiff films, but no significant changes were observed on stiff films with the RGD peptide. These results suggest that different signaling pathways may be activated depending on mechanical and biochemical properties of the multilayer films. This study emphasizes the superior advantage of the soft PLL/PGA films presenting the RGD peptide in terms of myogenic differentiation. This soft RGD-presenting film may be further used as coating of various polymeric scaffolds for muscle tissue engineering. PMID:23261924

  16. Expression Patterns and Function of Chromatin Protein HMGB2 during Mesenchymal Stem Cell Differentiation*

    PubMed Central

    Taniguchi, Noboru; Caramés, Beatriz; Hsu, Emily; Cherqui, Stephanie; Kawakami, Yasuhiko; Lotz, Martin

    2011-01-01

    The superficial zone (SZ) of articular cartilage is critical in maintaining tissue function and homeostasis and represents the site of the earliest changes in osteoarthritis (OA). The expression of chromatin protein HMGB2 is restricted to the SZ, which contains cells expressing mesenchymal stem cell (MSC) markers. Age-related loss of HMGB2 and gene deletion are associated with reduced SZ cellularity and early onset OA. This study addressed HMGB2 expression patterns in MSC and its role during differentiation. HMGB2 was detected at higher levels in human MSC as compared with human articular chondrocytes, and its expression declined during chondrogenic differentiation of MSC. Lentiviral HMGB2 transduction of MSC suppressed chondrogenesis as reflected by an inhibition of Col2a1 and Col10a1 expression. Conversely, in bone marrow MSC from Hmgb2−/− mice, Col10a1 was more strongly expressed than in wild-type MSC. This is consistent with in vivo results from mouse growth plates showing that Hmgb2 is expressed in proliferating and prehypertrophic zones but not in hypertrophic cartilage where Col10a1 is strongly expressed. Osteogenesis was also accelerated in Hmgb2−/− MSC. The expression of Runx2, which plays a major role in late stage chondrocyte differentiation, was enhanced in Hmgb2−/− MSC, and HMGB2 negatively regulated the stimulatory effect of Wnt/β-catenin signaling on the Runx2 proximal promoter. These results demonstrate that HMGB2 expression is inversely correlated with the differentiation status of MSC and that HMGB2 suppresses chondrogenic differentiation. The age-related loss of HMGB2 in articular cartilage may represent a mechanism responsible for the decline in adult cartilage stem cell populations. PMID:21890638

  17. Differentiating the stem cell pool of human hair follicle outer root sheath into functional melanocytes.

    PubMed

    Schneider, Marie; Dieckmann, Christina; Rabe, Katrin; Simon, Jan-Christoph; Savkovic, Vuk

    2014-01-01

    Bench-to-Bedside concepts for regenerative therapy place significant weight on noninvasive approaches, with harvesting of the starting material as a header. This is particularly important in autologous treatments, which use one's bodily constituents for therapy. Precisely the stretch between obtaining therapeutic elements invasively and noninvasively places non-intrusive "sampling" rather than "biopsy" in the center of the road map of developing an autologous regenerative therapy. We focus on such a noninvasively available source of adult stem cells that we carry with us throughout our life, available at our fingertips-or shall we say hair roots, by a simple plucking of hair: the human hair follicle. This chapter describes an explant procedure for cultivating melanocytes differentiated from the stem cell pool of the hair follicle Outer Root Sheath (ORS). In vivo, the most abundant derivatives of the heterogeneous ORS stem cell pool are epidermal cells-melanocytes and keratinocytes which complete their differentiation-either spontaneously or upon picking up regenerative cues from damaged skin-and migrate from the ORS towards the adjacent regenerating area of the epidermis. We have taken advantage of the ORS developmental potential by optimizing explant primary culture, expansion and melanogenic differentiation of resident ORS stem cells towards end-stage melanocytes in order to obtain functional melanocytes noninvasively for the purposes of transplantation and use them for the treatment of depigmentation disorders. Our protocol specifies sampling of hair with their ORS, follicle medium-air interface primary culture, stimulation of cell outgrowth, adherent culture and differentiation of ORS stem cells and precursors towards fully functional melanocytes. Along with cultivation, we describe selection techniques for establishing and maintaining a pure melanocyte population and methods suitable for determining melanocyte identity.

  18. Negative differential conductance in two-dimensional C-functionalized boronitrene

    NASA Astrophysics Data System (ADS)

    Obodo, J. T.; Obodo, K. O.; Schwingenschlögl, U.

    2015-09-01

    It recently has been demonstrated that the large band gap of boronitrene can be significantly reduced by C functionalization. We show that specific defect configurations even can result in metallicity, raising interest in the material for electronic applications. We thus study the transport properties of C-functionalized boronitrene using the non-equilibrium Green's function formalism. We investigate various zigzag and armchair defect configurations, spanning wide band gap semiconducting to metallic states. Unusual I-V characteristics are found and explained in terms of the energy and bias-dependent transmission coefficient and wavefunction. In particular, we demonstrate negative differential conductance with high peak-to-valley ratios, depending on the details of the substitutional doping, and identify the finite bias effects that are responsible for this behavior.

  19. Differential effects of hunger and satiety on insular cortex and hypothalamic functional connectivity.

    PubMed

    Wright, Hazel; Li, Xiaoyun; Fallon, Nicholas B; Crookall, Rebecca; Giesbrecht, Timo; Thomas, Anna; Halford, Jason C G; Harrold, Joanne; Stancak, Andrej

    2016-05-01

    The insula cortex and hypothalamus are implicated in eating behaviour, and contain receptor sites for peptides and hormones controlling energy balance. The insula encompasses multi-functional subregions, which display differential anatomical and functional connectivities with the rest of the brain. This study aimed to analyse the effect of fasting and satiation on the functional connectivity profiles of left and right anterior, middle, and posterior insula, and left and right hypothalamus. It was hypothesized that the profiles would be altered alongside changes in homeostatic energy balance. Nineteen healthy participants underwent two 7-min resting state functional magnetic resonance imaging scans, one when fasted and one when satiated. Functional connectivity between the left posterior insula and cerebellum/superior frontal gyrus, and between left hypothalamus and inferior frontal gyrus was stronger during fasting. Functional connectivity between the right middle insula and default mode structures (left and right posterior parietal cortex, cingulate cortex), and between right hypothalamus and superior parietal cortex was stronger during satiation. Differences in blood glucose levels between the scans accounted for several of the altered functional connectivities. The insula and hypothalamus appear to form a homeostatic energy balance network related to cognitive control of eating; prompting eating and preventing overeating when energy is depleted, and ending feeding or transferring attention away from food upon satiation. This study provides evidence of a lateralized dissociation of neural responses to energy modulations. PMID:26790868

  20. Differential effects of hunger and satiety on insular cortex and hypothalamic functional connectivity.

    PubMed

    Wright, Hazel; Li, Xiaoyun; Fallon, Nicholas B; Crookall, Rebecca; Giesbrecht, Timo; Thomas, Anna; Halford, Jason C G; Harrold, Joanne; Stancak, Andrej

    2016-05-01

    The insula cortex and hypothalamus are implicated in eating behaviour, and contain receptor sites for peptides and hormones controlling energy balance. The insula encompasses multi-functional subregions, which display differential anatomical and functional connectivities with the rest of the brain. This study aimed to analyse the effect of fasting and satiation on the functional connectivity profiles of left and right anterior, middle, and posterior insula, and left and right hypothalamus. It was hypothesized that the profiles would be altered alongside changes in homeostatic energy balance. Nineteen healthy participants underwent two 7-min resting state functional magnetic resonance imaging scans, one when fasted and one when satiated. Functional connectivity between the left posterior insula and cerebellum/superior frontal gyrus, and between left hypothalamus and inferior frontal gyrus was stronger during fasting. Functional connectivity between the right middle insula and default mode structures (left and right posterior parietal cortex, cingulate cortex), and between right hypothalamus and superior parietal cortex was stronger during satiation. Differences in blood glucose levels between the scans accounted for several of the altered functional connectivities. The insula and hypothalamus appear to form a homeostatic energy balance network related to cognitive control of eating; prompting eating and preventing overeating when energy is depleted, and ending feeding or transferring attention away from food upon satiation. This study provides evidence of a lateralized dissociation of neural responses to energy modulations.

  1. Endocrine disruptors and human corpus luteum: in vitro effects of phenols on luteal cells function.

    PubMed

    Romani, Federica; Tropea, Anna; Scarinci, Elisa; Dello Russo, Cinzia; Lisi, Lucia; Catino, Stefania; Lanzone, Antonio; Apa, Rosanna

    2013-01-01

    Endocrine disruptors are well known to impair fertility. The aim of the present study was to investigate the effects of bisphenol A (BPA) and nonylphenol (p-NP) on human luteal function in vitro. In particular, in luteal cells isolated from 21 human corpora lutea progesterone, prostaglandin (PG) F2α, PGE2 and vascular endothelial growth factor (VEGF) release, as well as VEGF expression were evaluated. BPA and p-NP negatively affected both luteal steroidogenesis and luteotrophic/ luteolytic factors balance, without influencing VEGF mRNA expression. Actually, BPA and p-NP impaired human luteal cells function in vitro, underlining the already suggested correlation between phenols and reproductive failure.

  2. Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling

    PubMed Central

    Hay, David C.; Fletcher, Judy; Payne, Catherine; Terrace, John D.; Gallagher, Ronald C. J.; Snoeys, Jan; Black, James R.; Wojtacha, Davina; Samuel, Kay; Hannoun, Zara; Pryde, Anne; Filippi, Celine; Currie, Ian S.; Forbes, Stuart J.; Ross, James A.; Newsome, Philip N.; Iredale, John P.

    2008-01-01

    Human embryonic stem cells (hESCs) are a valuable source of pluripotential primary cells. To date, however, their homogeneous cellular differentiation to specific cell types in vitro has proven difficult. Wnt signaling has been shown to play important roles in coordinating development, and we demonstrate that Wnt3a is differentially expressed at critical stages of human liver development in vivo. The essential role of Wnt3a in hepatocyte differentiation from hESCs is paralleled by our in vitro model, demonstrating the importance of a physiologic approach to cellular differentiation. Our studies provide compelling evidence that Wnt3a signaling is important for coordinated hepatocellular function in vitro and in vivo. In addition, we demonstrate that Wnt3a facilitates clonal plating of hESCs exhibiting functional hepatic differentiation. These studies represent an important step toward the use of hESC-derived hepatocytes in high-throughput metabolic analysis of human liver function. PMID:18719101

  3. Mitochondrial (Dys)function in Adipocyte (De)differentiation and Systemic Metabolic Alterations

    PubMed Central

    De Pauw, Aurélia; Tejerina, Silvia; Raes, Martine; Keijer, Jaap; Arnould, Thierry

    2009-01-01

    In mammals, adipose tissue, composed of BAT and WAT, collaborates in energy partitioning and performs metabolic regulatory functions. It is the most flexible tissue in the body, because it is remodeled in size and shape by modifications in adipocyte cell size and/or number, depending on developmental status and energy fluxes. Although numerous reviews have focused on the differentiation program of both brown and white adipocytes as well as on the pathophysiological role of white adipose tissues, the importance of mitochondrial activity in the differentiation or the dedifferentiation programs of adipose cells and in systemic metabolic alterations has not been extensively reviewed previously. Here, we address the crucial role of mitochondrial functions during adipogenesis and in mature adipocytes and discuss the cellular responses of white adipocytes to mitochondrial activity impairment. In addition, we discuss the increase in scientific knowledge regarding mitochondrial functions in the last 10 years and the recent suspicion of mitochondrial dysfunction in several 21st century epidemics (ie, obesity and diabetes), as well as in lipodystrophy found in HIV-treated patients, which can contribute to the development of new therapeutic strategies targeting adipocyte mitochondria. PMID:19700756

  4. Solutions to an advanced functional partial differential equation of the pantograph type

    PubMed Central

    Zaidi, Ali A.; Van Brunt, B.; Wake, G. C.

    2015-01-01

    A model for cells structured by size undergoing growth and division leads to an initial boundary value problem that involves a first-order linear partial differential equation with a functional term. Here, size can be interpreted as DNA content or mass. It has been observed experimentally and shown analytically that solutions for arbitrary initial cell distributions are asymptotic as time goes to infinity to a certain solution called the steady size distribution. The full solution to the problem for arbitrary initial distributions, however, is elusive owing to the presence of the functional term and the paucity of solution techniques for such problems. In this paper, we derive a solution to the problem for arbitrary initial cell distributions. The method employed exploits the hyperbolic character of the underlying differential operator, and the advanced nature of the functional argument to reduce the problem to a sequence of simple Cauchy problems. The existence of solutions for arbitrary initial distributions is established along with uniqueness. The asymptotic relationship with the steady size distribution is established, and because the solution is known explicitly, higher-order terms in the asymptotics can be readily obtained. PMID:26345391

  5. Differential expression and functional constraint of PRL-2 in hibernating bat.

    PubMed

    Yuan, Lihong; Chen, Jinping; Lin, Benfu; Zhang, Junpeng; Zhang, Shuyi

    2007-12-01

    Circannual hibernation is a biological adaptation to periods of cold and food shortage and the role of the brain in its control is poorly understood. An SSH library of hibernating bat brains (Rhinolophus ferrumequinum) was constructed in order to explore the molecular mechanism of hibernation. An up-regulated gene, PRL-2, was obtained from hibernating bat brains. PRL-2 is a member of PTP family and has an important function in controlling cell growth. Alignment of sequences showed that PRL-2 is highly conserved among species, including two species of hibernating bats (R. ferrumequinum and Myotis ricketti). Moreover, Maximum Likelihood Analysis suggested that it may experience strong selection pressure leading to functional constraint in evolution, which indicated the significance of PRL-2 in normal bio-function. RQ-PCR was performed and statistical analysis suggested that PRL-2 exhibited distinct differential expression patterns in different organs during hibernation. In heart, fat and brain tissue of hibernating bats, the transcriptional level of PRL-2 increased almost 170%, 35% and 12% respectively. However, in muscle it decreased nearly 70%. The change of mRNA level of PRL-2 in heart tissue of hibernating bats was significantly higher than that in heart tissue of active controls (P=0.043). However, the regulation mechanism of differential expression of PRL-2 and the signal pathway involved are still unknown. PMID:17683965

  6. Exposure of Monocytes to Lipoarabinomannan Promotes Their Differentiation into Functionally and Phenotypically Immature Macrophages

    PubMed Central

    Chávez-Galán, Leslie; Ocaña-Guzmán, Ranferi; Torre-Bouscoulet, Luis; García-de-Alba, Carolina; Sada-Ovalle, Isabel

    2015-01-01

    Lipoarabinomannan (LAM) is a lipid virulence factor secreted by Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis. LAM can be measured in the urine or serum of tuberculosis patients (TB-patients). Circulating monocytes are the precursor cells of alveolar macrophages and might be exposed to LAM in patients with active TB. We speculated that exposing monocytes to LAM could produce phenotypically and functionally immature macrophages. To test our hypothesis, human monocytes were stimulated with LAM (24–120 hours) and various readouts were measured. The study showed that when monocytes were exposed to LAM, the frequency of CD68+, CD33+, and CD86+ macrophages decreased, suggesting that monocyte differentiation into mature macrophages was affected. Regarding functionality markers, TLR2+ and TLR4+ macrophages also decreased, but the percentage of MMR+ expression did not change. LAM-exposed monocytes generated macrophages that were less efficient in producing proinflammatory cytokines such as TNF-α and IFN-γ; however, their phagocytic capacity was not modified. Taken together, these data indicate that LAM exposure influenced monocyte differentiation and produced poorly functional macrophages with a different phenotype. These results may help us understand how mycobacteria can limit the quality of the innate and adaptive immune responses. PMID:26347897

  7. Importance of renal depth correction for quantitation of differential renal function

    SciTech Connect

    Choi, H.; Kirchner, P.T.

    1985-05-01

    To assess the frequency and magnitude of errors caused by asymmetries in renal depth, when estimates of differential function are based only posterior projections (as in DTPA studies). The authors compared ratios of right-to-left (R/L) DMSA localization derived from posterior camera images with R/L ratios based on geometric mean of posterior and anterior counts of each kidney. The factor (X) required to convert the ratio of R/L posterior counts to the more accurate R/L geometric counts (Rp/Lp.X = Rg/Lg) was determined in 55 randomly selected patients referred for DMSA studies. Frequency distributions for X and l/X reveal that the use of posterior counts alone is likely to produce differential flow/function estimates with errors greater than 30% in 5% of patients, greater than 20% in 16 of patients. Lack of depth correction also widens the normal range derived from normal controls, thus reducing sensitivity and specificity of quantitative renal studies by two different mechanisms. The authors recommend routine application of depth correction by conjugate counting or ultrasound techniques for all quantitations of renal function.

  8. Existence, uniqueness, and stability of stochastic neutral functional differential equations of Sobolev-type

    SciTech Connect

    Yang, Xuetao; Zhu, Quanxin

    2015-12-15

    In this paper, we are mainly concerned with a class of stochastic neutral functional differential equations of Sobolev-type with Poisson jumps. Under two different sets of conditions, we establish the existence of the mild solution by applying the Leray-Schauder alternative theory and the Sadakovskii’s fixed point theorem, respectively. Furthermore, we use the Bihari’s inequality to prove the Osgood type uniqueness. Also, the mean square exponential stability is investigated by applying the Gronwall inequality. Finally, two examples are given to illustrate the theory results.

  9. Persistence and Permanence for a Class of Functional Differential Equations with Infinite Delay

    NASA Astrophysics Data System (ADS)

    Faria, Teresa

    2016-09-01

    The paper deals with a class of cooperative functional differential equations (FDEs) with infinite delay, for which sufficient conditions for persistence and permanence are established. Here, the persistence refers to all solutions with initial conditions that are positive, continuous and bounded. The present method applies to a very broad class of abstract systems of FDEs with infinite delay, both autonomous and non-autonomous, which include many important models used in mathematical biology. Moreover, the hypotheses imposed are in general very easy to check. The results are illustrated with some selected examples.

  10. [XS-DIF: program for analysis of Differential Item Functioning in Excel].

    PubMed

    Ordóñez, Xavier G; Romero, Sonia J

    2007-02-01

    XS-DIF is a program for detection of Differential Item Functioning (DIF) using Item Response Theory (IRT). It calculates Lords Chi-Square, Raju's Signed Area and Unsigned Area, and Kim and Cohen's Closed-interval signed area and Closed-interval unsigned area. XS-DIF was designed to be executed in Excel 2000 and it has a capacity of analysis of up to 100 items. It is useful to support data analysis of research projects and in detection and teaching processes in DIF.

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

    PubMed

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

    2016-01-01

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

  12. Differential PAX3 functions in normal skin melanocytes and melanoma cells

    SciTech Connect

    Medic, Sandra; Rizos, Helen; Ziman, Mel

    2011-08-12

    Highlights: {yields} PAX3 retains embryonic roles in adult melanocytes and melanoma cells. {yields} Promotes 'stem' cell-like phenotype via NES and SOX9 in both cells types. {yields} Regulates melanoma and melanocyte migration through MCAM and CSPG4. {yields} PAX3 regulates melanoma but not melanocyte proliferation via TPD52. {yields} Regulates melanoma cell (but not melanocyte) survival via BCL2L1 and PTEN. -- Abstract: The PAX3 transcription factor is the key regulator of melanocyte development during embryogenesis and is also frequently found in melanoma cells. While PAX3 is known to regulate melanocyte differentiation, survival, proliferation and migration during development, it is not clear if its function is maintained in adult melanocytes and melanoma cells. To clarify this we have assessed which genes are targeted by PAX3 in these cells. We show here that similar to its roles in development, PAX3 regulates complex differentiation networks in both melanoma cells and melanocytes, in order to maintain cells as 'stem' cell-like (via NES and SOX9). We show also that mediators of migration (MCAM and CSPG4) are common to both cell types but more so in melanoma cells. By contrast, PAX3-mediated regulation of melanoma cell proliferation (through TPD52) and survival (via BCL2L1 and PTEN) differs from that in melanocytes. These results suggest that by controlling cell proliferation, survival and migration as well as maintaining a less differentiated 'stem' cell like phenotype, PAX3 may contribute to melanoma development and progression.

  13. Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine.

    PubMed

    Lewis, Kanako L; Caton, Michele L; Bogunovic, Milena; Greter, Melanie; Grajkowska, Lucja T; Ng, Dennis; Klinakis, Apostolos; Charo, Israel F; Jung, Steffen; Gommerman, Jennifer L; Ivanov, Ivaylo I; Liu, Kang; Merad, Miriam; Reizis, Boris

    2011-11-23

    Dendritic cells (DCs) in tissues and lymphoid organs comprise distinct functional subsets that differentiate in situ from circulating progenitors. Tissue-specific signals that regulate DC subset differentiation are poorly understood. We report that DC-specific deletion of the Notch2 receptor caused a reduction of DC populations in the spleen. Within the splenic CD11b(+) DC subset, Notch signaling blockade ablated a distinct population marked by high expression of the adhesion molecule Esam. The Notch-dependent Esam(hi) DC subset required lymphotoxin beta receptor signaling, proliferated in situ, and facilitated CD4(+) T cell priming. The Notch-independent Esam(lo) DCs expressed monocyte-related genes and showed superior cytokine responses. In addition, Notch2 deletion led to the loss of CD11b(+)CD103(+) DCs in the intestinal lamina propria and to a corresponding decrease of IL-17-producing CD4(+) T cells in the intestine. Thus, Notch2 is a common differentiation signal for T cell-priming CD11b(+) DC subsets in the spleen and intestine.

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

    PubMed Central

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

    2016-01-01

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

  15. Bipolar and borderline patients display differential patterns of functional connectivity among resting state networks.

    PubMed

    Das, Pritha; Calhoun, Vince; Malhi, Gin S

    2014-09-01

    Bipolar disorder (BD) and borderline personality (BPD) disorder share clinical features such as emotional lability and poor interpersonal functioning but the course of illness and treatment differs in these groups, which suggests that the underlying neurobiology of BD and BPD is likely to be different. Understanding the neural mechanisms behind the pathophysiology of BD and BPD will facilitate accurate diagnosis and inform the administration of targeted treatment. Since deficits in social cognition or emotion regulation or in the self-referential processing system can give rise to these clinical features, and impairment in these domains have been observed in both patient groups, functional connectivity within and between networks subserving these processes during resting was investigated using functional magnetic resonance imaging. Data were acquired from 16 patients with BD, 14 patients with BPD, and 13 healthy controls (HC) and functional connectivity strength was correlated with scores using the Difficulties in Emotion Regulation Scale. Functional network connectivity (FNC) patterns differentiated BD and BPD patients from HC. In BD, FNC was increased while in BPD it was decreased. In BD impaired FNC was evident primarily among networks involved in self-referential processing while in BPD it also involved the emotion regulatory network. Impaired FNC displayed an association with impulsivity in BPD and emotional clarity and emotional awareness in BD. This study shows that BD and BPD can perhaps be differentiated using resting state FNC approach and that the neural mechanisms underpinning overlapping symptoms discernibly differ between the groups. These findings provide a potential platform for elucidating the targeted effects of psychological interventions in both disorders.

  16. Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity

    PubMed Central

    Quevedo, Henry C.; Hatzistergos, Konstantinos E.; Oskouei, Behzad N.; Feigenbaum, Gary S.; Rodriguez, Jose E.; Valdes, David; Pattany, Pradip M.; Zambrano, Juan P.; Hu, Qinghua; McNiece, Ian; Heldman, Alan W.; Hare, Joshua M.

    2009-01-01

    The mechanism(s) underlying cardiac reparative effects of bone marrow-derived mesenchymal stem cells (MSC) remain highly controversial. Here we tested the hypothesis that MSCs regenerate chronically infarcted myocardium through mechanisms comprising long-term engraftment and trilineage differentiation. Twelve weeks after myocardial infarction, female swine received catheter-based transendocardial injections of either placebo (n = 4) or male allogeneic MSCs (200 million; n = 6). Animals underwent serial cardiac magnetic resonance imaging, and in vivo cell fate was determined by co-localization of Y-chromosome (Ypos) cells with markers of cardiac, vascular muscle, and endothelial lineages. MSCs engrafted in infarct and border zones and differentiated into cardiomyocytes as ascertained by co-localization with GATA-4, Nkx2.5, and α-sarcomeric actin. In addition, Ypos MSCs exhibited vascular smooth muscle and endothelial cell differentiation, contributing to large and small vessel formation. Infarct size was reduced from 19.3 ± 1.7% to 13.9 ± 2.0% (P < 0.001), and ejection fraction (EF) increased from 35.0 ± 1.7% to 41.3 ± 2.7% (P < 0.05) in MSC but not placebo pigs over 12 weeks. This was accompanied by increases in regional contractility and myocardial blood flow (MBF), particularly in the infarct border zone. Importantly, MSC engraftment correlated with functional recovery in contractility (R = 0.85, P < 0.05) and MBF (R = 0.76, P < 0.01). Together these findings demonstrate long-term MSC survival, engraftment, and trilineage differentiation following transplantation into chronically scarred myocardium. MSCs are an adult stem cell with the capacity for cardiomyogenesis and vasculogenesis which contribute, at least in part, to their ability to repair chronically scarred myocardium. PMID:19666564

  17. Stimulus Set Meaningfulness and Neurophysiological Differentiation: A Functional Magnetic Resonance Imaging Study

    PubMed Central

    Boly, Melanie; Sasai, Shuntaro; Gosseries, Olivia; Oizumi, Masafumi; Casali, Adenauer; Massimini, Marcello; Tononi, Giulio

    2015-01-01

    A meaningful set of stimuli, such as a sequence of frames from a movie, triggers a set of different experiences. By contrast, a meaningless set of stimuli, such as a sequence of ‘TV noise’ frames, triggers always the same experience—of seeing ‘TV noise’—even though the stimuli themselves are as different from each other as the movie frames. We reasoned that the differentiation of cortical responses underlying the subject’s experiences, as measured by Lempel-Ziv complexity (incompressibility) of functional MRI images, should reflect the overall meaningfulness of a set of stimuli for the subject, rather than differences among the stimuli. We tested this hypothesis by quantifying the differentiation of brain activity patterns in response to a movie sequence, to the same movie scrambled in time, and to ‘TV noise’, where the pixels from each movie frame were scrambled in space. While overall cortical activation was strong and widespread in all conditions, the differentiation (Lempel-Ziv complexity) of brain activation patterns was correlated with the meaningfulness of the stimulus set, being highest in the movie condition, intermediate in the scrambled movie condition, and minimal for ‘TV noise’. Stimulus set meaningfulness was also associated with higher information integration among cortical regions. These results suggest that the differentiation of neural responses can be used to assess the meaningfulness of a given set of stimuli for a given subject, without the need to identify the features and categories that are relevant to the subject, nor the precise location of selective neural responses. PMID:25970444

  18. Differential Abundance of Microbial Functional Groups along the Elevation Gradient from the Coast to the Luquillo Mountains

    EPA Science Inventory

    Microbial communities respond to multiple abiotic and biotic factors that change along elevation gradients. We compare changes in microbial community composition in soil and review previous research on differential abundance of microbial functional groups along an elevation gradi...

  19. Substance use disorder symptoms: evidence of differential item functioning by age.

    PubMed

    Conrad, Kendon J; Dennis, Michael L; Bezruczko, Nikolaus; Funk, Rodney R; Riley, Barth B

    2007-01-01

    This study examined the applicability of substance abuse diagnostic criteria for adolescents, young adults, and adults using the Global Appraisal of Individual Need's Substance Problems Scale (SPS) from 7,408 clients. Rasch analysis was used to: 1) evaluate whether the SPS operationalized a single reliable dimension, and 2) examine the extent to which the severity of each symptom and the overall test functioned the same or differently by age. Rasch analysis indicated that the SPS was unidimensional with a person reliability of .84. Eight symptoms were significantly different between adolescents and adults. Young adult calibrations tended to fall between adolescents and adults. Differential test functioning was clinically negligible for adolescents but resulted in about 7% more adults being classified as high need. These findings have theoretical implications for screening and treatment of adolescents vs. adults. SPS can be used across age groups though age-specific calibrations enable greater precision of measurement.

  20. DAX-1, an unusual orphan receptor at the crossroads of steroidogenic function and sexual differentiation.

    PubMed

    Lalli, Enzo; Sassone-Corsi, Paolo

    2003-08-01

    The unusual orphan member of the nuclear hormone receptor superfamily DAX-1 (NR0B1) owes its name to its double role in human pathology. On one side, duplications in Xp21, containing the DAX-1 gene, cause phenotypic sex reversal in XY individuals. On the other side, DAX-1 gene mutations are responsible for adrenal hypoplasia congenita, invariably associated with hypogonadotropic hypogonadism. DAX-1 functions as a global negative regulator of steroid hormone production by repressing the expression of multiple genes involved in the steroidogenic pathway. Here we review the mechanism of DAX-1 function in adrenal and gonadal differentiation, with special emphasis on recent results showing the critical role of DAX-1 protein misfolding in the pathogenesis of adrenal hypoplasia congenita. PMID:12775766

  1. Cryptic diversity and ecosystem functioning: a complex tale of differential effects on decomposition.

    PubMed

    De Meester, N; Gingold, R; Rigaux, A; Derycke, S; Moens, T

    2016-10-01

    Marine ecosystems are experiencing accelerating population and species loss. Some ecosystem functions are decreasing and there is growing interest in the link between biodiversity and ecosystem functioning. The role of cryptic (morphologically identical but genetically distinct) species in this biodiversity-ecosystem functioning link is unclear and has not yet been formally tested. We tested if there is a differential effect of four cryptic species of the bacterivorous nematode Litoditis marina on the decomposition process of macroalgae. Bacterivorous nematodes can stimulate or slow down bacterial activity and modify the bacterial assemblage composition. Moreover, we tested if interspecific interactions among the four cryptic species influence the decomposition process. A laboratory experiment with both mono- and multispecific nematode cultures was conducted, and loss of organic matter and the activity of two key extracellular enzymes for the degradation of phytodetritus were assessed. L. marina mainly influenced qualitative aspects of the decomposition process rather than its overall rate: an effect of the nematodes on the enzymatic activities became manifest, although no clear nematode effect on bulk organic matter weight loss was found. We also demonstrated that species-specific effects on the decomposition process existed. Combining the four cryptic species resulted in high competition, with one dominant species, but without complete exclusion of other species. These interspecific interactions translated into different effects on the decomposition process. The species-specific differences indicated that each cryptic species may play an important and distinct role in ecosystem functioning. Functional differences may result in coexistence among very similar species. PMID:27337962

  2. Differential regulation of human T lymphoblast functions by IL-2 and IL-15.

    PubMed

    Bulfone-Paus, S; Dürkop, H; Paus, R; Krause, H; Pohl, T; Onu, A

    1997-07-01

    Interleukin 15 (IL-15) shares many functional properties with interleukin 2 (IL-2), although both cytokines probably also exert distinct functions. In order to screen for functional differences between IL-2 and IL-15 with respect to the control of T cell functions, we have stimulated human T lymphoblasts (hTBl) with IL-2 and/or IL-15 and have assessed the resulting changes in the following parameters: T cell proliferation; expression of various relevant surface markers; cytokine and receptor (alpha-chain) transcription; and IL-2 and IL-15 activity. Both cytokines equally upregulate standard activation markers such as CD25 and CD95 and downregulate CD27. However, IL-2 upregulates CD30, TNF receptor type II and CD40L expression significantly stronger than IL-15. IL-15 potentiates Con A-induced IL-2 secretion. Even though hTBl transcribe the IL-15 gene, they do not secrete IL-15 activity. These observations suggest that both cytokines can differentially regulate T cells, e.g. T cell functions relevant to the control of cell cycle progression and apoptosis, and/or that they can stimulate different T cell subsets. Moreover, IL-15 may potentiate IL-2-driven T cell responses.

  3. Cryptic diversity and ecosystem functioning: a complex tale of differential effects on decomposition.

    PubMed

    De Meester, N; Gingold, R; Rigaux, A; Derycke, S; Moens, T

    2016-10-01

    Marine ecosystems are experiencing accelerating population and species loss. Some ecosystem functions are decreasing and there is growing interest in the link between biodiversity and ecosystem functioning. The role of cryptic (morphologically identical but genetically distinct) species in this biodiversity-ecosystem functioning link is unclear and has not yet been formally tested. We tested if there is a differential effect of four cryptic species of the bacterivorous nematode Litoditis marina on the decomposition process of macroalgae. Bacterivorous nematodes can stimulate or slow down bacterial activity and modify the bacterial assemblage composition. Moreover, we tested if interspecific interactions among the four cryptic species influence the decomposition process. A laboratory experiment with both mono- and multispecific nematode cultures was conducted, and loss of organic matter and the activity of two key extracellular enzymes for the degradation of phytodetritus were assessed. L. marina mainly influenced qualitative aspects of the decomposition process rather than its overall rate: an effect of the nematodes on the enzymatic activities became manifest, although no clear nematode effect on bulk organic matter weight loss was found. We also demonstrated that species-specific effects on the decomposition process existed. Combining the four cryptic species resulted in high competition, with one dominant species, but without complete exclusion of other species. These interspecific interactions translated into different effects on the decomposition process. The species-specific differences indicated that each cryptic species may play an important and distinct role in ecosystem functioning. Functional differences may result in coexistence among very similar species.

  4. Differential contributions of executive and episodic memory functions to problem solving in younger and older adults.

    PubMed

    Vandermorris, Susan; Sheldon, Signy; Winocur, Gordon; Moscovitch, Morris

    2013-11-01

    The relationship of higher order problem solving to basic neuropsychological processes likely depends on the type of problems to be solved. Well-defined problems (e.g., completing a series of errands) may rely primarily on executive functions. Conversely, ill-defined problems (e.g., navigating socially awkward situations) may, in addition, rely on medial temporal lobe (MTL) mediated episodic memory processes. Healthy young (N = 18; M = 19; SD = 1.3) and old (N = 18; M = 73; SD = 5.0) adults completed a battery of neuropsychological tests of executive and episodic memory function, and experimental tests of problem solving. Correlation analyses and age group comparisons demonstrated differential contributions of executive and autobiographical episodic memory function to well-defined and ill-defined problem solving and evidence for an episodic simulation mechanism underlying ill-defined problem solving efficacy. Findings are consistent with the emerging idea that MTL-mediated episodic simulation processes support the effective solution of ill-defined problems, over and above the contribution of frontally mediated executive functions. Implications for the development of intervention strategies that target preservation of functional independence in older adults are discussed.

  5. Inhibition of differentiation and function of osteoclasts by dimethyl sulfoxide (DMSO).

    PubMed

    Yang, Chunxi; Madhu, Vedavathi; Thomas, Candace; Yang, Xinlin; Du, Xeujun; Dighe, Abhijit S; Cui, Quanjun

    2015-12-01

    Dimethyl sulfoxide (DMSO) is an FDA-approved organosulfur solvent that is reported to have therapeutic value in osteoarthritis and osteopenia. DMSO is used as a cryoprotectant for the cryopreservation of bone grafts and mesenchymal stem cells which are later used for bone repair. It is also used as a solvent in the preparation of various scaffolds used for bone tissue engineering purposes. DMSO has been reported to inhibit osteoclast formation in vitro but the mechanism involved has remained elusive. We investigated the effect of DMSO on osteoclast differentiation and function using a conventional model system of RAW 264.7 cells. The differentiation of RAW 264.7 cells was induced by adding 50 ng/ml RANKL and the effect of DMSO (0.01 and 1% v/v) on RANKL-induced osteoclastogenesis was investigated. Addition of 1% DMSO significantly inhibited RANKL-induced formation of TRAP+, multinucleated, mature osteoclasts and osteoclast late-stage precursors (c-Kit(-) c-Fms(+) Mac-1(+) RANK(+)). While DMSO did not inhibit proliferation per se, it did inhibit the effect of RANKL on proliferation of RAW 264.7 cells. Key genes related to osteoclast function (TRAP, Integrin αVβ3, Cathepsin K and MMP9) were significantly down-regulated by DMSO. RANKL-induced expression of RANK gene was significantly reduced in the presence of DMSO. Our data, and reports from other investigators, that DMSO enhances osteoblastic differentiation of mesenchymal stem cells and also prevents bone loss in ovarietcomized rats, suggest that DMSO has tremendous potential in the treatment of osteoporosis and bone diseases arising from uncontrolled activities of the osteoclasts.

  6. A Nanoscale Interface Promoting Molecular and Functional Differentiation of Neural Cells

    NASA Astrophysics Data System (ADS)

    Posati, Tamara; Pistone, Assunta; Saracino, Emanuela; Formaggio, Francesco; Mola, Maria Grazia; Troni, Elisabetta; Sagnella, Anna; Nocchetti, Morena; Barbalinardo, Marianna; Valle, Francesco; Bonetti, Simone; Caprini, Marco; Nicchia, Grazia Paola; Zamboni, Roberto; Muccini, Michele; Benfenati, Valentina

    2016-08-01

    Potassium channels and aquaporins expressed by astrocytes are key players in the maintenance of cerebral homeostasis and in brain pathophysiologies. One major challenge in the study of astrocyte membrane channels in vitro, is that their expression pattern does not resemble the one observed in vivo. Nanostructured interfaces represent a significant resource to control the cellular behaviour and functionalities at micro and nanoscale as well as to generate novel and more reliable models to study astrocytes in vitro. However, the potential of nanotechnologies in the manipulation of astrocytes ion channels and aquaporins has never been previously reported. Hydrotalcite-like compounds (HTlc) are layered materials with increasing potential as biocompatible nanoscale interface. Here, we evaluate the effect of the interaction of HTlc nanoparticles films with primary rat neocortical astrocytes. We show that HTlc films are biocompatible and do not promote gliotic reaction, while favouring astrocytes differentiation by induction of F-actin fibre alignment and vinculin polarization. Western Blot, Immunofluorescence and patch-clamp revealed that differentiation was accompanied by molecular and functional up-regulation of both inward rectifying potassium channel Kir 4.1 and aquaporin 4, AQP4. The reported results pave the way to engineering novel in vitro models to study astrocytes in a in vivo like condition.

  7. A Nanoscale Interface Promoting Molecular and Functional Differentiation of Neural Cells.

    PubMed

    Posati, Tamara; Pistone, Assunta; Saracino, Emanuela; Formaggio, Francesco; Mola, Maria Grazia; Troni, Elisabetta; Sagnella, Anna; Nocchetti, Morena; Barbalinardo, Marianna; Valle, Francesco; Bonetti, Simone; Caprini, Marco; Nicchia, Grazia Paola; Zamboni, Roberto; Muccini, Michele; Benfenati, Valentina

    2016-01-01

    Potassium channels and aquaporins expressed by astrocytes are key players in the maintenance of cerebral homeostasis and in brain pathophysiologies. One major challenge in the study of astrocyte membrane channels in vitro, is that their expression pattern does not resemble the one observed in vivo. Nanostructured interfaces represent a significant resource to control the cellular behaviour and functionalities at micro and nanoscale as well as to generate novel and more reliable models to study astrocytes in vitro. However, the potential of nanotechnologies in the manipulation of astrocytes ion channels and aquaporins has never been previously reported. Hydrotalcite-like compounds (HTlc) are layered materials with increasing potential as biocompatible nanoscale interface. Here, we evaluate the effect of the interaction of HTlc nanoparticles films with primary rat neocortical astrocytes. We show that HTlc films are biocompatible and do not promote gliotic reaction, while favouring astrocytes differentiation by induction of F-actin fibre alignment and vinculin polarization. Western Blot, Immunofluorescence and patch-clamp revealed that differentiation was accompanied by molecular and functional up-regulation of both inward rectifying potassium channel Kir 4.1 and aquaporin 4, AQP4. The reported results pave the way to engineering novel in vitro models to study astrocytes in a in vivo like condition. PMID:27503424

  8. Trichostatin A, a critical factor in maintaining the functional differentiation of primary cultured rat hepatocytes

    SciTech Connect

    Henkens, Tom . E-mail: Tom.Henkens@vub.ac.be; Papeleu, Peggy; Elaut, Greetje; Vinken, Mathieu; Rogiers, Vera; Vanhaecke, Tamara

    2007-01-01

    Histone deacetylase inhibitors (HDI) have been shown to increase differentiation-related gene expression in several tumor-derived cell lines by hyperacetylating core histones. Effects of HDI on primary cultured cells, however, have hardly been investigated. In the present study, the ability of trichostatin A (TSA), a prototype hydroxamate HDI, to counteract the loss of liver-specific functions in primary rat hepatocyte cultures has been investigated. Upon exposure to TSA, it was found that the cell viability of the cultured hepatocytes and their albumin secretion as a function of culture time were increased. TSA-treated hepatocytes also better maintained cytochrome P450 (CYP)-mediated phase I biotransformation capacity, whereas the activity of phase II glutathione S-transferases (GST) was not affected. Western blot and qRT-PCR analysis of CYP1A1, CYP2B1 and CYP3A11 protein and mRNA levels, respectively, further revealed that TSA acts at the transcriptional level. In addition, protein expression levels of the liver-enriched transcription factors (LETFs) hepatic nuclear factor 4 alpha (HNF4{alpha}) and CCAAT/enhancer binding protein alpha (C/EBP{alpha}) were accordingly increased by TSA throughout culture time. In conclusion, these findings indicate that TSA plays a major role in the preservation of the differentiated hepatic phenotype in culture. It is suggested that the effects of TSA on CYP gene expression are mediated via controlling the expression of LETFs.

