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Sample records for defines distinct functions

  1. Defining poverty as distinctively human

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    H.P.P. Lötter

    2007-05-01

    Full Text Available While it is relatively easy for most people to identify human beings suffering from poverty, it is rather more difficult to come to a proper understanding of poverty. In this article the author wants to deepen our understanding of poverty by interpreting the conventional definitions of poverty in a new light. The article starts with a defence of a claim that poverty is a concept uniquely applicable to humans. It then present a critical discussion of the distinction between absolute and relative poverty and it is then argued that a revision of this distinction can provide general standards applicable to humans everywhere.

  2. Memory Synapses Are Defined by Distinct Molecular Complexes: A Proposal.

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    Sossin, Wayne S

    2018-01-01

    Synapses are diverse in form and function. While there are strong evidential and theoretical reasons for believing that memories are stored at synapses, the concept of a specialized "memory synapse" is rarely discussed. Here, we review the evidence that memories are stored at the synapse and consider the opposing possibilities. We argue that if memories are stored in an active fashion at synapses, then these memory synapses must have distinct molecular complexes that distinguish them from other synapses. In particular, examples from Aplysia sensory-motor neuron synapses and synapses on defined engram neurons in rodent models are discussed. Specific hypotheses for molecular complexes that define memory synapses are presented, including persistently active kinases, transmitter receptor complexes and trans-synaptic adhesion proteins.

  3. Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells.

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    Velu, Vijayakumar; Mylvaganam, Geetha Hanna; Gangadhara, Sailaja; Hong, Jung Joo; Iyer, Smita S; Gumber, Sanjeev; Ibegbu, Chris C; Villinger, Francois; Amara, Rama Rao

    2016-09-01

    Chronic HIV infection is associated with accumulation of germinal center (GC) T follicular helper (Tfh) cells in the lymphoid tissue. The GC Tfh cells can be heterogeneous based on the expression of chemokine receptors associated with T helper lineages, such as CXCR3 (Th1), CCR4 (Th2), and CCR6 (Th17). However, the heterogeneous nature of GC Tfh cells in the lymphoid tissue and its association with viral persistence and Ab production during chronic SIV/HIV infection are not known. To address this, we characterized the expression of CXCR3, CCR4, and CCR6 on GC Tfh cells in lymph nodes following SIVmac251 infection in rhesus macaques. In SIV-naive rhesus macaques, only a small fraction of GC Tfh cells expressed CXCR3, CCR4, and CCR6. However, during chronic SIV infection, the majority of GC Tfh cells expressed CXCR3, whereas the proportion of CCR4(+) cells did not change, and CCR6(+) cells decreased. CXCR3(+), but not CXCR3(-), GC Tfh cells produced IFN-γ (Th1 cytokine) and IL-21 (Tfh cytokine), whereas both subsets expressed CD40L following stimulation. Immunohistochemistry analysis demonstrated an accumulation of CD4(+)IFN-γ(+) T cells within the hyperplastic follicles during chronic SIV infection. CXCR3(+) GC Tfh cells also expressed higher levels of ICOS, CCR5, and α4β7 and contained more copies of SIV DNA compared with CXCR3(-) GC Tfh cells. However, CXCR3(+) and CXCR3(-) GC Tfh cells delivered help to B cells in vitro for production of IgG. These data demonstrate that chronic SIV infection promotes expansion of Th1-biased GC Tfh cells, which are phenotypically and functionally distinct from conventional GC Tfh cells and contribute to hypergammaglobulinemia and viral reservoirs. Copyright © 2016 by The American Association of Immunologists, Inc.

  4. Plasma Cell Alloantigen 1 and IL-10 Secretion Define Two Distinct Peritoneal B1a B Cell Subsets With Opposite Functions, PC1high Cells Being Protective and PC1low Cells Harmful for the Growing Fetus

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    Anne Schumacher

    2018-05-01

    Full Text Available B cells possess various immuno regulatory functions. However, research about their participation in tolerance induction toward the fetus is just emerging. Accumulating evidence supports the idea that B cells can play seemingly conflicting roles during pregnancy, either protecting or harming the fetus. Previous findings indicated the presence of two different peritoneal B cell subsets, defined by the expression of the plasma cell alloantigen 1 (PC1 and with distinct immune modulatory functions. Here, we aimed to study the participation of these two B cell subsets, on pregnancy outcome in a murine model of disturbed fetal tolerance. The frequencies and cell numbers of peritoneal and splenic CD19+IL-10+ and CD19+CD5+IL-10+PC1+ cells were assessed in virgin as well as normal pregnant (NP and abortion-prone (AP females during the course of gestation. Peritoneal PC1low or PC1high B1a B cells were sorted, analyzed for their ability to secrete IL-10 and adoptively transferred into NP or AP females. On gestation day (gd 12, the abortion rate as well as the frequencies and cell numbers of regulatory T cells, TH1 and TH17 cells were determined in spleens and decidua. In addition, mRNA expression of IL-10, TGF-β, IFN-γ, and TNF-α was analyzed in decidual tissue. Peritoneal CD19+IL-10+ and CD19+CD5+IL-10+PC1+ frequencies fluctuated during the progression of normal pregnancies while no significant changes were observed in spleen. AP females showed significantly reduced frequencies of both B cell populations and exhibited an altered peritoneal PC1high/PC1low ratio at gd10. Adoptive transfers of PC1low B1a B cells into NP females increased the abortion rate in association with a reduced splenic regulatory T/TH17 ratio. By contrast, the transfer of PC1high B1a B cells into AP females significantly diminished the fetal rejection rate and significantly reduced the numbers of splenic TH17 cells. Our results suggest that the peritoneum harbors two distinct B1a B

  5. Distinct cardiac transcriptional profiles defining pregnancy and exercise.

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    Eunhee Chung

    Full Text Available BACKGROUND: Although the hypertrophic responses of the heart to pregnancy and exercise are both considered to be physiological processes, they occur in quite different hormonal and temporal settings. In this study, we have compared the global transcriptional profiles of left ventricular tissues at various time points during the progression of hypertrophy in exercise and pregnancy. METHODOLOGY/PRINCIPAL FINDINGS: The following groups of female mice were analyzed: non-pregnant diestrus cycle sedentary control, mid-pregnant, late-pregnant, and immediate-postpartum, and animals subjected to 7 and 21 days of voluntary wheel running. Hierarchical clustering analysis shows that while mid-pregnancy and both exercise groups share the closest relationship and similar gene ontology categories, late pregnancy and immediate post-partum are quite different with high representation of secreted/extracellular matrix-related genes. Moreover, pathway-oriented ontological analysis shows that metabolism regulated by cytochrome P450 and chemokine pathways are the most significant signaling pathways regulated in late pregnancy and immediate-postpartum, respectively. Finally, increases in expression of components of the proteasome observed in both mid-pregnancy and immediate-postpartum also result in enhanced proteasome activity. Interestingly, the gene expression profiles did not correlate with the degree of cardiac hypertrophy observed in the animal groups, suggesting that distinct pathways are employed to achieve similar amounts of cardiac hypertrophy. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that cardiac adaptation to the later stages of pregnancy is quite distinct from both mid-pregnancy and exercise. Furthermore, it is very dynamic since, by 12 hours post-partum, the heart has already initiated regression of cardiac growth, and 50 genes have changed expression significantly in the immediate-postpartum compared to late-pregnancy. Thus, pregnancy

  6. Normal Functions As A New Way Of Defining Computable Functions

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    Leszek Dubiel

    2004-01-01

    Full Text Available Report sets new method of defining computable functions. This is formalization of traditional function descriptions, so it allows to define functions in very intuitive way. Discovery of Ackermann function proved that not all functions that can be easily computed can be so easily described with Hilbert’s system of recursive functions. Normal functions lack this disadvantage.

  7. Normal Functions as a New Way of Defining Computable Functions

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    Leszek Dubiel

    2004-01-01

    Full Text Available Report sets new method of defining computable functions. This is formalization of traditional function descriptions, so it allows to define functions in very intuitive way. Discovery of Ackermann function proved that not all functions that can be easily computed can be so easily described with Hilbert's system of recursive functions. Normal functions lack this disadvantage.

  8. Spaces defined by the Paley function

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    Astashkin, S V [Samara State University, Samara (Russian Federation); Semenov, E M [Voronezh State University, Faculty of Mathematics, Voronezh (Russian Federation)

    2013-07-31

    The paper is concerned with Haar and Rademacher series in symmetric spaces, and also with the properties of spaces defined by the Paley function. In particular, the symmetric hull of the space of functions with uniformly bounded Paley function is found. Bibliography: 27 titles.

  9. Defining functional distances over Gene Ontology

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    del Pozo Angela

    2008-01-01

    Full Text Available Abstract Background A fundamental problem when trying to define the functional relationships between proteins is the difficulty in quantifying functional similarities, even when well-structured ontologies exist regarding the activity of proteins (i.e. 'gene ontology' -GO-. However, functional metrics can overcome the problems in the comparing and evaluating functional assignments and predictions. As a reference of proximity, previous approaches to compare GO terms considered linkage in terms of ontology weighted by a probability distribution that balances the non-uniform 'richness' of different parts of the Direct Acyclic Graph. Here, we have followed a different approach to quantify functional similarities between GO terms. Results We propose a new method to derive 'functional distances' between GO terms that is based on the simultaneous occurrence of terms in the same set of Interpro entries, instead of relying on the structure of the GO. The coincidence of GO terms reveals natural biological links between the GO functions and defines a distance model Df which fulfils the properties of a Metric Space. The distances obtained in this way can be represented as a hierarchical 'Functional Tree'. Conclusion The method proposed provides a new definition of distance that enables the similarity between GO terms to be quantified. Additionally, the 'Functional Tree' defines groups with biological meaning enhancing its utility for protein function comparison and prediction. Finally, this approach could be for function-based protein searches in databases, and for analysing the gene clusters produced by DNA array experiments.

  10. Embarrassment: its distinct form and appeasement functions.

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    Keltner, D; Buswell, B N

    1997-11-01

    The authors address 2 questions about embarrassment. First, Is embarrassment a distinct emotion? The evidence indicates that the antecedents, experience, and display of embarrassment, and to a limited extent its autonomic physiology, are distinct from shame, guilt, and amusement and share the dynamic, temporal characteristics of emotion. Second, What are the theoretical accounts of embarrassment? Three accounts focus on the causes of embarrassment, positioning that it follows the loss of self-esteem, concern for others' evaluations, or absence of scripts to guide interactions. A fourth account focuses on the effects of the remedial actions of embarrassment, which correct preceding transgressions. A fifth account focuses on the functional parallels between embarrassment and nonhuman appeasement. The discussion focuses on unanswered questions about embarrassment.

  11. MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression.

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    Christopher R Shaler

    2017-06-01

    Full Text Available Superantigens (SAgs are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS. Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections. Unlike in mouse models, the mechanisms underlying SAg-associated immunosuppression in humans are ill-defined. In this work, we have identified a population of innate-like T cells, called mucosa-associated invariant T (MAIT cells, as the most powerful source of pro-inflammatory cytokines after exposure to SAgs. We have utilized primary human peripheral blood and hepatic mononuclear cells, mouse MAIT hybridoma lines, HLA-DR4-transgenic mice, MAIThighHLA-DR4+ bone marrow chimeras, and humanized NOD-scid IL-2Rγnull mice to demonstrate for the first time that: i mouse and human MAIT cells are hyperresponsive to SAgs, typified by staphylococcal enterotoxin B (SEB; ii the human MAIT cell response to SEB is rapid and far greater in magnitude than that launched by unfractionated conventional T, invariant natural killer T (iNKT or γδ T cells, and is characterized by production of interferon (IFN-γ, tumor necrosis factor (TNF-α and interleukin (IL-2, but not IL-17A; iii high-affinity MHC class II interaction with SAgs, but not MHC-related protein 1 (MR1 participation, is required for MAIT cell activation; iv MAIT cell responses to SEB can occur in a T cell receptor (TCR Vβ-specific manner but are largely contributed by IL-12 and IL-18; v as MAIT cells are primed by SAgs, they also begin to

  12. On functions defined by sums of products of Bessel functions

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    Martin, P A

    2008-01-01

    Various functions, defined as infinite series of products of Bessel functions of the first kind, are studied. Integral representations are obtained, and then used to deduce asymptotic approximations. Although several methods have been investigated (including power series expansions and integral transforms), methods based on Fourier series emerge as the most useful

  13. Defining functional dyspepsia Definiendo la dispepsia funcional

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    Fermín Mearin

    2011-12-01

    Full Text Available Dyspepsia and functional dyspepsia represent a highly significant public health issue. A good definition of dyspepsia is key for helping us to better approach symptoms, decision making, and therapy indications. During the last few years many attempts were made at establishing a definition of dyspepsia. Results were little successful on most occasions, and clear discrepancies arose on whether symptoms should be associated with digestion, which types of symptoms were to be included, which anatomic location should symptoms have, etc. The Rome III Committee defined dyspepsia as "a symptom or set of symptoms that most physicians consider to originate from the gastroduodenal area", including the following: postprandial heaviness, early satiety, and epigastric pain or burning. Two new entities were defined: a food-induced dyspeptic symptoms (postprandial distress syndrome; and b epigastric pain (epigastric pain syndrome. These and other definitions have shown both strengths and weaknesses. At times they have been much too complex, at times much too simple; furthermore, they have commonly erred on the side of being inaccurate and impractical. On the other hand, some (the most recent ones are difficult to translate into the Spanish language. In a meeting of gastroenterologists with a special interest in digestive functional disorders, the various aspects of dyspepsia definition were discussed and put to the vote, and the following conclusions were arrived at: dyspepsia is defined as a set of symptoms, either related or unrelated to food ingestion, localized on the upper half of the abdomen. They include: a epigastric discomfort (as a category of severity or pain; b postprandial heaviness; and c early satiety. Associated complaints include: nausea, belching, bloating, and epigastric burn (heartburn. All these must be scored according to severity and frequency. Furthermore, psychological factors may be involved in the origin of functional dyspepsia. On the

  14. Wigner functions defined with Laplace transform kernels.

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    Oh, Se Baek; Petruccelli, Jonathan C; Tian, Lei; Barbastathis, George

    2011-10-24

    We propose a new Wigner-type phase-space function using Laplace transform kernels--Laplace kernel Wigner function. Whereas momentum variables are real in the traditional Wigner function, the Laplace kernel Wigner function may have complex momentum variables. Due to the property of the Laplace transform, a broader range of signals can be represented in complex phase-space. We show that the Laplace kernel Wigner function exhibits similar properties in the marginals as the traditional Wigner function. As an example, we use the Laplace kernel Wigner function to analyze evanescent waves supported by surface plasmon polariton. © 2011 Optical Society of America

  15. NAC transcription factors: structurally distinct, functionally diverse

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    Olsen, Addie Nina; Ernst, Heidi A; Leggio, Leila Lo

    2005-01-01

    level and localization, and to the first indications of NAC participation in transcription factor networks. The recent determination of the DNA and protein binding NAC domain structure offers insight into the molecular functions of the protein family. Research into NAC transcription factors has......NAC proteins constitute one of the largest families of plant-specific transcription factors, and the family is present in a wide range of land plants. Here, we summarize the biological and molecular functions of the NAC family, paying particular attention to the intricate regulation of NAC protein...

  16. Defining Functions of Danish Political Commentary

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    Bengtsson, Mette

    2011-01-01

    In Denmark political commentary is still a relatively new phenomenon. This paper analyzes the metadiscourse in relation to political commentary to identify the different understandings that have coalesced around political commentary as a genre. I argue that people in different positions (e.......g. citizens, politicians, journalists, political editors, chief editors and political commentators themselves) emphasize different explanations for the rise of the genre and thereby functions of political commentary as part of an argumentative strategy favouring their own interests...

  17. Three distinct subsets of thymic epithelial cells in rats and mice defined by novel antibodies.

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    Yasushi Sawanobori

    Full Text Available Thymic epithelial cells (TECs are thought to play an essential role in T cell development and have been detected mainly in mice using lectin binding and antibodies to keratins. Our aim in the present study was to create a precise map of rat TECs using antibodies to putative markers and novel monoclonal antibodies (i.e., ED 18/19/21 and anti-CD205 antibodies and compare it with a map from mouse counterparts and that of rat thymic dendritic cells.Rat TECs were subdivided on the basis of phenotype into three subsets; ED18+ED19+/-keratin 5 (K5+K8+CD205+ class II MHC (MHCII+ cortical TECs (cTECs, ED18+ED21-K5-K8+Ulex europaeus lectin 1 (UEA-1+CD205- medullary TECs (mTEC1s, and ED18+ED21+K5+K8dullUEA-1-CD205- medullary TECs (mTEC2s. Thymic nurse cells were defined in cytosmears as an ED18+ED19+/-K5+K8+ subset of cTECs. mTEC1s preferentially expressed MHCII, claudin-3, claudin-4, and autoimmune regulator (AIRE. Use of ED18 and ED21 antibodies revealed three subsets of TECs in mice as well. We also detected two distinct TEC-free areas in the subcapsular cortex and in the medulla. Rat dendritic cells in the cortex were MHCII+CD103+ but negative for TEC markers, including CD205. Those in the medulla were MHCII+CD103+ and CD205+ cells were found only in the TEC-free area.Both rats and mice have three TEC subsets with similar phenotypes that can be identified using known markers and new monoclonal antibodies. These findings will facilitate further analysis of TEC subsets and DCs and help to define their roles in thymic selection and in pathological states such as autoimmune disorders.

  18. MicroRNAs define distinct human neuroblastoma cell phenotypes and regulate their differentiation and tumorigenicity

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    Samaraweera, Leleesha; Grandinetti, Kathryn B; Huang, Ruojun; Spengler, Barbara A; Ross, Robert A

    2014-01-01

    Neuroblastoma (NB) is the most common extracranial solid tumor in children. NB tumors and derived cell lines are phenotypically heterogeneous. Cell lines are classified by phenotype, each having distinct differentiation and tumorigenic properties. The neuroblastic phenotype is tumorigenic, has neuronal features and includes stem cells (I-cells) and neuronal cells (N-cells). The non-neuronal phenotype (S-cell) comprises cells that are non-tumorigenic with features of glial/smooth muscle precursor cells. This study identified miRNAs associated with each distinct cell phenotypes and investigated their role in regulating associated differentiation and tumorigenic properties. A miRNA microarray was performed on the three cell phenotypes and expression verified by qRT-PCR. miRNAs specific for certain cell phenotypes were modulated using miRNA inhibitors or stable transfection. Neuronal differentiation was induced by RA; non-neuronal differentiation by BrdU. Changes in tumorigenicity were assayed by soft agar colony forming ability. N-myc binding to miR-375 promoter was assayed by chromatin-immunoprecipitation. Unsupervised hierarchical clustering of miRNA microarray data segregated neuroblastic and non-neuronal cell lines and showed that specific miRNAs define each phenotype. qRT-PCR validation confirmed that increased levels of miR-21, miR-221 and miR-335 are associated with the non-neuronal phenotype, whereas increased levels of miR-124 and miR-375 are exclusive to neuroblastic cells. Downregulation of miR-335 in non-neuronal cells modulates expression levels of HAND1 and JAG1, known modulators of neuronal differentiation. Overexpression of miR-124 in stem cells induces terminal neuronal differentiation with reduced malignancy. Expression of miR-375 is exclusive for N-myc-expressing neuroblastic cells and is regulated by N-myc. Moreover, miR-375 downregulates expression of the neuronal-specific RNA binding protein HuD. Thus, miRNAs define distinct NB cell phenotypes

  19. PKH26 staining defines distinct subsets of normal human colon epithelial cells at different maturation stages.

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    Anna Pastò

    Full Text Available BACKGROUND AND AIM: Colon crypts are characterized by a hierarchy of cells distributed along the crypt axis. Aim of this paper was to develop an in vitro system for separation of epithelial cell subsets in different maturation stages from normal human colon. METHODOLOGY AND MAJOR FINDINGS: Dissociated colonic epithelial cells were stained with PKH26, which allows identification of distinct populations based on their proliferation rate, and cultured in vitro in the absence of serum. The cytofluorimetric expression of CK20, Msi-1 and Lgr5 was studied. The mRNA levels of several stemness-associated genes were also compared in cultured cell populations and in three colon crypt populations isolated by microdissection. A PKH(pos population survived in culture and formed spheroids; this population included subsets with slow (PKH(high and rapid (PKH(low replicative rates. Molecular analysis revealed higher mRNA levels of both Msi-1 and Lgr-5 in PKH(high cells; by cytofluorimetric analysis, Msi-1(+/Lgr5(+ cells were only found within PKH(high cells, whereas Msi-1(+/Lgr5(- cells were also observed in the PKH(low population. As judged by qRT-PCR analysis, the expression of several stemness-associated markers (Bmi-1, EphB2, EpCAM, ALDH1 was highly enriched in Msi-1(+/Lgr5(+ cells. While CK20 expression was mainly found in PKH(low and PKH(neg cells, a small PKH(high subset co-expressed both CK20 and Msi-1, but not Lgr5; cells with these properties also expressed Mucin, and could be identified in vivo in colon crypts. These results mirrored those found in cells isolated from different crypt portions by microdissection, and based on proliferation rates and marker expression they allowed to define several subsets at different maturation stages: PKH(high/Lgr5(+/Msi-1(+/CK20(-, PKH(high/Lgr5(-/Msi-1(+/CK20(+, PKH(low/Lgr5(-/Msi-1(+/Ck20(-, and PKH(low/Lgr5(-/Msi-1(-/CK20(+ cells. CONCLUSIONS: Our data show the possibility of deriving in vitro, without any

  20. DEFINE: A Service-Oriented Dynamically Enabling Function Model

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    Tan Wei-Yi

    2017-01-01

    In this paper, we introduce an innovative Dynamically Enable Function In Network Equipment (DEFINE to allow tenant get the network service quickly. First, DEFINE decouples an application into different functional components, and connects these function components in a reconfigurable method. Second, DEFINE provides a programmable interface to the third party, who can develop their own processing modules according to their own needs. To verify the effectiveness of this model, we set up an evaluating network with a FPGA-based OpenFlow switch prototype, and deployed several applications on it. Our results show that DEFINE has excellent flexibility and performance.

  1. Reliability, Dimensionality, and Internal Consistency as Defined by Cronbach: Distinct Albeit Related Concepts

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    Davenport, Ernest C.; Davison, Mark L.; Liou, Pey-Yan; Love, Quintin U.

    2015-01-01

    This article uses definitions provided by Cronbach in his seminal paper for coefficient a to show the concepts of reliability, dimensionality, and internal consistency are distinct but interrelated. The article begins with a critique of the definition of reliability and then explores mathematical properties of Cronbach's a. Internal consistency…

  2. Distinct gene regulatory programs define the inhibitory effects of liver X receptors and PPARG on cancer cell proliferation.

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    Savic, Daniel; Ramaker, Ryne C; Roberts, Brian S; Dean, Emma C; Burwell, Todd C; Meadows, Sarah K; Cooper, Sara J; Garabedian, Michael J; Gertz, Jason; Myers, Richard M

    2016-07-11

    The liver X receptors (LXRs, NR1H2 and NR1H3) and peroxisome proliferator-activated receptor gamma (PPARG, NR1C3) nuclear receptor transcription factors (TFs) are master regulators of energy homeostasis. Intriguingly, recent studies suggest that these metabolic regulators also impact tumor cell proliferation. However, a comprehensive temporal molecular characterization of the LXR and PPARG gene regulatory responses in tumor cells is still lacking. To better define the underlying molecular processes governing the genetic control of cellular growth in response to extracellular metabolic signals, we performed a comprehensive, genome-wide characterization of the temporal regulatory cascades mediated by LXR and PPARG signaling in HT29 colorectal cancer cells. For this analysis, we applied a multi-tiered approach that incorporated cellular phenotypic assays, gene expression profiles, chromatin state dynamics, and nuclear receptor binding patterns. Our results illustrate that the activation of both nuclear receptors inhibited cell proliferation and further decreased glutathione levels, consistent with increased cellular oxidative stress. Despite a common metabolic reprogramming, the gene regulatory network programs initiated by these nuclear receptors were widely distinct. PPARG generated a rapid and short-term response while maintaining a gene activator role. By contrast, LXR signaling was prolonged, with initial, predominantly activating functions that transitioned to repressive gene regulatory activities at late time points. Through the use of a multi-tiered strategy that integrated various genomic datasets, our data illustrate that distinct gene regulatory programs elicit common phenotypic effects, highlighting the complexity of the genome. These results further provide a detailed molecular map of metabolic reprogramming in cancer cells through LXR and PPARG activation. As ligand-inducible TFs, these nuclear receptors can potentially serve as attractive therapeutic

  3. Distinct projection targets define subpopulations of mouse brainstem vagal neurons that express the autism-associated MET receptor tyrosine kinase.

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    Kamitakahara, Anna; Wu, Hsiao-Huei; Levitt, Pat

    2017-12-15

    Detailed anatomical tracing and mapping of the viscerotopic organization of the vagal motor nuclei has provided insight into autonomic function in health and disease. To further define specific cellular identities, we paired information based on visceral connectivity with a cell-type specific marker of a subpopulation of neurons in the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (nAmb) that express the autism-associated MET receptor tyrosine kinase. As gastrointestinal disturbances are common in children with autism spectrum disorder (ASD), we sought to define the relationship between MET-expressing (MET+) neurons in the DMV and nAmb, and the gastrointestinal tract. Using wholemount tissue staining and clearing, or retrograde tracing in a MET EGFP transgenic mouse, we identify three novel subpopulations of EGFP+ vagal brainstem neurons: (a) EGFP+ neurons in the nAmb projecting to the esophagus or laryngeal muscles, (b) EGFP+ neurons in the medial DMV projecting to the stomach, and (b) EGFP+ neurons in the lateral DMV projecting to the cecum and/or proximal colon. Expression of the MET ligand, hepatocyte growth factor (HGF), by tissues innervated by vagal motor neurons during fetal development reveal potential sites of HGF-MET interaction. Furthermore, similar cellular expression patterns of MET in the brainstem of both the mouse and nonhuman primate suggests that MET expression at these sites is evolutionarily conserved. Together, the data suggest that MET+ neurons in the brainstem vagal motor nuclei are anatomically positioned to regulate distinct portions of the gastrointestinal tract, with implications for the pathophysiology of gastrointestinal comorbidities of ASD. © 2017 Wiley Periodicals, Inc.

  4. Two distinct forms of functional lateralization in the human brain

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    Gotts, Stephen J.; Jo, Hang Joon; Wallace, Gregory L.; Saad, Ziad S.; Cox, Robert W.; Martin, Alex

    2013-01-01

    The hemispheric lateralization of certain faculties in the human brain has long been held to be beneficial for functioning. However, quantitative relationships between the degree of lateralization in particular brain regions and the level of functioning have yet to be established. Here we demonstrate that two distinct forms of functional lateralization are present in the left vs. the right cerebral hemisphere, with the left hemisphere showing a preference to interact more exclusively with itself, particularly for cortical regions involved in language and fine motor coordination. In contrast, right-hemisphere cortical regions involved in visuospatial and attentional processing interact in a more integrative fashion with both hemispheres. The degree of lateralization present in these distinct systems selectively predicted behavioral measures of verbal and visuospatial ability, providing direct evidence that lateralization is associated with enhanced cognitive ability. PMID:23959883

  5. On the analytic continuation of functions defined by Legendre series

    International Nuclear Information System (INIS)

    Grinstein, F.F.

    1981-07-01

    An infinite diagonal sequence of Punctual Pade Approximants is considered for the approximate analytical continuation of a function defined by a formal Legendre series. The technique is tested in the case of two series with exactly known analytical sum: the generating function for Legendre polynomials and the Coulombian scattering amplitude. (author)

  6. New approach to equipment quality evaluation method with distinct functions

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    Milisavljević Vladimir M.

    2016-01-01

    Full Text Available The paper presents new approach for improving method for quality evaluation and selection of equipment (devices and machinery by applying distinct functions. Quality evaluation and selection of devices and machinery is a multi-criteria problem which involves the consideration of numerous parameters of various origins. Original selection method with distinct functions is based on technical parameters with arbitrary evaluation of each parameter importance (weighting. Improvement of this method, presented in this paper, addresses the issue of weighting of parameters by using Delphi Method. Finally, two case studies are provided, which included quality evaluation of standard boilers for heating and evaluation of load-haul-dump (LHD machines, to demonstrate applicability of this approach. Analytical Hierarchical Process (AHP is used as a control method.

  7. Defining mental disorder. Exploring the 'natural function' approach

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    Varga Somogy

    2011-01-01

    Full Text Available Abstract Due to several socio-political factors, to many psychiatrists only a strictly objective definition of mental disorder, free of value components, seems really acceptable. In this paper, I will explore a variant of such an objectivist approach to defining metal disorder, natural function objectivism. Proponents of this approach make recourse to the notion of natural function in order to reach a value-free definition of mental disorder. The exploration of Christopher Boorse's 'biostatistical' account of natural function (1 will be followed an investigation of the 'hybrid naturalism' approach to natural functions by Jerome Wakefield (2. In the third part, I will explore two proposals that call into question the whole attempt to define mental disorder (3. I will conclude that while 'natural function objectivism' accounts fail to provide the backdrop for a reliable definition of mental disorder, there is no compelling reason to conclude that a definition cannot be achieved.

  8. Defining mental disorder. Exploring the 'natural function' approach.

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    Varga, Somogy

    2011-01-21

    Due to several socio-political factors, to many psychiatrists only a strictly objective definition of mental disorder, free of value components, seems really acceptable. In this paper, I will explore a variant of such an objectivist approach to defining metal disorder, natural function objectivism. Proponents of this approach make recourse to the notion of natural function in order to reach a value-free definition of mental disorder. The exploration of Christopher Boorse's 'biostatistical' account of natural function (1) will be followed an investigation of the 'hybrid naturalism' approach to natural functions by Jerome Wakefield (2). In the third part, I will explore two proposals that call into question the whole attempt to define mental disorder (3). I will conclude that while 'natural function objectivism' accounts fail to provide the backdrop for a reliable definition of mental disorder, there is no compelling reason to conclude that a definition cannot be achieved.

  9. Natural Microbial Assemblages Reflect Distinct Organismal and Functional Partitioning

    Science.gov (United States)

    Wilmes, P.; Andersson, A.; Kalnejais, L. H.; Verberkmoes, N. C.; Lefsrud, M. G.; Wexler, M.; Singer, S. W.; Shah, M.; Bond, P. L.; Thelen, M. P.; Hettich, R. L.; Banfield, J. F.

    2007-12-01

    The ability to link microbial community structure to function has long been a primary focus of environmental microbiology. With the advent of community genomic and proteomic techniques, along with advances in microscopic imaging techniques, it is now possible to gain insights into the organismal and functional makeup of microbial communities. Biofilms growing within highly acidic solutions inside the Richmond Mine (Iron Mountain, Redding, California) exhibit distinct macro- and microscopic morphologies. They are composed of microorganisms belonging to the three domains of life, including archaea, bacteria and eukarya. The proportion of each organismal type depends on sampling location and developmental stage. For example, mature biofilms floating on top of acid mine drainage (AMD) pools exhibit layers consisting of a densely packed bottom layer of the chemoautolithotroph Leptospirillum group II, a less dense top layer composed mainly of archaea, and fungal filaments spanning across the entire biofilm. The expression of cytochrome 579 (the most highly abundant protein in the biofilm, believed to be central to iron oxidation and encoded by Leptospirillum group II) is localized at the interface of the biofilm with the AMD solution, highlighting that biofilm architecture is reflected at the functional gene expression level. Distinct functional partitioning is also apparent in a biological wastewater treatment system that selects for distinct polyphosphate accumulating organisms. Community genomic data from " Candidatus Accumulibacter phosphatis" dominated activated sludge has enabled high mass-accuracy shotgun proteomics for identification of key metabolic pathways. Comprehensive genome-wide alignment of orthologous proteins suggests distinct partitioning of protein variants involved in both core-metabolism and specific metabolic pathways among the dominant population and closely related species. In addition, strain- resolved proteogenomic analysis of the AMD biofilms

  10. Extracellular signals that define distinct and coexisting cell fates in Bacillus subtilis.

    Science.gov (United States)

    López, Daniel; Kolter, Roberto

    2010-03-01

    The soil-dwelling bacterium Bacillus subtilis differentiates into distinct subpopulations of specialized cells that coexist within highly structured communities. The coordination and interplay between these cell types requires extensive extracellular communication driven mostly by sensing self-generated secreted signals. These extracellular signals activate a set of sensor kinases, which respond by phosphorylating three major regulatory proteins, Spo0A, DegU and ComA. Each phosphorylated regulator triggers a specific differentiation program while at the same time repressing other differentiation programs. This allows a cell to differentiate in response to a specific cue, even in the presence of other, possibly conflicting, signals. The sensor kinases involved respond to an eclectic group of extracellular signals, such as quorum-sensing molecules, natural products, temperature, pH or scarcity of nutrients. This article reviews the cascades of cell differentiation pathways that are triggered by sensing extracellular signals. We also present a tentative developmental model in which the diverse cell types sequentially differentiate to achieve the proper development of the bacterial community.

  11. Distinct forms of mitochondrial TOM-TIM supercomplexes define signal-dependent states of preprotein sorting.

    Science.gov (United States)

    Chacinska, Agnieszka; van der Laan, Martin; Mehnert, Carola S; Guiard, Bernard; Mick, David U; Hutu, Dana P; Truscott, Kaye N; Wiedemann, Nils; Meisinger, Chris; Pfanner, Nikolaus; Rehling, Peter

    2010-01-01

    Mitochondrial import of cleavable preproteins occurs at translocation contact sites, where the translocase of the outer membrane (TOM) associates with the presequence translocase of the inner membrane (TIM23) in a supercomplex. Different views exist on the mechanism of how TIM23 mediates preprotein sorting to either the matrix or inner membrane. On the one hand, two TIM23 forms were proposed, a matrix transport form containing the presequence translocase-associated motor (PAM; TIM23-PAM) and a sorting form containing Tim21 (TIM23(SORT)). On the other hand, it was reported that TIM23 and PAM are permanently associated in a single-entity translocase. We have accumulated distinct transport intermediates of preproteins to analyze the translocases in their active, preprotein-carrying state. We identified two different forms of active TOM-TIM23 supercomplexes, TOM-TIM23(SORT) and TOM-TIM23-PAM. These two supercomplexes do not represent separate pathways but are in dynamic exchange during preprotein translocation and sorting. Depending on the signals of the preproteins, switches between the different forms of supercomplex and TIM23 are required for the completion of preprotein import.

  12. Using greenhouse gas fluxes to define soil functional types

    Energy Technology Data Exchange (ETDEWEB)

    Petrakis, Sandra; Barba, Josep; Bond-Lamberty, Ben; Vargas, Rodrigo

    2017-12-04

    Soils provide key ecosystem services and directly control ecosystem functions; thus, there is a need to define the reference state of soil functionality. Most common functional classifications of ecosystems are vegetation-centered and neglect soil characteristics and processes. We propose Soil Functional Types (SFTs) as a conceptual approach to represent and describe the functionality of soils based on characteristics of their greenhouse gas (GHG) flux dynamics. We used automated measurements of CO2, CH4 and N2O in a forested area to define SFTs following a simple statistical framework. This study supports the hypothesis that SFTs provide additional insights on the spatial variability of soil functionality beyond information represented by commonly measured soil parameters (e.g., soil moisture, soil temperature, litter biomass). We discuss the implications of this framework at the plot-scale and the potential of this approach at larger scales. This approach is a first step to provide a framework to define SFTs, but a community effort is necessary to harmonize any global classification for soil functionality. A global application of the proposed SFT framework will only be possible if there is a community-wide effort to share data and create a global database of GHG emissions from soils.

  13. User defined function for transformation of ellipsoidal coordinates

    Directory of Open Access Journals (Sweden)

    Ganić Aleksandar

    2014-01-01

    Full Text Available The topographic plane of the Earth has irregular shape, and for the purpose of mathematical defining, it is to be approximated by rotational ellipsoid. As local geodetic datum, rotational ellipsoids of various sizes are used in the world. More widely usage of the GPS while performing surveying tasks has resulted in the need to define global geodetic datum in order to obtain the best approximation the entire Earth. For this purpose, geocentric rotational ellipsoid WGS84 was defined and the results of the GPS measurements are shown in relation to it. By applying the appropriate equations, the ellipsoidal coordinates are being transformed from WGS84 into the coordinates on the local rotational ellipsoid, i.e. on the view plane. The paper shows User Defined Function created for Excel, by which the coordinates in the territory of Belgrade are being transformed from WGS84 of rotational ellipsoid into the Gauss-Krüger projection plane.

  14. Distinct retroelement classes define evolutionary breakpoints demarcating sites of evolutionary novelty

    Science.gov (United States)

    Longo, Mark S; Carone, Dawn M; Green, Eric D; O'Neill, Michael J; O'Neill, Rachel J

    2009-01-01

    Background Large-scale genome rearrangements brought about by chromosome breaks underlie numerous inherited diseases, initiate or promote many cancers and are also associated with karyotype diversification during species evolution. Recent research has shown that these breakpoints are nonrandomly distributed throughout the mammalian genome and many, termed "evolutionary breakpoints" (EB), are specific genomic locations that are "reused" during karyotypic evolution. When the phylogenetic trajectory of orthologous chromosome segments is considered, many of these EB are coincident with ancient centromere activity as well as new centromere formation. While EB have been characterized as repeat-rich regions, it has not been determined whether specific sequences have been retained during evolution that would indicate previous centromere activity or a propensity for new centromere formation. Likewise, the conservation of specific sequence motifs or classes at EBs among divergent mammalian taxa has not been determined. Results To define conserved sequence features of EBs associated with centromere evolution, we performed comparative sequence analysis of more than 4.8 Mb within the tammar wallaby, Macropus eugenii, derived from centromeric regions (CEN), euchromatic regions (EU), and an evolutionary breakpoint (EB) that has undergone convergent breakpoint reuse and past centromere activity in marsupials. We found a dramatic enrichment for long interspersed nucleotide elements (LINE1s) and endogenous retroviruses (ERVs) and a depletion of short interspersed nucleotide elements (SINEs) shared between CEN and EBs. We analyzed the orthologous human EB (14q32.33), known to be associated with translocations in many cancers including multiple myelomas and plasma cell leukemias, and found a conserved distribution of similar repetitive elements. Conclusion Our data indicate that EBs tracked within the class Mammalia harbor sequence features retained since the divergence of marsupials

  15. Distinct retroelement classes define evolutionary breakpoints demarcating sites of evolutionary novelty

    Directory of Open Access Journals (Sweden)

    Green Eric D

    2009-07-01

    Full Text Available Abstract Background Large-scale genome rearrangements brought about by chromosome breaks underlie numerous inherited diseases, initiate or promote many cancers and are also associated with karyotype diversification during species evolution. Recent research has shown that these breakpoints are nonrandomly distributed throughout the mammalian genome and many, termed "evolutionary breakpoints" (EB, are specific genomic locations that are "reused" during karyotypic evolution. When the phylogenetic trajectory of orthologous chromosome segments is considered, many of these EB are coincident with ancient centromere activity as well as new centromere formation. While EB have been characterized as repeat-rich regions, it has not been determined whether specific sequences have been retained during evolution that would indicate previous centromere activity or a propensity for new centromere formation. Likewise, the conservation of specific sequence motifs or classes at EBs among divergent mammalian taxa has not been determined. Results To define conserved sequence features of EBs associated with centromere evolution, we performed comparative sequence analysis of more than 4.8 Mb within the tammar wallaby, Macropus eugenii, derived from centromeric regions (CEN, euchromatic regions (EU, and an evolutionary breakpoint (EB that has undergone convergent breakpoint reuse and past centromere activity in marsupials. We found a dramatic enrichment for long interspersed nucleotide elements (LINE1s and endogenous retroviruses (ERVs and a depletion of short interspersed nucleotide elements (SINEs shared between CEN and EBs. We analyzed the orthologous human EB (14q32.33, known to be associated with translocations in many cancers including multiple myelomas and plasma cell leukemias, and found a conserved distribution of similar repetitive elements. Conclusion Our data indicate that EBs tracked within the class Mammalia harbor sequence features retained since the

  16. deep-orange and carnation define distinct stages in late endosomal biogenesis in Drosophila melanogaster.

    Science.gov (United States)

    Sriram, V; Krishnan, K S; Mayor, Satyajit

    2003-05-12

    Endosomal degradation is severely impaired in primary hemocytes from larvae of eye color mutants of Drosophila. Using high resolution imaging and immunofluorescence microscopy in these cells, products of eye color genes, deep-orange (dor) and carnation (car), are localized to large multivesicular Rab7-positive late endosomes containing Golgi-derived enzymes. These structures mature into small sized Dor-negative, Car-positive structures, which subsequently fuse to form tubular lysosomes. Defective endosomal degradation in mutant alleles of dor results from a failure of Golgi-derived vesicles to fuse with morphologically arrested Rab7-positive large sized endosomes, which are, however, normally acidified and mature with wild-type kinetics. This locates the site of Dor function to fusion of Golgi-derived vesicles with the large Rab7-positive endocytic compartments. In contrast, endosomal degradation is not considerably affected in car1 mutant; fusion of Golgi-derived vesicles and maturation of large sized endosomes is normal. However, removal of Dor from small sized Car-positive endosomes is slowed, and subsequent fusion with tubular lysosomes is abolished. Overexpression of Dor in car1 mutant aggravates this defect, implicating Car in the removal of Dor from endosomes. This suggests that, in addition to an independent role in fusion with tubular lysosomes, the Sec1p homologue, Car, regulates Dor function.

  17. Arf6, Rab11 and transferrin receptor define distinct populations of recycling endosomes.

    Science.gov (United States)

    Kobayashi, Hotaka; Fukuda, Mitsunori

    2013-09-01

    Recycling endosomes are key platforms for endocytic recycling that return internalized molecules back to the plasma membrane. To determine how recycling endosomes perform their functions, searching for proteins and lipids that specifically localized at recycling endosomes has often been performed by colocalization analyses between candidate molecules and conventional recycling endosome markers. However, it remains unclear whether all the conventional markers have identical localizations. Here we report finding that three well-known recycling endosome markers, i.e., Arf6, Rab11 and transferrin receptor (TfR), have different intracellular localizations in PC12 cells. The results of immunofluorescence analyses showed that the signals of endogenous Arf6, Rab11 and TfR in nerve growth factor-stimulated PC12 cells generally differed, although there was some overlapping. Our findings provide new information about recycling endosome markers, and they highlight the heterogeneity of recycling endosomes.

  18. Spatial and Single-Cell Transcriptional Profiling Identifies Functionally Distinct Human Dermal Fibroblast Subpopulations.

    Science.gov (United States)

    Philippeos, Christina; Telerman, Stephanie B; Oulès, Bénédicte; Pisco, Angela O; Shaw, Tanya J; Elgueta, Raul; Lombardi, Giovanna; Driskell, Ryan R; Soldin, Mark; Lynch, Magnus D; Watt, Fiona M

    2018-04-01

    Previous studies have shown that mouse dermis is composed of functionally distinct fibroblast lineages. To explore the extent of fibroblast heterogeneity in human skin, we used a combination of comparative spatial transcriptional profiling of human and mouse dermis and single-cell transcriptional profiling of human dermal fibroblasts. We show that there are at least four distinct fibroblast populations in adult human skin, not all of which are spatially segregated. We define markers permitting their isolation and show that although marker expression is lost in culture, different fibroblast subpopulations retain distinct functionality in terms of Wnt signaling, responsiveness to IFN-γ, and ability to support human epidermal reconstitution when introduced into decellularized dermis. These findings suggest that ex vivo expansion or in vivo ablation of specific fibroblast subpopulations may have therapeutic applications in wound healing and diseases characterized by excessive fibrosis. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Cladribine and Fludarabine Nucleotides Induce Distinct Hexamers Defining a Common Mode of Reversible RNR Inhibition.

    Science.gov (United States)

    Wisitpitthaya, Somsinee; Zhao, Yi; Long, Marcus J C; Li, Minxing; Fletcher, Elaine A; Blessing, William A; Weiss, Robert S; Aye, Yimon

    2016-07-15

    The enzyme ribonucleotide reductase (RNR) is a major target of anticancer drugs. Until recently, suicide inactivation in which synthetic substrate analogs (nucleoside diphosphates) irreversibly inactivate the RNR-α2β2 heterodimeric complex was the only clinically proven inhibition pathway. For instance, this mechanism is deployed by the multifactorial anticancer agent gemcitabine diphosphate. Recently reversible targeting of RNR-α-alone coupled with ligand-induced RNR-α-persistent hexamerization has emerged to be of clinical significance. To date, clofarabine nucleotides are the only known example of this mechanism. Herein, chemoenzymatic syntheses of the active forms of two other drugs, phosphorylated cladribine (ClA) and fludarabine (FlU), allow us to establish that reversible inhibition is common to numerous drugs in clinical use. Enzyme inhibition and fluorescence anisotropy assays show that the di- and triphosphates of the two nucleosides function as reversible (i.e., nonmechanism-based) inhibitors of RNR and interact with the catalytic (C site) and the allosteric activity (A site) sites of RNR-α, respectively. Gel filtration, protease digestion, and FRET assays demonstrate that inhibition is coupled with formation of conformationally diverse hexamers. Studies in 293T cells capable of selectively inducing either wild-type or oligomerization-defective mutant RNR-α overexpression delineate the central role of RNR-α oligomerization in drug activity, and highlight a potential resistance mechanism to these drugs. These data set the stage for new interventions targeting RNR oligomeric regulation.

  20. WEC Farm Functions: Defining the Behaviors of the Farm

    Energy Technology Data Exchange (ETDEWEB)

    Bull, Diana L. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Costello, Ronan [Wave Venture Ltd, Penstraze (United Kingdom); Babarit, Aurelien [Ecole centrale de Nantes (France). Lab. of Research in Hydrodynamics, Energetics, and Atmospheric Environment (LHEEA); Malins, Robert Joseph [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Kennedy, Ben [Wave Venture Ltd, Penstraze (United Kingdom); Neilson, Kim [Ramboll, Copenhagen (Denmark); Bittencourt, Claudio [DNV GL, London (United Kingdom); Roberts, Jesse D. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Weber, Jochem [National Renewable Energy Lab. (NREL), Golden, CO (United States)

    2016-09-01

    Capabilities and functions are hierarchical structures (i.e. taxonomies) that are used in a systems engineering framework to identify complimentary requirements for the system: what the system must do to achieve what it must be. In the case of capabilities, the taxonomy embodies the list of characteristics that are desired, from the perspective of the stakeholders, for the system to be successful. In terms of the functions, the hierarchy represents the solution agnostic (i.e. independent of specific design embodiments) elements that are needed to meet the stakeholder requirements. This paper will focus on the development of the functions. The functions define the fundamental elements of the solution that must be provided in order to achieve the mission and deliver the capabilities. They identify the behaviors the farm must possess, i.e. the farm must be able to generate and deliver electricity from wave power. High-level functions are independent of the technology or design used to implement the function. However, detailed functions may begin to border on specific design choices. Hence a strong effort has been made to maintain functions that are design agnostic.

  1. Evolution of sequence-defined highly functionalized nucleic acid polymers

    Science.gov (United States)

    Chen, Zhen; Lichtor, Phillip A.; Berliner, Adrian P.; Chen, Jonathan C.; Liu, David R.

    2018-03-01

    The evolution of sequence-defined synthetic polymers made of building blocks beyond those compatible with polymerase enzymes or the ribosome has the potential to generate new classes of receptors, catalysts and materials. Here we describe a ligase-mediated DNA-templated polymerization and in vitro selection system to evolve highly functionalized nucleic acid polymers (HFNAPs) made from 32 building blocks that contain eight chemically diverse side chains on a DNA backbone. Through iterated cycles of polymer translation, selection and reverse translation, we discovered HFNAPs that bind proprotein convertase subtilisin/kexin type 9 (PCSK9) and interleukin-6, two protein targets implicated in human diseases. Mutation and reselection of an active PCSK9-binding polymer yielded evolved polymers with high affinity (KD = 3 nM). This evolved polymer potently inhibited the binding between PCSK9 and the low-density lipoprotein receptor. Structure-activity relationship studies revealed that specific side chains at defined positions in the polymers are required for binding to their respective targets. Our findings expand the chemical space of evolvable polymers to include densely functionalized nucleic acids with diverse, researcher-defined chemical repertoires.

  2. Distinct functional programming of human fetal and adult monocytes.

    Science.gov (United States)

    Krow-Lucal, Elisabeth R; Kim, Charles C; Burt, Trevor D; McCune, Joseph M

    2014-03-20

    Preterm birth affects 1 out of 9 infants in the United States and is the leading cause of long-term neurologic handicap and infant mortality, accounting for 35% of all infant deaths in 2008. Although cytokines including interferon-γ (IFN-γ), interleukin-10 (IL-10), IL-6, and IL-1 are produced in response to in utero infection and are strongly associated with preterm labor, little is known about how human fetal immune cells respond to these cytokines. We demonstrate that fetal and adult CD14(+)CD16(-) classical monocytes are distinct in terms of basal transcriptional profiles and in phosphorylation of signal transducers and activators of transcription (STATs) in response to cytokines. Fetal monocytes phosphorylate canonical and noncanonical STATs and respond more strongly to IFN-γ, IL-6, and IL-4 than adult monocytes. We demonstrate a higher ratio of SOCS3 to IL-6 receptor in adult monocytes than in fetal monocytes, potentially explaining differences in STAT phosphorylation. Additionally, IFN-γ signaling results in upregulation of antigen presentation and costimulatory machinery in adult, but not fetal, monocytes. These findings represent the first evidence that primary human fetal and adult monocytes are functionally distinct, potentially explaining how these cells respond differentially to cytokines implicated in development, in utero infections, and the pathogenesis of preterm labor.

  3. Distinct Functions of Endophilin Isoforms in Synaptic Vesicle Endocytosis

    Directory of Open Access Journals (Sweden)

    Jifeng Zhang

    2015-01-01

    Full Text Available Endophilin isoforms perform distinct characteristics in their interactions with N-type Ca2+ channels and dynamin. However, precise functional differences for the endophilin isoforms on synaptic vesicle (SV endocytosis remain unknown. By coupling RNA interference and electrophysiological recording techniques in cultured rat hippocampal neurons, we investigated the functional differences of three isoforms of endophilin in SV endocytosis. The results showed that the amplitude of normalized evoked excitatory postsynaptic currents in endophilin1 knockdown neurons decreased significantly for both single train and multiple train stimulations. Similar results were found using endophilin2 knockdown neurons, whereas endophilin3 siRNA exhibited no change compared with control neurons. Endophilin1 and endophilin2 affected SV endocytosis, but the effect of endophilin1 and endophilin2 double knockdown was not different from that of either knockdown alone. This result suggested that endophilin1 and endophilin2 functioned together but not independently during SV endocytosis. Taken together, our results indicate that SV endocytosis is sustained by endophilin1 and endophilin2 isoforms, but not by endophilin3, in primary cultured hippocampal neurons.

  4. The evolution of compositionally and functionally distinct actin filaments.

    Science.gov (United States)

    Gunning, Peter W; Ghoshdastider, Umesh; Whitaker, Shane; Popp, David; Robinson, Robert C

    2015-06-01

    The actin filament is astonishingly well conserved across a diverse set of eukaryotic species. It has essentially remained unchanged in the billion years that separate yeast, Arabidopsis and man. In contrast, bacterial actin-like proteins have diverged to the extreme, and many of them are not readily identified from sequence-based homology searches. Here, we present phylogenetic analyses that point to an evolutionary drive to diversify actin filament composition across kingdoms. Bacteria use a one-filament-one-function system to create distinct filament systems within a single cell. In contrast, eukaryotic actin is a universal force provider in a wide range of processes. In plants, there has been an expansion of the number of closely related actin genes, whereas in fungi and metazoa diversification in tropomyosins has increased the compositional variety in actin filament systems. Both mechanisms dictate the subset of actin-binding proteins that interact with each filament type, leading to specialization in function. In this Hypothesis, we thus propose that different mechanisms were selected in bacteria, plants and metazoa, which achieved actin filament compositional variation leading to the expansion of their functional diversity. © 2015. Published by The Company of Biologists Ltd.

  5. Defining functional DNA elements in the human genome

    Science.gov (United States)

    Kellis, Manolis; Wold, Barbara; Snyder, Michael P.; Bernstein, Bradley E.; Kundaje, Anshul; Marinov, Georgi K.; Ward, Lucas D.; Birney, Ewan; Crawford, Gregory E.; Dekker, Job; Dunham, Ian; Elnitski, Laura L.; Farnham, Peggy J.; Feingold, Elise A.; Gerstein, Mark; Giddings, Morgan C.; Gilbert, David M.; Gingeras, Thomas R.; Green, Eric D.; Guigo, Roderic; Hubbard, Tim; Kent, Jim; Lieb, Jason D.; Myers, Richard M.; Pazin, Michael J.; Ren, Bing; Stamatoyannopoulos, John A.; Weng, Zhiping; White, Kevin P.; Hardison, Ross C.

    2014-01-01

    With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease. PMID:24753594

  6. Heterogeneity in Neutrophil Microparticles Reveals Distinct Proteome and Functional Properties*

    Science.gov (United States)

    Dalli, Jesmond; Montero-Melendez, Trinidad; Norling, Lucy V; Yin, Xiaoke; Hinds, Charles; Haskard, Dorian; Mayr, Manuel; Perretti, Mauro

    2013-01-01

    Altered plasma neutrophil microparticle levels have recently been implicated in a number of vascular and inflammatory diseases, yet our understanding of their actions is very limited. Herein, we investigate the proteome of neutrophil microparticles in order to shed light on their biological actions. Stimulation of human neutrophils, either in suspension or adherent to an endothelial monolayer, led to the production of microparticles containing >400 distinct proteins with only 223 being shared by the two subsets. For instance, postadherent microparticles were enriched in alpha-2 macroglobulin and ceruloplasmin, whereas microparticles produced by neutrophils in suspension were abundant in heat shock 70 kDa protein 1. Annexin A1 and lactotransferrin were expressed in both microparticle subsets. We next determined relative abundance of these proteins in three types of human microparticle samples: healthy volunteer plasma, plasma of septic patients and skin blister exudates finding that these proteins were differentially expressed on neutrophil microparticles from these samples reflecting in part the expression profiles we found in vitro. Functional assessment of the neutrophil microparticles subsets demonstrated that in response to direct stimulation neutrophil microparticles produced reactive oxygen species and leukotriene B4 as well as locomoted toward a chemotactic gradient. Finally, we investigated the actions of the two neutrophil microparticles subsets described herein on target cell responses. Microarray analysis with human primary endothelial cells incubated with either microparticle subset revealed a discrete modulation of endothelial cell gene expression profile. These findings demonstrate that neutrophil microparticles are heterogenous and can deliver packaged information propagating the activation status of the parent cell, potentially exerting novel and fundamental roles both under homeostatic and disease conditions. PMID:23660474

  7. Single-cell quantitative HER2 measurement identifies heterogeneity and distinct subgroups within traditionally defined HER2-positive patients.

    Science.gov (United States)

    Onsum, Matthew D; Geretti, Elena; Paragas, Violette; Kudla, Arthur J; Moulis, Sharon P; Luus, Lia; Wickham, Thomas J; McDonagh, Charlotte F; MacBeath, Gavin; Hendriks, Bart S

    2013-11-01

    Human epidermal growth factor receptor 2 (HER2) is an important biomarker for breast and gastric cancer prognosis and patient treatment decisions. HER2 positivity, as defined by IHC or fluorescent in situ hybridization testing, remains an imprecise predictor of patient response to HER2-targeted therapies. Challenges to correct HER2 assessment and patient stratification include intratumoral heterogeneity, lack of quantitative and/or objective assays, and differences between measuring HER2 amplification at the protein versus gene level. We developed a novel immunofluorescence method for quantitation of HER2 protein expression at the single-cell level on FFPE patient samples. Our assay uses automated image analysis to identify and classify tumor versus non-tumor cells, as well as quantitate the HER2 staining for each tumor cell. The HER2 staining level is converted to HER2 protein expression using a standard cell pellet array stained in parallel with the tissue sample. This approach allows assessment of HER2 expression and heterogeneity within a tissue section at the single-cell level. By using this assay, we identified distinct subgroups of HER2 heterogeneity within traditional definitions of HER2 positivity in both breast and gastric cancers. Quantitative assessment of intratumoral HER2 heterogeneity may offer an opportunity to improve the identification of patients likely to respond to HER2-targeted therapies. The broad applicability of the assay was demonstrated by measuring HER2 expression profiles on multiple tumor types, and on normal and diseased heart tissues. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  8. Functional cell types in taste buds have distinct longevities.

    Directory of Open Access Journals (Sweden)

    Isabel Perea-Martinez

    Full Text Available Taste buds are clusters of polarized sensory cells embedded in stratified oral epithelium. In adult mammals, taste buds turn over continuously and are replenished through the birth of new cells in the basal layer of the surrounding non-sensory epithelium. The half-life of cells in mammalian taste buds has been estimated as 8-12 days on average. Yet, earlier studies did not address whether the now well-defined functional taste bud cell types all exhibit the same lifetime. We employed a recently developed thymidine analog, 5-ethynil-2'-deoxyuridine (EdU to re-evaluate the incorporation of newly born cells into circumvallate taste buds of adult mice. By combining EdU-labeling with immunostaining for selected markers, we tracked the differentiation and lifespan of the constituent cell types of taste buds. EdU was primarily incorporated into basal extragemmal cells, the principal source for replenishing taste bud cells. Undifferentiated EdU-labeled cells began migrating into circumvallate taste buds within 1 day of their birth. Type II (Receptor taste cells began to differentiate from EdU-labeled precursors beginning 2 days after birth and then were eliminated with a half-life of 8 days. Type III (Presynaptic taste cells began differentiating after a delay of 3 days after EdU-labeling, and they survived much longer, with a half-life of 22 days. We also scored taste bud cells that belong to neither Type II nor Type III, a heterogeneous group that includes mostly Type I cells, and also undifferentiated or immature cells. A non-linear decay fit described these cells as two sub-populations with half-lives of 8 and 24 days respectively. Our data suggest that many post-mitotic cells may remain quiescent within taste buds before differentiating into mature taste cells. A small number of slow-cycling cells may also exist within the perimeter of the taste bud. Based on their incidence, we hypothesize that these may be progenitors for Type III cells.

  9. Functional cell types in taste buds have distinct longevities.

    Science.gov (United States)

    Perea-Martinez, Isabel; Nagai, Takatoshi; Chaudhari, Nirupa

    2013-01-01

    Taste buds are clusters of polarized sensory cells embedded in stratified oral epithelium. In adult mammals, taste buds turn over continuously and are replenished through the birth of new cells in the basal layer of the surrounding non-sensory epithelium. The half-life of cells in mammalian taste buds has been estimated as 8-12 days on average. Yet, earlier studies did not address whether the now well-defined functional taste bud cell types all exhibit the same lifetime. We employed a recently developed thymidine analog, 5-ethynil-2'-deoxyuridine (EdU) to re-evaluate the incorporation of newly born cells into circumvallate taste buds of adult mice. By combining EdU-labeling with immunostaining for selected markers, we tracked the differentiation and lifespan of the constituent cell types of taste buds. EdU was primarily incorporated into basal extragemmal cells, the principal source for replenishing taste bud cells. Undifferentiated EdU-labeled cells began migrating into circumvallate taste buds within 1 day of their birth. Type II (Receptor) taste cells began to differentiate from EdU-labeled precursors beginning 2 days after birth and then were eliminated with a half-life of 8 days. Type III (Presynaptic) taste cells began differentiating after a delay of 3 days after EdU-labeling, and they survived much longer, with a half-life of 22 days. We also scored taste bud cells that belong to neither Type II nor Type III, a heterogeneous group that includes mostly Type I cells, and also undifferentiated or immature cells. A non-linear decay fit described these cells as two sub-populations with half-lives of 8 and 24 days respectively. Our data suggest that many post-mitotic cells may remain quiescent within taste buds before differentiating into mature taste cells. A small number of slow-cycling cells may also exist within the perimeter of the taste bud. Based on their incidence, we hypothesize that these may be progenitors for Type III cells.

  10. Empirically Defined Patterns of Executive Function Deficits in Schizophrenia and Their Relation to Everyday Functioning: A Person-Centered Approach

    Science.gov (United States)

    Iampietro, Mary; Giovannetti, Tania; Drabick, Deborah A. G.; Kessler, Rachel K.

    2013-01-01

    Executive function (EF) deficits in schizophrenia (SZ) are well documented, although much less is known about patterns of EF deficits and their association to differential impairments in everyday functioning. The present study empirically defined SZ groups based on measures of various EF abilities and then compared these EF groups on everyday action errors. Participants (n=45) completed various subtests from the Delis–Kaplan Executive Function System (D-KEFS) and the Naturalistic Action Test (NAT), a performance-based measure of everyday action that yields scores reflecting total errors and a range of different error types (e.g., omission, perseveration). Results of a latent class analysis revealed three distinct EF groups, characterized by (a) multiple EF deficits, (b) relatively spared EF, and (c) perseverative responding. Follow-up analyses revealed that the classes differed significantly on NAT total errors, total commission errors, and total perseveration errors; the two classes with EF impairment performed comparably on the NAT but performed worse than the class with relatively spared EF. In sum, people with SZ demonstrate variable patterns of EF deficits, and distinct aspects of these EF deficit patterns (i.e., poor mental control abilities) may be associated with everyday functioning capabilities. PMID:23035705

  11. 184 Compounding in Igala: Defining Criteria, Forms and Functions ...

    African Journals Online (AJOL)

    Ike Odimegwu

    West Benue-Congo language spoken in north central Nigeria. Defining ..... argues, in Ígálà, ọ́ma 'child', for instance, can stand in for the noun phrase 'ọ́ma óko' 'Oko's .... e.g. 'in Pawnee it is mainly body part words which are incorporated' (c.f. ...

  12. GenomeRunner web server: regulatory similarity and differences define the functional impact of SNP sets.

    Science.gov (United States)

    Dozmorov, Mikhail G; Cara, Lukas R; Giles, Cory B; Wren, Jonathan D

    2016-08-01

    The growing amount of regulatory data from the ENCODE, Roadmap Epigenomics and other consortia provides a wealth of opportunities to investigate the functional impact of single nucleotide polymorphisms (SNPs). Yet, given the large number of regulatory datasets, researchers are posed with a challenge of how to efficiently utilize them to interpret the functional impact of SNP sets. We developed the GenomeRunner web server to automate systematic statistical analysis of SNP sets within a regulatory context. Besides defining the functional impact of SNP sets, GenomeRunner implements novel regulatory similarity/differential analyses, and cell type-specific regulatory enrichment analysis. Validated against literature- and disease ontology-based approaches, analysis of 39 disease/trait-associated SNP sets demonstrated that the functional impact of SNP sets corresponds to known disease relationships. We identified a group of autoimmune diseases with SNPs distinctly enriched in the enhancers of T helper cell subpopulations, and demonstrated relevant cell type-specificity of the functional impact of other SNP sets. In summary, we show how systematic analysis of genomic data within a regulatory context can help interpreting the functional impact of SNP sets. GenomeRunner web server is freely available at http://www.integrativegenomics.org/ mikhail.dozmorov@gmail.com Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. Compositionally and functionally distinct sinus microbiota in chronic rhinosinusitis patients have immunological and clinically divergent consequences.

    Science.gov (United States)

    Cope, Emily K; Goldberg, Andrew N; Pletcher, Steven D; Lynch, Susan V

    2017-05-12

    Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by persistent sinonasal inflammation and sinus microbiome dysbiosis. The basis of this heterogeneity is poorly understood. We sought to address the hypothesis that a limited number of compositionally distinct pathogenic bacterial microbiota exist in CRS patients and invoke discrete immune responses and clinical phenotypes in CRS patients. Sinus brushings from patients with CRS (n = 59) and healthy individuals (n = 10) collected during endoscopic sinus surgery were analyzed using 16S rRNA gene sequencing, predicted metagenomics, and RNA profiling of the mucosal immune response. We show that CRS patients cluster into distinct sub-groups (DSI-III), each defined by specific pattern of bacterial co-colonization (permutational multivariate analysis of variance (PERMANOVA); p = 0.001, r 2  = 0.318). Each sub-group was typically dominated by a pathogenic family: Streptococcaceae (DSI), Pseudomonadaceae (DSII), Corynebacteriaceae [DSIII(a)], or Staphylococcaceae [DSIII(b)]. Each pathogenic microbiota was predicted to be functionally distinct (PERMANOVA; p = 0.005, r 2  = 0.217) and encode uniquely enriched gene pathways including ansamycin biosynthesis (DSI), tryptophan metabolism (DSII), two-component response [DSIII(b)], and the PPAR-γ signaling pathway [DSIII(a)]. Each is also associated with significantly distinct host immune responses; DSI, II, and III(b) invoked a variety of pro-inflammatory, T H 1 responses, while DSIII(a), which exhibited significantly increased incidence of nasal polyps (Fisher's exact; p = 0.034, relative risk = 2.16), primarily induced IL-5 expression (Kruskal Wallis; q = 0.045). A large proportion of CRS patient heterogeneity may be explained by the composition of their sinus bacterial microbiota and related host immune response-features which may inform strategies for tailored therapy in this patient population.

  14. Differential compartmentalization and distinct functions of GABAB receptor variants

    DEFF Research Database (Denmark)

    Vigot, Réjan; Barbieri, Samuel; Bräuner-Osborne, Hans

    2006-01-01

    , while predominantly GABAB1b mediates postsynaptic inhibition. Electron microscopy reveals a synaptic distribution of GABAB1 isoforms that agrees with the observed functional differences. Transfected CA3 neurons selectively express GABAB1a in distal axons, suggesting that the sushi repeats, a conserved...... protein interaction motif, specify heteroreceptor localization. The constitutive absence of GABAB1a but not GABAB1b results in impaired synaptic plasticity and hippocampus-dependent memory, emphasizing molecular differences in synaptic GABAB functions....

  15. Gain-of-function SOS1 mutations cause a distinctive form of noonansyndrome

    Energy Technology Data Exchange (ETDEWEB)

    Tartaglia, Marco; Pennacchio, Len A.; Zhao, Chen; Yadav, KamleshK.; Fodale, Valentina; Sarkozy, Anna; Pandit, Bhaswati; Oishi, Kimihiko; Martinelli, Simone; Schackwitz, Wendy; Ustaszewska, Anna; Martin, Joes; Bristow, James; Carta, Claudio; Lepri, Francesca; Neri, Cinzia; Vasta,Isabella; Gibson, Kate; Curry, Cynthia J.; Lopez Siguero, Juan Pedro; Digilio, Maria Cristina; Zampino, Giuseppe; Dallapiccola, Bruno; Bar-Sagi, Dafna; Gelb, Brude D.

    2006-09-01

    Noonan syndrome (NS) is a developmental disordercharacterized by short stature, facial dysmorphia, congenital heartdefects and skeletal anomalies1. Increased RAS-mitogenactivated proteinkinase (MAPK) signaling due to PTPN11 and KRAS mutations cause 50 percentof NS2-6. Here, we report that 22 of 129 NS patients without PTPN11 orKRAS mutation (17 percent) have missense mutations in SOS1, which encodesa RAS-specific guanine nucleotide exchange factor (GEF). SOS1 mutationscluster at residues implicated in the maintenance of SOS1 in itsautoinhibited form and ectopic expression of two NS-associated mutantsinduced enhanced RAS activation. The phenotype associated with SOS1defects is distinctive, although within NS spectrum, with a highprevalence of ectodermal abnormalities but generally normal developmentand linear growth. Our findings implicate for the first timegain-of-function mutations in a RAS GEF in inherited disease and define anew mechanism by which upregulation of the RAS pathway can profoundlychange human development.

  16. On some strongly functions defined by α-open

    International Nuclear Information System (INIS)

    Kocaman, A.H.; Yuksel, S.; Acikgoz, A.

    2009-01-01

    In this paper is to introduce and investigate new classes of generalizations of non-continuous functions, obtain some of their properties and to hold decompositions of strong α-irresolute in topological spaces.

  17. Arithmetic convergent sequence space defined by modulus function

    Directory of Open Access Journals (Sweden)

    Taja Yaying

    2019-10-01

    Full Text Available The aim of this article is to introduce the sequence spaces $AC(f$ and $AS(f$ using arithmetic convergence and modulus function, and study algebraic and topological properties of this space, and certain inclusion results.

  18. The distinction in radiobiology between medical and public health functions

    International Nuclear Information System (INIS)

    Bond, V.P.; Wielopolski, L.

    1995-01-01

    Starting with the classical threshold-sigmoid Medical-Toxicological plot, reasons are advanced for why the coordinates of this function are not appropriate for the analysis of Public Health-Epidemiological data. Misunderstanding with respect to both the level of biological organization and the word ''dose'' are pointed out, which explain why Public Health-Epidemiological data, anomalously, yield linear functions on medical-toxicological coordinates. It is then shown why substantially different coordinates must be used to obtain a function that describes properly and completely the cancer data obtained from epidemiological studies on the atomic bomb survivors. Arguments are put forth that seriously weaken the current interpretation of the ''linear, no-threshold hypothesis''. Reasons are advanced for why, if the amount of radiation energy is expressed in the proper terms, the numerical value for the cancer ''risk coefficient'' becomes substantially smaller than it now is

  19. Two distinct forms of functional lateralization in the human brain

    OpenAIRE

    Gotts, Stephen J.; Jo, Hang Joon; Wallace, Gregory L.; Saad, Ziad S.; Cox, Robert W.; Martin, Alex

    2013-01-01

    This study alters our fundamental understanding of the functional interactions between the cerebral hemispheres of the human brain by establishing that the left and right hemispheres have qualitatively different biases in how they dynamically interact with one another. Left-hemisphere regions are biased to interact more strongly within the same hemisphere, whereas right-hemisphere regions interact more strongly with both hemispheres. These two different patterns of interaction are associated ...

  20. Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions.

    Science.gov (United States)

    Raleigh, David R; Marchiando, Amanda M; Zhang, Yong; Shen, Le; Sasaki, Hiroyuki; Wang, Yingmin; Long, Manyuan; Turner, Jerrold R

    2010-04-01

    In vitro studies have demonstrated that occludin and tricellulin are important for tight junction barrier function, but in vivo data suggest that loss of these proteins can be overcome. The presence of a heretofore unknown, yet related, protein could explain these observations. Here, we report marvelD3, a novel tight junction protein that, like occludin and tricellulin, contains a conserved four-transmembrane MARVEL (MAL and related proteins for vesicle trafficking and membrane link) domain. Phylogenetic tree reconstruction; analysis of RNA and protein tissue distribution; immunofluorescent and electron microscopic examination of subcellular localization; characterization of intracellular trafficking, protein interactions, dynamic behavior, and siRNA knockdown effects; and description of remodeling after in vivo immune activation show that marvelD3, occludin, and tricellulin have distinct but overlapping functions at the tight junction. Although marvelD3 is able to partially compensate for occludin or tricellulin loss, it cannot fully restore function. We conclude that marvelD3, occludin, and tricellulin define the tight junction-associated MARVEL protein family. The data further suggest that these proteins are best considered as a group with both redundant and unique contributions to epithelial function and tight junction regulation.

  1. Helicobacter Pylori Related Functional Dyspepsia in a Defined Malaysian Population

    OpenAIRE

    Nafeeza, M.I.; Isa, M.R.; Kudva, M.V.; Ishak, M.S.; Mazlam, M.Z.; Haron, A.; Najib, R.; Shahimi, M.M.

    2000-01-01

    The objective of the study was to determine the prevalence of H. pylori in functional dyspepsia among the three main races in Malaysia. Gastric antral biopsies from 233 (98 males, 135 females; age range: 17–75 years, mean age 39.5 years) patients attending the Universiti Kebangsaan Malaysia (UKM) gastroenterology clinic were assessed for the presence of H. pylori by culture and histology. About a third of the cases (79 of 233 (34%); 34 males, 45 females; mean age 42.6 yrs) were positive for H...

  2. Asymptotically double lacunry equivalent sequences defined by Orlicz functions

    Directory of Open Access Journals (Sweden)

    Ayhan Esi

    2014-04-01

    Full Text Available This paper presents the following definition which is natural combition of the definition for asymptotically equivalent and Orlicz function. The two nonnegative double sequences x=(x_{k,l} and y=(y_{k,l} are said to be M-asymptotically double equivalent to multiple L provided that for every ε>0, P-lim_{k,l}M(((|((x_{k,l}/(y_{k,l}-L|/ρ=0, for some ρ>0, (denoted by x∽y and simply M-asymptotically double equivalent if L=1. Also we give some new concepts related to this definition and some inclusion theorems.

  3. Cell type-specific recruitment of Drosophila Lin-7 to distinct MAGUK-based protein complexes defines novel roles for Sdt and Dlg-S97.

    Science.gov (United States)

    Bachmann, André; Timmer, Marco; Sierralta, Jimena; Pietrini, Grazia; Gundelfinger, Eckart D; Knust, Elisabeth; Thomas, Ulrich

    2004-04-15

    Stardust (Sdt) and Discs-Large (Dlg) are membrane-associated guanylate kinases (MAGUKs) involved in the organization of supramolecular protein complexes at distinct epithelial membrane compartments in Drosophila. Loss of either Sdt or Dlg affects epithelial development with severe effects on apico-basal polarity. Moreover, Dlg is required for the structural and functional integrity of synaptic junctions. Recent biochemical and cell culture studies have revealed that various mammalian MAGUKs can interact with mLin-7/Veli/MALS, a small PDZ-domain protein. To substantiate these findings for their in vivo significance with regard to Sdt- and Dlg-based protein complexes, we analyzed the subcellular distribution of Drosophila Lin-7 (DLin-7) and performed genetic and biochemical assays to characterize its interaction with either of the two MAGUKs. In epithelia, Sdt mediates the recruitment of DLin-7 to the subapical region, while at larval neuromuscular junctions, a particular isoform of Dlg, Dlg-S97, is required for postsynaptic localization of DLin-7. Ectopic expression of Dlg-S97 in epithelia, however, was not sufficient to induce a redistribution of DLin-7. These results imply that the recruitment of DLin-7 to MAGUK-based protein complexes is defined by cell-type specific mechanisms and that DLin-7 acts downstream of Sdt in epithelia and downstream of Dlg at synapses.

  4. Distinct Functional Domains of Ubc9 Dictate Cell Survival and Resistance to Genotoxic Stress

    Science.gov (United States)

    van Waardenburg, Robert C. A. M.; Duda, David M.; Lancaster, Cynthia S.; Schulman, Brenda A.; Bjornsti, Mary-Ann

    2006-01-01

    Covalent modification with SUMO alters protein function, intracellular localization, or protein-protein interactions. Target recognition is determined, in part, by the SUMO E2 enzyme, Ubc9, while Siz/Pias E3 ligases may facilitate select interactions by acting as substrate adaptors. A yeast conditional Ubc9P123L mutant was viable at 36°C yet exhibited enhanced sensitivity to DNA damage. To define functional domains in Ubc9 that dictate cellular responses to genotoxic stress versus those necessary for cell viability, a 1.75-Å structure of yeast Ubc9 that demonstrated considerable conservation of backbone architecture with human Ubc9 was solved. Nevertheless, differences in side chain geometry/charge guided the design of human/yeast chimeras, where swapping domains implicated in (i) binding residues within substrates that flank canonical SUMOylation sites, (ii) interactions with the RanBP2 E3 ligase, and (iii) binding of the heterodimeric E1 and SUMO had distinct effects on cell growth and resistance to DNA-damaging agents. Our findings establish a functional interaction between N-terminal and substrate-binding domains of Ubc9 and distinguish the activities of E3 ligases Siz1 and Siz2 in regulating cellular responses to genotoxic stress. PMID:16782883

  5. Genome-Wide Requirements for Resistance to Functionally Distinct DNA-Damaging Agents.

    Directory of Open Access Journals (Sweden)

    2005-08-01

    Full Text Available The mechanistic and therapeutic differences in the cellular response to DNA-damaging compounds are not completely understood, despite intense study. To expand our knowledge of DNA damage, we assayed the effects of 12 closely related DNA-damaging agents on the complete pool of ~4,700 barcoded homozygous deletion strains of Saccharomyces cerevisiae. In our protocol, deletion strains are pooled together and grown competitively in the presence of compound. Relative strain sensitivity is determined by hybridization of PCR-amplified barcodes to an oligonucleotide array carrying the barcode complements. These screens identified genes in well-characterized DNA-damage-response pathways as well as genes whose role in the DNA-damage response had not been previously established. High-throughput individual growth analysis was used to independently confirm microarray results. Each compound produced a unique genome-wide profile. Analysis of these data allowed us to determine the relative importance of DNA-repair modules for resistance to each of the 12 profiled compounds. Clustering the data for 12 distinct compounds uncovered both known and novel functional interactions that comprise the DNA-damage response and allowed us to define the genetic determinants required for repair of interstrand cross-links. Further genetic analysis allowed determination of epistasis for one of these functional groups.

  6. Diversity of Pol IV function is defined by mutations at the maize rmr7 locus.

    Directory of Open Access Journals (Sweden)

    Jennifer L Stonaker

    2009-11-01

    Full Text Available Mutations affecting the heritable maintenance of epigenetic states in maize identify multiple small RNA biogenesis factors including NRPD1, the largest subunit of the presumed maize Pol IV holoenzyme. Here we show that mutations defining the required to maintain repression7 locus identify a second RNA polymerase subunit related to Arabidopsis NRPD2a, the sole second largest subunit shared between Arabidopsis Pol IV and Pol V. A phylogenetic analysis shows that, in contrast to representative eudicots, grasses have retained duplicate loci capable of producing functional NRPD2-like proteins, which is indicative of increased RNA polymerase diversity in grasses relative to eudicots. Together with comparisons of rmr7 mutant plant phenotypes and their effects on the maintenance of epigenetic states with parallel analyses of NRPD1 defects, our results imply that maize utilizes multiple functional NRPD2-like proteins. Despite the observation that RMR7/NRPD2, like NRPD1, is required for the accumulation of most siRNAs, our data indicate that different Pol IV isoforms play distinct roles in the maintenance of meiotically-heritable epigenetic information in the grasses.

  7. CAD/CAM splints for the functional and esthetic evaluation of newly defined occlusal dimensions.

    Science.gov (United States)

    Edelhoff, Daniel; Schweiger, Josef; Prandtner, Otto; Trimpl, Johannes; Stimmelmayr, Michael; Güth, Jan-Frederik

    2017-01-01

    Pretreatment with occlusal splints is a crucial step in a structured treatment approach for a complex rehabilitation that changes the vertical dimension of occlusion. Meticulous patient compliance is one of the essential prerequisites for overall treatment success. However, patient compliance is all too often insufficient due to esthetic, phonetic, and functional limitations when using conventional occlusal splints in one arch. Modern production technologies now allow the use of tooth-colored occlusal splints made of polycarbonate, whose quality and material properties are quite distinct from those of conventionally manufactured splints made of transparent polymethyl methacrylate (PMMA). These materials, produced under standardized polymerization conditions, are extremely homogenous, which provides benefits such as a greater accuracy of fit by eliminating the polymerization shrinkage, greater long-term stability of shapes and shades, better biocompatibility, less wear, and a more favorable esthetic appearance. In addition, tooth-colored polycarbonate splints can be fabricated very thin without significantly increasing the fracture risk, thanks to the flexibility of the material. The improved wearing comfort combined with acceptable esthetics result in significantly improved patient compliance in terms of a "23-hour splint." By providing separate splints for the maxilla and mandible in the case of major alterations of the vertical dimension of occlusion, the esthetic and functional aspects defined by the wax-up can be completely transferred to the removable splints for a "test drive" by the patient, reversibly, and under realistic conditions. This dual-splint approach additionally facilitates segmental transfer into the definitive restoration.

  8. Molecular cloning and pharmacology of functionally distinct isoforms of the human histamine H(3) receptor

    DEFF Research Database (Denmark)

    Wellendorph, Petrine; Goodman, M W; Burstein, E S

    2002-01-01

    The pharmacology of histamine H(3) receptors suggests the presence of distinct receptor isoforms or subtypes. We herein describe multiple, functionally distinct, alternatively spliced isoforms of the human H(3) receptor. Combinatorial splicing at three different sites creates at least six distinct...... receptor isoforms, of which isoforms 1, 2, and 4, encode functional proteins. Detailed pharmacology on isoforms 1 (unspliced receptor), and 2 (which has an 80 amino acid deletion within the third intracellular loop of the protein) revealed that both isoforms displayed robust responses to a series of known...... revealed a rank order of potency at both isoforms of clobenpropit>iodophenpropit>thioperamide, and these drugs are fivefold less potent at isoform 2 than isoform 1. To further explore the pharmacology of H(3) receptor function, we screened 150 clinically relevant neuropsychiatric drugs for H(3) receptor...

  9. Distinctive Correspondence Between Separable Visual Attention Functions and Intrinsic Brain Networks

    Science.gov (United States)

    Ruiz-Rizzo, Adriana L.; Neitzel, Julia; Müller, Hermann J.; Sorg, Christian; Finke, Kathrin

    2018-01-01

    Separable visual attention functions are assumed to rely on distinct but interacting neural mechanisms. Bundesen's “theory of visual attention” (TVA) allows the mathematical estimation of independent parameters that characterize individuals' visual attentional capacity (i.e., visual processing speed and visual short-term memory storage capacity) and selectivity functions (i.e., top-down control and spatial laterality). However, it is unclear whether these parameters distinctively map onto different brain networks obtained from intrinsic functional connectivity, which organizes slowly fluctuating ongoing brain activity. In our study, 31 demographically homogeneous healthy young participants performed whole- and partial-report tasks and underwent resting-state functional magnetic resonance imaging (rs-fMRI). Report accuracy was modeled using TVA to estimate, individually, the four TVA parameters. Networks encompassing cortical areas relevant for visual attention were derived from independent component analysis of rs-fMRI data: visual, executive control, right and left frontoparietal, and ventral and dorsal attention networks. Two TVA parameters were mapped on particular functional networks. First, participants with higher (vs. lower) visual processing speed showed lower functional connectivity within the ventral attention network. Second, participants with more (vs. less) efficient top-down control showed higher functional connectivity within the dorsal attention network and lower functional connectivity within the visual network. Additionally, higher performance was associated with higher functional connectivity between networks: specifically, between the ventral attention and right frontoparietal networks for visual processing speed, and between the visual and executive control networks for top-down control. The higher inter-network functional connectivity was related to lower intra-network connectivity. These results demonstrate that separable visual attention

  10. Distinctive Correspondence Between Separable Visual Attention Functions and Intrinsic Brain Networks.

    Science.gov (United States)

    Ruiz-Rizzo, Adriana L; Neitzel, Julia; Müller, Hermann J; Sorg, Christian; Finke, Kathrin

    2018-01-01

    Separable visual attention functions are assumed to rely on distinct but interacting neural mechanisms. Bundesen's "theory of visual attention" (TVA) allows the mathematical estimation of independent parameters that characterize individuals' visual attentional capacity (i.e., visual processing speed and visual short-term memory storage capacity) and selectivity functions (i.e., top-down control and spatial laterality). However, it is unclear whether these parameters distinctively map onto different brain networks obtained from intrinsic functional connectivity, which organizes slowly fluctuating ongoing brain activity. In our study, 31 demographically homogeneous healthy young participants performed whole- and partial-report tasks and underwent resting-state functional magnetic resonance imaging (rs-fMRI). Report accuracy was modeled using TVA to estimate, individually, the four TVA parameters. Networks encompassing cortical areas relevant for visual attention were derived from independent component analysis of rs-fMRI data: visual, executive control, right and left frontoparietal, and ventral and dorsal attention networks. Two TVA parameters were mapped on particular functional networks. First, participants with higher (vs. lower) visual processing speed showed lower functional connectivity within the ventral attention network. Second, participants with more (vs. less) efficient top-down control showed higher functional connectivity within the dorsal attention network and lower functional connectivity within the visual network. Additionally, higher performance was associated with higher functional connectivity between networks: specifically, between the ventral attention and right frontoparietal networks for visual processing speed, and between the visual and executive control networks for top-down control. The higher inter-network functional connectivity was related to lower intra-network connectivity. These results demonstrate that separable visual attention

  11. Distinctive Correspondence Between Separable Visual Attention Functions and Intrinsic Brain Networks

    Directory of Open Access Journals (Sweden)

    Adriana L. Ruiz-Rizzo

    2018-03-01

    Full Text Available Separable visual attention functions are assumed to rely on distinct but interacting neural mechanisms. Bundesen's “theory of visual attention” (TVA allows the mathematical estimation of independent parameters that characterize individuals' visual attentional capacity (i.e., visual processing speed and visual short-term memory storage capacity and selectivity functions (i.e., top-down control and spatial laterality. However, it is unclear whether these parameters distinctively map onto different brain networks obtained from intrinsic functional connectivity, which organizes slowly fluctuating ongoing brain activity. In our study, 31 demographically homogeneous healthy young participants performed whole- and partial-report tasks and underwent resting-state functional magnetic resonance imaging (rs-fMRI. Report accuracy was modeled using TVA to estimate, individually, the four TVA parameters. Networks encompassing cortical areas relevant for visual attention were derived from independent component analysis of rs-fMRI data: visual, executive control, right and left frontoparietal, and ventral and dorsal attention networks. Two TVA parameters were mapped on particular functional networks. First, participants with higher (vs. lower visual processing speed showed lower functional connectivity within the ventral attention network. Second, participants with more (vs. less efficient top-down control showed higher functional connectivity within the dorsal attention network and lower functional connectivity within the visual network. Additionally, higher performance was associated with higher functional connectivity between networks: specifically, between the ventral attention and right frontoparietal networks for visual processing speed, and between the visual and executive control networks for top-down control. The higher inter-network functional connectivity was related to lower intra-network connectivity. These results demonstrate that separable

  12. On Determinatives and the Category-Function Distinction: A Reply to Brett Reynolds

    Science.gov (United States)

    Lenchuk, Iryna; Ahmed, Amer

    2014-01-01

    This article examines the arguments made in the article "Determiners, Feline Marsupials, and the Category-Function Distinction: A Critique of ELT Grammars" by Brett Reynolds recently published in the "TESL Canada Journal" (2013). In our response, we demonstrate that the author's arguments are problematic on both…

  13. Distinct Patterns of Grey Matter Abnormality in High-Functioning Autism and Asperger's Syndrome

    Science.gov (United States)

    McAlonan, Grainne M.; Suckling, John; Wong, Naikei; Cheung, Vinci; Lienenkaemper, Nina; Cheung, Charlton; Chua, Siew E.

    2008-01-01

    Background: Autism exists across a wide spectrum and there is considerable debate as to whether children with Asperger's syndrome, who have normal language milestones, should be considered to comprise a subgroup distinct other from high-functioning children with autism (HFA), who have a history of delayed language development. Magnetic resonance…

  14. Distinct transmitter release properties determine differences in short-term plasticity at functional and silent synapses.

    Science.gov (United States)

    Cabezas, Carolina; Buño, Washington

    2006-05-01

    Recent evidence suggests that functional and silent synapses are not only postsynaptically different but also presynaptically distinct. The presynaptic differences may be of functional importance in memory formation because a proposed mechanism for long-term potentiation is the conversion of silent synapses into functional ones. However, there is little direct experimentally evidence of these differences. We have investigated the transmitter release properties of functional and silent Schaffer collateral synapses and show that on the average functional synapses displayed a lower percentage of failures and higher excitatory postsynaptic current (EPSC) amplitudes than silent synapses at +60 mV. Moreover, functional but not silent synapses show paired-pulse facilitation (PPF) at +60 mV and thus presynaptic short-term plasticity will be distinct in the two types of synapse. We examined whether intraterminal endoplasmic reticulum Ca2+ stores influenced the release properties of these synapses. Ryanodine (100 microM) and thapsigargin (1 microM) increased the percentage of failures and decreased both the EPSC amplitude and PPF in functional synapses. Caffeine (10 mM) had the opposite effects. In contrast, silent synapses were insensitive to both ryanodine and caffeine. Hence we have identified differences in the release properties of functional and silent synapses, suggesting that synaptic terminals of functional synapses express regulatory molecular mechanisms that are absent in silent synapses.

  15. A New Class of Analytic Functions Defined by Using Salagean Operator

    Directory of Open Access Journals (Sweden)

    R. M. El-Ashwah

    2013-01-01

    Full Text Available We derive some results for a new class of analytic functions defined by using Salagean operator. We give some properties of functions in this class and obtain numerous sharp results including for example, coefficient estimates, distortion theorem, radii of star-likeness, convexity, close-to-convexity, extreme points, integral means inequalities, and partial sums of functions belonging to this class. Finally, we give an application involving certain fractional calculus operators that are also considered.

  16. Functional differences between neurochemically defined populations of inhibitory interneurons in the rat spinal dorsal horn ?

    OpenAIRE

    Polg?r, Erika; Sardella, Thomas C.P.; Tiong, Sheena Y.X.; Locke, Samantha; Watanabe, Masahiko; Todd, Andrew J.

    2013-01-01

    In order to understand how nociceptive information is processed in the spinal dorsal horn we need to unravel the complex synaptic circuits involving interneurons, which constitute the vast majority of the neurons in laminae I?III. The main limitation has been the difficulty in defining functional populations among these cells. We have recently identified 4 non-overlapping classes of inhibitory interneuron, defined by expression of galanin, neuropeptide Y (NPY), neuronal nitric oxide synthase ...

  17. Tissue microenvironments in the nasal epithelium of rainbow trout (Oncorhynchus mykiss) define two distinct CD8α+ cell populations and establish regional immunity

    Science.gov (United States)

    Sepahi, Ali; Casadei, Elisa; Tacchi, Luca; Muñoz, Pilar; LaPatra, Scott E.; Salinas, Irene

    2016-01-01

    Mucosal surfaces require balancing different physiological roles and immune functions. In order to effectively achieve multifunctionality, mucosal epithelia have evolved unique microenvironments that create unique regional immune responses without impairing other normal physiological functions. Whereas examples of regional immunity are known in other mucosal epithelia, to date, no immune microenvironments have been described in the nasal mucosa, a site where the complex functions of olfaction and immunity need to be orchestrated. In this study we identified for the first time the presence of CD8α+ cells in the rainbow trout (Oncorhynchus mykiss) nasal epithelium. Nasal CD8α+ cells display a distinct phenotype suggestive of CD8+ T cells with high integrin β2 expression. Importantly, nasal CD8α+ cells are located in clusters at the mucosal tip of each olfactory lamella but scattered in the neuroepithelial region. The grouping of CD8α+ cells may be explained by the greater expression of CCL19, ICAM-1, and VCAM-1 in the mucosal tip compared to the neuroepithelium. Whilst viral antigen uptake occurred via both tip and lateral routes, tip resident MHC-II+ cells are located significantly closer to the lumen of the nasal cavity than their neuroepithelial counterparts, therefore having quicker access to invading pathogens. Our studies reveal for the first time compartmentalized mucosal immune responses within the nasal mucosa of a vertebrate species, a strategy that likely optimizes local immune responses while protecting olfactory sensory functions. PMID:27798156

  18. Genomic profiling using array comparative genomic hybridization define distinct subtypes of diffuse large b-cell lymphoma: a review of the literature

    Directory of Open Access Journals (Sweden)

    Tirado Carlos A

    2012-09-01

    Full Text Available Abstract Diffuse large B-cell lymphoma (DLBCL is the most common type of non-Hodgkin Lymphoma comprising of greater than 30% of adult non-Hodgkin Lymphomas. DLBCL represents a diverse set of lymphomas, defined as diffuse proliferation of large B lymphoid cells. Numerous cytogenetic studies including karyotypes and fluorescent in situ hybridization (FISH, as well as morphological, biological, clinical, microarray and sequencing technologies have attempted to categorize DLBCL into morphological variants, molecular and immunophenotypic subgroups, as well as distinct disease entities. Despite such efforts, most lymphoma remains undistinguishable and falls into DLBCL, not otherwise specified (DLBCL-NOS. The advent of microarray-based studies (chromosome, RNA, gene expression, etc has provided a plethora of high-resolution data that could potentially facilitate the finer classification of DLBCL. This review covers the microarray data currently published for DLBCL. We will focus on these types of data; 1 array based CGH; 2 classical CGH; and 3 gene expression profiling studies. The aims of this review were three-fold: (1 to catalog chromosome loci that are present in at least 20% or more of distinct DLBCL subtypes; a detailed list of gains and losses for different subtypes was generated in a table form to illustrate specific chromosome loci affected in selected subtypes; (2 to determine common and distinct copy number alterations among the different subtypes and based on this information, characteristic and similar chromosome loci for the different subtypes were depicted in two separate chromosome ideograms; and, (3 to list re-classified subtypes and those that remained indistinguishable after review of the microarray data. To the best of our knowledge, this is the first effort to compile and review available literatures on microarray analysis data and their practical utility in classifying DLBCL subtypes. Although conventional cytogenetic methods such

  19. Coding and decoding libraries of sequence-defined functional copolymers synthesized via photoligation.

    Science.gov (United States)

    Zydziak, Nicolas; Konrad, Waldemar; Feist, Florian; Afonin, Sergii; Weidner, Steffen; Barner-Kowollik, Christopher

    2016-11-30

    Designing artificial macromolecules with absolute sequence order represents a considerable challenge. Here we report an advanced light-induced avenue to monodisperse sequence-defined functional linear macromolecules up to decamers via a unique photochemical approach. The versatility of the synthetic strategy-combining sequential and modular concepts-enables the synthesis of perfect macromolecules varying in chemical constitution and topology. Specific functions are placed at arbitrary positions along the chain via the successive addition of monomer units and blocks, leading to a library of functional homopolymers, alternating copolymers and block copolymers. The in-depth characterization of each sequence-defined chain confirms the precision nature of the macromolecules. Decoding of the functional information contained in the molecular structure is achieved via tandem mass spectrometry without recourse to their synthetic history, showing that the sequence information can be read. We submit that the presented photochemical strategy is a viable and advanced concept for coding individual monomer units along a macromolecular chain.

  20. Mechanisms by Which Different Functional States of Mitochondria Define Yeast Longevity

    Science.gov (United States)

    Beach, Adam; Leonov, Anna; Arlia-Ciommo, Anthony; Svistkova, Veronika; Lutchman, Vicky; Titorenko, Vladimir I.

    2015-01-01

    Mitochondrial functionality is vital to organismal physiology. A body of evidence supports the notion that an age-related progressive decline in mitochondrial function is a hallmark of cellular and organismal aging in evolutionarily distant eukaryotes. Studies of the baker’s yeast Saccharomyces cerevisiae, a unicellular eukaryote, have led to discoveries of genes, signaling pathways and chemical compounds that modulate longevity-defining cellular processes in eukaryotic organisms across phyla. These studies have provided deep insights into mechanistic links that exist between different traits of mitochondrial functionality and cellular aging. The molecular mechanisms underlying the essential role of mitochondria as signaling organelles in yeast aging have begun to emerge. In this review, we discuss recent progress in understanding mechanisms by which different functional states of mitochondria define yeast longevity, outline the most important unanswered questions and suggest directions for future research. PMID:25768339

  1. Mechanisms by Which Different Functional States of Mitochondria Define Yeast Longevity

    Directory of Open Access Journals (Sweden)

    Adam Beach

    2015-03-01

    Full Text Available Mitochondrial functionality is vital to organismal physiology. A body of evidence supports the notion that an age-related progressive decline in mitochondrial function is a hallmark of cellular and organismal aging in evolutionarily distant eukaryotes. Studies of the baker’s yeast Saccharomyces cerevisiae, a unicellular eukaryote, have led to discoveries of genes, signaling pathways and chemical compounds that modulate longevity-defining cellular processes in eukaryotic organisms across phyla. These studies have provided deep insights into mechanistic links that exist between different traits of mitochondrial functionality and cellular aging. The molecular mechanisms underlying the essential role of mitochondria as signaling organelles in yeast aging have begun to emerge. In this review, we discuss recent progress in understanding mechanisms by which different functional states of mitochondria define yeast longevity, outline the most important unanswered questions and suggest directions for future research.

  2. Some double sequence spaces of interval numbers defined by Orlicz function

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    Ayhan Esi

    2014-10-01

    Full Text Available In this paper we introduce some interval valued double sequence spaces defined by Orlicz function and study different properties of these spaces like inclusion relations, solidity, etc. We establish some inclusion relations among them. Also we introduce the concept of double statistical convergence for interval number sequences and give an inclusion relation between interval valued double sequence spaces.

  3. The RNA Exosome Channeling and Direct Access Conformations Have Distinct In Vivo Functions

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    Jaeil Han

    2016-09-01

    Full Text Available The RNA exosome is a 3′–5′ ribonuclease complex that is composed of nine core subunits and an essential catalytic subunit, Rrp44. Two distinct conformations of Rrp44 were revealed in previous structural studies, suggesting that Rrp44 may change its conformation to exert its function. In the channeling conformation, (Rrp44ch, RNA accesses the active site after traversing the central channel of the RNA exosome, whereas in the other conformation, (Rrp44da, RNA gains direct access to the active site. Here, we show that the Rrp44da exosome is important for nuclear function of the RNA exosome. Defects caused by disrupting the direct access conformation are distinct from those caused by channel-occluding mutations, indicating specific functions for each conformation. Our genetic analyses provide in vivo evidence that the RNA exosome employs a direct-access route to recruit specific substrates, indicating that the RNA exosome uses alternative conformations to act on different RNA substrates.

  4. PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance.

    Science.gov (United States)

    van Oers, Johanna M M; Roa, Sergio; Werling, Uwe; Liu, Yiyong; Genschel, Jochen; Hou, Harry; Sellers, Rani S; Modrich, Paul; Scharff, Matthew D; Edelmann, Winfried

    2010-07-27

    The DNA mismatch repair protein PMS2 was recently found to encode a novel endonuclease activity. To determine the biological functions of this activity in mammals, we generated endonuclease-deficient Pms2E702K knock-in mice. Pms2EK/EK mice displayed increased genomic mutation rates and a strong cancer predisposition. In addition, class switch recombination, but not somatic hypermutation, was impaired in Pms2EK/EK B cells, indicating a specific role in Ig diversity. In contrast to Pms2-/- mice, Pms2EK/EK male mice were fertile, indicating that this activity is dispensable in spermatogenesis. Therefore, the PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance and tumor suppression.

  5. Distinct Functions of Specialized Dendritic Cell Subsets in Atherosclerosis and the Road Ahead

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    Alma Zernecke

    2014-01-01

    Full Text Available Atherosclerotic vascular disease is modulated by immune mechanisms. Dendritic cells (DCs and T cells are present within atherosclerotic lesions and function as central players in the initiation and modulation of adaptive immune responses. In previous years, we have studied the functional contribution of distinct DC subsets in disease development, namely, that of CCL17-expressing DCs as well as that of plasmacytoid DCs that play specialized roles in disease development. This review focuses on important findings gathered in these studies and dissects the multifaceted contribution of CCL17-expressing DCs and pDCs to the pathogenesis of atherosclerosis. Furthermore, an outlook on future challenges faced when studying DCs in this detrimental disease are provided, and hurdles that will need to be overcome in order to enable a better understanding of the contribution of DCs to atherogenesis are discussed, a prerequisite for their therapeutic targeting in atherosclerosis.

  6. Between morphology and function: How syntactic centers of the Beijing city are defined

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    Tao Yang

    2015-12-01

    Full Text Available The application of big data provides a new angle of view on investigating whether, and if so, how to define the urban center through analyzing urban spatial morphology intrinsically interacts with its functions. This article, using empirical research of the Beijing city, first seeking to explore spatial configuration-the complex relation between any pair of individual spaces regarding other contextual spaces – of urban network collected from Baidu. And then, focusing on conducting a statistical correlation between the configurational patterns of urban network and the aggregation patterns of functions. Based on the different patterns of aggregation or dispersion of those functions we discussed, as well as the multi-scale syntactic location choice underlying those patterns, it then can be identified four types of centers in the Beijing city, which may be called active center, ordinary center, brand centers and specified center, as well as the extent to which spatial layout influences functional distribution.

  7. The mitochondrial elongation factors MIEF1 and MIEF2 exert partially distinct functions in mitochondrial dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Tong; Yu, Rong [Department of Oncology–Pathology, Karolinska Institutet, CCK R8:05, Karolinska University Hospital Solna, SE-171 76 Stockholm (Sweden); Jin, Shao-Bo [Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm (Sweden); Han, Liwei [Department of Oncology–Pathology, Karolinska Institutet, CCK R8:05, Karolinska University Hospital Solna, SE-171 76 Stockholm (Sweden); Lendahl, Urban [Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm (Sweden); Zhao, Jian, E-mail: Jian.Zhao@ki.se [Department of Oncology–Pathology, Karolinska Institutet, CCK R8:05, Karolinska University Hospital Solna, SE-171 76 Stockholm (Sweden); Nistér, Monica [Department of Oncology–Pathology, Karolinska Institutet, CCK R8:05, Karolinska University Hospital Solna, SE-171 76 Stockholm (Sweden)

    2013-11-01

    Mitochondria are dynamic organelles whose morphology is regulated by a complex balance of fission and fusion processes, and we still know relatively little about how mitochondrial dynamics is regulated. MIEF1 (also called MiD51) has recently been characterized as a key regulator of mitochondrial dynamics and in this report we explore the functions of its paralog MIEF2 (also called MiD49), to learn to what extent MIEF2 is functionally distinct from MIEF1. We show that MIEF1 and MIEF2 have many functions in common. Both are anchored in the mitochondrial outer membrane, recruit Drp1 from the cytoplasm to the mitochondrial surface and cause mitochondrial fusion, and MIEF2, like MIEF1, can interact with Drp1 and hFis1. MIEF1 and MIEF2, however, also differ in certain aspects. MIEF1 and MIEF2 are differentially expressed in human tissues during development. When overexpressed, MIEF2 exerts a stronger fusion-promoting effect than MIEF1, and in line with this, hFis1 and Mff can only partially revert the MIEF2-induced fusion phenotype, whereas MIEF1-induced fusion is reverted to a larger extent by hFis1 and Mff. MIEF2 forms high molecular weight oligomers, while MIEF1 is largely present as a dimer. Furthermore, MIEF1 and MIEF2 use distinct domains for oligomerization: in MIEF1, the region from amino acid residues 109–154 is required, whereas oligomerization of MIEF2 depends on amino acid residues 1 to 49, i.e. the N-terminal end. We also show that oligomerization of MIEF1 is not required for its mitochondrial localization and interaction with Drp1. In conclusion, our data suggest that the mitochondrial regulators MIEF1 and MIEF2 exert partially distinct functions in mitochondrial dynamics. - Highlights: • MIEF1 and MIEF2 recruit Drp1 to mitochondria and cause mitochondrial fusion. • MIEF2, like MIEF1, can interact with Drp1 and hFis1. • MIEF1 and MIEF2 are differentially expressed in human tissues during development. • MIEF2 exerts a stronger fusion

  8. The mitochondrial elongation factors MIEF1 and MIEF2 exert partially distinct functions in mitochondrial dynamics

    International Nuclear Information System (INIS)

    Liu, Tong; Yu, Rong; Jin, Shao-Bo; Han, Liwei; Lendahl, Urban; Zhao, Jian; Nistér, Monica

    2013-01-01

    Mitochondria are dynamic organelles whose morphology is regulated by a complex balance of fission and fusion processes, and we still know relatively little about how mitochondrial dynamics is regulated. MIEF1 (also called MiD51) has recently been characterized as a key regulator of mitochondrial dynamics and in this report we explore the functions of its paralog MIEF2 (also called MiD49), to learn to what extent MIEF2 is functionally distinct from MIEF1. We show that MIEF1 and MIEF2 have many functions in common. Both are anchored in the mitochondrial outer membrane, recruit Drp1 from the cytoplasm to the mitochondrial surface and cause mitochondrial fusion, and MIEF2, like MIEF1, can interact with Drp1 and hFis1. MIEF1 and MIEF2, however, also differ in certain aspects. MIEF1 and MIEF2 are differentially expressed in human tissues during development. When overexpressed, MIEF2 exerts a stronger fusion-promoting effect than MIEF1, and in line with this, hFis1 and Mff can only partially revert the MIEF2-induced fusion phenotype, whereas MIEF1-induced fusion is reverted to a larger extent by hFis1 and Mff. MIEF2 forms high molecular weight oligomers, while MIEF1 is largely present as a dimer. Furthermore, MIEF1 and MIEF2 use distinct domains for oligomerization: in MIEF1, the region from amino acid residues 109–154 is required, whereas oligomerization of MIEF2 depends on amino acid residues 1 to 49, i.e. the N-terminal end. We also show that oligomerization of MIEF1 is not required for its mitochondrial localization and interaction with Drp1. In conclusion, our data suggest that the mitochondrial regulators MIEF1 and MIEF2 exert partially distinct functions in mitochondrial dynamics. - Highlights: • MIEF1 and MIEF2 recruit Drp1 to mitochondria and cause mitochondrial fusion. • MIEF2, like MIEF1, can interact with Drp1 and hFis1. • MIEF1 and MIEF2 are differentially expressed in human tissues during development. • MIEF2 exerts a stronger fusion

  9. The dinoflagellates Durinskia baltica and Kryptoperidinium foliaceum retain functionally overlapping mitochondria from two evolutionarily distinct lineages

    Directory of Open Access Journals (Sweden)

    Keeling Patrick J

    2007-09-01

    Full Text Available Abtract Background The dinoflagellates Durinskia baltica and Kryptoperidinium foliaceum are distinguished by the presence of a tertiary plastid derived from a diatom endosymbiont. The diatom is fully integrated with the host cell cycle and is so altered in structure as to be difficult to recognize it as a diatom, and yet it retains a number of features normally lost in tertiary and secondary endosymbionts, most notably mitochondria. The dinoflagellate host is also reported to retain mitochondrion-like structures, making these cells unique in retaining two evolutionarily distinct mitochondria. This redundancy raises the question of whether the organelles share any functions in common or have distributed functions between them. Results We show that both host and endosymbiont mitochondrial genomes encode genes for electron transport proteins. We have characterized cytochrome c oxidase 1 (cox1, cytochrome oxidase 2 (cox2, cytochrome oxidase 3 (cox3, cytochrome b (cob, and large subunit of ribosomal RNA (LSUrRNA of endosymbiont mitochondrial ancestry, and cox1 and cob of host mitochondrial ancestry. We show that all genes are transcribed and that those ascribed to the host mitochondrial genome are extensively edited at the RNA level, as expected for a dinoflagellate mitochondrion-encoded gene. We also found evidence for extensive recombination in the host mitochondrial genes and that recombination products are also transcribed, as expected for a dinoflagellate. Conclusion Durinskia baltica and K. foliaceum retain two mitochondria from evolutionarily distinct lineages, and the functions of these organelles are at least partially overlapping, since both express genes for proteins in electron transport.

  10. User-defined functions in the Arden Syntax: An extension proposal.

    Science.gov (United States)

    Karadimas, Harry; Ebrahiminia, Vahid; Lepage, Eric

    2015-12-11

    The Arden Syntax is a knowledge-encoding standard, started in 1989, and now in its 10th revision, maintained by the health level seven (HL7) organization. It has constructs borrowed from several language concepts that were available at that time (mainly the HELP hospital information system and the Regenstrief medical record system (RMRS), but also the Pascal language, functional languages and the data structure of frames, used in artificial intelligence). The syntax has a rationale for its constructs, and has restrictions that follow this rationale. The main goal of the Standard is to promote knowledge sharing, by avoiding the complexity of traditional programs, so that a medical logic module (MLM) written in the Arden Syntax can remain shareable and understandable across institutions. One of the restrictions of the syntax is that you cannot define your own functions and subroutines inside an MLM. An MLM can, however, call another MLM, where this MLM will serve as a function. This will add an additional dependency between MLMs, a known criticism of the Arden Syntax knowledge model. This article explains why we believe the Arden Syntax would benefit from a construct for user-defined functions, discusses the need, the benefits and the limitations of such a construct. We used the recent grammar of the Arden Syntax v.2.10, and both the Arden Syntax standard document and the Arden Syntax Rationale article as guidelines. We gradually introduced production rules to the grammar. We used the CUP parsing tool to verify that no ambiguities were detected. A new grammar was produced, that supports user-defined functions. 22 production rules were added to the grammar. A parser was built using the CUP parsing tool. A few examples are given to illustrate the concepts. All examples were parsed correctly. It is possible to add user-defined functions to the Arden Syntax in a way that remains coherent with the standard. We believe that this enhances the readability and the robustness

  11. Salmonella Persistence in Tomatoes Requires a Distinct Set of Metabolic Functions Identified by Transposon Insertion Sequencing

    Science.gov (United States)

    Desai, Prerak; Porwollik, Steffen; Canals, Rocio; Perez, Daniel R.; Chu, Weiping; McClelland, Michael; Teplitski, Max

    2016-01-01

    ABSTRACT Human enteric pathogens, such as Salmonella spp. and verotoxigenic Escherichia coli, are increasingly recognized as causes of gastroenteritis outbreaks associated with the consumption of fruits and vegetables. Persistence in plants represents an important part of the life cycle of these pathogens. The identification of the full complement of Salmonella genes involved in the colonization of the model plant (tomato) was carried out using transposon insertion sequencing analysis. With this approach, 230,000 transposon insertions were screened in tomato pericarps to identify loci with reduction in fitness, followed by validation of the screen results using competition assays of the isogenic mutants against the wild type. A comparison with studies in animals revealed a distinct plant-associated set of genes, which only partially overlaps with the genes required to elicit disease in animals. De novo biosynthesis of amino acids was critical to persistence within tomatoes, while amino acid scavenging was prevalent in animal infections. Fitness reduction of the Salmonella amino acid synthesis mutants was generally more severe in the tomato rin mutant, which hyperaccumulates certain amino acids, suggesting that these nutrients remain unavailable to Salmonella spp. within plants. Salmonella lipopolysaccharide (LPS) was required for persistence in both animals and plants, exemplifying some shared pathogenesis-related mechanisms in animal and plant hosts. Similarly to phytopathogens, Salmonella spp. required biosynthesis of amino acids, LPS, and nucleotides to colonize tomatoes. Overall, however, it appears that while Salmonella shares some strategies with phytopathogens and taps into its animal virulence-related functions, colonization of tomatoes represents a distinct strategy, highlighting this pathogen's flexible metabolism. IMPORTANCE Outbreaks of gastroenteritis caused by human pathogens have been increasingly associated with foods of plant origin, with tomatoes

  12. Model for defining the level of implementation of the management functions in small enterprises

    Directory of Open Access Journals (Sweden)

    Dragan Mišetić

    2001-01-01

    Full Text Available Small enterprises, based on private ownership and entrepreneurial capability, represent, for the majority of the scientific and professional public, the prime movers of economic growth, both in developed market economies and in the economies of countries in transition. At the same time, various studies show that the main reason for the bankruptcy of many small enterprises (more than 90% can be found in weak management, i.e. unacquaintance with management functions (planning, organization, human resources management, leading and control and with the need of implementing those functions in practice. Although it is not easy to define the ingredients of the recipe for success or to define precisely the importance of different elements, and regardless of the fact that many authors think that the management theory for large enterprises is inapplicable for the small ones, we all agree that the owner/manager and his implementation of the management theory has a decisive influence on small enterprises in modern economic circumstances. Therefore, the author of this work is hereby representing the model, which defines the level of implementation of management functions in small enterprises, as well as three systems/levels (danger, risk, progress in which small enterprises may find themselves. After the level of implementation of the management function is identified, it is possible to undertake some corrective actions, which will remove the found failures. While choosing the variables of the model, the author took into consideration specific features of a small enterprise, as well as specific features of its owner/manager.

  13. Alzheimer’s disease: How metal ions define β-amyloid function

    DEFF Research Database (Denmark)

    Kepp, Kasper Planeta

    2017-01-01

    focuses on the essential coordination chemistry and biochemistry that relate transition metal ions iron, copper, and zinc to β-amyloid (Aβ) and most likely define the peptide's roles in neurons. The metal-Aβ interactions have elements of both gain of toxic function, as usually considered, but also loss......Alzheimer’s disease is increasingly recognized to be linked to the function and status of metal ions, and recently, the amyloid hypothesis has been strongly intertwined with the metal ion hypothesis; in fact, these two hypotheses fit well together and are not mutually contradictory. This review...... of natural functions, as emphasized in this review. Both these aspects and their relationships are discussed and their implications for future therapeutic strategies are outlined....

  14. Distinct Shifts in Microbiota Composition during Drosophila Aging Impair Intestinal Function and Drive Mortality

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    Rebecca I. Clark

    2015-09-01

    Full Text Available Alterations in the composition of the intestinal microbiota have been correlated with aging and measures of frailty in the elderly. However, the relationships between microbial dynamics, age-related changes in intestinal physiology, and organismal health remain poorly understood. Here, we show that dysbiosis of the intestinal microbiota, characterized by an expansion of the Gammaproteobacteria, is tightly linked to age-onset intestinal barrier dysfunction in Drosophila. Indeed, alterations in the microbiota precede and predict the onset of intestinal barrier dysfunction in aged flies. Changes in microbial composition occurring prior to intestinal barrier dysfunction contribute to changes in excretory function and immune gene activation in the aging intestine. In addition, we show that a distinct shift in microbiota composition follows intestinal barrier dysfunction, leading to systemic immune activation and organismal death. Our results indicate that alterations in microbiota dynamics could contribute to and also predict varying rates of health decline during aging in mammals.

  15. Comprehensive proteomic analysis of human milk-derived extracellular vesicles unveils a novel functional proteome distinct from other milk components

    NARCIS (Netherlands)

    van Herwijnen, Martijn J C; Zonneveld, Marijke I; Goerdayal, Soenita; Nolte-'t Hoen, Esther N M; Garssen, Johan; Stahl, Bernd; Altelaar, A F Maarten; Redegeld, Frank A; Wauben, Marca H M

    2016-01-01

    Breast milk contains several macromolecular components with distinctive functions, whereby milk fat globules and casein micelles mainly provide nutrition to the newborn, while whey contains molecules that can stimulate the newborn's developing immune system and gastrointestinal tract. Although

  16. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Kober, Daniel L.; Alexander-Brett, Jennifer M.; Karch, Celeste M.; Cruchaga, Carlos; Colonna, Marco; Holtzman, Michael J.; Brett, Thomas J. (WU-MED)

    2016-12-20

    Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer’s disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function. Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer’s risk variants impact binding to a TREM2 ligand. Additionally, the Alzheimer’s risk variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family. These findings provide a guide to structural and functional differences among genetic variants of TREM2, indicating that therapies targeting the TREM2 pathway should be tailored to these genetic and functional differences with patient-specific medicine approaches for neurodegenerative disorders.