  9. A Nanoscale Interface Promoting Molecular and Functional Differentiation of Neural Cells

    PubMed Central

    Posati, Tamara; Pistone, Assunta; Saracino, Emanuela; Formaggio, Francesco; Mola, Maria Grazia; Troni, Elisabetta; Sagnella, Anna; Nocchetti, Morena; Barbalinardo, Marianna; Valle, Francesco; Bonetti, Simone; Caprini, Marco; Nicchia, Grazia Paola; Zamboni, Roberto; Muccini, Michele; Benfenati, Valentina

    2016-01-01

    Potassium channels and aquaporins expressed by astrocytes are key players in the maintenance of cerebral homeostasis and in brain pathophysiologies. One major challenge in the study of astrocyte membrane channels in vitro, is that their expression pattern does not resemble the one observed in vivo. Nanostructured interfaces represent a significant resource to control the cellular behaviour and functionalities at micro and nanoscale as well as to generate novel and more reliable models to study astrocytes in vitro. However, the potential of nanotechnologies in the manipulation of astrocytes ion channels and aquaporins has never been previously reported. Hydrotalcite-like compounds (HTlc) are layered materials with increasing potential as biocompatible nanoscale interface. Here, we evaluate the effect of the interaction of HTlc nanoparticles films with primary rat neocortical astrocytes. We show that HTlc films are biocompatible and do not promote gliotic reaction, while favouring astrocytes differentiation by induction of F-actin fibre alignment and vinculin polarization. Western Blot, Immunofluorescence and patch-clamp revealed that differentiation was accompanied by molecular and functional up-regulation of both inward rectifying potassium channel Kir 4.1 and aquaporin 4, AQP4. The reported results pave the way to engineering novel in vitro models to study astrocytes in a in vivo like condition. PMID:27503424

  10. Analyte species and concentration identification using differentially functionalized microcantilever arrays and artificial neural networks

    SciTech Connect

    Senesac, Larry R; Datskos, Panos G; Sepaniak, Michael J

    2006-01-01

    In the present work, we have performed analyte species and concentration identification using an array of ten differentially functionalized microcantilevers coupled with a back-propagation artificial neural network pattern recognition algorithm. The array consists of ten nanostructured silicon microcantilevers functionalized by polymeric and gas chromatography phases and macrocyclic receptors as spatially dense, differentially responding sensing layers for identification and quantitation of individual analyte(s) and their binary mixtures. The array response (i.e. cantilever bending) to analyte vapor was measured by an optical readout scheme and the responses were recorded for a selection of individual analytes as well as several binary mixtures. An artificial neural network (ANN) was designed and trained to recognize not only the individual analytes and binary mixtures, but also to determine the concentration of individual components in a mixture. To the best of our knowledge, ANNs have not been applied to microcantilever array responses previously to determine concentrations of individual analytes. The trained ANN correctly identified the eleven test analyte(s) as individual components, most with probabilities greater than 97%, whereas it did not misidentify an unknown (untrained) analyte. Demonstrated unique aspects of this work include an ability to measure binary mixtures and provide both qualitative (identification) and quantitative (concentration) information with array-ANN-based sensor methodologies.

  11. Role of Ets Proteins in Development, Differentiation, and Function of T-Cell Subsets.

    PubMed

    Liu, Mian; Gao, Weiwu; van Velkinburgh, Jennifer C; Wu, Yuzhang; Ni, Bing; Tian, Yi

    2016-03-01

    Through positive selection, double-positive cells in the thymus differentiate into CD4(+) or CD8(+) T single-positive cells that subsequently develop into different types of effective T cells, such as T-helper and cytotoxic T lymphocyte cells, that play distinctive roles in the immune system. Development, differentiation, and function of thymocytes and CD4(+) and CD8(+) T cells are controlled by a multitude of secreted and intracellular factors, ranging from cytokine signaling modules to transcription factors and epigenetic modifiers. Members of the E26 transformation specific (Ets) family of transcription factors, in particular, are potent regulators of these CD4(+) or CD8(+) T-cell processes. In this review, we summarize and discuss the functions and underlying mechanisms of the Ets family members that have been characterized as involved in these processes. Ongoing research of these factors is expected to identify practical applications for the Ets family members as novel therapeutic targets for inflammation-related diseases.

  12. Repair versus Checkpoint Functions of BRCA1 Are Differentially Regulated by Site of Chromatin Binding.

    PubMed

    Goldstein, Michael; Kastan, Michael B

    2015-07-01

    The product of the Brca1 tumor-suppressor gene is involved in multiple aspects of the cellular DNA damage response (DDR), including activation of cell-cycle arrests and DNA double-stranded break (DSB) repair by homologous recombination. Prior reports demonstrated that BRCA1 recruitment to areas of DNA breakage depended on RAP80 and the RNF8/RNF168 E3 ubiquitin ligases. Here, we extend these findings by showing that RAP80 is only required for the binding of BRCA1 to regions flanking the DSB, whereas BRCA1 binding directly to DNA breaks requires Nijmegen breakage syndrome 1 (NBS1). These differential recruitment mechanisms differentially affect BRCA1 functions: (i) RAP80-dependent recruitment of BRCA1 to chromatin flanking DNA breaks is required for BRCA1 phosphorylation at serine 1387 and 1423 by ATM and, consequently, for the activation of S and G(2) checkpoints; and (ii) BRCA1 interaction with NBS1 upon DSB induction results in an NBS1-dependent recruitment of BRCA1 directly to the DNA break and is required for nonhomologous end-joining repair. Together, these findings illustrate that spatially distinct fractions of BRCA1 exist at the DSB site, which are recruited by different mechanisms and execute different functions in the DDR.

  13. Structural and Mutational Analysis of Functional Differentiation between Synaptotagmins-1 and -7

    SciTech Connect

    Xue, Mingshan; Craig, Timothy K.; Shin, Ok-Ho; Li, Liyi; Brautigam, Chad A.; Tomchick, Diana R.; Südhof, Thomas C.; Rosenmund, Christian; Rizo, Josep

    2012-01-20

    Synaptotagmins are known to mediate diverse forms of Ca{sup 2+}-triggered exocytosis through their C{sub 2} domains, but the principles underlying functional differentiation among them are unclear. Synaptotagmin-1 functions as a Ca{sup 2+} sensor in neurotransmitter release at central nervous system synapses, but synaptotagmin-7 does not, and yet both isoforms act as Ca{sup 2+} sensors in chromaffin cells. To shed light into this apparent paradox, we have performed rescue experiments in neurons from synaptotagmin-1 knockout mice using a chimera that contains the synaptotagmin-1 sequence with its C{sub 2}B domain replaced by the synaptotagmin-7 C{sub 2}B domain (Syt1/7). Rescue was not achieved either with the WT Syt1/7 chimera or with nine mutants where residues that are distinct in synaptotagmin-7 were restored to those present in synaptotagmin-1. To investigate whether these results arise because of unique conformational features of the synaptotagmin-7 C{sub 2}B domain, we determined its crystal structure at 1.44 {angstrom} resolution. The synaptotagmin-7 C{sub 2}B domain structure is very similar to that of the synaptotagmin-1 C{sub 2}B domain and contains three Ca{sup 2+}-binding sites. Two of the Ca{sup 2+}-binding sites of the synaptotagmin-7 C{sub 2}B domain are also present in the synaptotagmin-1 C{sub 2}B domain and have analogous ligands to those determined for the latter by NMR spectroscopy, suggesting that a discrepancy observed in a crystal structure of the synaptotagmin-1 C{sub 2}B domain arose from crystal contacts. Overall, our results suggest that functional differentiation in synaptotagmins arises in part from subtle sequence changes that yield dramatic functional differences.

  14. Immunomodulation by neutrophil myeloperoxidase and hydrogen peroxide: differential susceptibility of human lymphocyte functions.

    PubMed

    el-Hag, A; Lipsky, P E; Bennett, M; Clark, R A

    1986-05-01

    The coexistence of activated polymorphonuclear leukocytes and lymphocytes in tumor masses and inflammatory tissues suggests the possibility of interaction between secreted neutrophil products and nearby lymphocytes. To test this hypothesis, we examined the effects of neutrophil myeloperoxidase and H2O2 on lymphocytes. Human peripheral blood mononuclear leukocytes were exposed to myeloperoxidase, an H2O2-generating system (glucose + glucose oxidase), and a halide, and were then tested for functional activities. Natural killer activity against K562 cells, lymphocyte proliferation in response to mitogens, and generation of immunoglobulin-secreting cells were all susceptible to oxidative injury by myeloperoxidase and H2O2. The degree as well as the mechanism of suppression was dependent on the glucose oxidase concentration (i.e., the rate of H2O2 delivery). At low H2O2 flux, myeloperoxidase was essential for induction of lymphocyte suppression; as the rate of H2O2 generation increased, suppression became myeloperoxidase-independent and was mediated by H2O2 alone. Various lymphocyte functions were differentially susceptible to oxidative injury by myeloperoxidase and H2O2. The proliferative response to poke-weed mitogen was the least sensitive, whereas antibody formation was the most sensitive. Proliferative responses to concanavalin A and phytohemagglutinin as well as natural killer activity displayed intermediate degrees of susceptibility. In all assays, lymphocyte viability was greater than 90%. Removal of monocytes from mononuclear leukocytes by adherence to glass increased susceptibility of lymphocytes to oxidative injury. Monocytes in proportions within the range present in peripheral blood mononuclear leukocytes protected lymphocyte functions against oxidative injury by myeloperoxidase and H2O2. This study demonstrates a differential susceptibility of various immune functions to oxidative injury by the neutrophil products myeloperoxidase and H2O2, and shows, in

  15. Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells

    PubMed Central

    Váraljai, Renáta; Islam, Abul B.M.M.K.; Beshiri, Michael L.; Rehman, Jalees; Lopez-Bigas, Nuria; Benevolenskaya, Elizaveta V.

    2015-01-01

    The retinoblastoma tumor suppressor protein pRb restricts cell growth through inhibition of cell cycle progression. Increasing evidence suggests that pRb also promotes differentiation, but the mechanisms are poorly understood, and the key question remains as to how differentiation in tumor cells can be enhanced in order to diminish their aggressive potential. Previously, we identified the histone demethylase KDM5A (lysine [K]-specific demethylase 5A), which demethylates histone H3 on Lys4 (H3K4), as a pRB-interacting protein counteracting pRB's role in promoting differentiation. Here we show that loss of Kdm5a restores differentiation through increasing mitochondrial respiration. This metabolic effect is both necessary and sufficient to induce the expression of a network of cell type-specific signaling and structural genes. Importantly, the regulatory functions of pRB in the cell cycle and differentiation are distinct because although restoring differentiation requires intact mitochondrial function, it does not necessitate cell cycle exit. Cells lacking Rb1 exhibit defective mitochondria and decreased oxygen consumption. Kdm5a is a direct repressor of metabolic regulatory genes, thus explaining the compensatory role of Kdm5a deletion in restoring mitochondrial function and differentiation. Significantly, activation of mitochondrial function by the mitochondrial biogenesis regulator Pgc-1α (peroxisome proliferator-activated receptor γ-coactivator 1α; also called PPARGC1A) a coactivator of the Kdm5a target genes, is sufficient to override the differentiation block. Overexpression of Pgc-1α, like KDM5A deletion, inhibits cell growth in RB-negative human cancer cell lines. The rescue of differentiation by loss of KDM5A or by activation of mitochondrial biogenesis reveals the switch to oxidative phosphorylation as an essential step in restoring differentiation and a less aggressive cancer phenotype. PMID:26314709

  16. Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells.

    PubMed

    Váraljai, Renáta; Islam, Abul B M M K; Beshiri, Michael L; Rehman, Jalees; Lopez-Bigas, Nuria; Benevolenskaya, Elizaveta V

    2015-09-01

    The retinoblastoma tumor suppressor protein pRb restricts cell growth through inhibition of cell cycle progression. Increasing evidence suggests that pRb also promotes differentiation, but the mechanisms are poorly understood, and the key question remains as to how differentiation in tumor cells can be enhanced in order to diminish their aggressive potential. Previously, we identified the histone demethylase KDM5A (lysine [K]-specific demethylase 5A), which demethylates histone H3 on Lys4 (H3K4), as a pRB-interacting protein counteracting pRB's role in promoting differentiation. Here we show that loss of Kdm5a restores differentiation through increasing mitochondrial respiration. This metabolic effect is both necessary and sufficient to induce the expression of a network of cell type-specific signaling and structural genes. Importantly, the regulatory functions of pRB in the cell cycle and differentiation are distinct because although restoring differentiation requires intact mitochondrial function, it does not necessitate cell cycle exit. Cells lacking Rb1 exhibit defective mitochondria and decreased oxygen consumption. Kdm5a is a direct repressor of metabolic regulatory genes, thus explaining the compensatory role of Kdm5a deletion in restoring mitochondrial function and differentiation. Significantly, activation of mitochondrial function by the mitochondrial biogenesis regulator Pgc-1α (peroxisome proliferator-activated receptor γ-coactivator 1α; also called PPARGC1A) a coactivator of the Kdm5a target genes, is sufficient to override the differentiation block. Overexpression of Pgc-1α, like KDM5A deletion, inhibits cell growth in RB-negative human cancer cell lines. The rescue of differentiation by loss of KDM5A or by activation of mitochondrial biogenesis reveals the switch to oxidative phosphorylation as an essential step in restoring differentiation and a less aggressive cancer phenotype.

  17. COP9-Hedgehog axis regulates the function of the germline stem cell progeny differentiation niche in the Drosophila ovary.

    PubMed

    Lu, Tinglin; Wang, Su; Gao, Yuan; Mao, Ying; Yang, Zhihao; Liu, Luping; Song, Xiaoqing; Ni, Jianquan; Xie, Ting

    2015-12-15

    Both stem cell self-renewal and lineage differentiation are controlled extrinsically as well as intrinsically. Germline stem cells (GSCs) in the Drosophila ovary provide an attractive model in which to study both stem cell self-renewal and lineage differentiation at the molecular and cellular level. Recently, we have proposed that escort cells (ECs) form a differentiation niche to control GSC lineage specification extrinsically. However, it remains poorly understood how the maintenance and function of the differentiation niche are regulated at the molecular level. Here, this study reveals a new role of COP9 in the differentiation niche to modulate autocrine Hedgehog (Hh) signaling, thereby promoting GSC lineage differentiation. COP9, which is a highly conserved protein complex composed of eight CSN subunits, catalyzes the removal of Nedd8 protein modification from target proteins. Our genetic results have demonstrated that all the COP9 components and the hh pathway components, including hh itself, are required in ECs to promote GSC progeny differentiation. Interestingly, COP9 is required in ECs to maintain Hh signaling activity, and activating Hh signaling in ECs can partially bypass the requirement for COP9 in GSC progeny differentiation. Finally, both COP9 and Hh signaling in ECs promote GSC progeny differentiation partly by preventing BMP signaling and maintaining cellular processes. Therefore, this study has demonstrated that the COP9-Hh signaling axis operates in the differentiation niche to promote GSC progeny differentiation partly by maintaining EC cellular processes and preventing BMP signaling. This provides new insight into how the function of the differentiation niche is regulated at the molecular level. PMID:26672093

  18. Differential Item and Person Functioning in Large-Scale Writing Assessments within the Context of the SAT®. Research Report 2013-6

    ERIC Educational Resources Information Center

    Engelhard, George, Jr.; Wind, Stefanie A.; Kobrin, Jennifer L.; Chajewski, Michael

    2013-01-01

    The purpose of this study is to illustrate the use of explanatory models based on Rasch measurement theory to detect systematic relationships between student and item characteristics and achievement differences using differential item functioning (DIF), differential group functioning (DGF), and differential person functioning (DPF) techniques. The…

  19. A Monte Carlo Examination of the Sensitivity of the Differential Functioning of Items and Tests Framework for Tests of Measurement Invariance with Likert Data

    ERIC Educational Resources Information Center

    Meade, Adam W.; Lautenschlager, Gary J.; Johnson, Emily C.

    2007-01-01

    This article highlights issues associated with the use of the differential functioning of items and tests (DFIT) methodology for assessing measurement invariance (or differential functioning) with Likert-type data. Monte Carlo analyses indicate relatively low sensitivity of the DFIT methodology for identifying differential item functioning (DIF)…

  20. Aberrant functional connectivity differentiates retrosplenial cortex from posterior cingulate cortex in prodromal Alzheimer's disease.

    PubMed

    Dillen, Kim N H; Jacobs, Heidi I L; Kukolja, Juraj; von Reutern, Boris; Richter, Nils; Onur, Özgür A; Dronse, Julian; Langen, Karl-Josef; Fink, Gereon R

    2016-08-01

    The posterior cingulate cortex (PCC) is a key hub of the default mode network, a resting-state network involved in episodic memory, showing functional connectivity (FC) changes in Alzheimer's disease (AD). However, PCC is a cytoarchitectonically heterogeneous region. Specifically, the retrosplenial cortex (RSC), often subsumed under the PCC, is an area functionally and microanatomically distinct from PCC. To investigate FC patterns of RSC and PCC separately, we used resting-state functional magnetic resonance imaging in healthy aging participants, patients with subjective cognitive impairment, and prodromal AD. Compared to the other 2 groups, we found higher FC from RSC to frontal cortex in subjective cognitive impairment but higher FC to occipital cortex in prodromal AD. Conversely, FC from PCC to the lingual gyrus was higher in prodromal AD. Furthermore, data indicate that RSC and PCC are characterized by differential FC patterns represented by hub-specific interactions with memory and attentions scores in prodromal AD compared to cognitively normal individuals, possibly reflecting compensatory mechanisms for RSC and neurodegenerative processes for PCC. Data thus confirm and extend previous studies suggesting that the RSC is functionally distinct from PCC.

  1. Aberrant functional connectivity differentiates retrosplenial cortex from posterior cingulate cortex in prodromal Alzheimer's disease.

    PubMed

    Dillen, Kim N H; Jacobs, Heidi I L; Kukolja, Juraj; von Reutern, Boris; Richter, Nils; Onur, Özgür A; Dronse, Julian; Langen, Karl-Josef; Fink, Gereon R

    2016-08-01

    The posterior cingulate cortex (PCC) is a key hub of the default mode network, a resting-state network involved in episodic memory, showing functional connectivity (FC) changes in Alzheimer's disease (AD). However, PCC is a cytoarchitectonically heterogeneous region. Specifically, the retrosplenial cortex (RSC), often subsumed under the PCC, is an area functionally and microanatomically distinct from PCC. To investigate FC patterns of RSC and PCC separately, we used resting-state functional magnetic resonance imaging in healthy aging participants, patients with subjective cognitive impairment, and prodromal AD. Compared to the other 2 groups, we found higher FC from RSC to frontal cortex in subjective cognitive impairment but higher FC to occipital cortex in prodromal AD. Conversely, FC from PCC to the lingual gyrus was higher in prodromal AD. Furthermore, data indicate that RSC and PCC are characterized by differential FC patterns represented by hub-specific interactions with memory and attentions scores in prodromal AD compared to cognitively normal individuals, possibly reflecting compensatory mechanisms for RSC and neurodegenerative processes for PCC. Data thus confirm and extend previous studies suggesting that the RSC is functionally distinct from PCC. PMID:27318139

  2. Application of functional analysis to perturbation theory of differential equations. [nonlinear perturbation of the harmonic oscillator

    NASA Technical Reports Server (NTRS)

    Bogdan, V. M.; Bond, V. B.

    1980-01-01

    The deviation of the solution of the differential equation y' = f(t, y), y(O) = y sub O from the solution of the perturbed system z' = f(t, z) + g(t, z), z(O) = z sub O was investigated for the case where f and g are continuous functions on I x R sup n into R sup n, where I = (o, a) or I = (o, infinity). These functions are assumed to satisfy the Lipschitz condition in the variable z. The space Lip(I) of all such functions with suitable norms forms a Banach space. By introducing a suitable norm in the space of continuous functions C(I), introducing the problem can be reduced to an equivalent problem in terminology of operators in such spaces. A theorem on existence and uniqueness of the solution is presented by means of Banach space technique. Norm estimates on the rate of growth of such solutions are found. As a consequence, estimates of deviation of a solution due to perturbation are obtained. Continuity of the solution on the initial data and on the perturbation is established. A nonlinear perturbation of the harmonic oscillator is considered a perturbation of equations of the restricted three body problem linearized at libration point.

  3. Differentiated adipose-derived stem cells promote the recovery of nociceptor function in rats.

    PubMed

    Nishibayashi, Akimitsu; Tomita, Koichi; Kiya, Koichiro; Yano, Kenji; Hosokawa, Ko

    2016-10-19

    The loss of nociceptive function in the skin because of trauma or surgery can impair the quality of life. The recovery of nociceptor function is mediated by two different axonal responses: nerve growth factor (NGF)-dependent collateral sprouting of undamaged nerves and NGF-independent regeneration of damaged nerves. We reported previously that adipose-derived stem cells (ASCs) can transdifferentiate into Schwann cell (SC)-like cells (dASCs) and that transplantation of dASCs increases axonal density in skin flaps. In the present study, we used an animal model that allowed for the individual assessment of collateral sprouting and regeneration. In-vitro differentiation of ASCs to dASCs significantly increased the production of NGF and brain-derived neurotrophic factor (BDNF) to levels comparable with SCs. In-vivo experiments showed that dASC and SC transplantation significantly increased the area of the mechano-nociceptive field in both collateral sprouting and regeneration models, whereas ASC transplantation exerted no significant effect. Antibody blocking experiment showed that these effects of dASC transplantation in the regeneration model were partly mediated by BDNF. Interestingly, the final areas of nociceptive fields between the two experimental models did not differ significantly for any treatment condition. These results indicate that dASC transplantation differentially facilitates collateral sprouting and axonal regeneration by delivering NGF and other neurotrophic factors (e.g. BDNF), respectively. Although there is a limit to nociceptive field enlargement irrespective of axonal response, dASC transplantation could present a new approach for improving nociceptive function in denervated skin. PMID:27513202

  4. Highly Efficient Differentiation of Functional Hepatocytes From Human Induced Pluripotent Stem Cells

    PubMed Central

    Ma, Xiaocui; Tschudy-Seney, Benjamin; Roll, Garrett; Behbahan, Iman Saramipoor; Ahuja, Tijess P.; Tolstikov, Vladimir; Wang, Charles; McGee, Jeannine; Khoobyari, Shiva; Nolta, Jan A.; Willenbring, Holger

    2013-01-01

    Human induced pluripotent stem cells (hiPSCs) hold great potential for use in regenerative medicine, novel drug development, and disease progression/developmental studies. Here, we report highly efficient differentiation of hiPSCs toward a relatively homogeneous population of functional hepatocytes. hiPSC-derived hepatocytes (hiHs) not only showed a high expression of hepatocyte-specific proteins and liver-specific functions, but they also developed a functional biotransformation system including phase I and II metabolizing enzymes and phase III transporters. Nuclear receptors, which are critical for regulating the expression of metabolizing enzymes, were also expressed in hiHs. hiHs also responded to different compounds/inducers of cytochrome P450 as mature hepatocytes do. To follow up on this observation, we analyzed the drug metabolizing capacity of hiHs in real time using a novel ultraperformance liquid chromatography-tandem mass spectrometry. We found that, like freshly isolated primary human hepatocytes, the seven major metabolic pathways of the drug bufuralol were found in hiHs. In addition, transplanted hiHs engrafted, integrated, and proliferated in livers of an immune-deficient mouse model, and secreted human albumin, indicating that hiHs also function in vivo. In conclusion, we have generated a method for the efficient generation of hepatocytes from induced pluripotent stem cells in vitro and in vivo, and it appears that the cells function similarly to primary human hepatocytes, including developing a complete metabolic function. These results represent a significant step toward using patient/disease-specific hepatocytes for cell-based therapeutics as well as for pharmacology and toxicology studies. PMID:23681950

  5. Differentiations and Functional State of Osteogenic Cells in Conditions of Microgravity

    NASA Astrophysics Data System (ADS)

    Onishchenko, Ganna; Rodionova, Natalia; Markevich, Ganna; Markevich, Ganna

    The space flight factors (space radiation, magnetic fields etc.) affect considerably the state of bone tissue, leading to the development of osteoporosis and osteopenia in the bone skeleton. Many aspects of reactions of bone tissue cells still remain unclear until now. With the use of electron microscopy and autoradiography with 3H-thymidine we studied the samples gathered from the femoral bone epiphyses and metaphyses of rats flown on board American Spacelab -2 and in experiments with modeling of microgravity ("tail suspension" method). In our work the main attention is focused on studying the ultrastructure and metabolism of osteogenetic cells. The degree of differentiation and functional state are evaluated according to the degree of development of organelles for specific biosynthesis: rough endoplasmic reticulum (RER), Golgy complex (GC), as well as the state of mitochondria and cell nucleus. As compared with a control, the population of osteogenetic cells from zones of bone reconstruction shows a decrease in the number of functionally active forms. We can judge of this from the reduction volume of RER, GC, mitochondria in osteoblasts. RER loses architectonics typical for osteoblasts and, as against the control, is represented by short narrow canaliculi distributed throughout the cy-toplasm; some canals disintegrate. GC is slightly pronounced, mitochondria become smaller in size and acquire an optically dark matrix. These phenomena are supposed to be associated with the desorganization of microtubules and microfilaments in the cells under microgravity condi-tions. The number of degrading and apoptotic cells increases in the population of osteoblasts. The dynamics of labeled cells following various intervals after 3H-thymidine injection testifies to a delay in the rates of osteoblasts' differentiation and their transformation to osteocytes in the experiment animals. A lower 3H-glycine uptake by the osteogenic cells and bone matrix as compared with a control is

  6. Evaluation of measurement equivalence of the Family Satisfaction with the End-of-Life Care in an ethnically diverse cohort: Tests of differential item functioning

    PubMed Central

    Teresi, Jeanne A; Ocepek-Welikson, Katja; Ramirez, Mildred; Kleinman, Marjorie; Ornstein, Katherine; Siu, Albert

    2016-01-01

    Background The Family Satisfaction with End-of-Life Care is an internationally used measure of satisfaction with cancer care. However, the Family Satisfaction with End-of-Life Care has not been studied for equivalence of item endorsement across different socio-demographic groups using differential item functioning. Aims The aims of this secondary data analysis were (1) to examine potential differential item functioning in the family satisfaction item set with respect to type of caregiver, race, and patient age, gender, and education and (2) to provide parameters and documentation of differential item functioning for an item bank. Design A mixed qualitative and quantitative analysis was conducted. A priori hypotheses regarding potential group differences in item response were established. Item response theory and Wald tests were used for the analyses of differential item functioning, accompanied by magnitude and impact measures. Results Very little significant differential item functioning was observed for patient's age and gender. For race, 13 items showed differential item functioning after multiple comparison adjustment, 10 with non-uniform differential item functioning. No items evidenced differential item functioning of high magnitude, and the impact was negligible. For education, 5 items evidenced uniform differential item functioning after adjustment, none of high magnitude. Differential item functioning impact was trivial. One item evidenced differential item functioning for the caregiver relationship variable. Conclusion Differential item functioning was observed primarily for race and education. No differential item functioning of high magnitude was observed for any item, and the overall impact of differential item functioning was negligible. One item, satisfaction with “the patient's pain relief,” might be singled out for further study, given that this item was both hypothesized and observed to show differential item functioning for race and education

  7. Laminin and biomimetic extracellular elasticity enhance functional differentiation in mammary epithelia

    SciTech Connect

    Alcaraz, Jordi; Xu, Ren; Mori, Hidetoshi; Nelson, Celeste M.; Mroue, Rana; Spencer, Virginia A.; Brownfield, Doug; Radisky, Derek C.; Bustamante, Carlos; Bissell, Mina J.

    2008-10-20

    In the mammary gland, epithelial cells are embedded in a 'soft' environment and become functionally differentiated in culture when exposed to a laminin-rich extracellular matrix gel. Here, we define the processes by which mammary epithelial cells integrate biochemical and mechanical extracellular cues to maintain their differentiated phenotype. We used single cells cultured on top of gels in conditions permissive for {beta}-casein expression using atomic force microscopy to measure the elasticity of the cells and their underlying substrata. We found that maintenance of {beta}-casein expression required both laminin signalling and a 'soft' extracellular matrix, as is the case in normal tissues in vivo, and biomimetic intracellular elasticity, as is the case in primary mammary epithelial organoids. Conversely, two hallmarks of breast cancer development, stiffening of the extracellular matrix and loss of laminin signalling, led to the loss of {beta}-casein expression and non-biomimetic intracellular elasticity. Our data indicate that tissue-specific gene expression is controlled by both the tissues unique biochemical milieu and mechanical properties, processes involved in maintenance of tissue integrity and protection against tumorigenesis.

  8. Influence of neurotransmitters on sexual differentiation of brain structure and function.

    PubMed

    Döhler, K D; Jarzab, B; Sickmöller, P M; Kokociñska, D; Kaminski, M; Gubala, E; Achtelik, W; Wagiel, J

    1991-01-01

    Newborn rats received daily subcutaneous treatment with compounds which influence serotoninergic, cholinergic, alpha-adrenergic and beta-adrenergic activity. In adulthood luteinizing hormone (LH) secretion pattern, female sexual behavior, and the volume of the sexually dimorphic nucleus of the preoptic are (SDN-POA) were determined. Postnatal administration of l-tryptophan increased the volume of the SDN-POA significantly when given alone or when given simultaneously with testosterone propionate (TP). Para-chlorophenyl-alanine (pCPA) also increased SDN-POA volume, but did not potentiate the stimulating influence of TP. Clonidine had no effect per se on SDN-POA development, but it significantly potentiated the effect of TP in females. Salbutamol increased SDN-POA volume in females and in males. Postnatal treatment of female rats with the alpha-adrenergic receptor antagonists prazosine and yohimbine or with the nicotin receptor antagonist mecamylamine had permanent potentiating effects on the pattern of LH secretion, whereas postnatal treatment with beta-adrenergic compounds reduced the LH-release response to gonadal steroids in adulthood. Postnatal treatment with clonidin or l-tryptophane inhibited differentiation of the capacity for lordosis behavior. Beta-receptor agonists postnatally had a potentiating effect on the capacity for lordosis behavior in female and male rats. Cholinergic stimulation postnatally inhibited differentiation of the capacity for lordosis behavior in female rats, but prevented the inhibitory effect of postnatal androgenization. There was no correlation between SDN-POA volume and any of the two functional parameters. PMID:1685710

  9. Biogenesis and function of non-coding RNAs in muscle differentiation and in Duchenne muscular dystrophy.

    PubMed

    Twayana, Shyam; Legnini, Ivano; Cesana, Marcella; Cacchiarelli, Davide; Morlando, Mariangela; Bozzoni, Irene

    2013-08-01

    It is now becoming largely accepted that the non-coding portion of the genome, rather than its coding counterpart, is likely to account for the greater complexity of higher eukaryotes. Moreover, non-coding RNAs have been demonstrated to participate in regulatory circuitries that are crucial for development and differentiation. Whereas the biogenesis and function of small non-coding RNAs, particularly miRNAs (microRNAs), has been extensively clarified in many eukaryotic systems, very little is known about the long non-coding counterpart of the transcriptome. In the present review, we revise the current knowledge of how small non-coding RNAs and lncRNAs (long non-coding RNAs) impinge on circuitries controlling proper muscle differentiation and homoeostasis and how their biogenesis is regulated. Moreover, we provide new insights into an additional mechanism of post-transcriptional regulation mediated by lncRNAs, which, acting as miRNA 'sponges', have an impact on the distribution of miRNA molecules on their targets with features similar to those described for ceRNAs (competing endogenous RNAs).

  10. Structural and functional characterization of the mouse fatty acid translocase promoter: activation during adipose differentiation.

    PubMed Central

    Teboul, L; Febbraio, M; Gaillard, D; Amri, E Z; Silverstein, R; Grimaldi, P A

    2001-01-01

    Fatty acid translocase (FAT/CD36) is a cell-surface glycoprotein that functions as a receptor/transporter for long-chain fatty acids (LCFAs), and interacts with other protein and lipid ligands. FAT/CD36 is expressed by various cell types, including platelets, monocytes/macrophages and endothelial cells, and tissues with an active LCFA metabolism, such as adipose, small intestine and heart. FAT/CD36 expression is induced during adipose cell differentiation and is transcriptionally up-regulated by LCFAs and thiazolidinediones in pre-adipocytes via a peroxisome-proliferator-activated receptor (PPAR)-mediated process. We isolated and analysed the murine FAT/CD36 promoter employing C(2)C(12)N cells directed to differentiate to either adipose or muscle. Transient transfection studies revealed that the 309 bp upstream from the start of exon 1 confer adipose specific activity. Sequence analysis of this DNA fragment revealed the presence of two imperfect direct repeat-1 elements. Electrophoretic mobility-shift assay demonstrated that these elements were peroxisome-proliferator-responsive elements (PPREs). Mutagenesis and transfection experiments indicated that both PPREs co-operate to drive strong promoter activity in adipose cells. We conclude that murine FAT/CD36 expression in adipose tissue is dependent upon transcriptional activation via PPARs through binding to two PPREs located at -245 to -233 bp and -120 to -108 bp from the transcription start site. PMID:11716758

  11. Manganese superoxide dismutase is required to maintain osteoclast differentiation and function under static force

    PubMed Central

    Guo, Tao; Zhang, Liqiang; Konermann, Anna; Zhou, Hong; Jin, Fang; Liu, Wenjia

    2015-01-01

    Bone homeostasis is maintained by the balance of osteoblasts (OBs) and osteoclasts (OCs). Increased activity of OCs not only contributes to pathological bone resorption, such as osteoporosis and periodontitis, but also is responsible for physiological conditions like orthodontic tooth movement (OTM). However, the detailed mechanism by which orthodontic force promotes the formation of OCs is still poorly understood. In this study, we confirmed that static force promoted the differentiation of human cord monocytes (HMNCs) into OCs depending on loading time and magnitude. Protein expression profiles among HMNCs, HMNCs subjected to static force and mature OCs were established via 2-DE and MALDI-TOF-MS analyses. Total respective protein spot numbers of 549 ± 13, 612 ± 19 and 634 ± 16 were detected in each of the gels by image analysis. The five proteins identified were plasminogen activator inhibitor 2 (PAI-2, Spot 1), peroxiredoxin-6 (PRD-6, Spot 3), manganese superoxide dismutase (SOD2, Spot 6), Rho GDP-dissociation inhibitor 2 (Rho-GDI2, Spot 11) and L-lactate dehydrogenase B chain (L-LDH, Spot 15). More importantly, we revealed that SOD2 was required to maintain monocyte differentiation into functional OCs and may become a potential target for regulating the efficiency of OTM in the future. PMID:25619900

  12. Differentiation of human induced pluripotent stem cells to mature functional Purkinje neurons.

    PubMed

    Wang, Shuyan; Wang, Bin; Pan, Na; Fu, Linlin; Wang, Chaodong; Song, Gongru; An, Jing; Liu, Zhongfeng; Zhu, Wanwan; Guan, Yunqian; Xu, Zhi-Qing David; Chan, Piu; Chen, Zhiguo; Zhang, Y Alex

    2015-01-01

    It remains a challenge to differentiate human induced pluripotent stem cells (iPSCs) or embryonic stem (ES) cells to Purkinje cells. In this study, we derived iPSCs from human fibroblasts and directed the specification of iPSCs first to Purkinje progenitors, by adding Fgf2 and insulin to the embryoid bodies (EBs) in a time-sensitive manner, which activates the endogenous production of Wnt1 and Fgf8 from EBs that further patterned the cells towards a midbrain-hindbrain-boundary tissue identity. Neph3-positive human Purkinje progenitors were sorted out by using flow cytometry and cultured either alone or with granule cell precursors, in a 2-dimensional or 3-dimensional environment. However, Purkinje progenitors failed to mature further under above conditions. By co-culturing human Purkinje progenitors with rat cerebellar slices, we observed mature Purkinje-like cells with right morphology and marker expression patterns, which yet showed no appropriate membrane properties. Co-culture with human fetal cerebellar slices drove the progenitors to not only morphologically correct but also electrophysiologically functional Purkinje neurons. Neph3-posotive human cells could also survive transplantation into the cerebellum of newborn immunodeficient mice and differentiate to L7- and Calbindin-positive neurons. Obtaining mature human Purkinje cells in vitro has significant implications in studying the mechanisms of spinocerebellar ataxias and other cerebellar diseases. PMID:25782665

  13. Differential and synergistic effects of mechanical stimulation and growth factor presentation on vascular wall function

    PubMed Central

    Liang, Mao-Shih; Koobatian, Maxwell T.; Lei, Pedro; Swartz, Daniel D.; Andreadis, Stelios T.

    2013-01-01

    We investigated the hypothesis that immobilizing TGF-β1 within fibrin hydrogels may act in synergy with cyclic mechanical stimulation to enhance the properties of vascular grafts. To this end, we engineered a fusion TGF-β1 protein that can covalently anchor to fibrin during polymerization upon the action of factor XIII. We also developed a 24-well based bioreactor in which vascular constructs can be mechanically stimulated by distending the silastic mandrel in the middle of each well. TGF-β1 was either conjugated to fibrin or supplied in the culture medium and the fibrin based constructs were cultured statically for a week followed by cyclic distention for another week. The tissues were examined for myogenic differentiation, vascular reactivity, mechanical properties and ECM content. Our results showed that some aspects of vascular function were differentially affected by growth factor presentation vs. pulsatile force application, while others were synergistically enhanced by both. Overall, this two-prong biomimetic approach improved ECM secretion, vascular reactivity and mechanical properties of vascular constructs. These findings may be applied in other tissue engineering applications such as cartilage, tendon or cardiac regeneration where growth factors TGF-β1 and mechano-stimulation play critical roles. PMID:23810080

  14. Acceleration of screened-exchange density-functional calculations with approximate differential overlap

    NASA Astrophysics Data System (ADS)

    Moussa, Jonathan; Schultz, Peter

    2014-03-01

    We implement the Heyd-Scuseria-Ernzerhof (HSE) screened-exchange density functional in the SEQQUEST electronic structure code. HSE calculations are accelerated by approximating differential overlap in the Fock exchange based on an atomic-orbital partitioning scheme. All one-center and two-center exchange integrals are calculated. A subset of three-center exchange integrals are calculated for one-center Fock exchange matrix elements and for exchange mediated by one-center density matrix elements. Four-center exchange integrals are not calculated. We test the validity of this approximation by examining the number and magnitude of these different classes of exchange integrals. Basis set and pseudopotential errors in HSE calculations are benchmarked on atoms. Differential overlap approximation errors are benchmarked on small molecules. Sandia National Labs is a multi-program laboratory managed and operated by Sandia Corp., a wholly owned subsidiary of Lockheed Martin Corp., for the U.S. Department of Energy's National Nuclear Security Administration under contract DE-AC04-94AL85000.