  17. Functionally distinct amygdala subregions identified using DTI and high-resolution fMRI

    Science.gov (United States)

    Balderston, Nicholas L.; Schultz, Douglas H.; Hopkins, Lauren

    2015-01-01

    Although the amygdala is often directly linked with fear and emotion, amygdala neurons are activated by a wide variety of emotional and non-emotional stimuli. Different subregions within the amygdala may be engaged preferentially by different aspects of emotional and non-emotional tasks. To test this hypothesis, we measured and compared the effects of novelty and fear on amygdala activity. We used high-resolution blood oxygenation level-dependent (BOLD) imaging and streamline tractography to subdivide the amygdala into three distinct functional subunits. We identified a laterobasal subregion connected with the visual cortex that responds generally to visual stimuli, a non-projecting region that responds to salient visual stimuli, and a centromedial subregion connected with the diencephalon that responds only when a visual stimulus predicts an aversive outcome. We provide anatomical and functional support for a model of amygdala function where information enters through the laterobasal subregion, is processed by intrinsic circuits in the interspersed tissue, and is then passed to the centromedial subregion, where activation leads to behavioral output. PMID:25969533

  18. Mineral and organic growing media have distinct community structure, stability and functionality in soilless culture systems.

    Science.gov (United States)

    Grunert, Oliver; Hernandez-Sanabria, Emma; Vilchez-Vargas, Ramiro; Jauregui, Ruy; Pieper, Dietmar H; Perneel, Maaike; Van Labeke, Marie-Christine; Reheul, Dirk; Boon, Nico

    2016-01-05

    The choice of soilless growing medium for plant nutrition, growth and support is crucial for improving the eco-sustainability of the production in horticultural systems. As our current understanding of the functional microbial communities inhabiting this ecosystem is still limited, we examined the microbial community development of the two most important growing media (organic and mineral) used in open soilless horticultural systems. We aimed to identify factors that influence community composition over time, and to compare the distribution of individual taxa across growing media, and their potential functionality. High throughput sequencing analysis revealed a distinctive and stable microbial community in the organic growing medium. Humidity, pH, nitrate-N, ammonium-N and conductivity were uncovered as the main factors associated with the resident bacterial communities. Ammonium-N was correlated with Rhizobiaceae abundance, while potential competitive interactions among both Methylophilaceae and Actinobacteridae with Rhizobiaceae were suggested. Our results revealed that soilless growing media are unique niches for diverse bacterial communities with temporal functional stability, which may possibly impact the resistance to external forces. These differences in communities can be used to develop strategies to move towards a sustainable horticulture with increased productivity and quality.

  19. Cross-study analysis of genomic data defines the ciliate multigenic epiplasmin family: strategies for functional analysis in Paramecium tetraurelia

    Directory of Open Access Journals (Sweden)

    Ravet Viviane

    2009-06-01

    Full Text Available Abstract Background The sub-membranous skeleton of the ciliate Paramecium, the epiplasm, is composed of hundreds of epiplasmic scales centered on basal bodies, and presents a complex set of proteins, epiplasmins, which belong to a multigenic family. The repeated duplications observed in the P. tetraurelia genome present an interesting model of the organization and evolution of a multigenic family within a single cell. Results To study this multigenic family, we used phylogenetic, structural, and analytical transcriptional approaches. The phylogenetic method defines 5 groups of epiplasmins in the multigenic family. A refined analysis by Hydrophobic Cluster Analysis (HCA identifies structural characteristics of 51 epiplasmins, defining five separate groups, and three classes. Depending on the sequential arrangement of their structural domains, the epiplasmins are defined as symmetric, asymmetric or atypical. The EST data aid in this classification, in the identification of putative regulating sequences such as TATA or CAAT boxes. When specific RNAi experiments were conducted using sequences from either symmetric or asymmetric classes, phenotypes were drastic. Local effects show either disrupted or ill-shaped epiplasmic scales. In either case, this results in aborted cell division. Using structural features, we show that 4 epiplasmins are also present in another ciliate, Tetrahymena thermophila. Their affiliation with the distinctive structural groups of Paramecium epiplasmins demonstrates an interspecific multigenic family. Conclusion The epiplasmin multigenic family illustrates the history of genomic duplication in Paramecium. This study provides a framework which can guide functional analysis of epiplasmins, the major components of the membrane skeleton in ciliates. We show that this set of proteins handles an important developmental information in Paramecium since maintenance of epiplasm organization is crucial for cell morphogenesis.

  20. CD146/MCAM defines functionality of human bone marrow stromal stem cell populations

    DEFF Research Database (Denmark)

    Harkness, Linda; Zaher, Walid; Ditzel, Nicholas

    2016-01-01

    BACKGROUND: Identification of surface markers for prospective isolation of functionally homogenous populations of human skeletal (stromal, mesenchymal) stem cells (hMSCs) is highly relevant for cell therapy protocols. Thus, we examined the possible use of CD146 to subtype a heterogeneous hMSC...... population. METHODS: Using flow cytometry and cell sorting, we isolated two distinct hMSC-CD146(+) and hMSC-CD146(-) cell populations from the telomerized human bone marrow-derived stromal cell line (hMSC-TERT). Cells were examined for differences in their size, shape and texture by using high...... and adipocytes on the basis of gene expression and protein production of lineage-specific markers. In vivo, hMSC-CD146(+) and hMSC-CD146(-) cells formed bone and bone marrow organ when implanted subcutaneously in immune-deficient mice. Bone was enriched in hMSC-CD146(-) cells (12.6 % versus 8.1 %) and bone...

  1. Association between two distinct executive tasks in schizophrenia: a functional transcranial Doppler sonography study

    Directory of Open Access Journals (Sweden)

    Theodoridou Anastasia

    2006-05-01

    Full Text Available Abstract Background Schizophrenia is a severe mental disorder involving impairments in executive functioning, which are important cognitive processes that can be assessed by planning tasks such as the Stockings of Cambridge (SOC, and tasks of rule learning/abstraction such as the Wisconsin Card Sorting Test (WCST. We undertook this study to investigate the association between performance during separate phases of SOC and WCST, including mean cerebral blood flow velocity (MFV measurements in chronic schizophrenia. Methods Functional transcranial Doppler sonography (fTCD was used to assess bilateral MFV changes in the middle (MCA and anterior (ACA cerebral arteries. Twenty-two patients with chronic schizophrenia and 20 healthy subjects with similar sociodemographic characteristics performed SOC and WCST during fTCD measurements of the MCA and the ACA. The SOC was varied in terms of easy and difficult problems, and also in terms of separate phases, namely mental planning and movement execution. The WCST performance was assessed separately for maintaining set and set shifting. This allowed us to examine the impact of problem difficulty and the impact of separate phases of a planning task on distinct intervals of WCST. Simultaneous registration of MFV was carried out to investigate the linkage of brain perfusion during the tasks. Results In patients, slowing of movement execution during easy problems (SOC was associated with slowing during maintaining set (WCST (P Conclusion The results of this study demonstrate performance and brain perfusion abnormalities in the association pattern of two different tasks of executive functioning in schizophrenia, and they support the notion that executive functions have a pathological functional correlate predominantly in the lateral hemispheres of the brain. This study also underpins the scientific potential of fTCD in assessing brain perfusion in patients with schizophrenia.

  2. Generation of functional inhibitory synapses incorporating defined combinations of GABA(A or glycine receptor subunits

    Directory of Open Access Journals (Sweden)

    Christine Laura Dixon

    2015-12-01

    Full Text Available Fast inhibitory neurotransmission in the brain is mediated by wide range of GABAA receptor (GABAAR and glycine receptor (GlyR isoforms, each with different physiological and pharmacological properties. Because multiple isoforms are expressed simultaneously in most neurons, it is difficult to define the properties of inhibitory postsynaptic currents mediated by individual isoforms in vivo. Although recombinant expression systems permit the expression of individual isoforms in isolation, they require exogenous agonist application which cannot mimic the dynamic neurotransmitter profile characteristic of native synapses. We describe a neuron-HEK293 cell co-culture technique for generating inhibitory synapses incorporating defined combinations of GABAAR or GlyR subunits. Primary neuronal cultures, prepared from embryonic rat cerebral cortex or spinal cord, are used to provide presynaptic GABAergic and glycinergic terminals, respectively. When the cultures are mature, HEK293 cells expressing the subunits of interest plus neuroligin 2A are plated onto the neurons, which rapidly form synapses onto HEK293 cells. Patch clamp electrophysiology is then used to analyze the physiological and pharmacological properties of the inhibitory postsynaptic currents mediated by the recombinant receptors. The method is suitable for investigating the kinetic properties or the effects of drugs on inhibitory postsynaptic currents mediated by defined GABAAR or GlyR isoforms of interest, the effects of hereditary disease mutations on the formation and function of both types of synapses, and synaptogenesis and synaptic clustering mechanisms. The entire cell preparation procedure takes 2 – 5 weeks.

  3. Neurocognitive function in HIV-infected patients: comparison of two methods to define impairment.

    Directory of Open Access Journals (Sweden)

    Alejandro Arenas-Pinto

    Full Text Available To compare two definitions of neurocognitive impairment (NCI in a large clinical trial of effectively-treated HIV-infected adults at baseline.Hopkins Verbal Learning test-Revised (HVLT-R, Colour Trail (CTT and Grooved Pegboard (GPT tests were applied exploring five cognitive domains. Raw scores were transformed into Z-scores and NCI defined as summary NPZ-5 score one standard deviation below the mean of the normative dataset (i.e. <-1SD or Z-scores <-1SD in at least two individual domains (categorical scale. Principal component analysis (PCA was performed to explore the contribution of individual tests to the total variance.Mean NPZ-5 score was -0.72 (SD 0.98 and 178/548 (32% participants had NPZ-5 scores <-1SD. When impairment was defined as <-1SD in at least two individual tests, 283 (52% patients were impaired. Strong correlations between the two components of the HVLT-R test (learning/recall (r = 0.73, and the CTT and (attention/executive functioning (r = 0.66 were observed. PCA showed a clustering with three components accounting for 88% of the total variance. When patients who scored <-1SD only in two correlated tests were considered as not impaired, prevalence of NCI was 43%. When correlated test scores were averaged, 36% of participants had NPZ-3 scores <-1SD and 32% underperformed in at least two individual tests.Controlling for differential contribution of individual test-scores on the overall performance and the level of correlation between components of the test battery used appear to be important when testing cognitive function. These two factors are likely to affect both summary scores and categorical scales in defining cognitive impairment.EUDRACT: 2007-006448-23 and ISRCTN04857074.

  4. TALE factors use two distinct functional modes to control an essential zebrafish gene expression program.

    Science.gov (United States)

    Ladam, Franck; Stanney, William; Donaldson, Ian J; Yildiz, Ozge; Bobola, Nicoletta; Sagerström, Charles G

    2018-06-18

    TALE factors are broadly expressed embryonically and known to function in complexes with transcription factors (TFs) like Hox proteins at gastrula/segmentation stages, but it is unclear if such generally expressed factors act by the same mechanism throughout embryogenesis. We identify a TALE-dependent gene regulatory network (GRN) required for anterior development and detect TALE occupancy associated with this GRN throughout embryogenesis. At blastula stages, we uncover a novel functional mode for TALE factors, where they occupy genomic DECA motifs with nearby NF-Y sites. We demonstrate that TALE and NF-Y form complexes and regulate chromatin state at genes of this GRN. At segmentation stages, GRN-associated TALE occupancy expands to include HEXA motifs near PBX:HOX sites. Hence, TALE factors control a key GRN, but utilize distinct DNA motifs and protein partners at different stages - a strategy that may also explain their oncogenic potential and may be employed by other broadly expressed TFs. © 2018, Ladam et al.

  5. Two Functionally Distinct Sources of Actin Monomers Supply the Leading Edge of Lamellipodia

    Science.gov (United States)

    Vitriol, Eric A.; McMillen, Laura M.; Kapustina, Maryna; Gomez, Shawn M.; Vavylonis, Dimitrios; Zheng, James Q.

    2015-01-01

    Summary Lamellipodia, the sheet-like protrusions of motile cells, consist of networks of actin filaments (F-actin) regulated by the ordered assembly from and disassembly into actin monomers (G-actin). Traditionally, G-actin is thought to exist as a homogeneous pool. Here, we show that there are two functionally and molecularly distinct sources of G-actin that supply lamellipodial actin networks. G-actin originating from the cytosolic pool requires the monomer binding protein thymosin β4 (Tβ4) for optimal leading edge localization, is targeted to formins, and is responsible for creating an elevated G/F-actin ratio that promotes membrane protrusion. The second source of G-actin comes from recycled lamellipodia F-actin. Recycling occurs independently of Tβ4 and appears to regulate lamellipodia homeostasis. Tβ4-bound G-actin specifically localizes to the leading edge because it doesn’t interact with Arp2/3-mediated polymerization sites found throughout the lamellipodia. These findings demonstrate that actin networks can be constructed from multiple sources of monomers with discrete spatiotemporal functions. PMID:25865895

  6. Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models.

    Directory of Open Access Journals (Sweden)

    Sethu Sankaranarayanan

    Full Text Available In Alzheimer's disease (AD, an extensive accumulation of extracellular amyloid plaques and intraneuronal tau tangles, along with neuronal loss, is evident in distinct brain regions. Staging of tau pathology by postmortem analysis of AD subjects suggests a sequence of initiation and subsequent spread of neurofibrillary tau tangles along defined brain anatomical pathways. Further, the severity of cognitive deficits correlates with the degree and extent of tau pathology. In this study, we demonstrate that phospho-tau (p-tau antibodies, PHF6 and PHF13, can prevent the induction of tau pathology in primary neuron cultures. The impact of passive immunotherapy on the formation and spread of tau pathology, as well as functional deficits, was subsequently evaluated with these antibodies in two distinct transgenic mouse tauopathy models. The rTg4510 transgenic mouse is characterized by inducible over-expression of P301L mutant tau, and exhibits robust age-dependent brain tau pathology. Systemic treatment with PHF6 and PHF13 from 3 to 6 months of age led to a significant decline in brain and CSF p-tau levels. In a second model, injection of preformed tau fibrils (PFFs comprised of recombinant tau protein encompassing the microtubule-repeat domains into the cortex and hippocampus of young P301S mutant tau over-expressing mice (PS19 led to robust tau pathology on the ipsilateral side with evidence of spread to distant sites, including the contralateral hippocampus and bilateral entorhinal cortex 4 weeks post-injection. Systemic treatment with PHF13 led to a significant decline in the spread of tau pathology in this model. The reduction in tau species after p-tau antibody treatment was associated with an improvement in novel-object recognition memory test in both models. These studies provide evidence supporting the use of tau immunotherapy as a potential treatment option for AD and other tauopathies.

  7. Performance verification of network function virtualization in software defined optical transport networks

    Science.gov (United States)

    Zhao, Yongli; Hu, Liyazhou; Wang, Wei; Li, Yajie; Zhang, Jie

    2017-01-01

    With the continuous opening of resource acquisition and application, there are a large variety of network hardware appliances deployed as the communication infrastructure. To lunch a new network application always implies to replace the obsolete devices and needs the related space and power to accommodate it, which will increase the energy and capital investment. Network function virtualization1 (NFV) aims to address these problems by consolidating many network equipment onto industry standard elements such as servers, switches and storage. Many types of IT resources have been deployed to run Virtual Network Functions (vNFs), such as virtual switches and routers. Then how to deploy NFV in optical transport networks is a of great importance problem. This paper focuses on this problem, and gives an implementation architecture of NFV-enabled optical transport networks based on Software Defined Optical Networking (SDON) with the procedure of vNFs call and return. Especially, an implementation solution of NFV-enabled optical transport node is designed, and a parallel processing method for NFV-enabled OTN nodes is proposed. To verify the performance of NFV-enabled SDON, the protocol interaction procedures of control function virtualization and node function virtualization are demonstrated on SDON testbed. Finally, the benefits and challenges of the parallel processing method for NFV-enabled OTN nodes are simulated and analyzed.

  8. Distinct effects of childhood ADHD and cannabis use on brain functional architecture in young adults.

    Science.gov (United States)

    Kelly, Clare; Castellanos, F Xavier; Tomaselli, Olivia; Lisdahl, Krista; Tamm, Leanne; Jernigan, Terry; Newman, Erik; Epstein, Jeffery N; Molina, Brooke S G; Greenhill, Laurence L; Potkin, Steven G; Hinshaw, Stephen; Swanson, James M

    2017-01-01

    One of the most salient long-term implications of a childhood diagnosis of ADHD is an increased risk for substance use, abuse, or dependence in adolescence and adulthood. The extent to which cannabis use affects ADHD-related alterations in brain functional organization is unknown, however. To address this research gap, we recruited a sample of 75 individuals aged 21-25 years with and without a childhood diagnosis of ADHD Combined Type, who were either frequent users or non-users of cannabis. These participants have been followed longitudinally since age 7-9.9 years as part of a large multi-site longitudinal study of ADHD, the Multimodal Treatment Study of Children with ADHD (MTA). We examined task-independent intrinsic functional connectivity (iFC) within 9 functional networks using a 2 × 2 design, which compared four groups of participants: (1) individuals with a childhood diagnosis of ADHD who currently use cannabis ( n  = 23); (2) individuals with ADHD who do not currently use cannabis ( n  = 22); (3) comparisons who currently use cannabis ( n  = 15); and (4) comparisons who do not currently use cannabis ( n  = 15). The main effects of childhood ADHD were primarily weakened iFC in networks supporting executive function and somatomotor control. Contrary to expectations, effects of cannabis use were distinct from those of diagnostic group and no interactions were observed. Exploratory brain-behavior analyses suggested that ADHD-related effects were primarily linked with poorer neurocognitive performance. Deficits in the integrity of functional networks supporting executive function and somatomotor control are consistent with the phenotypic and neurocognitive features of ADHD. Our data suggest that cannabis use does not exacerbate ADHD-related alterations, but this finding awaits replication in a larger sample. Longitudinal neuroimaging studies are urgently required to delineate the neurodevelopmental cascade that culminates in positive and negative

  9. Distinct effects of childhood ADHD and cannabis use on brain functional architecture in young adults

    Directory of Open Access Journals (Sweden)

    Clare Kelly, PhD

    2017-01-01

    Full Text Available One of the most salient long-term implications of a childhood diagnosis of ADHD is an increased risk for substance use, abuse, or dependence in adolescence and adulthood. The extent to which cannabis use affects ADHD-related alterations in brain functional organization is unknown, however. To address this research gap, we recruited a sample of 75 individuals aged 21–25 years with and without a childhood diagnosis of ADHD Combined Type, who were either frequent users or non-users of cannabis. These participants have been followed longitudinally since age 7–9.9 years as part of a large multi-site longitudinal study of ADHD, the Multimodal Treatment Study of Children with ADHD (MTA. We examined task-independent intrinsic functional connectivity (iFC within 9 functional networks using a 2 × 2 design, which compared four groups of participants: (1 individuals with a childhood diagnosis of ADHD who currently use cannabis (n = 23; (2 individuals with ADHD who do not currently use cannabis (n = 22; (3 comparisons who currently use cannabis (n = 15; and (4 comparisons who do not currently use cannabis (n = 15. The main effects of childhood ADHD were primarily weakened iFC in networks supporting executive function and somatomotor control. Contrary to expectations, effects of cannabis use were distinct from those of diagnostic group and no interactions were observed. Exploratory brain-behavior analyses suggested that ADHD-related effects were primarily linked with poorer neurocognitive performance. Deficits in the integrity of functional networks supporting executive function and somatomotor control are consistent with the phenotypic and neurocognitive features of ADHD. Our data suggest that cannabis use does not exacerbate ADHD-related alterations, but this finding awaits replication in a larger sample. Longitudinal neuroimaging studies are urgently required to delineate the neurodevelopmental cascade that culminates in positive and

  10. The C. elegans Connectome Consists of Homogenous Circuits with Defined Functional Roles.

    Directory of Open Access Journals (Sweden)

    Aharon Azulay

    2016-09-01

    Full Text Available A major goal of systems neuroscience is to decipher the structure-function relationship in neural networks. Here we study network functionality in light of the common-neighbor-rule (CNR in which a pair of neurons is more likely to be connected the more common neighbors it shares. Focusing on the fully-mapped neural network of C. elegans worms, we establish that the CNR is an emerging property in this connectome. Moreover, sets of common neighbors form homogenous structures that appear in defined layers of the network. Simulations of signal propagation reveal their potential functional roles: signal amplification and short-term memory at the sensory/inter-neuron layer, and synchronized activity at the motoneuron layer supporting coordinated movement. A coarse-grained view of the neural network based on homogenous connected sets alone reveals a simple modular network architecture that is intuitive to understand. These findings provide a novel framework for analyzing larger, more complex, connectomes once these become available.

  11. Different methods to define utility functions yield similar results but engage different neural processes

    Directory of Open Access Journals (Sweden)

    Marcus Heldmann

    2009-10-01

    Full Text Available Although the concept of utility is fundamental to many economic theories, up to now a generally accepted method determining a subject’s utility function is not available. We investigated two methods that are used in economic sciences for describing utility functions by using response-locked event-related potentials in order to assess their neural underpinnings. For defining the certainty equivalent (CE, we used a lottery game with probabilities to win p=0.5, for identifying the subjects’ utility functions directly a standard bisection task was applied. Although the lottery tasks’ payoffs were only hypothetical, a pronounced negativity was observed resembling the error related negativity (ERN previously described in action monitoring research, but this occurred only for choices far away from the indifference point between money and lottery. By contrast, the bisection task failed to evoke an ERN irrespective of the responses’ correctness. Based on these findings we are reasoning that only decisions made in the lottery task achieved a level of subjective relevance that activates cognitive-emotional monitoring. In terms of economic sciences, our findings support the view that the bisection method is unaffected by any kind of probability valuation or other parameters related to risk and in combination with the lottery task can, therefore, be used to differentiate between payoff and probability valuation.

  12. Correlation of Theory and Function in Well-Defined Bimetallic Electrocatalysts - Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Crooks, Richard M.

    2014-06-05

    The objective of this research proposal was to correlate the structure of nanoparticles that are comprised of ~100-200 atoms to their electrocatalytic function. This objective was based on the growing body of evidence suggesting that catalytic properties can be tailored through controlled synthesis of nanoparticles. What has been missing from many of these studies, and what we are contributing, is a model catalyst that is sufficiently small, structurally well-defined, and well-characterized that its function can be directly predicted by theory. Specifically, our work seeks to develop a fundamental and detailed understanding of the relationship between the structure of nanoscopic oxygen-reduction catalysts and their function. We assembled a team with expertise in theory, synthesis, and advanced characterization methods to address the primary objective of this project. We anticipated the outcomes of the study to be: (1) a better theoretical understanding of how nanoparticle structure affects catalytic properties; (2) the development of advanced, in-situ and ex-situ, atomic-scale characterization methods that are appropriate for particles containing about 100 atoms; and (3) improved synthetic methods that produce unique nanoparticle structures that can be used to test theoretical predictions. During the project period, we have made excellent progress on all three fronts.

  13. SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis.

    Science.gov (United States)

    Muhar, Matthias; Ebert, Anja; Neumann, Tobias; Umkehrer, Christian; Jude, Julian; Wieshofer, Corinna; Rescheneder, Philipp; Lipp, Jesse J; Herzog, Veronika A; Reichholf, Brian; Cisneros, David A; Hoffmann, Thomas; Schlapansky, Moritz F; Bhat, Pooja; von Haeseler, Arndt; Köcher, Thomas; Obenauf, Anna C; Popow, Johannes; Ameres, Stefan L; Zuber, Johannes

    2018-05-18

    Defining direct targets of transcription factors and regulatory pathways is key to understanding their roles in physiology and disease. We combined SLAM-seq [thiol(SH)-linked alkylation for the metabolic sequencing of RNA], a method for direct quantification of newly synthesized messenger RNAs (mRNAs), with pharmacological and chemical-genetic perturbation in order to define regulatory functions of two transcriptional hubs in cancer, BRD4 and MYC, and to interrogate direct responses to BET bromodomain inhibitors (BETis). We found that BRD4 acts as general coactivator of RNA polymerase II-dependent transcription, which is broadly repressed upon high-dose BETi treatment. At doses triggering selective effects in leukemia, BETis deregulate a small set of hypersensitive targets including MYC. In contrast to BRD4, MYC primarily acts as a selective transcriptional activator controlling metabolic processes such as ribosome biogenesis and de novo purine synthesis. Our study establishes a simple and scalable strategy to identify direct transcriptional targets of any gene or pathway. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  14. Self-defining future projections: exploring the identity function of thinking about the future.

    Science.gov (United States)

    D'Argembeau, Arnaud; Lardi, Claudia; Van der Linden, Martial

    2012-01-01

    The act of projecting oneself into meaningful future events may significantly contribute to a person's sense of self and identity. Yet if the role of memories, in particular self-defining memories (SDMs), in grounding the self is now well established, the identity function of anticipated future events has received comparatively little attention. This article introduces the construct of self-defining future projection (SDFP) to address this issue. Two studies show that people can readily identify significant future events that they frequently think about and that convey core information about who they are as individuals. Furthermore, a person's particular style of constructing SDMs is similarly manifested in SDFPs, suggesting that both types of events can be used to ground the self. Notably, people who display a stronger tendency to extract meaning from their past experiences also reflect more about the potential implications of imagined future events. The results further demonstrate that SDMs and SDFPs both give rise to a strong sense of personal continuity over time and are meaningfully related to self-esteem. Together these findings lend support to the idea that a person's sense of self and identity is in part nourished by the anticipation of significant future events.

  15. A Constrained Genetic Algorithm with Adaptively Defined Fitness Function in MRS Quantification

    Science.gov (United States)

    Papakostas, G. A.; Karras, D. A.; Mertzios, B. G.; Graveron-Demilly, D.; van Ormondt, D.

    MRS Signal quantification is a rather involved procedure and has attracted the interest of the medical engineering community, regarding the development of computationally efficient methodologies. Significant contributions based on Computational Intelligence tools, such as Neural Networks (NNs), demonstrated a good performance but not without drawbacks already discussed by the authors. On the other hand preliminary application of Genetic Algorithms (GA) has already been reported in the literature by the authors regarding the peak detection problem encountered in MRS quantification using the Voigt line shape model. This paper investigates a novel constrained genetic algorithm involving a generic and adaptively defined fitness function which extends the simple genetic algorithm methodology in case of noisy signals. The applicability of this new algorithm is scrutinized through experimentation in artificial MRS signals interleaved with noise, regarding its signal fitting capabilities. Although extensive experiments with real world MRS signals are necessary, the herein shown performance illustrates the method's potential to be established as a generic MRS metabolites quantification procedure.

  16. On calculating double logarithmical asymptotics of vertex functions defined on the mass shell

    International Nuclear Information System (INIS)

    Belokurov, V.V.; Usyukina, N.I.

    1981-01-01

    The essence of the calculation method of double logarithmical asymptotics of vertex functions defined on the mass shell is presented. Using the method the asymptotics of the form-factor of electron is calculated. The ladder and cross-ladder diagrams are asymptotically considerable in every order of the perturbation theory. The way in which the asymptotics of the 4-order diagrams is calculated has been shown. The diagrams of this order and reduction procedures for them are given in a graphic form. The photon mass μ 2 not equal to 0 plays the role of a regulator, removing infrared divergencies. The double logarithmical asymptotics of the form-factor of electron on the mass shell is calculated rigorously in an arbitrary order of the perturbation theory [ru

  17. Investigation of distinctive characteristics of children with specific learning disorder and borderline intellectual functioning

    Directory of Open Access Journals (Sweden)

    Selcuk Ozkan

    Full Text Available Abstract Background Borderline intelligence function (BIF and specific learning disorder (SLD are common diagnoses in children who are brought up for learning problems and school failure. Objective The aim of our study was to determine whether there were distinctive aspects of cognitive testing routinely used in evaluating SLD and BIF and investigate emotion regulation skills and minor neurologic symptoms. Method Sixty children (30 SLD and 30 BIF who are currently attending primary school are selected for study. Visual Aural Digit Span Test – Form B, Gessel Figure Drawing Test, Bender Gestalt Visual Motor Perception Test, WISC-R, Emotion Regulation Scale (ERS and Neurological Evaluation Scale (NES was administered. Results There was no statistically significant difference between groups in cognitive tests. The emotional regulation ability measured by the emotional regulation subscale was better in the SLD group than the BIF group (p = 0.014. In the NES, sensory integration (p = 0.008, motor coordination (p = 0.047 and other (p < 0.001 subscales showed higher scores in the BIF group. Discussion It has been shown that cognitive tests don’t have distinguishing features in the evaluation of SLD and BIF. Emotion regulation subscale score of ERS and sensory integration, motor coordination, and total scores of NES can be used in both discrimination of groups.

  18. Highlights on distinctive structural and functional properties of HTLV Tax proteins

    Science.gov (United States)

    Romanelli, Maria Grazia; Diani, Erica; Bergamo, Elisa; Casoli, Claudio; Ciminale, Vincenzo; Bex, Françoise; Bertazzoni, Umberto

    2013-01-01

    Human T cell leukemia viruses (HTLVs) are complex human retroviruses of the Deltaretrovirus genus. Four types have been identified thus far, with HTLV-1 and HTLV-2 much more prevalent than HTLV-3 or HTLV-4. HTLV-1 and HTLV-2 possess strictly related genomic structures, but differ significantly in pathogenicity, as HTLV-1 is the causative agent of adult T cell leukemia and of HTLV-associated myelopathy/tropical spastic paraparesis, whereas HTLV-2 is not associated with neoplasia. HTLVs code for a protein named Tax that is responsible for enhancing viral expression and drives cell transformation. Much effort has been invested to dissect the impact of Tax on signal transduction pathways and to identify functional differences between the HTLV Tax proteins that may explain the distinct oncogenic potential of HTLV-1 and HTLV-2. This review summarizes our current knowledge of Tax-1 and Tax-2 with emphasis on their structure, role in activation of the NF-κB (nuclear factor kappa-B) pathway, and interactions with host factors. PMID:24058363

  19. Mesenchymal stem cells generate distinct functional hybrids in vitro via cell fusion or entosis.

    Science.gov (United States)

    Sottile, Francesco; Aulicino, Francesco; Theka, Ilda; Cosma, Maria Pia

    2016-11-09

    Homotypic and heterotypic cell-to-cell fusion are key processes during development and tissue regeneration. Nevertheless, aberrant cell fusion can contribute to tumour initiation and metastasis. Additionally, a form of cell-in-cell structure called entosis has been observed in several human tumours. Here we investigate cell-to-cell interaction between mouse mesenchymal stem cells (MSCs) and embryonic stem cells (ESCs). MSCs represent an important source of adult stem cells since they have great potential for regenerative medicine, even though they are also involved in cancer progression. We report that MSCs can either fuse forming heterokaryons, or be invaded by ESCs through entosis. While entosis-derived hybrids never share their genomes and induce degradation of the target cell, fusion-derived hybrids can convert into synkaryons. Importantly we show that hetero-to-synkaryon transition occurs through cell division and not by nuclear membrane fusion. Additionally, we also observe that the ROCK-actin/myosin pathway is required for both fusion and entosis in ESCs but only for entosis in MSCs. Overall, we show that MSCs can undergo fusion or entosis in culture by generating distinct functional cellular entities. These two processes are profoundly different and their outcomes should be considered given the beneficial or possible detrimental effects of MSC-based therapeutic applications.

  20. A Distinct Inhibitory Function for miR-18a in Th17 Cell Differentiation.

    Science.gov (United States)

    Montoya, Misty M; Maul, Julia; Singh, Priti B; Pua, Heather H; Dahlström, Frank; Wu, Nanyan; Huang, Xiaozhu; Ansel, K Mark; Baumjohann, Dirk

    2017-07-15

    Th17 cell responses orchestrate immunity against extracellular pathogens but also underlie autoimmune disease pathogenesis. In this study, we uncovered a distinct and critical role for miR-18a in limiting Th17 cell differentiation. miR-18a was the most dynamically upregulated microRNA of the miR-17-92 cluster in activated T cells. miR-18a deficiency enhanced CCR6 + RAR-related orphan receptor (ROR)γt + Th17 cell differentiation in vitro and increased the number of tissue Th17 cells expressing CCR6, RORγt, and IL-17A in airway inflammation models in vivo. Sequence-specific miR-18 inhibitors increased CCR6 and RORγt expression in mouse and human CD4 + T cells, revealing functional conservation. miR-18a directly targeted Smad4 , Hif1a , and Rora , all key transcription factors in the Th17 cell gene-expression program. These findings indicate that activating signals influence the outcome of Th cell differentiation via differential regulation of mature microRNAs within a common cluster. Copyright © 2017 by The American Association of Immunologists, Inc.

  1. CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature

    DEFF Research Database (Denmark)

    Hu, Shimin; Xu-Monette, Zijun Y; Balasubramanyam, Aarthi

    2013-01-01

    CD30, originally identified as a cell-surface marker of Reed-Sternberg and Hodgkin cells of classical Hodgkin lymphoma, is also expressed by several types of non-Hodgkin lymphoma, including a subset of diffuse large B-cell lymphoma (DLBCL). However, the prognostic and biological importance of CD3...... value of CD30 as a therapeutic target for brentuximab vedotin in ongoing successful clinical trials, it seems appropriate to consider CD30(+) DLBCL as a distinct subgroup of DLBCL....

  2. MASTICATORY FUNCTION OF OBESE CANDIDATES TO BARIATRIC SURGERY FROM DISTINCT SOCIOECONOMIC CLASSES.

    Science.gov (United States)

    Passeri, Celso Roberto; Andrade, Jacira Alves Caracik de Camargo; Tomal, Karla Thaíza; Pracucho, Eduardo Marcucci; Campos, Livia Paschoalino de; Sales-Peres, Silvia Helena de Carvalho

    Obesity and metabolic syndrome can be labeled as worldwide outbreak; thus, both have led to serious public health problem. Oral health can be worsened by both, obesity and metabolic syndrome. Tooth loss harms masticatory function, essential status to whom will be submitted to bariatric surgery. Assess masticatory function of obese candidates to bariatric surgery, who belong to distinct socioeconomic class range, in order to recognize hazard factors and the bias of socioeconomic factor in this context. Observational cross-section study, with samples comprised by two groups of patients, with distinct socioeconomic class range, one of them belonging to public health system (SUSG) and the other to private clinic (CPG), candidates to bariatric surgery. Were assessed anthropometric data, comorbidities and medicines usage, blood tests, habits and the number of dental functional units. The groups SUSG and CPG were homogeneous taking into account gender (p=0,890) and age range (p=0,170). The number of dental functional units was higher in the private group (pmundial. A saúde bucal é agravada por ambas as condições. Perda dentária prejudica função mastigatória, condição essencial para o paciente que será submetido à cirurgia bariátrica. Avaliar a função mastigatória de pacientes obesos candidatos à cirurgia bariátrica pertencentes a dois serviços de saúde com padrões socioeconômicos distintos, afim de identificar fatores de risco e a influência do fator socioeconômico nesta condição. Estudo observacional transversal, com amostra constituída por dois grupos de pacientes obesos, com condições socioeconômicas distintas, um pertencente ao sistema público de saúde (GSUS) e outro à clínica privada (GCP), candidatos à cirurgia bariátrica. Foram analisados dados antropométricos, comorbidades e uso de medicamentos para seu controle, exames laboratoriais, hábitos e o número de unidades funcionais dentárias presentes. Os grupos GSUS e GCP foram

  3. Quantitative expression profile of distinct functional regions in the adult mouse brain.

    Directory of Open Access Journals (Sweden)

    Takeya Kasukawa

    Full Text Available The adult mammalian brain is composed of distinct regions with specialized roles including regulation of circadian clocks, feeding, sleep/awake, and seasonal rhythms. To find quantitative differences of expression among such various brain regions, we conducted the BrainStars (B* project, in which we profiled the genome-wide expression of ∼50 small brain regions, including sensory centers, and centers for motion, time, memory, fear, and feeding. To avoid confounds from temporal differences in gene expression, we sampled each region every 4 hours for 24 hours, and pooled the samples for DNA-microarray assays. Therefore, we focused on spatial differences in gene expression. We used informatics to identify candidate genes with expression changes showing high or low expression in specific regions. We also identified candidate genes with stable expression across brain regions that can be used as new internal control genes, and ligand-receptor interactions of neurohormones and neurotransmitters. Through these analyses, we found 8,159 multi-state genes, 2,212 regional marker gene candidates for 44 small brain regions, 915 internal control gene candidates, and 23,864 inferred ligand-receptor interactions. We also found that these sets include well-known genes as well as novel candidate genes that might be related to specific functions in brain regions. We used our findings to develop an integrated database (http://brainstars.org/ for exploring genome-wide expression in the adult mouse brain, and have made this database openly accessible. These new resources will help accelerate the functional analysis of the mammalian brain and the elucidation of its regulatory network systems.

  4. Functional Connectivity with Distinct Neural Networks Tracks Fluctuations in Gain/Loss Framing Susceptibility

    Science.gov (United States)

    Smith, David V.; Sip, Kamila E.; Delgado, Mauricio R.

    2016-01-01

    Multiple large-scale neural networks orchestrate a wide range of cognitive processes. For example, interoceptive processes related to self-referential thinking have been linked to the default-mode network (DMN); whereas exteroceptive processes related to cognitive control have been linked to the executive-control network (ECN). Although the DMN and ECN have been postulated to exert opposing effects on cognition, it remains unclear how connectivity with these spatially overlapping networks contribute to fluctuations in behavior. While previous work has suggested the medial prefrontal cortex (MPFC) is involved in behavioral change following feedback, these observations could be linked to interoceptive processes tied to DMN or exteroceptive processes tied to ECN because MPFC is positioned in both networks. To address this problem, we employed independent component analysis combined with dual-regression functional connectivity analysis. Participants made a series of financial decisions framed as monetary gains or losses. In some sessions, participants received feedback from a peer observing their choices; in other sessions, feedback was not provided. Following feedback, framing susceptibility—indexed as the increase in gambling behavior in loss frames compared to gain frames—was heightened in some participants and diminished in others. We examined whether these individual differences were linked to differences in connectivity by contrasting sessions containing feedback against those that did not contain feedback. We found two key results. As framing susceptibility increased, the MPFC increased connectivity with DMN; in contrast, temporal-parietal junction decreased connectivity with the ECN. Our results highlight how functional connectivity patterns with distinct neural networks contribute to idiosyncratic behavioral changes. PMID:25858445

  5. The usefulness of the grammaticality-acceptability distinction in functional approaches to language

    DEFF Research Database (Denmark)

    Poulsen, Mads

    2013-01-01

    between competence and performance, rather than on a distinction between syntax and meaning. The basic rationale for having such a distinction is that much of linguistics is concerned with describing relatively stable grammatical knowledge, rather than the psycholinguistic dynamics of language use...

  6. Introducing Alternative-Based Thresholding for Defining Functional Regions of Interest in fMRI

    Directory of Open Access Journals (Sweden)

    Jasper Degryse

    2017-04-01

    Full Text Available In fMRI research, one often aims to examine activation in specific functional regions of interest (fROIs. Current statistical methods tend to localize fROIs inconsistently, focusing on avoiding detection of false activation. Not missing true activation is however equally important in this context. In this study, we explored the potential of an alternative-based thresholding (ABT procedure, where evidence against the null hypothesis of no effect and evidence against a prespecified alternative hypothesis is measured to control both false positives and false negatives directly. The procedure was validated in the context of localizer tasks on simulated brain images and using a real data set of 100 runs per subject. Voxels categorized as active with ABT can be confidently included in the definition of the fROI, while inactive voxels can be confidently excluded. Additionally, the ABT method complements classic null hypothesis significance testing with valuable information by making a distinction between voxels that show evidence against both the null and alternative and voxels for which the alternative hypothesis cannot be rejected despite lack of evidence against the null.

  7. In vitro Differentiation of Functional Human Skeletal Myotubes in a Defined System.

    Science.gov (United States)

    Guo, Xiufang; Greene, Keshel; Akanda, Nesar; Smith, Alec; Stancescu, Maria; Lambert, Stephen; Vandenburgh, Herman; Hickman, James

    2014-01-01

    In vitro human skeletal muscle systems are valuable tools for the study of human muscular development, disease and treatment. However, published in vitro human muscle systems have so far only demonstrated limited differentiation capacities. Advanced differentiation features such as cross-striations and contractility have only been observed in co-cultures with motoneurons. Furthermore, it is commonly regarded that cultured human myotubes do not spontaneously contract, and any contraction has been considered to originate from innervation. This study developed a serum-free culture system in which human skeletal myotubes demonstrated advanced differentiation. Characterization by immunocytochemistry, electrophysiology and analysis of contractile function revealed these major features: A) well defined sarcomeric development, as demonstrated by the presence of cross-striations. B) finely developed excitation-contraction coupling apparatus characterized by the close apposition of dihydropyridine receptors on T-tubules and Ryanodine receptors on sarcoplasmic reticulum membranes. C) spontaneous and electrically controlled contractility. This report not only demonstrates an improved level of differentiation of cultured human skeletal myotubes, but also provides the first published evidence that such myotubes are capable of spontaneous contraction. Use of this functional in vitro human skeletal muscle system would advance studies concerning human skeletal muscle development and physiology, as well as muscle-related disease and therapy.

  8. CD45RC isoform expression identifies functionally distinct T cell subsets differentially distributed between healthy individuals and AAV patients.

    Directory of Open Access Journals (Sweden)

    Laurence Ordonez

    Full Text Available In animal models of anti-neutrophil cytoplasmic antibody (ANCA-associated vasculitis (AAV, the proportion of CD45RC T cell subsets is important for disease susceptibility. Their human counterparts are, however, functionally ill defined. In this report, we studied their distribution in healthy controls (HC, AAV patients and in Systemic lupus erythematous (SLE patients as disease controls. We showed that CD45RC expression level on human CD4 and CD8 T cells identifies subsets that are highly variable among individuals. Interestingly, AAV patients exhibit an increased proportion of CD45RC(low CD4 T cells as compared to HC and SLE patients. This increase is stable over time and independent of AAV subtype, ANCA specificity, disease duration, or number of relapses. We also analyzed the cytokine profile of purified CD4 and CD8 CD45RC T cell subsets from HC, after stimulation with anti-CD3 and anti-CD28 mAbs. The CD45RC subsets exhibit different cytokine profiles. Type-1 cytokines (IL-2, IFN-gamma and TNF-alpha were produced by all CD45RC T cell subsets, while the production of IL-17, type-2 (IL-4, IL-5 and regulatory (IL-10 cytokines was restricted to the CD45RC(low subset. In conclusion, we have shown that CD45RC expression divides human T cells in functionally distinct subsets that are imbalanced in AAV. Since this imbalance is stable over time and independent of several disease parameters, we hypothesize that this is a pre-existing immune abnormality involved in the etiology of AAV.

  9. KIR2DL4 differentially signals downstream functions in human NK cells through distinct structural modules.

    Science.gov (United States)

    Miah, S M Shahjahan; Hughes, Tracey L; Campbell, Kerry S

    2008-03-01

    KIR2DL4 (2DL4) is a member of the killer cell Ig-like receptor (KIR) family in human NK cells. It can stimulate potent cytokine production and weak cytolytic activity in resting NK cells, but the mechanism for 2DL4-mediated signaling remains unclear. In this study we characterized the signaling pathways stimulated by 2DL4 engagement. In a human NK-like cell line, KHYG-1, cross-linking of 2DL4 activated MAPKs including JNK, ERK, and p38. Furthermore, 2DL4 cross-linking resulted in phosphorylation of IkappaB kinase beta (IKKbeta) and the phosphorylation and degradation of IkappaBalpha, which indicate activation of the classical NF-kappaB pathway. Engagement of 2DL4 was also shown to activate the transcription and translation of a variety of cytokine genes, including TNF-alpha, IFN-gamma, MIP1alpha, MIP1beta, and IL-8. Pharmacological inhibitors of JNK, MEK1/2 and p38, blocked IFN-gamma, IL-8, and MIP1alpha production, suggesting that MAPKs are regulating 2DL4-mediated cytokine production in a nonredundant manner. Activation of both p38 and ERK appear to be upstream of the stimulation of NF-kappaB. Mutation of a transmembrane arginine in 2DL4 to glycine (R/G mutant) abrogated FcepsilonRI-gamma association, as well as receptor-mediated cytolytic activity and calcium responses. Surprisingly, the R/G mutant still activated MAPKs and the NF-kappaB pathway and selectively stimulated the production of MIP1alpha, but not that of IFN-gamma or IL-8. In conclusion, we provide evidence that the activating functions of 2DL4 can be compartmentalized into two distinct structural modules: 1) through transmembrane association with FcepsilonRI-gamma; and 2) through another receptor domain independent of the transmembrane arginine.

  10. Functionally distinct dopamine signals in nucleus accumbens core and shell in the freely moving rat

    DEFF Research Database (Denmark)

    Dreyer, Jakob K.; Vander Weele, Caitlin M.; Lovic, Vedran

    2016-01-01

    Dynamic signaling of mesolimbic dopamine (DA) neurons has been implicated in reward learning, drug abuse, and motivation. However, this system is complex because firing patterns of these neurons are heterogeneous; subpopulations receive distinct synaptic inputs, and project to anatomically...

  11. Distinct accessory cell requirements define two types of rat T cell hybridomas specific for unique determinants in the encephalitogenic 68-86 region of myelin basic protein

    International Nuclear Information System (INIS)

    Mannie, M.D.; Paterson, P.Y.; Thomas, D.W.; Nairn, R.

    1990-01-01

    Six clonotypically unique T cell hybridomas from Lewis rats were used to study accessory cell activities required for class II MHC restricted T cell responses to the 68-86 encephalitogenic sequence of myelin basic protein (MBP). T cell hybrids which were cultured with GP68-86 68-86 sequence of guinea pig MBP (GPMBP) and naive splenocytes (SPL) were induced to produce IL-2 as measured by the CTLL indicator cell line. The hybrids were categorized into two subsets (designated THYB-1 and THYB-2), because two distinct subset-specific pathways of communication between accessory cells and T cells were involved in GPMBP-induced IL-2 production. These pathways were distinguished by the following six observations. First, when the duration of a pulse of SPL with GPMBP was lengthened from 1 to 4 h, these SPL lost their ability to induce IL-2 production by THYB-2 hybrids yet nevertheless retained full stimulatory activity for THYB-1 hybrids. Second, paraformaldehyde fixation of GPMBP-pulsed SPL abrogated an activity necessary for Ag-induced IL-2 production by THYB-2 hybrids. These fixed SPL were nevertheless able to stimulate THYB-1 hybrids, albeit to a lesser extent than viable unfixed SPL. Third, the addition of either cycloheximide, cytochalasin B, or 2-deoxyglucose to an Ag pulse of SPL with GPMBP dramatically inhibited the subsequent responses of THYB-2 hybrids yet had little or no effect upon the reactivity of THYB-1 hybrids. Fourth, thymocytes lacked necessary activities for GPMBP evoked IL-2 production by THYB-2 hybrids yet strongly promoted THYB-1 hybrid responses. Fifth, exposure of SPL to as little as 500 rad of gamma-irradiation markedly attenuated THYB-2 hybrid response to GPMBP but did not affect THYB-1 responses. Sixth, anti-GPMBP responses by THYB-2 hybrids were observed only in the presence of both radioresistant adherent SPL and a distinct population of radiosensitive nonadherent SPL

  12. Direct conversion of human fibroblasts into functional osteoblasts by defined factors.

    Science.gov (United States)

    Yamamoto, Kenta; Kishida, Tsunao; Sato, Yoshiki; Nishioka, Keisuke; Ejima, Akika; Fujiwara, Hiroyoshi; Kubo, Toshikazu; Yamamoto, Toshiro; Kanamura, Narisato; Mazda, Osam

    2015-05-12

    Osteoblasts produce calcified bone matrix and contribute to bone formation and remodeling. In this study, we established a procedure to directly convert human fibroblasts into osteoblasts by transducing some defined factors and culturing in osteogenic medium. Osteoblast-specific transcription factors, Runt-related transcription factor 2 (Runx2), and Osterix, in combination with Octamer-binding transcription factor 3/4 (Oct4) and L-Myc (RXOL) transduction, converted ∼ 80% of the fibroblasts into osteocalcin-producing cells. The directly converted osteoblasts (dOBs) induced by RXOL displayed a similar gene expression profile as normal human osteoblasts and contributed to bone repair after transplantation into immunodeficient mice at artificial bone defect lesions. The dOBs expressed endogenous Runx2 and Osterix, and did not require continuous expression of the exogenous genes to maintain their phenotype. Another combination, Oct4 plus L-Myc (OL), also induced fibroblasts to produce bone matrix, but the OL-transduced cells did not express Osterix and exhibited a more distant gene expression profile to osteoblasts compared with RXOL-transduced cells. These findings strongly suggest successful direct reprogramming of fibroblasts into functional osteoblasts by RXOL, a technology that may provide bone regeneration therapy against bone disorders.

  13. Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures.

    Science.gov (United States)

    Bohlen, Christopher J; Bennett, F Chris; Tucker, Andrew F; Collins, Hannah Y; Mulinyawe, Sara B; Barres, Ben A

    2017-05-17

    Microglia, the resident macrophages of the CNS, engage in various CNS-specific functions that are critical for development and health. To better study microglia and the properties that distinguish them from other tissue macrophage populations, we have optimized serum-free culture conditions to permit robust survival of highly ramified adult microglia under defined-medium conditions. We find that astrocyte-derived factors prevent microglial death ex vivo and that this activity results from three primary components, CSF-1/IL-34, TGF-β2, and cholesterol. Using microglial cultures that have never been exposed to serum, we demonstrate a dramatic and lasting change in phagocytic capacity after serum exposure. Finally, we find that mature microglia rapidly lose signature gene expression after isolation, and that this loss can be reversed by engrafting cells back into an intact CNS environment. These data indicate that the specialized gene expression profile of mature microglia requires continuous instructive signaling from the intact CNS. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. RYBP and Cbx7 Define Specific Biological Functions of Polycomb Complexes in Mouse Embryonic Stem Cells

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    Lluis Morey

    2013-01-01

    Full Text Available The Polycomb repressive complex 1 (PRC1 is required for decisions of stem cell fate. In mouse embryonic stem cells (ESCs, two major variations of PRC1 complex, defined by the mutually exclusive presence of Cbx7 or RYBP, have been identified. Here, we show that although the genomic localization of the Cbx7- and RYBP-containing PRC1 complexes overlaps in certain genes, it can also be mutually exclusive. At the molecular level, Cbx7 is necessary for recruitment of Ring1B to chromatin, whereas RYBP enhances the PRC1 enzymatic activity. Genes occupied by RYBP show lower levels of Ring1B and H2AK119ub and are consequently more highly transcribed than those bound by Cbx7. At the functional level, we show that genes occupied by RYBP are primarily involved in the regulation of metabolism and cell-cycle progression, whereas those bound by Cbx7 predominantly control early-lineage commitment of ESCs. Altogether, our results indicate that different PRC1 subtypes establish a complex pattern of gene regulation that regulates common and nonoverlapping aspects of ESC pluripotency and differentiation.

  15. Evaluation of an Empirical Reservoir Shape Function to Define Sediment Distributions in Small Reservoirs

    Directory of Open Access Journals (Sweden)

    Bogusław Michalec

    2015-08-01

    Full Text Available Understanding and defining the spatial distribution of sediment deposited in reservoirs is essential not only at the design stage but also during the operation. The majority of research concerns the distribution of sediment deposition in medium and large water reservoirs. Most empirical methods do not provide satisfactory results when applied to the determination of sediment deposition in small reservoirs. Small reservoir’s volumes do not exceed 5 × 106 m3 and their capacity-inflow ratio is less than 10%. Long-term silting measurements of three small reservoirs were used to evaluate the method described by Rahmanian and Banihashemi for predicting sediment distributions in small reservoirs. Rahmanian and Banihashemi stated that their model of distribution of sediment deposition in water reservoir works well for a long duration operation. In the presented study, the silting rate was used in order to determine the long duration operation. Silting rate is a quotient of volume of the sediment deposited in the reservoir and its original volume. It was stated that when the silting rate had reached 50%, the sediment deposition in the reservoir may be described by an empirical reservoir depth shape function (RDSF.

  16. Hyperandrogenism in female athletes with functional hypothalamic amenorrhea: a distinct phenotype

    Directory of Open Access Journals (Sweden)

    Javed A

    2015-01-01

    /dL (P=0.01 but not different from FHA-AN (P=0.31. Percentage of women with stress fractures was lower in FHA-EX+HA (4.5% as compared to both FHA-EX (27.3% and FHA-AN (50%; P=0.04 and 0.01 respectively. The LH/FSH ratio was weakly positively associated with serum glucose (adjusted r2=0.102; P=0.01 as well as with dual-energy X-ray absorptiometry spine score (adjusted r2=0.191; P=0.04 in the entire cohort.Conclusion: In a small cohort of female athletes with hyperandrogenism, a distinct reproductive hormone profile consisting of higher LH to FHS ratio may be associated with adverse metabolic health markers but improved skeletal health. Keywords: functional hypothalamic amenorrhea, hyperandrogenism, polycystic ovary syndrome, young athletes

  17. Two Distinct Isoforms of Matrix Metalloproteinase-2 Are Associated with Human Delayed Kidney Graft Function.

    Directory of Open Access Journals (Sweden)

    Shaynah Wanga

    Full Text Available Delayed graft function (DGF is a frequent complication of renal transplantation, particularly in the setting of transplantation of kidneys derived from deceased donors and expanded-criteria donors. DGF results from tubular epithelial cell injury and has immediate and long term consequences. These include requirement for post-transplantation dialysis, increased incidence of acute rejection, and poorer long-term outcomes. DGF represents one of the clearest clinical examples of renal acute ischemia/reperfusion injury. Experimental studies have demonstrated that ischemia/reperfusion injury induces the synthesis of the full length secreted isoform of matrix metalloproteinase-2 (FL-MMP-2, as well as an intracellular N-terminal truncated MMP-2 isoform (NTT-MMP-2 that initiates an innate immune response. We hypothesized that the two MMP-2 isoforms mediate tubular epithelial cell injury in DGF. Archival renal biopsy sections from 10 protocol biopsy controls and 41 cases with a clinical diagnosis of DGF were analyzed for the extent of tubular injury, expression of the FL-MMP-2 and NTT-MMP-2 isoforms by immunohistochemistry (IHC, in situ hybridization, and qPCR to determine isoform abundance. Differences in transcript abundance were related to tubular injury score. Markers of MMP-2-mediated injury included TUNEL staining and assessment of peritubular capillary density. There was a clear relationship between tubular epithelial cell expression of both FL-MMP-2 and NTT-MMP-2 IHC with the extent of tubular injury. The MMP-2 isoforms were detected in the same tubular segments and were present at sites of tubular injury. qPCR demonstrated highly significant increases in both the FL-MMP-2 and NTT-MMP-2 transcripts. Statistical analysis revealed highly significant associations between FL-MMP-2 and NTT-MMP-2 transcript abundance and the extent of tubular injury, with NTT-MMP-2 having the strongest association. We conclude that two distinct MMP-2 isoforms are

  18. Specific Language Impairment and High Functioning Autism : Evidence for Distinct Etiologies and for Modularity of Grammar and Pragmatics

    NARCIS (Netherlands)

    Creemers, A.; Schaeffer, J.C.; Perkins, L.; Dudley, R.; Gerard, J.; Hitczenko, K.

    2015-01-01

    This study investigates whether grammar and pragmatics are separate linguistic components, and whether children with Specific Language Impairment (SLI) and children with High Functioning Autism (HFA) have similar or distinct etiologies. A group of 27 children with HFA aged 6-14, age and gender

  19. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes

    NARCIS (Netherlands)

    Movahedi, Kiavash; Laoui, Damya; Gysemans, Conny; Baeten, Martijn; Stangé, Geert; van den Bossche, Jan; Mack, Matthias; Pipeleers, Daniel; In't Veld, Peter; de Baetselier, Patrick; van Ginderachter, Jo A.

    2010-01-01

    Tumor-associated macrophages (TAM) form a major component of the tumor stroma. However, important concepts such as TAM heterogeneity and the nature of the monocytic TAM precursors remain speculative. Here, we show for the first time that mouse mammary tumors contained functionally distinct subsets

  20. Two distinct binding modes define the interaction of Brox with the C-terminal tails of CHMP5 and CHMP4B.

    Science.gov (United States)

    Mu, Ruiling; Dussupt, Vincent; Jiang, Jiansheng; Sette, Paola; Rudd, Victoria; Chuenchor, Watchalee; Bello, Nana F; Bouamr, Fadila; Xiao, Tsan Sam

    2012-05-09

    Interactions of the CHMP protein carboxyl terminal tails with effector proteins play important roles in retroviral budding, cytokinesis, and multivesicular body biogenesis. Here we demonstrate that hydrophobic residues at the CHMP4B C-terminal amphipathic α helix bind a concave surface of Brox, a mammalian paralog of Alix. Unexpectedly, CHMP5 was also found to bind Brox and specifically recruit endogenous Brox to detergent-resistant membrane fractions through its C-terminal 20 residues. Instead of an α helix, the CHMP5 C-terminal tail adopts a tandem β-hairpin structure that binds Brox at the same site as CHMP4B. Additional Brox:CHMP5 interface is furnished by a unique CHMP5 hydrophobic pocket engaging the Brox residue Y348 that is not conserved among the Bro1 domains. Our studies thus unveil a β-hairpin conformation of the CHMP5 protein C-terminal tail, and provide insights into the overlapping but distinct binding profiles of ESCRT-III and the Bro1 domain proteins. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. Hyperacetylation and differential deacetylation of histones H4 and H3 define two distinct classes of acetylated SV40 chromosomes early in infection

    International Nuclear Information System (INIS)

    Milavetz, Barry

    2004-01-01

    SV40 chromosomes undergoing encapsidation late in infection and SV40 chromatin in virions are hyperacetylated on histones H4 and H3. However, the fate of the SV40 chromosomes containing hyperacetylated histones in a subsequent round of infection has not been determined. In order to determine if SV40 chromosomes undergo changes in the extent of histone acetylation during early infection, we have analyzed SV40 chromosomes isolated 30 min and 3 h postinfection by quantitative ChIP assays, depletion ChIP assays, competitive ChIP assays, and ChIP assays combined with restriction endonuclease sensitivity using antibodies to hyperacetylated histones H4 and H3. We have shown that at 30 min postinfection, the hyperacetylated histones are associated with two distinct classes of SV40 chromosomes. One form is hyperacetylated specifically on histone H4 while a second form is hyperacetylated on both H4 and H3. Both forms of chromosomes appear to contain a nucleosome-free promoter region. Over the course of the next few hours of infection, the class of SV40 chromosomes hyperacetylated on only H4 is reduced or completely eliminated through deacetylation

  2. Overlapping effector interfaces define the multiple functions of the HIV-1 Nef polyproline helix

    Directory of Open Access Journals (Sweden)

    Kuo Lillian S

    2012-05-01

    Full Text Available Abstract Background HIV-1 Nef is a multifunctional protein required for full pathogenicity of the virus. As Nef has no known enzymatic activity, it necessarily functions through protein-protein interaction interfaces. A critical Nef protein interaction interface is centered on its polyproline segment (P69VRPQVPLRP78 which contains the helical SH3 domain binding protein motif, PXXPXR. We hypothesized that any Nef-SH3 domain interactions would be lost upon mutation of the prolines or arginine of PXXPXR. Further, mutation of the non-motif “X” residues, (Q73, V74, and L75 would give altered patterns of inhibition for different Nef/SH3 domain protein interactions. Results We found that mutations of either of the prolines or the arginine of PXXPXR are defective for Nef-Hck binding, Nef/activated PAK2 complex formation and enhancement of virion infectivity (EVI. Mutation of the non-motif “X” residues (Q, V and L gave similar patterns of inhibition for Nef/activated PAK2 complex formation and EVI which were distinct from the pattern for Hck binding. These results implicate an SH3 domain containing protein other than Hck for Nef/activated PAK2 complex formation and EVI. We have also mutated Nef residues at the N-and C-terminal ends of the polyproline segment to explore interactions outside of PXXPXR. We discovered a new locus GFP/F (G67, F68, P69 and F90 that is required for Nef/activated PAK2 complex formation and EVI. MHC Class I (MHCI downregulation was only partially inhibited by mutating the PXXPXR motif residues, but was fully inhibited by mutating the C-terminal P78. Further, we observed that MHCI downregulation strictly requires G67 and F68. Our mutational analysis confirms the recently reported structure of the complex between Nef, AP-1 μ1 and the cytoplasmic tail of MHCI, but does not support involvement of an SH3 domain protein in MHCI downregulation. Conclusion Nef has evolved to be dependent on interactions with multiple SH3 domain

  3. Hyperandrogenism in female athletes with functional hypothalamic amenorrhea: a distinct phenotype.

    Science.gov (United States)

    Javed, Asma; Kashyap, Rahul; Lteif, Aida N

    2015-01-01

    To compare the reproductive, metabolic, and skeletal profiles of young athletic women with functional hypothalamic amenorrhea (FHA) as well as clinical or biochemical hyperandrogenism (FHA-EX+HA) with body mass index matched women with FHA due to exercise (FHA-EX) or anorexia nervosa (FHA-AN) alone. Retrospective cohort study. Tertiary care teaching hospital. Adolescents and young women, 15-30 years of age, diagnosed with FHA along with concurrent signs of hyperandrogenism (n=22) and body mass index matched control groups consisting of 22 women in each group of FHA-EX and FHA-AN. 1) Reproductive hormone profile: luteinizing hormone (LH), follicle stimulating hormone (FSH), total testosterone, pelvic ultrasound features. 2) Metabolic function and skeletal health markers: fasting glucose, cholesterol, number of stress fractures and bone mineral density as assessed by spine dual-energy X-ray absorptiometry z scores. FHA-EX+HA group was older at diagnosis compared to the other groups with a median (interquartile range [IQR]) age of 22 (18.75-25.25) years versus (vs) 17.5 (15.75-19) for FHA-EX; (P<0.01) and 18 (16-22.25) years for FHA-AN (P=0.01). There were no differences among the groups based on number of hours of exercise per week, type of physical activity or duration of amenorrhea. Median (IQR) LH/FSH ratio was higher in FHA-EX+HA than both other groups, 1.44 (1.03-1.77) vs 0.50 (0.20-0.94) for FHA-EX and 0.67 (0.51-0.87) for FHA-AN (P<0.01 for both). Total testosterone concentrations were not different among the groups. Median (IQR) fasting serum glucose concentration was higher in FHA-EX+HA vs FHA-EX, 88.5 mg/dL (82.8-90 mg/dL) vs 83.5 mg/dL (78.8-86.3 mg/dL) (P=0.01) but not different from FHA-AN (P=0.31). Percentage of women with stress fractures was lower in FHA-EX+HA (4.5%) as compared to both FHA-EX (27.3%) and FHA-AN (50%); P=0.04 and 0.01 respectively. The LH/FSH ratio was weakly positively associated with serum glucose (adjusted r (2)=0.102; P=0.01) as

  4. Parametrically defined cerebral blood vessels as non-invasive blood input functions for brain PET studies

    International Nuclear Information System (INIS)

    Asselin, Marie-Claude; Cunningham, Vincent J; Amano, Shigeko; Gunn, Roger N; Nahmias, Claude

    2004-01-01

    A non-invasive alternative to arterial blood sampling for the generation of a blood input function for brain positron emission tomography (PET) studies is presented. The method aims to extract the dimensions of the blood vessel directly from PET images and to simultaneously correct the radioactivity concentration for partial volume and spillover. This involves simulation of the tomographic imaging process to generate images of different blood vessel and background geometries and selecting the one that best fits, in a least-squares sense, the acquired PET image. A phantom experiment was conducted to validate the method which was then applied to eight subjects injected with 6-[ 18 F]fluoro-L-DOPA and one subject injected with [ 11 C]CO-labelled red blood cells. In the phantom study, the diameter of syringes filled with an 11 C solution and inserted into a water-filled cylinder were estimated with an accuracy of half a pixel (1 mm). The radioactivity concentration was recovered to 100 ± 4% in the 8.7 mm diameter syringe, the one that most closely approximated the superior sagittal sinus. In the human studies, the method systematically overestimated the calibre of the superior sagittal sinus by 2-3 mm compared to measurements made in magnetic resonance venograms on the same subjects. Sources of discrepancies related to the anatomy of the blood vessel were found not to be fundamental limitations to the applicability of the method to human subjects. This method has the potential to provide accurate quantification of blood radioactivity concentration from PET images without the need for blood samples, corrections for delay and dispersion, co-registered anatomical images, or manually defined regions of interest

  5. Associations of anatomical measures from MRI with radiographically defined knee osteoarthritis score, pain, and physical functioning.

    Science.gov (United States)

    Sowers, Maryfran; Karvonen-Gutierrez, Carrie A; Jacobson, Jon A; Jiang, Yebin; Yosef, Matheos

    2011-02-02

    The prevalence of knee osteoarthritis is traditionally based on radiographic findings, but magnetic resonance imaging is now being used to provide better visualization of bone, cartilage, and soft tissues as well as the patellar compartment. The goal of this study was to estimate the prevalences of knee features defined on magnetic resonance imaging in a population and to relate these abnormalities to knee osteoarthritis severity scores based on radiographic findings, physical functioning, and reported knee pain in middle-aged women. Magnetic resonance images of the knee were evaluated for the location and severity of cartilage defects, bone marrow lesions, osteophytes, subchondral cysts, meniscal and/or ligamentous tears, effusion, and synovitis among 363 middle-aged women (724 knees) from the Michigan Study of Women's Health Across the Nation. These findings were related to Kellgren-Lawrence osteoarthritis severity scores from radiographs, self-reported knee pain, self-reported knee injury, perception of physical functioning, and physical performance measures to assess mobility. Radiographs, physical performance assessment, and interviews were undertaken at the 1996 study baseline and again (with the addition of magnetic resonance imaging assessment) at the follow-up visit during 2007 to 2008. The prevalence of moderate-to-severe knee osteoarthritis changed from 3.7% at the baseline assessment to 26.7% at the follow-up visit eleven years later. Full-thickness cartilage defects of the medial, lateral, and patellofemoral compartments were present in 14.5% (105 knees), 4.6% (thirty-three knees), and 26.2% (190 knees), respectively. Synovitis was identified in 24.7% (179) of the knees, and joint effusions were observed in 70% (507 knees); 21.7% (157) of the knees had complex or macerated meniscal tears. Large osteophytes, marked synovitis, macerated meniscal tears, and full-thickness tibial cartilage defects were associated with increased odds of knee pain and with

  6. Functional Proteomics Defines the Molecular Switch Underlying FGF Receptor Trafficking and Cellular Outputs

    DEFF Research Database (Denmark)

    Francavilla, Chiara; Rigbolt, Kristoffer T.G.; Emdal, Kristina B

    2013-01-01

    The stimulation of fibroblast growth factor receptors (FGFRs) with distinct FGF ligands generates specific cellular responses. However, the mechanisms underlying this paradigm have remained elusive. Here, we show that FGF-7 stimulation leads to FGFR2b degradation and, ultimately, cell proliferation...

  7. Cysteine Specific Targeting of the Functionally Distinct Peroxiredoxin and Glutaredoxin Proteins by the Investigational Disulfide BNP7787

    Directory of Open Access Journals (Sweden)

    Aulma R. Parker

    2015-03-01

    Full Text Available Glutaredoxin (Grx, peroxiredoxin (Prx, and thioredoxin (Trx are redoxin family proteins that catalyze different types of chemical reactions that impact cell growth and survival through functionally distinct intracellular pathways. Much research is focused on understanding the roles of these redoxin proteins in the development and/or progression of human diseases. Grx and Prx are overexpressed in human cancers, including human lung cancers. BNP7787 is a novel investigational agent that has been evaluated in previous clinical studies, including non-small cell lung cancer (NSCLC studies. Herein, data from activity assays, mass spectrometry analyses, and X-ray crystallographic studies indicate that BNP7787 forms mixed disulfides with select cysteine residues on Grx and Prx and modulates their function. Studies of interactions between BNP7787 and Trx have been conducted and reported separately. Despite the fact that Trx, Grx, and Prx are functionally distinct proteins that impact oxidative stress, cell proliferation and disease processes through different intracellular pathways, BNP7787 can modify each protein and appears to modulate function through mechanisms that are unique to each target protein. Tumor cells are often genomically heterogeneous containing subpopulations of cancer cells that often express different tumor-promoting proteins or that have multiple dysregulated signaling pathways modulating cell proliferation and drug resistance. A multi-targeted agent that simultaneously modulates activity of proteins important in mediating cell proliferation by functionally distinct intracellular pathways could have many potentially useful therapeutic applications.

  8. Compositionally and functionally distinct sinus microbiota in chronic rhinosinusitis patients have immunological and clinically divergent consequences

    OpenAIRE

    Cope, Emily K.; Goldberg, Andrew N.; Pletcher, Steven D.; Lynch, Susan V.

    2017-01-01

    Background Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by persistent sinonasal inflammation and sinus microbiome dysbiosis. The basis of this heterogeneity is poorly understood. We sought to address the hypothesis that a limited number of compositionally distinct pathogenic bacterial microbiota exist in CRS patients and invoke discrete immune responses and clinical phenotypes in CRS patients. Results Sinus brushings from patients with CRS (n?=?59) and healthy individ...

  9. Implement of the Owner Distinction Function for Healing-Type Pet Robots

    Science.gov (United States)

    Nambo, Hidetaka; Kimura, Haruhiko; Hirose, Sadaki

    In recent years, a robotics technology is extremely progressive, and robots are widely applied in many fields. One of the most typical robots is a pet robot. The pet robot is based on an animal pet, such as a dog or a cat. Also, it is known that an animal pet has a healing effect. Therefore, the study to apply pet robots to Animal Assisted Therapy instead of an animal pet has begun to be investigated. We, also, have investigated a method of an owner distinction for pet robot, to emphasize a healing effect of pet robots. In this paper, taking account of implementation into pet robots, a real-time owner distinction method is proposed. In the concrete, the method provides a real-time matching algorithm and an oblivion mechanism. The real-time matching means that a matching and a data acquisition are processed simultaneously. The oblivion mechanism is deleting features of owners in the database of the pet robots. Additionally, the mechanism enables to reduce matching costs or size of database and it enables to follow a change of owners. Furthermore, effectivity and a practicality of the method are evaluated by experiments.

  10. Advances in supramolecular polymer chemistry : well-defined terpyridine-functionalized materials

    NARCIS (Netherlands)

    Ott, C.

    2008-01-01

    Controlled/"living" polymerization techniques have attracted enormous attention in the field of polymer science since they have opened an avenue to the preparation of well-defined materials with precisely designed molecular architectures like random, block, graft and comb copolymers. These

  11. Distinct taxonomic and functional composition of soil microbiomes along the gradient forest-restinga-mangrove in southeastern Brazil.

    Science.gov (United States)

    Mendes, Lucas William; Tsai, Siu Mui

    2018-01-01

    Soil microorganisms play crucial roles in ecosystem functioning, and the central goal in microbial ecology studies is to elucidate which factors shape community structure. A better understanding of the relationship between microbial diversity, functions and environmental parameters would increase our ability to set conservation priorities. Here, the bacterial and archaeal community structure in Atlantic Forest, restinga and mangrove soils was described and compared based on shotgun metagenomics. We hypothesized that each distinct site would harbor a distinct taxonomic and functional soil community, which is influenced by environmental parameters. Our data showed that the microbiome is shaped by soil properties, with pH, base saturation, boron and iron content significantly correlated to overall community structure. When data of specific phyla were correlated to specific soil properties, we demonstrated that parameters such as boron, copper, sulfur, potassium and aluminum presented significant correlation with the most number of bacterial groups. Mangrove soil was the most distinct site and presented the highest taxonomic and functional diversity in comparison with forest and restinga soils. From the total 34 microbial phyla identified, 14 were overrepresented in mangrove soils, including several archaeal groups. Mangrove soils hosted a high abundance of sequences related to replication, survival and adaptation; forest soils included high numbers of sequences related to the metabolism of nutrients and other composts; while restinga soils included abundant genes related to the metabolism of carbohydrates. Overall, our finds show that the microbial community structure and functional potential were clearly different across the environmental gradient, followed by functional adaptation and both were related to the soil properties.

  12. Viral DNA Sensors IFI16 and Cyclic GMP-AMP Synthase Possess Distinct Functions in Regulating Viral Gene Expression, Immune Defenses, and Apoptotic Responses during Herpesvirus Infection

    Directory of Open Access Journals (Sweden)

    Benjamin A. Diner

    2016-11-01

    Full Text Available The human interferon-inducible protein IFI16 is an important antiviral factor that binds nuclear viral DNA and promotes antiviral responses. Here, we define IFI16 dynamics in space and time and its distinct functions from the DNA sensor cyclic dinucleotide GMP-AMP synthase (cGAS. Live-cell imaging reveals a multiphasic IFI16 redistribution, first to viral entry sites at the nuclear periphery and then to nucleoplasmic puncta upon herpes simplex virus 1 (HSV-1 and human cytomegalovirus (HCMV infections. Optogenetics and live-cell microscopy establish the IFI16 pyrin domain as required for nuclear periphery localization and oligomerization. Furthermore, using proteomics, we define the signature protein interactions of the IFI16 pyrin and HIN200 domains and demonstrate the necessity of pyrin for IFI16 interactions with antiviral proteins PML and cGAS. We probe signaling pathways engaged by IFI16, cGAS, and PML using clustered regularly interspaced short palindromic repeat (CRISPR/Cas9-mediated knockouts in primary fibroblasts. While IFI16 induces cytokines, only cGAS activates STING/TBK-1/IRF3 and apoptotic responses upon HSV-1 and HCMV infections. cGAS-dependent apoptosis upon DNA stimulation requires both the enzymatic production of cyclic dinucleotides and STING. We show that IFI16, not cGAS or PML, represses HSV-1 gene expression, reducing virus titers. This indicates that regulation of viral gene expression may function as a greater barrier to viral replication than the induction of antiviral cytokines. Altogether, our findings establish coordinated and distinct antiviral functions for IFI16 and cGAS against herpesviruses.

  13. Two distinct E3 ubiquitin ligases have complementary functions in the regulation of delta and serrate signaling in Drosophila.

    Directory of Open Access Journals (Sweden)

    Roland Le Borgne

    2005-04-01

    Full Text Available Signaling by the Notch ligands Delta (Dl and Serrate (Ser regulates a wide variety of essential cell-fate decisions during animal development. Two distinct E3 ubiquitin ligases, Neuralized (Neur and Mind bomb (Mib, have been shown to regulate Dl signaling in Drosophila melanogaster and Danio rerio, respectively. While the neur and mib genes are evolutionarily conserved, their respective roles in the context of a single organism have not yet been examined. We show here that the Drosophila mind bomb (D-mib gene regulates a subset of Notch signaling events, including wing margin specification, leg segmentation, and vein determination, that are distinct from those events requiring neur activity. D-mib also modulates lateral inhibition, a neur- and Dl-dependent signaling event, suggesting that D-mib regulates Dl signaling. During wing development, expression of D-mib in dorsal cells appears to be necessary and sufficient for wing margin specification, indicating that D-mib also regulates Ser signaling. Moreover, the activity of the D-mib gene is required for the endocytosis of Ser in wing imaginal disc cells. Finally, ectopic expression of neur in D-mib mutant larvae rescues the wing D-mib phenotype, indicating that Neur can compensate for the lack of D-mib activity. We conclude that D-mib and Neur are two structurally distinct proteins that have similar molecular activities but distinct developmental functions in Drosophila.

  14. Myocardial Perfusion and Function Are Distinctly Altered by Sevoflurane Anesthesia in Diet-Induced Prediabetic Rats.

    Science.gov (United States)

    van den Brom, Charissa E; Boly, Chantal A; Bulte, Carolien S E; van den Akker, Rob F P; Kwekkeboom, Rick F J; Loer, Stephan A; Boer, Christa; Bouwman, R Arthur

    2016-01-01

    Preservation of myocardial perfusion during surgery is particularly important in patients with increased risk for perioperative complications, such as diabetes. Volatile anesthetics, like sevoflurane, have cardiodepressive effects and may aggravate cardiovascular complications. We investigated the effect of sevoflurane on myocardial perfusion and function in prediabetic rats. Rats were fed a western diet (WD; n = 18) or control diet (CD; n = 18) for 8 weeks and underwent (contrast) echocardiography to determine perfusion and function during baseline and sevoflurane exposure. Myocardial perfusion was estimated based on the product of microvascular filling velocity and blood volume. WD-feeding resulted in a prediabetic phenotype characterized by obesity, hyperinsulinemia, hyperlipidemia, glucose intolerance, and hyperglycemia. At baseline, WD-feeding impaired myocardial perfusion and systolic function compared to CD-feeding. Exposure of healthy rats to sevoflurane increased the microvascular filling velocity without altering myocardial perfusion but impaired systolic function. In prediabetic rats, sevoflurane did also not affect myocardial perfusion; however, it further impaired systolic function. Diet-induced prediabetes is associated with impaired myocardial perfusion and function in rats. While sevoflurane further impaired systolic function, it did not affect myocardial perfusion in prediabetic rats. Our findings suggest that sevoflurane anesthesia leads to uncoupling of myocardial perfusion and function, irrespective of the metabolic state.

  15. Defining the Physiological Factors that Contribute to Postflight Changes in Functional Performance

    Science.gov (United States)

    Bloomberg, J. J.; Arzeno, N.; Buxton, R.; Feiveson, A. H.; Kofman, I.; Lawrence, E.; Lee, S. M. C.; Mulavara, A. P.; Peters, B. T.; Platts, S. H.; hide

    2009-01-01

    Astronauts experience alterations in multiple physiological systems due to exposure to the microgravity conditions of space flight. These physiological changes include sensorimotor disturbances, cardiovascular deconditioning and loss of muscle mass and strength. These changes might affect the ability of crewmembers to perform critical mission tasks immediately after landing on lunar and Martian surfaces. To date, changes in functional performance have not been systematically studied or correlated with physiological changes. To understand how changes in physiological function impact functional performance an interdisciplinary pre/postflight testing regimen (Functional Task Test, FTT) has been developed that systematically evaluates both astronaut postflight functional performance and related physiological changes. The overall objective of the FTT is to identify the key underlying physiological factors that contribute to performance of functional tests that are representative of critical mission tasks. This study will identify which physiological systems contribute the most to impaired performance on each functional test. This will allow us to identify the physiological systems that play the largest role in decrement in functional performance. Using this information we can then design and implement countermeasures that specifically target the physiological systems most responsible for the altered functional performance associated with space flight. The functional test battery was designed to address high priority tasks identified by the Constellation program as critical for mission success. The set of functional tests making up the FTT include the: 1) Seat Egress and Walk Test, 2) Ladder Climb Test, 3) Recovery from Fall/Stand Test, 4) Rock Translation Test, 5) Jump Down Test, 6) Torque Generation Test, and 7) Construction Activity Board Test. Corresponding physiological measures include assessments of postural and gait control, dynamic visual acuity, fine motor

  16. Defining the role of sensation, strength, and prehension for upper limb function in cervical spinal cord injury.

    Science.gov (United States)

    Kalsi-Ryan, Sukhvinder; Beaton, Dorcas; Curt, Armin; Duff, Susan; Jiang, Depeng; Popovic, Milos R; Rudhe, Claudia; Fehlings, Michael G; Verrier, Mary C

    2014-01-01

    Upper limb function plays a significant role in enhancing independence for individuals with tetraplegia. However, there is limited knowledge about the specific input of sensorimotor deficits on upper limb function. Thus the theoretical framework designed to develop the Graded Redefined Assessment of Strength Sensibility and Prehension (GRASSP) was used as a hypothetical model to analyze the impact of impairment on function. To define the association of impairment (sensation, strength, and prehension measured by the GRASSP) to upper limb function as defined by functional measures (Capabilities of Upper Extremity Questionnaire, Spinal Cord Independence Measure). A hypothetical model representing relationships by applying structural equation modeling was used to estimate the effect of the impairment domains in GRASSP on upper limb function. Data collected on 72 chronic individuals with tetraplegia was used to test the hypothetical model. Structural equation modeling confirmed strong associations between sensation, strength, and prehension with upper limb function, and determined 72% of the variance in "sensorimotor upper limb function" was explained by the model. Statistics of fit showed the data did fit the hypothesized model. Sensation and strength influence upper limb function directly and indirectly with prehension as the mediator. The GRASSP is a sensitive diagnostic tool in distinguishing the relative contribution of strength, sensation and prehension to function. Thus, the impact of interventions on specific domains of impairment and related contribution on clinical recovery of the upper limb can be detailed to optimize rehabilitation programs.

  17. Information processing architecture of functionally defined clusters in the macaque cortex.

    Science.gov (United States)

    Shen, Kelly; Bezgin, Gleb; Hutchison, R Matthew; Gati, Joseph S; Menon, Ravi S; Everling, Stefan; McIntosh, Anthony R

    2012-11-28

    Computational and empirical neuroimaging studies have suggested that the anatomical connections between brain regions primarily constrain their functional interactions. Given that the large-scale organization of functional networks is determined by the temporal relationships between brain regions, the structural limitations may extend to the global characteristics of functional networks. Here, we explored the extent to which the functional network community structure is determined by the underlying anatomical architecture. We directly compared macaque (Macaca fascicularis) functional connectivity (FC) assessed using spontaneous blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) to directed anatomical connectivity derived from macaque axonal tract tracing studies. Consistent with previous reports, FC increased with increasing strength of anatomical connection, and FC was also present between regions that had no direct anatomical connection. We observed moderate similarity between the FC of each region and its anatomical connectivity. Notably, anatomical connectivity patterns, as described by structural motifs, were different within and across functional modules: partitioning of the functional network was supported by dense bidirectional anatomical connections within clusters and unidirectional connections between clusters. Together, our data directly demonstrate that the FC patterns observed in resting-state BOLD-fMRI are dictated by the underlying neuroanatomical architecture. Importantly, we show how this architecture contributes to the global organizational principles of both functional specialization and integration.

  18. Are Some Attitudes More Self-Defining Than Others? Assessing Self-Related Attitude Functions and Their Consequences.

    Science.gov (United States)

    Zunick, Peter V; Teeny, Jacob D; Fazio, Russell H

    2017-08-01

    Attitudes serve multiple functions, some related to the self-concept. We call attitudes that help people define who they are "self-defining." Across four studies, we tested a brief self-report measure of the extent to which an attitude is self-defining. Studies 1 and 2 showed that self-defining attitudes tend to be extreme, positive, and unambivalent. Studies 3 and 4 produced two main findings. First, self-definition was related to, but not redundant with, a number of other characteristics of the attitude (e.g., attitude certainty). Second, self-definition predicted participants' intentions to spontaneously advocate and, in Study 4, their reactions to an opportunity to advocate behaviorally (i.e., writing about their attitude in an optional response box) following a self-threat. Overall, the results highlight the utility of this approach and, more broadly, demonstrate the value of considering the role of the self in attitudinal processes, and vice versa.

  19. Further Refinements of Jensen’s Type Inequalities for the Function Defined on the Rectangle

    Directory of Open Access Journals (Sweden)

    M. Adil Khan

    2013-01-01

    Full Text Available We give refinement of Jensen’s type inequalities given by Bakula and Pečarić (2006 for the co-ordinate convex function. Also we establish improvement of Jensen’s inequality for the convex function of two variables.

  20. Functionalization of Planet-Satellite Nanostructures Revealed by Nanoscopic Localization of Distinct Macromolecular Species

    KAUST Repository

    Rossner, Christian; Roddatis, Vladimir; Lopatin, Sergei; Vana, Philipp

    2016-01-01

    The development of a straightforward method is reported to form hybrid polymer/gold planet-satellite nanostructures (PlSNs) with functional polymer. Polyacrylate type polymer with benzyl chloride in its backbone as a macromolecular tracer

  1. Ecological function as a target for ecosystem-based management: Defining when change matters in decision making

    Science.gov (United States)

    Ecosystem-based management (EBM) accounts for both direct and indirect drivers of ecological change for decision making. Just as with direct management of a resource, EBM requires a definition of management thresholds that define when change in function is sufficient to merit ma...

  2. The Functional Quality of Soluble Recombinant Polypeptides Produced in Escherichia coli Is Defined by a Wide Conformational Spectrum▿

    Science.gov (United States)

    Martínez-Alonso, Mónica; González-Montalbán, Nuria; García-Fruitós, Elena; Villaverde, Antonio

    2008-01-01

    We have observed that a soluble recombinant green fluorescent protein produced in Escherichia coli occurs in a wide conformational spectrum. This results in differently fluorescent protein fractions in which morphologically diverse soluble aggregates abound. Therefore, the functional quality of soluble versions of aggregation-prone recombinant proteins is defined statistically rather than by the prevalence of a canonical native structure. PMID:18836021

  3. Viral DNA Sensors IFI16 and Cyclic GMP-AMP Synthase Possess Distinct Functions in Regulating Viral Gene Expression, Immune Defenses, and Apoptotic Responses during Herpesvirus Infection.

    Science.gov (United States)

    Diner, Benjamin A; Lum, Krystal K; Toettcher, Jared E; Cristea, Ileana M

    2016-11-15

    The human interferon-inducible protein IFI16 is an important antiviral factor that binds nuclear viral DNA and promotes antiviral responses. Here, we define IFI16 dynamics in space and time and its distinct functions from the DNA sensor cyclic dinucleotide GMP-AMP synthase (cGAS). Live-cell imaging reveals a multiphasic IFI16 redistribution, first to viral entry sites at the nuclear periphery and then to nucleoplasmic puncta upon herpes simplex virus 1 (HSV-1) and human cytomegalovirus (HCMV) infections. Optogenetics and live-cell microscopy establish the IFI16 pyrin domain as required for nuclear periphery localization and oligomerization. Furthermore, using proteomics, we define the signature protein interactions of the IFI16 pyrin and HIN200 domains and demonstrate the necessity of pyrin for IFI16 interactions with antiviral proteins PML and cGAS. We probe signaling pathways engaged by IFI16, cGAS, and PML using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated knockouts in primary fibroblasts. While IFI16 induces cytokines, only cGAS activates STING/TBK-1/IRF3 and apoptotic responses upon HSV-1 and HCMV infections. cGAS-dependent apoptosis upon DNA stimulation requires both the enzymatic production of cyclic dinucleotides and STING. We show that IFI16, not cGAS or PML, represses HSV-1 gene expression, reducing virus titers. This indicates that regulation of viral gene expression may function as a greater barrier to viral replication than the induction of antiviral cytokines. Altogether, our findings establish coordinated and distinct antiviral functions for IFI16 and cGAS against herpesviruses. How mammalian cells detect and respond to DNA viruses that replicate in the nucleus is poorly understood. Here, we decipher the distinct functions of two viral DNA sensors, IFI16 and cGAS, during active immune signaling upon infection with two herpesviruses, herpes simplex virus 1 (HSV-1) and human cytomegalovirus (HCMV). We show that IFI16

  4. On paranormed Zweier ideal convergent sequence spaces defined By Orlicz function

    Directory of Open Access Journals (Sweden)

    Bipan Hazarika

    2014-10-01

    Full Text Available In this article we introduce paranorm ideal convergent sequence spaces using Zweier transform and Orlicz function. We study some topological and algebraic properties. Further we prove some inclusion relations related to these new spaces.

  5. Distinct brain metabolic patterns separately associated with cognition, motor function, and aging in Parkinson's disease dementia.

    Science.gov (United States)

    Ko, Ji Hyun; Katako, Audrey; Aljuaid, Maram; Goertzen, Andrew L; Borys, Andrew; Hobson, Douglas E; Kim, Seok Min; Lee, Chong Sik

    2017-12-01

    We explored whether patients with Parkinson's disease dementia (PDD) show a distinct spatial metabolic pattern that characterizes cognitive deficits in addition to motor dysfunction. Eighteen patients with PDD underwent 3 separate positron emission tomography sessions with [ 18 F]fluorodeoxyglucose (for glucose metabolism), fluorinated N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane (for dopamine transporter density) and Pittsburgh compound-B (for beta-amyloid load). We confirmed in PDD versus normal controls, overall hypometabolism in the posterior and prefrontal brain regions accompanied with hypermetabolism in subcortical structures and the cerebellar vermis. A multivariate network analysis then revealed 3 metabolic patterns that are separately associated with cognitive performance (p = 0.042), age (p = 0.042), and motor symptom severity (p = 0.039). The age-related pattern's association with aging was replicated in healthy controls (p = 0.047) and patients with Alzheimer's disease (p = 0.002). The cognition-related pattern's association with cognitive performance was observed, with a trend-level of correlation, in patients with dementia with Lewy bodies (p = 0.084) but not in patients with Alzheimer's disease (p = 0.974). We found no association with fluorinated N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane and Pittsburgh compound-B positron emission tomography with patients' cognitive performance. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Bipolar disorder type I and II show distinct relationships between cortical thickness and executive function.

    Science.gov (United States)

    Abé, C; Rolstad, S; Petrovic, P; Ekman, C-J; Sparding, T; Ingvar, M; Landén, M

    2018-06-15

    Frontal cortical abnormalities and executive function impairment co-occur in bipolar disorder. Recent studies have shown that bipolar subtypes differ in the degree of structural and functional impairments. The relationships between cognitive performance and cortical integrity have not been clarified and might differ across patients with bipolar disorder type I, II, and healthy subjects. Using a vertex-wise whole-brain analysis, we investigated how cortical integrity, as measured by cortical thickness, correlates with executive performance in patients with bipolar disorder type I, II, and controls (N = 160). We found focal associations between executive function and cortical thickness in the medial prefrontal cortex in bipolar II patients and controls, but not in bipolar I disorder. In bipolar II patients, we observed additional correlations in lateral prefrontal and occipital regions. Our findings suggest that bipolar disorder patients show altered structure-function relationships, and importantly that those relationships may differ between bipolar subtypes. The findings are line with studies suggesting subtype-specific neurobiological and cognitive profiles. This study contributes to a better understanding of brain structure-function relationships in bipolar disorder and gives important insights into the neuropathophysiology of diagnostic subtypes. © 2018 The Authors Acta Psychiatrica Scandinavica Published by John Wiley & Sons Ltd.

  7. Distinct and shared cognitive functions mediate event- and time-based prospective memory impairment in normal ageing

    Science.gov (United States)

    Gonneaud, Julie; Kalpouzos, Grégoria; Bon, Laetitia; Viader, Fausto; Eustache, Francis; Desgranges, Béatrice

    2011-01-01

    Prospective memory (PM) is the ability to remember to perform an action at a specific point in the future. Regarded as multidimensional, PM involves several cognitive functions that are known to be impaired in normal aging. In the present study, we set out to investigate the cognitive correlates of PM impairment in normal aging. Manipulating cognitive load, we assessed event- and time-based PM, as well as several cognitive functions, including executive functions, working memory and retrospective episodic memory, in healthy subjects covering the entire adulthood. We found that normal aging was characterized by PM decline in all conditions and that event-based PM was more sensitive to the effects of aging than time-based PM. Whatever the conditions, PM was linked to inhibition and processing speed. However, while event-based PM was mainly mediated by binding and retrospective memory processes, time-based PM was mainly related to inhibition. The only distinction between high- and low-load PM cognitive correlates lays in an additional, but marginal, correlation between updating and the high-load PM condition. The association of distinct cognitive functions, as well as shared mechanisms with event- and time-based PM confirms that each type of PM relies on a different set of processes. PMID:21678154

  8. Uterine Natural Killer Cells: Functional Distinctions and Influence on Pregnancy in Humans and Mice

    Directory of Open Access Journals (Sweden)

    Francesco Colucci

    2017-04-01

    Full Text Available Our understanding of development and function of natural killer (NK cells has progressed significantly in recent years. However, exactly how uterine NK (uNK cells develop and function is still unclear. To help investigators that are beginning to study tissue NK cells, we summarize in this review our current knowledge of the development and function of uNK cells, and what is yet to be elucidated. We compare and contrast the biology of human and mouse uNK cells in the broader context of the biology of innate lymphoid cells and with reference to peripheral NK cells. We also review how uNK cells may regulate trophoblast invasion and uterine spiral arterial remodeling in human and murine pregnancy.

  9. Distinct functions of Crumbs regulating slit diaphragms and endocytosis in Drosophila nephrocytes.

    Science.gov (United States)

    Hochapfel, Florian; Denk, Lucia; Mendl, Gudrun; Schulze, Ulf; Maaßen, Christine; Zaytseva, Yulia; Pavenstädt, Hermann; Weide, Thomas; Rachel, Reinhard; Witzgall, Ralph; Krahn, Michael P

    2017-12-01

    Mammalian podocytes, the key determinants of the kidney's filtration barrier, differentiate from columnar epithelial cells and several key determinants of apical-basal polarity in the conventional epithelia have been shown to regulate podocyte morphogenesis and function. However, little is known about the role of Crumbs, a conserved polarity regulator in many epithelia, for slit-diaphragm formation and podocyte function. In this study, we used Drosophila nephrocytes as model system for mammalian podocytes and identified a conserved function of Crumbs proteins for cellular morphogenesis, nephrocyte diaphragm assembly/maintenance, and endocytosis. Nephrocyte-specific knock-down of Crumbs results in disturbed nephrocyte diaphragm assembly/maintenance and decreased endocytosis, which can be rescued by Drosophila Crumbs as well as human Crumbs2 and Crumbs3, which were both expressed in human podocytes. In contrast to the extracellular domain, which facilitates nephrocyte diaphragm assembly/maintenance, the intracellular FERM-interaction motif of Crumbs is essential for regulating endocytosis. Moreover, Moesin, which binds to the FERM-binding domain of Crumbs, is essential for efficient endocytosis. Thus, we describe here a new mechanism of nephrocyte development and function, which is likely to be conserved in mammalian podocytes.

  10. Functional SNPs in the human ficolin (FCN) genes reveal distinct geographical patterns

    DEFF Research Database (Denmark)

    Hummelshøj, Tina; Munthe-Fog, Lea; Madsen, Hans O

    2008-01-01

    -Xaa-Yaa repeats and a Trp279STOP introduces a stop codon, thereby destroying the fibrinogen-like domain of Ficolin-1. In contrast to FCN1 and FCN2, the number of SNPs in FCN3 was very low. In conclusion, large ethnic differences in the FCN genes that will affect the concentration, structure, and function...

  11. Independent component analysis of high-resolution imaging data identifies distinct functional domains

    DEFF Research Database (Denmark)

    Reidl, Juergen; Starke, Jens; Omer, David

    2007-01-01

    be automatically detected. In the visual cortex orientation columns can be extracted. In all cases artifacts due to movement, heartbeat or respiration were separated from the functional signal by sICA and could be removed from the data set. sICA is therefore a powerful technique for data compression, unbiased...

  12. Synthetic alleles at position 121 define a functional domain of human interleukin-1 beta.

    Science.gov (United States)

    Ambrosetti, D C; Palla, E; Mirtella, A; Galeotti, C; Solito, E; Navarra, P; Parente, L; Melli, M

    1996-06-01

    The non-conservative substitution of the tyrosine residue at position 121 of human interleukin-1 beta (IL-1 beta) generates protein mutants showing strong reduction of the capacity to induce (a) prostaglandin E2 (PGE2) release from fibroblasts and smooth muscle cells, (b) murine T-cells proliferation and (c) activation of interleukin-6 (IL-6) gene expression. It is generally accepted that these functions are mediated by the type-I interleukin-1 receptor (IL-1RI). However, the mutant proteins maintain the binding affinity to the types-I and II IL-1 receptors, which is the same as the control IL-1 beta, suggesting that this amino acid substitution does not alter the structure of the molecule, except locally. Thus we have identified a new functional site of IL-1 beta different from the known receptor binding region, responsible for fundamental IL-1 beta functions. Moreover, we show that the same mutants maintain at least two hypothalamic functions, that is, the in vitro short-term PGE2 release from rat hypothalamus and the induction of fever in rabbits. This result suggests that there is yet another site of the molecule responsible for the hypothalamic functions, implying that multiple active sites on the IL-1 beta molecule, possibly binding to more than one receptor chain, trigger different signals.

  13. Distinct properties of hexameric but functionally conserved Mycobacterium tuberculosis transcription-repair coupling factor.

    Science.gov (United States)

    Prabha, Swayam; Rao, Desirazu N; Nagaraja, Valakunja

    2011-04-29

    Transcription coupled nucleotide excision repair (TC-NER) is involved in correcting UV-induced damage and other road-blocks encountered in the transcribed strand. Mutation frequency decline (Mfd) is a transcription repair coupling factor, involved in repair of template strand during transcription. Mfd from M. tuberculosis (MtbMfd) is 1234 amino-acids long harboring characteristic modules for different activities. Mtbmfd complemented Escherichia coli mfd (Ecomfd) deficient strain, enhanced survival of UV irradiated cells and increased the road-block repression in vivo. The protein exhibited ATPase activity, which was stimulated ∼1.5-fold in the presence of DNA. While the C-terminal domain (CTD) comprising amino acids 630 to 1234 showed ∼2-fold elevated ATPase activity than MtbMfd, the N-terminal domain (NTD) containing the first 433 amino acid residues was able to bind ATP but deficient in hydrolysis. Overexpression of NTD of MtbMfd led to growth defect and hypersensitivity to UV light. Deletion of 184 amino acids from the C-terminal end of MtbMfd (MfdΔC) increased the ATPase activity by ∼10-fold and correspondingly exhibited efficient translocation along DNA as compared to the MtbMfd and CTD. Surprisingly, MtbMfd was found to be distributed in monomer and hexamer forms both in vivo and in vitro and the monomer showed increased susceptibility to proteases compared to the hexamer. MfdΔC, on the other hand, was predominantly monomeric in solution implicating the extreme C-terminal region in oligomerization of the protein. Thus, although the MtbMfd resembles EcoMfd in many of its reaction characteristics, some of its hitherto unknown distinct properties hint at its species specific role in mycobacteria during transcription-coupled repair.

  14. Distinct properties of hexameric but functionally conserved Mycobacterium tuberculosis transcription-repair coupling factor.

    Directory of Open Access Journals (Sweden)

    Swayam Prabha

    Full Text Available Transcription coupled nucleotide excision repair (TC-NER is involved in correcting UV-induced damage and other road-blocks encountered in the transcribed strand. Mutation frequency decline (Mfd is a transcription repair coupling factor, involved in repair of template strand during transcription. Mfd from M. tuberculosis (MtbMfd is 1234 amino-acids long harboring characteristic modules for different activities. Mtbmfd complemented Escherichia coli mfd (Ecomfd deficient strain, enhanced survival of UV irradiated cells and increased the road-block repression in vivo. The protein exhibited ATPase activity, which was stimulated ∼1.5-fold in the presence of DNA. While the C-terminal domain (CTD comprising amino acids 630 to 1234 showed ∼2-fold elevated ATPase activity than MtbMfd, the N-terminal domain (NTD containing the first 433 amino acid residues was able to bind ATP but deficient in hydrolysis. Overexpression of NTD of MtbMfd led to growth defect and hypersensitivity to UV light. Deletion of 184 amino acids from the C-terminal end of MtbMfd (MfdΔC increased the ATPase activity by ∼10-fold and correspondingly exhibited efficient translocation along DNA as compared to the MtbMfd and CTD. Surprisingly, MtbMfd was found to be distributed in monomer and hexamer forms both in vivo and in vitro and the monomer showed increased susceptibility to proteases compared to the hexamer. MfdΔC, on the other hand, was predominantly monomeric in solution implicating the extreme C-terminal region in oligomerization of the protein. Thus, although the MtbMfd resembles EcoMfd in many of its reaction characteristics, some of its hitherto unknown distinct properties hint at its species specific role in mycobacteria during transcription-coupled repair.

  15. Defining a similarity threshold for a functional proteinsequence pattern: The signal peptide cleavage site

    DEFF Research Database (Denmark)

    Nielsen, Henrik; Engelbrecht, Jacob; von Heijne, Gunnar

    1996-01-01

    When preparing data sets of amino acid or nucleotide sequences it is necessary to exclude redundant or homologous sequences in order to avoid overestimating the predictive performance of an algorithm. For some time methods for doing this have been available in the area of protein structure...... prediction. We have developed a similar procedure based on pair-wise alignments for sequences with functional sites. We show how a correlation coefficient between sequence similarity and functional homology can be used to compare the efficiency of different similarity measures and choose a nonarbitrary...

  16. Experimental Approaches for Defining Functional Roles of Microbes in the Human Gut

    DEFF Research Database (Denmark)

    Dantas, Gautam; Sommer, Morten; Degnan, Patrick H.

    2013-01-01

    The complex and intimate relationship between humans and their gut microbial communities is becoming less obscure, due in part to large-scale gut microbial genome-sequencing projects and culture-independent surveys of the composition and gene content of these communities.These studies build upon...... ofmicrobial genome and community profiling projects, and the loss-of-function and gain-of-function strategies long employed in model organisms are now being extended to microbial genes, species, and communities from the human gut. These developments promise to deepen our understanding of human gut host...

  17. On the generating function of Poincare plots defining one dimensional perturbed Hamiltonian systems

    International Nuclear Information System (INIS)

    Montvai, A.

    1989-01-01

    A simple numerical method has been devised, for deriving the generating function of an arbitrary, one dimensional Hamiltonian system represented by its Poincare plot. In this case, the plot to be numerically processed is an area preserving transformation of a two-dimensional surface onto itself. Although the method in its present form is capable of treating only this case, there are no principal restrictions excluding the analysis of systems with higher dimensionality as well. As an example, the generating function of the motion of alpha particles in a nonsymmetric, toroidal magnetic field is derived and studied numerically. (orig.)

  18. Functionalization of Planet-Satellite Nanostructures Revealed by Nanoscopic Localization of Distinct Macromolecular Species

    KAUST Repository

    Rossner, Christian

    2016-09-26

    The development of a straightforward method is reported to form hybrid polymer/gold planet-satellite nanostructures (PlSNs) with functional polymer. Polyacrylate type polymer with benzyl chloride in its backbone as a macromolecular tracer is synthesized to study its localization within PlSNs by analyzing the elemental distribution of chlorine. The functionalized nanohybrid structures are analyzed by scanning transmission electron microscopy, electron energy loss spectroscopy, and spectrum imaging. The results show that the RAFT (reversible addition-fragmentation chain transfer) polymers\\' sulfur containing end groups are colocalized at the gold cores, both within nanohybrids of simple core-shell morphology and within higher order PlSNs, providing microscopic evidence for the affinity of the RAFT group toward gold surfaces. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA., Weinheim.

  19. Genomic binding profiles of functionally distinct RNA polymerase III transcription complexes in human cells.

    Science.gov (United States)

    Moqtaderi, Zarmik; Wang, Jie; Raha, Debasish; White, Robert J; Snyder, Michael; Weng, Zhiping; Struhl, Kevin

    2010-05-01

    Genome-wide occupancy profiles of five components of the RNA polymerase III (Pol III) machinery in human cells identified the expected tRNA and noncoding RNA targets and revealed many additional Pol III-associated loci, mostly near short interspersed elements (SINEs). Several genes are targets of an alternative transcription factor IIIB (TFIIIB) containing Brf2 instead of Brf1 and have extremely low levels of TFIIIC. Strikingly, expressed Pol III genes, unlike nonexpressed Pol III genes, are situated in regions with a pattern of histone modifications associated with functional Pol II promoters. TFIIIC alone associates with numerous ETC loci, via the B box or a novel motif. ETCs are often near CTCF binding sites, suggesting a potential role in chromosome organization. Our results suggest that human Pol III complexes associate preferentially with regions near functional Pol II promoters and that TFIIIC-mediated recruitment of TFIIIB is regulated in a locus-specific manner.

  20. Plant functional types define magnitude of drought response in peatland CO2 exchange

    NARCIS (Netherlands)

    Kuiper, J.J.; Mooij, W.M.; Bragazza, L.; Robroek, B.J.M.

    2014-01-01

    Peatlands are important sinks for atmospheric carbon (C), yet the role of plant functional types (PFTs) for C sequestration under climatic perturbations is still unclear. A plant removal experiment was used to study the importance of vascular PFTs for the net ecosystem CO2 exchange (NEE) during

  1. Plant functional types define magnitude of drought response in peatland CO2 exchange

    NARCIS (Netherlands)

    Kuiper, J.J.; Mooij, W.M.; Bragazza, L.; Robroek, B.J.M.

    2014-01-01

    Peatlands are important sinks for atmospheric carbon (C), yet the role of plant functional types (PFTs) for C sequestration under climatic perturbations is still unclear. A plant-removal experiment was used to study the importance of vascular PFTs for the net ecosystem CO2 exchange (NEE) during

  2. Obesity is marked by distinct functional connectivity in brain networks involved in food reward and salience.

    Science.gov (United States)

    Wijngaarden, M A; Veer, I M; Rombouts, S A R B; van Buchem, M A; Willems van Dijk, K; Pijl, H; van der Grond, J

    2015-01-01

    We hypothesized that brain circuits involved in reward and salience respond differently to fasting in obese versus lean individuals. We compared functional connectivity networks related to food reward and saliency after an overnight fast (baseline) and after a prolonged fast of 48 h in lean versus obese subjects. We included 13 obese (2 males, 11 females, BMI 35.4 ± 1.2 kg/m(2), age 31 ± 3 years) and 11 lean subjects (2 males, 9 females, BMI 23.2 ± 0.5 kg/m(2), age 28 ± 3 years). Resting-state functional magnetic resonance imaging scans were made after an overnight fast (baseline) and after a prolonged 48 h fast. Functional connectivity of the amygdala, hypothalamus and posterior cingulate cortex (default-mode) networks was assessed using seed-based correlations. At baseline, we found a stronger connectivity between hypothalamus and left insula in the obese subjects. This effect diminished upon the prolonged fast. After prolonged fasting, connectivity of the hypothalamus with the dorsal anterior cingulate cortex (dACC) increased in lean subjects and decreased in obese subjects. Amygdala connectivity with the ventromedial prefrontal cortex was stronger in lean subjects at baseline, which did not change upon the prolonged fast. No differences in posterior cingulate cortex connectivity were observed. In conclusion, obesity is marked by alterations in functional connectivity networks involved in food reward and salience. Prolonged fasting differentially affected hypothalamic connections with the dACC and the insula between obese and lean subjects. Our data support the idea that food reward and nutrient deprivation are differently perceived and/or processed in obesity. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Hyperandrogenism in female athletes with functional hypothalamic amenorrhea: a distinct phenotype

    OpenAIRE

    Javed, Asma; Kashyap, Rahul; Lteif, Aida N

    2015-01-01

    Asma Javed,1 Rahul Kashyap,2 Aida N Lteif1 1Pediatric and Adolescent Medicine, Division of Pediatric Endocrinology Mayo Clinic, Rochester, MN, USA; 2Department of Anesthesia and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA Objective: To compare the reproductive, metabolic, and skeletal profiles of young athletic women with functional hypothalamic amenorrhea (FHA) as well as clinical or biochemical hyperandrogenism (FHA-EX+HA) with body mass index matched women with FHA due to exe...

  4. Distinct functions for the Drosophila piRNA pathway in genome maintenance and telomere protection.

    Directory of Open Access Journals (Sweden)

    Jaspreet S Khurana

    2010-12-01

    Full Text Available Transposons and other selfish DNA elements can be found in all phyla, and mobilization of these elements can compromise genome integrity. The piRNA (PIWI-interacting RNA pathway silences transposons in the germline, but it is unclear if this pathway has additional functions during development. Here we show that mutations in the Drosophila piRNA pathway genes, armi, aub, ago3, and rhi, lead to extensive fragmentation of the zygotic genome during the cleavage stage of embryonic divisions. Additionally, aub and armi show defects in telomere resolution during meiosis and the cleavage divisions; and mutations in lig-IV, which disrupt non-homologous end joining, suppress these fusions. By contrast, lig-IV mutations enhance chromosome fragmentation. Chromatin immunoprecipitation studies show that aub and armi mutations disrupt telomere binding of HOAP, which is a component of the telomere protection complex, and reduce expression of a subpopulation of 19- to 22-nt telomere-specific piRNAs. Mutations in rhi and ago3, by contrast, do not block HOAP binding or production of these piRNAs. These findings uncover genetically separable functions for the Drosophila piRNA pathway. The aub, armi, rhi, and ago3 genes silence transposons and maintain chromosome integrity during cleavage-stage embryonic divisions. However, the aub and armi genes have an additional function in assembly of the telomere protection complex.

  5. Crystal Structure Analysis and the Identification of Distinctive Functional Regions of the Protein Elicitor Mohrip2.

    Science.gov (United States)

    Liu, Mengjie; Duan, Liangwei; Wang, Meifang; Zeng, Hongmei; Liu, Xinqi; Qiu, Dewen

    2016-01-01

    The protein elicitor MoHrip2, which was extracted from Magnaporthe oryzae as an exocrine protein, triggers the tobacco immune system and enhances blast resistance in rice. However, the detailed mechanisms by which MoHrip2 acts as an elicitor remain unclear. Here, we investigated the structure of MoHrip2 to elucidate its functions based on molecular structure. The three-dimensional structure of MoHrip2 was obtained. Overall, the crystal structure formed a β-barrel structure and showed high similarity to the pathogenesis-related (PR) thaumatin superfamily protein thaumatin-like xylanase inhibitor (TL-XI). To investigate the functional regions responsible for MoHrip2 elicitor activities, the full length and eight truncated proteins were expressed in Escherichia coli and were evaluated for elicitor activity in tobacco. Biological function analysis showed that MoHrip2 triggered the defense system against Botrytis cinerea in tobacco. Moreover, only MoHrip2M14 and other fragments containing the 14 amino acids residues in the middle region of the protein showed the elicitor activity of inducing a hypersensitive response and resistance related pathways, which were similar to that of full-length MoHrip2. These results revealed that the central 14 amino acid residues were essential for anti-pathogenic activity.

  6. Crystal Structure Analysis and the Identification of Distinctive Functional Regions of the Protein Elicitor Mohrip2

    Directory of Open Access Journals (Sweden)

    Mengjie Liu

    2016-07-01

    Full Text Available The protein elicitor MoHrip2, which was extracted from Magnaporthe oryzae as an exocrine protein, triggers the tobacco immune system and enhances blast resistance in rice. However, the detailed mechanisms by which MoHrip2 acts as an elicitor remain unclear. Here, we investigated the structure of MoHrip2 to elucidate its functions based on molecular structure. The 3-dimensional structure of MoHrip2 was obtained. Overall, the crystal structure formed a β-barrel structure and showed high similarity to the pathogenesis-related (PR thaumatin superfamily protein thaumatin-like xylanase inhibitor (TL-XI. To investigate the functional regions responsible for MoHrip2 elicitor activities, the full length and 8 truncated proteins were expressed in Escherichia coli and were evaluated for elicitor activity in tobacco. Biological function analysis showed that MoHrip2 triggered the defense system against Botrytis cinerea in tobacco. Moreover, only MoHrip2M14 and other fragments containing the 14 amino acids residues in the middle region of the protein showed the elicitor activity of inducing a hypersensitive response and resistance related pathways, which were similar to that of full-length MoHrip2. These results revealed that the central 14 amino acid residues were essential for anti-pathogenic activity.

  7. Distinct functions and regulation of epithelial progesterone receptor in the mouse cervix, vagina, and uterus.

    Science.gov (United States)

    Mehta, Fabiola F; Son, Jieun; Hewitt, Sylvia C; Jang, Eunjung; Lydon, John P; Korach, Kenneth S; Chung, Sang-Hyuk

    2016-04-05

    While the function of progesterone receptor (PR) has been studied in the mouse vagina and uterus, its regulation and function in the cervix has not been described. We selectively deleted epithelial PR in the female reproductive tracts using the Cre/LoxP recombination system. We found that epithelial PR was required for induction of apoptosis and suppression of cell proliferation by progesterone (P4) in the cervical and vaginal epithelium. We also found that epithelial PR was dispensable for P4 to suppress apoptosis and proliferation in the uterine epithelium. PR is encoded by the Pgr gene, which is regulated by estrogen receptor α (ERα) in the female reproductive tracts. Using knock-in mouse models expressing ERα mutants, we determined that the DNA-binding domain (DBD) and AF2 domain of ERα were required for upregulation of Pgr in the cervix and vagina as well as the uterine stroma. The ERα AF1 domain was required for upregulation of Pgr in the vaginal stroma and epithelium and cervical epithelium, but not in the uterine and cervical stroma. ERα DBD, AF1, and AF2 were required for suppression of Pgr in the uterine epithelium, which was mediated by stromal ERα. Epithelial ERα was responsible for upregulation of epithelial Pgr in the cervix and vagina. Our results indicate that regulation and functions of epithelial PR are different in the cervix, vagina, and uterus.

  8. Defining the breeding goal for a sheep breed including production and functional traits using market data.

    Science.gov (United States)

    Theodoridis, A; Ragkos, A; Rose, G; Roustemis, D; Arsenos, G

    2017-11-16

    In this study, the economic values for production and functional traits of dairy sheep are estimated through the application of a profit function model using farm-level technical and economic data. The traits incorporated in the model were milk production, prolificacy, fertility, milking speed, longevity and mastitis occurrence. The economic values for these traits were derived as the approximate partial derivative of the specified profit function. A sensitivity analysis was also conducted in order to examine how potential changes in input and output prices would affect the breeding goal. The estimated economic values of the traits revealed their economic impact on the definition of the breeding goal for the specified production system. Milk production and fertility had the highest economic values (€40.30 and €20.28 per standard genetic deviation (SDa)), while, mastitis only had a low negative value of -0.57 €/SDa. Therefore, breeding for clinical mastitis will have a minor impact on farm profitability because it affects a small proportion of the flock and has low additive variance. The production traits, which include milk production, prolificacy and milking speed, contributed most to the breeding goal (70.0%), but functional traits still had a considerable share (30.0%). The results of this study highlight the importance of the knowledge of economic values of traits in the design of a breeding program. It is also suggested that the production and functional traits under consideration can be categorized as those which can be efficiently treated through genetic improvement (e.g. milk production and fertility) while others would be better dealt with through managerial interventions (e.g. mastitis occurrence). Also, sub-clinical mastitis that affects a higher proportion of flocks could have a higher contribution to breeding goals.

  9. Vitamin D activation of functionally distinct regulatory miRNAs in primary human osteoblasts.

    Science.gov (United States)

    Lisse, Thomas S; Chun, Rene F; Rieger, Sandra; Adams, John S; Hewison, Martin

    2013-06-01

    When bound to the vitamin D receptor (VDR), the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is a potent regulator of osteoblast transcription. Less clear is the impact of 1,25D on posttranscriptional events in osteoblasts, such as the generation and action of microRNAs (miRNAs). Microarray analysis using replicate (n = 3) primary cultures of human osteoblasts (HOBs) identified human miRNAs that were differentially regulated by >1.5-fold following treatment with 1,25D (10 nM, 6 hours), which included miRNAs 637 and 1228. Quantitative reverse transcription PCR analyses showed that the host gene for miR-1228, low-density lipoprotein receptor-related protein 1 (LRP1), was coinduced with miR-1228 in a dose-dependent fashion following treatment with 1,25D (0.1-10 nM, 6 hours). By contrast, the endogenous host gene for miR-637, death-associated protein kinase 3 (DAPK3), was transcriptionally repressed by following treatment with 1,25D. Analysis of two potential targets for miR-637 and miR-1228 in HOB, type IV collagen (COL4A1) and bone morphogenic protein 2 kinase (BMP2K), respectively, showed that 1,25D-mediates suppression of these targets via distinct mechanisms. In the case of miR-637, suppression of COL4A1 appears to occur via decreased levels of COL4A1 mRNA. By contrast, suppression of BMP2K by miR-1228 appears to occur by inhibition of protein translation. In mature HOBs, small interfering RNA (siRNA) inactivation of miR-1228 alone was sufficient to abrogate 1,25D-mediated downregulation of BMP2K protein expression. This was associated with suppression of prodifferentiation responses to 1,25D in HOB, as represented by parallel decrease in osteocalcin and alkaline phosphatase expression. These data show for the first time that the effects of 1,25D on human bone cells are not restricted to classical VDR-mediated transcriptional responses but also involve miRNA-directed posttranscriptional mechanisms. Copyright © 2013 American Society for Bone and

  10. Functional diversification of hsp40: distinct j-protein functional requirements for two prions allow for chaperone-dependent prion selection.