  15. Laminin and biomimetic extracellular elasticity enhance functional differentiation in mammary epithelia

    PubMed Central

    Alcaraz, Jordi; Xu, Ren; Mori, Hidetoshi; Nelson, Celeste M; Mroue, Rana; Spencer, Virginia A; Brownfield, Doug; Radisky, Derek C; Bustamante, Carlos; Bissell, Mina J

    2008-01-01

    In the mammary gland, epithelial cells are embedded in a ‘soft' environment and become functionally differentiated in culture when exposed to a laminin-rich extracellular matrix gel. Here, we define the processes by which mammary epithelial cells integrate biochemical and mechanical extracellular cues to maintain their differentiated phenotype. We used single cells cultured on top of gels in conditions permissive for β-casein expression using atomic force microscopy to measure the elasticity of the cells and their underlying substrata. We found that maintenance of β-casein expression required both laminin signalling and a ‘soft' extracellular matrix, as is the case in normal tissues in vivo, and biomimetic intracellular elasticity, as is the case in primary mammary epithelial organoids. Conversely, two hallmarks of breast cancer development, stiffening of the extracellular matrix and loss of laminin signalling, led to the loss of β-casein expression and non-biomimetic intracellular elasticity. Our data indicate that tissue-specific gene expression is controlled by both the tissues' unique biochemical milieu and mechanical properties, processes involved in maintenance of tissue integrity and protection against tumorigenesis. PMID:18843297

  16. miR-300 mediates Bmi1 function and regulates differentiation in primitive cardiac progenitors

    PubMed Central

    Cruz, F M; Tomé, M; Bernal, J A; Bernad, A

    2015-01-01

    B lymphoma Mo-MLV insertion region 1 (Bmi1) is a polycomb-family transcriptional factor critical for self-renewal in many adult stem cells and human neoplasia. We sought to identify microRNAs regulated by Bmi1 that could play a role in multipotent cardiac progenitor cell (CPC) decisions. We found that miR-300, a poorly characterized microRNA mapping in the Dlk1-Dio3 microRNA cluster, was positively regulated by Bmi1 in CPCs. Forced expression of miR-300 in CPCs promoted an improved stemness signature with a significant increase in Oct4 levels, a reduction in senescence progression and an enhanced proliferative status via p19 activation and inhibition of p16 accumulation. Endothelial and cardiogenic differentiation were clearly compromised by sustained miR-300 expression. Additionally, RNA and protein analysis revealed a significant reduction in key cardiac transcription factors, including Nkx2.5 and Tbx5. Collectively, these results suggest that some functions attributed to Bmi1 are due to induction of miR-300, which decreases the cardiogenic differentiation potential of multipotent CPCs in vitro and promotes self-renewal. PMID:26512961

  17. Differentiation of human induced pluripotent stem cells to mature functional Purkinje neurons

    PubMed Central

    Wang, Shuyan; Wang, Bin; Pan, Na; Fu, Linlin; Wang, Chaodong; Song, Gongru; An, Jing; Liu, Zhongfeng; Zhu, Wanwan; Guan, Yunqian; Xu, Zhi-Qing David; Chan, Piu; Chen, Zhiguo; Zhang, Y. Alex

    2015-01-01

    It remains a challenge to differentiate human induced pluripotent stem cells (iPSCs) or embryonic stem (ES) cells to Purkinje cells. In this study, we derived iPSCs from human fibroblasts and directed the specification of iPSCs first to Purkinje progenitors, by adding Fgf2 and insulin to the embryoid bodies (EBs) in a time-sensitive manner, which activates the endogenous production of Wnt1 and Fgf8 from EBs that further patterned the cells towards a midbrain-hindbrain-boundary tissue identity. Neph3-positive human Purkinje progenitors were sorted out by using flow cytometry and cultured either alone or with granule cell precursors, in a 2-dimensional or 3-dimensional environment. However, Purkinje progenitors failed to mature further under above conditions. By co-culturing human Purkinje progenitors with rat cerebellar slices, we observed mature Purkinje-like cells with right morphology and marker expression patterns, which yet showed no appropriate membrane properties. Co-culture with human fetal cerebellar slices drove the progenitors to not only morphologically correct but also electrophysiologically functional Purkinje neurons. Neph3-posotive human cells could also survive transplantation into the cerebellum of newborn immunodeficient mice and differentiate to L7- and Calbindin-positive neurons. Obtaining mature human Purkinje cells in vitro has significant implications in studying the mechanisms of spinocerebellar ataxias and other cerebellar diseases. PMID:25782665

  18. Restoring ciliary function to differentiated Primary Ciliary Dyskinesia cells with a lentiviral vector

    PubMed Central

    Ostrowski, Lawrence E; Yin, Weining; Patel, Manij; Sechelski, John; Rogers, Troy; Burns, Kimberlie; Grubb, Barbara R; Olsen, John C

    2014-01-01

    Primary ciliary dyskinesia is a genetically heterogeneous autosomal recessive disease in which mutations disrupt ciliary function, leading to impaired mucociliary clearance and life-long lung disease. Mouse tracheal cells with a targeted deletion in the axonemal dynein intermediated chain gene Dnaic1 differentiate normally in culture but lack ciliary activity. Gene transfer to undifferentiated cultures of mouse Dnaic1−/− cells with a lentiviral vector pseudotyped with avian influenza hemagglutinin restored Dnaic1 expression and ciliary activity. Importantly, apical treatment of well-differentiated cultures of mouse Dnaic1−/− with lentiviral vector also restored ciliary activity, demonstrating successful gene transfer from the apical surface. Treatment of Dnaic1flox/flox mice expressing an estrogen responsive Cre recombinase with different doses of tamoxifen indicated that restoration of ~20% of ciliary activity may be sufficient to prevent the development of rhinosinusitis. However, while administration of a β-galactosidase expressing vector to control mice demonstrated efficient gene transfer to the nasal epithelium, treatment of Dnaic1−/− mice resulted in a low level of gene transfer, demonstrating that the severe rhinitis present in these animals impedes gene transfer. The results demonstrate that gene replacement therapy may be a viable treatment option for primary ciliary dyskinesia, but further improvements in the efficiency of gene transfer are necessary. PMID:24451115

  19. mTOR, metabolism, and the regulation of T-cell differentiation and function

    PubMed Central

    Waickman, Adam T; Powell, Jonathan D.

    2012-01-01

    Summary Upon antigen recognition, naive T cells undergo rapid expansion and activation. The energy requirements for this expansion are formidable, and T-cell activation is accompanied by dramatic changes in cellular metabolism. Furthermore, the outcome of antigen engagement is guided by multiple cues derived from the immune microenvironment. Mammalian target of rapamycin (mTOR) is emerging as a central integrator of these signals playing a critical role in driving T-cell differentiation and function. Indeed, multiple metabolic programs are controlled by mTOR signaling. In this review, we discuss the role of mTOR in regulating metabolism and how these pathways intersect with the ability of mTOR to integrate cues that guide the outcome of T-cell receptor engagement. PMID:22889214

  20. Differential Diagnosis: Shape and Function, Fractal Tools in the Pathology Lab.

    PubMed

    Bianciardi, Giorgio

    2015-10-01

    Fractal analysis is a useful objective tool in describing complexity of shapes and signals providing information for understanding pathological changes. We present fractal approaches and software used in our pathology laboratory to analyze shapes of tumors in tissues and cells, to evaluate the microvessel network complexity in hereditary diseases or the complexity of the surface of blood cells in atherosclerosis-linked condition, as well to analyze function in vasculopathic subjects by chaotic analysis of electrocardiographic signals, in order to perform differential diagnosis. The fractal parameters appear to converge towards distinct values in pathological conditions compared to healthy, approaching the characteristics values of a percolation process or the diffusion-limited aggregation process, respectively: a bifurcation that allows to support the diagnostic process of the pathologist in his daily work. These methods, presented here as a kind of a cookbook ready for the pathologist, are low cost and not time consuming. PMID:26375935

  1. A Degenerate Hopf Bifurcation in Retarded Functional Differential Equations, and Applications to Endemic Bubbles

    NASA Astrophysics Data System (ADS)

    LeBlanc, Victor G.

    2016-02-01

    In this paper, we study degenerate Hopf bifurcations in a class of parametrized retarded functional differential equations. Specifically, we are interested in the case where the eigenvalue crossing condition of the classical Hopf bifurcation theorem is violated. Our approach is based on center manifold reduction and Poincaré-Birkhoff normal forms, and a singularity theoretical classification of this degenerate Hopf bifurcation. Our results are applied to a recently developed SIS model incorporating a delayed behavioral response. We show the phenomenon of endemic bubbles, which is characterized by a branch of periodic solutions which bifurcates from the endemic equilibrium at some value of the basic reproduction number R_0, and then reconnects to the endemic equilibrium at a larger value of R_0, originates in a codimension-two organizing center where the eigenvalue crossing condition for the Hopf bifurcation theorem is violated.

  2. [Differential item functioning: a bibliometric analysis of journals published in Spanish].

    PubMed

    Guilera, Georgina; Gómez, Juana; Hidalgo, M Dolores

    2006-11-01

    Differential item functioning: a bibliometric analysis of journals published in Spanish. This study aims to provide an overview of scientific productivity with respect to articles published in Spanish on the issue of DIF. The documents included in the study were identified using the Psicodoc database, as well as the Science Citation Index and Social Science Citation Index from the Web of Science. The analyses carried out are focused mainly on presenting the frequencies and percentages of publications with respect to various bibliometric indicators. The results reveal that interest in the issue of DIF has increased, and that the universities are the most productive institutions. The majority of articles have been published in the journal Psicothema.

  3. Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function.

    PubMed

    Storm, Elaine E; Durinck, Steffen; de Sousa e Melo, Felipe; Tremayne, Jarrod; Kljavin, Noelyn; Tan, Christine; Ye, Xiaofen; Chiu, Cecilia; Pham, Thinh; Hongo, Jo-Anne; Bainbridge, Travis; Firestein, Ron; Blackwood, Elizabeth; Metcalfe, Ciara; Stawiski, Eric W; Yauch, Robert L; Wu, Yan; de Sauvage, Frederic J

    2016-01-01

    Colorectal cancer remains a major unmet medical need, prompting large-scale genomics efforts in the field to identify molecular drivers for which targeted therapies might be developed. We previously reported the identification of recurrent translocations in R-spondin genes present in a subset of colorectal tumours. Here we show that targeting RSPO3 in PTPRK-RSPO3-fusion-positive human tumour xenografts inhibits tumour growth and promotes differentiation. Notably, genes expressed in the stem-cell compartment of the intestine were among those most sensitive to anti-RSPO3 treatment. This observation, combined with functional assays, suggests that a stem-cell compartment drives PTPRK-RSPO3 colorectal tumour growth and indicates that the therapeutic targeting of stem-cell properties within tumours may be a clinically relevant approach for the treatment of colorectal tumours.

  4. Differential Diagnosis: Shape and Function, Fractal Tools in the Pathology Lab.

    PubMed

    Bianciardi, Giorgio

    2015-10-01

    Fractal analysis is a useful objective tool in describing complexity of shapes and signals providing information for understanding pathological changes. We present fractal approaches and software used in our pathology laboratory to analyze shapes of tumors in tissues and cells, to evaluate the microvessel network complexity in hereditary diseases or the complexity of the surface of blood cells in atherosclerosis-linked condition, as well to analyze function in vasculopathic subjects by chaotic analysis of electrocardiographic signals, in order to perform differential diagnosis. The fractal parameters appear to converge towards distinct values in pathological conditions compared to healthy, approaching the characteristics values of a percolation process or the diffusion-limited aggregation process, respectively: a bifurcation that allows to support the diagnostic process of the pathologist in his daily work. These methods, presented here as a kind of a cookbook ready for the pathologist, are low cost and not time consuming.

  5. Dual amyloid domains promote differential functioning of the chaplin proteins during Streptomyces aerial morphogenesis

    PubMed Central

    Capstick, David S.; Jomaa, Ahmad; Hanke, Chistopher; Ortega, Joaquin; Elliot, Marie A.

    2011-01-01

    The chaplin proteins are functional amyloids found in the filamentous Streptomyces bacteria. These secreted proteins are required for the aerial development of Streptomyces coelicolor, and contribute to an intricate rodlet ultrastructure that decorates the surfaces of aerial hyphae and spores. S. coelicolor encodes eight chaplin proteins. Previous studies have revealed that only three of these proteins (ChpC, ChpE, and ChpH) are necessary for promoting aerial development, and of these three, ChpH is the primary developmental determinant. Here, we show that the model chaplin, ChpH, contains two amyloidogenic domains: one in the N terminus and one in the C terminus of the mature protein. These domains have different polymerization properties as determined using fluorescence spectroscopy, secondary structure analyses, and electron microscopy. We coupled these in vitro assays with in vivo genetic studies to probe the connection between ChpH amyloidogenesis and its biological function. Using mutational analyses, we demonstrated that both N- and C-terminal amyloid domains of ChpH were required for promoting aerial hypha formation, while the N-terminal domain was dispensable for assembly of the rodlet ultrastructure. These results suggest that there is a functional differentiation of the dual amyloid domains in the chaplin proteins. PMID:21628577

  6. Strategies to promote differentiation of newborn neurons into mature functional cells in Alzheimer brain.

    PubMed

    Schaeffer, Evelin L; Novaes, Barbara A; da Silva, Emanuelle R; Skaf, Heni D; Mendes-Neto, Alvaro G

    2009-10-01

    Adult neurogenesis occurs in the subgranular zone (SGZ) and subventricular zone (SVZ). New SGZ neurons migrate into the granule cell layer of the dentate gyrus (DG). New SVZ neurons seem to enter the association neocortex and entorhinal cortex besides the olfactory bulb. Alzheimer disease (AD) is characterized by neuron loss in the hippocampus (DG and CA1 field), entorhinal cortex, and association neocortex, which underlies the learning and memory deficits. We hypothesized that, if the AD brain can support neurogenesis, strategies to stimulate the neurogenesis process could have therapeutic value in AD. We reviewed the literature on: (a) the functional significance of adult-born neurons; (b) the occurrence of endogenous neurogenesis in AD; and (c) strategies to stimulate the adult neurogenesis process. We found that: (a) new neurons in the adult DG contribute to memory function; (b) new neurons are generated in the SGZ and SVZ of AD brains, but they fail to differentiate into mature neurons in the target regions; and (c) numerous strategies (Lithium, Glatiramer Acetate, nerve growth factor, environmental enrichment) can enhance adult neurogenesis and promote maturation of newly generated neurons. Such strategies might help to compensate for the loss of neurons and improve the memory function in AD.

  7. Stimulation of proliferation, differentiation, and function of human cells by primate interleukin 3

    SciTech Connect

    Lopez, A.F.; To, L.B.; Yang, Y.C.; Gamble, J.R.; Shannon, M.F.; Burns, G.F.; Dyson, P.G.; Juttner, C.A.; Clark, S.; Vadas, M.A.

    1987-05-01

    Cloned gibbon interleukin 3 (gIL-3) was found to stimulate the proliferation and differentiation of human bone marrow cells to produce day-14 granulocyte, macrophage, granulocyte-macrophage, and eosinophil colonies in semisolid agar. In the presence of normal human plasma, gIL-3 stimulated megakaryocytes. In methylcellulose cultures, it stimulated erythroid colonies in the presence, but not in the absence, of erythropoietin. When mature human leukocytes were used, gIL-3 stimulated the function of purified mature eosinophils as measured by the capacity to kill /sup 51/Cr-labeled antibody-coated target cells, to produce superoxide anions, and to phagocytize opsonized yeast particles in a manner similar to recombinant human granulocyte-macrophage colony-stimulating factor. In contrast, gIL-3 did not significantly stimulate any of the neutrophil functions tested, whereas human recombinant granulocyte-macrophage colony-stimulating factor was active in these assay. Among cytokines that are active on human hematopoietic cells, gIL-3 thus has a distinct set of functions and may predict the range of actions of the human molecule.

  8. Effectiveness of Combining Statistical Tests and Effect Sizes When Using Logistic Discriminant Function Regression to Detect Differential Item Functioning for Polytomous Items

    ERIC Educational Resources Information Center

    Gómez-Benito, Juana; Hidalgo, Maria Dolores; Zumbo, Bruno D.

    2013-01-01

    The objective of this article was to find an optimal decision rule for identifying polytomous items with large or moderate amounts of differential functioning. The effectiveness of combining statistical tests with effect size measures was assessed using logistic discriminant function analysis and two effect size measures: R[superscript 2] and…

  9. THE WEIGHTED SPACES L_{p,r}^\\alpha(\\rho_1,\\,\\rho_2) OF DIFFERENTIABLE FUNCTIONS OF FRACTIONAL SMOOTHNESS

    NASA Astrophysics Data System (ADS)

    Nogin, V. A.

    1988-02-01

    This is an investigation of weighted spaces of differentiable functions of fractional smoothness consisting of functions f(x) which are r-integrable with a weight \\rho_1 and have "fractional derivatives" which are p-integrable with a weight \\rho_2.Bibliography: 20 titles.

  10. Differential Item Functioning for Lesbians, Bisexual, and Heterosexual Women in the Center for Epidemiological Studies Depression Scale

    ERIC Educational Resources Information Center

    Birnholz, Justin L.; Young, Michael A.

    2012-01-01

    This study assessed whether the Center for Epidemiological Studies Depression Scale (CES-D) functions equivalently in assessing depressive symptom severity in lesbian, bisexual, and heterosexual women. Using differential item functioning methods, the authors examined (a) whether there is a bias in CES-D total scores and in individual item scores…

  11. Empirical Bayes versus Standard Mantel-Haenszel Statistics for Detecting Differential Item Functioning under Small Sample Conditions

    ERIC Educational Resources Information Center

    Fidalgo, Angel M.; Hashimoto, Kanako; Bartram, Dave; Muniz, Jose

    2007-01-01

    In this study, the authors assess several strategies created on the basis of the Mantel-Haenszel (MH) procedure for conducting differential item functioning (DIF) analysis with small samples. One of the analytical strategies is a loss function (LF) that uses empirical Bayes Mantel-Haenszel estimators, whereas the other strategies use the classical…

  12. A Formulation of the Mantel-Haenszel Differential Item Functioning Parameter with Practical Implications. Statistical Report. LSAC Research Report Series.

    ERIC Educational Resources Information Center

    Roussos, Louis A.; Schnipke, Deborah L.; Pashley, Peter J.

    The Mantel-Haenszel (MH) differential item functioning (DIF) parameter for uniform DIF is well defined when item responses follow the two-parameter-logistic (2PPL) item response function (IRF), but not when they follow the three-parameter-logistic (3PL) IRF, the model typically used with multiple choice items. This research report presents a…

  13. Novel ipriflavone receptors coupled to calcium influx regulate osteoclast differentiation and function.

    PubMed

    Miyauchi, A; Notoya, K; Taketomi, S; Takagi, Y; Fujii, Y; Jinnai, K; Takahashi, K; Chihara, K; Fujita, T

    1996-08-01

    Ipriflavone (7-isopropoxyisoflavone) is an effective antiresorptive agent used to treat osteoporosis. However, the mechanism of its action on osteoclasts and their precursor cells is not well understood. To determine whether the mechanism involves direct effects on osteoclasts or their precursors, we examined the effects of ipriflavone on cytosolic free calcium ([Ca2+]i) in osteoclasts and their precursors and measured specific binding of 3H-labeled ipriflavone. Highly purified chicken osteoclast precursors, which spontaneously differentiate into multinucleated osteoclasts in 3-6 days, were loaded with fura-2, and the subcellular [Ca2+]i distribution was monitored by videoimaging. Ipriflavone induced a rapid increase in [Ca2+]i followed by a sustained elevation [EC50 = 5 x 10(-7) M, 263 +/- 74 nM (SE) (n = 8) above basal levels, by 10(-6) M ipriflavone, sustained phase]. The responses were the same in differentiated chicken osteoclasts and isolated rabbit osteoclasts. An influx of extracellular Ca2+ is likely to be responsible for the ipriflavone-induced change in [Ca2+]i because the response was abolished by 0.5 mM LaCl3, or by Ca-free medium containing EGTA. Moreover, high [Ca2+]i levels were detected adjacent to the cell membrane after ipriflavone addition. Ipriflavone induced Ca influx mainly through dihydropyridine-insensitive Ca2+ channels, because nicardipine (10(-7)M) and verapamil (10(-7)M) had no effects on ipriflavone-induced [Ca2+]i responses. [3H]Ipriflavone binding studies indicated the presence of specific ipriflavone binding sites (two classes), both in precursor cells [dissociation constant (Kd), 7.60 x 10(-8)M, 2.67 x 10(-6)M] and in mature osteoclasts (Kd, 4.98 x 10(-8)M, 3.70 x 10(-6)M). Specific ipriflavone binding was not displaced by various modulators of avian osteoclast function, such as estradiol (10(-8)M) or retinoic acid (10(-6)M), indicating that ipriflavone receptors differ from the receptors for these Ca-regulating hormones. The

  14. Loquat leaf extract enhances myogenic differentiation, improves muscle function and attenuates muscle loss in aged rats.

    PubMed

    Sung, Bokyung; Hwang, Seong Yeon; Kim, Min Jo; Kim, Minjung; Jeong, Ji Won; Kim, Cheol Min; Chung, Hae Young; Kim, Nam Deuk

    2015-09-01

    A main characteristic of aging is the debilitating, progressive and generalized impairment of biological functions, resulting in an increased vulnerability to disease and death. Skeletal muscle comprises approximately 40% of the human body; thus, it is the most abundant tissue. At the age of 30 onwards, 0.5‑1% of human muscle mass is lost each year, with a marked acceleration in the rate of decline after the age of 65. Thus, novel strategies that effectively attenuate skeletal muscle loss and enhance muscle function are required to improve the quality of life of older subjects. The aim of the present study was to determine whether loquat (Eriobotrya japonica) leaf extract (LE) can prevent the loss of skeletal muscle function in aged rats. Young (5-month-old) and aged (18‑19-month-old) rats were fed LE (50 mg/kg/day) for 35 days and the changes in muscle mass and strength were evaluated. The age‑associated loss of grip strength was attenuated, and muscle mass and muscle creatine kinase (CK) activity were enhanced following the administration of LE. Histochemical analysis also revealed that LE abrogated the age‑associated decrease in cross‑sectional area (CSA) and decreased the amount of connective tissue in the muscle of aged rats. To investigate the mode of action of LE, C2C12 murine myoblasts were used to evaluate the myogenic potential of LE. The expression levels of myogenic proteins (MyoD and myogenin) and functional myosin heavy chain (MyHC) were measured by western blot analysis. LE enhanced MyoD, myogenin and MyHC expression. The changes in the expression of myogenic genes corresponded with an increase in the activity of CK, a myogenic differentiation marker. Finally, LE activated the Akt/mammalian target of rapamycin (mTOR) signaling pathway, which is involved in muscle protein synthesis during myogenesis. These findings suggest that LE attenuates sarcopenia by promoting myogenic differentiation and subsequently promoting muscle protein synthesis

  15. Loquat leaf extract enhances myogenic differentiation, improves muscle function and attenuates muscle loss in aged rats.

    PubMed

    Sung, Bokyung; Hwang, Seong Yeon; Kim, Min Jo; Kim, Minjung; Jeong, Ji Won; Kim, Cheol Min; Chung, Hae Young; Kim, Nam Deuk

    2015-09-01

    A main characteristic of aging is the debilitating, progressive and generalized impairment of biological functions, resulting in an increased vulnerability to disease and death. Skeletal muscle comprises approximately 40% of the human body; thus, it is the most abundant tissue. At the age of 30 onwards, 0.5‑1% of human muscle mass is lost each year, with a marked acceleration in the rate of decline after the age of 65. Thus, novel strategies that effectively attenuate skeletal muscle loss and enhance muscle function are required to improve the quality of life of older subjects. The aim of the present study was to determine whether loquat (Eriobotrya japonica) leaf extract (LE) can prevent the loss of skeletal muscle function in aged rats. Young (5-month-old) and aged (18‑19-month-old) rats were fed LE (50 mg/kg/day) for 35 days and the changes in muscle mass and strength were evaluated. The age‑associated loss of grip strength was attenuated, and muscle mass and muscle creatine kinase (CK) activity were enhanced following the administration of LE. Histochemical analysis also revealed that LE abrogated the age‑associated decrease in cross‑sectional area (CSA) and decreased the amount of connective tissue in the muscle of aged rats. To investigate the mode of action of LE, C2C12 murine myoblasts were used to evaluate the myogenic potential of LE. The expression levels of myogenic proteins (MyoD and myogenin) and functional myosin heavy chain (MyHC) were measured by western blot analysis. LE enhanced MyoD, myogenin and MyHC expression. The changes in the expression of myogenic genes corresponded with an increase in the activity of CK, a myogenic differentiation marker. Finally, LE activated the Akt/mammalian target of rapamycin (mTOR) signaling pathway, which is involved in muscle protein synthesis during myogenesis. These findings suggest that LE attenuates sarcopenia by promoting myogenic differentiation and subsequently promoting muscle protein synthesis.

  16. Correlation function analysis of the COBE differential microwave radiometer sky maps

    SciTech Connect

    Lineweaver, C.H. |

    1994-08-01

    The Differential Microwave Radiometer (DMR) aboard the COBE satellite has detected anisotropies in the cosmic microwave background (CMB) radiation. A two-point correlation function analysis which helped lead to this discovery is presented in detail. The results of a correlation function analysis of the two year DMR data set is presented. The first and second year data sets are compared and found to be reasonably consistent. The positive correlation for separation angles less than {approximately}20{degree} is robust to Galactic latitude cuts and is very stable from year to year. The Galactic latitude cut independence of the correlation function is strong evidence that the signal is not Galactic in origin. The statistical significance of the structure seen in the correlation function of the first, second and two year maps is respectively > 9{sigma}, > 10{sigma} and > 18{sigma} above the noise. The noise in the DMR sky maps is correlated at a low level. The structure of the pixel temperature covariance matrix is given. The noise covariance matrix of a DMR sky map is diagonal to an accuracy of better than 1%. For a given sky pixel, the dominant noise covariance occurs with the ring of pixels at an angular separation of 60{degree} due to the 60{degree} separation of the DMR horns. The mean covariance of 60{degree} is 0.45%{sub {minus}0.14}{sup +0.18} of the mean variance. The noise properties of the DMR maps are thus well approximated by the noise properties of maps made by a single-beam experiment. Previously published DMR results are not significantly affected by correlated noise.

  17. Functional heterogeneity and differential priming of circulating neutrophils in human experimental endotoxemia.

    PubMed

    Pillay, Janesh; Ramakers, Bart P; Kamp, Vera M; Loi, Adele Lo Tam; Lam, Siu W; Hietbrink, Falco; Leenen, Luke P; Tool, Anton T; Pickkers, Peter; Koenderman, Leo

    2010-07-01

    Neutrophils play an important role in host defense. However, deregulation of neutrophils contributes to tissue damage in severe systemic inflammation. In contrast to complications mediated by an overactive neutrophil compartment, severe systemic inflammation is a risk factor for development of immune suppression and as a result, infectious complications. The role of neutrophils in this clinical paradox is poorly understood, and in this study, we tested whether this paradox could be explained by distinct neutrophil subsets and their functionality. We studied the circulating neutrophil compartment immediately after induction of systemic inflammation by administering 2 ng/kg Escherichia coli LPS i.v. to healthy volunteers. Neutrophils were phenotyped by expression of membrane receptors visualized by flow cytometry, capacity to interact with fluorescently labeled microbes, and activation of the NADPH-oxidase by oxidation of Amplex Red and dihydrorhodamine. After induction of systemic inflammation, expression of membrane receptors on neutrophils, such as CXCR1 and -2 (IL-8Rs), C5aR, FcgammaRII, and TLR4, was decreased. Neutrophils were also refractory to fMLF-induced up-regulation of membrane receptors, and suppression of antimicrobial function was shown by decreased interaction with Staphylococcus epidermis. Simultaneously, activation of circulating neutrophils was demonstrated by a threefold increase in release of ROS. The paradoxical phenotype can be explained by the selective priming of the respiratory burst. In contrast, newly released, CD16(dim) banded neutrophils display decreased antimicrobial function. We conclude that systemic inflammation leads to a functionally heterogeneous neutrophil compartment, in which newly released refractory neutrophils can cause susceptibility to infections, and activated, differentiated neutrophils can mediate tissue damage. PMID:20400675

  18. Numerical solution of differential equations using multiquadric radial basis functions networks.

    PubMed

    Mai-Duy, N; Tran-Cong, T

    2001-03-01

    This paper presents mesh-free procedures for solving linear differential equations (ODEs and elliptic PDEs) based on multiquadric (MQ) radial basis function networks (RBFNs). Based on our study of approximation of function and its derivatives using RBFNs that was reported in an earlier paper (Mai-Duy, N. & Tran-Cong, T. (1999). Approximation of function and its derivatives using radial basis function networks. Neural networks, submitted), new RBFN approximation procedures are developed in this paper for solving DEs, which can also be classified into two types: a direct (DRBFN) and an indirect (IRBFN) RBFN procedure. In the present procedures, the width of the RBFs is the only adjustable parameter according to a(i) = betad(i), where d(i) is the distance from the ith centre to the nearest centre. The IRBFN method is more accurate than the DRBFN one and experience so far shows that beta can be chosen in the range 7 < or = beta 10 for the former. Different combinations of RBF centres and collocation points (uniformly and randomly distributed) are tested on both regularly and irregularly shaped domains. The results for a 1D Poisson's equation show that the DRBFN and the IRBFN procedures achieve a norm of error of at least O(1.0 x 10(-4)) and O(1.0 x 10(-8)), respectively, with a centre density of 50. Similarly, the results for a 2D Poisson's equation show that the DRBFN and the IRBFN procedures achieve a norm of error of at least O(1.0 x 10(-3)) and O(1.0 x10(-6)) respectively, with a centre density of 12 X 12.

  19. Pharmacological activation of estrogen receptors-α and -β differentially modulates keratinocyte differentiation with functional impact on wound healing

    PubMed Central

    PERŽEĽOVÁ, VLASTA; SABOL, FRANTIŠEK; VASILENKO, TOMÁŠ; NOVOTNÝ, MARTIN; KOVÁČ, IVAN; SLEZÁK, MARTIN; ĎURKÁČ, JÁN; HOLLÝ, MARTIN; PILÁTOVÁ, MARTINA; SZABO, PAVOL; VARINSKÁ, LENKA; ČRIEPOKOVÁ, ZUZANA; KUČERA, TOMÁŠ; KALTNER, HERBERT; ANDRÉ, SABINE; GABIUS, HANS-JOACHIM; MUČAJI, PAVEL; SMETANA, KAREL; GÁL, PETER

    2016-01-01

    Estrogen deprivation is considered responsible for many age-related processes, including poor wound healing. Guided by previous observations that estradiol accelerates re-epithelialization through estrogen receptor (ER)-β, in the present study, we examined whether selective ER agonists [4,4′,4″-(4-propyl [1H] pyrazole-1,3,5-triyl)-trisphenol (PPT), ER-α agonist; 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), ER-β agonist] affect the expression of basic proliferation and differentiation markers (Ki-67, keratin-10, -14 and -19, galectin-1 and Sox-2) of keratinocytes using HaCaT cells. In parallel, ovariectomized rats were treated daily with an ER modulator, and wound tissue was removed 21 days after wounding and routinely processed for basic histological analysis. Our results revealed that the HaCaT keratinocytes expressed both ER-α and -β, and thus are well-suited for studying the effects of ER agonists on epidermal regeneration. The activation of ER-α produced a protein expression pattern similar to that observed in the control culture, with a moderate expression of Ki-67 being observed. However, the activation of ER-β led to an increase in cell proliferation and keratin-19 expression, as well as a decrease in galectin-1 expression. Fittingly, in rat wounds treated with the ER-β agonist (DPN), epidermal regeneration was accelerated. In the present study, we provide information on the mechanisms through which estrogens affect the expression patterns of selected markers, thus modulating keratinocyte proliferation and differentiation; in addition, we demonstrate that the pharmacological activation of ER-α and -β has a direct impact on wound healing. PMID:26397183

  20. The Grainyhead-like epithelial transactivator Get-1/Grhl3 regulates epidermal terminal differentiation and interacts functionally with LMO4.

    PubMed

    Yu, Zhengquan; Lin, Kevin K; Bhandari, Ambica; Spencer, Joel A; Xu, Xiaoman; Wang, Ning; Lu, Zhongxian; Gill, Gordon N; Roop, Dennis R; Wertz, Philip; Andersen, Bogi

    2006-11-01

    Defective permeability barrier is an important feature of many skin diseases and causes mortality in premature infants. To investigate the control of barrier formation, we characterized the epidermally expressed Grainyhead-like epithelial transactivator (Get-1)/Grhl3, a conserved mammalian homologue of Grainyhead, which plays important roles in cuticle development in Drosophila. Get-1 interacts with the LIM-only protein LMO4, which is co-expressed in the developing mammalian epidermis. The epidermis of Get-1(-/-) mice showed a severe barrier function defect associated with impaired differentiation of the epidermis, including defects of the stratum corneum, extracellular lipid composition and cell adhesion in the granular layer. The Get-1 mutation affects multiple genes linked to terminal differentiation and barrier function, including most genes of the epidermal differentiation complex. Get-1 therefore directly or indirectly regulates a broad array of epidermal differentiation genes encoding structural proteins, lipid metabolizing enzymes and cell adhesion molecules. Although deletion of the LMO4 gene had no overt consequences for epidermal development, the epidermal terminal differentiation defect in mice deleted for both Get-1 and LMO4 is much more severe than in Get-1(-/-) mice with striking impairment of stratum corneum formation. These findings indicate that the Get-1 and LMO4 genes interact functionally to regulate epidermal terminal differentiation.

  1. Differential item functioning analysis of the Vanderbilt Expertise Test for cars

    PubMed Central

    Lee, Woo-Yeol; Cho, Sun-Joo; McGugin, Rankin W.; Van Gulick, Ana Beth; Gauthier, Isabel

    2015-01-01

    The Vanderbilt Expertise Test for cars (VETcar) is a test of visual learning for contemporary car models. We used item response theory to assess the VETcar and in particular used differential item functioning (DIF) analysis to ask if the test functions the same way in laboratory versus online settings and for different groups based on age and gender. An exploratory factor analysis found evidence of multidimensionality in the VETcar, although a single dimension was deemed sufficient to capture the recognition ability measured by the test. We selected a unidimensional three-parameter logistic item response model to examine item characteristics and subject abilities. The VETcar had satisfactory internal consistency. A substantial number of items showed DIF at a medium effect size for test setting and for age group, whereas gender DIF was negligible. Because online subjects were on average older than those tested in the lab, we focused on the age groups to conduct a multigroup item response theory analysis. This revealed that most items on the test favored the younger group. DIF could be more the rule than the exception when measuring performance with familiar object categories, therefore posing a challenge for the measurement of either domain-general visual abilities or category-specific knowledge. PMID:26418499

  2. A differential equation model for functional mapping of a virus-cell dynamic system.

    PubMed

    Luo, Jiangtao; Hager, William W; Wu, Rongling

    2010-07-01

    The dynamic pattern of viral load in a patient's body critically depends on the host's genes. For this reason, the identification of those genes responsible for virus dynamics, although difficult, is of fundamental importance to design an optimal drug therapy based on patients' genetic makeup. Here, we present a differential equation (DE) model for characterizing specific genes or quantitative trait loci (QTLs) that affect viral load trajectories within the framework of a dynamic system. The model is formulated with the principle of functional mapping, originally derived to map dynamic QTLs, and implemented with a Markov chain process. The DE-integrated model enhances the mathematical robustness of functional mapping, its quantitative prediction about the temporal pattern of genetic expression, and therefore its practical utilization and effectiveness for gene discovery in clinical settings. The model was used to analyze simulated data for viral dynamics, aimed to investigate its statistical properties and validate its usefulness. With an increasing availability of genetic polymorphic data, the model will have great implications for probing the molecular genetic mechanism of virus dynamics and disease progression. PMID:19685244

  3. Differential Requirements of TCR Signaling in Homeostatic Maintenance and Function of Dendritic Epidermal T Cells.

    PubMed

    Zhang, Baojun; Wu, Jianxuan; Jiao, Yiqun; Bock, Cheryl; Dai, Meifang; Chen, Benny; Chao, Nelson; Zhang, Weiguo; Zhuang, Yuan

    2015-11-01

    Dendritic epidermal T cells (DETCs) are generated exclusively in the fetal thymus and maintained in the skin epithelium throughout postnatal life of the mouse. DETCs have restricted antigenic specificity as a result of their exclusive usage of a canonical TCR. Although the importance of the TCR in DETC development has been well established, the exact role of TCR signaling in DETC homeostasis and function remains incompletely defined. In this study, we investigated TCR signaling in fully matured DETCs by lineage-restricted deletion of the Lat gene, an essential signaling molecule downstream of the TCR. We found that Lat deletion impaired TCR-dependent cytokine gene activation and the ability of DETCs to undergo proliferative expansion. However, linker for activation of T cells-deficient DETCs were able to maintain long-term population homeostasis, although with a reduced proliferation rate. Mice with Lat deletion in DETCs exhibited delayed wound healing accompanied by impaired clonal expansion within the wound area. Our study revealed differential requirements for TCR signaling in homeostatic maintenance of DETCs and in their effector function during wound healing. PMID:26408667

  4. Differential Expression of Functional Fc-Receptors and Additional Immune Complex Receptors on Mouse Kidney Cells

    PubMed Central

    Suwanichkul, Adisak; Wenderfer, Scott E.

    2013-01-01

    The precise mechanisms by which circulating immune complexes accumulate in the kidney to form deposits in glomerulonephritis are not well understood. In particular, the role of resident cells within glomeruli of the kidney has been widely debated. Immune complexes have been shown to bind one glomerular cell type (mesangial cells) leading to functional responses such as pro-inflammatory cytokine production. To further assess the presence of functional immunoreceptors on resident glomerular cells, cultured mouse renal epithelial, endothelial, and mesangial cells were treated with heat-aggregated mouse IgG or preformed murine immune complexes. Mesangial and renal endothelial cells were found to bind IgG complexes, whereas glomerular epithelial cell binding was minimal. A blocking antibody for Fc-gamma receptors reduced binding to mesangial cells but not renal endothelial cells, suggesting differential immunoreceptor utilization. RT-PCR and immunostaining based screening of cultured renal endothelial cells showed limited low-level expression of known Fc-receptors and Igbinding proteins. The interaction between mesangial cells and renal endothelial cells and immune complexes resulted in distinct, cell-specific patterns of chemokine and cytokine production. This novel pathway involving renal endothelial cells likely contributes to the predilection of circulating immune complex accumulation within the kidney and to the inflammatory responses that drive kidney injury. PMID:23911392

  5. Differential item functioning analysis of the Vanderbilt Expertise Test for cars.

    PubMed

    Lee, Woo-Yeol; Cho, Sun-Joo; McGugin, Rankin W; Van Gulick, Ana Beth; Gauthier, Isabel

    2015-01-01

    The Vanderbilt Expertise Test for cars (VETcar) is a test of visual learning for contemporary car models. We used item response theory to assess the VETcar and in particular used differential item functioning (DIF) analysis to ask if the test functions the same way in laboratory versus online settings and for different groups based on age and gender. An exploratory factor analysis found evidence of multidimensionality in the VETcar, although a single dimension was deemed sufficient to capture the recognition ability measured by the test. We selected a unidimensional three-parameter logistic item response model to examine item characteristics and subject abilities. The VETcar had satisfactory internal consistency. A substantial number of items showed DIF at a medium effect size for test setting and for age group, whereas gender DIF was negligible. Because online subjects were on average older than those tested in the lab, we focused on the age groups to conduct a multigroup item response theory analysis. This revealed that most items on the test favored the younger group. DIF could be more the rule than the exception when measuring performance with familiar object categories, therefore posing a challenge for the measurement of either domain-general visual abilities or category-specific knowledge.

  6. James Webb Space Telescope segment phasing using differential optical transfer functions

    NASA Astrophysics Data System (ADS)

    Codona, Johanan L.; Doble, Nathan

    2015-04-01

    Differential optical transfer function (dOTF) is an image-based, noniterative wavefront sensing method that uses two star images with a single small change in the pupil. We describe two possible methods for introducing the required pupil modification to the James Webb Space Telescope, one using a small (<λ/4) displacement of a single segment's actuator and another that uses small misalignments of the NIRCam's filter wheel. While both methods should work with NIRCam, the actuator method will allow both MIRI and NIRISS to be used for segment phasing, which is a new functionality. Since the actuator method requires only small displacements, it should provide a fast and safe phasing alternative that reduces the mission risk and can be performed frequently for alignment monitoring and maintenance. Since a single actuator modification can be seen by all three cameras, it should be possible to calibrate the non-common-path aberrations between them. Large segment discontinuities can be measured using dOTFs in two filter bands. Using two images of a star field, aberrations along multiple lines of sight through the telescope can be measured simultaneously. Also, since dOTF gives the pupil field amplitude as well as the phase, it could provide a first approximation or constraint to the planned iterative phase retrieval algorithms.

  7. Differential item functioning analysis of the Vanderbilt Expertise Test for cars.

    PubMed

    Lee, Woo-Yeol; Cho, Sun-Joo; McGugin, Rankin W; Van Gulick, Ana Beth; Gauthier, Isabel

    2015-01-01

    The Vanderbilt Expertise Test for cars (VETcar) is a test of visual learning for contemporary car models. We used item response theory to assess the VETcar and in particular used differential item functioning (DIF) analysis to ask if the test functions the same way in laboratory versus online settings and for different groups based on age and gender. An exploratory factor analysis found evidence of multidimensionality in the VETcar, although a single dimension was deemed sufficient to capture the recognition ability measured by the test. We selected a unidimensional three-parameter logistic item response model to examine item characteristics and subject abilities. The VETcar had satisfactory internal consistency. A substantial number of items showed DIF at a medium effect size for test setting and for age group, whereas gender DIF was negligible. Because online subjects were on average older than those tested in the lab, we focused on the age groups to conduct a multigroup item response theory analysis. This revealed that most items on the test favored the younger group. DIF could be more the rule than the exception when measuring performance with familiar object categories, therefore posing a challenge for the measurement of either domain-general visual abilities or category-specific knowledge. PMID:26418499

  8. Approaches for analyzing the differential activities and functions of eIF4E family members.

    PubMed

    Rhoads, Robert E; Dinkova, Tzvetanka D; Jagus, Rosemary

    2007-01-01

    The translational initiation factor eIF4E binds to the m(7)G-containing cap of mRNA and participates in recruitment of mRNA to ribosomes for protein synthesis. eIF4E also functions in nucleocytoplasmic transport of mRNA, sequestration of mRNA in a nontranslatable state, and stabilization of mRNA against decay in the cytosol. Multiple eIF4E family members have been identified in a wide range of organisms that includes plants, flies, mammals, frogs, birds, nematodes, fish, and various protists. This chapter reviews methods that have been applied to learn the biochemical properties and physiological functions that differentiate eIF4E family members within a given organism. Much has been learned to date about approaches to discover new eIF4E family members, their in vitro properties (cap binding, stimulation of cell-free translation systems), tissue and developmental expression patterns, protein-binding partners, and their effects on the translation or repression of specific subsets of mRNA. Despite these advances, new eIF4E family members continue to be found and new physiological roles discovered.

  9. James Webb Space Telescope segment phasing using differential optical transfer functions

    PubMed Central

    Codona, Johanan L.; Doble, Nathan

    2015-01-01

    Differential optical transfer function (dOTF) is an image-based, noniterative wavefront sensing method that uses two star images with a single small change in the pupil. We describe two possible methods for introducing the required pupil modification to the James Webb Space Telescope, one using a small (<λ/4) displacement of a single segment's actuator and another that uses small misalignments of the NIRCam's filter wheel. While both methods should work with NIRCam, the actuator method will allow both MIRI and NIRISS to be used for segment phasing, which is a new functionality. Since the actuator method requires only small displacements, it should provide a fast and safe phasing alternative that reduces the mission risk and can be performed frequently for alignment monitoring and maintenance. Since a single actuator modification can be seen by all three cameras, it should be possible to calibrate the non-common-path aberrations between them. Large segment discontinuities can be measured using dOTFs in two filter bands. Using two images of a star field, aberrations along multiple lines of sight through the telescope can be measured simultaneously. Also, since dOTF gives the pupil field amplitude as well as the phase, it could provide a first approximation or constraint to the planned iterative phase retrieval algorithms. PMID:27042684

  10. Differential Pair Distribution Function Study of the Structure of Arsenate Adsorbed on Nanocrystalline [gamma]-Alumina

    SciTech Connect

    Li, Wei; Harrington, Richard; Tang, Yuanzhi; Kubicki, James D.; Aryanpour, Masoud; Reeder, Richard J.; Parise, John B.; Phillips, Brian L.

    2012-03-15

    Structural information is important for understanding surface adsorption mechanisms of contaminants on metal (hydr)oxides. In this work, a novel technique was employed to study the interfacial structure of arsenate oxyanions adsorbed on {gamma}-alumina nanoparticles, namely, differential pair distribution function (d-PDF) analysis of synchrotron X-ray total scattering. The d-PDF is the difference of properly normalized PDFs obtained for samples with and without arsenate adsorbed, otherwise identically prepared. The real space pattern contains information on atomic pair correlations between adsorbed arsenate and the atoms on {gamma}-alumina surface (Al, O, etc.). PDF results on the arsenate adsorption sample on {gamma}-alumina prepared at 1 mM As concentration and pH 5 revealed two peaks at 1.66 {angstrom} and 3.09 {angstrom}, corresponding to As-O and As-Al atomic pair correlations. This observation is consistent with those measured by extended X-ray absorption fine structure (EXAFS) spectroscopy, which suggests a first shell of As-O at 1.69 {+-} 0.01 {angstrom} with a coordination number of 4 and a second shell of As-Al at 3.13 {+-} 0.04 {angstrom} with a coordination number of 2. These results are in agreement with a bidentate binuclear coordination environment to the octahedral Al of {gamma}-alumina as predicted by density functional theory (DFT) calculation.

  11. Functional integrity of thalamocortical circuits differentiates normal aging from mild cognitive impairment.

    PubMed

    Cantero, Jose L; Atienza, Mercedes; Gomez-Herrero, German; Cruz-Vadell, Abel; Gil-Neciga, Eulogio; Rodriguez-Romero, Rafael; Garcia-Solis, David

    2009-12-01

    Resonance in thalamocortical networks is critically involved in sculpting oscillatory behavior in large ensembles of neocortical cells. Neocortical oscillations provide critical information about the integrity of thalamocortical circuits and functional connectivity of cortical networks, which seem to be significantly disrupted by the neuronal death and synapse loss characterizing Alzheimer's disease (AD). By applying a novel analysis methodology to overcome volume conduction effects between scalp electroencephalographic (EEG) measurements, we were able to estimate the temporal activation of EEG-alpha sources in the thalamus and parieto-occipital regions of the cortex. We found that synaptic flow underlying the lower alpha band (7.5-10 Hz) was abnormally facilitated in patients with mild cognitive impairment (MCI) as compared to healthy elderly individuals, particularly from thalamus to cortex (approximately 38% higher). In addition, the thalamic generator of lower alpha oscillations was also abnormally activated in patients with MCI. Regarding the upper alpha subdivision (10.1-12.5 Hz), both controls and patients with MCI showed a bidirectional decrease of thalamocortical synaptic transmission, which was age-dependent only in the control group. Altogether, our results suggest that functional dynamics of thalamocortical networks differentiate individuals at high risk of developing AD from healthy elderly subjects, supporting the hypothesis that neurodegeneration mechanisms are active years before the patient is clinically diagnosed with dementia.

  12. Differential Contributions of Dopamine and Serotonin to Orbitofrontal Cortex Function in the Marmoset

    PubMed Central

    Walker, S.C.; Robbins, T.W.

    2009-01-01

    We have shown previously that the inhibitory control functions of the orbitofrontal cortex (OFC) are disrupted by serotonin, but not dopamine depletions. However, both dopamine and serotonin terminals and receptors are present within the OFC and thus the aim of the present study was to determine the differential contributions of these neurotransmitters to orbitofrontal function. OFC and dopamine are involved in the process by which neutral stimuli take on reinforcing properties, by virtue of their prior association with reward, and guide behavior. Thus, we compared the performance of marmosets with dopaminergic or serotoninergic OFC depletions on a test of conditioned reinforcement. To further our understanding of serotonin in behavioral flexibility, the effect of these depletions was also compared on the extinction of a visual discrimination. Monkeys with serotonin depletions of the OFC displayed stimulus-bound responding on both tests of conditioned reinforcement and discrimination extinction suggesting that orbitofrontal serotonin plays a specific role in preventing competing, task irrelevant, salient stimuli from biasing responding. In contrast, monkeys with dopamine depletion were insensitive to conditioned reinforcers and displayed persistent responding in the absence of reward in extinction, a pattern of deficits that may reflect basic deficits in the associative processing of reward. PMID:18723695

  13. Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor suppressor activities

    PubMed Central

    Kagawa, Shingo; Natsuizaka, Mitsuteru; Whelan, Kelly A.; Facompre, Nicole; Naganuma, Seiji; Ohashi, Shinya; Kinugasa, Hideaki; Egloff, Ann Marie; Basu, Devraj; Gimotty, Phyllis A.; Klein-Szanto, Andres J; Bass, Adam; Wong, Kwok-Kin; Diehl, J. Alan; Rustgi, Anil K.; Nakagawa, Hiroshi

    2014-01-01

    Notch activity regulates tumor biology in a context-dependent and complex manner. Notch may act as an oncogene or a tumor suppressor gene even within the same tumor type. Recently, Notch signaling has been implicated in cellular senescence. Yet, it remains unclear as to how cellular senescence checkpoint functions may interact with Notch-mediated oncogenic and tumor suppressor activities. Herein, we used genetically engineered human esophageal keratinocytes and esophageal squamous cell carcinoma cells to delineate the functional consequences of Notch activation and inhibition along with pharmacological intervention and RNA interference (RNAi) experiments. When expressed in a tetracycline-inducible manner, the ectopically expressed activated form of Notch1 (ICN1) displayed oncogene-like characteristics inducing cellular senescence corroborated by the induction of G0/G1 cell-cycle arrest, Rb dephosphorylation, flat and enlarged cell morphology and senescence-associated β-galactosidase activity. Notch-induced senescence involves canonical CSL/RBPJ-dependent transcriptional activity and the p16INK4A-Rb pathway. Loss of p16INK4A or the presence of human papilloma virus (HPV) E6/E7 oncogene products not only prevented ICN1 from inducing senescence, but permitted ICN1 to facilitate anchorage-independent colony formation and xenograft tumor growth with increased cell proliferation and reduced squamous-cell differentiation. Moreover, Notch1 appears to mediate replicative senescence as well as TGF-β-induced cellular senescence in non-transformed cells and that HPV E6/E7 targets Notch1 for inactivation to prevent senescence, revealing a tumor suppressor attribute of endogenous Notch1. In aggregate, cellular senescence checkpoint functions may influence dichotomous Notch activities in the neoplastic context. PMID:24931169

  14. Differentiating Nonrestorative Sleep from Nocturnal Insomnia Symptoms: Demographic, Clinical, Inflammatory, and Functional Correlates

    PubMed Central

    Zhang, Jihui; Lamers, Femke; Hickie, Ian B.; He, Jian-Ping; Feig, Emily; Merikangas, Kathleen R.

    2013-01-01

    Study Objectives: Recent studies have suggested that nonrestorative sleep (NRS) symptoms may be distinct from nocturnal insomnia symptoms (NIS). However, there is limited information on the demographic, medical, and biologic correlates of NRS independent from NIS in the general population. This report presents the sociodemographic correlates, patterns of comorbidity with other sleep and physical disorders, C-reactive protein (CRP) levels, and general productivity associated with NIS and NRS in a nationally representative sample of US adults. Design: National Health and Nutrition Examination Survey (NHANES). Setting: The 2005-2008 surveys of the general population in the United States. Participants: There were 10,908 individuals (20 years or older) Interventions: N/A. Measurements and Results: Respondents were classified by the presence or absence of NIS and NRS. Compared with those without insomnia symptoms, respondents with NIS were older and had lower family income and educational levels than those with NRS. In addition, there was a significant association between NIS and cardiovascular disease, whereas NRS was associated with other primary sleep disorders (including habitual snoring, sleep apnea, and restless legs syndrome), respiratory diseases (emphysema and chronic bronchitis), thyroid disease, and cancer as well as increased CRP levels. In addition, the study participants with NRS only reported poorer scores on the Functional Outcomes of Sleep Questionnaire (FOSQ) than those without insomnia symptoms or those with NIS only. Conclusions: These findings suggest that there are substantial differences between NIS and NRS in terms of sociodemographic factors, comorbidity with other sleep and physical disorders, increased CRP level, and functional impairment. An inflammatory response might play a unique role in the pathogenesis of NRS. Citation: Zhang J; Lamers F; Hickie IB; He JP; Feig E; Merikangas KR. Differentiating nonrestorative sleep from nocturnal insomnia

  15. Comparing Two Intestinal Porcine Epithelial Cell Lines (IPECs): Morphological Differentiation, Function and Metabolism

    PubMed Central

    Nossol, Constanze; Barta-Böszörményi, Anicò; Kahlert, Stefan; Zuschratter, Werner; Faber-Zuschratter, Heidi; Reinhardt, Nicole; Ponsuksili, Siriluk; Wimmers, Klaus; Diesing, Anne-Kathrin; Rothkötter, Hermann-Josef

    2015-01-01

    The pig shows genetical and physiological resemblance to human, which predestines it as an experimental animal model especially for mucosal physiology. Therefore, the intestinal epithelial cell lines 1 and J2 (IPEC-1, IPEC-J2) - spontaneously immortalised cell lines from the porcine intestine - are important tools for studying intestinal function. A microarray (GeneChip Porcine Genome Array) was performed to compare the genome wide gene expression of IPECs. Different significantly up-regulated pathways were identified, like “lysosome”, “pathways in cancer”, “regulation of actin cytoskeleton” and “oxidative phosphorylation” in IPEC-J2 in comparison to IPEC-1. On the other hand, “spliceosome”, “ribosome”, “RNA-degradation” and “tight junction” are significantly down-regulated pathways in IPEC-J2 in comparison to IPEC-1. Examined pathways were followed up by functional analyses. ATP-, oxygen, glucose and lactate-measurement provide evidence for up-regulation of oxidative phosphorylation in IPEC-J2. These cells seem to be more active in their metabolism than IPEC-1 cells due to a significant higher ATP-content as well as a higher O2- and glucose-consumption. The down-regulated pathway “ribosome” was followed up by measurement of RNA- and protein content. In summary, IPEC-J2 is a morphologically and functionally more differentiated cell line in comparison to IPEC-1. In addition, IPEC-J2 cells are a preferential tool for in vitro studies with the focus on metabolism. PMID:26147118

  16. S. macrurus myogenic regulatory factors induce mammalian skeletal muscle differentiation: Evidence for functional conservation of MRFs

    PubMed Central

    Kim, Hyun-Jung; Güth, Robert; Jonsson, Colleen B.; Unguez, Graciela A.

    2009-01-01

    The current-producing cells of the electric organ (EO), i.e., electrocytes, in Sternopygus macrurus derive from skeletal muscle fibers. Mature electrocytes are not contractile but they do retain some muscle proteins, are multinucleated, and receive cholinergic innervation. Electrocytes express the myogenic regulatory factors (MRFs) MyoD, myogenin, Myf5 and MRF4 despite their incomplete muscle phenotype. Although S. macrurus MRFs share functional domains that are highly conserved and their expression is confined to the myogenic lineage, their capability to induce the muscle phenotype has not been determined. To test the functional conservation of S. macrurus MRFs to transcriptionally activate skeletal muscle gene expression and induce the myogenic program, we transiently over-expressed S. macrurus MyoD (SmMyoD) and myogenin (SmMyoG) in mouse C3H/10T1/2 and NIH3T3 embryonic cells. RT-PCR and immunolabeling studies showed that SmMyoD and SmMyoG efficiently can convert these two cell lines into multinucleated myotubes that expressed differentiated muscle markers. The levels of myogenic induction by SmMyoD and SmMyoG were comparable to those obtained with mouse MRF homologs. Furthermore, SmMyoD and SmMyoG proteins were able to induce mouse MyoD and myogenin in C3H/10T1/2 cells. We conclude that S. macrurus MRFs are functionally conserved as they can transcriptionally activate skeletal muscle gene expression and induce the myogenic program in mammalian non-muscle cells. Hence, these data suggest that the partial muscle phenotype of electrocytes is not likely due to differences in the MRF-dependent transcriptional program between skeletal muscle and electric organ. PMID:19598116

  17. Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities.

    PubMed

    Kagawa, S; Natsuizaka, M; Whelan, K A; Facompre, N; Naganuma, S; Ohashi, S; Kinugasa, H; Egloff, A M; Basu, D; Gimotty, P A; Klein-Szanto, A J; Bass, A J; Wong, K-K; Diehl, J A; Rustgi, A K; Nakagawa, H

    2015-04-30

    Notch activity regulates tumor biology in a context-dependent and complex manner. Notch may act as an oncogene or a tumor-suppressor gene even within the same tumor type. Recently, Notch signaling has been implicated in cellular senescence. Yet, it remains unclear as to how cellular senescence checkpoint functions may interact with Notch-mediated oncogenic and tumor-suppressor activities. Herein, we used genetically engineered human esophageal keratinocytes and esophageal squamous cell carcinoma cells to delineate the functional consequences of Notch activation and inhibition along with pharmacological intervention and RNA interference experiments. When expressed in a tetracycline-inducible manner, the ectopically expressed activated form of Notch1 (ICN1) displayed oncogene-like characteristics inducing cellular senescence corroborated by the induction of G0/G1 cell-cycle arrest, Rb dephosphorylation, flat and enlarged cell morphology and senescence-associated β-galactosidase activity. Notch-induced senescence involves canonical CSL/RBPJ-dependent transcriptional activity and the p16(INK4A)-Rb pathway. Loss of p16(INK4A) or the presence of human papilloma virus (HPV) E6/E7 oncogene products not only prevented ICN1 from inducing senescence but permitted ICN1 to facilitate anchorage-independent colony formation and xenograft tumor growth with increased cell proliferation and reduced squamous-cell differentiation. Moreover, Notch1 appears to mediate replicative senescence as well as transforming growth factor-β-induced cellular senescence in non-transformed cells and that HPV E6/E7 targets Notch1 for inactivation to prevent senescence, revealing a tumor-suppressor attribute of endogenous Notch1. In aggregate, cellular senescence checkpoint functions may influence dichotomous Notch activities in the neoplastic context.

  18. A Differential Evolution Algorithm Based on Nikaido-Isoda Function for Solving Nash Equilibrium in Nonlinear Continuous Games

    PubMed Central

    He, Feng; Zhang, Wei; Zhang, Guoqiang

    2016-01-01

    A differential evolution algorithm for solving Nash equilibrium in nonlinear continuous games is presented in this paper, called NIDE (Nikaido-Isoda differential evolution). At each generation, parent and child strategy profiles are compared one by one pairwisely, adapting Nikaido-Isoda function as fitness function. In practice, the NE of nonlinear game model with cubic cost function and quadratic demand function is solved, and this method could also be applied to non-concave payoff functions. Moreover, the NIDE is compared with the existing Nash Domination Evolutionary Multiplayer Optimization (NDEMO), the result showed that NIDE was significantly better than NDEMO with less iterations and shorter running time. These numerical examples suggested that the NIDE method is potentially useful. PMID:27589229

  19. A Differential Evolution Algorithm Based on Nikaido-Isoda Function for Solving Nash Equilibrium in Nonlinear Continuous Games.

    PubMed

    He, Feng; Zhang, Wei; Zhang, Guoqiang

    2016-01-01

    A differential evolution algorithm for solving Nash equilibrium in nonlinear continuous games is presented in this paper, called NIDE (Nikaido-Isoda differential evolution). At each generation, parent and child strategy profiles are compared one by one pairwisely, adapting Nikaido-Isoda function as fitness function. In practice, the NE of nonlinear game model with cubic cost function and quadratic demand function is solved, and this method could also be applied to non-concave payoff functions. Moreover, the NIDE is compared with the existing Nash Domination Evolutionary Multiplayer Optimization (NDEMO), the result showed that NIDE was significantly better than NDEMO with less iterations and shorter running time. These numerical examples suggested that the NIDE method is potentially useful. PMID:27589229

  20. Knocking down of heat-shock protein 27 directs differentiation of functional glutamatergic neurons from placenta-derived multipotent cells

    PubMed Central

    Cheng, Yu-Che; Huang, Chi-Jung; Lee, Yih-Jing; Tien, Lu-Tai; Ku, Wei-Chi; Chien, Raymond; Lee, Fa-Kung; Chien, Chih-Cheng

    2016-01-01

    This study presents human placenta-derived multipotent cells (PDMCs) as a source from which functional glutamatergic neurons can be derived. We found that the small heat-shock protein 27 (HSP27) was downregulated during the neuronal differentiation process. The in vivo temporal and spatial profiles of HSP27 expression were determined and showed inverted distributions with neuronal proteins during mouse embryonic development. Overexpression of HSP27 in stem cells led to the arrest of neuronal differentiation; however, the knockdown of HSP27 yielded a substantially enhanced ability of PDMCs to differentiate into neurons. These neurons formed synaptic networks and showed positive staining for multiple neuronal markers. Additionally, cellular phenomena including the absence of apoptosis and rare proliferation in HSP27-silenced PDMCs, combined with molecular events such as cleaved caspase-3 and the loss of stemness with cleaved Nanog, indicated that HSP27 is located upstream of neuronal differentiation and constrains that process. Furthermore, the induced neurons showed increasing intracellular calcium concentrations upon glutamate treatment. These differentiated cells co-expressed the N-methyl-D-aspartate receptor, vesicular glutamate transporter, and synaptosomal-associated protein 25 but did not show expression of tyrosine hydroxylase, choline acetyltransferase or glutamate decarboxylase 67. Therefore, we concluded that HSP27-silenced PDMCs differentiated into neurons possessing the characteristics of functional glutamatergic neurons. PMID:27444754

  1. Psychosocial risk factors which may differentiate between women with Functional Voice Disorder, Organic Voice Disorder and a Control group.

    PubMed

    Baker, Janet; Ben-Tovim, David; Butcher, Andrew; Esterman, Adrian; McLaughlin, Kristin

    2013-12-01

    This study aimed to explore psychosocial factors contributing to the development of functional voice disorders (FVD) and those differentiating between organic voice disorders (OVD) and a non-voice-disordered control group. A case-control study was undertaken of 194 women aged 18-80 years diagnosed with FVD (n = 73), OVD (n = 55), and controls (n = 66). FVD women were allocated into psychogenic voice disorder (PVD) (n = 37) and muscle tension voice disorder (MTVD) (n = 36) for sub-group analysis. Dependent variables included biographical and voice assessment data, the number and severity of life events and difficulties and conflict over speaking out (COSO) situations derived from the Life Events and Difficulties Schedule (LEDS), and psychological traits including emotional expressiveness scales. Four psychosocial components differentiated between the FVD and control group accounting for 84.9% of the variance: severe events, moderate events, severe COSO, and mild COSO difficulties. Severe events, severe and mild COSO difficulties differentiated between FVD and OVD groups, accounting for 80.5% of the variance. Moderate events differentiated between PVD and MTVD sub-groups, accounting for 58.9% of the variance. Psychological traits did not differentiate between groups. Stressful life events and COSO situations best differentiated FVD from OVD and control groups. More refined aetiological studies are needed to differentiate between PVD and MTVD.

  2. microRNA-449a functions as a tumor suppressor in neuroblastoma through inducing cell differentiation and cell cycle arrest

    PubMed Central

    Zhao, Zhenze; Ma, Xiuye; Sung, Derek; Li, Monica; Kosti, Adam; Lin, Gregory; Chen, Yidong; Pertsemlidis, Alexander; Hsiao, Tzu-Hung; Du, Liqin

    2015-01-01

    microRNA-449a (miR-449a) has been identified to function as a tumor suppressor in several types of cancers. However, the role of miR-449a in neuroblastoma has not been intensively investigated. We recently found that the overexpression of miR-449a significantly induces neuroblastoma cell differentiation, suggesting its potential tumor suppressor function in neuroblastoma. In this study, we further investigated the mechanisms underlying the tumor suppressive function of miR-449a in neuroblastoma. We observed that miR-449a inhibits neuroblastoma cell survival and growth through 2 mechanisms—inducing cell differentiation and cell cycle arrest. Our comprehensive investigations on the dissection of the target genes of miR-449a revealed that 3 novel targets- MFAP4, PKP4 and TSEN15 -play important roles in mediating its differentiation-inducing function. In addition, we further found that its function in inducing cell cycle arrest involves down-regulating its direct targets CDK6 and LEF1. To determine the clinical significance of the miR-449a-mediated tumor suppressive mechanism, we examined the correlation between the expression of these 5 target genes in neuroblastoma tumor specimens and the survival of neuroblastoma patients. Remarkably, we noted that high tumor expression levels of all the 3 miR-449a target genes involved in regulating cell differentiation, but not the target genes involved in regulating cell cycle, are significantly correlated with poor survival of neuroblastoma patients. These results suggest the critical role of the differentiation-inducing function of miR-449a in determining neuroblastoma progression. Overall, our study provides the first comprehensive characterization of the tumor-suppressive function of miR-449a in neuroblastoma, and reveals the potential clinical significance of the miR-449a-mediated tumor suppressive pathway in neuroblastoma prognosis. PMID:25760387

  3. Surface-Functionalized Silk Fibroin Films as a Platform To Guide Neuron-like Differentiation of Human Mesenchymal Stem Cells.

    PubMed

    Manchineella, Shivaprasad; Thrivikraman, Greeshma; Basu, Bikramjit; Govindaraju, T

    2016-09-01

    Surface interactions at the biomaterial-cellular interface determine the proliferation and differentiation of stem cells. Manipulating such interactions through the surface chemistry of scaffolds renders control over directed stem cell differentiation into the cell lineage of interest. This approach is of central importance for stem cell-based tissue engineering and regenerative therapy applications. In the present study, silk fibroin films (SFFs) decorated with integrin-binding laminin peptide motifs (YIGSR and GYIGSR) were prepared and employed for in vitro adult stem cell-based neural tissue engineering applications. Functionalization of SFFs with short peptides showcased the peptide sequence and nature of functionalization-dependent differentiation of bone marrow-derived human mesenchymal stem cells (hMSCs). Intriguingly, covalently functionalized SFFs with GYIGSR hexapeptide (CL2-SFF) supported hMSC proliferation and maintenance in an undifferentiated pluripotent state and directed the differentiation of hMSCs into neuron-like cells in the presence of a biochemical cue, on-demand. The observed morphological changes were further corroborated by the up-regulation of neuronal-specific marker gene expression (MAP2, TUBB3, NEFL), confirmed through semiquantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis. The enhanced proliferation and on-demand directed differentiation of adult stem cells (hMSCs) by the use of an economically viable short recognition peptide (GYIGSR), as opposed to the integrin recognition protein laminin, establishes the potential of SFFs for neural tissue engineering and regenerative therapy applications. PMID:27518901

  4. Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane

    SciTech Connect

    BARCELLOS-HOFF, M. H; AGGELER, J.; RAM, T. G; BISSELL, M. J

    1989-02-01

    An essential feature of mammary gland differentiation during pregnancy is the formation of alveoli composed of polarized epithelial cells, which, under the influence of lactogenic hormones, secrete vectorially and sequester milk proteins. Previous culture studies have described either organization of cells polarized towards lumina containing little or no demonstrable tissue-specific protein, or establishment of functional secretory cells exhibiting little or no glandular architecture. In this paper, we report that tissue-specific vectorial secretion coincides with the formation of functional alveoli-like structures by primary mammary epithelial cells cultured on a reconstituted basement membrane matrix (derived from Engelbreth-Holm-Swarm murine tumour). Morphogenesis of these unique three-dimensional structures was initiated by cell-directed remodelling of the exogenous matrix leading to reorganization of cells into matrixensheathed aggregates by 24 h after plating. The aggregates subsequently cavitated, so that by day 6 the cells were organized into hollow spheres in which apical cell surfaces faced lumina sealed by tight junctions and basal surfaces were surrounded by a distinct basal lamina. The profiles of proteins secreted into the apical (luminal) and basal (medium) compartments indicated that these alveoli-like structures were capable of an appreciable amount of vectorial secretion. Immunoprecipitation with a broad spectrum milk antiserum showed that more than 80% of caseins were secreted into the lumina, whereas iron-binding proteins (both lactoferrin and transferrin) were present in comparable amounts in each compartment. Thus, these mammary cells established protein targeting pathways directing milk-specific proteins to the luminal compartment. A time course monitoring secretory activity demonstrated that establishment of tissue-specific vectorial secretion and increased total and milk protein secretion coincided with functional alveolar

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

    NASA Astrophysics Data System (ADS)

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

    2011-10-01

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

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

    PubMed

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

    1979-02-01

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

  7. Factor structure and differential item functioning of the BASC-2 BESS Spanish Language Parent Form.

    PubMed

    Dever, Bridget V; Raines, Tara C; Dowdy, Erin

    2016-06-01

    Given the steady increase of students from diverse backgrounds in the U.S. educational system, in particular immigrant and Latino students, it is important to consider how to best support all students within our schools. The present study focuses on the Behavior Assessment System for Children-Second Edition (BASC-2) Behavioral and Emotional Screening System (BESS) Parent Spanish form, which is a promising assessment tool for those who are interested in screening for behavioral and emotional risk among Spanish-speaking populations. The present study included 725 students of Latino descent in Grades K-6 in an urban school district and their parents or legal guardians, who served as the informants. All parents completed the BESS language form (English or Spanish) of their choice. A confirmatory factor analysis (CFA) supported a 4-factor structure (Externalizing, Internalizing, Inattention, and Adaptive Skills) similar to that of the BESS Parent English form: χ2(77) = 248.06, p < .001; CFI = 0.903; TLI = 0.940. However, differential item functioning (DIF) analyses revealed 5 items (16.7%) demonstrated significant levels of DIF, with 4 of the 5 being easier to endorse in English. This study provides preliminary evidence of partial invariance of the BESS Parent across language forms. Although some evidence of invariance across language forms at the structural and item levels exists, more research is necessary to determine whether the DIF found in the present study results in any perceptible test bias. (PsycINFO Database Record PMID:27243244

  8. Functional idiotypic mimicry of an adhesion- and differentiation-promoting site on acetylcholinesterase.

    PubMed

    Johnson, Glynis; Moore, Samuel W

    2004-04-01

    Acetylcholinesterase mediates cell adhesion and neurite outgrowth through a site associated with the peripheral anionic site (PAS). Monoclonal antibodies raised to this site block cell adhesion. We have raised anti-idiotypic antibodies to one of these antibodies. The anti-idiotypic antibodies recognized the immunogenic antibody and non-specific mouse IgG, but not acetylcholinesterase. Five antibodies (out of 143 clones, an incidence of 3.5%) were able to promote neurite outgrowth in human neuroblastoma cells in vitro in a similar manner to acetylcholinesterase itself, suggesting that these antibodies carry an internal image of the neuritogenic site. Two of the antibodies were significantly more effective (P < 0.01) than acetylcholinesterase in this regard. The antibodies also bound specifically to mouse laminin-1 and human collagen IV, as does acetylcholinesterase. This binding was displaced by unlabelled antibody, as well as by acetylcholinesterase itself, indicating competition with acetylcholinesterase. We have also investigated the development of anti-anti-idiotypic antibodies in mice in vivo, and have observed that four of these (out of 318 clones, an incidence of 1.26%) mimic the idiotypic antibody and abrogate adhesion in neuroblastoma cells. We have thus demonstrated functional mimicry of the neuritogenic site on acetylcholinesterase in anti-idiotypic antibodies, enhancement of this activity in one antibody, and mimicry of the idiotypic antibody site in anti-anti-idiotypic antibodies. Implications of these findings for differentiation-promoting cancer therapy are discussed.

  9. Formaldehyde Crosses the Human Placenta and Affects Human Trophoblast Differentiation and Hormonal Functions.

    PubMed

    Pidoux, Guillaume; Gerbaud, Pascale; Guibourdenche, Jean; Thérond, Patrice; Ferreira, Fatima; Simasotchi, Christelle; Evain-Brion, Danièle; Gil, Sophie

    2015-01-01

    The chorionic villus of the human placenta is the source of specific endocrine functions and nutrient exchanges. These activities are ensured by the syncytiotrophobast (ST), which bathes in maternal blood. The ST arises and regenerates throughout pregnancy by fusion of underlying cytotrophoblasts (CT). Any anomaly of ST formation or regeneration can affect pregnancy outcome and fetal growth. Because of its direct interaction with maternal blood, the ST is sensitive to drugs, pollutants and xenohormones. Ex vivo assays of perfused cotyledon show that formaldehyde, a common pollutant present in furniture, paint and plastics, can accumulate in the human placenta and cross to the fetal compartment. By means of RT-qPCR, immunoblot and immunocytochemistry experiments, we demonstrate in vitro that formaldehyde exerts endocrine toxicity on human trophoblasts, including a decrease in the production of protein hormones of pregnancy. In addition, formaldehyde exposure triggered human trophoblast fusion by upregulating syncitin-1 receptor expression (ASC-type amino-acid transporter 2: ASCT2). Moreover, we show that formaldehyde-exposed trophoblasts present an altered redox status associated with oxidative stress, and an increase in ASCT2 expression intended to compensate for this stress. Finally, we demonstrate that the adverse effects of formaldehyde on trophoblast differentiation and fusion are reversed by N-acetyl-L-cysteine (Nac), an antioxidant.

  10. Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy.

    PubMed

    Yu, Xinlei; Long, Yun Chau; Shen, Han-Ming

    2015-01-01

    Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3-kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiation and progression of autophagy. The class II enzyme emerged only recently as an alternative source of PtdIns3P and autophagic initiator. However, the orthodox paradigm is challenged by findings that the PIK3CB catalytic subunit of class I PI3K acts as a positive regulator of autophagy, and PIK3C3 was thought to be an amino acid sensor for MTOR, which curbs autophagy. At present, a number of PtdIns3K and PI3K inhibitors, including specific PIK3C3 inhibitors, have been developed for suppression of autophagy and for clinical applications in autophagy-related human diseases.

  11. Simultaneous Differential Scanning Calorimetry and Thermogravimetric Analysis of Portland Cement as a Function of Age

    NASA Astrophysics Data System (ADS)

    Trník, Anton; Scheinherrová, Lenka; Kulovaná, Tereza; Černý, Robert

    2016-01-01

    We study the hydration and pozzolanic reactions of an ordinary Portland cement as a function of age, using the differential scanning calorimetry and thermogravimetry. The measurements are done for 2 days, 7 days, 28 days, 90 days, 180 days, and 360 days cured samples in order to monitor the rate of hydration. The investigation is performed in the temperature range from 25° C to 1000° C with a heating rate 5° C {\\cdot} min^{-1} in an argon atmosphere. The temperature, enthalpy, and mass change during the decomposition of calcium silicate hydrate gels, ettringite, portlandite, vaterite, and calcite are determined, and the changes in the portlandite amount are estimated in dependence on the time of hydration. We found out that the temperature and enthalpy of liberation of physically bound water, C-S-H gels and ettringite decomposition (all occurring from 50° C to 250° C) and Portlandite decomposition (420° C to 530° C) decrease with hydration time of studied samples. On the other hand, vaterite and calcite decomposition (530° C to 850° C) the temperature varies and the enthalpy increases with hydration time of samples.

  12. Maternal reflective functioning as a multidimensional construct: Differential associations with children's temperament and externalizing behavior.

    PubMed

    Smaling, H J A; Huijbregts, S C J; van der Heijden, K B; van Goozen, S H M; Swaab, H

    2016-08-01

    Maternal reflective functioning (RF) has been associated with children's behavioral development. This study examined maternal prenatal and postnatal RF, as measured by the Pregnancy Interview and Parent Development Interview, as multidimensional constructs. It was also examined whether the RF-dimensions were associated with children's temperament and externalizing behavior, as assessed by several questionnaires. The sample consisted of 123 first-time mothers (M age=22.85years, SD=2.21) and their children (M age=19.97months, SD=0.85, 56% male). Two related but distinct dimensions were found for prenatal RF, termed self-focused and child-focused mentalization. Three dimensions were observed for postnatal RF, termed self-focused, child-focused, and relation-focused mentalization. Results showed that prenatal RF negatively related to reported child physical aggression. Postnatal self-focused RF was positively linked to externalizing behavior and negative emotionality in offspring, while relation-focused RF scores were negatively associated with child physical aggression. Findings show that it is important to also look at the specific RF-dimensions when examining the effects of maternal RF on children's behavioral development, as differential associations with behavioral outcomes exist. Discussion further focuses on the importance of these findings in prevention and clinical practice, and suggestions are being made to further improve the measurement of maternal RF-dimensions. PMID:27522031

  13. Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

    PubMed Central

    Yu, Xinlei; Long, Yun Chau; Shen, Han-Ming

    2015-01-01

    Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3-kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiation and progression of autophagy. The class II enzyme emerged only recently as an alternative source of PtdIns3P and autophagic initiator. However, the orthodox paradigm is challenged by findings that the PIK3CB catalytic subunit of class I PI3K acts as a positive regulator of autophagy, and PIK3C3 was thought to be an amino acid sensor for MTOR, which curbs autophagy. At present, a number of PtdIns3K and PI3K inhibitors, including specific PIK3C3 inhibitors, have been developed for suppression of autophagy and for clinical applications in autophagy-related human diseases. PMID:26018563

  14. Formaldehyde Crosses the Human Placenta and Affects Human Trophoblast Differentiation and Hormonal Functions

    PubMed Central

    Pidoux, Guillaume; Gerbaud, Pascale; Guibourdenche, Jean; Thérond, Patrice; Ferreira, Fatima; Simasotchi, Christelle; Evain-Brion, Danièle; Gil, Sophie

    2015-01-01

    The chorionic villus of the human placenta is the source of specific endocrine functions and nutrient exchanges. These activities are ensured by the syncytiotrophobast (ST), which bathes in maternal blood. The ST arises and regenerates throughout pregnancy by fusion of underlying cytotrophoblasts (CT). Any anomaly of ST formation or regeneration can affect pregnancy outcome and fetal growth. Because of its direct interaction with maternal blood, the ST is sensitive to drugs, pollutants and xenohormones. Ex vivo assays of perfused cotyledon show that formaldehyde, a common pollutant present in furniture, paint and plastics, can accumulate in the human placenta and cross to the fetal compartment. By means of RT-qPCR, immunoblot and immunocytochemistry experiments, we demonstrate in vitro that formaldehyde exerts endocrine toxicity on human trophoblasts, including a decrease in the production of protein hormones of pregnancy. In addition, formaldehyde exposure triggered human trophoblast fusion by upregulating syncitin-1 receptor expression (ASC-type amino-acid transporter 2: ASCT2). Moreover, we show that formaldehyde-exposed trophoblasts present an altered redox status associated with oxidative stress, and an increase in ASCT2 expression intended to compensate for this stress. Finally, we demonstrate that the adverse effects of formaldehyde on trophoblast differentiation and fusion are reversed by N-acetyl-L-cysteine (Nac), an antioxidant. PMID:26186596

  15. Differential expression and function of CD27 in chronic lymphocytic leukemia cells expressing ZAP-70.

    PubMed

    Lafarge, Sandrine T; Hou, Sen; Pauls, Samantha D; Johnston, James B; Gibson, Spencer B; Marshall, Aaron J

    2015-07-01

    Chronic lymphocytic leukemia is a malignancy driven by abberant B cell signaling and survival. Leukemic B cells accumulate in the peripheral blood and the lymphoid organs where contact with stromal cells and T cells provide critical survival signals. Clinical severity of CLL is associated with several prognostic markers including expression of the kinase ZAP-70. ZAP-70 expression enhances signaling via the B cell antigen receptor and is associated with increased cell adhesion and migration capacity. Here we report that ZAP-70-positive CLL patients display significantly higher expression of the TNF superfamily receptor and memory marker CD27 than do ZAP-70 negative patients. CD27 expression by CLL was acutely elevated upon BCR cross-linking, or upon ectopic expression of ZAP-70. CD27 expression correlated with functional capacity to adhere to stromal cells and antibody blockade of CD27 impaired CLL binding to stroma. These results provide the first evidence for differential expression of CD27 among CLL prognostic groups, suggest a role for ZAP-70 dependent signaling in CD27 induction and implicate CD27 in cell-cell interactions with the lymphoid tissue microenvironment.

  16. Acetylcholinesterase staining differentiates functionally distinct auditory pathways in the barn owl.

    PubMed

    Adolphs, R

    1993-03-15

    The aim of this study was to examine how the functional specialization of the barn owl's auditory brainstem might correlate with histochemical compartmentalization. The barn owl uses interaural intensity and time differences to encode, respectively, the vertical and azimuthal positions of sound sources in space. These two auditory cues are processed in parallel ascending pathways that separate from each other at the level of the cochlear nuclei. Sections through the auditory brainstem were stained for acetylcholinesterase (AChE) to examine whether nuclei that process different auditory cues stain differentially for this enzyme. Of the two cochlear nuclei, angularis showed more intense staining than nucleus magnocellularis. Nucleus angularis projects to all of the nuclei and subdivisions of nuclei that belong to the intensity processing pathway. Acetylcholinesterase stained all regions that contain terminal fields of nucleus angularis and thus provided discrimination between the time and intensity pathways. Moreover, staining patterns with acetylcholinesterase were complementary to those previously reported with an anti-calbindin antibody, which stains terminal fields of nucleus laminaris, and thus stains all the nuclei and subdivisions of nuclei that belong to the time pathway. Some of the gross staining patterns observed with AChE were similar to those reported with antibodies to glutamate decarboxylase. However, AChE is a more convenient and definitive marker in discriminating between these pathways than is calbindin or glutamate decarboxylase. Acetylcholinesterase staining of the intensity pathway in the owl may be related to encoding of sound intensity by spike rate over large dynamic ranges. PMID:7681456

  17. Functionally competent eosinophils differentiated ex vivo in high purity from normal mouse bone marrow

    PubMed Central

    Dyer, Kimberly D.; Moser, Jennifer M.; Czapiga, Meggan; Siegel, Steven J.; Percopo, Caroline M.; Rosenberg, Helene F.

    2009-01-01

    We have devised an ex vivo culture system which generates large numbers of eosinophils at high purity (>90%) from unselected mouse bone marrow progenitors. In response to four days of culture with recombinant mouse (rm)FLT3-L and rmSCF followed by rmIL-5 alone thereafter, the resulting bone-marrow derived eosinophils (bmEos) express immunoreactive major basic protein, Siglec F, IL-5 receptor alpha chain, and transcripts encoding mouse eosinophil peroxidase, CC chemokine receptor 3, the IL-3/IL-5/GMCSF receptor common beta-chain (βc), and the transcription factor GATA-1. BmEos are functionally competent: they undergo chemotaxis toward mouse eotaxin-1 and produce characteristic cytokines, including interferon-γ, IL-4, MIP-1α and IL-6. The rodent pathogen, pneumonia virus of mice (PVM) replicates in bmEos, and elevated levels of IL-6 are detected in supernatants of bmEos cultures in response to active infection. Finally, differentiating bmEos are readily transfected with lentiviral vectors, suggesting a means for rapid production of genetically manipulated cells. PMID:18768855

  18. Proteomics of Human Dendritic Cell Subsets Reveals Subset-Specific Surface Markers and Differential Inflammasome Function.