    Science.gov (United States)

    Harris, Julia M; Nguyen, Phil P; Patel, Milan J; Sporn, Zachary A; Hines, Justin K

    2014-07-01

    Yeast prions are heritable amyloid aggregates of functional yeast proteins; their propagation to subsequent cell generations is dependent upon fragmentation of prion protein aggregates by molecular chaperone proteins. Mounting evidence indicates the J-protein Sis1 may act as an amyloid specificity factor, recognizing prion and other amyloid aggregates and enabling Ssa and Hsp104 to act in prion fragmentation. Chaperone interactions with prions, however, can be affected by variations in amyloid-core structure resulting in distinct prion variants or 'strains'. Our genetic analysis revealed that Sis1 domain requirements by distinct variants of [PSI+] are strongly dependent upon overall variant stability. Notably, multiple strong [PSI+] variants can be maintained by a minimal construct of Sis1 consisting of only the J-domain and glycine/phenylalanine-rich (G/F) region that was previously shown to be sufficient for cell viability and [RNQ+] prion propagation. In contrast, weak [PSI+] variants are lost under the same conditions but maintained by the expression of an Sis1 construct that lacks only the G/F region and cannot support [RNQ+] propagation, revealing mutually exclusive requirements for Sis1 function between these two prions. Prion loss is not due to [PSI+]-dependent toxicity or dependent upon a particular yeast genetic background. These observations necessitate that Sis1 must have at least two distinct functional roles that individual prions differentially require for propagation and which are localized to the glycine-rich domains of the Sis1. Based on these distinctions, Sis1 plasmid-shuffling in a [PSI+]/[RNQ+] strain permitted J-protein-dependent prion selection for either prion. We also found that, despite an initial report to the contrary, the human homolog of Sis1, Hdj1, is capable of [PSI+] prion propagation in place of Sis1. This conservation of function is also prion-variant dependent, indicating that only one of the two Sis1-prion functions may have

  11. Using riboswitches to regulate gene expression and define gene function in mycobacteria.

    Science.gov (United States)

    Van Vlack, Erik R; Seeliger, Jessica C

    2015-01-01

    Mycobacteria include both environmental species and many pathogenic species such as Mycobacterium tuberculosis, an intracellular pathogen that is the causative agent of tuberculosis in humans. Inducible gene expression is a powerful tool for examining gene function and essentiality, both in in vitro culture and in host cell infections. The theophylline-inducible artificial riboswitch has recently emerged as an alternative to protein repressor-based systems. The riboswitch is translationally regulated and is combined with a mycobacterial promoter that provides transcriptional control. We here provide methods used by our laboratory to characterize the riboswitch response to theophylline in reporter strains, recombinant organisms containing riboswitch-regulated endogenous genes, and in host cell infections. These protocols should facilitate the application of both existing and novel artificial riboswitches to the exploration of gene function in mycobacteria. © 2015 Elsevier Inc. All rights reserved.

  12. Defining planktonic protist functional groups on mechanisms for energy and nutrient acquisition

    DEFF Research Database (Denmark)

    Mitra, Aditee; Flynn, Kevin J.; Tillmann, Urban

    2016-01-01

    Arranging organisms into functional groups aids ecological research by grouping organisms (irrespective of phylogenetic origin) that interact with environmental factors in similar ways. Planktonic protists traditionally have been split between photoautotrophic “phytoplankton” and phagotrophic...... “microzooplankton”. However, there is a growing recognition of the importance of mixotrophy in euphotic aquatic systems, where many protists often combine photoautotrophic and phagotrophic modes of nutrition. Such organisms do not align with the traditional dichotomy of phytoplankton and microzooplankton...... for phototrophy, and (iv) non-constitutive mixotrophs (NCMs) that acquire their phototrophic capacity by ingesting specific (SNCM) or general non-specific (GNCM) prey. For the first time, we incorporate these functional groups within a foodweb structure and show, using model outputs, that there is scope...

  13. Distinct and overlapping functions of ptpn11 genes in Zebrafish development.

    Directory of Open Access Journals (Sweden)

    Monica Bonetti

    Full Text Available The PTPN11 (protein-tyrosine phosphatase, non-receptor type 11 gene encodes SHP2, a cytoplasmic PTP that is essential for vertebrate development. Mutations in PTPN11 are associated with Noonan and LEOPARD syndrome. Human patients with these autosomal dominant disorders display various symptoms, including short stature, craniofacial defects and heart abnormalities. We have used the zebrafish as a model to investigate the role of Shp2 in embryonic development. The zebrafish genome encodes two ptpn11 genes, ptpn11a and ptpn11b. Here, we report that ptpn11a is expressed constitutively and ptpn11b expression is strongly upregulated during development. In addition, the products of both ptpn11 genes, Shp2a and Shp2b, are functional. Target-selected inactivation of ptpn11a and ptpn11b revealed that double homozygous mutants are embryonic lethal at 5-6 days post fertilization (dpf. Ptpn11a-/-ptpn11b-/- embryos showed pleiotropic defects from 4 dpf onwards, including reduced body axis extension and craniofacial defects, which was accompanied by low levels of phosphorylated Erk at 5 dpf. Interestingly, defects in homozygous ptpn11a-/- mutants overlapped with defects in the double mutants albeit they were milder, whereas ptpn11b-/- single mutants did not show detectable developmental defects and were viable and fertile. Ptpn11a-/-ptpn11b-/- mutants were rescued by expression of exogenous ptpn11a and ptpn11b alike, indicating functional redundance of Shp2a and Shp2b. The ptpn11 mutants provide a good basis for further unravelling of the function of Shp2 in vertebrate development.

  14. DISTINCT FUNCTIONS OF JNK AND C-JUN IN OXIDANT-INDUCED HEPATOCYTE DEATH

    Science.gov (United States)

    Amir, Muhammad; Liu, Kun; Zhao, Enpeng; Czaja, Mark J.

    2013-01-01

    Overactivation of c-Jun N-terminal kinase (JNK)/c-Jun signaling is a central mechanism of hepatocyte injury and death including that from oxidative stress. However, the functions of JNK and c-Jun are still unclear, and this pathway also inhibits hepatocyte death. Previous studies of menadione-induced oxidant stress demonstrated that toxicity resulted from sustained JNK/c-Jun activation as death was blocked by the c-Jun dominant negative TAM67. To further delineate the function of JNK/c-Jun signaling in hepatocyte injury from oxidant stress, the effects of direct JNK inhibition on menadione-induced death were examined. In contrast to the inhibitory effect of TAM67, pharmacological JNK inhibition by SP600125 sensitized the rat hepatocyte cell line RALA255-10G to death from menadione. SP600125 similarly sensitized mouse primary hepatocytes to menadione toxicity. Death from SP600125/menadione was c-Jun dependent as it was blocked by TAM67, but independent of c-Jun phosphorylation. Death occurred by apoptosis and necrosis and activation of the mitochondrial death pathway. Short hairpin RNA knockdowns of total JNK or JNK2 sensitized to death from menadione, whereas a jnk1 knockdown was protective. Jnk2 null mouse primary hepatocytes were also sensitized to menadione death. JNK inhibition magnified decreases in cellular ATP content and β-oxidation induced by menadione. This effect mediated cell death as chemical inhibition of β-oxidation also sensitized cells to death from menadione, and supplementation with the β-oxidation substrate oleate blocked death. Components of the JNK/c-Jun signaling pathway have opposing functions in hepatocyte oxidant stress with JNK2 mediating resistance to cell death and c-Jun promoting death. PMID:22644775

  15. Using Bilateral Functional and Anthropometric Tests to Define Symmetry in Cross-Country Skiers

    Directory of Open Access Journals (Sweden)

    Björklund Glenn

    2017-12-01

    Full Text Available The aim of this study was to evaluate the symmetry of anthropometry and muscle function in cross-country skiers and their association to vertical jumping power. Twenty cross-country skiers were recruited (21.7 ± 3.8 yrs, 180.6 ± 7.6 cm, 73.2 ± 7.6 kg. Anthropometric data was obtained using an iDXA scan. VO2max was determined using the diagonal stride technique on a ski treadmill. Bilateral functional tests for the upper and lower body were the handgrip and standing heel-rise tests. Vertical jump height and power were assessed with a counter movement jump. Percent asymmetry was calculated using a symmetry index and four absolute symmetry index levels. At a group level the upper body was more asymmetrical with regard to lean muscle mass (p = 0.022, d = 0.17 and functional strength (p = 0.019, d = 0.51 than the lower body. At an individual level the expected frequencies for absolute symmetry level indexes showed the largest deviation from zero for the heel-rise test (χ2 = 16.97, p = 0.001, while the leg lean mass deviated the least (χ2 = 0.42, p = 0.517. No relationships were observed between absolute symmetry level indexes of the lower body and counter movement jump performance (p > 0.05. As a group the skiers display a more asymmetrical upper body than lower body regarding muscle mass and strength. Interestingly at the individual level, despite symmetrical lean leg muscle mass the heel-rise test showed the largest asymmetry. This finding indicates a mismatch in muscle function for the lower body.

  16. Using Bilateral Functional and Anthropometric Tests to Define Symmetry in Cross-Country Skiers.

    Science.gov (United States)

    Björklund, Glenn; Alricsson, Marie; Svantesson, Ulla

    2017-12-01

    The aim of this study was to evaluate the symmetry of anthropometry and muscle function in cross-country skiers and their association to vertical jumping power. Twenty cross-country skiers were recruited (21.7 ± 3.8 yrs, 180.6 ± 7.6 cm, 73.2 ± 7.6 kg). Anthropometric data was obtained using an iDXA scan. VO 2max was determined using the diagonal stride technique on a ski treadmill. Bilateral functional tests for the upper and lower body were the handgrip and standing heel-rise tests. Vertical jump height and power were assessed with a counter movement jump. Percent asymmetry was calculated using a symmetry index and four absolute symmetry index levels. At a group level the upper body was more asymmetrical with regard to lean muscle mass (p = 0.022, d = 0.17) and functional strength (p = 0.019, d = 0.51) than the lower body. At an individual level the expected frequencies for absolute symmetry level indexes showed the largest deviation from zero for the heel-rise test (χ2 = 16.97, p = 0.001), while the leg lean mass deviated the least (χ2 = 0.42, p = 0.517). No relationships were observed between absolute symmetry level indexes of the lower body and counter movement jump performance (p > 0.05). As a group the skiers display a more asymmetrical upper body than lower body regarding muscle mass and strength. Interestingly at the individual level, despite symmetrical lean leg muscle mass the heel-rise test showed the largest asymmetry. This finding indicates a mismatch in muscle function for the lower body.

  17. Defining ATM-Independent Functions of the Mre11 Complex with a Novel Mouse Model.

    Science.gov (United States)

    Balestrini, Alessia; Nicolas, Laura; Yang-Lott, Katherine; Guryanova, Olga A; Levine, Ross L; Bassing, Craig H; Chaudhuri, Jayanta; Petrini, John H J

    2016-02-01

    The Mre11 complex (Mre11, Rad50, and Nbs1) occupies a central node of the DNA damage response (DDR) network and is required for ATM activation in response to DNA damage. Hypomorphic alleles of MRE11 and NBS1 confer embryonic lethality in ATM-deficient mice, indicating that the complex exerts ATM-independent functions that are essential when ATM is absent. To delineate those functions, a conditional ATM allele (ATM(flox)) was crossed to hypomorphic NBS1 mutants (Nbs1(ΔB/ΔB) mice). Nbs1(ΔB/ΔB) Atm(-/-) hematopoietic cells derived by crossing to vav(cre) were viable in vivo. Nbs1(ΔB/ΔB) Atm(-/-) (VAV) mice exhibited a pronounced defect in double-strand break repair and completely penetrant early onset lymphomagenesis. In addition to repair defects observed, fragile site instability was noted, indicating that the Mre11 complex promotes genome stability upon replication stress in vivo. The data suggest combined influences of the Mre11 complex on DNA repair, as well as the responses to DNA damage and DNA replication stress. A novel mouse model was developed, by combining a vav(cre)-inducible ATM knockout mouse with an NBS1 hypomorphic mutation, to analyze ATM-independent functions of the Mre11 complex in vivo. These data show that the DNA repair, rather than DDR signaling functions of the complex, is acutely required in the context of ATM deficiency to suppress genome instability and lymphomagenesis. ©2015 American Association for Cancer Research.

  18. Distinct effects of childhood ADHD and cannabis use on brain functional architecture in young adults

    OpenAIRE

    Kelly, C; Castellanos, FX; Tomaselli, O; Lisdahl, K; Tamm, L; Jernigan, T; Newman, E; Epstein, JN; Molina, BSG; Greenhill, LL; Potkin, SG; Hinshaw, S; Swanson, JM

    2017-01-01

    © 2016 The Authors One of the most salient long-term implications of a childhood diagnosis of ADHD is an increased risk for substance use, abuse, or dependence in adolescence and adulthood. The extent to which cannabis use affects ADHD-related alterations in brain functional organization is unknown, however. To address this research gap, we recruited a sample of 75 individuals aged 21–25 years with and without a childhood diagnosis of ADHD Combined Type, who were either frequent users or non-...

  19. Defining structural and functional dimensions of the extracellular thyrotropin receptor region.

    Science.gov (United States)

    Kleinau, Gunnar; Mueller, Sandra; Jaeschke, Holger; Grzesik, Paul; Neumann, Susanne; Diehl, Anne; Paschke, Ralf; Krause, Gerd

    2011-06-24

    The extracellular region of the thyrotropin receptor (TSHR) can be subdivided into the leucine-rich repeat domain (LRRD) and the hinge region. Both the LRRD and the hinge region interact with thyrotropin (TSH) or autoantibodies. Structural data for the TSHR LRRD were previously determined by crystallization (amino acids Glu(30)-Thr(257), 10 repeats), but the structure of the hinge region is still undefined. Of note, the amino acid sequence (Trp(258)-Tyr(279)) following the crystallized LRRD comprises a pattern typical for leucine-rich repeats with conserved hydrophobic side chains stabilizing the repeat fold. Moreover, functional data for amino acids between the LRRD and the transmembrane domain were fragmentary. We therefore investigated systematically these TSHR regions by mutagenesis to reveal insights into their functional contribution and potential structural features. We found that mutations of conserved hydrophobic residues between Thr(257) and Tyr(279) cause TSHR misfold, which supports a structural fold of this peptide, probably as an additional leucine-rich repeat. Furthermore, we identified several new mutations of hydrophilic amino acids in the entire hinge region leading to partial TSHR inactivation, indicating that these positions are important for intramolecular signal transduction. In summary, we provide new information regarding the structural features and functionalities of extracellular TSHR regions. Based on these insights and in context with previous results, we suggest an extracellular activation mechanism that supports an intramolecular agonistic unit as a central switch for activating effects at the extracellular region toward the serpentine domain.

  20. Parental Psychological Control and Autonomy Granting: Distinctions and Associations with Child and Family Functioning

    Science.gov (United States)

    Kunz, Jennifer Hauser; Grych, John H.

    2012-01-01

    Objective This study utilized an observational coding scheme to identify parenting behavior reflecting psychological control and autonomy granting and examined relations between these parenting dimensions and indices of child and family functioning. Design A community sample of 90 preadolescents (aged 10.5 to 12 years) and both of their parents engaged in a triadic interaction that was coded for parental psychological control and autonomy granting. Participants also completed measures of child adjustment, interparental conflict, and triangulation. Results Factor analyses indicated that a two-factor model better fit the data than a one-factor model, suggesting that psychological control and autonomy granting are best conceptualized as independent but related constructs. Parental psychological control and autonomy granting exhibited some shared and some unique correlates with indices of child and family functioning. Hierarchical regressions revealed significant interactions between these dimensions, suggesting that the strength of some associations between parents’ use of psychological control and youth adjustment problems depends on the level of autonomy granting exhibited by the parent. Conclusions By examining psychological control and autonomy granting simultaneously as unique constructs, this study identifies patterns of psychological control and autonomy granting that undermine youth adjustment. Findings inform targeted intervention efforts for families of preadolescent youth. PMID:23418403

  1. Distinct patterns of brain function in children with isolated spelling impairment: new insights.

    Science.gov (United States)

    Gebauer, Daniela; Enzinger, Christian; Kronbichler, Martin; Schurz, Matthias; Reishofer, Gernot; Koschutnig, Karl; Kargl, Reinhard; Purgstaller, Christian; Fazekas, Franz; Fink, Andreas

    2012-06-01

    Studies investigating reading and spelling difficulties heavily focused on the neural correlates of reading impairments, whereas spelling impairments have been largely neglected so far. Hence, the aim of the present study was to investigate brain structure and function of children with isolated spelling difficulties. Therefore, 31 children, aged ten to 15 years, were investigated by means of functional MRI and DTI. This study revealed that children with isolated spelling impairment exhibit a stronger right hemispheric activation compared to children with reading and spelling difficulties and controls, when engaged in an orthographic decision task, presumably reflecting a highly efficient serial grapheme-phoneme decoding compensation strategy. In addition, children with spelling impairment activated bilateral inferior and middle frontal gyri during processing correctly spelled words and misspelled words, whereas the other two groups showed bilateral activation only in the misspelled condition, suggesting that additional right frontal engagement could be related to generally higher task demand and effort. DTI analyses revealed stronger frontal white matter integrity (fractional anisotropy) in controls (compared to spelling and reading impaired children), whereas no structural differences between controls and spelling impaired children were observed. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function

    Directory of Open Access Journals (Sweden)

    Peter Canning

    2018-01-01

    Full Text Available Various kinases, including a cyclin-dependent kinase (CDK family member, regulate the growth and functions of primary cilia, which perform essential roles in signaling and development. Neurological disorders linked to CDK-Like (CDKL proteins suggest that these underexplored kinases may have similar functions. Here, we present the crystal structures of human CDKL1, CDKL2, CDKL3, and CDKL5, revealing their evolutionary divergence from CDK and mitogen-activated protein kinases (MAPKs, including an unusual αJ helix important for CDKL2 and CDKL3 activity. C. elegans CDKL-1, most closely related to CDKL1–4 and localized to neuronal cilia transition zones, modulates cilium length; this depends on its kinase activity and αJ helix-containing C terminus. Human CDKL5, linked to Rett syndrome, also localizes to cilia, and it impairs ciliogenesis when overexpressed. CDKL5 patient mutations modeled in CDKL-1 cause localization and/or cilium length defects. Together, our studies establish a disease model system suggesting cilium length defects as a pathomechanism for neurological disorders, including epilepsy.

  3. Prospective memory in multiple sclerosis: The impact of cue distinctiveness and executive functioning.

    Science.gov (United States)

    Dagenais, Emmanuelle; Rouleau, Isabelle; Tremblay, Alexandra; Demers, Mélanie; Roger, Élaine; Jobin, Céline; Duquette, Pierre

    2016-11-01

    Prospective memory (PM), the ability to remember to do something at the appropriate time in the future, is crucial in everyday life. One way to improve PM performance is to increase the salience of a cue announcing that it is time to act. Multiple sclerosis (MS) patients often report PM failures and there is growing evidence of PM deficits among this population. However, such deficits are poorly characterized and their relation to cognitive status remains unclear. To better understand PM deficits in MS patients, this study investigated the impact of cue salience on PM, and its relation to retrospective memory (RM) and executive deficits. Thirty-nine (39) MS patients were compared to 18 healthy controls on a PM task modulating cue salience during an ongoing general knowledge test. MS patients performed worse than controls on the PM task, regardless of cue salience. MS patients' executive functions contributed significantly to the variance in PM performance, whereas age, education and RM did not. Interestingly, low- and high-executive patients' performance differed when the cue was not salient, but not when it was, suggesting that low-executive MS patients benefited more from cue salience. These findings add to the growing evidence of PM deficits in MS and highlight the contribution of executive functions to certain aspects of PM. In low-executive MS patients, high cue salience improves PM performance by reducing the detection threshold and need for environmental monitoring. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Microvessel organization and structure in experimental brain tumors: microvessel populations with distinctive structural and functional properties.

    Science.gov (United States)

    Schlageter, K E; Molnar, P; Lapin, G D; Groothuis, D R

    1999-11-01

    We studied microvessel organization in five brain tumor models (ENU, MSV, RG-2, S635cl15, and D-54MG) and normal brain, including microvessel diameter (LMVD), intermicrovessel distance (IMVD), microvessel density (MVD), surface area (S(v)), and orientation. LMVD and IMVD were larger and MVD was lower in tumors than normal brain. S(v) in tumors overlapped normal brain values and orientation was random in both tumors and brain. ENU and RG-2 tumors and brain were studied by electron microscopy. Tumor microvessel wall was thicker than that of brain. ENU and normal brain microvessels were continuous and nonfenestrated. RG-2 microvessels contained fenestrations and endothelial gaps; the latter had a maximum major axis of 3.0 microm. Based on anatomic measurements, the pore area of RG-2 tumors was estimated at 7.4 x 10(-6) cm(2) g(-1) from fenestrations and 3.5 x 10(-5) cm(2) g(-1) from endothelial gaps. Increased permeability of RG-2 microvessels to macromolecules is most likely attributable to endothelial gaps. Three microvessel populations may occur in brain tumors: (1) continuous nonfenestrated, (2) continuous fenestrated, and (3) discontinuous (with or without fenestrations). The first group may be unique to brain tumors; the latter two are similar to microvessels found in systemic tumors. Since structure-function properties of brain tumor microvessels will affect drug delivery, studies of microvessel function should be incorporated into clinical trials of brain tumor therapy, especially those using macromolecules. Copyright 1999 Academic Press.

  5. Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways.

    Science.gov (United States)

    Narayanan, Ramesh; Coss, Christopher C; Yepuru, Muralimohan; Kearbey, Jeffrey D; Miller, Duane D; Dalton, James T

    2008-11-01

    Androgen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.

  6. Anxa4 Genes are Expressed in Distinct Organ Systems in Xenopus laevis and tropicalis But are Functionally Conserved

    OpenAIRE

    Massé, Karine L; Collins, Robert J; Bhamra, Surinder; Seville, Rachel A; Jones, Elizabeth A

    2007-01-01

    Anxa4 belongs to the multigenic annexin family of proteins which are characterized by their ability to interact with membranes in a calcium-dependent manner. Defined as a marker for polarized epithelial cells, Anxa4 is believed to be involved in many cellular processes but its functions in vivo are still poorly understood. Previously, we cloned Xanx4 in Xenopus laevis (now referred to as anxa4a) and demonstrated its role during organogenesis of the pronephros, providing the first evidence of ...

  7. The Hidden World within Plants: Ecological and Evolutionary Considerations for Defining Functioning of Microbial Endophytes

    Science.gov (United States)

    van Overbeek, Leonard S.; Berg, Gabriele; Pirttilä, Anna Maria; Compant, Stéphane; Campisano, Andrea; Döring, Matthias; Sessitsch, Angela

    2015-01-01

    SUMMARY All plants are inhabited internally by diverse microbial communities comprising bacterial, archaeal, fungal, and protistic taxa. These microorganisms showing endophytic lifestyles play crucial roles in plant development, growth, fitness, and diversification. The increasing awareness of and information on endophytes provide insight into the complexity of the plant microbiome. The nature of plant-endophyte interactions ranges from mutualism to pathogenicity. This depends on a set of abiotic and biotic factors, including the genotypes of plants and microbes, environmental conditions, and the dynamic network of interactions within the plant biome. In this review, we address the concept of endophytism, considering the latest insights into evolution, plant ecosystem functioning, and multipartite interactions. PMID:26136581

  8. Minimization of Linear Functionals Defined on| Solutions of Large-Scale Discrete Ill-Posed Problems

    DEFF Research Database (Denmark)

    Elden, Lars; Hansen, Per Christian; Rojas, Marielba

    2003-01-01

    The minimization of linear functionals de ned on the solutions of discrete ill-posed problems arises, e.g., in the computation of con dence intervals for these solutions. In 1990, Elden proposed an algorithm for this minimization problem based on a parametric-programming reformulation involving...... the solution of a sequence of trust-region problems, and using matrix factorizations. In this paper, we describe MLFIP, a large-scale version of this algorithm where a limited-memory trust-region solver is used on the subproblems. We illustrate the use of our algorithm in connection with an inverse heat...

  9. Fixed points for some non-obviously contractive operators defined in a space of continuous functions

    OpenAIRE

    C. Avramescu; Cristian Vladimirescu

    2004-01-01

    Let $X$ be an arbitrary (real or complex) Banach space, endowed with the norm $\\left| \\cdot \\right| .$ Consider the space of the continuous functions $C\\left( \\left[ 0,T\\right] ,X\\right) $ $\\left( T>0\\right) $, endowed with the usual topology, and let $M$ be a closed subset of it. One proves that each operator $A:M\\rightarrow M$ fulfilling for all $x,y\\in M$ and for all $t\\in \\left[ 0,T\\right] $ the condition \\begin{eqnarray*} \\left| \\left( Ax\\right) \\left( t\\right) -\\left( Ay\\right) \\l...

  10. Pentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function.

    Science.gov (United States)

    Therien, J P Daniel; Baenziger, John E

    2017-03-27

    Although transmembrane helix-helix interactions must be strong enough to drive folding, they must still permit the inter-helix movements associated with conformational change. Interactions between the outermost M4 and adjacent M1 and M3 α-helices of pentameric ligand-gated ion channels have been implicated in folding and function. Here, we evaluate the role of different physical interactions at this interface in the function of two prokaryotic homologs, GLIC and ELIC. Strikingly, disruption of most interactions in GLIC lead to either a reduction or a complete loss of expression and/or function, while analogous disruptions in ELIC often lead to gains in function. Structural comparisons suggest that GLIC and ELIC represent distinct transmembrane domain archetypes. One archetype, exemplified by GLIC, the glycine and GABA receptors and the glutamate activated chloride channel, has extensive aromatic contacts that govern M4-M1/M3 interactions and that are essential for expression and function. The other archetype, exemplified by ELIC and both the nicotinic acetylcholine and serotonin receptors, has relatively few aromatic contacts that are detrimental to function. These archetypes likely have evolved different mechanisms to balance the need for strong M4 "binding" to M1/M3 to promote folding/expression, and the need for weaker interactions that allow for greater conformational flexibility.

  11. Distinct functions of human RecQ helicases during DNA replication.

    Science.gov (United States)

    Urban, Vaclav; Dobrovolna, Jana; Janscak, Pavel

    2017-06-01

    DNA replication is the most vulnerable process of DNA metabolism in proliferating cells and therefore it is tightly controlled and coordinated with processes that maintain genomic stability. Human RecQ helicases are among the most important factors involved in the maintenance of replication fork integrity, especially under conditions of replication stress. RecQ helicases promote recovery of replication forks being stalled due to different replication roadblocks of either exogenous or endogenous source. They prevent generation of aberrant replication fork structures and replication fork collapse, and are involved in proper checkpoint signaling. The essential role of human RecQ helicases in the genome maintenance during DNA replication is underlined by association of defects in their function with cancer predisposition. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Evidence of two distinct functionally specialized fibroblast lineages in breast stroma

    DEFF Research Database (Denmark)

    Morsing, Mikkel; Klitgaard, Marie Christine; Jafari Kermani, Abbas

    2016-01-01

    Background The terminal duct lobular unit (TDLU) is the most dynamic structure in the human breast and the putative site of origin of human breast cancer. Although stromal cells contribute to a specialized microenvironment in many organs, this component remains largely understudied in the human...... conditions followed by analysis of adipogenic and osteogenic differentiation. To test whether the two fibroblast lineages are functionally imprinted by their site of origin, single cell sorted CD271low/MUC1high normal breast luminal epithelial cells are plated on fibroblast feeders for the observation...... fibroblast lineages exist in the normal human breast, of which the lobular fibroblasts have properties in common with mesenchymal stem cells and support epithelial growth and morphogenesis. We propose that lobular fibroblasts constitute a specialized microenvironment for human breast luminal epithelial...

  13. Functions of two distinct prolactin-releasing peptides evolved from a common ancestral gene

    Directory of Open Access Journals (Sweden)

    Tetsuya eTachibana

    2014-11-01

    Full Text Available Prolactin-releasing peptide (PrRP is one of the RF-amide peptides and was originally identified in the bovine hypothalamus as a stimulator of prolactin (PRL release. Independently, another RF-amide peptide was found in Japanese crucian carp and named Carassius RFa (C-RFa, which shows high homology to PrRP and stimulates PRL secretion in teleost fish. Therefore, C-RFa has been recognized as fish PrRP. However, recent work has revealed that PrRP and C-RFa in non-mammalian vertebrates are encoded by separate genes originated through duplication of an ancestral gene. Indeed, both PrRP and C-RFa are suggested to exist in teleost, amphibian, reptile, and avian species. Therefore, we propose that non-mammalian PrRP (C-RFa be renamed PrRP2. Despite a common evolutionary origin, PrRP2 appears to be a physiological regulator of PRL, whereas this is not a consistent role for PrRP itself. Further work revealed that the biological functions of PrRP and PrRP2 are not limited solely to PRL release, because they are also neuromodulators of several hypothalamus-pituitary axes and are involved in some brain circuits related to the regulation of food intake, stress, and cardiovascular functions. However, these actions appear to be different among vertebrates. For example, central injection of PrRP inhibits feeding behavior in rodents and teleosts while it stimulates it in chicks. Therefore, both PrRP and PrRP2 have acquired diverse actions through evolution. In this review, we integrate the burgeoning information of structures, expression profiles, and multiple biological actions of PrRP in higher vertebrates, as well as those of PrRP2 in non-mammals.

  14. Prominence vs. aboutness in sequencing: a functional distinction within the left inferior frontal gyrus.

    Science.gov (United States)

    Bornkessel-Schlesewsky, Ina; Grewe, Tanja; Schlesewsky, Matthias

    2012-02-01

    Prior research on the neural bases of syntactic comprehension suggests that activation in the left inferior frontal gyrus (lIFG) correlates with the processing of word order variations. However, there are inconsistencies with respect to the specific subregion within the IFG that is implicated by these findings: the pars opercularis or the pars triangularis. Here, we examined the hypothesis that the dissociation between pars opercularis and pars triangularis activation may reflect functional differences between clause-medial and clause-initial word order permutations, respectively. To this end, we directly compared clause-medial and clause-initial object-before-subject orders in German in a within-participants, event-related fMRI design. Our results showed increased activation for object-initial sentences in a bilateral network of frontal, temporal and subcortical regions. Within the lIFG, posterior and inferior subregions showed only a main effect of word order, whereas more anterior and superior subregions showed effects of word order and sentence type, with higher activation for sentences with an argument in the clause-initial position. These findings are interpreted as evidence for a functional gradation of sequence processing within the left IFG: posterior subportions correlate with argument prominence-based (local) aspects of sequencing, while anterior subportions correlate with aboutness-based aspects of sequencing, which are crucial in linking the current sentence to the wider discourse. This proposal appears compatible with more general hypotheses about information processing gradients in prefrontal cortex (Koechlin & Summerfield, 2007). Copyright © 2010 Elsevier Inc. All rights reserved.

  15. Live Imaging of Calcium Dynamics during Axon Degeneration Reveals Two Functionally Distinct Phases of Calcium Influx

    Science.gov (United States)

    Yamagishi, Yuya; Tessier-Lavigne, Marc

    2015-01-01

    Calcium is a key regulator of axon degeneration caused by trauma and disease, but its specific spatial and temporal dynamics in injured axons remain unclear. To clarify the function of calcium in axon degeneration, we observed calcium dynamics in single injured neurons in live zebrafish larvae and tested the temporal requirement for calcium in zebrafish neurons and cultured mouse DRG neurons. Using laser axotomy to induce Wallerian degeneration (WD) in zebrafish peripheral sensory axons, we monitored calcium dynamics from injury to fragmentation, revealing two stereotyped phases of axonal calcium influx. First, axotomy triggered a transient local calcium wave originating at the injury site. This initial calcium wave only disrupted mitochondria near the injury site and was not altered by expression of the protective WD slow (WldS) protein. Inducing multiple waves with additional axotomies did not change the kinetics of degeneration. In contrast, a second phase of calcium influx occurring minutes before fragmentation spread as a wave throughout the axon, entered mitochondria, and was abolished by WldS expression. In live zebrafish, chelating calcium after the first wave, but before the second wave, delayed the progress of fragmentation. In cultured DRG neurons, chelating calcium early in the process of WD did not alter degeneration, but chelating calcium late in WD delayed fragmentation. We propose that a terminal calcium wave is a key instructive component of the axon degeneration program. SIGNIFICANCE STATEMENT Axon degeneration resulting from trauma or neurodegenerative disease can cause devastating deficits in neural function. Understanding the molecular and cellular events that execute axon degeneration is essential for developing treatments to address these conditions. Calcium is known to contribute to axon degeneration, but its temporal requirements in this process have been unclear. Live calcium imaging in severed zebrafish neurons and temporally controlled

  16. Two Cdc2 Kinase Genes with Distinct Functions in Vegetative and Infectious Hyphae in Fusarium graminearum.

    Directory of Open Access Journals (Sweden)

    Huiquan Liu

    2015-06-01

    Full Text Available Eukaryotic cell cycle involves a number of protein kinases important for the onset and progression through mitosis, most of which are well characterized in the budding and fission yeasts and conserved in other fungi. However, unlike the model yeast and filamentous fungi that have a single Cdc2 essential for cell cycle progression, the wheat scab fungus Fusarium graminearum contains two CDC2 orthologs. The cdc2A and cdc2B mutants had no obvious defects in growth rate and conidiation but deletion of both of them is lethal, indicating that these two CDC2 orthologs have redundant functions during vegetative growth and asexual reproduction. However, whereas the cdc2B mutant was normal, the cdc2A mutant was significantly reduced in virulence and rarely produced ascospores. Although deletion of CDC2A had no obvious effect on the formation of penetration branches or hyphopodia, the cdc2A mutant was limited in the differentiation and growth of infectious growth in wheat tissues. Therefore, CDC2A plays stage-specific roles in cell cycle regulation during infectious growth and sexual reproduction. Both CDC2A and CDC2B are constitutively expressed but only CDC2A was up-regulated during plant infection and ascosporogenesis. Localization of Cdc2A- GFP to the nucleus but not Cdc2B-GFP was observed in vegetative hyphae, ascospores, and infectious hyphae. Complementation assays with chimeric fusion constructs showed that both the N- and C-terminal regions of Cdc2A are important for its functions in pathogenesis and ascosporogenesis but only the N-terminal region is important for its subcellular localization. Among the Sordariomycetes, only three Fusarium species closely related to F. graminearum have two CDC2 genes. Furthermore, F. graminearum uniquely has two Aurora kinase genes and one additional putative cyclin gene, and its orthologs of CAK1 and other four essential mitotic kinases in the budding yeast are dispensable for viability. Overall, our data

  17. Two Cdc2 Kinase Genes with Distinct Functions in Vegetative and Infectious Hyphae in Fusarium graminearum.

    Science.gov (United States)

    Liu, Huiquan; Zhang, Shijie; Ma, Jiwen; Dai, Yafeng; Li, Chaohui; Lyu, Xueliang; Wang, Chenfang; Xu, Jin-Rong

    2015-06-01

    Eukaryotic cell cycle involves a number of protein kinases important for the onset and progression through mitosis, most of which are well characterized in the budding and fission yeasts and conserved in other fungi. However, unlike the model yeast and filamentous fungi that have a single Cdc2 essential for cell cycle progression, the wheat scab fungus Fusarium graminearum contains two CDC2 orthologs. The cdc2A and cdc2B mutants had no obvious defects in growth rate and conidiation but deletion of both of them is lethal, indicating that these two CDC2 orthologs have redundant functions during vegetative growth and asexual reproduction. However, whereas the cdc2B mutant was normal, the cdc2A mutant was significantly reduced in virulence and rarely produced ascospores. Although deletion of CDC2A had no obvious effect on the formation of penetration branches or hyphopodia, the cdc2A mutant was limited in the differentiation and growth of infectious growth in wheat tissues. Therefore, CDC2A plays stage-specific roles in cell cycle regulation during infectious growth and sexual reproduction. Both CDC2A and CDC2B are constitutively expressed but only CDC2A was up-regulated during plant infection and ascosporogenesis. Localization of Cdc2A- GFP to the nucleus but not Cdc2B-GFP was observed in vegetative hyphae, ascospores, and infectious hyphae. Complementation assays with chimeric fusion constructs showed that both the N- and C-terminal regions of Cdc2A are important for its functions in pathogenesis and ascosporogenesis but only the N-terminal region is important for its subcellular localization. Among the Sordariomycetes, only three Fusarium species closely related to F. graminearum have two CDC2 genes. Furthermore, F. graminearum uniquely has two Aurora kinase genes and one additional putative cyclin gene, and its orthologs of CAK1 and other four essential mitotic kinases in the budding yeast are dispensable for viability. Overall, our data indicate that cell cycle

  18. Distinct functional and temporal requirements for zebrafish Hdac1 during neural crest-derived craniofacial and peripheral neuron development.

    Science.gov (United States)

    Ignatius, Myron S; Unal Eroglu, Arife; Malireddy, Smitha; Gallagher, Glen; Nambiar, Roopa M; Henion, Paul D

    2013-01-01

    The regulation of gene expression is accomplished by both genetic and epigenetic means and is required for the precise control of the development of the neural crest. In hdac1(b382) mutants, craniofacial cartilage development is defective in two distinct ways. First, fewer hoxb3a, dlx2 and dlx3-expressing posterior branchial arch precursors are specified and many of those that are consequently undergo apoptosis. Second, in contrast, normal numbers of progenitors are present in the anterior mandibular and hyoid arches, but chondrocyte precursors fail to terminally differentiate. In the peripheral nervous system, there is a disruption of enteric, DRG and sympathetic neuron differentiation in hdac1(b382) mutants compared to wildtype embryos. Specifically, enteric and DRG-precursors differentiate into neurons in the anterior gut and trunk respectively, while enteric and DRG neurons are rarely present in the posterior gut and tail. Sympathetic neuron precursors are specified in hdac1(b382) mutants and they undergo generic neuronal differentiation but fail to undergo noradrenergic differentiation. Using the HDAC inhibitor TSA, we isolated enzyme activity and temporal requirements for HDAC function that reproduce hdac1(b382) defects in craniofacial and sympathetic neuron development. Our study reveals distinct functional and temporal requirements for zebrafish hdac1 during neural crest-derived craniofacial and peripheral neuron development.

  19. Distinct functional and temporal requirements for zebrafish Hdac1 during neural crest-derived craniofacial and peripheral neuron development.

    Directory of Open Access Journals (Sweden)

    Myron S Ignatius

    Full Text Available The regulation of gene expression is accomplished by both genetic and epigenetic means and is required for the precise control of the development of the neural crest. In hdac1(b382 mutants, craniofacial cartilage development is defective in two distinct ways. First, fewer hoxb3a, dlx2 and dlx3-expressing posterior branchial arch precursors are specified and many of those that are consequently undergo apoptosis. Second, in contrast, normal numbers of progenitors are present in the anterior mandibular and hyoid arches, but chondrocyte precursors fail to terminally differentiate. In the peripheral nervous system, there is a disruption of enteric, DRG and sympathetic neuron differentiation in hdac1(b382 mutants compared to wildtype embryos. Specifically, enteric and DRG-precursors differentiate into neurons in the anterior gut and trunk respectively, while enteric and DRG neurons are rarely present in the posterior gut and tail. Sympathetic neuron precursors are specified in hdac1(b382 mutants and they undergo generic neuronal differentiation but fail to undergo noradrenergic differentiation. Using the HDAC inhibitor TSA, we isolated enzyme activity and temporal requirements for HDAC function that reproduce hdac1(b382 defects in craniofacial and sympathetic neuron development. Our study reveals distinct functional and temporal requirements for zebrafish hdac1 during neural crest-derived craniofacial and peripheral neuron development.

  20. Functional approach for pairing in finite systems: How to define restoration of broken symmetries in Energy Density Functional theory?

    International Nuclear Information System (INIS)

    Hupin, G; Lacroix, D; Bender, M

    2011-01-01

    The Multi-Reference Energy Density Functional (MR-EDF) approach (also called configuration mixing or Generator Coordinate Method), that is commonly used to treat pairing in finite nuclei and project onto particle number, is re-analyzed. It is shown that, under certain conditions, the MR-EDF energy can be interpreted as a functional of the one-body density matrix of the projected state with good particle number. Based on this observation, we propose a new approach, called Symmetry-Conserving EDF (SC-EDF), where the breaking and restoration of symmetry are accounted for simultaneously. We show, that such an approach is free from pathologies recently observed in MR-EDF and can be used with a large flexibility on the density dependence of the functional.

  1. The Hidden World within Plants: Ecological and Evolutionary Considerations for Defining Functioning of Microbial Endophytes.

    Science.gov (United States)

    Hardoim, Pablo R; van Overbeek, Leonard S; Berg, Gabriele; Pirttilä, Anna Maria; Compant, Stéphane; Campisano, Andrea; Döring, Matthias; Sessitsch, Angela

    2015-09-01

    All plants are inhabited internally by diverse microbial communities comprising bacterial, archaeal, fungal, and protistic taxa. These microorganisms showing endophytic lifestyles play crucial roles in plant development, growth, fitness, and diversification. The increasing awareness of and information on endophytes provide insight into the complexity of the plant microbiome. The nature of plant-endophyte interactions ranges from mutualism to pathogenicity. This depends on a set of abiotic and biotic factors, including the genotypes of plants and microbes, environmental conditions, and the dynamic network of interactions within the plant biome. In this review, we address the concept of endophytism, considering the latest insights into evolution, plant ecosystem functioning, and multipartite interactions. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  2. Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver.

    Science.gov (United States)

    Mauvoisin, Daniel; Wang, Jingkui; Jouffe, Céline; Martin, Eva; Atger, Florian; Waridel, Patrice; Quadroni, Manfredo; Gachon, Frédéric; Naef, Felix

    2014-01-07

    Diurnal oscillations of gene expression controlled by the circadian clock underlie rhythmic physiology across most living organisms. Although such rhythms have been extensively studied at the level of transcription and mRNA accumulation, little is known about the accumulation patterns of proteins. Here, we quantified temporal profiles in the murine hepatic proteome under physiological light-dark conditions using stable isotope labeling by amino acids quantitative MS. Our analysis identified over 5,000 proteins, of which several hundred showed robust diurnal oscillations with peak phases enriched in the morning and during the night and related to core hepatic physiological functions. Combined mathematical modeling of temporal protein and mRNA profiles indicated that proteins accumulate with reduced amplitudes and significant delays, consistent with protein half-life data. Moreover, a group comprising about one-half of the rhythmic proteins showed no corresponding rhythmic mRNAs, indicating significant translational or posttranslational diurnal control. Such rhythms were highly enriched in secreted proteins accumulating tightly during the night. Also, these rhythms persisted in clock-deficient animals subjected to rhythmic feeding, suggesting that food-related entrainment signals influence rhythms in circulating plasma factors.

  3. Distinct ubiquitin binding modes exhibited by SH3 domains: molecular determinants and functional implications.

    Directory of Open Access Journals (Sweden)

    Jose L Ortega Roldan

    Full Text Available SH3 domains constitute a new type of ubiquitin-binding domains. We previously showed that the third SH3 domain (SH3-C of CD2AP binds ubiquitin in an alternative orientation. We have determined the structure of the complex between first CD2AP SH3 domain and ubiquitin and performed a structural and mutational analysis to decipher the determinants of the SH3-C binding mode to ubiquitin. We found that the Phe-to-Tyr mutation in CD2AP and in the homologous CIN85 SH3-C domain does not abrogate ubiquitin binding, in contrast to previous hypothesis and our findings for the first two CD2AP SH3 domains. The similar alternative binding mode of the SH3-C domains of these related adaptor proteins is characterised by a higher affinity to C-terminal extended ubiquitin molecules. We conclude that CD2AP/CIN85 SH3-C domain interaction with ubiquitin constitutes a new ubiquitin-binding mode involved in a different cellular function and thus changes the previously established mechanism of EGF-dependent CD2AP/CIN85 mono-ubiquitination.

  4. Ontogeny of surface markers on functionally distinct T cell subsets in the chicken.

    Science.gov (United States)

    Traill, K N; Böck, G; Boyd, R L; Ratheiser, K; Wick, G

    1984-01-01

    Three subsets of chicken peripheral T cells (T1, T2 and T3) have been identified in peripheral blood of adult chickens on the basis of fluorescence intensity after staining with certain xenogeneic anti-thymus cell sera (from turkeys and rabbits). They differentiate between 3-10 weeks of age in parallel with development of responsiveness to the mitogens concanavalin A (Con A), phytohemagglutinin (PHA) and pokeweed mitogen (PWM). Functional tests on the T subsets, sorted with a fluorescence-activated cell sorter, have shown that T2, 3 cells respond to Con A, PHA and PWM and are capable of eliciting a graft-vs.-host reaction (GvHR). In contrast, although T1 cells respond to Con A, they respond poorly to PHA and not at all to PWM or in GvHR. There was some indication of cooperation between T1 and T2,3 cells for the PHA response. Parallels between these chicken subsets and helper and suppressor/cytotoxic subsets in mammalian systems are discussed.

  5. Different concentrations of kaempferol distinctly modulate murine embryonic stem cell function.

    Science.gov (United States)

    Correia, Marcelo; Rodrigues, Ana S; Perestrelo, Tânia; Pereira, Sandro L; Ribeiro, Marcelo F; Sousa, Maria I; Ramalho-Santos, João

    2016-01-01

    Kaempferol (3,4',5,7-tetrahydroxyflavone) is a natural flavonoid with several beneficial and protective effects. It has been demonstrated that kaempferol has anticancer properties, particularly due to its effects on proliferation, apoptosis and the cell cycle. However, possible effects on pluripotent embryonic stem cell function have not yet been addressed. Embryonic stem cells have the ability to self-renew and to differentiate into all three germ layers with potential applications in regenerative medicine and in vitro toxicology. We show that exposure of murine embryonic stem cells (mESC) to high concentrations of kaempferol (200 μM) leads to decreased cell numbers, although the resulting smaller cell colonies remain pluripotent. However, lower concentrations of this compound (20 μM) increase the expression of pluripotency markers in mESCs. Mitochondrial membrane potential and mitochondrial mass are not affected, but a dose-dependent increase in apoptosis takes place. Moreover, mESC differentiation is impaired by kaempferol, which was not related to apoptosis induction. Our results show that low concentrations of kaempferol can be beneficial for pluripotency, but inhibit proper differentiation of mESCs. Additionally, high concentrations induce apoptosis and increase mitochondrial reactive oxygen species (ROS). Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Layer 5 Callosal Parvalbumin-Expressing Neurons: A Distinct Functional Group of GABAergic Neurons.

    Science.gov (United States)

    Zurita, Hector; Feyen, Paul L C; Apicella, Alfonso Junior

    2018-01-01

    Previous studies have shown that parvalbumin-expressing neurons (CC-Parv neurons) connect the two hemispheres of motor and sensory areas via the corpus callosum, and are a functional part of the cortical circuit. Here we test the hypothesis that layer 5 CC-Parv neurons possess anatomical and molecular mechanisms which dampen excitability and modulate the gating of interhemispheric inhibition. In order to investigate this hypothesis we use viral tracing to determine the anatomical and electrophysiological properties of layer 5 CC-Parv and parvalbumin-expressing (Parv) neurons of the mouse auditory cortex (AC). Here we show that layer 5 CC-Parv neurons had larger dendritic fields characterized by longer dendrites that branched farther from the soma, whereas layer 5 Parv neurons had smaller dendritic fields characterized by shorter dendrites that branched nearer to the soma. The layer 5 CC-Parv neurons are characterized by delayed action potential (AP) responses to threshold currents, lower firing rates, and lower instantaneous frequencies compared to the layer 5 Parv neurons. Kv1.1 containing K + channels are the main source of the AP repolarization of the layer 5 CC-Parv and have a major role in determining both the spike delayed response, firing rate and instantaneous frequency of these neurons.

  7. Functionally distinct contributions of the anterior and posterior putamen during sublexical and lexical reading

    Directory of Open Access Journals (Sweden)

    Marion eOberhuber

    2013-11-01

    Full Text Available Previous studies have investigated orthographic-to-phonological mapping during reading by comparing brain activation for (1 reading words to object naming, or (2 reading pseudowords (e.g. phume to words (e.g. plume. Here we combined both approaches to provide new insights into the underlying neural mechanisms. In fMRI data from 25 healthy adult readers, we first identified activation that was greater for reading words and pseudowords relative to picture and color naming. The most significant effect was observed in the left putamen, extending to both anterior and posterior borders. Second, consistent with previous studies, we show that both the anterior and posterior putamen are involved in articulating speech with greater activation during our overt speech production tasks (reading, repetition, object naming and color naming than silent one-back-matching on the same stimuli. Third, we compared putamen activation for words versus pseudowords during overt reading and auditory repetition. This revealed that the anterior putamen was most activated by reading pseudowords, whereas the posterior putamen was most activated by words irrespective of whether the task was reading words or auditory word repetition. The pseudoword effect in the anterior putamen is consistent with prior studies that associated this region with the initiation of novel sequences of movements. In contrast, the heightened word response in the posterior putamen is consistent with other studies that associated this region with memory guided movement. Our results illustrate how the functional dissociation between the anterior and posterior putamen supports sublexical and lexical processing during reading.

  8. Whole-brain functional connectivity during acquisition of novel grammar: Distinct functional networks depend on language learning abilities.

    Science.gov (United States)

    Kepinska, Olga; de Rover, Mischa; Caspers, Johanneke; Schiller, Niels O

    2017-03-01

    In an effort to advance the understanding of brain function and organisation accompanying second language learning, we investigate the neural substrates of novel grammar learning in a group of healthy adults, consisting of participants with high and average language analytical abilities (LAA). By means of an Independent Components Analysis, a data-driven approach to functional connectivity of the brain, the fMRI data collected during a grammar-learning task were decomposed into maps representing separate cognitive processes. These included the default mode, task-positive, working memory, visual, cerebellar and emotional networks. We further tested for differences within the components, representing individual differences between the High and Average LAA learners. We found high analytical abilities to be coupled with stronger contributions to the task-positive network from areas adjacent to bilateral Broca's region, stronger connectivity within the working memory network and within the emotional network. Average LAA participants displayed stronger engagement within the task-positive network from areas adjacent to the right-hemisphere homologue of Broca's region and typical to lower level processing (visual word recognition), and increased connectivity within the default mode network. The significance of each of the identified networks for the grammar learning process is presented next to a discussion on the established markers of inter-individual learners' differences. We conclude that in terms of functional connectivity, the engagement of brain's networks during grammar acquisition is coupled with one's language learning abilities. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Plant functional types define magnitude of drought response in peatland CO2 exchange.

    Science.gov (United States)

    Kuiper, Jan J; Mooij, Wolf M; Bragazza, Luca; Robroek, Bjorn J M

    2014-01-01

    Peatlands are important sinks for atmospheric carbon (C), yet the role of plant functional types (PFTs) for C sequestration under climatic perturbations is still unclear. A plant-removal experiment was used to study the importance of vascular PFTs for the net ecosystem CO2 exchange (NEE) during (i.e., resistance) and after (i.e., recovery) an experimental drought. The removal of PFTs caused a decrease of NEE, but the rate differed between microhabitats (i.e., hummocks and lawns) and the type of PFTs. Ericoid removal had a large effect on NEE in hummocks, while the graminoids played a major role in the lawns. The removal of PFTs did not affect the resistance or the recovery after the experimental drought. We argue that the response of Sphagnum mosses (the only PFT present in all treatments) to drought is dominant over that of coexisting PFTs. However, we observed that the moment in time when the system switched from C sink to C source during the drought was controlled by the vascular PFTs. In the light of climate change, the shifts in species composition or even the loss of certain PFTs are expected to strongly affect the future C dynamics in response to environmental stress.

  10. Practical background modification fermented beverage technology for the formation of defined functional properties

    Directory of Open Access Journals (Sweden)

    V. V. Botvinnikova

    2016-01-01

    Full Text Available The problem of provision of population with dairy products is escalating due to the fact that today, throughout the world, particularly in Russia, there is a shortage of milk as raw material, increasing every year. In the future, the consumption of milk and dairy products will continue to outpace growth in milk production is solid. To solve this problem, domestic producers need to find new ways to increase production of raw milk and improve the consumer and functional properties of fermented dairy products. The work was proposed the use of acoustic effects of ultrasound, triggered by the ultrasound, the technological model UTA ABOUT, 4/22 OM (frequency mechanical vibrations 22 ± 1,65 kHz. The main factors determining consumer characteristics, were taken physico-chemical parameters, structural and mechanical characteristics and the accumulation of minor biologically active substances – kefiran. In the study was obtained results confirming the necessity of using ultrasonic impact (RAS in the production technology of dairy products.

  11. Defining functioning levels in patients with schizophrenia: A combination of a novel clustering method and brain SPECT analysis.

    Science.gov (United States)

    Catherine, Faget-Agius; Aurélie, Vincenti; Eric, Guedj; Pierre, Michel; Raphaëlle, Richieri; Marine, Alessandrini; Pascal, Auquier; Christophe, Lançon; Laurent, Boyer

    2017-12-30

    This study aims to define functioning levels of patients with schizophrenia by using a method of interpretable clustering based on a specific functioning scale, the Functional Remission Of General Schizophrenia (FROGS) scale, and to test their validity regarding clinical and neuroimaging characterization. In this observational study, patients with schizophrenia have been classified using a hierarchical top-down method called clustering using unsupervised binary trees (CUBT). Socio-demographic, clinical, and neuroimaging SPECT perfusion data were compared between the different clusters to ensure their clinical relevance. A total of 242 patients were analyzed. A four-group functioning level structure has been identified: 54 are classified as "minimal", 81 as "low", 64 as "moderate", and 43 as "high". The clustering shows satisfactory statistical properties, including reproducibility and discriminancy. The 4 clusters consistently differentiate patients. "High" functioning level patients reported significantly the lowest scores on the PANSS and the CDSS, and the highest scores on the GAF, the MARS and S-QoL 18. Functioning levels were significantly associated with cerebral perfusion of two relevant areas: the left inferior parietal cortex and the anterior cingulate. Our study provides relevant functioning levels in schizophrenia, and may enhance the use of functioning scale. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Coexistence of reduced function of natural killer cells and osteoclasts in two distinct osteopetrotic mutations in the rat

    International Nuclear Information System (INIS)

    Popoff, S.N.; Jackson, M.E.; Koevary, S.B.; Marks, S.C. Jr.

    1991-01-01

    Recent evidence suggesting that immune cells and their products (cytokines) play an important role in the regulation of skeletal development and function, particularly of the osteoclast, implies that immune cell dysfunction may be involved in the pathogenesis of certain skeletal disorders. The mammalian osteopetroses are a pathogenetically heterogeneous group of skeletal disorders characterized by skeletal sclerosis resulting from reduced osteoclast-mediated bone resorption. Using a 51 Cr release microcytotoxicity assay we demonstrated that splenic natural killer (NK) cell activity was significantly reduced in two distinctly different osteopetrotic mutations in the rat, osteopetrosis (op) and toothless (tl). To determine whether this reduction in NK cell-mediated cytotoxicity is caused by decreased cell number and/or function in these osteopetrotic mutants, we quantitated NK cells by analyzing mononuclear cell suspensions labeled for two-color fluorescence with OX8 and OX19 monoclonal antibodies in a fluorescence-activated cell sorter. Flow cytometry of these double-labeled cells revealed that the percentage of NK cells (OX8+/OX19- subset) in op and tl spleens was not significantly different from that of normal spleens. These results suggest that NK cells in these osteopetrotic mutants are functionally defective. Thus aberrations in osteoclast and NK cell function coexist in these mutations, and their developmental relationships deserve further study

  13. Complete identification of E-selectin ligands on neutrophils reveals distinct functions of PSGL-1, ESL-1, and CD44.

    Science.gov (United States)

    Hidalgo, Andrés; Peired, Anna J; Wild, Martin; Vestweber, Dietmar; Frenette, Paul S

    2007-04-01

    The selectins and their ligands are required for leukocyte extravasation during inflammation. Several glycoproteins have been suggested to bind to E-selectin in vitro, but the complete identification of its physiological ligands has remained elusive. Here, we showed that E-selectin ligand-1 (ESL-1), P-selectin glycoprotein ligand-1 (PSGL-1), and CD44 encompassed all endothelial-selectin ligand activity on neutrophils by using gene- and RNA-targeted loss of function. PSGL-1 played a major role in the initial leukocyte capture, whereas ESL-1 was critical for converting initial tethers into steady slow rolling. CD44 controlled rolling velocity and mediated E-selectin-dependent redistribution of PSGL-1 and L-selectin to a major pole on slowly rolling leukocytes through p38 signaling. These results suggest distinct and dynamic contributions of these three glycoproteins in selectin-mediated neutrophil adhesion and signaling.

  14. A Service-Oriented Approach for Dynamic Chaining of Virtual Network Functions over Multi-Provider Software-Defined Networks

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    Barbara Martini

    2016-06-01

    Full Text Available Emerging technologies such as Software-Defined Networks (SDN and Network Function Virtualization (NFV promise to address cost reduction and flexibility in network operation while enabling innovative network service delivery models. However, operational network service delivery solutions still need to be developed that actually exploit these technologies, especially at the multi-provider level. Indeed, the implementation of network functions as software running over a virtualized infrastructure and provisioned on a service basis let one envisage an ecosystem of network services that are dynamically and flexibly assembled by orchestrating Virtual Network Functions even across different provider domains, thereby coping with changeable user and service requirements and context conditions. In this paper we propose an approach that adopts Service-Oriented Architecture (SOA technology-agnostic architectural guidelines in the design of a solution for orchestrating and dynamically chaining Virtual Network Functions. We discuss how SOA, NFV, and SDN may complement each other in realizing dynamic network function chaining through service composition specification, service selection, service delivery, and placement tasks. Then, we describe the architecture of a SOA-inspired NFV orchestrator, which leverages SDN-based network control capabilities to address an effective delivery of elastic chains of Virtual Network Functions. Preliminary results of prototype implementation and testing activities are also presented. The benefits for Network Service Providers are also described that derive from the adaptive network service provisioning in a multi-provider environment through the orchestration of computing and networking services to provide end users with an enhanced service experience.

  15. Design and synthesis of structurally well-defined functional polypropylenes via transition metal-mediated olefin polymerization chemistry

    Institute of Scientific and Technical Information of China (English)

    Dong Jinyong

    2006-01-01

    Functionalization of polyolefins is an industrially important yet scientifically challenging research subject.This paper summarizes our recent effort to access structurally well-defined functional polypropylenes via transition metal-mediated olefin polymerization.In one approach,polypropylenes containing side chain functional groups of controlled concentrations were obtained by Ziegler-Natta-catalyzed copolymerization of propylene in combination with either living anionic or controlled radical polymerization of polar monomers.The copolymerization of propylene with 1,4-divinylbenzene using an isospecific MgC12-supported TIC14 catalyst yielded potypropylenes containing pendant styrene moieties.Both metalation reaction with n-butyllithium and hydrochlorination reaction with dry hydrogen chloride selectively and quantitatively occurred at the pendant reactive sites,generating polymeric benzyllithium and 1-chloroethylbenzene species.These species initiated living anionic polymerization of styrene(S)and atom transfer radical polymerization(in the presence of CuC1 and pentamethyldiethylenetriamine) of methyl methacrylate(MMA),respectively,resulting in functional polypropylene graft copolymers(PP-g-PS and PP-g-PMMA)with controllable graft lengths.In another approach,chain end-functionalized polypropylenes containing a terminal OH-group with controlled molecular weights were directly prepared by propylene polymerization with a metaUocene catalyst through a selective aluminum chain transfer reaction.Both approaches proved to be desirable polyolefin functionalization routes in terms of efficiency and polymer structure controllability.

  16. Identification of a functionally distinct truncated BDNF mRNA splice variant and protein in Trachemys scripta elegans.

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    Ganesh Ambigapathy

    Full Text Available Brain-derived neurotrophic factor (BDNF has a diverse functional role and complex pattern of gene expression. Alternative splicing of mRNA transcripts leads to further diversity of mRNAs and protein isoforms. Here, we describe the regulation of BDNF mRNA transcripts in an in vitro model of eyeblink classical conditioning and a unique transcript that forms a functionally distinct truncated BDNF protein isoform. Nine different mRNA transcripts from the BDNF gene of the pond turtle Trachemys scripta elegans (tBDNF are selectively regulated during classical conditioning: exon I mRNA transcripts show no change, exon II transcripts are downregulated, while exon III transcripts are upregulated. One unique transcript that codes from exon II, tBDNF2a, contains a 40 base pair deletion in the protein coding exon that generates a truncated tBDNF protein. The truncated transcript and protein are expressed in the naïve untrained state and are fully repressed during conditioning when full-length mature tBDNF is expressed, thereby having an alternate pattern of expression in conditioning. Truncated BDNF is not restricted to turtles as a truncated mRNA splice variant has been described for the human BDNF gene. Further studies are required to determine the ubiquity of truncated BDNF alternative splice variants across species and the mechanisms of regulation and function of this newly recognized BDNF protein.

  17. Identification of a functionally distinct truncated BDNF mRNA splice variant and protein in Trachemys scripta elegans.

    Science.gov (United States)

    Ambigapathy, Ganesh; Zheng, Zhaoqing; Li, Wei; Keifer, Joyce

    2013-01-01

    Brain-derived neurotrophic factor (BDNF) has a diverse functional role and complex pattern of gene expression. Alternative splicing of mRNA transcripts leads to further diversity of mRNAs and protein isoforms. Here, we describe the regulation of BDNF mRNA transcripts in an in vitro model of eyeblink classical conditioning and a unique transcript that forms a functionally distinct truncated BDNF protein isoform. Nine different mRNA transcripts from the BDNF gene of the pond turtle Trachemys scripta elegans (tBDNF) are selectively regulated during classical conditioning: exon I mRNA transcripts show no change, exon II transcripts are downregulated, while exon III transcripts are upregulated. One unique transcript that codes from exon II, tBDNF2a, contains a 40 base pair deletion in the protein coding exon that generates a truncated tBDNF protein. The truncated transcript and protein are expressed in the naïve untrained state and are fully repressed during conditioning when full-length mature tBDNF is expressed, thereby having an alternate pattern of expression in conditioning. Truncated BDNF is not restricted to turtles as a truncated mRNA splice variant has been described for the human BDNF gene. Further studies are required to determine the ubiquity of truncated BDNF alternative splice variants across species and the mechanisms of regulation and function of this newly recognized BDNF protein.

  18. Dynamic Recruitment of Functionally Distinct Swi/Snf Chromatin Remodeling Complexes Modulates Pdx1 Activity in Islet β Cells

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    Brian McKenna

    2015-03-01

    Full Text Available Pdx1 is a transcription factor of fundamental importance to pancreas formation and adult islet β cell function. However, little is known about the positive- and negative-acting coregulators recruited to mediate transcriptional control. Here, we isolated numerous Pdx1-interacting factors possessing a wide range of cellular functions linked with this protein, including, but not limited to, coregulators associated with transcriptional activation and repression, DNA damage response, and DNA replication. Because chromatin remodeling activities are essential to developmental lineage decisions and adult cell function, our analysis focused on investigating the influence of the Swi/Snf chromatin remodeler on Pdx1 action. The two mutually exclusive and indispensable Swi/Snf core ATPase subunits, Brg1 and Brm, distinctly affected target gene expression in β cells. Furthermore, physiological and pathophysiological conditions dynamically regulated Pdx1 binding to these Swi/Snf complexes in vivo. We discuss how context-dependent recruitment of coregulatory complexes by Pdx1 could impact pancreas cell development and adult islet β cell activity.

  19. Noradrenaline, oxymetazoline and phorbol myristate acetate induce distinct functional actions and phosphorylation patterns of α1A-adrenergic receptors.

    Science.gov (United States)

    Alcántara-Hernández, Rocío; Hernández-Méndez, Aurelio; Romero-Ávila, M Teresa; Alfonzo-Méndez, Marco A; Pupo, André S; García-Sáinz, J Adolfo

    2017-12-01

    In LNCaP cells that stably express α 1A -adrenergic receptors, oxymetazoline increased intracellular calcium and receptor phosphorylation, however, this agonist was a weak partial agonist, as compared to noradrenaline, for calcium signaling. Interestingly, oxymetazoline-induced receptor internalization and desensitization displayed greater effects than those induced by noradrenaline. Phorbol myristate acetate induced modest receptor internalization and minimal desensitization. α 1A -Adrenergic receptor interaction with β-arrestins (colocalization/coimmunoprecipitation) was induced by noradrenaline and oxymetazoline and, to a lesser extent, by phorbol myristate acetate. Oxymetazoline was more potent and effective than noradrenaline in inducing ERK 1/2 phosphorylation. Mass spectrometric analysis of immunopurified α 1A -adrenergic receptors from cells treated with adrenergic agonists and the phorbol ester clearly showed that phosphorylated residues were present both at the third intracellular loop and at the carboxyl tail. Distinct phosphorylation patterns were observed under the different conditions. The phosphorylated residues were: a) Baseline and all treatments: T233; b) noradrenaline: S220, S227, S229, S246, S250, S389; c) oxymetazoline: S227, S246, S381, T384, S389; and d) phorbol myristate acetate: S246, S250, S258, S351, S352, S401, S402, S407, T411, S413, T451. Our novel data, describing the α 1A -AR phosphorylation sites, suggest that the observed different phosphorylation patterns may participate in defining adrenoceptor localization and action, under the different conditions examined. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Distinct Domains of CheA Confer Unique Functions in Chemotaxis and Cell Length in Azospirillum brasilense Sp7.

    Science.gov (United States)

    Gullett, Jessica M; Bible, Amber; Alexandre, Gladys

    2017-07-01

    Chemotaxis is the movement of cells in response to gradients of diverse chemical cues. Motile bacteria utilize a conserved chemotaxis signal transduction system to bias their motility and navigate through a gradient. A central regulator of chemotaxis is the histidine kinase CheA. This cytoplasmic protein interacts with membrane-bound receptors, which assemble into large polar arrays, to propagate the signal. In the alphaproteobacterium Azospirillum brasilense , Che1 controls transient increases in swimming speed during chemotaxis, but it also biases the cell length at division. However, the exact underlying molecular mechanisms for Che1-dependent control of multiple cellular behaviors are not known. Here, we identify specific domains of the CheA1 histidine kinase implicated in modulating each of these functions. We show that CheA1 is produced in two isoforms: a membrane-anchored isoform produced as a fusion with a conserved seven-transmembrane domain of unknown function (TMX) at the N terminus and a soluble isoform similar to prototypical CheA. Site-directed and deletion mutagenesis combined with behavioral assays confirm the role of CheA1 in chemotaxis and implicate the TMX domain in mediating changes in cell length. Fluorescence microscopy further reveals that the membrane-anchored isoform is distributed around the cell surface while the soluble isoform localizes at the cell poles. Together, the data provide a mechanism for the role of Che1 in controlling multiple unrelated cellular behaviors via acquisition of a new domain in CheA1 and production of distinct functional isoforms. IMPORTANCE Chemotaxis provides a significant competitive advantage to bacteria in the environment, and this function has been transferred laterally multiple times, with evidence of functional divergence in different genomic contexts. The molecular principles that underlie functional diversification of chemotaxis in various genomic contexts are unknown. Here, we provide a molecular

  1. Phenotypic and functional profiling of CD4 T cell compartment in distinct populations of healthy adults with different antigenic exposure.

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    Sophie Roetynck

    Full Text Available Multiparameter flow cytometry has revealed extensive phenotypic and functional heterogeneity of CD4 T cell responses in mice and humans, emphasizing the importance of assessing multiple aspects of the immune response in correlation with infection or vaccination outcome. The aim of this study was to establish and validate reliable and feasible flow cytometry assays, which will allow us to characterize CD4 T cell population in humans in field studies more fully.We developed polychromatic flow cytometry antibody panels for immunophenotyping the major CD4 T cell subsets as well as broadly characterizing the functional profiles of the CD4 T cells in peripheral blood. We then validated these assays by conducting a pilot study comparing CD4 T cell responses in distinct populations of healthy adults living in either rural or urban Kenya. This study revealed that the expression profile of CD4 T cell activation and memory markers differed significantly between African and European donors but was similar amongst African individuals from either rural or urban areas. Adults from rural Kenya had, however, higher frequencies and greater polyfunctionality among cytokine producing CD4 T cells compared to both urban populations, particularly for "Th1" type of response. Finally, endemic exposure to malaria in rural Kenya may have influenced the expansion of few discrete CD4 T cell populations with specific functional signatures.These findings suggest that environmentally driven T cell activation does not drive the dysfunction of CD4 T cells but is rather associated with greater magnitude and quality of CD4 T cell response, indicating that the level or type of microbial exposure and antigenic experience may influence and shape the functionality of CD4 T cell compartment. Our data confirm that it is possible and mandatory to assess multiple functional attributes of CD4 T cell response in the context of infection.

  2. Anxa4 Genes are Expressed in Distinct Organ Systems in Xenopus laevis and tropicalis But are Functionally Conserved

    Science.gov (United States)

    Massé, Karine L; Collins, Robert J; Bhamra, Surinder; Seville, Rachel A

    2007-01-01

    Anxa4 belongs to the multigenic annexin family of proteins which are characterized by their ability to interact with membranes in a calcium-dependent manner. Defined as a marker for polarized epithelial cells, Anxa4 is believed to be involved in many cellular processes but its functions in vivo are still poorly understood. Previously, we cloned Xanx4 in Xenopus laevis (now referred to as anxa4a) and demonstrated its role during organogenesis of the pronephros, providing the first evidence of a specific function for this protein during the development of a vertebrate. Here, we describe the strict conservation of protein sequence and functional domains of anxa4 during vertebrate evolution. We also identify the paralog of anxa4a, anxa4b and show its specific temporal and spatial expression pattern is different from anxa4a. We show that anxa4 orthologs in X. laevis and tropicalis display expression domains in different organ systems. Whilst the anxa4a gene is mainly expressed in the kidney, Xt anxa4 is expressed in the liver. Finally, we demonstrate Xt anxa4 and anxa4a can display conserved function during kidney organogenesis, despite the fact that Xt anxa4 transcripts are not expressed in this domain. This study highlights the divergence of expression of homologous genes during Xenopus evolution and raises the potential problems of using X. tropicalis promoters in X. laevis. PMID:19279706

  3. Distinct expression profiles and different functions of odorant binding proteins in Nilaparvata lugens Stål.

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    Peng He

    Full Text Available BACKGROUND: Odorant binding proteins (OBPs play important roles in insect olfaction. The brown planthopper (BPH, Nilaparvata lugens Stål (Delphacidae, Auchenorrhyncha, Hemiptera is one of the most important rice pests. Its monophagy (only feeding on rice, wing form (long and short wing variation, and annual long distance migration (seeking for rice plants of high nutrition imply that the olfaction would play a central role in BPH behavior. However, the olfaction related proteins have not been characterized in this insect. METHODOLOGY/PRINCIPAL FINDINGS: Full length cDNA of three OBPs were obtained and distinct expression profiles were revealed regarding to tissue, developmental stage, wing form and gender for the first time for the species. The results provide important clues in functional differentiation of these genes. Binding assays with 41 compounds demonstrated that NlugOBP3 had markedly higher binding ability and wider binding spectrum than the other two OBPs. Terpenes and Ketones displayed higher binding while Alkanes showed no binding to the three OBPs. Focused on NlugOBP3, RNA interference experiments showed that NlugOBP3 not only involved in nymph olfaction on rice seedlings, but also had non-olfactory functions, as it was closely related to nymph survival. CONCLUSIONS: NlugOBP3 plays important roles in both olfaction and survival of BPH. It may serve as a potential target for developing behavioral disruptant and/or lethal agent in N. lugens.

  4. Comprehensive Proteomic Analysis of Human Milk-derived Extracellular Vesicles Unveils a Novel Functional Proteome Distinct from Other Milk Components*

    Science.gov (United States)

    van Herwijnen, Martijn J.C.; Zonneveld, Marijke I.; Goerdayal, Soenita; Nolte – 't Hoen, Esther N.M.; Garssen, Johan; Stahl, Bernd; Maarten Altelaar, A.F.; Redegeld, Frank A.; Wauben, Marca H.M.

    2016-01-01

    Breast milk contains several macromolecular components with distinctive functions, whereby milk fat globules and casein micelles mainly provide nutrition to the newborn, and whey contains molecules that can stimulate the newborn's developing immune system and gastrointestinal tract. Although extracellular vesicles (EV) have been identified in breast milk, their physiological function and composition has not been addressed in detail. EV are submicron sized vehicles released by cells for intercellular communication via selectively incorporated lipids, nucleic acids, and proteins. Because of the difficulty in separating EV from other milk components, an in-depth analysis of the proteome of human milk-derived EV is lacking. In this study, an extensive LC-MS/MS proteomic analysis was performed of EV that had been purified from breast milk of seven individual donors using a recently established, optimized density-gradient-based EV isolation protocol. A total of 1963 proteins were identified in milk-derived EV, including EV-associated proteins like CD9, Annexin A5, and Flotillin-1, with a remarkable overlap between the different donors. Interestingly, 198 of the identified proteins are not present in the human EV database Vesiclepedia, indicating that milk-derived EV harbor proteins not yet identified in EV of different origin. Similarly, the proteome of milk-derived EV was compared with that of other milk components. For this, data from 38 published milk proteomic studies were combined in order to construct the total milk proteome, which consists of 2698 unique proteins. Remarkably, 633 proteins identified in milk-derived EV have not yet been identified in human milk to date. Interestingly, these novel proteins include proteins involved in regulation of cell growth and controlling inflammatory signaling pathways, suggesting that milk-derived EVs could support the newborn's developing gastrointestinal tract and immune system. Overall, this study provides an expansion of

  5. Distinct Neural Signatures Detected for ADHD Subtypes After Controlling for Micro-Movements in Resting State Functional Connectivity MRI Data

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    Damien eFair

    2013-02-01

    Full Text Available In recent years, there has been growing enthusiasm that functional MRI could achieve clinical utility for a broad range of neuropsychiatric disorders. However, several barriers remain. For example, the acquisition of large-scale datasets capable of clarifying the marked heterogeneity that exists in psychiatric illnesses will need to be realized. In addition, there continues to be a need for the development of image processing and analysis methods capable of separating signal from artifact. As a prototypical hyperkinetic disorder, and movement related artifact being a significant confound in functional imaging studies, ADHD offers a unique challenge. As part of the ADHD-200 Global Competition and this special edition of Frontiers, the ADHD-200 Consortium demonstrates the utility of an aggregate dataset pooled across five institutions in addressing these challenges. The work aimed to A examine the impact of emerging techniques for controlling for micro-movements, and B provide novel insights into the neural correlates of ADHD subtypes. Using SVM based MVPA we show that functional connectivity patterns in individuals are capable of differentiating the two most prominent ADHD subtypes. The application of graph-theory revealed that the Combined (ADHD-C and Inattentive (ADHD-I subtypes demonstrated some overlapping (particularly sensorimotor systems, but unique patterns of atypical connectivity. For ADHD-C, atypical connectivity was prominent in midline default network components, as well as insular cortex; in contrast, the ADHD-I group exhibited atypical patterns within the dlPFC regions and cerebellum. Systematic motion-related artifact was noted, and highlighted the need for stringent motion correction. Findings reported were robust to the specific motion correction strategy employed. These data suggest that rs-fcMRI data can be used to characterize individual patients with ADHD and to identify neural distinctions underlying the clinical

  6. The function of the yeast molecular chaperone Sse1 is mechanistically distinct from the closely related hsp70 family.

    Science.gov (United States)

    Shaner, Lance; Trott, Amy; Goeckeler, Jennifer L; Brodsky, Jeffrey L; Morano, Kevin A

    2004-05-21

    The Sse1/Hsp110 molecular chaperones are a poorly understood subgroup of the Hsp70 chaperone family. Hsp70 can refold denatured polypeptides via a C-terminal peptide binding domain (PBD), which is regulated by nucleotide cycling in an N-terminal ATPase domain. However, unlike Hsp70, both Sse1 and mammalian Hsp110 bind unfolded peptide substrates but cannot refold them. To test the in vivo requirement for interdomain communication, SSE1 alleles carrying amino acid substitutions in the ATPase domain were assayed for their ability to complement sse1Delta yeast. Surprisingly, all mutants predicted to abolish ATP hydrolysis (D8N, K69Q, D174N, D203N) complemented the temperature sensitivity of sse1Delta and lethality of sse1Deltasse2Delta cells, whereas mutations in predicted ATP binding residues (G205D, G233D) were non-functional. Complementation ability correlated well with ATP binding assessed in vitro. The extreme C terminus of the Hsp70 family is required for substrate targeting and heterocomplex formation with other chaperones, but mutant Sse1 proteins with a truncation of up to 44 C-terminal residues that were not included in the PBD were active. Remarkably, the two domains of Sse1, when expressed in trans, functionally complement the sse1Delta growth phenotype and interact by coimmunoprecipitation analysis. In addition, a functional PBD was required to stabilize the Sse1 ATPase domain, and stabilization also occurred in trans. These data represent the first structure-function analysis of this abundant but ill defined chaperone, and establish several novel aspects of Sse1/Hsp110 function relative to Hsp70.

  7. Chemical construction and structural permutation of potent cytotoxin polytheonamide B: discovery of artificial peptides with distinct functions.

    Science.gov (United States)

    Itoh, Hiroaki; Inoue, Masayuki

    2013-07-16

    Polytheonamide B (1), isolated from the marine sponge Theonella swinhoei, is a posttranslationally modified ribosomal peptide (MW 5030 Da) that displays extraordinary cytotoxicity. Among its 48 amino acid residues, this peptide includes a variety D- and L-amino acids that do not occur in proteins, and the chiralities of these amino acids alternate in sequence. These structural features induce the formation of a stable β6.3-helix, giving rise to a tubular structure of over 4 nm in length. In the biological setting, this fold is believed to transport cations across the lipid bilayer through a pore, thereby acting as an ion channel. In this Account, we discuss the construction and structural permutations of this potent cytotoxin. First we describe the 161-step chemical construction of this unusual peptide 1. By developing a synthetic route to 1, we established the chemical basis for subsequent SAR studies to pinpoint the proteinogenic and nonproteinogenic building blocks within the molecule that confer its toxicity and channel function. Using fully synthetic 1, we generated seven analogues with point mutations, and studies of their activity revealed the importance of the N-terminal moiety. Next, we simplified the structure of 1 by substituting six amino acid residues of 1 to design a more synthetically accessible analogue 9. This dansylated polytheonamide mimic 9 was synthesized in 127 total steps, and we evaluated its function to show that it can emulate the toxic and ion channel activities of 1 despite its multiple structural modifications. Finally, we applied a highly automated synthetic route to 48-mer 9 to generate 13 substructures of 27-39-mers. The 37-mer 12 exhibited nanomolar level toxicity through a potentially distinct mode of action from 1 and 9. The SAR studies of polytheonamide B and the 21 artificial analogues have deepened our understanding of the precise structural requirements for the biological functions of 1. They have also led to the discovery of

  8. Functional physiology of the human terminal antrum defined by high-resolution electrical mapping and computational modeling.

    Science.gov (United States)

    Berry, Rachel; Miyagawa, Taimei; Paskaranandavadivel, Niranchan; Du, Peng; Angeli, Timothy R; Trew, Mark L; Windsor, John A; Imai, Yohsuke; O'Grady, Gregory; Cheng, Leo K

    2016-11-01

    High-resolution (HR) mapping has been used to study gastric slow-wave activation; however, the specific characteristics of antral electrophysiology remain poorly defined. This study applied HR mapping and computational modeling to define functional human antral physiology. HR mapping was performed in 10 subjects using flexible electrode arrays (128-192 electrodes; 16-24 cm 2 ) arranged from the pylorus to mid-corpus. Anatomical registration was by photographs and anatomical landmarks. Slow-wave parameters were computed, and resultant data were incorporated into a computational fluid dynamics (CFD) model of gastric flow to calculate impact on gastric mixing. In all subjects, extracellular mapping demonstrated normal aboral slow-wave propagation and a region of increased amplitude and velocity in the prepyloric antrum. On average, the high-velocity region commenced 28 mm proximal to the pylorus, and activation ceased 6 mm from the pylorus. Within this region, velocity increased 0.2 mm/s per mm of tissue, from the mean 3.3 ± 0.1 mm/s to 7.5 ± 0.6 mm/s (P human terminal antral contraction is controlled by a short region of rapid high-amplitude slow-wave activity. Distal antral wave acceleration plays a major role in antral flow and mixing, increasing particle strain and trituration. Copyright © 2016 the American Physiological Society.

  9. Recombinant vitronectin is a functionally defined substrate that supports human embryonic stem cell self-renewal via alphavbeta5 integrin.

    NARCIS (Netherlands)

    Braam, S.R.; Zeinstra, L.M.; Litjens, S.H.M.; Ward-van Oostwaard, D.; van den Brink, S.; van Laake, L.W.; Lebrin, F.; Kats, P.; Hochstenbach, R.; Passier, R.; Sonnenberg, A.; Mummery, C.L.

    2008-01-01

    Defined growth conditions are essential for many applications of human embryonic stem cells (hESC). Most defined media are presently used in combination with Matrigel, a partially defined extracellular matrix (ECM) extract from mouse sarcoma. Here, we defined ECM requirements of hESC by analyzing

  10. Lipid-laden cells differentially distributed in the aging brain are functionally active and correspond to distinct phenotypes.

    Science.gov (United States)

    Shimabukuro, Marilia Kimie; Langhi, Larissa Gutman Paranhos; Cordeiro, Ingrid; Brito, José M; Batista, Claudia Maria de Castro; Mattson, Mark P; Mello Coelho, Valeria de

    2016-03-31

    We characterized cerebral Oil Red O-positive lipid-laden cells (LLC) of aging mice evaluating their distribution, morphology, density, functional activities and inflammatory phenotype. We identified LLC in meningeal, cortical and neurogenic brain regions. The density of cerebral LLC increased with age. LLC presenting small lipid droplets were visualized adjacent to blood vessels or deeper in the brain cortical and striatal parenchyma of aging mice. LLC with larger droplets were asymmetrically distributed in the cerebral ventricle walls, mainly located in the lateral wall. We also found that LLC in the subventricular region co-expressed beclin-1 or LC3, markers for autophagosome or autophagolysosome formation, and perilipin (PLIN), a lipid droplet-associated protein, suggesting lipophagic activity. Some cerebral LLC exhibited β galactosidase activity indicating a senescence phenotype. Moreover, we detected production of the pro-inflammatory cytokine TNF-α in cortical PLIN(+) LLC. Some cortical NeuN(+) neurons, GFAP(+) glia limitans astrocytes, Iba-1(+) microglia and S100β(+) ependymal cells expressed PLIN in the aging brain. Our findings suggest that cerebral LLC exhibit distinct cellular phenotypes and may participate in the age-associated neuroinflammatory processes.

  11. Distinct functional characteristics of levocabastine sensitive rat neurotensin NT2 receptor expressed in Chinese hamster ovary cells.

    Science.gov (United States)

    Yamada, M; Yamada, M; Lombet, A; Forgez, P; Rostène, W

    1998-01-01

    Neurotensin has been shown to produce pharmacological effects both in brain and periphery. Several of these effects are mediated by a high-affinity neurotensin NT1 receptor. On the other hand, a low-affinity levocabastine-sensitive neurotensin NT2 receptor was molecularly cloned from rodent brain recently. In this study, in contrast to NT1 receptor, levocabastine (a histamine H1 receptor antagonist) and SR48692 (an antagonist for NT1 receptor) strongly stimulated intracellular Ca2+ mobilization in transfected Chinese hamster ovary cells expressing rat NT2 receptor, thus acting as potent NT2 receptor. Furthermore, despite of their affinities for NT2 receptor, the Ca2+ responses to potent NT1 agonists, neurotensin or JMV449 ([Lys8-(CH2NH)-Lys9]Pro-Tyr-Ile-Leu, a peptidase resistant analogue of neurotensin) were much smaller than that observed with SR48692. These findings suggest that NT1 and NT2 receptors present distinct functional characteristics and that SR48692 may act as a potent agonist for NT2 receptor.

  12. A novel ATM-dependent checkpoint defect distinct from loss of function mutation promotes genomic instability in melanoma.

    Science.gov (United States)

    Spoerri, Loredana; Brooks, Kelly; Chia, KeeMing; Grossman, Gavriel; Ellis, Jonathan J; Dahmer-Heath, Mareike; Škalamera, Dubravka; Pavey, Sandra; Burmeister, Bryan; Gabrielli, Brian

    2016-05-01

    Melanomas have high levels of genomic instability that can contribute to poor disease prognosis. Here, we report a novel defect of the ATM-dependent cell cycle checkpoint in melanoma cell lines that promotes genomic instability. In defective cells, ATM signalling to CHK2 is intact, but the cells are unable to maintain the cell cycle arrest due to elevated PLK1 driving recovery from the arrest. Reducing PLK1 activity recovered the ATM-dependent checkpoint arrest, and over-expressing PLK1 was sufficient to overcome the checkpoint arrest and increase genomic instability. Loss of the ATM-dependent checkpoint did not affect sensitivity to ionizing radiation demonstrating that this defect is distinct from ATM loss of function mutations. The checkpoint defective melanoma cell lines over-express PLK1, and a significant proportion of melanomas have high levels of PLK1 over-expression suggesting this defect is a common feature of melanomas. The inability of ATM to impose a cell cycle arrest in response to DNA damage increases genomic instability. This work also suggests that the ATM-dependent checkpoint arrest is likely to be defective in a higher proportion of cancers than previously expected. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Lipid-laden cells differentially distributed in the aging brain are functionally active and correspond to distinct phenotypes

    Science.gov (United States)

    Shimabukuro, Marilia Kimie; Langhi, Larissa Gutman Paranhos; Cordeiro, Ingrid; Brito, José M.; Batista, Claudia Maria de Castro; Mattson, Mark P.; de Mello Coelho, Valeria

    2016-01-01

    We characterized cerebral Oil Red O-positive lipid-laden cells (LLC) of aging mice evaluating their distribution, morphology, density, functional activities and inflammatory phenotype. We identified LLC in meningeal, cortical and neurogenic brain regions. The density of cerebral LLC increased with age. LLC presenting small lipid droplets were visualized adjacent to blood vessels or deeper in the brain cortical and striatal parenchyma of aging mice. LLC with larger droplets were asymmetrically distributed in the cerebral ventricle walls, mainly located in the lateral wall. We also found that LLC in the subventricular region co-expressed beclin-1 or LC3, markers for autophagosome or autophagolysosome formation, and perilipin (PLIN), a lipid droplet-associated protein, suggesting lipophagic activity. Some cerebral LLC exhibited β galactosidase activity indicating a senescence phenotype. Moreover, we detected production of the pro-inflammatory cytokine TNF-α in cortical PLIN+ LLC. Some cortical NeuN+ neurons, GFAP+ glia limitans astrocytes, Iba-1+ microglia and S100β+ ependymal cells expressed PLIN in the aging brain. Our findings suggest that cerebral LLC exhibit distinct cellular phenotypes and may participate in the age-associated neuroinflammatory processes. PMID:27029648

  14. BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Krüppel-like Factors.

    Science.gov (United States)

    Morikawa, Masato; Koinuma, Daizo; Mizutani, Anna; Kawasaki, Natsumi; Holmborn, Katarina; Sundqvist, Anders; Tsutsumi, Shuichi; Watabe, Tetsuro; Aburatani, Hiroyuki; Heldin, Carl-Henrik; Miyazono, Kohei

    2016-01-12

    Bone morphogenetic protein (BMP) signaling exerts paradoxical roles in pluripotent stem cells (PSCs); it sustains self-renewal of mouse embryonic stem cells (ESCs), while it induces differentiation in other PSCs, including human ESCs. Here, we revisit the roles of BMP-4 using mouse ESCs (mESCs) in naive and primed states. SMAD1 and SMAD5, which transduce BMP signals, recognize enhancer regions together with KLF4 and KLF5 in naive mESCs. KLF4 physically interacts with SMAD1 and suppresses its activity. Consistently, a subpopulation of cells with active BMP-SMAD can be ablated without disturbing the naive state of the culture. Moreover, Smad1/5 double-knockout mESCs stay in the naive state, indicating that the BMP-SMAD pathway is dispensable for it. In contrast, the MEK5-ERK5 pathway mediates BMP-4-induced self-renewal of mESCs by inducing Klf2, a critical factor for the ground state pluripotency. Our study illustrates that BMP exerts its self-renewing effect through distinct functions of different Krüppel-like factors. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  15. Picornaviruses and nuclear functions: targeting a cellular compartment distinct from the replication site of a positive-strand RNA virus

    Directory of Open Access Journals (Sweden)

    Dylan eFlather

    2015-06-01

    Full Text Available The compartmentalization of DNA replication and gene transcription in the nucleus and protein production in the cytoplasm is a defining feature of eukaryotic cells. The nucleus functions to maintain the integrity of the nuclear genome of the cell and to control gene expression based on intracellular and environmental signals received through the cytoplasm. The spatial separation of the major processes that lead to the expression of protein-coding genes establishes the necessity of a transport network to allow biomolecules to translocate between these two regions of the cell. The nucleocytoplasmic transport network is therefore essential for regulating normal cellular functioning. The Picornaviridae virus family is one of many viral families that disrupt the nucleocytoplasmic trafficking of cells to promote viral replication. Picornaviruses contain positive-sense, single-stranded RNA genomes and replicate in the cytoplasm of infected cells. As a result of the limited coding capacity of these viruses, cellular proteins are required by these intracellular parasites for both translation and genomic RNA replication. Being of messenger RNA polarity, a picornavirus genome can immediately be translated upon entering the cell cytoplasm. However, the replication of viral RNA requires the activity of RNA-binding proteins, many of which function in host gene expression, and are consequently localized to the nucleus. As a result, picornaviruses disrupt nucleocytoplasmic trafficking to exploit protein functions normally localized to a different cellular compartment from which they translate their genome to facilitate efficient replication. Furthermore, picornavirus proteins are also known to enter the nucleus of infected cells to limit host-cell transcription and down-regulate innate antiviral responses. The interactions of picornavirus proteins and host-cell nuclei are extensive, required for a productive infection, and are the focus of this review.

  16. Long-lasting, distinct changes in central opioid receptor and urinary bladder functions in models of schizophrenia in rats.

    Science.gov (United States)

    Kekesi, Orsolya; Tuboly, Gabor; Szucs, Maria; Birkas, Erika; Morvay, Zita; Benedek, Gyorgy; Horvath, Gyongyi

    2011-07-01

    Ketamine treatments and social isolation of rats reflect certain features of schizophrenia, among them altered pain sensitivity. To study the underlying mechanisms of these phenomena, rats were either housed individually or grouped for 33 days after weaning, and treated with either ketamine or saline for 14 days. After one month re-socialization, the urinary bladder capacity by ultrasound examination in the anesthetized animals, and changes of μ-opioid receptors by saturation binding experiments using a specific μ-opioid agonist [(3)H]DAMGO were determined. G-protein signaling was investigated in DAMGO-stimulated [(35)S]GTPγS functional assays. Ketamine treatment significantly decreased the bladder volume and isolation decreased the receptor density in cortical membranes. Among all groups, the only change in binding affinity was an increase induced by social isolation in the cortex. G-protein signaling was significantly decreased by either ketamine or social isolation in this tissue. Ketamine treatment, but not housing, significantly increased μ-opioid receptor densities in hippocampal membranes. Both ketamine and isolation increased the efficacy, while the potency of signaling was decreased by any treatment. Ketamine increased the receptor density and G-protein activation; while isolation decreased the efficacy of G-protein signaling in hippocampal membranes. The changes in the co-treated group were similar to those of the isolated animals in most tests. The distinct changes of opioid receptor functioning in different areas of the CNS may, at least partially, explain the augmented nociceptive threshold and morphine potency observed in these animals. Changes in the relative urinary bladder suggest a detrusor hyperreflexia, another sign of schizophrenia. Copyright © 2011 Elsevier B.V. All rights reserved.

  17. Specific leaf areas of the tank bromeliad Guzmania monostachia perform distinct functions in response to water shortage.

    Science.gov (United States)

    Freschi, Luciano; Takahashi, Cassia Ayumi; Cambui, Camila Aguetoni; Semprebom, Thais Ribeiro; Cruz, Aline Bertinatto; Mioto, Paulo Tamoso; de Melo Versieux, Leonardo; Calvente, Alice; Latansio-Aidar, Sabrina Ribeiro; Aidar, Marcos Pereira Marinho; Mercier, Helenice

    2010-05-01

    Leaves comprise most of the vegetative body of tank bromeliads and are usually subjected to strong longitudinal gradients. For instance, while the leaf base is in contact with the water accumulated in the tank, the more light-exposed middle and upper leaf sections have no direct access to this water reservoir. Therefore, the present study attempted to investigate whether different leaf portions of Guzmania monostachia, a tank-forming C(3)-CAM bromeliad, play distinct physiological roles in response to water shortage, which is a major abiotic constraint in the epiphytic habitat. Internal and external morphological features, relative water content, pigment composition and the degree of CAM expression were evaluated in basal, middle and apical leaf portions in order to allow the establishment of correlations between the structure and the functional importance of each leaf region. Results indicated that besides marked structural differences, a high level of functional specialization is also present along the leaves of this bromeliad. When the tank water was depleted, the abundant hydrenchyma of basal leaf portions was the main reservoir for maintaining a stable water status in the photosynthetic tissues of the apical region. In contrast, the CAM pathway was intensified specifically in the upper leaf section, which is in agreement with the presence of features more suitable for the occurrence of photosynthesis at this portion. Gas exchange data indicated that internal recycling of respiratory CO(2) accounted for virtually all nighttime acid accumulation, characterizing a typical CAM-idling pathway in the drought-exposed plants. Altogether, these data reveal a remarkable physiological complexity along the leaves of G. monostachia, which might be a key adaptation to the intermittent water supply of the epiphytic niche. Copyright 2009 Elsevier GmbH. All rights reserved.

  18. Contrasting expression of membrane metalloproteinases, MT1-MMP and MT3-MMP, suggests distinct functions in skeletal development.

    Science.gov (United States)

    Yang, Maozhou; Zhang, Bingbing; Zhang, Liang; Gibson, Gary

    2008-07-01

    Membrane-type 1 matrix metalloproteinase (MT1-MMP) is the most ubiquitous and widely studied of the membrane-type metalloproteinases (MT-MMPs). It was thus surprising to find no published data on chicken MT1-MMP. We report here the characterization of the chicken gene. Its low sequence identity with the MT1-MMP genes of other species, high GC content, and divergent catalytic domain explains the absence of data and our difficulties in characterizing the gene. The absence of structural features in the chicken gene that have been suggested to be critical for the activation of MMP-2 by MT1-MMP; for the effect of MT1-MMP on cell migration and for the recycling of MT1-MMP suggest these features are either not essential or that MT1-MMP does not perform these functions in chickens. Comparison of the expression of chicken MT1-MMP with MT3-MMP and with MMP-2 and MMP-13 has confirmed the previously recognized co-expression of MT1-MMP with MMP-2 and MMP-13 in fibrous and vascular tissues, particularly those surrounding the developing long bones in other species. By contrast, MT3-MMP expression differs markedly from that of MT1-MMP and of both MMP-2 and MMP-13. MT3-MMP is expressed by chondrocytes of the developing articular surface. Similar expression patterns of this group of MT-MMPs and MMPs have been observed in mouse embryos and suggest distinct and specific functions for MT1-MMP and MT3-MMP in skeletal development.

  19. Defining Cyberbullying.

    Science.gov (United States)

    Englander, Elizabeth; Donnerstein, Edward; Kowalski, Robin; Lin, Carolyn A; Parti, Katalin

    2017-11-01

    Is cyberbullying essentially the same as bullying, or is it a qualitatively different activity? The lack of a consensual, nuanced definition has limited the field's ability to examine these issues. Evidence suggests that being a perpetrator of one is related to being a perpetrator of the other; furthermore, strong relationships can also be noted between being a victim of either type of attack. It also seems that both types of social cruelty have a psychological impact, although the effects of being cyberbullied may be worse than those of being bullied in a traditional sense (evidence here is by no means definitive). A complicating factor is that the 3 characteristics that define bullying (intent, repetition, and power imbalance) do not always translate well into digital behaviors. Qualities specific to digital environments often render cyberbullying and bullying different in circumstances, motivations, and outcomes. To make significant progress in addressing cyberbullying, certain key research questions need to be addressed. These are as follows: How can we define, distinguish between, and understand the nature of cyberbullying and other forms of digital conflict and cruelty, including online harassment and sexual harassment? Once we have a functional taxonomy of the different types of digital cruelty, what are the short- and long-term effects of exposure to or participation in these social behaviors? What are the idiosyncratic characteristics of digital communication that users can be taught? Finally, how can we apply this information to develop and evaluate effective prevention programs? Copyright © 2017 by the American Academy of Pediatrics.

  20. Syntheses and Post-Polymerization Modifications of Well-Defined Styrenic Polymers Containing Three-Membered Heterocyclic Functionalities

    Science.gov (United States)

    McLeod, David Charles

    Macromolecules that contain electrophilic moieties, such as benzyl halides, activated esters, and epoxides, will readily undergo efficient nucleophilic substitution reactions with a wide variety of compounds under mild conditions, and are therefore ideally suited to act as "universal" precursors to functional materials. Epoxide-containing polymers derived from the radical polymerization of commercially-available glycidyl methacrylate are often employed in this role; however, methacrylic polymers suffer from certain limitations as a result of the incorporated ester groups, which are not stabile in the presence of strong nucleophiles, acids, bases, or esterase enzymes. Styrenic polymers that do not contain labile carbonyl moieties are usually the precursors of choice when high chemical stability is desired in the end product, but the production of functional materials from epoxide-containing styrenic polymers is relatively unexplored. In this dissertation, improved methods were developed for synthesizing 4-vinylphenyloxirane (4VPO) and 4-vinylphenyl glycidyl ether (4VPGE), two of the better-known epoxide-containing styrenic monomers, in high-yield and purity. Well-defined, epoxide-containing styrenic polymers with targeted molecular weights, narrow molecular weight distributions, and controlled architectures (specifically, linear and star-shaped homopolymers, as well as linear block copolymers with styrene) were produced from 4VPO and 4VPGE for the first time using reversible-deactivation radical polymerization techniques, such as low-catalyst-concentration atom transfer radical polymerization (LCC ATRP) and reversible addition-fragmentation chain-transfer (RAFT) polymerization. The robust nature and utility of poly4VPO and poly4VPGE were then demonstrated by the efficient, ring-opening modification of the pendant epoxide groups with a structurally- and functionally-diverse array of alcohols under acidic conditions at ambient temperature. The macromolecular

  1. The Ultimate Big Data Enterprise Initiative: Defining Functional Capabilities for an International Information System (IIS) for Orbital Space Data (OSD)

    Science.gov (United States)

    Raygan, R.

    Global collaboration in support of an International Information System (IIS) for Orbital Space Data (OSD) literally requires a global enterprise. As with many information technology enterprise initiatives attempting to coral the desires of business with the budgets and limitations of technology, Space Situational Awareness (SSA) includes many of the same challenges: 1) Adaptive / Intuitive Dash Board that facilitates User Experience Design for a variety of users. 2) Asset Management of hundreds of thousands of objects moving at thousands of miles per hour hundreds of miles in space. 3) Normalization and integration of diverse data in various languages, possibly hidden or protected from easy access. 4) Expectations of near real-time information availability coupled with predictive analysis to affect decisions before critical points of no return, such as Space Object Conjunction Assessment (CA). 5) Data Ownership, management, taxonomy, and accuracy. 6) Integrated metrics and easily modified algorithms for "what if" analysis. This paper proposes an approach to define the functional capabilities for an IIS for OSD. These functional capabilities not only address previously identified gaps in current systems but incorporate lessons learned from other big data, enterprise, and agile information technology initiatives that correlate to the space domain. Viewing the IIS as the "data service provider" allows adoption of existing information technology processes which strengthen governance and ensure service consumers certain levels of service dependability and accuracy.

  2. Comprehensive Proteomic Analysis of Human Milk-derived Extracellular Vesicles Unveils a Novel Functional Proteome Distinct from Other Milk Components.

    Science.gov (United States)

    van Herwijnen, Martijn J C; Zonneveld, Marijke I; Goerdayal, Soenita; Nolte-'t Hoen, Esther N M; Garssen, Johan; Stahl, Bernd; Maarten Altelaar, A F; Redegeld, Frank A; Wauben, Marca H M

    2016-11-01

    Breast milk contains several macromolecular components with distinctive functions, whereby milk fat globules and casein micelles mainly provide nutrition to the newborn, and whey contains molecules that can stimulate the newborn's developing immune system and gastrointestinal tract. Although extracellular vesicles (EV) have been identified in breast milk, their physiological function and composition has not been addressed in detail. EV are submicron sized vehicles released by cells for intercellular communication via selectively incorporated lipids, nucleic acids, and proteins. Because of the difficulty in separating EV from other milk components, an in-depth analysis of the proteome of human milk-derived EV is lacking. In this study, an extensive LC-MS/MS proteomic analysis was performed of EV that had been purified from breast milk of seven individual donors using a recently established, optimized density-gradient-based EV isolation protocol. A total of 1963 proteins were identified in milk-derived EV, including EV-associated proteins like CD9, Annexin A5, and Flotillin-1, with a remarkable overlap between the different donors. Interestingly, 198 of the identified proteins are not present in the human EV database Vesiclepedia, indicating that milk-derived EV harbor proteins not yet identified in EV of different origin. Similarly, the proteome of milk-derived EV was compared with that of other milk components. For this, data from 38 published milk proteomic studies were combined in order to construct the total milk proteome, which consists of 2698 unique proteins. Remarkably, 633 proteins identified in milk-derived EV have not yet been identified in human milk to date. Interestingly, these novel proteins include proteins involved in regulation of cell growth and controlling inflammatory signaling pathways, suggesting that milk-derived EVs could support the newborn's developing gastrointestinal tract and immune system. Overall, this study provides an expansion of

  3. MeV gamma-ray observation with a well-defined point spread function based on electron tracking

    Science.gov (United States)

    Takada, A.; Tanimori, T.; Kubo, H.; Mizumoto, T.; Mizumura, Y.; Komura, S.; Kishimoto, T.; Takemura, T.; Yoshikawa, K.; Nakamasu, Y.; Matsuoka, Y.; Oda, M.; Miyamoto, S.; Sonoda, S.; Tomono, D.; Miuchi, K.; Kurosawa, S.; Sawano, T.

    2016-07-01

    The field of MeV gamma-ray astronomy has not opened up until recently owing to imaging difficulties. Compton telescopes and coded-aperture imaging cameras are used as conventional MeV gamma-ray telescopes; however their observations are obstructed by huge background, leading to uncertainty of the point spread function (PSF). Conventional MeV gamma-ray telescopes imaging utilize optimizing algorithms such as the ML-EM method, making it difficult to define the correct PSF, which is the uncertainty of a gamma-ray image on the celestial sphere. Recently, we have defined and evaluated the PSF of an electron-tracking Compton camera (ETCC) and a conventional Compton telescope, and thereby obtained an important result: The PSF strongly depends on the precision of the recoil direction of electron (scatter plane deviation, SPD) and is not equal to the angular resolution measure (ARM). Now, we are constructing a 30 cm-cubic ETCC for a second balloon experiment, Sub-MeV gamma ray Imaging Loaded-on-balloon Experiment: SMILE-II. The current ETCC has an effective area of 1 cm2 at 300 keV, a PSF of 10° at FWHM for 662 keV, and a large field of view of 3 sr. We will upgrade this ETCC to have an effective area of several cm2 and a PSF of 5° using a CF4-based gas. Using the upgraded ETCC, our observation plan for SMILE-II is to map of the electron-positron annihilation line and the 1.8 MeV line from 26Al. In this paper, we will report on the current performance of the ETCC and on our observation plan.

  4. Geometric morphometrics of functionally distinct floral organs in Iris pumila: Analyzing patterns of symmetric and asymmetric shape variations

    Directory of Open Access Journals (Sweden)

    Radović Sanja

    2017-01-01

    Full Text Available The Iris flower is a complex morphological structure composed of two trimerous whorls of functionally distinct petaloid organs (the falls and the standards, one whorl of the stamens and one tricarpellary gynoecium. The petal-like style arms of the carpels are banded over the basal part of the falls, forming three pollination tunnels, each of which is perceived by the Iris pollinators as a single bilaterally symmetrical flower. Apart from the stamens, all petaloid floral organs are preferentially involved in advertising rewards to potential pollinators. Here we used the methods of geometric morphometrics to explore the shape variation in falls, standards and style arms of the Iris pumila flowers and to disentangle the symmetric and the asymmetric component of the total shape variance. Our results show that symmetric variation contributes mostly to the total shape variance in each of the three floral organs. Fluctuating asymmetry (FA was the dominant component of the asymmetric shape variation in the falls and the standards, but appeared to be marginally significant in the style arms. The values of FA indexes for the shape of falls (insects’ landing platforms and for the shape of standards (long-distance reward signals were found to be two orders of magnitude greater compared to that of the style arms. Directional asymmetry appeared to be very low, but highly statistically significant for all analyzed floral organs. Because floral symmetry can reliably indicate the presence of floral rewards, an almost perfect symmetry recorded for the style arm shape might be the outcome of pollinator preferences for symmetrical pollination units. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 173007

  5. Defining and Selecting Independent Directors

    Directory of Open Access Journals (Sweden)

    Eric Pichet

    2017-10-01

    Full Text Available Drawing from the Enlightened Shareholder Theory that the author first developed in 2011, this theoretical paper with practical and normative ambitions achieves a better definition of independent director, while improving the understanding of the roles he fulfils on boards of directors. The first part defines constructs like firms, Governance system and Corporate governance, offering a clear distinction between the latter two concepts before explaining the four main missions of a board. The second part defines the ideal independent director by outlining the objective qualities that are necessary and adding those subjective aspects that have turned this into a veritable profession. The third part defines the ideal process for selecting independent directors, based on nominating committees that should themselves be independent. It also includes ways of assessing directors who are currently in function, as well as modalities for renewing their mandates. The paper’s conclusion presents the Paradox of the Independent Director.

  6. Taxonomic and functional distinctness of the fish assemblages in three coastal environments (bays, coastal lagoons and oceanic beaches) in Southeastern Brazil.

    Science.gov (United States)

    Azevedo, Márcia Cristina Costa; Gomes-Gonçalves, Rafaela de Sousa; Mattos, Tailan Moretti; Uehara, Wagner; Guedes, Gustavo Henrique Soares; Araújo, Francisco Gerson

    2017-08-01

    Several species of marine fish use different coastal systems especially during their early development. However, these habitats are jeopardized by anthropogenic influences threatening the success of fish populations, and urgent measures are needed to priorize areas to protect their sustainability. We applied taxonomic (Δ+) and functional (X+) distinctiveness indices that represent taxonomic composition and functional roles to assess biodiversity of three different costal systems: bays, coastal lagoons and oceanic beaches. We hypothesized that difference in habitat characteristics, especially in the more dynamism and habitat homogeneity of oceanic beaches compared with more habitat diversity and sheltered conditions of bays and coastal lagoons results in differences in fish richness and taxonomic and functional diversity. The main premise is that communities phylogenetically and functionally more distinct have more interest in conservation policies. Significant differences (P PERMANOVA. Fish richness was higher in bays compared with the coastal lagoons and oceanic beaches. Higher Δ+ was found for the coastal lagoons compared with the bays and oceanic beaches, with the bays having some values below the confidence limit. Similar patterns were found for X+, although all values were within the confidence limits for the bays, suggesting that the absence of some taxa does not interfere in functional diversity. The hypothesis that taxonomic and functional structure of fish assemblages differ among the three systems was accepted and we suggest that coastal lagoons should be priorized in conservation programs because they support more taxonomic and functional distinctiveness. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Analysis of C. elegans NR2E nuclear receptors defines three conserved clades and ligand-independent functions

    Directory of Open Access Journals (Sweden)

    Weber Katherine P

    2012-06-01

    Full Text Available Abstract Background The nuclear receptors (NRs are an important class of transcription factors that are conserved across animal phyla. Canonical NRs consist of a DNA-binding domain (DBD and ligand-binding domain (LBD. While most animals have 20–40 NRs, nematodes of the genus Caenorhabditis have experienced a spectacular proliferation and divergence of NR genes. The LBDs of evolutionarily-conserved Caenorhabditis NRs have diverged sharply from their Drosophila and vertebrate orthologs, while the DBDs have been strongly conserved. The NR2E family of NRs play critical roles in development, especially in the nervous system. In this study, we explore the phylogenetics and function of the NR2E family of Caenorhabditis elegans, using an in vivo assay to test LBD function. Results Phylogenetic analysis reveals that the NR2E family of NRs consists of three broadly-conserved clades of orthologous NRs. In C. elegans, these clades are defined by nhr-67, fax-1 and nhr-239. The vertebrate orthologs of nhr-67 and fax-1 are Tlx and PNR, respectively. While the nhr-239 clade includes orthologs in insects (Hr83, an echinoderm, and a hemichordate, the gene appears to have been lost from vertebrate lineages. The C. elegans and C. briggsae nhr-239 genes have an apparently-truncated and highly-diverged LBD region. An additional C. elegans NR2E gene, nhr-111, appears to be a recently-evolved paralog of fax-1; it is present in C. elegans, but not C. briggsae or other animals with completely-sequenced genomes. Analysis of the relatively unstudied nhr-111 and nhr-239 genes demonstrates that they are both expressed—nhr-111 very broadly and nhr-239 in a small subset of neurons. Analysis of the FAX-1 LBD in an in vivo assay revealed that it is not required for at least some developmental functions. Conclusions Our analysis supports three conserved clades of NR2E receptors, only two of which are represented in vertebrates, indicating three ancestral NR2E genes in the

  8. Analytical study of the effects of soft tissue artefacts on functional techniques to define axes of rotation.

    Science.gov (United States)

    De Rosario, Helios; Page, Álvaro; Besa, Antonio

    2017-09-06

    The accurate location of the main axes of rotation (AoR) is a crucial step in many applications of human movement analysis. There are different formal methods to determine the direction and position of the AoR, whose performance varies across studies, depending on the pose and the source of errors. Most methods are based on minimizing squared differences between observed and modelled marker positions or rigid motion parameters, implicitly assuming independent and uncorrelated errors, but the largest error usually results from soft tissue artefacts (STA), which do not have such statistical properties and are not effectively cancelled out by such methods. However, with adequate methods it is possible to assume that STA only account for a small fraction of the observed motion and to obtain explicit formulas through differential analysis that relate STA components to the resulting errors in AoR parameters. In this paper such formulas are derived for three different functional calibration techniques (Geometric Fitting, mean Finite Helical Axis, and SARA), to explain why each technique behaves differently from the others, and to propose strategies to compensate for those errors. These techniques were tested with published data from a sit-to-stand activity, where the true axis was defined using bi-planar fluoroscopy. All the methods were able to estimate the direction of the AoR with an error of less than 5°, whereas there were errors in the location of the axis of 30-40mm. Such location errors could be reduced to less than 17mm by the methods based on equations that use rigid motion parameters (mean Finite Helical Axis, SARA) when the translation component was calculated using the three markers nearest to the axis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Genomic androgen receptor-occupied regions with different functions, defined by histone acetylation, coregulators and transcriptional capacity.

    Directory of Open Access Journals (Sweden)

    Li Jia

    Full Text Available The androgen receptor (AR is a steroid-activated transcription factor that binds at specific DNA locations and plays a key role in the etiology of prostate cancer. While numerous studies have identified a clear connection between AR binding and expression of target genes for a limited number of loci, high-throughput elucidation of these sites allows for a deeper understanding of the complexities of this process.We have mapped 189 AR occupied regions (ARORs and 1,388 histone H3 acetylation (AcH3 loci to a 3% continuous stretch of human genomic DNA using chromatin immunoprecipitation (ChIP microarray analysis. Of 62 highly reproducible ARORs, 32 (52% were also marked by AcH3. While the number of ARORs detected in prostate cancer cells exceeded the number of nearby DHT-responsive genes, the AcH3 mark defined a subclass of ARORs much more highly associated with such genes -- 12% of the genes flanking AcH3+ARORs were DHT-responsive, compared to only 1% of genes flanking AcH3-ARORs. Most ARORs contained enhancer activities as detected in luciferase reporter assays. Analysis of the AROR sequences, followed by site-directed ChIP, identified binding sites for AR transcriptional coregulators FoxA1, CEBPbeta, NFI and GATA2, which had diverse effects on endogenous AR target gene expression levels in siRNA knockout experiments.We suggest that only some ARORs function under the given physiological conditions, utilizing diverse mechanisms. This diversity points to differential regulation of gene expression by the same transcription factor related to the chromatin structure.

  10. Well-Defined Bilayered Molecular Cobrushes with Internal Polyethylene Blocks and ω-Hydroxyl-Functionalized Polyethylene Homobrushes

    KAUST Repository

    Zhang, Hefeng; Hadjichristidis, Nikolaos

    2016-01-01

    Novel well-defined bilayered molecular cobrushes with internal polyethylene blocks, P(PEcore-b-PScorona) (PE: polyethylene; PS: polystyrene), and ω-hydroxyl-functionalized polyethylene homobrushes, P(PE-OH), were synthesized through the macromonomer strategy. Two main steps were involved in the synthesis of the P(PEcore-b-PScorona) bilayered cobrushes: (i) formation of norbornyl-terminated macromonomer (Nor-PE-b-PS) by esterification of PS-b-PE-OH (combination of anionic polymerization, hydroboration, and polyhomologation) with 5-norbornene-2-carboxylic acid and (ii) ring-opening metathesis polymerization (ROMP) of Nor-PE-b-PS. The synthesis of P(PE-OH) was achieved by (i) hydroboration of tert-butyldimethylsilyl-protected allyl alcohol, followed by polyhomologation of dimethylsulfoxoniun methylide with the formed tri[3-(tert-butyldimethylsilyloxyl)propyl]borane initiator, oxidation/hydrolysis, and esterification of the TBDMS-O-PE-OH with 5-norbornene-2-carboxylic acid to afford the macromonomer TBDMS-O-PE-Nor, and (ii) ROMP of TBDMS-O-PE-Nor, followed by deprotection. Nuclear magnetic resonance spectroscopy (1H and 13C NMR) and high temperature gel permeation chromatography (HT-GPC) were used to characterize all macromonomers/molecular brushes and differential scanning calorimetry (DSC) to study the thermal properties. The molecular brush P(PE-b-PS) showed lower melting point (Tm) and better solubility in toluene than the corresponding macromonomer PS-b-PE-Nor. In the case of homobrushes, the thermal properties were strongly affected by the presence of the PE end-groups. © 2016 American Chemical Society.