    PubMed

    Worah, Kuntal; Mathan, Till S M; Vu Manh, Thien Phong; Keerthikumar, Shivakumar; Schreibelt, Gerty; Tel, Jurjen; Duiveman-de Boer, Tjitske; Sköld, Annette E; van Spriel, Annemiek B; de Vries, I Jolanda M; Huynen, Martijn A; Wessels, Hans J; Gloerich, Jolein; Dalod, Marc; Lasonder, Edwin; Figdor, Carl G; Buschow, Sonja I

    2016-09-13

    Dendritic cells (DCs) play a key role in orchestrating adaptive immune responses. In human blood, three distinct subsets exist: plasmacytoid DCs (pDCs) and BDCA3+ and CD1c+ myeloid DCs. In addition, a DC-like CD16+ monocyte has been reported. Although RNA-expression profiles have been previously compared, protein expression data may provide a different picture. Here, we exploited label-free quantitative mass spectrometry to compare and identify differences in primary human DC subset proteins. Moreover, we integrated these proteomic data with existing mRNA data to derive robust cell-specific expression signatures with more than 400 differentially expressed proteins between subsets, forming a solid basis for investigation of subset-specific functions. We illustrated this by extracting subset identification markers and by demonstrating that pDCs lack caspase-1 and only express low levels of other inflammasome-related proteins. In accordance, pDCs were incapable of interleukin (IL)-1β secretion in response to ATP. PMID:27626665

  19. Solid-phase differential display and bacterial expression systems in selection and functional analysis of cDNAs.

    PubMed

    Ståhl, S; Odeberg, J; Larsson, M; Røsok, O; Ree, A H; Lundeberg, J

    1999-01-01

    Differential gene expression can be expected during activation and differentiation of cells as well as during pathological conditions, such as cancer. A number of strategies have been described to identify and understand isolated differentially expressed genes. The differential display methodology has rapidly become a widely used technique to identify differentially expressed mRNAs. In this chapter we described a variant of the differential display method based on solid-phase technology. The solid-phase procedure offers an attractive alternative to solution-based differential display because minute amounts of sample can be analyzed in considerably less time than previously. The employed solid support, monodisperse super paramagnetic beads, which circumvents precipitation and centrifugations steps, has also allowed for optimization of the critical enzymatic and preparative steps in the differential display methodology. We also described how bacterial expression can be used as a means to elucidate gene function. An efficient dual-expression system was presented, together with a basic concept describing how parallel expression of selected portions of cDNAs can be used for production of cDNA-encoded proteins as parts of affinity-tagged fusion proteins. The fusion proteins are suitable both for the generation of antibodies reactive to the target cDNA-encoded protein and for the subsequent affinity enrichment of such antibodies. Affinity-enriched antibodies have proved to be valuable tools in various assays, including immunoblotting and immunocytochemical staining, and can thus be used to localize the target cDNA-encoded protein to certain cells in a tissue section or even to a specific cell compartment or organelle within a cell. High-resolution localization of a cDNA-encoded protein would provide valuable information toward the understanding of protein function. PMID:10349662

  20. Testicular function in patients with differentiated thyroid carcinoma treated with radioiodine

    SciTech Connect

    Pacini, F.; Gasperi, M.; Fugazzola, L.

    1994-09-01

    The aim of the present study was to assess whether {sup 131}I therapy for differentiated thyroid carcinoma (DTC) can affect endocrine testicular function. Serum follicle-stimulating hormone (FSH) and testosterone (T) concentrations were measured in 103 patients periodically submitted for radioiodine therapy for residual or metastatic disease. Mean follow-up was 93.7{+-}54 mo (range 10-243 mo). Mean FSH values in {sup 131}I-treated patients tested after their last treatment were 15.3{+-}9.9 mU/ml, significantly higher than those of 19 untreated patients (6.5{+-}3.1 mU/ml). Considering the mean +3 s.d. FSH of untreated subjects as the upper limit of normal range, 36.8% of the patients had an abnormal increase in serum FSH. Longitudinal analysis performed in 21 patients showed that the behavior of FSH in response to {sup 131}I therapy was not universal. Six patients had no change or a slight increase in serum FSH after {sup 131}I administration; eleven patients had a transient increase above normal values 6-12 mo after {sup 131}I treatment, with return to normal levels in subsequent months. The administration of a second dose was followed by a similar increase in FSH levels. Finally, four patients, followed for a long period of time and treated with several {sup 131}I doses, showed a progressive increase in serum FSH, which eventually became permanent. Semen analysis, performed in a small subgroup of patients, showed a consistent reduction in the number of normokinetic sperm. No change was found in serum T levels between treated and untreated patients. The results indicate that {sup 131}I therapy for thyroid carcinoma is associated with transient impairment of testicular germinal cell function. The damage may become permanent for high-radiation activities delivered year after year and might pose a significant risk of infertility. 14 refs., 8 figs., 1 tab.

  1. Modeling human neural functionality in vitro: three-dimensional culture for dopaminergic differentiation.

    PubMed

    Simão, Daniel; Pinto, Catarina; Piersanti, Stefania; Weston, Anne; Peddie, Christopher J; Bastos, André E P; Licursi, Valerio; Schwarz, Sigrid C; Collinson, Lucy M; Salinas, Sara; Serra, Margarida; Teixeira, Ana P; Saggio, Isabella; Lima, Pedro A; Kremer, Eric J; Schiavo, Giampietro; Brito, Catarina; Alves, Paula M

    2015-02-01

    Advances in mechanistic knowledge of human neurological disorders have been hindered by the lack of adequate human in vitro models. Three-dimensional (3D) cellular models displaying higher biological relevance are gaining momentum; however, their lack of robustness and scarcity of analytical tools adapted to three dimensions hampers their widespread implementation. Herein we show that human midbrain-derived neural progenitor cells, cultured as 3D neurospheres in stirred culture systems, reproducibly differentiate into complex tissue-like structures containing functional dopaminergic neurons, as well as astrocytes and oligodendrocytes. Moreover, an extensive toolbox of analytical methodologies has been adapted to 3D neural cell models, allowing molecular and phenotypic profiling and interrogation. The generated neurons underwent synaptogenesis and elicit spontaneous Ca(2+) transients. Synaptic vesicle trafficking and release of dopamine in response to depolarizing stimuli was also observed. Under whole-cell current-and-voltage clamp, recordings showed polarized neurons (Vm=-70 mV) and voltage-dependent potassium currents, which included A-type-like currents. Glutamate-induced currents sensitive to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate antagonists revealed the existence of functional glutamate receptors. Molecular and phenotypic profiling showed recapitulation of midbrain patterning events, and remodeling toward increased similarity to human brain features, such as extracellular matrix composition and metabolic signature. We have developed a robust and reproducible human 3D neural cell model, which may be extended to patient-derived induced pluripotent stem cells, broadening the applicability of this model. PMID:25257211

  2. Growth differentiation factor 9:bone morphogenetic protein 15 heterodimers are potent regulators of ovarian functions.

    PubMed

    Peng, Jia; Li, Qinglei; Wigglesworth, Karen; Rangarajan, Adithya; Kattamuri, Chandramohan; Peterson, Randall T; Eppig, John J; Thompson, Thomas B; Matzuk, Martin M

    2013-02-19

    The TGF-β superfamily is the largest family of secreted proteins in mammals, and members of the TGF-β family are involved in most developmental and physiological processes. Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15), oocyte-secreted paralogs of the TGF-β superfamily, have been shown genetically to control ovarian physiology. Although previous studies found that GDF9 and BMP15 homodimers can modulate ovarian pathways in vitro, the functional species-specific significance of GDF9:BMP15 heterodimers remained unresolved. Therefore, we engineered and produced purified recombinant mouse and human GDF9 and BMP15 homodimers and GDF9:BMP15 heterodimers to compare their molecular characteristics and physiological functions. In mouse granulosa cell and cumulus cell expansion assays, mouse GDF9 and human BMP15 homodimers can up-regulate cumulus expansion-related genes (Ptx3, Has2, and Ptgs2) and promote cumulus expansion in vitro, whereas mouse BMP15 and human GDF9 homodimers are essentially inactive. However, we discovered that mouse GDF9:BMP15 heterodimer is ∼10- to 30-fold more biopotent than mouse GDF9 homodimer, and human GDF9:BMP15 heterodimer is ∼1,000- to 3,000-fold more bioactive than human BMP15 homodimer. We also demonstrate that the heterodimers require the kinase activities of ALK4/5/7 and BMPR2 to activate SMAD2/3 but unexpectedly need ALK6 as a coreceptor in the signaling complex in granulosa cells. Our findings that GDF9:BMP15 heterodimers are the most bioactive ligands in mice and humans compared with homodimers explain many puzzling genetic and physiological data generated during the last two decades and have important implications for improving female fertility in mammals.

  3. Deletion of Smad2 in Mouse Liver Reveals Novel Functions in Hepatocyte Growth and Differentiation

    PubMed Central

    Ju, Wenjun; Ogawa, Atsushi; Heyer, Joerg; Nierhof, Dirk; Yu, Liping; Kucherlapati, Raju; Shafritz, David A.; Böttinger, Erwin P.

    2006-01-01

    Smad family proteins Smad2 and Smad3 are activated by transforming growth factor β (TGF-β)/activin/nodal receptors and mediate transcriptional regulation. Although differential functional roles of Smad2 and Smad3 are apparent in mammalian development, the relative functional roles of Smad2 and Smad3 in postnatal systems remain unclear. We used Cre/loxP-mediated gene targeting for hepatocyte-specific deletion of Smad2 (S2HeKO) in adult mice and generated hepatocyte-selective Smad2/Smad3 double knockouts by intercrossing AlbCre/Smad2f/f (S2HeKO) and Smad3-deficient Smad3ex8/ex8 (S3KO) mice. All strains were viable and had normal adult liver. However, necrogenic CCL4-induced hepatocyte proliferation was significantly increased in S2HeKO compared to Ctrl and S3KO livers, and transplanted S2HeKO hepatocytes repopulated recipient liver at dramatically increased rates compared to Ctrl hepatocytes in vivo. Using primary hepatocytes, we found that TGF-β-induced G1 arrest, apoptosis, and epithelial-to-mesenchymal transition in Ctrl and S2HeKO but not in S3KO hepatocytes. Interestingly, S2HeKO cells spontaneously acquired mesenchymal features characteristic of epithelial-to-mesenchymal transition (EMT). Collectively, these results demonstrate that Smad2 suppresses hepatocyte growth and dedifferentiation independent of TGF-β signaling. Smad2 is not required for TGF-β-stimulated apoptosis, EMT, and growth inhibition in hepatocytes. PMID:16382155

  4. Platelet-derived CXCL12 regulates monocyte function, survival, differentiation into macrophages and foam cells through differential involvement of CXCR4–CXCR7

    PubMed Central

    Chatterjee, M; von Ungern-Sternberg, S N I; Seizer, P; Schlegel, F; Büttcher, M; Sindhu, N A; Müller, S; Mack, A; Gawaz, M

    2015-01-01

    Platelets store and release CXCL12 (SDF-1), which governs differentiation of hematopoietic progenitors into either endothelial or macrophage-foam cells. CXCL12 ligates CXCR4 and CXCR7 and regulates monocyte/macrophage functions. This study deciphers the relative contribution of CXCR4–CXCR7 in mediating the effects of platelet-derived CXCL12 on monocyte function, survival, and differentiation. CXCL12 and macrophage migration inhibitory factor (MIF) that ligate CXCR4–CXCR7 induced a dynamic bidirectional trafficking of the receptors, causing CXCR4 internalization and CXCR7 externalization during chemotaxis, thereby influencing relative receptor availability, unlike MCP-1. In vivo we found enhanced accumulation of platelets and platelet-macrophage co-aggregates in peritoneal fluid following induction of peritonitis in mice. The relative surface expression of CXCL12, CXCR4, and CXCR7 among infiltrated monocytes was also enhanced as compared with peripheral blood. Platelet-derived CXCL12 from collagen-adherent platelets and recombinant CXCL12 induced monocyte chemotaxis specifically through CXCR4 engagement. Adhesion of monocytes to immobilized CXCL12 and CXCL12-enriched activated platelet surface under static and dynamic arterial flow conditions were mediated primarily through CXCR7 and were counter-regulated by neutralizing platelet-derived CXCL12. Monocytes and culture-derived-M1–M2 macrophages phagocytosed platelets, with the phagocytic potential of culture-derived-M1 macrophages higher than M2 involving CXCR4–CXCR7 participation. CXCR7 was the primary receptor in promoting monocyte survival as exerted by platelet-derived CXCL12 against BH3-mimetic induced apoptosis (phosphatidylserine exposure, caspase-3 activation, loss of mitochondrial transmembrane potential). In co-culture experiments with platelets, monocytes predominantly differentiated into CD163+ macrophages, which was attenuated upon CXCL12 neutralization and CXCR4/CXCR7 blocking antibodies

  5. Carbon monoxide improves neuronal differentiation and yield by increasing the functioning and number of mitochondria.

    PubMed

    Almeida, Ana S; Sonnewald, Ursula; Alves, Paula M; Vieira, Helena L A

    2016-08-01

    The process of cell differentiation goes hand-in-hand with metabolic adaptations, which are needed to provide energy and new metabolites. Carbon monoxide (CO) is an endogenous cytoprotective molecule able to inhibit cell death and improve mitochondrial metabolism. Neuronal differentiation processes were studied using the NT2 cell line, which is derived from human testicular embryonic teratocarcinoma and differentiates into post-mitotic neurons upon retinoic acid treatment. CO-releasing molecule A1 (CORM-A1) was used do deliver CO into cell culture. CO treatment improved NT2 neuronal differentiation and yield, since there were more neurons and the total cell number increased following the differentiation process. CO supplementation enhanced the mitochondrial population in post-mitotic neurons derived from NT2 cells, as indicated by an increase in mitochondrial DNA. CO treatment during neuronal differentiation increased the extent of the classical metabolic change that occurs during neuronal differentiation, from glycolytic to more oxidative metabolism, by decreasing the ratio of lactate production and glucose consumption. The expression of pyruvate and lactate dehydrogenases was higher, indicating an augmented oxidative metabolism. Moreover, these findings were corroborated by an increased percentage of (13) C incorporation from [U-(13) C]glucose into the tricarboxylic acid cycle metabolites malate and citrate, and also glutamate and aspartate in CO-treated cells. Finally, under low levels of oxygen (5%), which enhances glycolytic metabolism, some of the enhancing effects of CO on mitochondria were not observed. In conclusion, our data show that CO improves neuronal and mitochondrial yield by stimulation of tricarboxylic acid cycle activity, and thus oxidative metabolism of NT2 cells during the process of neuronal differentiation. The process of cell differentiation is coupled with metabolic adaptations. Carbon monoxide (CO) is an endogenous cytoprotective

  6. Differential Motivational Properties of Ethanol During Early Ontogeny as a Function of Dose and Postadministration Time

    PubMed Central

    Molina, Juan Carlos; Pautassi, Ricardo Marcos; Truxell, Eric; Spear, Norman

    2007-01-01

    While appetitive reinforcement effects of ethanol (EtOH) are easily detected in rat neonates, such phenomena rarely have been observed in older infants. Recently, Molina et al. (2006) reported such effects of ethanol in 14-days olds using a second-order conditioning procedure. Infants also appear to be sensitive to biphasic reinforcement or general motivational effects of ethanol, with appetitive effects seeming to occur early in the state of intoxication and aversive effects predominant during late stages, but tests have been inconclusive. The present study examined the possibility of biphasic motivational effects of ethanol during infancy through the use of second-order conditioning procedures. Preweanling rats (14 days old) experienced intraoral water infusions (conditioned stimulus, CS) either 5-20 or 30-45 min after administration of 0.5 or 2.0 g/kg i.g. ethanol. Pups were then exposed to the CS while over a novel texture (second-order phase). Tests of tactile preference for that texture followed. Locomotive, thermal, hormonal (corticosterone release) and pharmacokinetic patterns likely to underlie the acquisition of ethanol-mediated conditioning were also examined in subsequent experiments. Intraoral CSs paired with either early or late effects of low dose ethanol [0.5 g/kg, blood ethanol concentration (BEC): 40 mg%] became positive second-order reinforcers. Appetitive effects were also exhibited by pups exposed to the CS during commencement of the toxic episode induced by a 2.0 g/kg EtOH dose, 5-20 min after administration of ethanol, whereas aversions emerged when CS presentation occurred 30-45 min postadministration time (BECs: 157 and 200 mg%, respectively). Overall, the results indicate that infants rapidly detect differential motivational properties of ethanol as a function of dose or drug postadministration time. Relatively neutral stimuli associated with these properties are later capable of acting as either positive or aversive reinforcers. Thermal

  7. Differential and Synergistic Functionality of Acylsugars in Suppressing Oviposition by Insect Herbivores.

    PubMed

    Leckie, Brian M; D'Ambrosio, Damon A; Chappell, Thomas M; Halitschke, Rayko; De Jong, Darlene M; Kessler, André; Kennedy, George G; Mutschler, Martha A

    2016-01-01

    Acylsugars are secondary metabolites exuded from type IV glandular trichomes that provide broad-spectrum insect suppression for Solanum pennellii Correll, a wild relative of cultivated tomato. Acylsugars produced by different S. pennellii accessions vary by sugar moieties (glucose or sucrose) and fatty acid side chains (lengths and branching patterns). Our objective was to determine which acylsugar compositions more effectively suppressed oviposition of the whitefly Bemisia tabaci (Gennadius) (Middle East--Asia Minor 1 Group), tobacco thrips, Frankliniella fusca (Hinds), and western flower thrips, Frankliniella occidentalis (Pergande). We extracted and characterized acylsugars from four S. pennellii accessions with different compositions, as well as from an acylsugar-producing tomato breeding line. We also fractionated the acylsugars of one S. pennellii accession to examine the effects of its components. Effects of acylsugars on oviposition were evaluated by administering a range of doses to oviposition sites of adult whiteflies and thrips in non-choice and choice bioassays, respectively. The acylsugars from S. pennellii accessions and the tomato breeding line demonstrated differential functionality in their ability to alter the distribution of whitefly oviposition and suppress oviposition on acylsugar treated substrates. Tobacco thrips were sensitive to all compositions while western flower thrips and whiteflies were more sensitive to acylsugars from a subset of S. pennellii accessions. It follows that acylsugars could thus mediate plant-enemy interactions in such a way as to affect evolution of host specialization, resistance specificity, and potentially host differentiation or local adaptation. The acylsugars from S. pennellii LA1376 were separated by polarity into two fractions that differed sharply for their sugar moieties and fatty acid side chains. These fractions had different efficacies, with neither having activity approaching that of the original exudate

  8. Differential and Synergistic Functionality of Acylsugars in Suppressing Oviposition by Insect Herbivores

    PubMed Central

    Chappell, Thomas M.; Halitschke, Rayko; De Jong, Darlene M.; Kessler, André; Kennedy, George G.; Mutschler, Martha A.

    2016-01-01

    Acylsugars are secondary metabolites exuded from type IV glandular trichomes that provide broad-spectrum insect suppression for Solanum pennellii Correll, a wild relative of cultivated tomato. Acylsugars produced by different S. pennellii accessions vary by sugar moieties (glucose or sucrose) and fatty acid side chains (lengths and branching patterns). Our objective was to determine which acylsugar compositions more effectively suppressed oviposition of the whitefly Bemisia tabaci (Gennadius) (Middle East—Asia Minor 1 Group), tobacco thrips, Frankliniella fusca (Hinds), and western flower thrips, Frankliniella occidentalis (Pergande). We extracted and characterized acylsugars from four S. pennellii accessions with different compositions, as well as from an acylsugar-producing tomato breeding line. We also fractionated the acylsugars of one S. pennellii accession to examine the effects of its components. Effects of acylsugars on oviposition were evaluated by administering a range of doses to oviposition sites of adult whiteflies and thrips in non-choice and choice bioassays, respectively. The acylsugars from S. pennellii accessions and the tomato breeding line demonstrated differential functionality in their ability to alter the distribution of whitefly oviposition and suppress oviposition on acylsugar treated substrates. Tobacco thrips were sensitive to all compositions while western flower thrips and whiteflies were more sensitive to acylsugars from a subset of S. pennellii accessions. It follows that acylsugars could thus mediate plant-enemy interactions in such a way as to affect evolution of host specialization, resistance specificity, and potentially host differentiation or local adaptation. The acylsugars from S. pennellii LA1376 were separated by polarity into two fractions that differed sharply for their sugar moieties and fatty acid side chains. These fractions had different efficacies, with neither having activity approaching that of the original

  9. Differential Item Functioning and Language Translation: A Cross-National Study with a Test Developed for Certification.

    ERIC Educational Resources Information Center

    Price, Larry R.; Oshima, T. C.

    Often, educational and psychological measurement instruments must be translated from one language to another when they are administered to different cultural groups. The translation process often necessarily introduces measurement inequivalence. Therefore, an examination may be said to exhibit differential functioning if the test provides a…

  10. Green function of the double-fractional Fokker-Planck equation: path integral and stochastic differential equations.

    PubMed

    Kleinert, H; Zatloukal, V

    2013-11-01

    The statistics of rare events, the so-called black-swan events, is governed by non-Gaussian distributions with heavy power-like tails. We calculate the Green functions of the associated Fokker-Planck equations and solve the related stochastic differential equations. We also discuss the subject in the framework of path integration.

  11. Differential Item Functioning Assessment in Cognitive Diagnostic Modeling: Application of the Wald Test to Investigate DIF in the DINA Model

    ERIC Educational Resources Information Center

    Hou, Likun; de la Torre, Jimmy; Nandakumar, Ratna

    2014-01-01

    Analyzing examinees' responses using cognitive diagnostic models (CDMs) has the advantage of providing diagnostic information. To ensure the validity of the results from these models, differential item functioning (DIF) in CDMs needs to be investigated. In this article, the Wald test is proposed to examine DIF in the context of CDMs. This…

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

    ERIC Educational Resources Information Center

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

    2007-01-01

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

  13. T Cell Fates Zipped Up: How the Bach2 Basic Leucine Zipper Transcriptional Repressor Directs T Cell Differentiation and Function.

    PubMed

    Richer, Martin J; Lang, Mark L; Butler, Noah S

    2016-08-15

    Recent data illustrate a key role for the transcriptional regulator bric-a-brac, tramtrack, and broad complex and cap'n'collar homology (Bach)2 in orchestrating T cell differentiation and function. Although Bach2 has a well-described role in B cell differentiation, emerging data show that Bach2 is a prototypical member of a novel class of transcription factors that regulates transcriptional activity in T cells at super-enhancers, or regions of high transcriptional activity. Accumulating data demonstrate specific roles for Bach2 in favoring regulatory T cell generation, restraining effector T cell differentiation, and potentiating memory T cell development. Evidence suggests that Bach2 regulates various facets of T cell function by repressing other key transcriptional regulators such as B lymphocyte-induced maturation protein 1. In this review, we examine our present understanding of the role of Bach2 in T cell function and highlight the growing evidence that this transcriptional repressor functions as a key regulator involved in maintenance of T cell quiescence, T cell subset differentiation, and memory T cell generation.

  14. Analysis of the Gender Variable in the Eysenck Personality Questionnaire--Revised Scales Using Differential Item Functioning Techniques

    ERIC Educational Resources Information Center

    Escorial, Sergio; Navas, Maria J.

    2007-01-01

    Studies in the field of personality have systematically found gender differences in two of the three dimensions of the Eysenck model: neuroticism and psychoticism. This study aims to analyze these differences in the Eysenck Personality Questionnaire--Revised (EPQ-R) scales using differential item functioning (DIF) techniques to determine whether…

  15. Differential Item Functioning Analysis of the Science and Mathematics Items in the University Entrance Examinations in Turkey

    ERIC Educational Resources Information Center

    Kalaycioglu, Dilara Bakan; Berberoglu, Giray

    2011-01-01

    This study is aimed to detect differential item functioning (DIF) items across gender groups, analyze item content for the possible sources of DIF, and eventually investigate the effect of DIF items on the criterion-related validity of the test scores in the quantitative section of the university entrance examination (UEE) in Turkey. The reason…

  16. Identifying Differential Item Functioning of Rating Scale Items with the Rasch Model: An Introduction and an Application

    ERIC Educational Resources Information Center

    Myers, Nicholas D.; Wolfe, Edward W.; Feltz, Deborah L.; Penfield, Randall D.

    2006-01-01

    This study (a) provided a conceptual introduction to differential item functioning (DIF), (b) introduced the multifaceted Rasch rating scale model (MRSM) and an associated statistical procedure for identifying DIF in rating scale items, and (c) applied this procedure to previously collected data from American coaches who responded to the coaching…

  17. What's the DIF? Why Differential Item Functioning Analyses Are an Important Part of Instrument Development and Validation

    ERIC Educational Resources Information Center

    Walker, Cindy M.

    2011-01-01

    The purpose of this manuscript was to help researchers better understand the causes and implications of differential item functioning (DIF), as well as the importance of testing for DIF in the process of test development and validation. The underlying theoretical reason for the presence of DIF is explicated, followed by a discussion of how to test…

  18. Detecting Differential Item Functioning across Examinees Tested in Their Dominant Language and Examinees Tested in a Second Language

    ERIC Educational Resources Information Center

    Hauger, Jeffrey B.; Sireci, Stephen G.

    2008-01-01

    In this study, we examined the presence of differential item functioning (DIF) among groups of students who were tested in their native language or in a different language when participating in the 1999 Trends in International Mathematics and Science Study. Data from 18,837 examinees from three countries (Singapore, United States, and Iran) were…

  19. Gender Bias and Construct Validity in Vocational Interest Measurement: Differential Item Functioning in the Strong Interest Inventory

    ERIC Educational Resources Information Center

    Einarsdottir, Sif; Rounds, James

    2009-01-01

    Item response theory was used to address gender bias in interest measurement. Differential item functioning (DIF) technique, SIBTEST and DIMTEST for dimensionality, were applied to the items of the six General Occupational Theme (GOT) and 25 Basic Interest (BI) scales in the Strong Interest Inventory. A sample of 1860 women and 1105 men was used.…

  20. Mixture Item Response Theory-MIMIC Model: Simultaneous Estimation of Differential Item Functioning for Manifest Groups and Latent Classes

    ERIC Educational Resources Information Center

    Bilir, Mustafa Kuzey

    2009-01-01

    This study uses a new psychometric model (mixture item response theory-MIMIC model) that simultaneously estimates differential item functioning (DIF) across manifest groups and latent classes. Current DIF detection methods investigate DIF from only one side, either across manifest groups (e.g., gender, ethnicity, etc.), or across latent classes…

  1. Functional Cross-Talking between Differentially Expressed and Alternatively Spliced Genes in Human Liver Cancer Cells Treated with Berberine.

    PubMed

    Sheng, Zhen; Sun, Yi; Zhu, Ruixin; Jiao, Na; Tang, Kailin; Cao, Zhiwei; Ma, Chao

    2015-01-01

    Berberine has been identified with anti-proliferative effects on various cancer cells. Many researchers have been trying to elucidate the anti-cancer mechanisms of berberine based on differentially expressed genes. However, differentially alternative splicing genes induced by berberine might also contribute to its pharmacological actions and have not been reported yet. Moreover, the potential functional cross-talking between the two sets of genes deserves further exploration. In this study, RNA-seq technology was used to detect the differentially expressed genes and differentially alternative spliced genes in BEL-7402 cancer cells induced by berberine. Functional enrichment analysis indicated that these genes were mainly enriched in the p53 and cell cycle signalling pathway. In addition, it was statistically proven that the two sets of genes were locally co-enriched along chromosomes, closely connected to each other based on protein-protein interaction and functionally similar on Gene Ontology tree. These results suggested that the two sets of genes regulated by berberine might be functionally cross-talked and jointly contribute to its cell cycle arresting effect. It has provided new clues for further researches on the pharmacological mechanisms of berberine as well as the other botanical drugs.

  2. T Cell Fates Zipped Up: How the Bach2 Basic Leucine Zipper Transcriptional Repressor Directs T Cell Differentiation and Function.

    PubMed

    Richer, Martin J; Lang, Mark L; Butler, Noah S

    2016-08-15

    Recent data illustrate a key role for the transcriptional regulator bric-a-brac, tramtrack, and broad complex and cap'n'collar homology (Bach)2 in orchestrating T cell differentiation and function. Although Bach2 has a well-described role in B cell differentiation, emerging data show that Bach2 is a prototypical member of a novel class of transcription factors that regulates transcriptional activity in T cells at super-enhancers, or regions of high transcriptional activity. Accumulating data demonstrate specific roles for Bach2 in favoring regulatory T cell generation, restraining effector T cell differentiation, and potentiating memory T cell development. Evidence suggests that Bach2 regulates various facets of T cell function by repressing other key transcriptional regulators such as B lymphocyte-induced maturation protein 1. In this review, we examine our present understanding of the role of Bach2 in T cell function and highlight the growing evidence that this transcriptional repressor functions as a key regulator involved in maintenance of T cell quiescence, T cell subset differentiation, and memory T cell generation. PMID:27496973

  3. Centering, Scale Indeterminacy, and Differential Item Functioning Detection in Hierarchical Generalized Linear and Generalized Linear Mixed Models

    ERIC Educational Resources Information Center

    Cheong, Yuk Fai; Kamata, Akihito

    2013-01-01

    In this article, we discuss and illustrate two centering and anchoring options available in differential item functioning (DIF) detection studies based on the hierarchical generalized linear and generalized linear mixed modeling frameworks. We compared and contrasted the assumptions of the two options, and examined the properties of their DIF…

  4. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment.

    PubMed

    Corzo, Cesar A; Condamine, Thomas; Lu, Lily; Cotter, Matthew J; Youn, Je-In; Cheng, Pingyan; Cho, Hyun-Il; Celis, Esteban; Quiceno, David G; Padhya, Tapan; McCaffrey, Thomas V; McCaffrey, Judith C; Gabrilovich, Dmitry I

    2010-10-25

    Myeloid-derived suppressor cells (MDSCs) are a major component of the immune-suppressive network described in cancer and many other pathological conditions. We demonstrate that although MDSCs from peripheral lymphoid organs and the tumor site share similar phenotype and morphology, these cells display profound functional differences. MDSC from peripheral lymphoid organs suppressed antigen-specific CD8(+) T cells but failed to inhibit nonspecific T cell function. In sharp contrast, tumor MDSC suppressed both antigen-specific and nonspecific T cell activity. The tumor microenvironment caused rapid and dramatic up-regulation of arginase I and inducible nitric oxide synthase in MDSC, which was accompanied by down-regulation of nicotinamide adenine dinucleotide phosphate-oxidase and reactive oxygen species in these cells. In contrast to MDSC from the spleen, MDSC from the tumor site rapidly differentiated into macrophages. Exposure of spleen MDSC to hypoxia resulted in the conversion of these cells to nonspecific suppressors and their preferential differentiation to macrophages. Hypoxia-inducible factor (HIF) 1α was found to be primarily responsible for the observed effects of the tumor microenvironment on MDSC differentiation and function. Thus, hypoxia via HIF-1α dramatically alters the function of MDSC in the tumor microenvironment and redirects their differentiation toward tumor-associated macrophages, hence providing a mechanistic link between different myeloid suppressive cells in the tumor microenvironment.

  5. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment

    PubMed Central

    Corzo, Cesar A.; Condamine, Thomas; Lu, Lily; Cotter, Matthew J.; Youn, Je-In; Cheng, Pingyan; Cho, Hyun-Il; Celis, Esteban; Quiceno, David G.; Padhya, Tapan; McCaffrey, Thomas V.; McCaffrey, Judith C.

    2010-01-01

    Myeloid-derived suppressor cells (MDSCs) are a major component of the immune-suppressive network described in cancer and many other pathological conditions. We demonstrate that although MDSCs from peripheral lymphoid organs and the tumor site share similar phenotype and morphology, these cells display profound functional differences. MDSC from peripheral lymphoid organs suppressed antigen-specific CD8+ T cells but failed to inhibit nonspecific T cell function. In sharp contrast, tumor MDSC suppressed both antigen-specific and nonspecific T cell activity. The tumor microenvironment caused rapid and dramatic up-regulation of arginase I and inducible nitric oxide synthase in MDSC, which was accompanied by down-regulation of nicotinamide adenine dinucleotide phosphate–oxidase and reactive oxygen species in these cells. In contrast to MDSC from the spleen, MDSC from the tumor site rapidly differentiated into macrophages. Exposure of spleen MDSC to hypoxia resulted in the conversion of these cells to nonspecific suppressors and their preferential differentiation to macrophages. Hypoxia-inducible factor (HIF) 1α was found to be primarily responsible for the observed effects of the tumor microenvironment on MDSC differentiation and function. Thus, hypoxia via HIF-1α dramatically alters the function of MDSC in the tumor microenvironment and redirects their differentiation toward tumor-associated macrophages, hence providing a mechanistic link between different myeloid suppressive cells in the tumor microenvironment. PMID:20876310

  6. Teacher Implementation of Trial-Based Functional Analysis and Differential Reinforcement of Alternative Behavior for Students with Challenging Behavior

    ERIC Educational Resources Information Center

    Flynn, Susan D.; Lo, Ya-yu

    2016-01-01

    The purpose of this study was to examine the effects of a training package on three middle school special education teachers' accurate implementation of trial-based functional analysis (TBFA) and differential reinforcement of alternative behavior (DRA) with their students with autism spectrum disorders or emotional and behavioral disorders in the…

  7. Identifying Differential Item Functioning Related to Student Socioeconomic Status and Investigating Sources Related to Classroom Opportunities to Learn

    ERIC Educational Resources Information Center

    Burkes, LaShona L.

    2009-01-01

    The current study identified socioeconomic status (SES) group differences in student performance on an eighth grade mathematics assessment derived from the Third/Trends in International Mathematics and Science Study (TIMSS) 2003. Differential item functioning (DIF) methodology was applied to examine SES group differences on item performance for…

  8. Differential Item Functioning (DIF) Analysis of Computation, Word Problem and Geometry Questions across Gender and SES Groups.

    ERIC Educational Resources Information Center

    Berberoglu, Giray

    1995-01-01

    Item characteristic curves were compared across gender and socioeconomic status (SES) groups for the university entrance mathematics examination in Turkey to see if any group had an advantage in solving computation, word-problem, or geometry questions. Differential item functioning was found, and patterns are discussed. (SLD)

  9. A Bifactor Multidimensional Item Response Theory Model for Differential Item Functioning Analysis on Testlet-Based Items

    ERIC Educational Resources Information Center

    Fukuhara, Hirotaka; Kamata, Akihito

    2011-01-01

    A differential item functioning (DIF) detection method for testlet-based data was proposed and evaluated in this study. The proposed DIF model is an extension of a bifactor multidimensional item response theory (MIRT) model for testlets. Unlike traditional item response theory (IRT) DIF models, the proposed model takes testlet effects into…

  10. The Interaction of Ability Differences and Guessing When Modeling Differential Item Functioning with the Rasch Model: Conventional and Tailored Calibration

    ERIC Educational Resources Information Center

    DeMars, Christine E.; Jurich, Daniel P.

    2015-01-01

    In educational testing, differential item functioning (DIF) statistics must be accurately estimated to ensure the appropriate items are flagged for inspection or removal. This study showed how using the Rasch model to estimate DIF may introduce considerable bias in the results when there are large group differences in ability (impact) and the data…

  11. Examining Differential Item Functioning Trends for English Language Learners in a Reading Test: A Meta-Analytical Approach

    ERIC Educational Resources Information Center

    Koo, Jin; Becker, Betsy Jane; Kim, Young-Suk

    2014-01-01

    In this study, differential item functioning (DIF) trends were examined for English language learners (ELLs) versus non-ELL students in third and tenth grades on a large-scale reading assessment. To facilitate the analyses, a meta-analytic DIF technique was employed. The results revealed that items requiring knowledge of words and phrases in…

  12. Differential Item Functioning Detection with the Mantel-Haenszel Procedure: The Effects of Matching Types and Other Factors

    ERIC Educational Resources Information Center

    Socha, Alan; DeMars, Christine E.; Zilberberg, Anna; Phan, Ha

    2015-01-01

    The Mantel-Haenszel (MH) procedure is commonly used to detect items that function differentially for groups of examinees from various demographic and linguistic backgrounds--for example, in international assessments. As in some other DIF methods, the total score is used to match examinees on ability. In thin matching, each of the total score…

  13. The Mantel-Haenszel Method for Detecting Differential Item Functioning in Dichotomously Scored Items: A Multilevel Approach

    ERIC Educational Resources Information Center

    MacInnes, Jann Marie Wise

    2009-01-01

    Multilevel data often exist in educational studies. The focus of this study is to consider differential item functioning (DIF) for dichotomous items from a multilevel perspective. One of the most often used methods for detecting DIF in dichotomously scored items is the Mantel-Haenszel log odds-ratio. However, the Mantel-Haenszel reduces the…

  14. Dystroglycan Depletion Impairs Actin-Dependent Functions of Differentiated Kasumi-1 Cells

    PubMed Central

    Escárcega-Tame, Marco Antonio; Martínez-Vieyra, Ivette; Alonso-Rangel, Lea; Cisneros, Bulmaro; Winder, Steve J.; Cerecedo, Doris

    2015-01-01

    Background Dystroglycan has recently been characterised in blood tissue cells, as part of the dystrophin glycoprotein complex involved in the differentiation process of neutrophils. Purpose In the present study we have investigated the role of dystroglycan in the human promyelocytic leukemic cell line Kasumi-1 differentiated to macrophage-like cells. Methods We characterised the pattern expression and subcellular distribution of dystroglycans in non-differentiated and differentiated Kasumi-1 cells. Results Our results demonstrated by WB and flow cytometer assays that during the differentiation process to macrophages, dystroglycans were down-regulated; these results were confirmed with qRT-PCR assays. Additionally, depletion of dystroglycan by RNAi resulted in altered morphology and reduced properties of differentiated Kasumi-1 cells, including morphology, migration and phagocytic activities although secretion of IL-1β and expression of markers of differentiation are not altered. Conclusion Our findings strongly implicate dystroglycan as a key membrane adhesion protein involved in actin-based structures during the differentiation process in Kasumi-1 cells. PMID:26630171

  15. New bioactive motifs and their use in functionalized self-assembling peptides for NSC differentiation and neural tissue engineering

    NASA Astrophysics Data System (ADS)

    Gelain, F.; Cigognini, D.; Caprini, A.; Silva, D.; Colleoni, B.; Donegá, M.; Antonini, S.; Cohen, B. E.; Vescovi, A.

    2012-04-01

    Developing functionalized biomaterials for enhancing transplanted cell engraftment in vivo and stimulating the regeneration of injured tissues requires a multi-disciplinary approach customized for the tissue to be regenerated. In particular, nervous tissue engineering may take a great advantage from the discovery of novel functional motifs fostering transplanted stem cell engraftment and nervous fiber regeneration. Using phage display technology we have discovered new peptide sequences that bind to murine neural stem cell (NSC)-derived neural precursor cells (NPCs), and promote their viability and differentiation in vitro when linked to LDLK12 self-assembling peptide (SAPeptide). We characterized the newly functionalized LDLK12 SAPeptides via atomic force microscopy, circular dichroism and rheology, obtaining nanostructured hydrogels that support human and murine NSC proliferation and differentiation in vitro. One functionalized SAPeptide (Ac-FAQ), showing the highest stem cell viability and neural differentiation in vitro, was finally tested in acute contusive spinal cord injury in rats, where it fostered nervous tissue regrowth and improved locomotor recovery. Interestingly, animals treated with the non-functionalized LDLK12 had an axon sprouting/regeneration intermediate between Ac-FAQ-treated animals and controls. These results suggest that hydrogels functionalized with phage-derived peptides may constitute promising biomimetic scaffolds for in vitro NSC differentiation, as well as regenerative therapy of the injured nervous system. Moreover, this multi-disciplinary approach can be used to customize SAPeptides for other specific tissue engineering applications.Developing functionalized biomaterials for enhancing transplanted cell engraftment in vivo and stimulating the regeneration of injured tissues requires a multi-disciplinary approach customized for the tissue to be regenerated. In particular, nervous tissue engineering may take a great advantage from the

  16. The effect of cultureware surfaces on functional and structural components of differentiated 3T3-L1 preadipocytes.

    PubMed

    Pavlikova, Nela; Weiszenstein, Martin; Pala, Jan; Halada, Petr; Seda, Ondrej; Elkalaf, Moustafa; Trnka, Jan; Kovar, Jan; Polak, Jan

    2015-12-01

    Experiments using cultured primary cells or cell lines are a routine in vitro approach used across multiple biological disciplines, However, the structural and functional influences of various cultureware materials on cultured cells is not clearly understood. Surface treatments of cultureware have proven to have profound effects on cell viability and proliferation. In this study, we investigated the impact of polystyrene and fluorocarbon cultureware dishes on the proteomic profile of differentiated 3T3-L1 preadipocytes. After expansion and differentiation of cells on appropriate cultureware dishes, cell lysates were separated using two-dimensional gel electrophoresis and proteins were visualized with Coomassie blue staining. Spots with the highest differential expression between the two culture conditions were subsequently analyzed using matrix-assisted laser desorption/ionization mass spectrometry and the identified proteins were subjected to pathway analysis. We observed that 43% of all spots were differentially expressed depending on the cultureware. Pathway analysis revealed that glucose metabolism, mitochondrial structure and cell differentiation, represented by 14-3-3 protein-mediated signaling and the mitochondrial inner membrane organizing system (MINOS), were significantly affected by cultureware material. These results indicate that cultureware material can have a profound effect on key adipocyte functional pathways. These effects modifications of the cells should be reflected in the design of in vitro experiments and interpretation of their results.