  11. Well-Defined Bilayered Molecular Cobrushes with Internal Polyethylene Blocks and ω-Hydroxyl-Functionalized Polyethylene Homobrushes

    KAUST Repository

    Zhang, Hefeng

    2016-02-15

    Novel well-defined bilayered molecular cobrushes with internal polyethylene blocks, P(PEcore-b-PScorona) (PE: polyethylene; PS: polystyrene), and ω-hydroxyl-functionalized polyethylene homobrushes, P(PE-OH), were synthesized through the macromonomer strategy. Two main steps were involved in the synthesis of the P(PEcore-b-PScorona) bilayered cobrushes: (i) formation of norbornyl-terminated macromonomer (Nor-PE-b-PS) by esterification of PS-b-PE-OH (combination of anionic polymerization, hydroboration, and polyhomologation) with 5-norbornene-2-carboxylic acid and (ii) ring-opening metathesis polymerization (ROMP) of Nor-PE-b-PS. The synthesis of P(PE-OH) was achieved by (i) hydroboration of tert-butyldimethylsilyl-protected allyl alcohol, followed by polyhomologation of dimethylsulfoxoniun methylide with the formed tri[3-(tert-butyldimethylsilyloxyl)propyl]borane initiator, oxidation/hydrolysis, and esterification of the TBDMS-O-PE-OH with 5-norbornene-2-carboxylic acid to afford the macromonomer TBDMS-O-PE-Nor, and (ii) ROMP of TBDMS-O-PE-Nor, followed by deprotection. Nuclear magnetic resonance spectroscopy (1H and 13C NMR) and high temperature gel permeation chromatography (HT-GPC) were used to characterize all macromonomers/molecular brushes and differential scanning calorimetry (DSC) to study the thermal properties. The molecular brush P(PE-b-PS) showed lower melting point (Tm) and better solubility in toluene than the corresponding macromonomer PS-b-PE-Nor. In the case of homobrushes, the thermal properties were strongly affected by the presence of the PE end-groups. © 2016 American Chemical Society.

  12. Transcranial magnetic stimulation reveals two functionally distinct stages of motor cortex involvement during perception of emotional body language

    NARCIS (Netherlands)

    Borgomaneri, Sara; Gazzola, Valeria; Avenanti, Alessio

    Studies indicate that perceiving emotional body language recruits fronto-parietal regions involved in action execution. However, the nature of such motor activation is unclear. Using transcranial magnetic stimulation (TMS) we provide correlational and causative evidence of two distinct stages of

  13. Transcranial magnetic stimulation reveals two functionally distinct stages of motor cortex involvement during perception of emotional body language

    NARCIS (Netherlands)

    Borgomaneri, S.; Gazzola, V.; Avenanti, A.

    2015-01-01

    Studies indicate that perceiving emotional body language recruits fronto-parietal regions involved in action execution. However, the nature of such motor activation is unclear. Using transcranial magnetic stimulation (TMS) we provide correlational and causative evidence of two distinct stages of

  14. Genetic architecture of the Delis-Kaplan Executive Function System Trail Making Test: evidence for distinct genetic influences on executive function.

    Science.gov (United States)

    Vasilopoulos, Terrie; Franz, Carol E; Panizzon, Matthew S; Xian, Hong; Grant, Michael D; Lyons, Michael J; Toomey, Rosemary; Jacobson, Kristen C; Kremen, William S

    2012-03-01

    To examine how genes and environments contribute to relationships among Trail Making Test (TMT) conditions and the extent to which these conditions have unique genetic and environmental influences. Participants included 1,237 middle-aged male twins from the Vietnam Era Twin Study of Aging. The Delis-Kaplan Executive Function System TMT included visual searching, number and letter sequencing, and set-shifting components. Phenotypic correlations among TMT conditions ranged from 0.29 to 0.60, and genes accounted for the majority (58-84%) of each correlation. Overall heritability ranged from 0.34 to 0.62 across conditions. Phenotypic factor analysis suggested a single factor. In contrast, genetic models revealed a single common genetic factor but also unique genetic influences separate from the common factor. Genetic variance (i.e., heritability) of number and letter sequencing was completely explained by the common genetic factor while unique genetic influences separate from the common factor accounted for 57% and 21% of the heritabilities of visual search and set shifting, respectively. After accounting for general cognitive ability, unique genetic influences accounted for 64% and 31% of those heritabilities. A common genetic factor, most likely representing a combination of speed and sequencing, accounted for most of the correlation among TMT 1-4. Distinct genetic factors, however, accounted for a portion of variance in visual scanning and set shifting. Thus, although traditional phenotypic shared variance analysis techniques suggest only one general factor underlying different neuropsychological functions in nonpatient populations, examining the genetic underpinnings of cognitive processes with twin analysis can uncover more complex etiological processes.

  15. Distinctive Citizenship

    DEFF Research Database (Denmark)

    Kaur, Ravinder

    2009-01-01

    The refugee, in India's Partition history, appears as an enigmatic construct - part pitiful, part heroic, though mostly shorn of agency - representing the surface of the human tragedy of Partition. Yet this archetype masks the undercurrent of social distinctions that produced hierarchies of post...

  16. Stat5 Exerts Distinct, Vital Functions in the Cytoplasm and Nucleus of Bcr-Abl+ K562 and Jak2(V617F)+ HEL Leukemia Cells

    International Nuclear Information System (INIS)

    Weber, Axel; Borghouts, Corina; Brendel, Christian; Moriggl, Richard; Delis, Natalia; Brill, Boris; Vafaizadeh, Vida; Groner, Bernd

    2015-01-01

    Signal transducers and activators of transcription (Stats) play central roles in the conversion of extracellular signals, e.g., cytokines, hormones and growth factors, into tissue and cell type specific gene expression patterns. In normal cells, their signaling potential is strictly limited in extent and duration. The persistent activation of Stat3 or Stat5 is found in many human tumor cells and contributes to their growth and survival. Stat5 activation plays a pivotal role in nearly all hematological malignancies and occurs downstream of oncogenic kinases, e.g., Bcr-Abl in chronic myeloid leukemias (CML) and Jak2(V617F) in other myeloproliferative diseases (MPD). We defined the mechanisms through which Stat5 affects growth and survival of K562 cells, representative of Bcr-Abl positive CML, and HEL cells, representative for Jak2(V617F) positive acute erythroid leukemia. In our experiments we suppressed the protein expression levels of Stat5a and Stat5b through shRNA mediated downregulation and demonstrated the dependence of cell survival on the presence of Stat5. Alternatively, we interfered with the functional capacities of the Stat5 protein through the interaction with a Stat5 specific peptide ligand. This ligand is a Stat5 specific peptide aptamer construct which comprises a 12mer peptide integrated into a modified thioredoxin scaffold, S5-DBD-PA. The peptide sequence specifically recognizes the DNA binding domain (DBD) of Stat5. Complex formation of S5-DBD-PA with Stat5 causes a strong reduction of P-Stat5 in the nuclear fraction of Bcr-Abl-transformed K562 cells and a suppression of Stat5 target genes. Distinct Stat5 mediated survival mechanisms were detected in K562 and Jak2(V617F)-transformed HEL cells. Stat5 is activated in the nuclear and cytosolic compartments of K562 cells and the S5-DBD-PA inhibitor most likely affects the viability of Bcr-Abl + K562 cells through the inhibition of canonical Stat5 induced target gene transcription. In HEL cells, Stat5

  17. DMPD: Distinct functions of IRF-3 and IRF-7 in IFN-alpha gene regulation and controlof anti-tumor activity in primary macrophages. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16846591 Distinct functions of IRF-3 and IRF-7 in IFN-alpha gene regulation and con...cott J. Biochem Pharmacol. 2006 Nov 30;72(11):1469-76. Epub 2006 Jul 17. (.png) (.svg) (.html) (.csml) Show Distinct function...anti-tumor activity in primary macrophages. PubmedID 16846591 Title Distinct functions of IRF-3 and IRF-7 in

  18. Computational Identification and Analysis of Signaling Subnetworks with Distinct Functional Roles in the Regulation of TNF Production

    Science.gov (United States)

    2016-01-04

    extract four distinct quantitative features of response timing and intensity: the trajectory peak height, the peak time, the area under the curve, and...J., 2007, 21, 325–332. 16 S. L. Werner, J. D. Kearns, V. Zadorozhnaya, C. Lynch, E. O’Dea, M. P. Boldin , A. Ma, D. Baltimore and A. Hoffmann, Genes...Werner, J. D. Kearns, V. Zadorozhnaya, C. Lynch, E. O’Dea, M. P. Boldin , A. Ma, D. Baltimore and A. Hoffmann, Genes Dev., 2008, 22, 2093–2101. 58 J

  19. Vorschlag zur Erarbeitung einer operationalen Fremdwortdefinition (A Proposal for Establishing a Functional System for Defining Foreign Words)

    Science.gov (United States)

    Schank, Gerd

    1974-01-01

    In order to define words borrowed from other languages, dialects or varieties within a dialect, a synchronic definition, including the degree of integration into the borrowing language, is more useful and flexible than the traditional etymological approach. (Text is in German.) (TL)

  20. Transcranial magnetic stimulation reveals two functionally distinct stages of motor cortex involvement during perception of emotional body language.

    Science.gov (United States)

    Borgomaneri, Sara; Gazzola, Valeria; Avenanti, Alessio

    2015-09-01

    Studies indicate that perceiving emotional body language recruits fronto-parietal regions involved in action execution. However, the nature of such motor activation is unclear. Using transcranial magnetic stimulation (TMS) we provide correlational and causative evidence of two distinct stages of motor cortex engagement during emotion perception. Participants observed pictures of body expressions and categorized them as happy, fearful or neutral while receiving TMS over the left or right motor cortex at 150 and 300 ms after picture onset. In the early phase (150 ms), we observed a reduction of excitability for happy and fearful emotional bodies that was specific to the right hemisphere and correlated with participants' disposition to feel personal distress. This 'orienting' inhibitory response to emotional bodies was also paralleled by a general drop in categorization accuracy when stimulating the right but not the left motor cortex. Conversely, at 300 ms, greater excitability for negative, positive and neutral movements was found in both hemispheres. This later motor facilitation marginally correlated with participants' tendency to assume the psychological perspectives of others and reflected simulation of the movement implied in the neutral and emotional body expressions. These findings highlight the motor system's involvement during perception of emotional bodies. They suggest that fast orienting reactions to emotional cues--reflecting neural processing necessary for visual perception--occur before motor features of the observed emotional expression are simulated in the motor system and that distinct empathic dispositions influence these two neural motor phenomena. Implications for theories of embodied simulation are discussed.

  1. Functional discrepancies between tumor necrosis factor and lymphotoxin alpha explained by trimer stability and distinct receptor interactions

    DEFF Research Database (Denmark)

    Schuchmann, M; Hess, S; Bufler, P

    1995-01-01

    Tumor necrosis factor (TNF) and lymphotoxin alpha (LT alpha) are closely related cytokines which bind with nearly identical affinities to the same pair of cell surface receptors, p55 and p75TNFR. Therefore it is assumed that TNF and LT alpha are redundant cytokines. This study, however......, demonstrates that TNF and LT alpha differ significantly with regard to their mitogenic and cytotoxic potentials. LT alpha's superior mitogenic effect could be explained by its formation of a more stable trimer. In contrast to the TNF trimer, which disintegrated under physiological conditions into biologically...... inactive monomers, the LT alpha trimer remained stable for several days. Accordingly, LT alpha more effectively induced fibroblast growth which demands long-term presence of the cytokine. TNF's superior cytotoxicity, which requires only short-term impact of the cytokine, could be attributed to a distinct...

  2. Define Project

    DEFF Research Database (Denmark)

    Munk-Madsen, Andreas

    2005-01-01

    "Project" is a key concept in IS management. The word is frequently used in textbooks and standards. Yet we seldom find a precise definition of the concept. This paper discusses how to define the concept of a project. The proposed definition covers both heavily formalized projects and informally...... organized, agile projects. Based on the proposed definition popular existing definitions are discussed....

  3. "Dermatitis" defined.

    Science.gov (United States)

    Smith, Suzanne M; Nedorost, Susan T

    2010-01-01

    The term "dermatitis" can be defined narrowly or broadly, clinically or histologically. A common and costly condition, dermatitis is underresourced compared to other chronic skin conditions. The lack of a collectively understood definition of dermatitis and its subcategories could be the primary barrier. To investigate how dermatologists define the term "dermatitis" and determine if a consensus on the definition of this term and other related terms exists. A seven-question survey of dermatologists nationwide was conducted. Of respondents (n  =  122), half consider dermatitis to be any inflammation of the skin. Nearly half (47.5%) use the term interchangeably with "eczema." Virtually all (> 96%) endorse the subcategory "atopic" under the terms "dermatitis" and "eczema," but the subcategories "contact," "drug hypersensitivity," and "occupational" are more highly endorsed under the term "dermatitis" than under the term "eczema." Over half (55.7%) personally consider "dermatitis" to have a broad meaning, and even more (62.3%) believe that dermatologists as a whole define the term broadly. There is a lack of consensus among experts in defining dermatitis, eczema, and their related subcategories.

  4. Towards spatially smart abatement of human pharmaceuticals in surface waters: defining impact of sewage treatment plants on susceptible functions

    NARCIS (Netherlands)

    Gils, J.A.G.; Coppens, L.J.C.; Laak, ter T.L.; Raterman, B.W.; Wezel, van A.P.

    2015-01-01

    For human pharmaceuticals, sewage treatment plants (STPs) are a major point of entry to surface waters. The receiving waters provide vital functions. Modeling the impact of STPs on susceptible functions of the surface water system allows for a spatially smart implementation of abatement options at,

  5. Towards spatially smart abatement of human pharmaceuticals in surface waters : Defining impact of sewage treatment plants on susceptible functions

    NARCIS (Netherlands)

    Coppens, Lieke J C; van Gils, Jos A G; Ter Laak, Thomas L|info:eu-repo/dai/nl/304831026; Raterman, Bernard W; van Wezel, Annemarie P|info:eu-repo/dai/nl/141376074

    2015-01-01

    For human pharmaceuticals, sewage treatment plants (STPs) are a major point of entry to surface waters. The receiving waters provide vital functions. Modeling the impact of STPs on susceptible functions of the surface water system allows for a spatially smart implementation of abatement options at,

  6. Goal directed worry rules are associated with distinct patterns of amygdala functional connectivity and vagal modulation during perseverative cognition

    OpenAIRE

    Meeten, Frances; Davey, Graham C L; Makovac, Elena; Watson, David R.; Garfinkel, Sarah N.; Critchley, Hugo D.; Ottaviani, Cristina

    2016-01-01

    Excessive and uncontrollable worry is a defining feature of Generalized Anxiety Disorder (GAD). An important endeavor in the treatment of pathological worry is to understand why some people are unable to stop worrying once they have started. Worry perseveration is associated with a tendency to deploy goal-directed worry rules (known as “as many as can” worry rules; AMA). These require attention to the goal of the worry task and continuation of worry until the aims of the “worry bout” are achi...

  7. Inter-areal causal interactions in the gamma and beta frequency bands define a functional hierarchy in the primate visual system

    NARCIS (Netherlands)

    Vezoli, J.; Bastos, A.; Bosman, C.; Schoffelen, J.M.; Oostenveld, R.; Weerd, P. De; Kennedy, H.; Fries, P.

    2013-01-01

    Cortico-cortical connectivity has been shown to be hierarchically organized such that bottom-up and top-down information are conveyed through the well-defined feedforward and feedback counter-streams, respectively. It remains however unclear what mechanisms the cortex might use to functionally

  8. Quantitative Imaging of Cholinergic Interneurons Reveals a Distinctive Spatial Organization and a Functional Gradient across the Mouse Striatum.

    Directory of Open Access Journals (Sweden)

    Miriam Matamales

    Full Text Available Information processing in the striatum requires the postsynaptic integration of glutamatergic and dopaminergic signals, which are then relayed to the output nuclei of the basal ganglia to influence behavior. Although cellularly homogeneous in appearance, the striatum contains several rare interneuron populations which tightly modulate striatal function. Of these, cholinergic interneurons (CINs have been recently shown to play a critical role in the control of reward-related learning; however how the striatal cholinergic network is functionally organized at the mesoscopic level and the way this organization influences striatal function remains poorly understood. Here, we systematically mapped and digitally reconstructed the entire ensemble of CINs in the mouse striatum and quantitatively assessed differences in densities, spatial arrangement and neuropil content across striatal functional territories. This approach demonstrated that the rostral portion of the striatum contained a higher concentration of CINs than the caudal striatum and that the cholinergic content in the core of the ventral striatum was significantly lower than in the rest of the regions. Additionally, statistical comparison of spatial point patterns in the striatal cholinergic ensemble revealed that only a minor portion of CINs (17% aggregated into cluster and that they were predominantly organized in a random fashion. Furthermore, we used a fluorescence reporter to estimate the activity of over two thousand CINs in naïve mice and found that there was a decreasing gradient of CIN overall function along the dorsomedial-to-ventrolateral axis, which appeared to be independent of their propensity to aggregate within the striatum. Altogether this work suggests that the regulation of striatal function by acetylcholine across the striatum is highly heterogeneous, and that signals originating in external afferent systems may be principally determining the function of CINs in the

  9. Frontal Cognitive Function and Memory in Parkinson’s Disease: Toward a Distinction between Prospective and Declarative Memory Impairments?

    Directory of Open Access Journals (Sweden)

    A. I. Tröster

    1995-01-01

    Full Text Available Memory dysfunction is a frequent concomitant of Parkinson's disease (PD. Historically, two classes of hypotheses, focusing on different cognitive mechanisms, have been advanced to explain this memory impairment: one postulating retrieval deficits (common to several neurodegenerative disorders involving the basal ganglia, and the other postulating frontally mediated executive deficits as fundamental to memory impairment. After outlining empirical support for the retrieval deficit hypothesis, research on the more recent “frontal executive deficit hypothesis” is reviewed, and major challenges to this hypothesis are identified. It is concluded that the frontal executive deficit hypothesis cannot adequately account for all memory impairments in PD, and that a more parsimonious theoretical account might invoke a distinction between prospective and declarative memory impairments. It is suggested that there may be three subgroups of PD patients: one demonstrating prospective memory dysfunction only, one with declarative memory dysfunction only, and one with both prospective and declarative memory dysfunction. Consequently, PD might provide a useful model within which to investigate the relationship between prospective and declarative memory.

  10. Distinct regulatory functions of calpain 1 and 2 during neural stem cell self-renewal and differentiation.

    Directory of Open Access Journals (Sweden)

    Daniela M Santos

    Full Text Available Calpains are calcium regulated cysteine proteases that have been described in a wide range of cellular processes, including apoptosis, migration and cell cycle regulation. In addition, calpains have been implicated in differentiation, but their impact on neural differentiation requires further investigation. Here, we addressed the role of calpain 1 and calpain 2 in neural stem cell (NSC self-renewal and differentiation. We found that calpain inhibition using either the chemical inhibitor calpeptin or the endogenous calpain inhibitor calpastatin favored differentiation of NSCs. This effect was associated with significant changes in cell cycle-related proteins and may be regulated by calcium. Interestingly, calpain 1 and calpain 2 were found to play distinct roles in NSC fate decision. Calpain 1 expression levels were higher in self-renewing NSC and decreased with differentiation, while calpain 2 increased throughout differentiation. In addition, calpain 1 silencing resulted in increased levels of both neuronal and glial markers, β-III Tubulin and glial fibrillary acidic protein (GFAP. Calpain 2 silencing elicited decreased levels of GFAP. These results support a role for calpain 1 in repressing differentiation, thus maintaining a proliferative NSC pool, and suggest that calpain 2 is involved in glial differentiation.

  11. Tentonin 3/TMEM150c Confers Distinct Mechanosensitive Currents in Dorsal-Root Ganglion Neurons with Proprioceptive Function.

    Science.gov (United States)

    Hong, Gyu-Sang; Lee, Byeongjun; Wee, Jungwon; Chun, Hyeyeon; Kim, Hyungsup; Jung, Jooyoung; Cha, Joo Young; Riew, Tae-Ryong; Kim, Gyu Hyun; Kim, In-Beom; Oh, Uhtaek

    2016-07-06

    Touch sensation or proprioception requires the transduction of mechanical stimuli into electrical signals by mechanoreceptors in the periphery. These mechanoreceptors are equipped with various transducer channels. Although Piezo1 and 2 are mechanically activated (MA) channels with rapid inactivation, MA molecules with other inactivation kinetics have not been identified. Here we report that heterologously expressed Tentonin3 (TTN3)/TMEM150C is activated by mechanical stimuli with distinctly slow inactivation kinetics. Genetic ablation of Ttn3/Tmem150c markedly reduced slowly adapting neurons in dorsal-root ganglion neurons. The MA TTN3 currents were inhibited by known blockers of mechanosensitive ion channels. Moreover, TTN3 was localized in muscle spindle afferents. Ttn3-deficient mice exhibited the loss of coordinated movements and abnormal gait. Thus, TTN3 appears to be a component of a mechanosensitive channel with a slow inactivation rate and contributes to motor coordination. Identification of this gene advances our understanding of the various types of mechanosensations, including proprioception. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Distinct requirements for signal peptidase processing and function in the stable signal peptide subunit of the Junin virus envelope glycoprotein

    International Nuclear Information System (INIS)

    York, Joanne; Nunberg, Jack H.

    2007-01-01

    The arenavirus envelope glycoprotein (GP-C) retains a cleaved and stable signal peptide (SSP) as an essential subunit of the mature complex. This 58-amino-acid residue peptide serves as a signal sequence and is additionally required to enable transit of the assembled GP-C complex to the Golgi, and for pH-dependent membrane fusion activity. We have investigated the C-terminal region of the Junin virus SSP to study the role of the cellular signal peptidase (SPase) in generating SSP. Site-directed mutagenesis at the cleavage site (positions - 1 and - 3) reveals a pattern of side-chain preferences consistent with those of SPase. Although position - 2 is degenerate for SPase cleavage, this residue in the arenavirus SSP is invariably a cysteine. In the Junin virus, this cysteine is not involved in disulfide bonding. We show that replacement with alanine or serine is tolerated for SPase cleavage but prevents the mutant SSP from associating with GP-C and enabling transport to the cell surface. Conversely, an arginine mutation at position - 1 that prevents SPase cleavage is fully compatible with GP-C-mediated membrane fusion activity when the mutant SSP is provided in trans. These results point to distinct roles of SSP sequences in SPase cleavage and GP-C biogenesis. Further studies of the unique structural organization of the GP-C complex will be important in identifying novel opportunities for antiviral intervention against arenaviral hemorrhagic disease

  13. Testis-expressed profilins 3 and 4 show distinct functional characteristics and localize in the acroplaxome-manchette complex in spermatids

    Directory of Open Access Journals (Sweden)

    Rothkegel Martin

    2009-05-01

    Full Text Available Abstract Background Multiple profilin isoforms exist in mammals; at least four are expressed in the mammalian testis. The testis-specific isoforms profilin-3 (PFN3 and profilin-4 (PFN4 may have specialized roles in spermatogenic cells which are distinct from known functions fulfilled by the "somatic" profilins, profilin-1 (PFN1 and profilin-2 (PFN2. Results Ligand interactions and spatial distributions of PFN3 and PFN4 were compared by biochemical, molecular and immunological methods; PFN1 and PFN2 were employed as controls. β-actin, phosphoinositides, poly-L-proline and mDia3, but not VASP, were confirmed as in vitro interaction partners of PFN3. In parallel experiments, PFN4 bound to selected phosphoinositides but not to poly-L-proline, proline-rich proteins, or actin. Immunofluorescence microscopy of PFN3 and PFN4 revealed distinct subcellular locations in differentiating spermatids. Both were associated first with the acroplaxome and later with the transient manchette. Predicted 3D structures indicated that PFN3 has the actin-binding site conserved, but retains only approximately half of the common poly-L-proline binding site. PFN4, in comparison, has lost both, polyproline and actin binding sites completely, which is well in line with the experimental data. Conclusion The testis-specific isoform PFN3 showed major hallmarks of the well characterized "somatic" profilin isoforms, albeit with distinct binding affinities. PFN4, on the other hand, did not interact with actin or polyproline in vitro. Rather, it seemed to be specialized for phospholipid binding, possibly providing cellular functions which are distinct from actin dynamics regulation.

  14. Microbial Community and Functional Structure Significantly Varied among Distinct Types of Paddy Soils But Responded Differently along Gradients of Soil Depth Layers

    Directory of Open Access Journals (Sweden)

    Ren Bai

    2017-05-01

    Full Text Available Paddy rice fields occupy broad agricultural area in China and cover diverse soil types. Microbial community in paddy soils is of great interest since many microorganisms are involved in soil functional processes. In the present study, Illumina Mi-Seq sequencing and functional gene array (GeoChip 4.2 techniques were combined to investigate soil microbial communities and functional gene patterns across the three soil types including an Inceptisol (Binhai, an Oxisol (Leizhou, and an Ultisol (Taoyuan along four profile depths (up to 70 cm in depth in mesocosm incubation columns. Detrended correspondence analysis revealed that distinctly differentiation in microbial community existed among soil types and profile depths, while the manifest variance in functional structure was only observed among soil types and two rice growth stages, but not across profile depths. Along the profile depth within each soil type, Acidobacteria, Chloroflexi, and Firmicutes increased whereas Cyanobacteria, β-proteobacteria, and Verrucomicrobia declined, suggesting their specific ecophysiological properties. Compared to bacterial community, the archaeal community showed a more contrasting pattern with the predominant groups within phyla Euryarchaeota, Thaumarchaeota, and Crenarchaeota largely varying among soil types and depths. Phylogenetic molecular ecological network (pMEN analysis further indicated that the pattern of bacterial and archaeal communities interactions changed with soil depth and the highest modularity of microbial community occurred in top soils, implying a relatively higher system resistance to environmental change compared to communities in deeper soil layers. Meanwhile, microbial communities had higher connectivity in deeper soils in comparison with upper soils, suggesting less microbial interaction in surface soils. Structure equation models were developed and the models indicated that pH was the most representative characteristics of soil type and

  15. Microbial Community and Functional Structure Significantly Varied among Distinct Types of Paddy Soils But Responded Differently along Gradients of Soil Depth Layers.

    Science.gov (United States)

    Bai, Ren; Wang, Jun-Tao; Deng, Ye; He, Ji-Zheng; Feng, Kai; Zhang, Li-Mei

    2017-01-01

    Paddy rice fields occupy broad agricultural area in China and cover diverse soil types. Microbial community in paddy soils is of great interest since many microorganisms are involved in soil functional processes. In the present study, Illumina Mi-Seq sequencing and functional gene array (GeoChip 4.2) techniques were combined to investigate soil microbial communities and functional gene patterns across the three soil types including an Inceptisol (Binhai), an Oxisol (Leizhou), and an Ultisol (Taoyuan) along four profile depths (up to 70 cm in depth) in mesocosm incubation columns. Detrended correspondence analysis revealed that distinctly differentiation in microbial community existed among soil types and profile depths, while the manifest variance in functional structure was only observed among soil types and two rice growth stages, but not across profile depths. Along the profile depth within each soil type, Acidobacteria , Chloroflexi , and Firmicutes increased whereas Cyanobacteria , β -proteobacteria , and Verrucomicrobia declined, suggesting their specific ecophysiological properties. Compared to bacterial community, the archaeal community showed a more contrasting pattern with the predominant groups within phyla Euryarchaeota , Thaumarchaeota , and Crenarchaeota largely varying among soil types and depths. Phylogenetic molecular ecological network (pMEN) analysis further indicated that the pattern of bacterial and archaeal communities interactions changed with soil depth and the highest modularity of microbial community occurred in top soils, implying a relatively higher system resistance to environmental change compared to communities in deeper soil layers. Meanwhile, microbial communities had higher connectivity in deeper soils in comparison with upper soils, suggesting less microbial interaction in surface soils. Structure equation models were developed and the models indicated that pH was the most representative characteristics of soil type and

  16. A pilot study of the relations within which hearing voices participates: Towards a functional distinction between voice hearers and controls

    NARCIS (Netherlands)

    McEnteggart, C.; Barnes-Holmes, Y.; Egger, J.I.M.; Barnes-Holmes, D.

    2016-01-01

    The current research used the Implicit Relational Assessment Procedure (IRAP) as a preliminary step toward bringing a broad, functional approach to understanding psychosis, by focusing on the specific phenomenon of auditory hallucinations of voices and sounds (often referred to as hearing voices).

  17. Collateralization of cerebellar output to functionally distinct brainstem areas. A retrograde, non-fluorescent tracing study in the rat

    NARCIS (Netherlands)

    T.J.H. Ruigrok (Tom); T.M. Teune (Thea)

    2014-01-01

    textabstractThe organization of the cerebellum is characterized by a number of longitudinally organized connection patterns that consist of matching olivo-cortico-nuclear zones. These entities, referred to as modules, have been suggested to act as functional units. The various parts of the

  18. Parent-of-Origin Effects in ADHD: Distinct Influences of Paternal and Maternal ADHD on Neuropsychological Functioning in Offspring

    NARCIS (Netherlands)

    Thissen, A.J.A.M.; Rommelse, N.N.J.; Altink, M.E.; Oosterlaan, J.; Buitelaar, J.

    2014-01-01

    Objective: The authors examined parent-of-origin effects in transmission of ADHD and neuropsychological functioning. Proof of these effects can identify more etiologically homogeneous ADHD subgroups and facilitate genetic studies. Method: The authors included 238 ADHD and 147 control families. ADHD

  19. Effects of erosion from mounds of different termite genera on distinct functional grassland types in an African savannah

    NARCIS (Netherlands)

    Gosling, Cleo M.; Cromsigt, Joris P. G. M.; Mpanza, Nokukhanya; Olff, Han

    A key aspect of savannah vegetation heterogeneity is mosaics formed by two functional grassland types, bunch grasslands, and grazing lawns. We investigated the role of termites, important ecosystem engineers, in creating high-nutrient patches in the form of grazing lawns. Some of the ways termites

  20. Distinct and nonredundant in vivo functions of TNF produced by T cells and macrophages/neutrophils: Protective and deleterious effects

    NARCIS (Netherlands)

    Grivennikov, Sergei I.; Tumanov, Alexei V.; Liepinsh, Dmitry J.; Kruglov, Andrei A.; Marakusha, Boris I.; Shakhov, Alexander N.; Murakami, Takaya; Drutskaya, Ludmila N.; Förster, Irmgard; Clausen, Björn E.; Tessarollo, Lino; Ryffel, Bernhard; Kuprash, Dmitry V.; Nedospasov, Sergei A.

    2005-01-01

    Tumor necrosis factor (TNF, TNFalpha) is implicated in various pathophysiological processes and can be either protective, as in host defense, or deleterious, as in autoimmunity or toxic shock. To uncover the in vivo functions of TNF produced by different cell types, we generated mice with TNF

  1. Murine epidermal Langerhans cells and langerin-expressing dermal dendritic cells are unrelated and exhibit distinct functions

    NARCIS (Netherlands)

    Nagao, Keisuke; Ginhoux, Florent; Leitner, Wolfgang W.; Motegi, Sei-Ichiro; Bennett, Clare L.; Clausen, Björn E.; Merad, Miriam; Udey, Mark C.

    2009-01-01

    A new langerin(+) DC subset has recently been identified in murine dermis (langerin(+) dDC), but the lineage and functional relationships between these cells and langerin(+) epidermal Langerhans cells (LC) are incompletely characterized. Selective expression of the cell adhesion molecule EpCAM by LC

  2. CD34 defines an osteoprogenitor cell population in mouse bone marrow stromal cells

    DEFF Research Database (Denmark)

    Abdallah, Basem M; Al-Shammary, Asma; Skagen, Peter

    2015-01-01

    Bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) and their progenitors have been identified based on retrospective functional criteria. CD markers are employed to define cell populations with distinct functional characteristics. However, defining and pro...

  3. Defining chaos.

    Science.gov (United States)

    Hunt, Brian R; Ott, Edward

    2015-09-01

    In this paper, we propose, discuss, and illustrate a computationally feasible definition of chaos which can be applied very generally to situations that are commonly encountered, including attractors, repellers, and non-periodically forced systems. This definition is based on an entropy-like quantity, which we call "expansion entropy," and we define chaos as occurring when this quantity is positive. We relate and compare expansion entropy to the well-known concept of topological entropy to which it is equivalent under appropriate conditions. We also present example illustrations, discuss computational implementations, and point out issues arising from attempts at giving definitions of chaos that are not entropy-based.

  4. Defining Quantum Control Flow

    OpenAIRE

    Ying, Mingsheng; Yu, Nengkun; Feng, Yuan

    2012-01-01

    A remarkable difference between quantum and classical programs is that the control flow of the former can be either classical or quantum. One of the key issues in the theory of quantum programming languages is defining and understanding quantum control flow. A functional language with quantum control flow was defined by Altenkirch and Grattage [\\textit{Proc. LICS'05}, pp. 249-258]. This paper extends their work, and we introduce a general quantum control structure by defining three new quantu...

  5. Profound differences in spontaneous long-term functional recovery after defined spinal tract lesions in the rat

    NARCIS (Netherlands)

    Hendriks, William T J; Eggers, R.; Ruitenberg, Marc J; Blits, Bas; Hamers, Frank P T; Verhaagen, J.; Boer, Gerard J

    The purpose of this study was to compare spontaneous functional recovery after different spinal motor tract lesions in the rat spinal cord using three methods of analysis, the BBB, the rope test, and the CatWalk. We transected the dorsal corticospinal tract (CSTx) or the rubrospinal tract (RSTx) or

  6. Distinct contributions of functional and deep neural network features to representational similarity of scenes in human brain and behavior.

    Science.gov (United States)

    Groen, Iris Ia; Greene, Michelle R; Baldassano, Christopher; Fei-Fei, Li; Beck, Diane M; Baker, Chris I

    2018-03-07

    Inherent correlations between visual and semantic features in real-world scenes make it difficult to determine how different scene properties contribute to neural representations. Here, we assessed the contributions of multiple properties to scene representation by partitioning the variance explained in human behavioral and brain measurements by three feature models whose inter-correlations were minimized a priori through stimulus preselection. Behavioral assessments of scene similarity reflected unique contributions from a functional feature model indicating potential actions in scenes as well as high-level visual features from a deep neural network (DNN). In contrast, similarity of cortical responses in scene-selective areas was uniquely explained by mid- and high-level DNN features only, while an object label model did not contribute uniquely to either domain. The striking dissociation between functional and DNN features in their contribution to behavioral and brain representations of scenes indicates that scene-selective cortex represents only a subset of behaviorally relevant scene information.

  7. Distinct regions of the Phytophthora essential effector Avh238 determine its function in cell death activation and plant immunity suppression.

    Science.gov (United States)

    Yang, Bo; Wang, Qunqing; Jing, Maofeng; Guo, Baodian; Wu, Jiawei; Wang, Haonan; Wang, Yang; Lin, Long; Wang, Yan; Ye, Wenwu; Dong, Suomeng; Wang, Yuanchao

    2017-04-01

    Phytophthora pathogens secrete effectors to manipulate host innate immunity, thus facilitating infection. Among the RXLR effectors highly induced during Phytophthora sojae infection, Avh238 not only contributes to pathogen virulence but also triggers plant cell death. However, the detailed molecular basis of Avh238 functions remains largely unknown. We mapped the regions responsible for Avh238 functions in pathogen virulence and plant cell death induction using a strategy that combines investigation of natural variation and large-scale mutagenesis assays. The correlation between cellular localization and Avh238 functions was also evaluated. We found that the 79 th residue (histidine or leucine) of Avh238 determined its cell death-inducing activity, and that the 53 amino acids in its C-terminal region are responsible for promoting Phytophthora infection. Transient expression of Avh238 in Nicotiana benthamiana revealed that nuclear localization is essential for triggering cell death, while Avh238-mediated suppression of INF1-triggered cell death requires cytoplasmic localization. Our results demonstrate that a representative example of an essential Phytophthora RXLR effector can evolve to escape recognition by the host by mutating one nucleotide site, and can also retain plant immunosuppressive activity to enhance pathogen virulence in planta. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

  8. Active fragments from pro- and antiapoptotic BCL-2 proteins have distinct membrane behavior reflecting their functional divergence.

    Directory of Open Access Journals (Sweden)

    Yannis Guillemin

    Full Text Available BACKGROUND: The BCL-2 family of proteins includes pro- and antiapoptotic members acting by controlling the permeabilization of mitochondria. Although the association of these proteins with the outer mitochondrial membrane is crucial for their function, little is known about the characteristics of this interaction. METHODOLOGY/PRINCIPAL FINDINGS: Here, we followed a reductionist approach to clarify to what extent membrane-active regions of homologous BCL-2 family proteins contribute to their functional divergence. Using isolated mitochondria as well as model lipid Langmuir monolayers coupled with Brewster Angle Microscopy, we explored systematically and comparatively the membrane activity and membrane-peptide interactions of fragments derived from the central helical hairpin of BAX, BCL-xL and BID. The results show a connection between the differing abilities of the assayed peptide fragments to contact, insert, destabilize and porate membranes and the activity of their cognate proteins in programmed cell death. CONCLUSION/SIGNIFICANCE: BCL-2 family-derived pore-forming helices thus represent structurally analogous, but functionally dissimilar membrane domains.

  9. Distinct Metabolic Requirements of Exhausted and Functional Virus-Specific CD8 T Cells in the Same Host.

    Science.gov (United States)

    Schurich, Anna; Pallett, Laura J; Jajbhay, Danyal; Wijngaarden, Jessica; Otano, Itziar; Gill, Upkar S; Hansi, Navjyot; Kennedy, Patrick T; Nastouli, Eleni; Gilson, Richard; Frezza, Christian; Henson, Sian M; Maini, Mala K

    2016-08-02

    T cells undergo profound metabolic changes to meet the increased energy demands of maintaining an antiviral response. We postulated that differences in metabolic reprogramming would shape the efficacy of CD8 T cells mounted against persistent viral infections. We found that the poorly functional PD-1(hi) T cell response against hepatitis B virus (HBV) had upregulated the glucose transporter, Glut1, an effect recapitulated by oxygen deprivation to mimic the intrahepatic environment. Glut1(hi) HBV-specific T cells were dependent on glucose supplies, unlike the more functional cytomegalovirus (CMV)-specific T cells that could utilize oxidative phosphorylation in the absence of glucose. The inability of HBV-specific T cells to switch to oxidative phosphorylation was accompanied by increased mitochondrial size and lower mitochondrial potential, indicative of mitochondrial dysfunction. Interleukin (IL)-12, which recovers HBV-specific T cell effector function, increased their mitochondrial potential and reduced their dependence on glycolysis. Our findings suggest that mitochondrial defects limit the metabolic plasticity of exhausted HBV-specific T cells. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. Distinct Metabolic Requirements of Exhausted and Functional Virus-Specific CD8 T Cells in the Same Host

    Directory of Open Access Journals (Sweden)

    Anna Schurich

    2016-08-01

    Full Text Available T cells undergo profound metabolic changes to meet the increased energy demands of maintaining an antiviral response. We postulated that differences in metabolic reprogramming would shape the efficacy of CD8 T cells mounted against persistent viral infections. We found that the poorly functional PD-1hi T cell response against hepatitis B virus (HBV had upregulated the glucose transporter, Glut1, an effect recapitulated by oxygen deprivation to mimic the intrahepatic environment. Glut1hi HBV-specific T cells were dependent on glucose supplies, unlike the more functional cytomegalovirus (CMV-specific T cells that could utilize oxidative phosphorylation in the absence of glucose. The inability of HBV-specific T cells to switch to oxidative phosphorylation was accompanied by increased mitochondrial size and lower mitochondrial potential, indicative of mitochondrial dysfunction. Interleukin (IL-12, which recovers HBV-specific T cell effector function, increased their mitochondrial potential and reduced their dependence on glycolysis. Our findings suggest that mitochondrial defects limit the metabolic plasticity of exhausted HBV-specific T cells.

  11. Top-down and bottom-up attention-to-memory: mapping functional connectivity in two distinct networks that underlie cued and uncued recognition memory.

    Science.gov (United States)

    Burianová, Hana; Ciaramelli, Elisa; Grady, Cheryl L; Moscovitch, Morris

    2012-11-15

    The objective of this study was to examine the functional connectivity of brain regions active during cued and uncued recognition memory to test the idea that distinct networks would underlie these memory processes, as predicted by the attention-to-memory (AtoM) hypothesis. The AtoM hypothesis suggests that dorsal parietal cortex (DPC) allocates effortful top-down attention to memory retrieval during cued retrieval, whereas ventral parietal cortex (VPC) mediates spontaneous bottom-up capture of attention by memory during uncued retrieval. To identify networks associated with these two processes, we conducted a functional connectivity analysis of a left DPC and a left VPC region, both identified by a previous analysis of task-related regional activations. We hypothesized that the two parietal regions would be functionally connected with distinct neural networks, reflecting their engagement in the differential mnemonic processes. We found two spatially dissociated networks that overlapped only in the precuneus. During cued trials, DPC was functionally connected with dorsal attention areas, including the superior parietal lobules, right precuneus, and premotor cortex, as well as relevant memory areas, such as the left hippocampus and the middle frontal gyri. During uncued trials, VPC was functionally connected with ventral attention areas, including the supramarginal gyrus, cuneus, and right fusiform gyrus, as well as the parahippocampal gyrus. In addition, activity in the DPC network was associated with faster response times for cued retrieval. This is the first study to show a dissociation of the functional connectivity of posterior parietal regions during episodic memory retrieval, characterized by a top-down AtoM network involving DPC and a bottom-up AtoM network involving VPC. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Computation-Facilitated Assignment of Function in the Enolase Superfamily: A Regiochemically Distinct Galactarate Dehydratase from Oceanobacillus iheyensis†

    Science.gov (United States)

    Rakus, John F.; Kalyanaraman, Chakrapani; Fedorov, Alexander A.; Fedorov, Elena V.; Mills-Groninger, Fiona P.; Toro, Rafael; Bonanno, Jeffrey; Bain, Kevin; Sauder, J. Michael; Burley, Stephen K.; Almo, Steven C.; Jacobson, Matthew P.; Gerlt, John A.

    2009-01-01

    The structure of an uncharacterized member of the enolase superfamily from Oceanobacillus iheyensis (GI: 23100298; IMG locus tag Ob2843; PDB Code 2OQY) was determined by the New York SGX Research Center for Structural Genomics (NYSGXRC). The structure contained two Mg2+ ions located 10.4 Å from one another, with one located in the canonical position in the (β/α)7β-barrel domain (although the ligand at the end of the fifth β-strand is His, unprecedented in structurally characterized members of the superfamily); the second is located in a novel site within the capping domain. In silico docking of a library of mono- and diacid sugars to the active site predicted a diacid sugar as a likely substrate. Activity screening of a physical library of acid sugars identified galactarate as the substrate (kcat = 6.8 s−1, KM = 620 μM; kcat/KM = 1.1 × 104 M−1 s−1), allowing functional assignment of Ob2843 as galactarate dehydratase (GalrD-II) The structure of a complex of the catalytically impaired Y90F mutant with Mg2+ and galactarate allowed identification of a Tyr 164-Arg 162 dyad as the base that initiates the reaction by abstraction of the α-proton and Tyr 90 as the acid that facilitates departure of the β-OH leaving group. The enzyme product is 2-keto-3-deoxy-D-threo-4,5-dihydroxyadipate, the enantiomer of the product obtained in the GalrD reaction catalyzed by a previously characterized bifunctional L-talarate/galactarate dehydratase (TalrD/GalrD). On the basis of the different active site structures and different regiochemistries, we recognize that these functions represent an example of apparent, not actual, convergent evolution of function. The structure of GalrD-II and its active site architecture allow identification of the seventh functionally and structurally characterized subgroup in the enolase superfamily. This study provides an additional example that an integrated sequence/structure-based strategy employing computational approaches is a viable

  13. Distinct functions of Period2 and Period3 in the mouse circadian system revealed by in vitro analysis.

    Directory of Open Access Journals (Sweden)

    Julie S Pendergast

    2010-01-01

    Full Text Available The mammalian circadian system, which is composed of a master pacemaker in the suprachiasmatic nuclei (SCN as well as other oscillators in the brain and peripheral tissues, controls daily rhythms of behavior and physiology. Lesions of the SCN abolish circadian rhythms of locomotor activity and transplants of fetal SCN tissue restore rhythmic behavior with the periodicity of the donor's genotype, suggesting that the SCN determines the period of the circadian behavioral rhythm. According to the model of timekeeping in the SCN, the Period (Per genes are important elements of the transcriptional/translational feedback loops that generate the endogenous circadian rhythm. Previous studies have investigated the functions of the Per genes by examining locomotor activity in mice lacking functional PERIOD proteins. Variable behavioral phenotypes were observed depending on the line and genetic background of the mice. In the current study we assessed both wheel-running activity and Per1-promoter-driven luciferase expression (Per1-luc in cultured SCN, pituitary, and lung explants from Per2(-/- and Per3(-/- mice congenic with the C57BL/6J strain. We found that the Per2(-/- phenotype is enhanced in vitro compared to in vivo, such that the period of Per1-luc expression in Per2(-/- SCN explants is 1.5 hours shorter than in Per2+/+ SCN, while the free-running period of wheel-running activity is only 11 minutes shorter in Per2(-/- compared to Per2+/+ mice. In contrast, circadian rhythms in SCN explants from Per3(-/- mice do not differ from Per3+/+ mice. Instead, the period and phase of Per1-luc expression are significantly altered in Per3(-/- pituitary and lung explants compared to Per3+/+ mice. Taken together these data suggest that the function of each Per gene may differ between tissues. Per2 appears to be important for period determination in the SCN, while Per3 participates in timekeeping in the pituitary and lung.

  14. Renal function following three distinct weight loss dietary strategies during 2 years of a randomized controlled trial.

    Science.gov (United States)

    Tirosh, Amir; Golan, Rachel; Harman-Boehm, Ilana; Henkin, Yaakov; Schwarzfuchs, Dan; Rudich, Assaf; Kovsan, Julia; Fiedler, Georg M; Blüher, Matthias; Stumvoll, Michael; Thiery, Joachim; Stampfer, Meir J; Shai, Iris

    2013-08-01

    This study addressed the long-term effect of various diets, particularly low-carbohydrate high-protein, on renal function on participants with or without type 2 diabetes. In the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT), 318 participants (age, 51 years; 86% men; BMI, 31 kg/m(2); mean estimated glomerular filtration rate [eGFR], 70.5 mL/min/1.73 m(2); mean urine microalbumin-to-creatinine ratio, 12:12) with serum creatinine low-fat, Mediterranean, or low-carbohydrate diets. The 2-year compliance was 85%, and the proportion of protein intake significantly increased to 22% of energy only in the low-carbohydrate diet (P vs. low-fat and Mediterranean). We examined changes in urinary microalbumin and eGFR, estimated by Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration formulas. Significant (P low-carbohydrate (+5.3% [95% CI 2.1-8.5]), Mediterranean (+5.2% [3.0-7.4]), and low-fat diets (+4.0% [0.9-7.1]) with similar magnitude (P > 0.05) across diet groups. The increased eGFR was at least as prominent in participants with (+6.7%) or without (+4.5%) type 2 diabetes or those with lower baseline renal function of eGFR low-carbohydrate diet is as safe as Mediterranean or low-fat diets in preserving/improving renal function among moderately obese participants with or without type 2 diabetes, with baseline serum creatinine <176 μmol/L. Potential improvement is likely to be mediated by weight loss-induced improvements in insulin sensitivity and blood pressure.

  15. The leukemia-specific fusion gene ETV6/RUNX1 perturbs distinct key biological functions primarily by gene repression.

    Directory of Open Access Journals (Sweden)

    Gerhard Fuka

    Full Text Available BACKGROUND: ETV6/RUNX1 (E/R (also known as TEL/AML1 is the most frequent gene fusion in childhood acute lymphoblastic leukemia (ALL and also most likely the crucial factor for disease initiation; its role in leukemia propagation and maintenance, however, remains largely elusive. To address this issue we performed a shRNA-mediated knock-down (KD of the E/R fusion gene and investigated the ensuing consequences on genome-wide gene expression patterns and deducible regulatory functions in two E/R-positive leukemic cell lines. FINDINGS: Microarray analyses identified 777 genes whose expression was substantially altered. Although approximately equal proportions were either up- (KD-UP or down-regulated (KD-DOWN, the effects on biological processes and pathways differed considerably. The E/R KD-UP set was significantly enriched for genes included in the "cell activation", "immune response", "apoptosis", "signal transduction" and "development and differentiation" categories, whereas in the E/R KD-DOWN set only the "PI3K/AKT/mTOR signaling" and "hematopoietic stem cells" categories became evident. Comparable expression signatures obtained from primary E/R-positive ALL samples underline the relevance of these pathways and molecular functions. We also validated six differentially expressed genes representing the categories "stem cell properties", "B-cell differentiation", "immune response", "cell adhesion" and "DNA damage" with RT-qPCR. CONCLUSION: Our analyses provide the first preliminary evidence that the continuous expression of the E/R fusion gene interferes with key regulatory functions that shape the biology of this leukemia subtype. E/R may thus indeed constitute the essential driving force for the propagation and maintenance of the leukemic process irrespective of potential consequences of associated secondary changes. Finally, these findings may also provide a valuable source of potentially attractive therapeutic targets.

  16. Renal Function Following Three Distinct Weight Loss Dietary Strategies During 2 Years of a Randomized Controlled Trial

    OpenAIRE

    Tirosh, Amir; Golan, Rachel; Harman-Boehm, Ilana; Henkin, Yaakov; Schwarzfuchs, Dan; Rudich, Assaf; Kovsan, Julia; Fiedler, Georg M.; Blüher, Matthias; Stumvoll, Michael; Thiery, Joachim; Stampfer, Meir J.; Shai, Iris

    2013-01-01

    OBJECTIVE This study addressed the long-term effect of various diets, particularly low-carbohydrate high-protein, on renal function on participants with or without type 2 diabetes. RESEARCH DESIGN AND METHODS In the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT), 318 participants (age, 51 years; 86% men; BMI, 31 kg/m2; mean estimated glomerular filtration rate [eGFR], 70.5 mL/min/1.73 m2; mean urine microalbumin-to-creatinine ratio, 12:12) with serum creatinine 0.05) across...

  17. Generation of Regionally Specified Neural Progenitors and Functional Neurons from Human Embryonic Stem Cells under Defined Conditions

    Directory of Open Access Journals (Sweden)

    Agnete Kirkeby

    2012-06-01

    Full Text Available To model human neural-cell-fate specification and to provide cells for regenerative therapies, we have developed a method to generate human neural progenitors and neurons from human embryonic stem cells, which recapitulates human fetal brain development. Through the addition of a small molecule that activates canonical WNT signaling, we induced rapid and efficient dose-dependent specification of regionally defined neural progenitors ranging from telencephalic forebrain to posterior hindbrain fates. Ten days after initiation of differentiation, the progenitors could be transplanted to the adult rat striatum, where they formed neuron-rich and tumor-free grafts with maintained regional specification. Cells patterned toward a ventral midbrain (VM identity generated a high proportion of authentic dopaminergic neurons after transplantation. The dopamine neurons showed morphology, projection pattern, and protein expression identical to that of human fetal VM cells grafted in parallel. VM-patterned but not forebrain-patterned neurons released dopamine and reversed motor deficits in an animal model of Parkinson's disease.

  18. Distinct Patterns of Everyday Executive Function Problems Distinguish Children With Tourette Syndrome From Children With ADHD or Autism Spectrum Disorders.

    Science.gov (United States)

    Hovik, Kjell Tore; Egeland, Jens; Isquith, Peter K; Gioia, Gerard; Skogli, Erik Winther; Andersen, Per Normann; Øie, Merete

    2017-08-01

    The aim is to investigate the everyday executive function (EF) in children with Tourette syndrome (TS), Inattentive or Combined presentations of ADHD (ADHD-I/ADHD-C), autism spectrum disorders (ASD), and typically developing children (TDC). Nineteen TS, 33 ADHD-C, 43 ADHD-I, 34 ASD, and 50 TDC participated (8-17 years). Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). TS, ADHD-C, ADHD-I, or ASD were rated with significantly more regulation problems on all scales compared with TDC. Considerable overlap of symptoms between clinical groups made differentiation difficult on individual scales. Scale configurations showed children with TS to have more problems with emotional control (EC) than cognitive flexibility in relation to children with ASD, more problems with EC than inhibitory control in relation to ADHD-C, and more problems with EC than planning/organizing in relation to ADHD-I. Paired BRIEF scales dissociated EF problems in children with TS from children with ADHD-C, ADHD-I, or ASD. Clinical relevance is discussed.

  19. Respective Functions of Two Distinct Siwi Complexes Assembled during PIWI-Interacting RNA Biogenesis in Bombyx Germ Cells

    Directory of Open Access Journals (Sweden)

    Kazumichi M. Nishida

    2015-01-01

    Full Text Available PIWI-interacting RNA (piRNA biogenesis consists of two sequential steps: primary piRNA processing and the ping-pong cycle that depends on reciprocal Slicer-mediated RNA cleavage by PIWI proteins. However, the molecular functions of the factors involved remain elusive. Here, we show that RNAs cleaved by a Bombyx mori PIWI, Siwi, remain bound to the protein upon cleavage but are released by a DEAD box protein BmVasa. BmVasa copurifies with Siwi but not another PIWI BmAgo3. A lack of BmVasa does not affect primary piRNA processing but abolishes the ping-pong cycle. Siwi also forms a complex with BmSpn-E and BmQin. This complex is physically separable from the Siwi/BmVasa complex. BmSpn-E, unlike BmVasa, is necessary for primary piRNA production. We propose a model for piRNA biogenesis, where the BmSpn-E/BmQin dimer binds Siwi to function in primary piRNA processing, whereas BmVasa, by associating with Siwi, ensures target RNA release upon cleavage to facilitate the ping-pong cycle.

  20. Distinct effects of protracted withdrawal on affect, craving, selective attention and executive functions among alcohol-dependent patients.

    Science.gov (United States)

    Cordovil De Sousa Uva, Mariana; Luminet, Olivier; Cortesi, Marie; Constant, Eric; Derely, Marc; De Timary, Philippe

    2010-01-01

    The present study examined the effects of protracted alcohol withdrawal on affectivity, craving, selective attention and executive functions (EFs) in alcohol-dependent patients. Selective attention (The D2 Cancellation Test), flexibility (Trail Making Test), inhibition (Stroop Task), decision making (Iowa Gambling Task), craving (Obsessive-Compulsive Drinking Scale) and state affectivity (Positive and Negative Affectivity Schedule) were assessed in alcohol-dependent patients (DSM-IV, n = 35) matched to non-alcohol-dependent participants (n = 22) at the onset (T1: day 1 or 2) and at the end (T2: days 14-18) of protracted withdrawal during rehab. Alcohol-dependent patients' abilities to focus their attention on relevant information, to switch from one pattern to another, to inhibit irrelevant information and to make advantageous choices were lower than those of control participants during both times of a withdrawal cure. No effect of time emerged from analyses for selective attention and EF deficits. Conversely, significant differences between T1 and T2 were observed for craving and affect scores indicating a weakening of alcohol craving and negative affect as well as an improvement of positive affect among patients from onset to the end of cure. Control functions of the Supervisory Attentional System (Norman and Shallice, 1986) were impaired and did not improve during a 3-week withdrawal cure, whereas alcohol craving and negative state affectivity significantly improved in parallel during this period. Implications for understanding the clinical processes of withdrawal are discussed.

  1. A Family of Salmonella Virulence Factors Functions as a Distinct Class of Autoregulated E3 Ubiquitin Ligases

    Energy Technology Data Exchange (ETDEWEB)

    Quezada, C.; Hicks, S; Galan, J; Stebbins, C

    2009-01-01

    Processes as diverse as receptor binding and signaling, cytoskeletal dynamics, and programmed cell death are manipulated by mimics of host proteins encoded by pathogenic bacteria. We show here that the Salmonella virulence factor SspH2 belongs to a growing class of bacterial effector proteins that harness and subvert the eukaryotic ubiquitination pathway. This virulence protein possesses ubiquitination activity that depends on a conserved cysteine residue. A crystal structure of SspH2 reveals a canonical leucine-rich repeat (LRR) domain that interacts with a unique E{sub 3} ligase [which we have termed NEL for Novel E{sub 3} Ligase] C-terminal fold unrelated to previously observed HECT or RING-finger E{sub 3} ligases. Moreover, the LRR domain sequesters the catalytic cysteine residue contained in the NEL domain, and we suggest a mechanism for activation of the ligase requiring a substantial conformational change to release the catalytic domain for function. We also show that the N-terminal domain targets SspH2 to the apical plasma membrane of polarized epithelial cells and propose a model whereby binding of the LRR to proteins at the target site releases the ligase domain for site-specific function.

  2. Distinct Molecular Signature of Murine Fetal Liver and Adult Hematopoietic Stem Cells Identify Novel Regulators of Hematopoietic Stem Cell Function.