  17. The transcriptional coactivator DRIP/mediator complex is involved in vitamin D receptor function and regulates keratinocyte proliferation and differentiation.

    PubMed

    Oda, Yuko; Chalkley, Robert J; Burlingame, Alma L; Bikle, Daniel D

    2010-10-01

    Mediator is a multisubunit coactivator complex that facilitates transcription of nuclear receptors. We investigated the role of the mediator complex as a coactivator for vitamin D receptor (VDR) in keratinocytes. Using VDR affinity beads, the vitamin D receptor interacting protein (DRIP)/mediator complex was purified from primary keratinocytes, and its subunit composition was determined by mass spectrometry. The complex included core subunits, such as DRIP205/MED1 (MED1), that directly binds to VDR. Additional subunits were identified that are components of the RNA polymerase II complex. The functions of different mediator components were investigated by silencing its subunits. The core subunit MED1 facilitates VDR activity and regulating keratinocyte proliferation and differentiation. A newly described subunit MED21 also has a role in promoting keratinocyte proliferation and differentiation, whereas MED10 has an inhibitory role. Blocking MED1/MED21 expression caused hyperproliferation of keratinocytes, accompanied by increases in mRNA expression of the cell cycle regulator cyclin D1 and/or glioma-associated oncogene homolog. Blocking MED1 or MED21 expression also resulted in defects in calcium-induced keratinocyte differentiation, as indicated by decreased expression of differentiation markers and decreased translocation of E-cadherin to the membrane. These results show that keratinocytes use the transcriptional coactivator mediator to regulate VDR functions and control keratinocyte proliferation and differentiation.

  18. Effects of Prostaglandin F2α on Corpora Lutea Formation and Function in Mated Bitches

    PubMed Central

    Paradis, M.; Post, K.; Mapletoft, R. J.

    1983-01-01

    Fifteen mated bitches were used to study the effects of prostaglandin F2α on ovarian endocrine function during the early and midluteal phase. Five dogs were kept as controls, five were given 250 μg/kg prostaglandin F2α twice daily between the first and fifth day of metestrus, and five were similarly treated with prostaglandin F2α between 31 and 35 days of metestrus. Function of corpora lutea was monitored by measuring serum progesterone concentrations during the first 45 days of gestation. Dogs treated with prostaglandin F2α during the early luteal phase had progesterone concentrations similar to controls and pregnancies were undisturbed in both groups. A dramatic decrease in serum progesterone concentration and abortion resulted after prostaglandin F2α administration at midpregnancy. These results indicate that prostaglandin F2α was not luteolytic during the early luteal phase and was therefore ineffective for preventing pregnancy at that time. However, at the dosage and frequency used in this study, prostaglandin F2α was luteolytic and abortifacient at midgestation. PMID:17422289

  19. The Differentiation and Protective Function of Cytolytic CD4 T Cells in Influenza Infection

    PubMed Central

    Brown, Deborah M.; Lampe, Anna T.; Workman, Aspen M.

    2016-01-01

    CD4 T cells that recognize peptide antigen in the context of class II MHC can differentiate into various subsets that are characterized by their helper functions. However, increasing evidence indicates that CD4 cells with direct cytolytic activity (CD4 CTL) play a role in chronic as well as acute infections, such as influenza A virus (IAV) infection. In the last couple of decades, techniques to measure the frequency and activity of these cytolytic cells has demonstrated their abundance in infections, such as human immunodeficiency virus, mouse pox, murine gamma herpes virus, cytomegalovirus, Epstein–Barr virus, and influenza among others. We now appreciate a greater role for CD4 CTL as direct effectors in viral infections and antitumor immunity through their ability to acquire perforin-mediated cytolytic activity and contribution to lysis of virally infected targets or tumors. As early as the 1980s, CD4 T cell clones with cytolytic potential were identified after influenza virus infection, yet much of this early work was dependent on in vitro culture and little was known about the physiological relevance of CD4 CTL. Here, we discuss the direct role CD4 CTL play in protection against lethal IAV infection and the factors that drive the generation of perforin-mediated lytic activity in CD4 cells in vivo during IAV infection. While focusing on CD4 CTL generated during IAV infection, we pull comparisons from the literature in other antiviral and antitumor systems. Further, we highlight what is currently known about CD4 CTL secondary and memory responses, as well as vaccination strategies to induce these potent killer cells that provide an extra layer of cell-mediated immune protection against heterosubtypic IAV infection. PMID:27014272

  20. Polymorphism of Sporothrix schenckii surface polysaccharides as a function of morphological differentiation.

    PubMed

    Mendonça, L; Gorin, P A; Lloyd, K O; Travassos, L R

    1976-06-01

    The alkali-extractable polysaccharides from different morphological types of two Sporothrix schenckii strains (1099.12 and 1099.18) were investigated. Dissociation of morphological phase transition and temperature effects was possible in a synthetic medium which produced cultures with 100% yeast forms either at 25 or at 37 degrees C. Only rhamnomannans with single-unit alpha-L-rhamnopyranosyl side chains were formed by the yeast forms irrespective of the incubation temperature. The higher temperature inhibited formation of 4-O- and 2,4-di-O-substituted alpha-D-mannopyranose units in the rhamnomannan. An apparently unsporulated mycelium culture of one S. schenckii strain (1099.12) synthesized a galactomannan whose structure was partially determined by methylation analysis and by proton and 13C nuclear magnetic resonance spectroscopy. In another strain (1099.18), a mannan was excreted in the medium of an apparently conidia-less mycelial form at 25 degrees C with short incubation. Its structure was also partially determined. An apparent mixture of this mannan and a rhamnomannan rich in alpha-L-rhamnopyranosyl-(1 leads to 2)-alpha-L-rhamnopyranose side chains formed in these cultures on prolonged incubation. The proportion of the excreted rhamnomannan increased as the mycelium sporulated and conidia were more numerous. Mannans or galactomannans may be transient polysaccharides in the young mycelium of S. schenckii. As the culture develops, rhamnomannans are formed in amounts usually masking the presence of other mannose-containing polysaccharides. It is suggested that in S. schenckii different polysaccharides are formed with side chains containing different proportions of rhamnose, mannose, or galactose, as a function of morphological differentiation.

  1. Spatial memory extinction differentially affects dorsal and ventral hippocampal metabolic activity and associated functional brain networks.

    PubMed

    Méndez-Couz, Marta; González-Pardo, Héctor; Vallejo, Guillermo; Arias, Jorge L; Conejo, Nélida M

    2016-10-01

    Previous studies showed the involvement of brain regions associated with both spatial learning and associative learning in spatial memory extinction, although the specific role of the dorsal and ventral hippocampus and the extended hippocampal system including the mammillary body in the process is still controversial. The present study aimed to identify the involvement of the dorsal and ventral hippocampus, together with cortical regions, the amygdaloid nuclei, and the mammillary bodies in the extinction of a spatial memory task. To address these issues, quantitative cytochrome c oxidase histochemistry was applied as a metabolic brain mapping method. Rats were trained in a reference memory task using the Morris water maze, followed by an extinction procedure of the previously acquired memory task. Results show that rats learned successfully the spatial memory task as shown by the progressive decrease in measured latencies to reach the escape platform and the results obtained in the probe test. Spatial memory was subsequently extinguished as shown by the descending preference for the previously reinforced location. A control naïve group was added to ensure that brain metabolic changes were specifically related with performance in the spatial memory extinction task. Extinction of the original spatial learning task significantly modified the metabolic activity in the dorsal and ventral hippocampus, the amygdala and the mammillary bodies. Moreover, the ventral hippocampus, the lateral mammillary body and the retrosplenial cortex were differentially recruited in the spatial memory extinction task, as shown by group differences in brain metabolic networks. These findings provide new insights on the brain regions and functional brain networks underlying spatial memory, and specifically spatial memory extinction. © 2016 Wiley Periodicals, Inc.

  2. The Differentiation and Protective Function of Cytolytic CD4 T Cells in Influenza Infection.

    PubMed

    Brown, Deborah M; Lampe, Anna T; Workman, Aspen M

    2016-01-01

    CD4 T cells that recognize peptide antigen in the context of class II MHC can differentiate into various subsets that are characterized by their helper functions. However, increasing evidence indicates that CD4 cells with direct cytolytic activity (CD4 CTL) play a role in chronic as well as acute infections, such as influenza A virus (IAV) infection. In the last couple of decades, techniques to measure the frequency and activity of these cytolytic cells has demonstrated their abundance in infections, such as human immunodeficiency virus, mouse pox, murine gamma herpes virus, cytomegalovirus, Epstein-Barr virus, and influenza among others. We now appreciate a greater role for CD4 CTL as direct effectors in viral infections and antitumor immunity through their ability to acquire perforin-mediated cytolytic activity and contribution to lysis of virally infected targets or tumors. As early as the 1980s, CD4 T cell clones with cytolytic potential were identified after influenza virus infection, yet much of this early work was dependent on in vitro culture and little was known about the physiological relevance of CD4 CTL. Here, we discuss the direct role CD4 CTL play in protection against lethal IAV infection and the factors that drive the generation of perforin-mediated lytic activity in CD4 cells in vivo during IAV infection. While focusing on CD4 CTL generated during IAV infection, we pull comparisons from the literature in other antiviral and antitumor systems. Further, we highlight what is currently known about CD4 CTL secondary and memory responses, as well as vaccination strategies to induce these potent killer cells that provide an extra layer of cell-mediated immune protection against heterosubtypic IAV infection. PMID:27014272

  3. Lipid Peroxidation-Derived Reactive Aldehydes Directly and Differentially Impair Spinal Cord and Brain Mitochondrial Function

    PubMed Central

    Vaishnav, Radhika A.; Singh, Indrapal N.; Miller, Darren M.

    2010-01-01

    Abstract Mitochondrial bioenergetic dysfunction in traumatic spinal cord and brain injury is associated with post-traumatic free radical–mediated oxidative damage to proteins and lipids. Lipid peroxidation by-products, such as 4-hydroxy-2-nonenal and acrolein, can form adducts with proteins and exacerbate the effects of direct free radical–induced protein oxidation. The aim of the present investigation was to determine and compare the direct contribution of 4-hydroxy-2-nonenal and acrolein to spinal cord and brain mitochondrial dysfunction. Ficoll gradient–isolated mitochondria from normal rat spinal cords and brains were treated with carefully selected doses of 4-hydroxy-2-nonenal or acrolein, followed by measurement of complex I– and complex II–driven respiratory rates. Both compounds were potent inhibitors of mitochondrial respiration in a dose-dependent manner. 4-Hydroxy-2-nonenal significantly compromised spinal cord mitochondrial respiration at a 0.1-μM concentration, whereas 10-fold greater concentrations produced a similar effect in brain. Acrolein was more potent than 4-hydroxy-2-nonenal, significantly decreasing spinal cord and brain mitochondrial respiration at 0.01 μM and 0.1 μM concentrations, respectively. The results of this study show that 4-hydroxy-2-nonenal and acrolein can directly and differentially impair spinal cord and brain mitochondrial function, and that the targets for the toxic effects of aldehydes appear to include pyruvate dehydrogenase and complex I–associated proteins. Furthermore, they suggest that protein modification by these lipid peroxidation products may directly contribute to post-traumatic mitochondrial damage, with spinal cord mitochondria showing a greater sensitivity than those in brain. PMID:20392143

  4. Item analysis and differential item functioning of a brief conduct problem screen.

    PubMed

    Wu, Johnny; King, Kevin M; Witkiewitz, Katie; Racz, Sarah Jensen; McMahon, Robert J

    2012-06-01

    Research has shown that boys display higher levels of childhood conduct problems than girls, and Black children display higher levels than White children, but few studies have tested for scalar equivalence of conduct problems across gender and race. The authors conducted a 2-parameter item response theory (IRT) model to examine item characteristics of the Authority Acceptance scale from the Teacher Observation of Classroom Adaptation-Revised (AA-TOCA-R; L. Larsson-Werthamer, S. G. Kellam, & L. Wheeler, 1991) in 8,820 kindergarten children and estimated the degree of differential item functioning (DIF) by gender and race/urban status. The mean level of latent conduct problems was best represented by behaviors such as being stubborn, breaking rules, and being disobedient, whereas breaking things and taking others' property best represented the construct at one standard deviation above the mean. DIF by gender was detected, such that at equivalent levels of latent conduct problems, males received more endorsements of overt behaviors from teachers, whereas females received more endorsements of nonphysical behaviors. Moreover, overt behaviors were better discriminators of latent conduct problems for males, and nonphysical behaviors were better discriminators of latent conduct problems for females. Differences across race/urban status were not found to be conceptually meaningful. The authors' analyses also suggest that the item scaling of the AA-TOCA-R may be best represented by 5e categories instead of 6. These findings provide support for the use of IRT modeling to examine item characteristics of conduct problem scales and DIF to test for scalar equivalence across diverse subpopulations.

  5. Differential expression of CD8 epitopes amongst porcine CD8-positive functional lymphocyte subsets.

    PubMed Central

    Yang, H; Parkhouse, R M

    1997-01-01

    The swine is a useful model for immunobiological studies as it has a highly heterogeneous lymphocyte pool, containing several subsets not easily accessible in humans and rodents. In particular, the CD8-positive (CD8+) cells contain a variety of lymphocyte subsets, such as alpha beta-T cells, gamma delta-T cells, CD4 CD8 double-positive (DP) cells and natural killer (NK) cells. In order to define these subsets further, we have selected four monoclonal antibodies (mAb) with differential reactivity on CD8+ cells. Thus, mAb CD8.1 (PPT20) bound to CD8hi and CD8lo subpopulations in a similar way to the conventional anti-CD8. The mAb CD8.2 (PPT21), though binding to all of the CD8+ cells, reacted preferably with CD8hi. Two other mAb, CD8.3 (PPT22) and CD8.4 (PPT23), were specific for CD8hi alpha beta-T-cell subpopulation. These results, complemented by immunoprecipitation, co-modulation and enzyme-linked immunosorbent assay experiments, suggest that CD8.1 and CD8.2 react putatively with the CD8 alpha-chain and CD8.3 and CD8.4 with the CD8 beta-chain. Tissue distribution studies revealed that CD8+ thymocytes and peripheral CD8hi alpha beta-T cells expressed both putative CD8 alpha- and beta-chains while peripheral CD4+ CD8+ alpha beta-T cells, CD8lo gamma delta-T cells and NK cells expressed only putative CD8 alpha-chain. Functional studies indicated that the CD8hi alpha beta-T and CD8lo gamma delta-T cells were effector cells in the CD3-redirected cytotoxicity. Images Figure 4 PMID:9370923

  6. The TNF family in T cell differentiation and function--unanswered questions and future directions.

    PubMed

    Croft, Michael

    2014-06-01

    Proteins in the TNF/TNFR superfamily are recognized as major regulators of the activity of conventional CD4 and CD8 T cells, and also of regulatory T cells (Treg). Stimulatory molecules such as OX40, CD27, GITR, DR3, CD30, 4-1BB, TACI, and TNFR2 can promote division and survival in T cells, enhance effector activity including cytokine production, and drive the generation of T cell memory. They also display the capacity to block the development of inducible Treg cells or inhibit suppressive activity in Treg cells. Additionally, molecules such as Fas, TNFR1, and TRAILR promote apoptotic death in T cells and generally limit T cell activity. Although our knowledge of these proteins is quite good at this point in time, there are still many unknowns regarding their function, their expression patterns, and the involvement of these different molecules at various stages of the T cell response that occurs in autoimmunity, cancer, infectious disease, and during vaccination. Importantly, it is still unresolved how similar or dissimilar each of these receptors are to one another, the extent to which cooperation occurs between family members, and whether alternate TNF-TNFR interactions induce qualitatively different cellular responses. All of the molecules are attractive targets for immunotherapy of human disease, but it is not yet clear how to differentiate between them and make an informed decision as to whether any one protein may be the preferred focus of clinical development for a given specific disease indication. This review will highlight unanswered questions related to these molecules and the biology of T cells, and describe possible future directions for research in this area. Expanding our knowledge of how the TNF/TNFR family control T cells will undoubtedly help fulfill the promise of these molecules for providing efficacious clinical therapy of immune system disease.

  7. Stress differentially impacts reserve pools and root exudation: implications for ecosystem functioning and carbon balance

    NASA Astrophysics Data System (ADS)

    Landhäusser, Simon; Karst, Justine; Wiley, Erin; Gaster, Jacob

    2016-04-01

    Environmental stress can influence carbon assimilation and the accumulation and distribution of carbon between growth, reserves, and exudation; however, it is unclear how these processes vary by different stress types. Partitioning of carbon to growth and reserves in plants might also vary between different organs. Roots reserves are of particular interest as they link the plant with the soil carbon cycle through exudation. Simple models of diffusion across concentration gradients predict the more C reserves in roots, the more C should be exuded from roots. However, the mechanisms underlying the accumulation and loss of C from roots may differ depending on the stress experienced by the plants. In a controlled study we tested whether different types of stresses (shade, cold soil, and drought) have differential effects on the distribution, abundance, and form (sugar vs. starch) of carbohydrates in seedlings, and whether these changes alone could explain differences in root exudation between stress types. Non-structural carbohydrate (NSC) concentration and pool sizes varied by stress type and between organs. Mass-specific C exudation increased with fine root sugar concentration; however, stress type affected exudation independently of reserve concentration. Seedlings exposed to cold soils exuded the most C on a per root mass basis followed by shade and drought. Through 13C labeling, we also found that depending on the stress type, aspen seedlings may be less able to control the loss of C to the soil compared with unstressed seedlings, resulting in more C leaked to the rhizosphere. The loss of C beyond that predicted by simple concentration gradients might have important implications for ecosystem functioning and carbon balance. If stressed plants lose proportionally more carbon to the soil, existing interactions between plants and soils may decouple under stress, and may include unexpected C fluxes between trees, soils and the atmosphere with a changing climate.

  8. The Differentiation and Protective Function of Cytolytic CD4 T Cells in Influenza Infection.

    PubMed

    Brown, Deborah M; Lampe, Anna T; Workman, Aspen M

    2016-01-01

    CD4 T cells that recognize peptide antigen in the context of class II MHC can differentiate into various subsets that are characterized by their helper functions. However, increasing evidence indicates that CD4 cells with direct cytolytic activity (CD4 CTL) play a role in chronic as well as acute infections, such as influenza A virus (IAV) infection. In the last couple of decades, techniques to measure the frequency and activity of these cytolytic cells has demonstrated their abundance in infections, such as human immunodeficiency virus, mouse pox, murine gamma herpes virus, cytomegalovirus, Epstein-Barr virus, and influenza among others. We now appreciate a greater role for CD4 CTL as direct effectors in viral infections and antitumor immunity through their ability to acquire perforin-mediated cytolytic activity and contribution to lysis of virally infected targets or tumors. As early as the 1980s, CD4 T cell clones with cytolytic potential were identified after influenza virus infection, yet much of this early work was dependent on in vitro culture and little was known about the physiological relevance of CD4 CTL. Here, we discuss the direct role CD4 CTL play in protection against lethal IAV infection and the factors that drive the generation of perforin-mediated lytic activity in CD4 cells in vivo during IAV infection. While focusing on CD4 CTL generated during IAV infection, we pull comparisons from the literature in other antiviral and antitumor systems. Further, we highlight what is currently known about CD4 CTL secondary and memory responses, as well as vaccination strategies to induce these potent killer cells that provide an extra layer of cell-mediated immune protection against heterosubtypic IAV infection.

  9. Differential Item Functioning (DIF) among Spanish-Speaking English Language Learners (ELLs) in State Science Tests

    NASA Astrophysics Data System (ADS)

    Ilich, Maria O.

    Psychometricians and test developers evaluate standardized tests for potential bias against groups of test-takers by using differential item functioning (DIF). English language learners (ELLs) are a diverse group of students whose native language is not English. While they are still learning the English language, they must take their standardized tests for their school subjects, including science, in English. In this study, linguistic complexity was examined as a possible source of DIF that may result in test scores that confound science knowledge with a lack of English proficiency among ELLs. Two years of fifth-grade state science tests were analyzed for evidence of DIF using two DIF methods, Simultaneous Item Bias Test (SIBTest) and logistic regression. The tests presented a unique challenge in that the test items were grouped together into testlets---groups of items referring to a scientific scenario to measure knowledge of different science content or skills. Very large samples of 10, 256 students in 2006 and 13,571 students in 2007 were examined. Half of each sample was composed of Spanish-speaking ELLs; the balance was comprised of native English speakers. The two DIF methods were in agreement about the items that favored non-ELLs and the items that favored ELLs. Logistic regression effect sizes were all negligible, while SIBTest flagged items with low to high DIF. A decrease in socioeconomic status and Spanish-speaking ELL diversity may have led to inconsistent SIBTest effect sizes for items used in both testing years. The DIF results for the testlets suggested that ELLs lacked sufficient opportunity to learn science content. The DIF results further suggest that those constructed response test items requiring the student to draw a conclusion about a scientific investigation or to plan a new investigation tended to favor ELLs.

  10. Differential effect of age on posterior and anterior hippocampal functional connectivity.

    PubMed

    Damoiseaux, Jessica S; Viviano, Raymond P; Yuan, Peng; Raz, Naftali

    2016-06-01

    Aging is associated with declines in cognitive performance and multiple changes in the brain, including reduced default mode functional connectivity (FC). However, conflicting results have been reported regarding age differences in FC between hippocampal and default mode regions. This discrepancy may stem from the variation in selection of hippocampal regions. We therefore examined the effect of age on resting state FC of anterior and posterior hippocampal regions in an adult life-span sample. Advanced age was associated with lower FC between the posterior hippocampus and three regions: the posterior cingulate cortex, medial prefrontal cortex, and lateral parietal cortex. In addition, age-related reductions of FC between the left and right posterior hippocampus, and bilaterally along the posterior to anterior hippocampal axis were noted. Age differences in medial prefrontal and inter-hemispheric FC significantly differed between anterior and posterior hippocampus. Older age was associated with lower performance in all cognitive domains, but we observed no associations between FC and cognitive performance after controlling for age. We observed a significant effect of gender and a linear effect of COMT val158met polymorphism on hippocampal FC. Females showed higher FC of anterior and posterior hippocampus and medial prefrontal cortex than males, and the dose of val allele was associated with lower posterior hippocampus - posterior cingulate FC, independent of age. Vascular and metabolic factors showed no significant effects on FC. These results suggest differential age-related reduction in the posterior hippocampal FC compared to the anterior hippocampus, and an age-independent effect of gender and COMT on hippocampal FC.

  11. Spatial memory extinction differentially affects dorsal and ventral hippocampal metabolic activity and associated functional brain networks.

    PubMed

    Méndez-Couz, Marta; González-Pardo, Héctor; Vallejo, Guillermo; Arias, Jorge L; Conejo, Nélida M

    2016-10-01

    Previous studies showed the involvement of brain regions associated with both spatial learning and associative learning in spatial memory extinction, although the specific role of the dorsal and ventral hippocampus and the extended hippocampal system including the mammillary body in the process is still controversial. The present study aimed to identify the involvement of the dorsal and ventral hippocampus, together with cortical regions, the amygdaloid nuclei, and the mammillary bodies in the extinction of a spatial memory task. To address these issues, quantitative cytochrome c oxidase histochemistry was applied as a metabolic brain mapping method. Rats were trained in a reference memory task using the Morris water maze, followed by an extinction procedure of the previously acquired memory task. Results show that rats learned successfully the spatial memory task as shown by the progressive decrease in measured latencies to reach the escape platform and the results obtained in the probe test. Spatial memory was subsequently extinguished as shown by the descending preference for the previously reinforced location. A control naïve group was added to ensure that brain metabolic changes were specifically related with performance in the spatial memory extinction task. Extinction of the original spatial learning task significantly modified the metabolic activity in the dorsal and ventral hippocampus, the amygdala and the mammillary bodies. Moreover, the ventral hippocampus, the lateral mammillary body and the retrosplenial cortex were differentially recruited in the spatial memory extinction task, as shown by group differences in brain metabolic networks. These findings provide new insights on the brain regions and functional brain networks underlying spatial memory, and specifically spatial memory extinction. © 2016 Wiley Periodicals, Inc. PMID:27102086

  12. Aging and differentiation in yeast populations: elders with different properties and functions.

    PubMed

    Palková, Zdena; Wilkinson, Derek; Váchová, Libuše

    2014-02-01

    Over the past decade, it has become evident that similarly to cells forming metazoan tissues, yeast cells have the ability to differentiate and form specialized cell types. Examples of yeast cellular differentiation have been identified both in yeast liquid cultures and within multicellular structures occupying solid surfaces. Most current knowledge on different cell types comes from studies of the spatiotemporal internal architecture of colonies developing on various media. With a few exceptions, yeast cell differentiation often concerns nongrowing, stationary-phase cells and leads to the formation of cell subpopulations differing in stress resistance, cell metabolism, respiration, ROS production, and others. These differences can affect longevity of particular subpopulations. In contrast to liquid cultures, where various cell types are dispersed within stationary-phase populations, cellular differentiation depends on the specific position of particular cells within multicellular colonies. Differentiated colonies, thus, resemble primitive multicellular organisms, in which the gradients of certain compounds and the position of cells within the structure affect cellular differentiation. In this review, we summarize and compare the properties of diverse types of differentiated chronologically aging yeast cells that have been identified in colonies growing on different media, as well as of those found in liquid cultures.

  13. Movement preparation and execution: differential functional activation patterns after traumatic brain injury.

    PubMed

    Gooijers, Jolien; Beets, Iseult A M; Albouy, Genevieve; Beeckmans, Kurt; Michiels, Karla; Sunaert, Stefan; Swinnen, Stephan P

    2016-09-01

    Years following the insult, patients with traumatic brain injury often experience persistent motor control problems, including bimanual coordination deficits. Previous studies revealed that such deficits are related to brain structural white and grey matter abnormalities. Here, we assessed, for the first time, cerebral functional activation patterns during bimanual movement preparation and performance in patients with traumatic brain injury, using functional magnetic resonance imaging. Eighteen patients with moderate-to-severe traumatic brain injury (10 females; aged 26.3 years, standard deviation = 5.2; age range: 18.4-34.6 years) and 26 healthy young adults (15 females; aged 23.6 years, standard deviation = 3.8; age range: 19.5-33 years) performed a complex bimanual tracking task, divided into a preparation (2 s) and execution (9 s) phase, and executed either in the presence or absence of augmented visual feedback. Performance on the bimanual tracking task, expressed as the average target error, was impaired for patients as compared to controls (P < 0.001) and for trials in the absence as compared to the presence of augmented visual feedback (P < 0.001). At the cerebral level, movement preparation was characterized by reduced neural activation in the patient group relative to the control group in frontal (bilateral superior frontal gyrus, right dorsolateral prefrontal cortex), parietal (left inferior parietal lobe) and occipital (right striate and extrastriate visual cortex) areas (P's < 0.05). During the execution phase, however, the opposite pattern emerged, i.e. traumatic brain injury patients showed enhanced activations compared with controls in frontal (left dorsolateral prefrontal cortex, left lateral anterior prefrontal cortex, and left orbitofrontal cortex), parietal (bilateral inferior parietal lobe, bilateral superior parietal lobe, right precuneus, right primary somatosensory cortex), occipital (right striate and extrastriate visual cortices), and

  14. Influence of IL-3 functional fragment on cord blood stem cell ex vivo expansion and differentiation

    PubMed Central

    Ren, Zhihua; Zhang, Yu; Zhang, Yanxi; Jiang, Wenhong; Dai, Wei; Ding, Xinxin

    2016-01-01

    Background Recombinant human interleukin-3 (rhIL-3) is a multiple hematopoietic growth factor, which enhances stem cell expansion and hematopoiesis regeneration in vitro and in vivo, when administrated in combination with other cytokines. However, the structure-function study of rhIL-3 remains rarely studied, so far. The purpose of this study was to recognize the short peptide with similar function as rhIL-3, and assess the hematopoietic efficacy in umbilical cord blood (UCB) stem cell culture as well. Methods Two novel monoclonal antibodies (mAb) (C1 and E1) were generated against rhIL-3 using hybridoma technique. Eleven short peptides were depicted and synthesized to overlap covering the full length sequence of rhIL-3. ELISA was employed to distinguish the antibody-binding peptide from the negative peptides. In addition, the multi-potential hematopoiesis capabilities of the positive peptides were evaluated by adding 25 ng/mL of each peptide to the culture medium of hematopoietic stem cells (HSCs) derived from UCB. Total nucleated cell number and the CD34+ cell number from each individual treatment group were calculated on day 7. Correlated antibodies at 0.5 or 2 molar fold to each peptide were also tested in the stem cell expansion experiment, to further confirm the bioactivity of the peptides. Results Two peptides were recognized by the novel generated antibodies, using ELISA. Peptide 3 and 8 exhibited comparable hematopoiesis potentials, with 25.01±0.14 fold, and 19.89±0.12 fold increase of total nucleated cell number on day 7, respectively, compared with the basal medium control (4.93±0.55 fold). These biological effects were neutralized by adding the corresponding mAb at a dose dependent manner. Conclusions Our results identified two specific regions of rhIL-3 responsible for HSC proliferation and differentiation, which were located from 28 to 49 amino acids (P3), and 107 to 127 amino acids (P8), respectively. The short peptide 3 and 8 might act

  15. Movement preparation and execution: differential functional activation patterns after traumatic brain injury.

    PubMed

    Gooijers, Jolien; Beets, Iseult A M; Albouy, Genevieve; Beeckmans, Kurt; Michiels, Karla; Sunaert, Stefan; Swinnen, Stephan P

    2016-09-01

    Years following the insult, patients with traumatic brain injury often experience persistent motor control problems, including bimanual coordination deficits. Previous studies revealed that such deficits are related to brain structural white and grey matter abnormalities. Here, we assessed, for the first time, cerebral functional activation patterns during bimanual movement preparation and performance in patients with traumatic brain injury, using functional magnetic resonance imaging. Eighteen patients with moderate-to-severe traumatic brain injury (10 females; aged 26.3 years, standard deviation = 5.2; age range: 18.4-34.6 years) and 26 healthy young adults (15 females; aged 23.6 years, standard deviation = 3.8; age range: 19.5-33 years) performed a complex bimanual tracking task, divided into a preparation (2 s) and execution (9 s) phase, and executed either in the presence or absence of augmented visual feedback. Performance on the bimanual tracking task, expressed as the average target error, was impaired for patients as compared to controls (P < 0.001) and for trials in the absence as compared to the presence of augmented visual feedback (P < 0.001). At the cerebral level, movement preparation was characterized by reduced neural activation in the patient group relative to the control group in frontal (bilateral superior frontal gyrus, right dorsolateral prefrontal cortex), parietal (left inferior parietal lobe) and occipital (right striate and extrastriate visual cortex) areas (P's < 0.05). During the execution phase, however, the opposite pattern emerged, i.e. traumatic brain injury patients showed enhanced activations compared with controls in frontal (left dorsolateral prefrontal cortex, left lateral anterior prefrontal cortex, and left orbitofrontal cortex), parietal (bilateral inferior parietal lobe, bilateral superior parietal lobe, right precuneus, right primary somatosensory cortex), occipital (right striate and extrastriate visual cortices), and

  16. The potential functional interaction of biglycan and WISP-1 in controlling differentiation and proliferation of osteogenic cells.

    PubMed

    Inkson, Colette A; Ono, Mitsuaki; Bi, Yanming; Kuznetsov, Sergei A; Fisher, Larry W; Young, Marian F

    2009-01-01

    Biglycan (BGN) and WISP-1 are 2 extracellular matrix proteins that bind to each other and colocalize in mineralizing tissue. Here we show that WISP-1 abrogates the repression of proliferation in bone marrow stromal cells induced by BGN. We also demonstrate that WISP-1 and its variant WISP-1va can alleviate the repressed osteogenic differentiation caused by the absence of BGN. These preliminary data suggest that WISP-1 and BGN may functionally interact and control each other's activity, thus regulating the differentiation and proliferation of osteogenic cells.

  17. YY1 inhibits differentiation and function of regulatory T cells by blocking Foxp3 expression and activity.

    PubMed

    Hwang, Soo Seok; Jang, Sung Woong; Kim, Min Kyung; Kim, Lark Kyun; Kim, Bong-Sung; Kim, Hyeong Su; Kim, Kiwan; Lee, Wonyong; Flavell, Richard A; Lee, Gap Ryol

    2016-01-01

    Regulatory T (T(reg)) cells are essential for maintenance of immune homeostasis. Foxp3 is the key transcription factor for T(reg)-cell differentiation and function; however, molecular mechanisms for its negative regulation are poorly understood. Here we show that YY1 expression is lower in T(reg) cells than T(conv) cells, and its overexpression causes a marked reduction of Foxp3 expression and abrogation of suppressive function of Treg cells. YY1 is increased in T(reg) cells under inflammatory conditions with concomitant decrease of suppressor activity in dextran sulfate-induced colitis model. YY1 inhibits Smad3/4 binding to and chromatin remodelling of the Foxp3 locus. In addition, YY1 interrupts Foxp3-dependent target gene expression by physically interacting with Foxp3 and by directly binding to the Foxp3 target genes. Thus, YY1 inhibits differentiation and function of T(reg) cells by blocking Foxp3. PMID:26892542

  18. Inner ear stem cells derived feeder layer promote directional differentiation of amniotic fluid stem cells into functional neurons.

    PubMed

    Zong, Ling; Chen, Kaitian; Zhou, Wei; Jiang, Di; Sun, Liang; Zhang, Xuemei; Jiang, Hongyan

    2014-10-01

    Intact spiral ganglion neurons are required for cochlear implantation or conventional hearing amplification as an intervention for sensorineural hearing loss. Treatment strategies to replace the loss of spiral ganglion neurons are needed. Recent reports have suggested that amniotic fluid-derived stem cells are capable of differentiating into neuron-like cells in response to cytokines and are not tumorigenic. Amniotic fluid stem cells represent a potential resource for cellular therapy of neural deafness due to spiral ganglion pathology. However, the directional differentiation of amniotic fluid stem cells is undetermined in the absence of cytokines and the consequence of inner ear supporting cells from the mouse cochlea organ of Corti on the differentiation of amniotic fluid stem cells remains to be defined. In an effort to circumvent these limitations, we investigated the effect of inner ear stem cells derived feeder layer on amniotic fluid stem cells differentiation in vitro. An inner ear stem cells derived feeder layer direct contact system was established to induce differentiation of amniotic fluid stem cells. Our results showed that inner ear stem cells derived feeder layer successfully promoted directional differentiation of amniotic fluid stem cells into neurons with characteristics of functionality. Furthermore, we showed that Wnt signaling may play an essential role in triggering neurogenesis. These findings indicate the potential use of inner ear stem cells derived feeder layer as a nerve-regenerative scaffold. A reliable and effective amniotic fluid stem cell differentiation support structure provided by inner ear stem cells derived feeder layer should contribute to efforts to translate cell-based strategies to the clinic.

  19. Neurog1 can partially substitute for Atoh1 function in hair cell differentiation and maintenance during organ of Corti development

    PubMed Central

    Jahan, Israt; Pan, Ning; Kersigo, Jennifer; Fritzsch, Bernd

    2015-01-01

    Atoh1, a basic helix-loop-helix (bHLH) transcription factor (TF), is essential for the differentiation of hair cells (HCs), mechanotransducers that convert sound into auditory signals in the mammalian organ of Corti (OC). Previous work demonstrated that replacing mouse Atoh1 with the fly ortholog atonal rescues HC differentiation, indicating functional replacement by other bHLH genes. However, replacing Atoh1 with Neurog1 resulted in reduced HC differentiation compared with transient Atoh1 expression in a ‘self-terminating’ Atoh1 conditional null mouse (Atoh1-Cre; Atoh1f/f). We now show that combining Neurog1 in one allele with removal of floxed Atoh1 in a self-terminating conditional mutant (Atoh1-Cre; Atoh1f/kiNeurog1) mouse results in significantly more differentiated inner HCs and outer HCs that have a prolonged longevity of 9 months compared with Atoh1 self-terminating littermates. Stereocilia bundles are partially disorganized, disoriented and not HC type specific. Replacement of Atoh1 with Neurog1 maintains limited expression of Pou4f3 and Barhl1 and rescues HCs quantitatively, but not qualitatively. OC patterning and supporting cell differentiation are also partially disrupted. Diffusible factors involved in patterning are reduced (Fgf8) and factors involved in cell-cell interactions are affected (Jag1, Hes5). Despite the presence of many HCs with stereocilia these mice are deaf, possibly owing to HC and OC patterning defects. This study provides a novel approach to disrupt OC development through modulating the HC-specific intracellular TF network. The resulting disorganized OC indicates that normally differentiated HCs act as ‘self-organizers’ for OC development and that Atoh1 plays a crucial role to initiate HC stereocilia differentiation independently of HC viability. PMID:26209643

  20. High Physiological Concentrations of Progesterone Reverse Estradiol-Mediated Changes in Differentiation and Functions of Bone Marrow Derived Dendritic Cells

    PubMed Central

    Xiu, Fangming; Anipindi, Varun C.; Nguyen, Philip V.; Boudreau, Jeanette; Liang, Hong; Wan, Yonghong; Snider, Denis P.; Kaushic, Charu

    2016-01-01

    Female sex steroids, estradiol (E2) and progesterone (P4), play a key role in regulating immune responses in women, including dendritic cell (DC) development, and functions. Although the two hormones co-occur in the body of women throughout the reproductive years, no studies have explored their complex combinatorial effects on DCs, given their ability to regulate each other’s actions. We examined murine bone marrow derived dendritic cells (BMDC) differentiation and functions, in the presence of a wide range of physiological concentrations of each hormone, as well as the combination of the two hormones. E2 (10−12 to 10-8M) enhanced the differentiation of CD11b+CD11c+ DCs from BM precursor cells, and promoted the expression of CD40 and MHC Class-II, in a dose-dependent manner. In contrast, P4 (10−9 to 10-5M) inhibited DC differentiation, but only at the highest concentrations. These effects on BMDCs were observed both in the presence or absence of LPS. When both hormones were combined, higher concentrations of P4, at levels seen in pregnancy (10-6M) reversed the E2 effects, regardless of the concentration of E2, especially in the absence of LPS. Functionally, antigen uptake was decreased and pro-inflammatory cytokines, IL-12, IL-1 and IL-6 production by CD11b+CD11c+ DCs, was increased in the presence of E2 and these effects were reversed by high concentrations of P4. Our results demonstrate the distinct effects of E2 and P4 on differentiation and functions of bone marrow myeloid DCs. The dominating effect of higher physiological concentrations of P4 provides insight into how DC functions could be modulated during pregnancy. PMID:27064901

  1. High Physiological Concentrations of Progesterone Reverse Estradiol-Mediated Changes in Differentiation and Functions of Bone Marrow Derived Dendritic Cells.

    PubMed

    Xiu, Fangming; Anipindi, Varun C; Nguyen, Philip V; Boudreau, Jeanette; Liang, Hong; Wan, Yonghong; Snider, Denis P; Kaushic, Charu

    2016-01-01

    Female sex steroids, estradiol (E2) and progesterone (P4), play a key role in regulating immune responses in women, including dendritic cell (DC) development, and functions. Although the two hormones co-occur in the body of women throughout the reproductive years, no studies have explored their complex combinatorial effects on DCs, given their ability to regulate each other's actions. We examined murine bone marrow derived dendritic cells (BMDC) differentiation and functions, in the presence of a wide range of physiological concentrations of each hormone, as well as the combination of the two hormones. E2 (10(-12) to 10(-8)M) enhanced the differentiation of CD11b+CD11c+ DCs from BM precursor cells, and promoted the expression of CD40 and MHC Class-II, in a dose-dependent manner. In contrast, P4 (10(-9) to 10(-5)M) inhibited DC differentiation, but only at the highest concentrations. These effects on BMDCs were observed both in the presence or absence of LPS. When both hormones were combined, higher concentrations of P4, at levels seen in pregnancy (10(-6)M) reversed the E2 effects, regardless of the concentration of E2, especially in the absence of LPS. Functionally, antigen uptake was decreased and pro-inflammatory cytokines, IL-12, IL-1 and IL-6 production by CD11b+CD11c+ DCs, was increased in the presence of E2 and these effects were reversed by high concentrations of P4. Our results demonstrate the distinct effects of E2 and P4 on differentiation and functions of bone marrow myeloid DCs. The dominating effect of higher physiological concentrations of P4 provides insight into how DC functions could be modulated during pregnancy. PMID:27064901

  2. The Rab GTPase RabG3b functions in autophagy and contributes to tracheary element differentiation in Arabidopsis.

    PubMed

    Kwon, Soon Il; Cho, Hong Joo; Jung, Jin Hee; Yoshimoto, Kohki; Shirasu, Ken; Park, Ohkmae K

    2010-10-01

    The tracheary elements (TEs) of the xylem serve as the water-conducting vessels of the plant vascular system. To achieve this, TEs undergo secondary cell wall thickening and cell death, during which the cell contents are completely removed. Cell death of TEs is a typical example of developmental programmed cell death that has been suggested to be autophagic. However, little evidence of autophagy in TE differentiation has been provided. The present study demonstrates that the small GTP binding protein RabG3b plays a role in TE differentiation through its function in autophagy. Differentiating wild type TE cells were found to undergo autophagy in an Arabidopsis culture system. Both autophagy and TE formation were significantly stimulated by overexpression of a constitutively active mutant (RabG3bCA), and were inhibited in transgenic plants overexpressing a dominant negative mutant (RabG3bDN) or RabG3b RNAi (RabG3bRNAi), a brassinosteroid insensitive mutant bri1-301, and an autophagy mutant atg5-1. Taken together, our results suggest that autophagy occurs during TE differentiation, and that RabG3b, as a component of autophagy, regulates TE differentiation.

  3. Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta Opioid Receptor Function

    PubMed Central

    Perroy, Julie; Walwyn, Wendy M.; Smith, Monique L.; Vicente-Sanchez, Ana; Segura, Laura; Bana, Alia; Kieffer, Brigitte L.; Evans, Christopher J.

    2016-01-01

    Ligand-specific recruitment of arrestins facilitates functional selectivity of G-protein-coupled receptor signaling. Here, we describe agonist-selective recruitment of different arrestin isoforms to the delta opioid receptor in mice. A high-internalizing delta opioid receptor agonist (SNC80) preferentially recruited arrestin 2 and, in arrestin 2 knock-outs (KOs), we observed a significant increase in the potency of SNC80 to inhibit mechanical hyperalgesia and decreased acute tolerance. In contrast, the low-internalizing delta agonists (ARM390, JNJ20788560) preferentially recruited arrestin 3 with unaltered behavioral effects in arrestin 2 KOs. Surprisingly, arrestin 3 KO revealed an acute tolerance to these low-internalizing agonists, an effect never observed in wild-type animals. Furthermore, we examined delta opioid receptor–Ca2+ channel coupling in dorsal root ganglia desensitized by ARM390 and the rate of resensitization was correspondingly decreased in arrestin 3 KOs. Live-cell imaging in HEK293 cells revealed that delta opioid receptors are in pre-engaged complexes with arrestin 3 at the cell membrane and that ARM390 strengthens this membrane interaction. The disruption of these complexes in arrestin 3 KOs likely accounts for the altered responses to low-internalizing agonists. Together, our results show agonist-selective recruitment of arrestin isoforms and reveal a novel endogenous role of arrestin 3 as a facilitator of resensitization and an inhibitor of tolerance mechanisms. SIGNIFICANCE STATEMENT Agonists that bind to the same receptor can produce highly distinct signaling events and arrestins are a major mediator of this ligand bias. Here, we demonstrate that delta opioid receptor agonists differentially recruit arrestin isoforms. We found that the high-internalizing agonist SNC80 preferentially recruits arrestin 2 and knock-out (KO) of this protein results in increased efficacy of SNC80. In contrast, low-internalizing agonists (ARM390 and JNJ20788560

  4. Serum IL-10 from systemic lupus erythematosus patients suppresses the differentiation and function of monocyte-derived dendritic cells

    PubMed Central

    Sun, Zhida; Zhang, Rong; Wang, Huijuan; Jiang, Pengtao; Zhang, Jiangquan; Zhang, Mingshun; Gu, Lei; Yang, Xiaofan; Zhang, Miaojia; Ji, Xiaohui

    2012-01-01

    The role played by cytokines, other than interferon (IFN)-α, in the differentiation and function of dendritic cells (DCs) in systemic lupus erythematosus (SLE), remains unclear. Serum interleukin-10 (IL-10) levels are generally elevated in SLE patients, which might modulate the differentiation of DCs. In this study, DCs were induced from monocytes either by transendothelial trafficking or by culture with granulocyte-macrophage colony-stimulating factor (GM-CSF) + IL-4 + tumor necrosis factor (TNF)-α. Both systems were used to investigate the effects of elevated serum IL-10 level on DC differentiation in SLE patients. The results showed that monocyte-derived DCs induced by either SLE serum or exogenous IL-10 reduced the expression of human leukocyte antigen (HLA)-DR and CD80, decreased IL-12p40 level, and increased IL-10 level, and exhibited an impaired capacity to stimulate allogenic T-cell proliferation. These results indicate that serum IL-10 may be involved in the pathogenesis of SLE by modulating the differentiation and function of DCs. PMID:23554785

  5. IRF8 Transcription Factor Controls Survival and Function of Terminally Differentiated Conventional and Plasmacytoid Dendritic Cells, Respectively.

    PubMed

    Sichien, Dorine; Scott, Charlotte L; Martens, Liesbet; Vanderkerken, Matthias; Van Gassen, Sofie; Plantinga, Maud; Joeris, Thorsten; De Prijck, Sofie; Vanhoutte, Leen; Vanheerswynghels, Manon; Van Isterdael, Gert; Toussaint, Wendy; Madeira, Filipe Branco; Vergote, Karl; Agace, William W; Clausen, Björn E; Hammad, Hamida; Dalod, Marc; Saeys, Yvan; Lambrecht, Bart N; Guilliams, Martin

    2016-09-20

    Interferon regulatory factor-8 (IRF8) has been proposed to be essential for development of monocytes, plasmacytoid dendritic cells (pDCs) and type 1 conventional dendritic cells (cDC1s) and remains highly expressed in differentiated DCs. Transcription factors that are required to maintain the identity of terminally differentiated cells are designated "terminal selectors." Using BM chimeras, conditional Irf8(fl/fl) mice and various promotors to target Cre recombinase to different stages of monocyte and DC development, we have identified IRF8 as a terminal selector of the cDC1 lineage controlling survival. In monocytes, IRF8 was necessary during early but not late development. Complete or late deletion of IRF8 had no effect on pDC development or survival but altered their phenotype and gene-expression profile leading to increased T cell stimulatory function but decreased type 1 interferon production. Thus, IRF8 differentially controls the survival and function of terminally differentiated monocytes, cDC1s, and pDCs. PMID:27637148

  6. Differentiation between cooking bananas and dessert bananas. 2. Thermal and functional characterization of cultivated Colombian Musaceae (Musa sp.).

    PubMed

    Dufour, Dominique; Gibert, Olivier; Giraldo, Andrés; Sánchez, Teresa; Reynes, Max; Pain, Jean-Pierre; González, Alonso; Fernández, Alejandro; Díaz, Alberto

    2009-09-01

    The starch and flour thermal and functional characteristics of 23 cultivated varieties of bananas in Colombia were assessed. Onset temperature for gelatinization of starches measured by differential scanning calorimetry (DSC) varied from 59.7 to 67.8 degrees C, thereby significantly differentiating dessert bananas (63.2 degrees C) from nonplantain cooking bananas (65.7 degrees C) from FHIA hybrids (66.6 degrees C) and plantains (67.1 degrees C). FHIA hybrids are significantly discriminated from dessert banana landraces but not from the cooking group. The starch amylose contents varied from 15.4 to 24.9%; most dessert banana starch amylose contents were below 19%, whereas in cooking banana starches the contents were over 21%. Flour functional properties were assessed by Rapid ViscoAnalyser (RVA) using silver nitrate as alpha-amylase inhibitor. The flour pasting temperature was relevant to differentiate dessert bananas (69.5 degrees C) from FHIA dessert hybrids and nonplantain cooking bananas (72.8 degrees C) from cooking hybrids and plantains (75.8 degrees C). Among other criteria, the cooking ability also helped to differentiate dessert bananas and FHIA hybrids from cooking bananas. A close relation between cultivar genotypes and uses with the thermal and pasting properties were revealed.

  7. Functional dissection and evidence for intercellular transfer of the heterocyst-differentiation PatS morphogen.

    PubMed

    Corrales-Guerrero, Laura; Mariscal, Vicente; Flores, Enrique; Herrero, Antonia

    2013-06-01

    The formation of a diazotrophic cyanobacterial filament represents a simple example of biological development. In Anabaena, a non-random pattern of one nitrogen-fixing heterocyst separated by about 10 photosynthetic vegetative cells results from lateral inhibition elicited by the cells differentiating into heterocysts. Key to this process is the patS gene, which has been shown to produce an inhibitor of heterocyst differentiation that involves the C-terminal RGSGR pentapeptide. Complementation of a ΔpatS Anabaena mutant with different versions of PatS, including point mutations or tag fusions, showed that patS is translated into a 17-amino acid polypeptide. Alterations in the N-terminal part of PatS produced inhibition of heterocyst differentiation, thus this part of the peptide appears necessary for proper processing and self-immunity in the producing cells. Alterations in the C-terminal part of PatS led to over-differentiation, thus supporting its role in inhibition of heterocyst differentiation. A polypeptide, produced in proheterocysts, consisting of a methionine followed by the eight, but not the five, terminal amino acids of PatS recreated the full activity of the native peptide. Immunofluorescence detection showed that an RGSGR-containing peptide accumulated in the cells adjacent to the producing proheterocysts, illustrating intercellular transfer of a morphogen in the cyanobacterial filaments. PMID:23663167

  8. Specific trans-synaptic interaction with inhibitory interneuronal neurexin underlies differential ability of neuroligins to induce functional inhibitory synapses.

    PubMed

    Futai, Kensuke; Doty, Christopher D; Baek, Brian; Ryu, Jubin; Sheng, Morgan

    2013-02-20

    Synaptic transmission depends on the matching and alignment of presynaptically released transmitters and postsynaptic neurotransmitter receptors. Neuroligin (NL) and Neurexin (Nrxn) proteins are trans-synaptic adhesion molecules that are important in validation and maturation of specific synapses. NL isoforms NL1 and NL2 have specific functional roles in excitatory and inhibitory synapses, respectively, but the molecular basis behind this distinction is still unclear. We show here that the extracellular domain of NL2 confers its unique ability to enhance inhibitory synaptic function when overexpressed in rat hippocampal pyramidal neurons, whereas NL1 normally only promotes excitatory synapses. This specificity is conferred by presynaptic Nrxn isoforms, as NL1 can also induce functional inhibitory synapse connections when the presynaptic interneurons ectopically express an Nrxn isoform that binds to NL1. Our results indicate that trans-synaptic interaction with differentially expressed presynaptic Nrxns underlies the distinct functions of NL1 and NL2, and is sufficient to induce functional inhibitory synapse formation.

  9. Rb and N-ras Function Together To Control Differentiation in the Mouse

    PubMed Central

    Takahashi, Chiaki; Bronson, Roderick T.; Socolovsky, Merav; Contreras, Bernardo; Lee, Kwang Youl; Jacks, Tyler; Noda, Makoto; Kucherlapati, Raju; Ewen, Mark E.

    2003-01-01

    The product of the retinoblastoma tumor suppressor gene (Rb) can control cell proliferation and promote dif-ferentiation. Murine embryos nullizygous for Rb die midgestation with defects in cell cycle regulation, control of apoptosis, and terminal differentiation of several tissues, including skeletal muscle, nervous system, and lens. Previous cell culture-based experiments have suggested that the retinoblastoma protein (pRb) and Ras operate in a common pathway to control cellular differentiation. Here we have tested the hypothesis that the proto-oncogene N-ras participates in Rb-dependent regulation of differentiation by generating and characterizing murine embryos deficient in both N-ras and Rb. We show that deletion of N-ras rescues a unique subset of the developmental defects associated with nullizygosity of Rb, resulting in a significant extension of life span. Rb−/−; N-ras−/− skeletal muscle has normal fiber density, myotube length and thickness, in contrast to Rb-deficient embryos. Additionally, Rb−/−; N-ras−/− muscle shows a restoration in the expression of the late muscle-specific gene MCK, and this correlates with a significant potentiation of MyoD transcriptional activity in Rb−/−; N-ras−/−, compared to Rb−/− myoblasts in culture. The improved differentiation of skeletal muscle in Rb−/−; N-ras−/− embryos occurs despite evidence of deregulated proliferation and apoptosis, as seen in Rb-deficient animals. Our findings suggest that the control of differentiation and proliferation by Rb are genetically separable. PMID:12861012

  10. Expansion and osteogenic differentiation of bone marrow-derived mesenchymal stem cells on a vitamin C functionalized polymer.

    PubMed

    Wang, Yongzhong; Singh, Amarjit; Xu, Peng; Pindrus, Mariya A; Blasioli, Dominick J; Kaplan, David L

    2006-06-01

    In human body ascorbic acid plays an essential role in the synthesis and function of skeletal tissues and immune system factors. Ascorbic acid is also a major physiological antioxidant, repairing oxidatively damaged biomolecules, preventing the formation of excessive reactive oxygen species or scavenging these species. We recently reported the synthesis of ascorbic acid-functionalized polymers in which the antioxidant features of the pendant ascorbic acid groups was preserved. In the present work we demonstrate that ascorbic acid-functionalized poly(methyl methacrylate) (AA-PMMA) can modulate the proliferation and osteogenic differentiation of early and late-passage bone marrow-derived human mesenchymal stem cells (MSCs). The covalently coupled ascorbic acid impacted MSCs differently than when ascorbic acid was presented to the cells in soluble form. At optimal concentration, the covalently coupled ascorbic acid and soluble ascorbic acid synergistically promoted and retained the ability of MSCs to respond to osteogenic stimulation over extensive cell expansions in vitro. In the presence of soluble ascorbic acid, AA-PMMA films prepared at optimal concentrations (0.1 mg/ml in the present study) showed a significant promotive effect over other concentrations and tissue culture plastic (TCP) with respect to osteogenic differentiation of both EP (young) and LP (old) MSCs. These results suggest that the coupled ascorbic acid is acting mainly at the extracellular level and, at optimal concentrations, the immobilized extracellular ascorbic acid and soluble ascorbic acid synergistically promote osteogenic differentiation of MSCs. Importantly, the covalently coupled ascorbic acid on the films of optimal concentration was able to preserve the capacity of MSCs to undergo osteogenic differentiation in vitro. These results suggest an important role for functionalized biomaterials with antioxidant features in control of cell physiology and cell aging phenomena.

  11. Alcohol and Cannabinoids Differentially Affect HIV Infection and Function of Human Monocyte-Derived Dendritic Cells (MDDC)

    PubMed Central

    Agudelo, Marisela; Figueroa, Gloria; Yndart, Adriana; Casteleiro, Gianna; Muñoz, Karla; Samikkannu, Thangavel; Atluri, Venkata; Nair, Madhavan P.

    2015-01-01

    During human immunodeficiency virus (HIV) infection, alcohol has been known to induce inflammation while cannabinoids have been shown to have an anti-inflammatory role. For instance cannabinoids have been shown to reduce susceptibility to HIV-1 infection and attenuate HIV replication in macrophages. Recently, we demonstrated that alcohol induces cannabinoid receptors and regulates cytokine production by monocyte-derived dendritic cells (MDDC). However, the ability of alcohol and cannabinoids to alter MDDC function during HIV infection has not been clearly elucidated yet. In order to study the potential impact of alcohol and cannabinoids on differentiated MDDC infected with HIV, monocytes were cultured for 7 days with GM-CSF and IL-4, differentiated MDDC were infected with HIV-1Ba-L and treated with EtOH (0.1 and 0.2%), THC (5 and 10 μM), or JWH-015 (5 and 10 μM) for 4–7 days. HIV infection of MDDC was confirmed by p24 and Long Terminal Repeats (LTR) estimation. MDDC endocytosis assay and cytokine array profiles were measured to investigate the effects of HIV and substances of abuse on MDDC function. Our results show the HIV + EtOH treated MDDC had the highest levels of p24 production and expression when compared with the HIV positive controls and the cannabinoid treated cells. Although both cannabinoids, THC and JWH-015 had lower levels of p24 production and expression, the HIV + JWH-015 treated MDDC had the lowest levels of p24 when compared to the HIV + THC treated cells. In addition, MDDC endocytic function and cytokine production were also differentially altered after alcohol and cannabinoid treatments. Our results show a differential effect of alcohol and cannabinoids, which may provide insights into the divergent inflammatory role of alcohol and cannabinoids to modulate MDDC function in the context of HIV infection. PMID:26733986

  12. Differential Item Functioning by Gender on a Large-Scale Science Performance Assessment: A Comparison across Grade Levels.

    ERIC Educational Resources Information Center

    Holweger, Nancy; Taylor, Grace

    The fifth-grade and eighth-grade science items on a state performance assessment were compared for differential item functioning (DIF) due to gender. The grade 5 sample consisted of 8,539 females and 8,029 males and the grade 8 sample consisted of 7,477 females and 7,891 males. A total of 30 fifth grade items and 26 eighth grade items were…

  13. Investigating Linguistic Sources of Differential Item Functioning Using Expert Think-Aloud Protocols in Science Achievement Tests

    NASA Astrophysics Data System (ADS)

    Roth, Wolff-Michael; Oliveri, Maria Elena; Dallie Sandilands, Debra; Lyons-Thomas, Juliette; Ercikan, Kadriye

    2013-03-01

    Even if national and international assessments are designed to be comparable, subsequent psychometric analyses often reveal differential item functioning (DIF). Central to achieving comparability is to examine the presence of DIF, and if DIF is found, to investigate its sources to ensure differentially functioning items that do not lead to bias. In this study, sources of DIF were examined using think-aloud protocols. The think-aloud protocols of expert reviewers were conducted for comparing the English and French versions of 40 items previously identified as DIF (N = 20) and non-DIF (N = 20). Three highly trained and experienced experts in verifying and accepting/rejecting multi-lingual versions of curriculum and testing materials for government purposes participated in this study. Although there is a considerable amount of agreement in the identification of differentially functioning items, experts do not consistently identify and distinguish DIF and non-DIF items. Our analyses of the think-aloud protocols identified particular linguistic, general pedagogical, content-related, and cognitive factors related to sources of DIF. Implications are provided for the process of arriving at the identification of DIF, prior to the actual administration of tests at national and international levels.

  14. Differentiability of a projection functional in ray-tracing processes: applied study to estimate the coefficients of a single lens with conic surfaces.

    PubMed

    Téllez-Quiñones, Alejandro; Malacara-Doblado, Daniel; García-Márquez, Jorge

    2015-01-01

    In optical design, many error functions can be used to generate an optical system with desired characteristics. These error functions are optimized by iterative algorithms. However, these error functions should be theoretically and mathematically differentiable to be optimized. In this paper, the differentiability of an error function is partially justified. The error function herein is called the projection functional. This proposed projection functional can be used to estimate the coefficients of an arbitrary lens with conic surfaces by means of the spot distributions on two planes produced by a fixed Hartmann plate. The differentiability of the projection functional is required to guarantee the existence of its Jacobian matrix, which is a suitable condition to minimize this functional by iterative methods. Numerical examples of the functional minimization are given.

  15. Sex Differential Item Functioning in the Inventory of Early Development III Social-Emotional Skills

    ERIC Educational Resources Information Center

    Beaver, Jessica L.; French, Brian F.; Finch, W. Holmes; Ullrich-French, Sarah C.

    2014-01-01

    Social-emotional (SE) skills in the early developmental years of children influence outcomes in psychological, behavioral, and learning domains. The adult ratings of a child's SE skills can be influenced by sex stereotypes. These rating differences could lead to differential conclusions about developmental progress or risk. To ensure that…

  16. Differential Language Functioning of Monolinguals and Bilinguals on Positive-Negative Emotional Expression

    ERIC Educational Resources Information Center

    Kheirzadeh, Shiela; Hajiabed, Mohammadreza

    2016-01-01

    The present interdisciplinary research investigates the differential emotional expression between Persian monolinguals and Persian-English bilinguals. In other words, the article was an attempt to answer the questions whether bilinguals and monolinguals differ in the expression of positive and negative emotions elicited through sad and happy…

  17. The Manifest and Latent Functions of Differential Response in Child Welfare

    ERIC Educational Resources Information Center

    Ji, Daniel; Sullivan, Richard

    2016-01-01

    Although previous research has explored the efficacy of differential response (DR) programs in child welfare, there have been no studies to date about coding decisions between designations by child protection service agencies. Research has explored client satisfaction with DR as well as rates of recidivism and removal/placement but with limited…

  18. Predictive Validity of Attentional Functions in Differentiating Children with and without ADHD: A Componential Analysis

    ERIC Educational Resources Information Center

    Kaufmann, Liane; Zieren, Nikola; Zotter, Sibylle; Karall, Daniela; Scholl-Burgi, Sabine; Haberlandt, Edda; Fimm, Bruno

    2010-01-01

    Aim: The objective of this study was to investigate which attentional components are of predictive utility in differentiating children with attention-deficit-hyperactivity disorder, combined type (ADHD-C) from their peers without ADHD. Methods: Thirty-four children participated in the study: 17 males with ADHD-C (mean age 10y 4mo, SD 1y 9mo) and…

  19. Experiences of identification and differentiation as functions of leprosy, personality and age.

    PubMed

    Chauhan, N S; Dhar, U; Singh, Y

    1984-01-01

    It is a study of sociogenic need satisfactions that determines the homeostasis of 'being' by remaining contingent conditions of perpetuation or debasement of the social 'self'. The paper has a focus on identification satisfaction and differentiation experience of patients of the highly stigmatized leprosy. The study proceeds with an 'Experimental Group--Control-Group' randomized design. Experimental Groups are two, viz., those of Lepromatous and Non-lepromatous patients. 'Control Group' consists of 'disease-free' normal people. The three independent variables are disease types, age, personality factors. The dependent variables are two, viz., score of identification satisfaction and differentiation experience, measured by standardized tools. Each dependent variable has four '3 X 3 X 2' factorial experiments to test 56 'Null Hypotheses'. The sample consists of 360 elements for each one of the eight experiments. Leprosy elements are drawn from the Central JALMA Institute for Leprosy and the 'Kushta Seva Sadan' (Agra). The 'F' test is run for statistical verification of 'Null hypotheses'. Results show presence of 'role-reversion' and 'role negation' of age and personality factors. The disease possesses 'anti-roles'. It does not allow age and personality factors to promote identification satisfaction and to demote differentiation and experience. The disease actively promotes differentiation and demotes identification through its own 'alien system'. The senescents are the greatest sufferers. 'Social Stigma' works a 'social thanatos' and exposes senescents to substantial 'self-erosion'. PMID:6548499

  20. Fucoidan, a Sulfated Polysaccharide, Inhibits Osteoclast Differentiation and Function by Modulating RANKL Signaling

    PubMed Central

    Kim, Young Woo; Baek, Seung-Hoon; Lee, Sang-Han; Kim, Tae-Ho; Kim, Shin-Yoon

    2014-01-01

    Multinucleated osteoclasts differentiate from hematopoietic progenitors of the monocyte/macrophage lineage. Because of its pivotal role in bone resorption, regulation of osteoclast differentiation is a potential therapeutic approach to the treatment of erosive bone disease. In this study, we have found that fucoidan, a sulfated polysaccharide extracted from brown seaweed, inhibited osteoclast differentiation. In particular, addition of fucoidan into the early stage osteoclast cultures significantly inhibited receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL)-induced osteoclast formation, thus suggesting that fucoidan affects osteoclast progenitors. Furthermore, fucoidan significantly inhibited the activation of RANKL-dependent mitogen-activated protein kinases (MAPKs) such as JNK, ERK, and p38, and also c-Fos and NFATc1, which are crucial transcription factors for osteoclastogenesis. In addition, the activation of NF-κB, which is an upstream transcription factor modulating NFATc1 expression, was alleviated in the fucoidan-treated cells. These results collectively suggest that fucoidan inhibits osteoclastogenesis from bone marrow macrophages by inhibiting RANKL-induced p38, JNK, ERK and NF-κB activation, and by downregulating the expression of genes that partake in both osteoclast differentiation and resorption. PMID:25334060

  1. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA.

    PubMed

    Cesana, Marcella; Cacchiarelli, Davide; Legnini, Ivano; Santini, Tiziana; Sthandier, Olga; Chinappi, Mauro; Tramontano, Anna; Bozzoni, Irene

    2011-10-14

    Recently, a new regulatory circuitry has been identified in which RNAs can crosstalk with each other by competing for shared microRNAs. Such competing endogenous RNAs (ceRNAs) regulate the distribution of miRNA molecules on their targets and thereby impose an additional level of post-transcriptional regulation. Here we identify a muscle-specific long noncoding RNA, linc-MD1, which governs the time of muscle differentiation by acting as a ceRNA in mouse and human myoblasts. Downregulation or overexpression of linc-MD1 correlate with retardation or anticipation of the muscle differentiation program, respectively. We show that linc-MD1 "sponges" miR-133 and miR-133 [corrected] to regulate the expression of MAML1 and MEF2C, transcription factors that activate muscle-specific gene expression. Finally, we demonstrate that linc-MD1 exerts the same control over differentiation timing in human myoblasts, and that its levels are strongly reduced in Duchenne muscle cells. We conclude that the ceRNA network plays an important role in muscle differentiation.

  2. Production and Functional Characterization of Murine Osteoclasts Differentiated from ER-Hoxb8-Immortalized Myeloid Progenitor Cells.

    PubMed

    Zach, Frank; Mueller, Alexandra; Gessner, André

    2015-01-01

    In vitro differentiation into functional osteoclasts is routinely achieved by incubation of embryonic stem cells, induced pluripotent stem cells, or primary as well as cryopreserved spleen and bone marrow-derived cells with soluble receptor activator of nuclear factor kappa-B ligand and macrophage colony-stimulating factor. Additionally, osteoclasts can be derived from co-cultures with osteoblasts or by direct administration of soluble receptor activator of nuclear factor kappa-B ligand to RAW 264.7 macrophage lineage cells. However, despite their benefits for osteoclast-associated research, these different methods have several drawbacks with respect to differentiation yields, time and animal consumption, storage life of progenitor cells or the limited potential for genetic manipulation of osteoclast precursors. In the present study, we therefore established a novel protocol for the differentiation of osteoclasts from murine ER-Hoxb8-immortalized myeloid stem cells. We isolated and immortalized bone marrow cells from wild type and genetically manipulated mouse lines, optimized protocols for osteoclast differentiation and compared these cells to osteoclasts derived from conventional sources. In vitro generated ER-Hoxb8 osteoclasts displayed typical osteoclast characteristics such as multi-nucleation, tartrate-resistant acid phosphatase staining of supernatants and cells, F-actin ring formation and bone resorption activity. Furthermore, the osteoclast differentiation time course was traced on a gene expression level. Increased expression of osteoclast-specific genes and decreased expression of stem cell marker genes during differentiation of osteoclasts from ER-Hoxb8-immortalized myeloid progenitor cells were detected by gene array and confirmed by semi-quantitative and quantitative RT-PCR approaches. In summary, we established a novel method for the quantitative production of murine bona fide osteoclasts from ER-Hoxb8 stem cells generated from wild type or

  3. Production and Functional Characterization of Murine Osteoclasts Differentiated from ER-Hoxb8-Immortalized Myeloid Progenitor Cells

    PubMed Central

    Zach, Frank; Mueller, Alexandra; Gessner, André

    2015-01-01

    In vitro differentiation into functional osteoclasts is routinely achieved by incubation of embryonic stem cells, induced pluripotent stem cells, or primary as well as cryopreserved spleen and bone marrow-derived cells with soluble receptor activator of nuclear factor kappa-B ligand and macrophage colony-stimulating factor. Additionally, osteoclasts can be derived from co-cultures with osteoblasts or by direct administration of soluble receptor activator of nuclear factor kappa-B ligand to RAW 264.7 macrophage lineage cells. However, despite their benefits for osteoclast-associated research, these different methods have several drawbacks with respect to differentiation yields, time and animal consumption, storage life of progenitor cells or the limited potential for genetic manipulation of osteoclast precursors. In the present study, we therefore established a novel protocol for the differentiation of osteoclasts from murine ER-Hoxb8-immortalized myeloid stem cells. We isolated and immortalized bone marrow cells from wild type and genetically manipulated mouse lines, optimized protocols for osteoclast differentiation and compared these cells to osteoclasts derived from conventional sources. In vitro generated ER-Hoxb8 osteoclasts displayed typical osteoclast characteristics such as multi-nucleation, tartrate-resistant acid phosphatase staining of supernatants and cells, F-actin ring formation and bone resorption activity. Furthermore, the osteoclast differentiation time course was traced on a gene expression level. Increased expression of osteoclast-specific genes and decreased expression of stem cell marker genes during differentiation of osteoclasts from ER-Hoxb8-immortalized myeloid progenitor cells were detected by gene array and confirmed by semi-quantitative and quantitative RT-PCR approaches. In summary, we established a novel method for the quantitative production of murine bona fide osteoclasts from ER-Hoxb8 stem cells generated from wild type or

  4. Transcriptome Sequencing Analysis and Functional Identification of Sex Differentiation Genes from the Mosquito Parasitic Nematode, Romanomermis wuchangensis

    PubMed Central

    Duan, Mingyue; Xiong, Jinfeng; Lu, Dandan; Wang, Guoxiu; Ai, Hui

    2016-01-01

    Mosquito-transmitted diseases like malaria and dengue fever are global problem and an estimated 50–100 million of dengue or dengue hemorrhagic fever cases are reported worldwide every year. The mermithid nematode Romanomermis wuchangensis has been successfully used as an ecosystem-friendly biocontrol agent for mosquito prevention in laboratory studies. However, this nematode can not undergo sex differentiation in vitro culture, which has seriously affected their application of biocontrol in the field. In this study, based on transcriptome sequencing analysis of R. wuchangensis, Rwucmab-3, Rwuclaf-1 and Rwuctra-2 were cloned and used to investigate molecular regulatory function of sex differentiation. qRT-PCR results demonstrated that the expression level of Rwucmab-3 between male and female displayed obvious difference on the 3rd day of parasitic stage, which was earlier than Rwuclaf-1 and Rwuctra-2, highlighting sex differentiation process may start on the 3rd day of parasitic stage. Besides, FITC was used as a marker to test dsRNA uptake efficiency of R. wuchangensis, which fluorescence intensity increased with FITC concentration after 16 h incubation, indicating this nematode can successfully ingest soaking solution via its cuticle. RNAi results revealed the sex ratio of R. wuchangensis from RNAi treated groups soaked in dsRNA of Rwucmab-3 was significantly higher than gfp dsRNA treated groups and control groups, highlighting RNAi of Rwumab-3 may hinder the development of male nematodes. These results suggest that Rwucmab-3 mainly involves in the initiation of sex differentiation and the development of male sexual dimorphism. Rwuclaf-1 and Rwuctra-2 may play vital role in nematode reproductive and developmental system. In conclusion, transcript sequences presented in this study could provide more bioinformatics resources for future studies on gene cloning and other molecular regulatory mechanism in R. wuchangensis. Moreover, identification and functional

  5. Expression of PKC iota affects neuronal differentiation of PC12 cells at least partly independent of kinase function

    PubMed Central

    Doonachar, Alana; Schoenfeld, Alan R.

    2014-01-01

    Atypical PKC (aPKC) plays a role in establishing cell polarity and has been indicated in neuronal differentiation and polarization, including neurite formation in rat pheochromocytoma PC12 cells, albeit by unclear mechanisms. Here, the role of the aPKC isoform, PKC iota (PKCι), in the early neuronal differentiation of PC12 cells was investigated. NGF-treated PC12 cells with stably expressed exogenous wild-type PKCι showed decreased expression of a neuroendocrine marker, increased expression of a neuronal marker, and increased neurite formation. Stable expression of a kinase- inactive PKCι, but not constitutively active PKCι lacking a regulatory domain, had similar although less potent effects. Pharmacological inhibition of endogenous aPKC kinase activity in parental PC12 cells did not inhibit neurite formation, suggesting that some of the observed effects of PKCι expression on neuronal differentiation are kinase- independent. Interestingly, exogenous expression of wild-type and kinase-inactive PKCι had little effect on overall PKCι activity, but caused a decrease in PKC zeta (PKCζ) kinase activity, suggesting an interplay between the two isoforms that may underlie the observed results. Overall, these findings suggest that in PC12 and perhaps other neuroendocrine precursor cells, PKCι influences an early differentiation decision between the neuroendocrine (chromaffin) and sympathetic neuron cell lineages, potentially by affecting PKCζ function. PMID:24910851

  6. Integrated Functions of Pax3 and Pax7 in the Regulation of Proliferation, Cell Size and Myogenic Differentiation

    PubMed Central

    White, Robert B.; Boldrin, Luisa; Perez-Ruiz, Ana; Relaix, Frederic; Morgan, Jennifer E.; Zammit, Peter S.

    2009-01-01

    Pax3 and Pax7 are paired-box transcription factors with roles in developmental and adult regenerative myogenesis. Pax3 and Pax7 are expressed by postnatal satellite cells or their progeny but are down regulated during myogenic differentiation. We now show that constitutive expression of Pax3 or Pax7 in either satellite cells or C2C12 myoblasts results in an increased proliferative rate and decreased cell size. Conversely, expression of dominant-negative constructs leads to slowing of cell division, a dramatic increase in cell size and altered morphology. Similarly to the effects of Pax7, retroviral expression of Pax3 increases levels of Myf5 mRNA and MyoD protein, but does not result in sustained inhibition of myogenic differentiation. However, expression of Pax3 or Pax7 dominant-negative constructs inhibits expression of Myf5, MyoD and myogenin, and prevents differentiation from proceeding. In fibroblasts, expression of Pax3 or Pax7, or dominant-negative inhibition of these factors, reproduce the effects on cell size, morphology and proliferation seen in myoblasts. Our results show that in muscle progenitor cells, Pax3 and Pax7 function to maintain expression of myogenic regulatory factors, and promote population expansion, but are also required for myogenic differentiation to proceed. PMID:19221588

  7. Uncoupling Protein 2 and 4 Expression Pattern during Stem Cell Differentiation Provides New Insight into Their Putative Function

    PubMed Central

    Rupprecht, Anne; Sittner, Dana; Smorodchenko, Alina; Hilse, Karolina E.; Goyn, Justus; Moldzio, Rudolf; Seiler, Andrea E. M.; Bräuer, Anja U.; Pohl, Elena E.

    2014-01-01

    Apart from the first family member, uncoupling protein 1 (UCP1), the functions of other UCPs (UCP2-UCP5) are still unknown. In analyzing our own results and those previously published by others, we have assumed that UCP's cellular expression pattern coincides with a specific cell metabolism and changes if the latter is altered. To verify this hypothesis, we analyzed the expression of UCP1-5 in mouse embryonic stem cells before and after their differentiation to neurons. We have shown that only UCP2 is present in undifferentiated stem cells and it disappears simultaneously with the initiation of neuronal differentiation. In contrast, UCP4 is simultaneously up-regulated together with typical neuronal marker proteins TUJ-1 and NeuN during mESC differentiation in vitro as well as during murine brain development in vivo. Notably, several tested cell lines express UCP2, but not UCP4. In line with this finding, neuroblastoma cells that display metabolic features of tumor cells express UCP2, but not UCP4. UCP2's occurrence in cancer, immunological and stem cells indicates that UCP2 is present in cells with highly proliferative potential, which have a glycolytic type of metabolism as a common feature, whereas UCP4 is strongly associated with non-proliferative highly differentiated neuronal cells. PMID:24523901

  8. A potent and selective small molecule inhibitor of sirtuin 1 promotes differentiation of pluripotent P19 cells into functional neurons

    PubMed Central

    Kim, Beom Seok; Lee, Chang-Hee; Chang, Gyeong-Eon; Cheong, Eunji; Shin, Injae

    2016-01-01

    Sirtuin 1 (SIRT1) is known to suppress differentiation of pluripotent/multipotent cells and neural progenitor cells into neurons by blocking activation of transcription factors critical for neurogenesis. EX-527 is a highly selective and potent inhibitor against SIRT1 and has been used as a chemical probe that modulates SIRT1-associated biological processes. However, the effect of EX-527 on neuronal differentiation in pluripotent cells has not been well elucidated. Here, we report an examination of EX-527 effects on neurogenesis of pluripotent P19 cells. The results showed that EX-527 greatly accelerated differentiation of P19 cells into neurons without generation of cardiac cells and astrocytes. Importantly, neurons derived from P19 cells treated with EX-527 generated voltage-dependent sodium currents and depolarization-induced action potentials. The findings indicate that the differentiated cells have electrophysiological properties. The present study suggests that the selective SIRT1 inhibitor could have the potential of being employed as a chemical inducer to generate functionally active neurons. PMID:27680533

  9. Cadherin-11 regulates both mesenchymal stem cell differentiation into smooth muscle cells and the development of contractile function in vivo

    PubMed Central

    Alimperti, Stella; You, Hui; George, Teresa; Agarwal, Sandeep K.; Andreadis, Stelios T.

    2014-01-01

    ABSTRACT Although soluble factors, such as transforming growth factor β1 (TGF-β1), induce mesenchymal stem cell (MSC) differentiation towards the smooth muscle cell (SMC) lineage, the role of adherens junctions in this process is not well understood. In this study, we found that cadherin-11 but not cadherin-2 was necessary for MSC differentiation into SMCs. Cadherin-11 regulated the expression of TGF-β1 and affected SMC differentiation through a pathway that was dependent on TGF-β receptor II (TGFβRII) but independent of SMAD2 or SMAD3. In addition, cadherin-11 activated the expression of serum response factor (SRF) and SMC proteins through the Rho-associated protein kinase (ROCK) pathway. Engagement of cadherin-11 increased its own expression through SRF, indicative of the presence of an autoregulatory feedback loop that committed MSCs to the SMC fate. Notably, SMC-containing tissues (such as aorta and bladder) from cadherin-11-null (Cdh11−/−) mice showed significantly reduced levels of SMC proteins and exhibited diminished contractility compared with controls. This is the first report implicating cadherin-11 in SMC differentiation and contractile function in vitro as well as in vivo. PMID:24741067

  10. Isolation and cultivation of dermal stem cells that differentiate into functional epidermal melanocytes.

    PubMed

    Li, Ling; Fukunaga-Kalabis, Mizuho; Herlyn, Meenhard

    2012-01-01

    Human melanocytes have been extensively studied, but a melanocyte stem cell reservoir in glabrous skin has not yet been found. Human dermis contains cells that are nonpigmented but can differentiate to several different cell types. We have recently shown that multipotent dermal stem cells isolated from human neonatal foreskins are able to differentiate to multiple cell lineages, including pigmented melanocytes. The dermal stem cells grow as three-dimensional spheres in human embryonic stem cell medium and express some neural crest stem cell and embryonic stem cell markers. Melanocytes derived from dermal stem cells express melanocytic markers and act the same way as mature epidermal melanocytes. Dermal spheres, embedded in the reconstructed dermis consisting of collagen with fibroblasts, can migrate to the basement membrane, where they become pigmented in the same way as epidermal melanocytes suggesting that dermal stem cells can give rise to epidermal melanocytes.

  11. Legendre-tau approximation for functional differential equations. II - The linear quadratic optimal control problem

    NASA Technical Reports Server (NTRS)

    Ito, Kazufumi; Teglas, Russell

    1987-01-01

    The numerical scheme based on the Legendre-tau approximation is proposed to approximate the feedback solution to the linear quadratic optimal control problem for hereditary differential systems. The convergence property is established using Trotter ideas. The method yields very good approximations at low orders and provides an approximation technique for computing closed-loop eigenvalues of the feedback system. A comparison with existing methods (based on averaging and spline approximations) is made.

  12. Differential sensitization to amphetamine and stress responsivity as a function of inherent laterality.

    PubMed

    LaHoste, G J; Mormède, P; Rivet, J M; Le Moal, M

    1988-06-21

    With repeated administrations, rodents become increasingly sensitive to the stimulant properties of amphetamine, a phenomenon termed sensitization. Rats differentiated on the basis of their preferred direction of rotation following peripheral administration of amphetamine were found to differ in their sensitization to amphetamine in two different behavioral paradigms. Rats which displayed leftward rotational biases developed greater sensitization and greater hormonal response to stress following sensitization. PMID:2841013

  13. Expression and function of heterotypic adhesion molecules during differentiation of human skeletal muscle in culture.

    PubMed Central

    Beauchamp, J. R.; Abraham, D. J.; Bou-Gharios, G.; Partridge, T. A.; Olsen, I.

    1992-01-01

    The infiltration of skeletal muscle by leukocytes occurs in a variety of myopathies and frequently accompanies muscle degeneration and regeneration. The latter involves development of new myofibers from precursor myoblasts, and so infiltrating cells may interact with muscle at all stages of differentiation. The authors have investigated the surface expression of ligands for T-cell adhesion during the differentiation of human skeletal muscle in vitro. Myoblasts expressed low levels of ICAM-1 (CD54), which remained constant during muscle cell differentiation and could be induced by cytokines such as gamma-interferon. It is therefore likely that ICAM-1 is involved in the invasive accumulation of lymphocytes during skeletal muscle inflammation. In contrast, LFA-3 (CD58) was expressed at higher levels than ICAM-1 on myoblasts, decreased significantly during myogenesis, and was unaffected by immune mediators. Both ICAM-1 and LFA-3 were able to mediate T cell binding to myoblasts, whereas adhesion to myotubes was independent of the LFA-3 ligand. Although expressed throughout myogenesis, human leukocyte antigen class I and CD44 did not appear to mediate T cell binding. The expression of ligands that facilitate interaction of myogenic cells with lymphocytes may have important implications for myoblast transplantation. Images Figure 1 Figure 3 Figure 4 PMID:1739132

  14. Glucose metabolite patterns as markers of functional differentiation in freshly isolated and cultured mouse mammary epithelial cells

    SciTech Connect

    Emerman, J.T.; Bartley, J.C.; Bissel, M.J.

    1981-01-01

    In the mammary gland of non-ruminant animals, glucose is utilized in a characteristic and unique way during lacation. By measuring the incorporation of glucose carbon from (U-/sup 14/C)glucose into intermediary metabolitees and metabolic products in mammary epithelia cells from virgin, pregnant, and lacating mice, we domonstrate that glucose metabolite patterns can be used to recognize stages of differentiated function. For these cells, the rates of synthesis of glycogen and lactose, the ratio of lactate to alanine, and the ratio of citrate to malate are important parameters in identifying the degree of expression of differentiation. We further show that these patterns can be used as markers to determine the differentiated state of cultured mammary epithelial cells. Cells maintained on plastic substrates lose their distinctive glucose metabolite patterns while those on floating collagen gels do not. Cells isolated from pregnant mice and cultured on collagen gels have a pattern similar to that of their freshly isolated counter-parts. When isolated from lacating mice, the metabolite patterns of cells cultured on collagen gels are different from that of the cells of origin, and resembles that of freshly isolated cells from pregnant mice. Our findings suggest that the floating collagen gels under the culture conditions used in these experiments provide an environment for the functional expression of the pregnant state, while additional factors are needed for the expression of the lactating state.

  15. GLUCOSE METABOLITE PATTERNS AS MARKERS OF FUNCTIONAL DIFFERENTIATION IN FRESHLY ISOLATED AND CULTURED MOUSE MAMMARY EPITHELIAL CELLS

    SciTech Connect

    Emerman, J.T.; Bartley, J.C.; Bissell, M.J.

    1980-06-01

    In the mammary gland of nonruminant animals, glucose is utilized in a characteristic and unique way during lactation. We have measured the incorporation of glucose carbon from [U-{sup 14}C] glucose into intermediary metabolites and metabolic products in mammary epithelial cells from virgin, pregnant, and lactating mice and demonstrate that glucose metabolite patterns can be used to recognize stages of differentiated function. For these cells, the rates of synthesis of glycogen and lactose, the ratio of lactate to alanine, and the ratio of citrate to malate were important parameters in identifying the degree of expression of differentiation. We further show that these patterns can be used as markers to determine the differentiated state of cultured mammary epithelial cells. Cells maintained on plastic substrates lose their distinctive glucose metabolite patterns while those on floating collagen gels do not. Cells from pregnant mice have a pattern similar to freshly isolated cells from pregnant mice. The pattern of cells from lactating mice is different from that of the cells of origin, and resembles that of the cells from pregnant mice. Our findings suggest that the floating collagen gels under the culture conditions used in these experiments provide an environment for the functional expression of the pregnant state, while additional factors are needed for the expression of the lactating state.

  16. Forced involution of the functionally differentiated mammary gland by overexpression of the pro-apoptotic protein Bax

    PubMed Central

    Rucker, Edmund B.; Hale, Amber N.; Durtschi, David C.; Sakamoto, Kazuhito; Wagner, Kay-Uwe

    2013-01-01

    The mammary gland is a developmentally dynamic, hormone-responsive organ that undergoes proliferation and differentiation within the secretory epithelial compartment during pregnancy. The epithelia are maintained by pro-survival signals (e.g. Stat5, Akt1) during lactation, but undergo apoptosis during involution through inactivation of cell survival pathways and upregulation of pro-apoptotic proteins. To assess if the survival signals in the functionally differentiated mammary epithelial cells can override a pro-apoptotic signal, we generated transgenic mice that express Bax under the whey acidic protein (WAP) promoter. WAP-Bax females exhibited a lactation defect and were unable to nourish their offspring. Mammary glands demonstrated: 1) a reduction in epithelial content, 2) hallmark signs of mitochondria-mediated cell death, 3) an increase in apoptotic cells by TUNEL assay, and 4) precocious Stat3 activation. This suggests that upregulation of a single proapoptotic factor of the Bcl-2 family is sufficient to initiate apoptosis of functionally differentiated mammary epithelial cells in vivo. PMID:21254334

  17. A WD40 repeat protein regulates fungal cell differentiation and can be replaced functionally by the mammalian homologue striatin.

    PubMed

    Pöggeler, Stefanie; Kück, Ulrich

    2004-02-01

    Fruiting body development in fungi is a complex cellular differentiation process that is controlled by more than 100 developmental genes. Mutants of the filamentous fungus Sordaria macrospora showing defects in fruiting body formation are pertinent sources for the identification of components of this multicellular differentiation process. Here we show that the sterile mutant pro11 carries a defect in the pro11 gene encoding a multimodular WD40 repeat protein. Complementation analysis indicates that the wild-type gene or C-terminally truncated versions of the wild-type protein are able to restore the fertile phenotype in mutant pro11. PRO11 shows significant homology to several vertebrate WD40 proteins, such as striatin and zinedin, which seem to be involved in Ca2+-dependent signaling in cells of the central nervous system and are supposed to function as scaffolding proteins linking signaling and eukaryotic endocytosis. Cloning of a mouse cDNA encoding striatin allowed functional substitution of the wild-type protein with restoration of fertility in mutant pro11. Our data strongly suggest that an evolutionarily conserved cellular process controlling eukaryotic cell differentiation may regulate fruiting body formation.

  18. A Differential Item Functional Analysis by Age of Perceived Interpersonal Discrimination in a Multi-racial/ethnic Sample of Adults.

    PubMed

    Owens, Sherry; Kristjansson, Alfgeir L; Hunte, Haslyn E R

    2015-01-01

    We investigated whether individual items on the nine item William's Perceived Everyday Discrimination Scale (EDS) functioned differently by age (<45 vs ≥ 45) within five racial groups in the United States: Asians (n=2,017); Hispanics (n=2,688); Black Caribbeans (n=1,377); African Americans (n=3,434); and Whites (n=854). We used data from the 2001-2003 National Survey of American Lives and the 2001-2003 National Latino and Asian Studies. Multiple-indicator, multiple-cause models (MIMIC) were used to examine differential item functioning (DIF) on the EDS by age within each racial/ethnic group. Overall, Asian and Hispanic respondents reported less discrimination than Whites; on the other hand, African Americans and Black Caribbeans reported more discrimination than Whites. Regardless of race/ethnicity, the younger respondents (aged <45 years) reported less discrimination than the older respondents (aged ≥ 45 years). In terms of age by race/ethnicity, the results were mixed for 19 out of 45 tests of DIF (40%). No differences in item function were observed among Black Caribbeans. "Being called names or insulted" and others acting as "if they are afraid" of the respondents were the only two items that did not exhibit differential item functioning by age across all racial/ethnic groups. Overall, our findings suggest that the EDS scale should be used with caution in multi-age multi-racial/ethnic samples.

  19. A Differential Item Functional Analysis by Age of Perceived Interpersonal Discrimination in a Multi-racial/ethnic Sample of Adults.

    PubMed

    Owens, Sherry; Kristjansson, Alfgeir L; Hunte, Haslyn E R

    2015-01-01

    We investigated whether individual items on the nine item William's Perceived Everyday Discrimination Scale (EDS) functioned differently by age (<45 vs ≥ 45) within five racial groups in the United States: Asians (n=2,017); Hispanics (n=2,688); Black Caribbeans (n=1,377); African Americans (n=3,434); and Whites (n=854). We used data from the 2001-2003 National Survey of American Lives and the 2001-2003 National Latino and Asian Studies. Multiple-indicator, multiple-cause models (MIMIC) were used to examine differential item functioning (DIF) on the EDS by age within each racial/ethnic group. Overall, Asian and Hispanic respondents reported less discrimination than Whites; on the other hand, African Americans and Black Caribbeans reported more discrimination than Whites. Regardless of race/ethnicity, the younger respondents (aged <45 years) reported less discrimination than the older respondents (aged ≥ 45 years). In terms of age by race/ethnicity, the results were mixed for 19 out of 45 tests of DIF (40%). No differences in item function were observed among Black Caribbeans. "Being called names or insulted" and others acting as "if they are afraid" of the respondents were the only two items that did not exhibit differential item functioning by age across all racial/ethnic groups. Overall, our findings suggest that the EDS scale should be used with caution in multi-age multi-racial/ethnic samples. PMID:26673317

  20. Biomechanical strain vehicles for fibroblast-directed skeletal myoblast differentiation and myotube functionality in a novel coculture.

    PubMed

    Hicks, Michael R; Cao, Thanh V; Standley, Paul R

    2014-10-15

    Skeletal muscle functionality is governed by multiple stimuli, including cytokines and biomechanical strain. Fibroblasts embedded within muscle connective tissue respond to biomechanical strain by secreting cytokines that induce myoblast differentiation and, we hypothesize, regulate myotube function. A coculture was established to allow cross talk between fibroblasts in Bioflex wells and myoblasts on nondeformable coverslips situated above Bioflex wells. Cyclic short-duration strain (CSDS) modeling repetitive stress/injury, acyclic long-duration strain (ALDS) modeling manipulative therapy, and combined strain paradigms (CSDS + ALDS) were applied to fibroblasts. Nonstrained myoblasts in uniculture and coculture served as controls. After fibroblasts had induced myoblast differentiation, myotube contraction was assessed by perfusion of ACh (10(-11)-10(-3) M). CSDS-treated fibroblasts increased myotube contractile sensitivity vs. uniculture (P < 0.05). As contraction is dependent on ACh binding, expression and clustering of nicotinic ACh receptors (nAChRs) were measured. CSDS-treated fibroblasts increased nAChR expression (P < 0.05), which correlated with myotube contraction. ALDS-treated fibroblasts did not significantly affect contraction or nAChR expression. Agrin-treated myotubes were then used to design a computer algorithm to identify α-bungarotoxin-stained nAChR clusters. ALDS-treated fibroblasts increased nAChR clustering (P < 0.05), while CSDS-treated fibroblasts disrupted cluster formation. CSDS-treated fibroblasts produced nAChRs preferentially located in nonclustered regions (P < 0.05). Strain-activated fibroblasts mediate myotube differentiation with multiple functional phenotypes. Similar to muscle injury, CSDS-treated fibroblasts disrupted nAChR clusters and hypersensitized myotube contraction, while ALDS-treated fibroblasts aggregated nAChRs in large clusters, which may have important clinical implications. Cellular strategies aimed at improving muscle

  1. Association of tissue lineage and gene expression: conservatively and differentially expressed genes define common and special functions of tissues

    PubMed Central

    2010-01-01

    Background Embryogenesis is the process by which the embryo is formed, develops, and establishes developmental hierarchies of tissues. The recent advance in microarray technology made it possible to investigate the tissue specific patterns of gene expression and their relationship with tissue lineages. This study is focused on how tissue specific functions, tissue lineage, and cell differentiation are correlated, which is essential to understand embryonic development and organism complexity. Results We performed individual gene and gene set based analysis on multiple tissue expression data, in association with the classic topology of mammalian fate maps of embryogenesis. For each sub-group of tissues on the fate map, conservatively, differentially and correlatively expressed genes or gene sets were identified. Tissue distance was found to correlate with gene expression divergence. Tissues of the ectoderm or mesoderm origins from the same segments on the fate map shared more similar expression pattern than those from different origins. Conservatively expressed genes or gene sets define common functions in a tissue group and are related to tissue specific diseases, which is supported by results from Gene Ontology and KEGG pathway analysis. Gene expression divergence is larger in certain human tissues than in the mouse homologous tissues. Conclusion The results from tissue lineage and gene expression analysis indicate that common function features of neighbor tissue groups were defined by the conservatively expressed genes and were related to tissue specific diseases, and differentially expressed genes contribute to the functional divergence of tissues. The difference of gene expression divergence in human and mouse homologous tissues reflected the organism complexity, i.e. distinct neural development levels and different body sizes. PMID:21172044

  2. From crater functions to partial differential equations: a new approach to ion bombardment induced nonequilibrium pattern formation.

    PubMed

    Norris, Scott A; Brenner, Michael P; Aziz, Michael J

    2009-06-01

    We develop a methodology for deriving continuum partial differential equations for the evolution of large-scale surface morphology directly from molecular dynamics simulations of the craters formed from individual ion impacts. Our formalism relies on the separation between the length scale of ion impact and the characteristic scale of pattern formation, and expresses the surface evolution in terms of the moments of the crater function. We demonstrate that the formalism reproduces the classical Bradley-Harper results, as well as ballistic atomic drift, under the appropriate simplifying assumptions. Given an actual set of converged molecular dynamics moments and their derivatives with respect to the incidence angle, our approach can be applied directly to predict the presence and absence of surface morphological instabilities. This analysis represents the first work systematically connecting molecular dynamics simulations of ion bombardment to partial differential equations that govern topographic pattern-forming instabilities. PMID:21715755

  3. Differential item functioning on the Five Facet Mindfulness Questionnaire is minimal in demographically matched meditators and nonmeditators.

    PubMed

    Baer, Ruth A; Samuel, Douglas B; Lykins, Emily L B

    2011-03-01

    A recent study of the Five Facet Mindfulness Questionnaire reported high levels of differential item functioning (DIF) for 18 of its 39 items in meditating and nonmeditating samples that were not demographically matched. In particular, meditators were more likely to endorse positively worded items whereas nonmeditators were more likely to deny negatively worded (reverse-scored) items. The present study replicated these analyses in demographically matched samples of meditators and nonmeditators (n = 115 each) and found that evidence for DIF was minimal. There was little or no evidence for differential relationships between positively and negatively worded items for meditators and nonmeditators. Findings suggest that DIF based on items' scoring direction is not problematic when the Five Facet Mindfulness Questionnaire is used to compare demographically similar meditators and nonmeditators.

  4. An optimal point spread function subtraction algorithm for high-contrast imaging: a demonstration with angular differential imaging

    SciTech Connect

    Lafreniere, D; Marois, C; Doyon, R; Artigau, E; Nadeau, D

    2006-09-19

    Direct imaging of exoplanets is limited by bright quasi-static speckles in the point spread function (PSF) of the central star. This limitation can be reduced by subtraction of reference PSF images. We have developed an algorithm to construct an optimal reference PSF image from an arbitrary set of reference images. This image is built as a linear combination of all available images and is optimized independently inside multiple subsections of the image to ensure that the absolute minimum residual noise is achieved within each subsection. The algorithm developed is completely general and can be used with many high contrast imaging observing strategies, such as angular differential imaging (ADI), roll subtraction, spectral differential imaging, reference star observations, etc. The performance of the algorithm is demonstrated for ADI data. It is shown that for this type of data the new algorithm provides a gain in sensitivity by up 22 to a factor 3 at small separation over the algorithm previously used.

  5. PKR is a novel functional direct player that coordinates skeletal muscle differentiation via p38MAPK/AKT pathways.

    PubMed

    Alisi, A; Spaziani, A; Anticoli, S; Ghidinelli, M; Balsano, C

    2008-03-01

    Myogenic differentiation is a highly orchestrated multistep process controlled by extracellular growth factors that modulate largely unknown signals into the cell affecting the muscle-transcription program. P38MAPK-dependent signalling, as well as PI3K/Akt pathway, has a key role in the control of muscle gene expression at different stages during the myogenic process. P38MAPK affects the activities of transcription factors, such as MyoD and myogenin, and contributes, together with PI3K/Akt pathway, to control the early and late steps of myogenic differentiation. The aim of our work was to better define the role of PKR, a dsRNA-activated protein kinase, as potential component in the differentiation program of C2C12 murine myogenic cells and to correlate its activity with p38MAPK and PI3K/Akt myogenic regulatory pathways. Here, we demonstrate that PKR is an essential component of the muscle development machinery and forms a functional complex with p38MAPK and/or Akt, contributing to muscle differentiation of committed myogenic cells in vitro. Inhibition of endogenous PKR activity by a specific (si)RNA and a PKR dominant-negative interferes with the myogenic program of C2C12 cells, causing a delay in activation of myogenic specific genes and inducing the formation of thinner myofibers. In addition, the construction of three PKR mutants allowed us to demonstrate that both N and C-terminal regions of PKR are critical for the interaction with p38MAPK and Akt. The novel discovered complex permits PKR to timely regulate the inhibition/activation of p38MAPK and Akt, controlling in this way the different steps characterizing skeletal muscle differentiation.

  6. Use of Gilliam Asperger's disorder scale in differentiating high and low functioning autism and ADHD.

    PubMed

    Mayes, Susan Dickerson; Calhoun, Susan L; Murray, Michael J; Morrow, Jill D; Yurich, Kirsten K L; Cothren, Shiyoko; Purichia, Heather; Bouder, James N

    2011-02-01

    Little is known about the validity of Gilliam Asperger's Disorder Scale (GADS), although it is widely used. This study of 199 children with high functioning autism or Asperger's disorder, 195 with low functioning autism, and 83 with attention deficit hyperactivity disorder (ADHD) showed high classification accuracy (autism vs. ADHD) for clinicians' GADS Quotients (92%), and somewhat lower accuracy (77%) for parents' Quotients. Both children with high and low functioning autism had clinicians' Quotients (M=99 and 101, respectively) similar to the Asperger's Disorder mean of 100 for the GADS normative sample. Children with high functioning autism scored significantly higher on the cognitive patterns subscale than children with low functioning autism, and the latter had higher scores on the remaining subscales: social interaction, restricted patterns of behavior, and pragmatic skills. Using the clinicians' Quotient and Cognitive Patterns score, 70% of children were correctly identified as having high or low functioning autism or ADHD.

  7. IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation.

    PubMed

    Xi, Gang; Shen, Xinchun; Rosen, Clifford J; Clemmons, David R

    2016-06-01

    Insulin like growth factor I (IGF-I) and insulin like growth factor binding protein-2 (IGFBP-2) function coordinately to stimulate AKT and osteoblast differentiation. IGFBP-2 binding to receptor protein tyrosine phosphatase β (RPTPβ) stimulates polymerization and inactivation of phosphatase activity. Because phosphatase and tensin homolog (PTEN) is the primary target of RPTPβ, this leads to enhanced PTEN tyrosine phosphorylation and inactivation. However RPTPβ inactivation also requires IGF-I receptor activation. The current studies were undertaken to determine the mechanism by which IGF-I mediates changes in RPTPβ function in osteoblasts. IGFBP-2/IGF-I stimulated vimentin binding to RPTPβ and this was required for RPTPβ polymerization. Vimentin serine phosphorylation mediated its binding to RPTPβ and PKCζ was identified as the kinase that phosphorylated vimentin. To determine the mechanism underlying IGF-I stimulation of PKCζ-mediated vimentin phosphorylation, we focused on insulin receptor substrate-1 (IRS-1). IGF-I stimulated IRS-1 phosphorylation and recruitment of PKCζ and vimentin to phospho-IRS-1. IRS-1 immunoprecipitates containing PKCζ and vimentin were used to confirm that activated PKCζ directly phosphorylated vimentin. PKCζ does not contain a SH-2 domain that is required to bind to phospho-IRS-1. To determine the mechanism of PKCζ recruitment we analyzed the role of p62 (a PKCζ binding protein) that contains a SH2 domain. Exposure to differentiation medium plus IGF-I stimulated PKCζ/p62 association. Subsequent analysis showed the p62/PKCζ complex was co-recruited to IRS-1. Peptides that disrupted p62/PKCζ or p62/IRS-1 inhibited IGF-I/IGFBP-2 stimulated PKCζ activation, vimentin phosphorylation, PTEN tyrosine phosphorylation, AKT activation, and osteoblast differentiation. The importance of these signaling events for differentiation was confirmed in primary mouse calvarial osteoblasts. These results demonstrate the cooperative

  8. Linking differential domain functions of the GS3 protein to natural variation of grain size in rice.

    PubMed

    Mao, Hailiang; Sun, Shengyuan; Yao, Jialing; Wang, Chongrong; Yu, Sibin; Xu, Caiguo; Li, Xianghua; Zhang, Qifa

    2010-11-01

    Grain yield in many cereal crops is largely determined by grain size. Here we report the genetic and molecular characterization of GS3, a major quantitative trait locus for grain size. It functions as a negative regulator of grain size and organ size. The wild-type isoform is composed of four putative domains: a plant-specific organ size regulation (OSR) domain in the N terminus, a transmembrane domain, a tumor necrosis factor receptor/nerve growth factor receptor (TNFR/NGFR) family cysteine-rich domain, and a von Willebrand factor type C (VWFC) in the C terminus. These domains function differentially in grain size regulation. The OSR domain is both necessary and sufficient for functioning as a negative regulator. The wild-type allele corresponds to medium grain. Loss of function of OSR results in long grain. The C-terminal TNFR/NGFR and VWFC domains show an inhibitory effect on the OSR function; loss-of-function mutations of these domains produced very short grain. This study linked the functional domains of the GS3 protein to natural variation of grain size in rice. PMID:20974950

  9. Variation in trait trade-offs allows differentiation among predefined plant functional types: implications for predictive ecology.

    PubMed

    Verheijen, Lieneke M; Aerts, Rien; Bönisch, Gerhard; Kattge, Jens; Van Bodegom, Peter M

    2016-01-01

    Plant functional types (PFTs) aggregate the variety of plant species into a small number of functionally different classes. We examined to what extent plant traits, which reflect species' functional adaptations, can capture functional differences between predefined PFTs and which traits optimally describe these differences. We applied Gaussian kernel density estimation to determine probability density functions for individual PFTs in an n-dimensional trait space and compared predicted PFTs with observed PFTs. All possible combinations of 1-6 traits from a database with 18 different traits (total of 18 287 species) were tested. A variety of trait sets had approximately similar performance, and 4-5 traits were sufficient to classify up to 85% of the species into PFTs correctly, whereas this was 80% for a bioclimatically defined tree PFT classification. Well-performing trait sets included combinations of correlated traits that are considered functionally redundant within a single plant strategy. This analysis quantitatively demonstrates how structural differences between PFTs are reflected in functional differences described by particular traits. Differentiation between PFTs is possible despite large overlap in plant strategies and traits, showing that PFTs are differently positioned in multidimensional trait space. This study therefore provides the foundation for important applications for predictive ecology. PMID:26352461

  10. Deleted in breast cancer 1 plays a functional role in adipocyte differentiation.

    PubMed

    Moreno-Navarrete, José María; Moreno, María; Vidal, Marta; Ortega, Francisco; Serrano, Marta; Xifra, Gemma; Ricart, Wifredo; Fernández-Real, José Manuel

    2015-04-01

    Genetic deletion of Dbc1 in mice reduced adipose tissue senescence and inflammation while promoting an expansion of this tissue. Here, we aimed to investigate DBC1 mRNA and protein levels in human adipose tissue from subjects with a wide spectrum of fat mass (cohort 1; n = 105) and insulin resistance (cohort 2; n = 47); we also investigated the effects of DBC1 knockdown on 3T3-L1 adipocyte differentiation. DBC1 mRNA was relatively abundant in both visceral (VAT) and subcutaneous adipose tissue (SAT) (mainly in the adipocyte fraction), being decreased in adipose tissue from obese compared with lean subjects. In both VAT and SAT, DBC1 mRNA levels were negatively associated with BMI and positively associated with age and the expression of PPARγ, GLUT4, IRS1, lipogenic (FASN, ACACA), lipid droplet-associated genes (PLIN1, FSP27, ADRP, and TIP47), and lipolytic (ABDH5, AKAP, and PRKACA) genes but negatively associated with ADIPOQ in VAT. DBC1 mRNA and protein levels were increased in the early stages of adipocyte differentiation of human and 3T3-L1 adipocytes. Dbc1 knockdown (KD) with lentivirus led to enhanced adipocyte differentiation, increasing intracellular lipid accumulation and adipogenic gene expression. In conclusion, although DBC1 gene expression was reduced in adipose tissue from obese subjects, it was negatively associated with ADIPOQ gene expression in VAT, suggesting that DBC1 might promote visceral adipose tissue dysfunction. In vitro data supported the antiadipogenic effects of DBC1.

  11. Biotic homogenization and differentiation of soil faunal communities in the production forest landscape: taxonomic and functional perspectives.

    PubMed

    Mori, Akira S; Ota, Aino T; Fujii, Saori; Seino, Tatsuyuki; Kabeya, Daisuke; Okamoto, Toru; Ito, Masamichi T; Kaneko, Nobuhiro; Hasegawa, Motohiro

    2015-02-01

    Biotic homogenization has been reported worldwide. Although simplification of communities across space is often significant at larger scales, it could also occur at the local scale by changing biotic interactions. This study aimed to elucidate local community processes driving biotic homogenization of soil faunal communities, and the possibility of biotic re-differentiation. We recorded species of oribatid mites in litter and soil layers along a gradient of forest conversion from monoculture larch plantation to primary forests in central Japan. We collected data for functional traits of the recorded species to quantify functional diversity. Then we quantified their taxonomic/functional turnover. Litter diversity was reduced in the larch-dominated stands, leading to habitat homogenization. Consequently, litter communities were biologically homogenized and differentiated in the plantations and in the natural forest, respectively. Turnover of functional traits for litter communities was lower and higher than expected by chance in the plantations and in the natural stand, respectively. This result suggests that the dominant assembly process shifts from limiting similarity to habitat filtering along the forest restoration gradient. However, support for such niche-based explanations was not observed for communities in the soil layer. In the monocultures, functional diversity expected from a given regional species pool significantly decreased for litter communities but not for those in the soil layer. Such discrepancy between communities in different layers suggests that communities more exposed to anthropogenic stresses are more vulnerable to the loss of their functional roles. Our study explains possible community processes behind the observed patterns of biological organization, which can be potentially useful in guiding approaches for restoring biodiversity.

  12. Biotic homogenization and differentiation of soil faunal communities in the production forest landscape: taxonomic and functional perspectives.

    PubMed

    Mori, Akira S; Ota, Aino T; Fujii, Saori; Seino, Tatsuyuki; Kabeya, Daisuke; Okamoto, Toru; Ito, Masamichi T; Kaneko, Nobuhiro; Hasegawa, Motohiro

    2015-02-01

    Biotic homogenization has been reported worldwide. Although simplification of communities across space is often significant at larger scales, it could also occur at the local scale by changing biotic interactions. This study aimed to elucidate local community processes driving biotic homogenization of soil faunal communities, and the possibility of biotic re-differentiation. We recorded species of oribatid mites in litter and soil layers along a gradient of forest conversion from monoculture larch plantation to primary forests in central Japan. We collected data for functional traits of the recorded species to quantify functional diversity. Then we quantified their taxonomic/functional turnover. Litter diversity was reduced in the larch-dominated stands, leading to habitat homogenization. Consequently, litter communities were biologically homogenized and differentiated in the plantations and in the natural forest, respectively. Turnover of functional traits for litter communities was lower and higher than expected by chance in the plantations and in the natural stand, respectively. This result suggests that the dominant assembly process shifts from limiting similarity to habitat filtering along the forest restoration gradient. However, support for such niche-based explanations was not observed for communities in the soil layer. In the monocultures, functional diversity expected from a given regional species pool significantly decreased for litter communities but not for those in the soil layer. Such discrepancy between communities in different layers suggests that communities more exposed to anthropogenic stresses are more vulnerable to the loss of their functional roles. Our study explains possible community processes behind the observed patterns of biological organization, which can be potentially useful in guiding approaches for restoring biodiversity. PMID:25322821

  13. Lipid-binding properties of human ApoD and Lazarillo-related lipocalins: functional implications for cell differentiation.

    PubMed

    Ruiz, Mario; Sanchez, Diego; Correnti, Colin; Strong, Roland K; Ganfornina, Maria D

    2013-08-01

    Lipocalins are a family of proteins characterized by a conserved eight-stranded β-barrel structure with a ligand-binding pocket. They perform a wide range of biological functions and this functional multiplicity must relate to the lipid partner involved. Apolipoprotein D (ApoD) and its insect homologues, Lazarillo (Laz) and neural Lazarillo (NLaz), share common ancestral functions like longevity, stress resistance and lipid metabolism regulation, coexisting with very specialized functions, like courtship behavior. Using tryptophan fluorescence titration, we screened the binding of 15 potential lipid partners for NLaz, ApoD and Laz and uncovered several novel ligands with apparent dissociation constants in the low micromolar range. Retinoic acid (RA), retinol, fatty acids and sphingomyelin are shared ligands. Sterols, however, showed a species-specific binding pattern: cholesterol did not show strong binding to human ApoD, whereas NLaz and Laz did bind ergosterol. Among the lipocalin-specific ligands, we found that ApoD selectively binds the endocannabinoid anandamide but not 2-acylglycerol, and that NLaz binds the pheromone 7-tricosene, but not 7,11-heptacosadiene or 11-cis-vaccenyl acetate. To test the functional relevance of lipocalin ligand binding at the cellular level, we analyzed the effect of ApoD, Laz and NLaz preloaded with RA on neuronal differentiation. Our results show that ApoD is necessary and sufficient to allow for RA differentiating activity. Both human ApoD and Drosophila NLaz successfully deliver RA to immature neurons, driving neurite outgrowth. We conclude that ApoD, NLaz and Laz bind selectively to a different but overlapping set of lipid ligands. This multispecificity can explain their varied physiological functions.

  14. Differential effects of Hsc70 and Hsp70 on the intracellular trafficking and functional expression of epithelial sodium channels.

    PubMed

    Goldfarb, Samuel B; Kashlan, Ossama B; Watkins, Jeffrey N; Suaud, Laurence; Yan, Wusheng; Kleyman, Thomas R; Rubenstein, Ronald C

    2006-04-11

    The members of the cytoplasmic 70-kDa heat shock protein family are involved in appropriate folding and trafficking of newly synthesized proteins in the cell. Hsc70, which is expressed constitutively, and Hsp70, the expression of which is stress- and heat shock-induced, are often considered to have similar cellular functions in this regard, but there are suggestions that the intracellular functions of these homologous but not identical proteins may differ. We tested the hypothesis that Hsc70 and Hsp70 would have differential effects on the expression of the epithelial sodium channel (ENaC). In Xenopus oocytes, overexpression of human Hsc70 decreased the functional (defined as amiloride-sensitive whole-oocyte current) and surface expression of murine ENaC (mENaC) in a concentration-dependent fashion. In contrast, coinjection of a moderate amount of Hsp70 cRNA (10 ng) increased the functional and surface expression of mENaC, whereas a higher amount of coinjected Hsp70 cRNA (30 ng) decreased mENaC functional and surface expression. The increase in mENaC functional expression with coinjection of 10 ng of Hsp70 cRNA was antagonized by the additional coinjection of Hsc70 cRNA in a concentration-dependent fashion. These data are consistent with Hsc70 and Hsp70 having differential and antagonistic effects with regard to the intracellular trafficking of mENaC in oocytes, which may have an impact on our understanding and potential treatment of diseases of aberrant ion channel trafficking. PMID:16585520

  15. An Evolution-Based Screen for Genetic Differentiation between Anopheles Sister Taxa Enriches for Detection of Functional Immune Factors

    PubMed Central

    Takashima, Eizo; Williams, Marni; Eiglmeier, Karin; Pain, Adrien; Guelbeogo, Wamdaogo M.; Gneme, Awa; Brito-Fravallo, Emma; Holm, Inge; Lavazec, Catherine; Sagnon, N’Fale; Baxter, Richard H.; Riehle, Michelle M.; Vernick, Kenneth D.

    2015-01-01

    Nucleotide variation patterns across species are shaped by the processes of natural selection, including exposure to environmental pathogens. We examined patterns of genetic variation in two sister species, Anopheles gambiae and Anopheles coluzzii, both efficient natural vectors of human malaria in West Africa. We used the differentiation signature displayed by a known coordinate selective sweep of immune genes APL1 and TEP1 in A. coluzzii to design a population genetic screen trained on the sweep, classified a panel of 26 potential immune genes for concordance with the signature, and functionally tested their immune phenotypes. The screen results were strongly predictive for genes with protective immune phenotypes: genes meeting the screen criteria were significantly more likely to display a functional phenotype against malaria infection than genes not meeting the criteria (p = 0.0005). Thus, an evolution-based screen can efficiently prioritize candidate genes for labor-intensive downstream functional testing, and safely allow the elimination of genes not meeting the screen criteria. The suite of immune genes with characteristics similar to the APL1-TEP1 selective sweep appears to be more widespread in the A. coluzzii genome than previously recognized. The immune gene differentiation may be a consequence of adaptation of A. coluzzii to new pathogens encountered in its niche expansion during the separation from A. gambiae, although the role, if any of natural selection by Plasmodium is unknown. Application of the screen allowed identification of new functional immune factors, and assignment of new functions to known factors. We describe biochemical binding interactions between immune proteins that underlie functional activity for malaria infection, which highlights the interplay between pathogen specificity and the structure of immune complexes. We also find that most malaria-protective immune factors display phenotypes for either human or rodent malaria, with

  16. An Evolution-Based Screen for Genetic Differentiation between Anopheles Sister Taxa Enriches for Detection of Functional Immune Factors.

    PubMed

    Mitri, Christian; Bischoff, Emmanuel; Takashima, Eizo; Williams, Marni; Eiglmeier, Karin; Pain, Adrien; Guelbeogo, Wamdaogo M; Gneme, Awa; Brito-Fravallo, Emma; Holm, Inge; Lavazec, Catherine; Sagnon, N'Fale; Baxter, Richard H; Riehle, Michelle M; Vernick, Kenneth D

    2015-12-01

    Nucleotide variation patterns across species are shaped by the processes of natural selection, including exposure to environmental pathogens. We examined patterns of genetic variation in two sister species, Anopheles gambiae and Anopheles coluzzii, both efficient natural vectors of human malaria in West Africa. We used the differentiation signature displayed by a known coordinate selective sweep of immune genes APL1 and TEP1 in A. coluzzii to design a population genetic screen trained on the sweep, classified a panel of 26 potential immune genes for concordance with the signature, and functionally tested their immune phenotypes. The screen results were strongly predictive for genes with protective immune phenotypes: genes meeting the screen criteria were significantly more likely to display a functional phenotype against malaria infection than genes not meeting the criteria (p = 0.0005). Thus, an evolution-based screen can efficiently prioritize candidate genes for labor-intensive downstream functional testing, and safely allow the elimination of genes not meeting the screen criteria. The suite of immune genes with characteristics similar to the APL1-TEP1 selective sweep appears to be more widespread in the A. coluzzii genome than previously recognized. The immune gene differentiation may be a consequence of adaptation of A. coluzzii to new pathogens encountered in its niche expansion during the separation from A. gambiae, although the role, if any of natural selection by Plasmodium is unknown. Application of the screen allowed identification of new functional immune factors, and assignment of new functions to known factors. We describe biochemical binding interactions between immune proteins that underlie functional activity for malaria infection, which highlights the interplay between pathogen specificity and the structure of immune complexes. We also find that most malaria-protective immune factors display phenotypes for either human or rodent malaria, with

  17. Conserved role for the Drosophila Pax6 homolog Eyeless in differentiation and function of insulin-producing neurons

    PubMed Central

    Clements, Jason; Hens, Korneel; Francis, Carmen; Schellens, Ann; Callaerts, Patrick

    2008-01-01

    Insulin/insulin-like growth factor (IGF) signaling constitutes an evolutionarily conserved pathway that controls growth, energy homeostasis, and longevity. In Drosophila melanogaster, key components of this pathway are the insulin-like peptides (Dilps). The major source of Dilps is a cluster of large neurons in the brain, the insulin-producing cells (IPCs). The genetic control of IPC development and function is poorly understood. Here, we demonstrate that the Pax6 homolog Eyeless is required in the IPCs to control their differentiation and function. Loss of eyeless results in phenotypes associated with loss of insulin signaling, including decreased animal size and increased carbohydrate levels in larval hemolymph. We show that mutations in eyeless lead to defective differentiation and morphologically abnormal IPCs. We also demonstrate that Eyeless controls IPC function by the direct transcriptional control of one of the major Dilps, dilp5. We propose that Eyeless has an evolutionarily conserved role in IPCs with remarkable similarities to the role of vertebrate Pax6 in β cells of the pancreas. PMID:18852455

  18. Genome-wide Functional Analysis of Plasmodium Protein Phosphatases Reveals Key Regulators of Parasite Development and Differentiation

    PubMed Central

    Guttery, David S.; Poulin, Benoit; Ramaprasad, Abhinay; Wall, Richard J.; Ferguson, David J.P.; Brady, Declan; Patzewitz, Eva-Maria; Whipple, Sarah; Straschil, Ursula; Wright, Megan H.; Mohamed, Alyaa M.A.H.; Radhakrishnan, Anand; Arold, Stefan T.; Tate, Edward W.; Holder, Anthony A.; Wickstead, Bill; Pain, Arnab; Tewari, Rita

    2014-01-01

    Summary Reversible protein phosphorylation regulated by kinases and phosphatases controls many cellular processes. Although essential functions for the malaria parasite kinome have been reported, the roles of most protein phosphatases (PPs) during Plasmodium development are unknown. We report a functional analysis of the Plasmodium berghei protein phosphatome, which exhibits high conservation with the P. falciparum phosphatome and comprises 30 predicted PPs with differential and distinct expression patterns during various stages of the life cycle. Gene disruption analysis of P. berghei PPs reveals that half of the genes are likely essential for asexual blood stage development, whereas six are required for sexual development/sporogony in mosquitoes. Phenotypic screening coupled with transcriptome sequencing unveiled morphological changes and altered gene expression in deletion mutants of two N-myristoylated PPs. These findings provide systematic functional analyses of PPs in Plasmodium, identify how phosphatases regulate parasite development and differentiation, and can inform the identification of drug targets for malaria. PMID:25011111

  19. An Animal Model with a Cardiomyocyte-Specific Deletion of Estrogen Receptor Alpha: Functional, Metabolic, and Differential Network Analysis

    PubMed Central

    Devanathan, Sriram; Whitehead, Timothy; Schweitzer, George G.; Fettig, Nicole; Kovacs, Attila; Korach, Kenneth S.; Finck, Brian N.; Shoghi, Kooresh I.

    2014-01-01

    Estrogen exerts diverse biological effects in multiple tissues in both animals and humans. Much of the accumulated knowledge on the role of estrogen receptor (ER) in the heart has been obtained from studies using ovariectomized mice, whole body ER gene knock-out animal models, ex vivo heart studies, or from isolated cardiac myocytes. In light of the wide systemic influence of ER signaling in regulating a host of biological functions in multiple tissues, it is difficult to infer the direct role of ER on the heart. Therefore, we developed a mouse model with a cardiomyocyte-specific deletion of the ERα allele (cs-ERα−/−). Male and female cs-ERα−/− mice with age/sex-matched wild type controls were examined for differences in cardiac structure and function by echocardiogram and differential gene expression microarray analysis. Our study revealed sex-differences in structural parameters in the hearts of cs-ERα−/− mice, with minimal functional differences. Analysis of microarray data revealed differential variations in the expression of 208 genes affecting multiple transcriptional networks. Furthermore, we report sex-specific differences in the expression of 56 genes. Overall, we developed a mouse model with cardiac-specific deletion of ERα to characterize the role of ERα in the heart independent of systemic effects. Our results suggest that ERα is involved in controlling the expression of diverse genes and networks in the cardiomyocyte in a sex-dependent manner. PMID:25000186

  20. Functional characterization of retromer in GLUT4 storage vesicle formation and adipocyte differentiation.

    PubMed

    Yang, Zhe; Hong, Lee Kian; Follett, Jordan; Wabitsch, Martin; Hamilton, Nicholas A; Collins, Brett M; Bugarcic, Andrea; Teasdale, Rohan D

    2016-03-01

    Insulin-stimulated translocation of glucose transporter 4 (GLUT4) storage vesicles (GSVs), the specialized intracellular compartments within mature adipocytes, to the plasma membrane (PM) is a fundamental cellular process for maintaining glucose homeostasis. Using 2 independent adipocyte cell line models, human primary Simpson-Golabi-Behmel syndrome and mouse 3T3-L1 fibroblast cell lines, we demonstrate that the endosome-associated protein-sorting complex retromer colocalizes with GLUT4 on the GSVs by confocal microscopy in mature adipocytes. By use of both confocal microscopy and differential ultracentrifugation techniques, retromer is redistributed to the PM of mature adipocytes upon insulin stimulation. Furthermore, stable knockdown of the retromer subunit-vacuolar protein-sorting 35, or the retromer-associated protein sorting nexin 27, by lentivirus-delivered small hairpin RNA impaired the adipogenesis process when compared to nonsilence control. The knockdown of retromer decreased peroxisome proliferator activated receptor γ expression during differentiation, generating adipocytes with decreased levels of GSVs, lipid droplet accumulation, and insulin-stimulated glucose uptake. In conclusion, our study demonstrates a role for retromer in the GSV formation and adipogenesis. PMID:26581601