    Science.gov (United States)

    Manesia, Javed K; Franch, Monica; Tabas-Madrid, Daniel; Nogales-Cadenas, Ruben; Vanwelden, Thomas; Van Den Bosch, Elisa; Xu, Zhuofei; Pascual-Montano, Alberto; Khurana, Satish; Verfaillie, Catherine M

    2017-04-15

    During ontogeny, fetal liver (FL) acts as a major site for hematopoietic stem cell (HSC) maturation and expansion, whereas HSCs in the adult bone marrow (ABM) are largely quiescent. HSCs in the FL possess faster repopulation capacity as compared with ABM HSCs. However, the molecular mechanism regulating the greater self-renewal potential of FL HSCs has not yet extensively been assessed. Recently, we published RNA sequencing-based gene expression analysis on FL HSCs from 14.5-day mouse embryo (E14.5) in comparison to the ABM HSCs. We reanalyzed these data to identify key transcriptional regulators that play important roles in the expansion of HSCs during development. The comparison of FL E14.5 with ABM HSCs identified more than 1,400 differentially expressed genes. More than 200 genes were shortlisted based on the gene ontology (GO) annotation term "transcription." By morpholino-based knockdown studies in zebrafish, we assessed the function of 18 of these regulators, previously not associated with HSC proliferation. Our studies identified a previously unknown role for tdg, uhrf1, uchl5, and ncoa1 in the emergence of definitive hematopoiesis in zebrafish. In conclusion, we demonstrate that identification of genes involved in transcriptional regulation differentially expressed between expanding FL HSCs and quiescent ABM HSCs, uncovers novel regulators of HSC function.

  3. Extension of $b{sub f}$-continuous functions defined on a product of $b{sub f}$-groups

    Energy Technology Data Exchange (ETDEWEB)

    Sanchis, M.

    2017-07-01

    Let X be a bf -space and let G be a bf -group. By means of the exponential mapping we characterize when a bf -continuous function on X × G with values in a topologically complete sapce Z has a bf -continuous extension to β(X) × G. As a consequence we show that the product of a pseudocompact space and a bf -group is a bf -group. This result generalizes the fact that the product of a pseudocompact space and a pseudocompact group is pseudocompact. (Author)

  4. FURTHER DEFINING SPECTRAL TYPE 'Y' AND EXPLORING THE LOW-MASS END OF THE FIELD BROWN DWARF MASS FUNCTION

    International Nuclear Information System (INIS)

    Davy Kirkpatrick, J.; Gelino, Christopher R.; Griffith, Roger L.; Marsh, Kenneth A.; Cushing, Michael C.; Mace, Gregory N.; Wright, Edward L.; McLean, Ian S.; Skrutskie, Michael F.; Eisenhardt, Peter R.; Mainzer, Amanda K.; Burgasser, Adam J.; Tinney, C. G.; Parker, Stephen; Salter, Graeme

    2012-01-01

    We present the discovery of another seven Y dwarfs from the Wide-field Infrared Survey Explorer (WISE). Using these objects, as well as the first six WISE Y dwarf discoveries from Cushing et al., we further explore the transition between spectral types T and Y. We find that the T/Y boundary roughly coincides with the spot where the J – H colors of brown dwarfs, as predicted by models, turn back to the red. Moreover, we use preliminary trigonometric parallax measurements to show that the T/Y boundary may also correspond to the point at which the absolute H (1.6 μm) and W2 (4.6 μm) magnitudes plummet. We use these discoveries and their preliminary distances to place them in the larger context of the solar neighborhood. We present a table that updates the entire stellar and substellar constituency within 8 pc of the Sun, and we show that the current census has hydrogen-burning stars outnumbering brown dwarfs by roughly a factor of six. This factor will decrease with time as more brown dwarfs are identified within this volume, but unless there is a vast reservoir of cold brown dwarfs invisible to WISE, the final space density of brown dwarfs is still expected to fall well below that of stars. We also use these new Y dwarf discoveries, along with newly discovered T dwarfs from WISE, to investigate the field substellar mass function. We find that the overall space density of late-T and early-Y dwarfs matches that from simulations describing the mass function as a power law with slope –0.5 < α < 0.0; however, a power law may provide a poor fit to the observed object counts as a function of spectral type because there are tantalizing hints that the number of brown dwarfs continues to rise from late-T to early-Y. More detailed monitoring and characterization of these Y dwarfs, along with dedicated searches aimed at identifying more examples, are certainly required.

  5. Common and distinct neural correlates of emotional processing in Bipolar Disorder and Major Depressive Disorder: A voxel-based meta-analysis of functional magnetic resonance imaging studies

    International Nuclear Information System (INIS)

    Delvecchio, Giuseppe; Frangou, Sophia; Fossati, Philippe; Boyer, Patrice; Brambilla, Paolo; Falkai, Peter; Gruber, Olivier; Hietala, Jarmo; Lawrie, Stephen M.; Martinot, Jean-Luc; McIntosh, Andrew M.; Meisenzahl, Eva

    2012-01-01

    Neuroimaging studies have consistently shown functional brain abnormalities in patients with Bipolar Disorder (BD) and Major Depressive Disorder (MDD). However, the extent to which these two disorders are associated with similar or distinct neural changes remains unclear. We conducted a systematic review of functional magnetic resonance imaging studies comparing BD and MDD patients to healthy participants using facial affect processing paradigms. Relevant spatial coordinates from twenty original studies were subjected to quantitative Activation Likelihood Estimation meta-analyses based on 168 BD and 189 MDD patients and 344 healthy controls. We identified common and distinct patterns of neural engagement for BD and MDD within the facial affect processing network. Both disorders were associated with increased engagement of limbic regions. Diagnosis-specific differences were observed in cortical, thalamic and striatal regions. Decreased ventro-lateral prefrontal cortical engagement was associated with BD while relative hypo-activation of the sensorimotor cortices was seen in MDD. Increased responsiveness in the thalamus and basal ganglia were associated with BD. These findings were modulated by stimulus valence. These data suggest that whereas limbic over-activation is reported consistently in patients with mood disorders, future research should consider the relevance of a wider network of regions in formulating conceptual models of BD and MDD. (authors)

  6. The Research Search For The Least Beneficial Overcast Sky And Progress In Defining Its Luminance Gradation Function

    Directory of Open Access Journals (Sweden)

    Kittler R.

    2014-09-01

    Full Text Available Recently illuminance levels under ISO/CIE homogeneous standard sky types were characterised in their relative terms after ISO/CIE (2004, 2003 standardised as normalised by the luminance in the zenith. Sky luminance and horizontal illuminance based on the gradation and scattering indicatrix functions, including the extreme overcast cases frequently encountered in nature, were recently determined in absolute physical units of luminance in kilocandles per meter square and of illuminance in kilolux. The historical search to find energy and visibility critical sky luminance distributions shows a progression of steps in studying the worst or critical overcast situations. That progression has enabled the determination and evaluation of interior illuminance for comparison of the merits of dual daylighting and artificial lighting under established criteria for comfortable visibility.

  7. Defining the contributions of permanent electrostatics, Pauli repulsion, and dispersion in density functional theory calculations of intermolecular interaction energies

    Energy Technology Data Exchange (ETDEWEB)

    Horn, Paul R., E-mail: prhorn@berkeley.edu; Mao, Yuezhi; Head-Gordon, Martin, E-mail: mhg@cchem.berkeley.edu [Kenneth S. Pitzer Center for Theoretical Chemistry, Department of Chemistry, University of California, Berkeley, California 94720, USA and Chemical Sciences Division Lawrence Berkeley National Laboratory Berkeley, California 94720 (United States)

    2016-03-21

    In energy decomposition analysis of Kohn-Sham density functional theory calculations, the so-called frozen (or pre-polarization) interaction energy contains contributions from permanent electrostatics, dispersion, and Pauli repulsion. The standard classical approach to separate them suffers from several well-known limitations. We introduce an alternative scheme that employs valid antisymmetric electronic wavefunctions throughout and is based on the identification of individual fragment contributions to the initial supersystem wavefunction as determined by an energetic optimality criterion. The density deformations identified with individual fragments upon formation of the initial supersystem wavefunction are analyzed along with the distance dependence of the new and classical terms for test cases that include the neon dimer, ammonia borane, water-Na{sup +}, water-Cl{sup −}, and the naphthalene dimer.

  8. Association between MRI-defined osteoarthritis, pain, function and strength 3-10 years following knee joint injury in youth sport.

    Science.gov (United States)

    Whittaker, Jackie L; Toomey, Clodagh M; Woodhouse, Linda J; Jaremko, Jacob L; Nettel-Aguirre, Alberto; Emery, Carolyn A

    2017-10-10

    Youth and young adults who participate in sport have an increased risk of knee injury and subsequent osteoarthritis. Improved understanding of the relationship between structural and clinical outcomes postinjury could inform targeted osteoarthritis prevention interventions. This secondary analysis examines the association between MRI-defined osteoarthritis and self-reported and functional outcomes, 3-10 years following youth sport-related knee injury in comparison to healthy controls. Participants included a subsample (n=146) of the Alberta Youth Prevention of Early Osteoarthritis cohort: specifically, 73 individuals with 3-10 years history of sport-related intra-articular knee injury and 73 age-matched, sex-matched and sport-matched controls with completed MRI studies. Outcomes included: MRI-defined osteoarthritis, radiographic osteoarthritis, Knee Injury and Osteoarthritis Outcome Score, Intermittent and Constant Osteoarthritis Pain, knee extensor/flexor strength, triple-hop and Y-balance test. Descriptive statistics and univariate logistic regression were used to compare those with and without MRI-defined osteoarthritis. Associations between MRI-defined osteoarthritis and each outcome were assessed using multivariable linear regression considering the influence of injury history, sex, body mass index and time since injury. Participant median age was 23 years (range 15-27), and 63% were female. MRI-defined osteoarthritis varied by injury history, injury type and surgical history and was not isolated to participants with ACL and/or meniscal injuries. Those with a previous knee injury had 10-fold (95% CI 2.3 to 42.8) greater odds of MRI-defined osteoarthritis than uninjured participants. MRI-defined osteoarthritis was independently significantly associated with quality of life, but not symptoms, strength or function. MRI-detected structural changes 3-10 years following youth sport-related knee injury may not dictate clinical symptomatology, strength or function

  9. Effects of Erosion from Mounds of Different Termite Genera on Distinct Functional Grassland Types in an African Savannah.

    Science.gov (United States)

    Gosling, Cleo M; Cromsigt, Joris P G M; Mpanza, Nokukhanya; Olff, Han

    A key aspect of savannah vegetation heterogeneity is mosaics formed by two functional grassland types, bunch grasslands, and grazing lawns. We investigated the role of termites, important ecosystem engineers, in creating high-nutrient patches in the form of grazing lawns. Some of the ways termites can contribute to grazing lawn development is through erosion of soil from aboveground mounds to the surrounding soil surface. This may alter the nutrient status of the surrounding soils. We hypothesize that the importance of this erosion varies with termite genera, depending on feeding strategy and mound type. To test this, we simulated erosion by applying mound soil from three termite genera ( Macrotermes , Odontotermes , and Trinervitermes ) in both a field experiment and a greenhouse experiment. In the greenhouse experiment, we found soils with the highest macro nutrient levels (formed by Trinervitermes ) promoted the quality and biomass of both a lawn ( Digitaria longiflora ) and a bunch ( Sporobolus pyramidalis ) grass species. In the field we found that soils with the highest micro nutrient levels (formed by Macrotermes ) showed the largest increase in cover of grazing lawn species. By linking the different nutrient availability of the mounds to the development of different grassland states, we conclude that the presence of termite mounds influences grassland mosaics, but that the type of mound plays a crucial role in determining the nature of the effects.

  10. Intransience of functional components and distinctive properties of amla (Indian gooseberry) ice cream during short-term storage.

    Science.gov (United States)

    Goraya, Rajpreet Kaur; Bajwa, Usha

    2018-05-01

    Inclusion of processed amla have been found to enhance the functional properties and nutritional value of ice cream by augmenting the fiber content, total phenols, tannins, ascorbic acid and antioxidant activity. The present investigation assessed the changes in these constituents, color values (L, a* and b*), melting rate, sensory scores and microbiological quality of ice cream containing amla shreds, pulp, preserve, candy and powder during 60 days' storage at - 18 to - 20 °C. The total solids increased slightly whereas the antioxidant activity, total phenols, ascorbic acid and tannins decreased on storage. The L values declined whereas a* and b* values amplified, the rate of change being highest in candy containing sample followed by preserve. The first drip time of all the samples increased whereas melting rate decreased. The overall acceptability scores declined non significantly. Standard plate count of all the ice cream samples decreased significantly whereas yeast and molds were not detected throughout the storage. The psychrophiles were not spotted up to 30 days, thereafter, a small increase was observed.

  11. Mutant Allele-Specific Uncoupling of PENETRATION3 Functions Reveals Engagement of the ATP-Binding Cassette Transporter in Distinct Tryptophan Metabolic Pathways1[OPEN

    Science.gov (United States)

    Lu, Xunli; Dittgen, Jan; Piślewska-Bednarek, Mariola; Molina, Antonio; Schneider, Bernd; Doubský, Jan; Schneeberger, Korbinian; Schulze-Lefert, Paul

    2015-01-01

    Arabidopsis (Arabidopsis thaliana) PENETRATION (PEN) genes quantitatively contribute to the execution of different forms of plant immunity upon challenge with diverse leaf pathogens. PEN3 encodes a plasma membrane-resident pleiotropic drug resistance-type ATP-binding cassette transporter and is thought to act in a pathogen-inducible and PEN2 myrosinase-dependent metabolic pathway in extracellular defense. This metabolic pathway directs the intracellular biosynthesis and activation of tryptophan-derived indole glucosinolates for subsequent PEN3-mediated efflux across the plasma membrane at pathogen contact sites. However, PEN3 also functions in abiotic stress responses to cadmium and indole-3-butyric acid (IBA)-mediated auxin homeostasis in roots, raising the possibility that PEN3 exports multiple functionally unrelated substrates. Here, we describe the isolation of a pen3 allele, designated pen3-5, that encodes a dysfunctional protein that accumulates in planta like wild-type PEN3. The specific mutation in pen3-5 uncouples PEN3 functions in IBA-stimulated root growth modulation, callose deposition induced with a conserved peptide epitope of bacterial flagellin (flg22), and pathogen-inducible salicylic acid accumulation from PEN3 activity in extracellular defense, indicating the engagement of multiple PEN3 substrates in different PEN3-dependent biological processes. We identified 4-O-β-d-glucosyl-indol-3-yl formamide (4OGlcI3F) as a pathogen-inducible, tryptophan-derived compound that overaccumulates in pen3 leaf tissue and has biosynthesis that is dependent on an intact PEN2 metabolic pathway. We propose that a precursor of 4OGlcI3F is the PEN3 substrate in extracellular pathogen defense. These precursors, the shared indole core present in IBA and 4OGlcI3F, and allele-specific uncoupling of a subset of PEN3 functions suggest that PEN3 transports distinct indole-type metabolites in distinct biological processes. PMID:26023163

  12. The centrosomin CM2 domain is a multi-functional binding domain with distinct cell cycle roles.

    Science.gov (United States)

    Citron, Y Rose; Fagerstrom, Carey J; Keszthelyi, Bettina; Huang, Bo; Rusan, Nasser M; Kelly, Mark J S; Agard, David A

    2018-01-01

    The centrosome serves as the main microtubule-organizing center in metazoan cells, yet despite its functional importance, little is known mechanistically about the structure and organizational principles that dictate protein organization in the centrosome. In particular, the protein-protein interactions that allow for the massive structural transition between the tightly organized interphase centrosome and the highly expanded matrix-like arrangement of the mitotic centrosome have been largely uncharacterized. Among the proteins that undergo a major transition is the Drosophila melanogaster protein centrosomin that contains a conserved carboxyl terminus motif, CM2. Recent crystal structures have shown this motif to be dimeric and capable of forming an intramolecular interaction with a central region of centrosomin. Here we use a combination of in-cell microscopy and in vitro oligomer assessment to show that dimerization is not necessary for CM2 recruitment to the centrosome and that CM2 alone undergoes significant cell cycle dependent rearrangement. We use NMR binding assays to confirm this intramolecular interaction and show that residues involved in solution are consistent with the published crystal structure and identify L1137 as critical for binding. Additionally, we show for the first time an in vitro interaction of CM2 with the Drosophila pericentrin-like-protein that exploits the same set of residues as the intramolecular interaction. Furthermore, NMR experiments reveal a calcium sensitive interaction between CM2 and calmodulin. Although unexpected because of sequence divergence, this suggests that centrosomin-mediated assemblies, like the mammalian pericentrin, may be calcium regulated. From these results, we suggest an expanded model where during interphase CM2 interacts with pericentrin-like-protein to form a layer of centrosomin around the centriole wall and that at the onset of mitosis this population acts as a nucleation site of intramolecular

  13. CYP79F1 and CYP79F2 have distinct functions in the biosynthesis of aliphatic glucosinolates in Arabidopsis.

    Science.gov (United States)

    Chen, Sixue; Glawischnig, Erich; Jørgensen, Kirsten; Naur, Peter; Jørgensen, Bodil; Olsen, Carl-Erik; Hansen, Carsten H; Rasmussen, Hasse; Pickett, John A; Halkier, Barbara A

    2003-03-01

    Cytochromes P450 of the CYP79 family catalyze the conversion of amino acids to oximes in the biosynthesis of glucosinolates, a group of natural plant products known to be involved in plant defense and as a source of flavor compounds, cancer-preventing agents and bioherbicides. We report a detailed biochemical analysis of the substrate specificity and kinetics of CYP79F1 and CYP79F2, two cytochromes P450 involved in the biosynthesis of aliphatic glucosinolates in Arabidopsis thaliana. Using recombinant CYP79F1 and CYP79F2 expressed in Escherichia coli and Saccharomyces cerevisiae, respectively, we show that CYP79F1 metabolizes mono- to hexahomomethionine, resulting in both short- and long-chain aliphatic glucosinolates. In contrast, CYP79F2 exclusively metabolizes long-chain elongated penta- and hexahomomethionines. CYP79F1 and CYP79F2 are spatially and developmentally regulated, with different gene expression patterns. CYP79F2 is highly expressed in hypocotyl and roots, whereas CYP79F1 is strongly expressed in cotyledons, rosette leaves, stems, and siliques. A transposon-tagged CYP79F1 knockout mutant completely lacks short-chain aliphatic glucosinolates, but has an increased level of long-chain aliphatic glucosinolates, especially in leaves and seeds. The level of long-chain aliphatic glucosinolates in a transposon-tagged CYP79F2 knockout mutant is substantially reduced, whereas the level of short-chain aliphatic glucosinolates is not affected. Biochemical characterization of CYP79F1 and CYP79F2, and gene expression analysis, combined with glucosinolate profiling of knockout mutants demonstrate the functional role of these enzymes. This provides valuable insights into the metabolic network leading to the biosynthesis of aliphatic glucosinolates, and into metabolic engineering of altered aliphatic glucosinolate profiles to improve nutritional value and pest resistance.

  14. Gain-of-Function Mutations in STAT1: A Recently Defined Cause for Chronic Mucocutaneous Candidiasis Disease Mimicking Combined Immunodeficiencies

    Directory of Open Access Journals (Sweden)

    Sanem Eren Akarcan

    2017-01-01

    Full Text Available Chronic Mucocutaneous Candidiasis (CMC is the chronic, recurrent, noninvasive Candida infections of the skin, mucous membranes, and nails. A 26-month-old girl was admitted with the complaints of recurrent oral Candidiasis, diarrhea, and respiratory infections. Candida albicans grew in oral mucosa swab. CMV and EBV DNA titers were elevated. She had hypergammaglobulinemia; IgE level, percentages of lymphocyte subgroups, and in vitro T-cell proliferation responses were normal. She had parenchymal nodules within the lungs and a calcific nodule in the liver. Chronic-recurrent infections with different pathogens leading to significant morbidity suggested combined immunodeficiency, CMC, or Mendelian susceptibility to mycobacterial diseases. Genetic analysis revealed a predefined heterozygous gain-of-function mutation (GOF (c.1154 C>T, p.Thr385Met in the gene coding STAT1 molecule. Hematopoietic stem cell transplantation (HSCT was planned because of severe recurring infections. Patients with STAT1 GOF mutations may exhibit diverse phenotypes including infectious and noninfectious findings. HSCT should be considered as an early treatment option before permanent organ damage leading to morbidity and mortality develops. This case is presented to prompt clinicians to consider STAT1 GOF mutations in the differential diagnosis of patients with chronic Candidiasis and recurrent infections with multiple organisms, since these mutations are responsible for nearly half of CMC cases reported.

  15. Co-ordinated functions of Mms proteins define the surface structure of cubo-octahedral magnetite crystals in magnetotactic bacteria.

    Science.gov (United States)

    Arakaki, Atsushi; Yamagishi, Ayana; Fukuyo, Ayumi; Tanaka, Masayoshi; Matsunaga, Tadashi

    2014-08-01

    Magnetotactic bacteria synthesize magnetosomes comprised of membrane-enveloped single crystalline magnetite (Fe3 O4 ). The size and morphology of the nano-sized magnetite crystals (Mms (Mms5, Mms6, Mms7, and Mms13), was previously isolated from the surface of cubo-octahedral magnetite crystals in Magnetospirillum magneticum strain AMB-1. Analysis of an mms6 gene deletion mutant suggested that the Mms6 protein plays a major role in the regulation of magnetite crystal size and morphology. In this study, we constructed various mms gene deletion mutants and characterized the magnetite crystals formed by the mutant strains. Comparative analysis showed that all mms genes were involved in the promotion of crystal growth in different manners. The phenotypic characterization of magnetites also suggested that these proteins are involved in controlling the geometries of the crystal surface structures. Thus, the co-ordinated functions of Mms proteins regulate the morphology of the cubo-octahedral magnetite crystals in magnetotactic bacteria. © 2014 John Wiley & Sons Ltd.

  16. Optimization of soaking stage in technological process of wheat germination by hydroponic method when objective function is defined implicitly

    Science.gov (United States)

    Koneva, M. S.; Rudenko, O. V.; Usatikov, S. V.; Bugayets, N. A.; Tamova, M. Yu; Fedorova, M. A.

    2018-05-01

    The increase in the efficiency of the "numerical" technology for solving computational problems of parametric optimization of the technological process of hydroponic germination of wheat grains is considered. In this situation, the quality criteria are contradictory and a part of them is given by implicit functions of many variables. One of the main stages, soaking, determining the time and quality of germinated wheat grain is studied, when grain receives the required amount of moisture and air oxygen for germination and subsequently accumulates enzymes. A solution algorithm for this problem is suggested implemented by means of software packages Statistica v.10 and MathCAD v.15. The use of the proposed mathematical models describing the processes of hydroponic soaking of spring soft wheat varieties made it possible to determine optimal conditions of germination. The results of investigations show that the type of aquatic environment used for soaking has a great influence on the process of water absorption, especially the chemical composition of the germinated material. The use of the anolyte of electrochemically activated water (ECHA-water) intensifies the process from 5.83 to 4 hours for wheat variety «Altayskaya 105» and from 13 to 8.8 hours - for «Pobla Runo».

  17. Defining the functional domain of programmed cell death 10 through its interactions with phosphatidylinositol-3,4,5-trisphosphate.

    Directory of Open Access Journals (Sweden)

    Christopher F Dibble

    2010-07-01

    Full Text Available Cerebral cavernous malformations (CCM are vascular abnormalities of the central nervous system predisposing blood vessels to leakage, leading to hemorrhagic stroke. Three genes, Krit1 (CCM1, OSM (CCM2, and PDCD10 (CCM3 are involved in CCM development. PDCD10 binds specifically to PtdIns(3,4,5P3 and OSM. Using threading analysis and multi-template modeling, we constructed a three-dimensional model of PDCD10. PDCD10 appears to be a six-helical-bundle protein formed by two heptad-repeat-hairpin structures (alpha1-3 and alpha4-6 sharing the closest 3D homology with the bacterial phosphate transporter, PhoU. We identified a stretch of five lysines forming an amphipathic helix, a potential PtdIns(3,4,5P3 binding site, in the alpha5 helix. We generated a recombinant wild-type (WT and three PDCD10 mutants that have two (Delta2KA, three (Delta3KA, and five (Delta5KA K to A mutations. Delta2KA and Delta3KA mutants hypothetically lack binding residues to PtdIns(3,4,5P3 at the beginning and the end of predicted helix, while Delta5KA completely lacks all predicted binding residues. The WT, Delta2KA, and Delta3KA mutants maintain their binding to PtdIns(3,4,5P3. Only the Delta5KA abolishes binding to PtdIns(3,4,5P3. Both Delta5KA and WT show similar secondary and tertiary structures; however, Delta5KA does not bind to OSM. When WT and Delta5KA are co-expressed with membrane-bound constitutively-active PI3 kinase (p110-CAAX, the majority of the WT is co-localized with p110-CAAX at the plasma membrane where PtdIns(3,4,5P3 is presumably abundant. In contrast, the Delta5KA remains in the cytoplasm and is not present in the plasma membrane. Combining computational modeling and biological data, we propose that the CCM protein complex functions in the PI3K signaling pathway through the interaction between PDCD10 and PtdIns(3,4,5P3.

  18. Distinct phosphorylation sites on the ghrelin receptor, GHSR1a, establish a code that determines the functions of ß-arrestins

    Science.gov (United States)

    Bouzo-Lorenzo, Monica; Santo-Zas, Icía; Lodeiro, Maria; Nogueiras, Rubén; Casanueva, Felipe F.; Castro, Marian; Pazos, Yolanda; Tobin, Andrew B; Butcher, Adrian J.; Camiña, Jesús P.

    2016-01-01

    The growth hormone secretagogue receptor, GHSR1a, mediates the biological activities of ghrelin, which includes the secretion of growth hormone, as well as the stimulation of appetite, food intake and maintenance of energy homeostasis. Mapping phosphorylation sites on GHSR1a and knowledge of how these sites control specific functional consequences unlocks new strategies for the development of therapeutic agents targeting individual functions. Herein, we have identified the phosphorylation of different sets of sites within GHSR1a which engender distinct functionality of ß-arrestins. More specifically, the Ser362, Ser363 and Thr366 residues at the carboxyl-terminal tail were primarily responsible for ß-arrestin 1 and 2 binding, internalization and ß-arrestin-mediated proliferation and adipogenesis. The Thr350 and Ser349 are not necessary for ß-arrestin recruitment, but are involved in the stabilization of the GHSR1a-ß-arrestin complex in a manner that determines the ultimate cellular consequences of ß-arrestin signaling. We further demonstrated that the mitogenic and adipogenic effect of ghrelin were mainly dependent on the ß-arrestin bound to the phosphorylated GHSR1a. In contrast, the ghrelin function on GH secretion was entirely mediated by G protein signaling. Our data is consistent with the hypothesis that the phosphorylation pattern on the C terminus of GHSR1a determines the signaling and physiological output. PMID:26935831

  19. PAF-receptor is preferentially expressed in a distinct synthetic phenotype of smooth muscle cells cloned from human internal thoracic artery: Functional implications in cell migration

    International Nuclear Information System (INIS)

    Stengel, Dominique; O'Neil, Caroline; Brocheriou, Isabelle; Karabina, Sonia-Athina; Durand, Herve; Caplice, Noel M.; Pickering, J. Geoffrey; Ninio, Ewa

    2006-01-01

    Platelet-activating-Factor (PAF) and its structural analogues formed upon low density lipoprotein oxidation are involved in atherosclerotic plaque formation and may signal through PAF-receptor (PAF-R) expressed in human macrophages and in certain smooth muscle cells (SMCs) in the media, but rarely in the intima of human plaques. Our aim was to determine which SMC phenotype expresses PAF-R and whether this receptor is functional in cell migration. Circulating SMC progenitors and two phenotypically distinct clones of proliferative, epithelioid phenotype vs contractile, spindle-shaped SMCs from the media of adult internal thoracic artery were studied for the presence of PAF-receptor (PAF-R). The levels of specific mRNA were obtained by reverse transcription/real-time PCR, the protein expression was deduced from immunohistochemistry staining, and the functional transmigration assay was performed by Boyden chamber-type chemotaxis assay. Only SMCs of spindle-shape and synthetic phenotype expressed both mRNA and PAF-R protein and in the functional test migrated at low concentrations of PAF. Two unrelated, specific PAF-R antagonists inhibited PAF-induced migration, but did not modify the migration initiated by PDGF. The presence of functional PAF-R in arterial spindle-shaped SMCs of synthetic phenotype may be important for their migration from the media into the intima and atherosclerotic plaques formation

  20. Feature-based attention is functionally distinct from relation-based attention: The double dissociation between color-based capture and color-relation-based capture of attention.

    Science.gov (United States)

    Du, Feng; Jiao, Jun

    2016-04-01

    The present study used a spatial blink task and a cuing task to examine the boundary between feature-based capture and relation-based capture. Feature-based capture occurs when distractors match the target feature such as target color. The occurrence of relation-based capture is contingent upon the feature relation between target and distractor (e.g., color relation). The results show that color distractors that match the target-nontarget color relation do not consistently capture attention when they appear outside of the attentional window, but distractors appearing outside the attentional window that match the target color consistently capture attention. In contrast, color distractors that best match the target-nontarget color relation but not the target color, are more likely to capture attention when they appear within the attentional window. Consistently, color cues that match the target-nontarget color relation produce a cuing effect when they appear within the attentional window, while target-color matched cues do not. Such a double dissociation between color-based capture and color-relation-based capture indicates functionally distinct mechanisms for these 2 types of attentional selection. This also indicates that the spatial blink task and the uninformative cuing task are measuring distinctive aspects of involuntary attention. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  1. Complete identification of E-selectin ligand activity on neutrophils reveals a dynamic interplay and distinct functions of PSGL-1, ESL-1 and CD44

    Science.gov (United States)

    Wild, Martin; Vestweber, Dietmar; Frenette, Paul S.

    2014-01-01

    SUMMARY The selectins and their ligands are required for leukocyte extravasation during inflammation. Several glycoproteins have been suggested to bind to E-selectin in vitro but the complete identification of its physiological ligands has remained elusive. Here, we show using gene- and RNA-targeted loss-of-function that E-selectin ligand-1 (ESL-1), PSGL-1 and CD44 encompass all endothelial selectin ligand activity on neutrophils. PSGL-1 plays a major role in the initial leukocyte capture, while ESL-1 is critical to convert initial tethers into steady slow rolling. CD44 controls rolling velocity and mediates E-selectin-dependent redistribution of PSGL-1 and L-selectin to a major pole on slowly rolling leukocytes through p38 signaling. These results suggest distinct and dynamic contributions of these three glycoproteins in selectin-mediated neutrophil adhesion and signaling. PMID:17442598

  2. De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

    Science.gov (United States)

    Reijnders, Margot R F; Miller, Kerry A; Alvi, Mohsan; Goos, Jacqueline A C; Lees, Melissa M; de Burca, Anna; Henderson, Alex; Kraus, Alison; Mikat, Barbara; de Vries, Bert B A; Isidor, Bertrand; Kerr, Bronwyn; Marcelis, Carlo; Schluth-Bolard, Caroline; Deshpande, Charu; Ruivenkamp, Claudia A L; Wieczorek, Dagmar; Baralle, Diana; Blair, Edward M; Engels, Hartmut; Lüdecke, Hermann-Josef; Eason, Jacqueline; Santen, Gijs W E; Clayton-Smith, Jill; Chandler, Kate; Tatton-Brown, Katrina; Payne, Katelyn; Helbig, Katherine; Radtke, Kelly; Nugent, Kimberly M; Cremer, Kirsten; Strom, Tim M; Bird, Lynne M; Sinnema, Margje; Bitner-Glindzicz, Maria; van Dooren, Marieke F; Alders, Marielle; Koopmans, Marije; Brick, Lauren; Kozenko, Mariya; Harline, Megan L; Klaassens, Merel; Steinraths, Michelle; Cooper, Nicola S; Edery, Patrick; Yap, Patrick; Terhal, Paulien A; van der Spek, Peter J; Lakeman, Phillis; Taylor, Rachel L; Littlejohn, Rebecca O; Pfundt, Rolph; Mercimek-Andrews, Saadet; Stegmann, Alexander P A; Kant, Sarina G; McLean, Scott; Joss, Shelagh; Swagemakers, Sigrid M A; Douzgou, Sofia; Wall, Steven A; Küry, Sébastien; Calpena, Eduardo; Koelling, Nils; McGowan, Simon J; Twigg, Stephen R F; Mathijssen, Irene M J; Nellaker, Christoffer; Brunner, Han G; Wilkie, Andrew O M

    2018-06-07

    Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Variation in tibial functionality and fracture susceptibility among healthy, young adults arises from the acquisition of biologically distinct sets of traits.

    Science.gov (United States)

    Jepsen, Karl J; Evans, Rachel; Negus, Charles H; Gagnier, Joel J; Centi, Amanda; Erlich, Tomer; Hadid, Amir; Yanovich, Ran; Moran, Daniel S

    2013-06-01

    Physiological systems like bone respond to many genetic and environmental factors by adjusting traits in a highly coordinated, compensatory manner to establish organ-level function. To be mechanically functional, a bone should be sufficiently stiff and strong to support physiological loads. Factors impairing this process are expected to compromise strength and increase fracture risk. We tested the hypotheses that individuals with reduced stiffness relative to body size will show an increased risk of fracturing and that reduced strength arises from the acquisition of biologically distinct sets of traits (ie, different combinations of morphological and tissue-level mechanical properties). We assessed tibial functionality retrospectively for 336 young adult women and men engaged in military training, and calculated robustness (total area/bone length), cortical area (Ct.Ar), and tissue-mineral density (TMD). These three traits explained 69% to 72% of the variation in tibial stiffness (p stress fracture based on radiography and scintigraphy. K-means cluster analysis was used to segregate men and women into subgroups based on robustness, Ct.Ar, and TMD adjusted for body size. Stiffness varied 37% to 42% among the clusters (p stress fracture cases segregated to three clusters (p fracture risk. Our results have important implications for developing personalized preventative diagnostics and treatments. Copyright © 2013 American Society for Bone and Mineral Research.

  4. Defining Platelet Function During Polytrauma

    Science.gov (United States)

    2014-04-01

    scaffold of the clot after its thrombin-induced polymerization to fibrin fibers. Formation of a stiff fibrin fiber network and its contraction by platelet...In another study (PROTEC T) Refused Participat ion (Yes=Y, No=N, W=Unqua lified , Refused further draws (agreed to keep previous data

  5. Defining Legal Moralism

    DEFF Research Database (Denmark)

    Thaysen, Jens Damgaard

    2015-01-01

    This paper discusses how legal moralism should be defined. It is argued that legal moralism should be defined as the position that “For any X, it is always a pro tanto reason for justifiably imposing legal regulation on X that X is morally wrong (where “morally wrong” is not conceptually equivalent...... to “harmful”)”. Furthermore, a distinction between six types of legal moralism is made. The six types are grouped according to whether they are concerned with the enforcement of positive or critical morality, and whether they are concerned with criminalising, legally restricting, or refraining from legally...... protecting morally wrong behaviour. This is interesting because not all types of legal moralism are equally vulnerable to the different critiques of legal moralism that have been put forth. Indeed, I show that some interesting types of legal moralism have not been criticised at all....

  6. Xeno-Free and Defined Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells Functionally Integrate in a Large-Eyed Preclinical Model

    Directory of Open Access Journals (Sweden)

    Alvaro Plaza Reyes

    2016-01-01

    Full Text Available Human embryonic stem cell (hESC-derived retinal pigment epithelial (RPE cells could replace lost tissue in geographic atrophy (GA but efficacy has yet to be demonstrated in a large-eyed model. Also, production of hESC-RPE has not yet been achieved in a xeno-free and defined manner, which is critical for clinical compliance and reduced immunogenicity. Here we describe an effective differentiation methodology using human laminin-521 matrix with xeno-free and defined medium. Differentiated cells exhibited characteristics of native RPE including morphology, pigmentation, marker expression, monolayer integrity, and polarization together with phagocytic activity. Furthermore, we established a large-eyed GA model that allowed in vivo imaging of hESC-RPE and host retina. Cells transplanted in suspension showed long-term integration and formed polarized monolayers exhibiting phagocytic and photoreceptor rescue capacity. We have developed a xeno-free and defined hESC-RPE differentiation method and present evidence of functional integration of clinically compliant hESC-RPE in a large-eyed disease model.

  7. Performance evaluation of multi-stratum resources integration based on network function virtualization in software defined elastic data center optical interconnect.

    Science.gov (United States)

    Yang, Hui; Zhang, Jie; Ji, Yuefeng; Tian, Rui; Han, Jianrui; Lee, Young

    2015-11-30

    Data center interconnect with elastic optical network is a promising scenario to meet the high burstiness and high-bandwidth requirements of data center services. In our previous work, we implemented multi-stratum resilience between IP and elastic optical networks that allows to accommodate data center services. In view of this, this study extends to consider the resource integration by breaking the limit of network device, which can enhance the resource utilization. We propose a novel multi-stratum resources integration (MSRI) architecture based on network function virtualization in software defined elastic data center optical interconnect. A resource integrated mapping (RIM) scheme for MSRI is introduced in the proposed architecture. The MSRI can accommodate the data center services with resources integration when the single function or resource is relatively scarce to provision the services, and enhance globally integrated optimization of optical network and application resources. The overall feasibility and efficiency of the proposed architecture are experimentally verified on the control plane of OpenFlow-based enhanced software defined networking (eSDN) testbed. The performance of RIM scheme under heavy traffic load scenario is also quantitatively evaluated based on MSRI architecture in terms of path blocking probability, provisioning latency and resource utilization, compared with other provisioning schemes.

  8. Distinct functional domains within the acidic cluster of tegument protein pp28 required for trafficking and cytoplasmic envelopment of human cytomegalovirus.

    Science.gov (United States)

    Seo, Jun-Young; Jeon, Hyejin; Hong, Sookyung; Britt, William J

    2016-10-01

    Human cytomegalovirus UL99-encoded tegument protein pp28 contains a 16 aa acidic cluster that is required for pp28 trafficking to the assembly compartment (AC) and the virus assembly. However, functional signals within the acidic cluster of pp28 remain undefined. Here, we demonstrated that an acidic cluster rather than specific sorting signals was required for trafficking to the AC. Recombinant viruses with chimeric pp28 proteins expressing non-native acidic clusters exhibited delayed viral growth kinetics and decreased production of infectious virus, indicating that the native acidic cluster of pp28 was essential for wild-type virus assembly. These results suggested that the acidic cluster of pp28 has distinct functional domains required for trafficking and for efficient virus assembly. The first half (aa 44-50) of the acidic cluster was sufficient for pp28 trafficking, whereas the native acidic cluster consisting of aa 51-59 was required for the assembly of wild-type levels of infectious virus.

  9. Viewing the human microbiome through three-dimensional glasses: integrating structural and functional studies to better define the properties of myriad carbohydrate-active enzymes

    International Nuclear Information System (INIS)

    Turnbaugh, Peter J.; Henrissat, Bernard; Gordon, Jeffrey I.

    2010-01-01

    Metagenomics has unleashed a deluge of sequencing data describing the organismal, genetic, and transcriptional diversity of the human microbiome. To better understand the precise functions of the myriad proteins encoded by the microbiome, including carbohydrate-active enzymes, it will be critical to combine structural studies with functional analyses. Recent studies have provided an unprecedented view of the trillions of microbes associated with the human body. The human microbiome harbors tremendous diversity at multiple levels: the species that colonize each individual and each body habitat; the genes that are found in each organism’s genome; the expression of these genes and the interactions and activities of their protein products. The sources of this diversity are wide-ranging and reflect both environmental and host factors. A major challenge moving forward is defining the precise functions of members of various families of proteins represented in our microbiomes, including the highly diverse carbohydrate-active enzymes (CAZymes) involved in numerous biologically important chemical transformations, such as the degradation of complex dietary polysaccharides. Coupling metagenomic analyses to structural genomics initiatives and to biochemical and other functional assays of CAZymes will be essential for determining how these as well as other microbiome-encoded proteins operate to shape the properties of microbial communities and their human hosts

  10. Ex-Th17 (Nonclassical Th1) Cells Are Functionally Distinct from Classical Th1 and Th17 Cells and Are Not Constrained by Regulatory T Cells.

    Science.gov (United States)

    Basdeo, Sharee A; Cluxton, Deborah; Sulaimani, Jamal; Moran, Barry; Canavan, Mary; Orr, Carl; Veale, Douglas J; Fearon, Ursula; Fletcher, Jean M

    2017-03-15

    Th17 cells are an important therapeutic target in autoimmunity. However, it is known that Th17 cells exhibit considerable plasticity, particularly at sites of autoimmune inflammation. Th17 cells can switch to become ex-Th17 cells that no longer produce IL-17 but produce IFN-γ. These ex-Th17 cells are also called nonclassical Th1 cells because of their ability to produce IFN-γ, similar to Th1 cells; however, it is unclear whether they resemble Th1 or Th17 cells in terms of their function and regulation, and whether they have a pathogenic role in autoimmunity. We compared the phenotypic and functional features of human Th17, Th1, and ex-Th17 cell populations. Our data showed that despite their loss of IL-17 expression, ex-Th17 cells were more polyfunctional in terms of cytokine production than either Th1 or bona fide Th17 cells, and produced increased amounts of proinflammatory cytokines. The proliferative brake on Th17 cells appeared to be lifted because ex-Th17 cells proliferated more than Th17 cells after stimulation. In contrast with Th1 and Th17 cells, ex-Th17 cells were highly resistant to suppression of proliferation and cytokines by regulatory T cells. Finally, we showed that ex-Th17 cells accumulated in the joints of rheumatoid arthritis patients. Taken together, these data indicate that human ex-Th17 cells are functionally distinct from Th1 and Th17 cells, and suggest that they may play a pathogenic role at sites of autoimmunity, such as the rheumatoid arthritis joint where they accumulate. These findings have implications for therapeutic strategies that target IL-17, because these may not inhibit pathogenic ex-Th17 cells. Copyright © 2017 by The American Association of Immunologists, Inc.

  11. Albinism in phylogenetically and geographically distinct populations of Astyanax cavefish arises through the same loss-of-function Oca2 allele

    Science.gov (United States)

    Gross, J B; Wilkens, H

    2013-01-01

    The Mexican tetra, Astyanax mexicanus, comprises 29 populations of cave-adapted fish distributed across a vast karst region in northeastern Mexico. These populations have a complex evolutionary history, having descended from ‘old' and ‘young' ancestral surface-dwelling stocks that invaded the region ∼6.7 and ∼2.8 MYa, respectively. This study investigates a set of captive, pigmented Astyanax cavefish collected from the Micos cave locality in 1970, in which albinism appeared over the past two decades. We combined novel coloration analyses, coding sequence comparisons and mRNA expression level studies to investigate the origin of albinism in captive-bred Micos cavefish. We discovered that albino Micos cavefish harbor two copies of a loss-of-function ocular and cutaneous albinism type II (Oca2) allele previously identified in the geographically distant Pachón cave population. This result suggests that phylogenetically young Micos cavefish and phylogenetically old Pachón cave fish inherited this Oca2 allele from the ancestral surface-dwelling taxon. This likely resulted from the presence of the loss-of-function Oca2 haplotype in the ‘young' ancestral surface-dwelling stock that colonized the Micos cave and also introgressed into the ancient Pachón cave population. The appearance of albinism in captive Micos cavefish, caused by the same loss-of-function allele present in Pachón cavefish, implies that geographically and phylogenetically distinct cave populations can evolve the same troglomorphic phenotype from standing genetic variation present in the ancestral taxon. PMID:23572122

  12. Distinct Neural-Functional Effects of Treatments With Selective Serotonin Reuptake Inhibitors, Electroconvulsive Therapy, and Transcranial Magnetic Stimulation and Their Relations to Regional Brain Function in Major Depression: A Meta-analysis.

    Science.gov (United States)

    Chau, David T; Fogelman, Phoebe; Nordanskog, Pia; Drevets, Wayne C; Hamilton, J Paul

    2017-05-01

    Functional neuroimaging studies have examined the neural substrates of treatments for major depressive disorder (MDD). Low sample size and methodological heterogeneity, however, undermine the generalizability of findings from individual studies. We conducted a meta-analysis to identify reliable neural changes resulting from different modes of treatment for MDD and compared them with each other and with reliable neural functional abnormalities observed in depressed versus control samples. We conducted a meta-analysis of studies reporting changes in brain activity (e.g., as indexed by positron emission tomography) following treatments with selective serotonin reuptake inhibitors (SSRIs), electroconvulsive therapy (ECT), or transcranial magnetic stimulation. Additionally, we examined the statistical reliability of overlap among thresholded meta-analytic SSRI, ECT, and transcranial magnetic stimulation maps as well as a map of abnormal neural function in MDD. Our meta-analysis revealed that 1) SSRIs decrease activity in the anterior insula, 2) ECT decreases activity in central nodes of the default mode network, 3) transcranial magnetic stimulation does not result in reliable neural changes, and 4) regional effects of these modes of treatment do not significantly overlap with each other or with regions showing reliable functional abnormality in MDD. SSRIs and ECT produce neurally distinct effects relative to each other and to the functional abnormalities implicated in depression. These treatments therefore may exert antidepressant effects by diminishing neural functions not implicated in depression but that nonetheless impact mood. We discuss how the distinct neural changes resulting from SSRIs and ECT can account for both treatment effects and side effects from these therapies as well as how to individualize these treatments. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  13. Two functional motifs define the interaction, internalization and toxicity of the cell-penetrating antifungal peptide PAF26 on fungal cells.

    Directory of Open Access Journals (Sweden)

    Alberto Muñoz

    Full Text Available The synthetic, cell penetrating hexapeptide PAF26 (RKKWFW is antifungal at low micromolar concentrations and has been proposed as a model for cationic, cell-penetrating antifungal peptides. Its short amino acid sequence facilitates the analysis of its structure-activity relationships using the fungal models Neurospora crassa and Saccharomyces cerevisiae, and human and plant pathogens Aspergillus fumigatus and Penicillium digitatum, respectively. Previously, PAF26 at low fungicidal concentrations was shown to be endocytically internalized, accumulated in vacuoles and then actively transported into the cytoplasm where it exerts its antifungal activity. In the present study, two PAF26 derivatives, PAF95 (AAAWFW and PAF96 (RKKAAA, were designed to characterize the roles of the N-terminal cationic and the C-terminal hydrophobic motifs in PAF26's mode-of-action. PAF95 and PAF96 exhibited substantially reduced antifungal activity against all the fungi analyzed. PAF96 localized to fungal cell envelopes and was not internalized by the fungi. In contrast, PAF95 was taken up into vacuoles of N. crassa, wherein it accumulated and was trapped without toxic effects. Also, the PAF26 resistant Δarg1 strain of S. cerevisiae exhibited increased PAF26 accumulation in vacuoles. Live-cell imaging of GFP-labelled nuclei in A. fumigatus showed that transport of PAF26 from the vacuole to the cytoplasm was followed by nuclear breakdown and dissolution. This work demonstrates that the amphipathic PAF26 possesses two distinct motifs that allow three stages in its antifungal action to be defined: (i its interaction with the cell envelope; (ii its internalization and transport to vacuoles mediated by the aromatic hydrophobic domain; and (iii its transport from vacuoles to the cytoplasm. Significantly, cationic residues in PAF26 are important not only for the electrostatic attraction and interaction with the fungal cell but also for transport from the vacuole to the

  14. Defining a procedure for predicting the duration of the approximately isothermal segments within the proposed drying regime as a function of the drying air parameters

    Science.gov (United States)

    Vasić, M.; Radojević, Z.

    2017-08-01

    One of the main disadvantages of the recently reported method, for setting up the drying regime based on the theory of moisture migration during drying, lies in a fact that it is based on a large number of isothermal experiments. In addition each isothermal experiment requires the use of different drying air parameters. The main goal of this paper was to find a way how to reduce the number of isothermal experiments without affecting the quality of the previously proposed calculation method. The first task was to define the lower and upper inputs as well as the output of the “black box” which will be used in the Box-Wilkinson’s orthogonal multi-factorial experimental design. Three inputs (drying air temperature, humidity and velocity) were used within the experimental design. The output parameter of the model represents the time interval between any two chosen characteristic points presented on the Deff - t. The second task was to calculate the output parameter for each planed experiments. The final output of the model is the equation which can predict the time interval between any two chosen characteristic points as a function of the drying air parameters. This equation is valid for any value of the drying air parameters which are within the defined area designated with lower and upper limiting values.

  15. The ARG1-LIKE2 gene of Arabidopsis functions in a gravity signal transduction pathway that is genetically distinct from the PGM pathway

    Science.gov (United States)

    Guan, Changhui; Rosen, Elizabeth S.; Boonsirichai, Kanokporn; Poff, Kenneth L.; Masson, Patrick H.

    2003-01-01

    The arl2 mutants of Arabidopsis display altered root and hypocotyl gravitropism, whereas their inflorescence stems are fully gravitropic. Interestingly, mutant roots respond like the wild type to phytohormones and an inhibitor of polar auxin transport. Also, their cap columella cells accumulate starch similarly to wild-type cells, and mutant hypocotyls display strong phototropic responses to lateral light stimulation. The ARL2 gene encodes a DnaJ-like protein similar to ARG1, another protein previously implicated in gravity signal transduction in Arabidopsis seedlings. ARL2 is expressed at low levels in all organs of seedlings and plants. arl2-1 arg1-2 double mutant roots display kinetics of gravitropism similar to those of single mutants. However, double mutants carrying both arl2-1 and pgm-1 (a mutation in the starch-biosynthetic gene PHOSPHOGLUCOMUTASE) at the homozygous state display a more pronounced root gravitropic defect than the single mutants. On the other hand, seedlings with a null mutation in ARL1, a paralog of ARG1 and ARL2, behave similarly to the wild type in gravitropism and other related assays. Taken together, the results suggest that ARG1 and ARL2 function in the same gravity signal transduction pathway in the hypocotyl and root of Arabidopsis seedlings, distinct from the pathway involving PGM.

  16. Distinct domains within the NITROGEN LIMITATION ADAPTATION protein mediate its subcellular localization and function in the nitrate-dependent phosphate homeostasis pathway

    Science.gov (United States)

    The NITROGEN LIMITATION ADAPTATION (NLA) protein is a RING-type E3 ubiquitin ligase that plays an essential role in the regulation of nitrogen and phosphate homeostasis. NLA is localized to two distinct subcellular sites, the plasma membrane and nucleus, and contains four distinct domains: i) a RING...

  17. Modeling Asymmetric Flow of Viscoelastic Fluid in Symmetric Planar Sudden Expansion Geometry Based on User-Defined Function in FLUENT CFD Package

    Directory of Open Access Journals (Sweden)

    Zhi-Ying Zheng

    2013-01-01

    Full Text Available Through embedding an in-house subroutine into FLUENT code by utilizing the functionalization of user-defined function provided by the software, a new numerical simulation methodology on viscoelastic fluid flows has been established. In order to benchmark this methodology, numerical simulations under different viscoelastic fluid solution concentrations (with solvent viscosity ratio varied from 0.2 to 0.9, extensibility parameters (100≤L2≤500, Reynolds numbers (0.1 ≤ Re ≤ 100, and Weissenberg numbers (0 ≤ Wi ≤ 20 are conducted on unsteady laminar flows through a symmetric planar sudden expansion with expansion ratio of 1: 3 for viscoelastic fluid flows. The constitutive model used to describe the viscoelastic effect of viscoelastic fluid flow is FENE-P (finitely extensive nonlinear elastic-Peterlin model. The numerical simulation results show that the influences of elasticity, inertia, and concentration on the flow bifurcation characteristics are more significant than those of extensibility. The present simulation results including the critical Reynolds number for which the flow becomes asymmetric, vortex size, bifurcation diagram, velocity distribution, streamline, and pressure loss show good agreements with some published results. That means the newly established method based on FLUENT software platform for simulating peculiar flow behaviors of viscoelastic fluid is credible and suitable for the study of viscoelastic fluid flows.

  18. Distinctive functions of Syk N-terminal and C-terminal SH2 domains in the signaling cascade elicited by oxidative stress in B cells.

    Science.gov (United States)

    Ding, J; Takano, T; Hermann, P; Gao, S; Han, W; Noda, C; Yanagi, S; Yamamura, H

    2000-05-01

    Syk plays a crucial role in the transduction of oxidative stress signaling. In this paper, we investigated the roles of Src homology 2 (SH2) domains of Syk in oxidative stress signaling, using Syk-negative DT40 cells expressing the N- or C-terminal SH2 domain mutant [mSH2(N) or mSH2(C)] of Syk. Tyrosine phosphorylation of Syk in cells expressing mSH2(N) Syk after H(2)O(2) treatment was higher than that in cells expressing wild-type Syk or mSH2(C) Syk. The tyrosine phosphorylation of wild-type Syk and mSH2(C) Syk, but not that of mSH2(N), was sensitive to PP2, a specific inhibitor of Src-family protein-tyrosine kinase. In oxidative stress, the C-terminal SH2 domain of Syk was demonstrated to be required for induction of tyrosine phosphorylation of cellular proteins, phospholipase C (PLC)-gamma2 phosphorylation, inositol 1,4, 5-triphosphate (IP(3)) generation, Ca(2)(+) release from intracellular stores, and c-Jun N-terminal kinase activation. In contrast, in mSH2(N) Syk-expressing cells, tyrosine phosphorylation of intracellular proteins including PLC-gamma2 was markedly induced in oxidative stress. The enhanced phosphorylation of mSH2(N) Syk and PLC-gamma2, however, did not link to Ca(2)(+) mobilization from intracellular pools and IP(3) generation. Thus, the N- and C-terminal SH2 domains of Syk possess distinctive functions in oxidative stress signaling.

  19. Identification and functional analysis of three distinct mutations in the human galactose-1-phosphate uridyltransferase gene associated with galactosemia in a single family

    Energy Technology Data Exchange (ETDEWEB)

    Fridovich-Keil, J.L.; Langley, S.D.; Mazur, L.A.; Lennon, J.C.; Dembure, P.O.; Elsas, L.J. II [Emory Univ. School of Medicine, Atlanta, GA (United States)

    1995-03-01

    We have identified three mutations associated with transferase-deficiency galactosemia in a three-generation family including affected members in two generations and have modeled all three mutations in a yeast-expression system. A sequence of pedigree, biochemical, and molecular analyses of the galactose-1-phosphate uridyltransferase (GALT) enzyme and genetic locus in both affected and carrier individuals revealed three distinct base substitutions in this family, two (Q188R and S135L) that had been reported previously and one (V151A) that was novel. Biochemical analyses of red-blood-cell lysates from the relevant family members suggested that each of these mutations was associated with dramatic impairment of GALT activity in these cells. While this observation was consistent with our previous findings concerning the Q188R mutation expressed both in humans and in a yeast-model system, it was at odds with a report by Reichardt and colleagues, indicating that in their COS cell-expression system the S135L substitution behaved as a neutral polymorphism. To address this apparent paradox, as well as to investigate the functional significance of the newly identified V151A substitution, all three mutations were recreated by site-directed mutagenesis of the otherwise wild-type human GALT sequence and were expressed both individually and in the appropriate allelic combinations in a GALT-deficient strain of the yeast Saccharomyces cerevisiae. The results of these yeast-modeling studies were fully consistent with the patient data, leading us to conclude that, at least within the context of the cell types studied, in the homozygous state Q188R is a mutation that eliminates GALT activity, and S135L and V151A are both mutations that impair GALT activity to <6% of wild-type values. 22 refs., 5 figs.

  20. Antigen presentation by resting B cells. Radiosensitivity of the antigen-presentation function and two distinct pathways of T cell activation

    International Nuclear Information System (INIS)

    Ashwell, J.D.; DeFranco, A.L.; Paul, W.E.; Schwartz, R.H.

    1984-01-01

    In this report we have examined the ability of small resting B cells to act as antigen-presenting cells (APC) to antigen-specific MHC-restricted T cells as assessed by either T cell proliferation or T cell-dependent B cell stimulation. We found that 10 of 14 in vitro antigen-specific MHC-restricted T cell clones and lines and three of four T cell hybridomas could be induced to either proliferate or secrete IL-2 in the presence of lightly irradiated (1,000 rads) purified B cells and the appropriate foreign antigen. All T cell lines and hybridomas were stimulated to proliferate or make IL-2 by macrophage- and dendritic cell-enriched populations and all T cells tested except one hybridoma caused B cell activation when stimulated with B cells as APC. Furthermore, lightly irradiated, highly purified syngeneic B cells were as potent a source of APC for inducing B cell activation as were low density dendritic and macrophage-enriched cells. Lymph node T cells freshly taken from antigen-primed animals were also found to proliferate when cultured with purified B cells and the appropriate antigen. This APC function was easily measured when the cells were irradiated with 1,000 rads, but was greatly diminished or absent when they were irradiated with 3,300 rads. In addition, this radiosensitivity allowed us to easily distinguish B cell antigen presentation from presentation by the dendritic cell and macrophage, as the latter was resistant to 3,300 rads. Finally, one T cell clone that failed to proliferate when B cells were used as APC was able to recruit allogeneic B cells to proliferate in the presence of syngeneic B cells and the appropriate antigen. This result suggests that there are at least two distinct pathways of activation in T cells, one that leads to T cell proliferation and one that leads to the secretion of B cell recruitment factor(s)

  1. Supraspliceosomes at Defined Functional States Portray the Pre-Assembled Nature of the Pre-mRNA Processing Machine in the Cell Nucleus

    Directory of Open Access Journals (Sweden)

    Hani Kotzer-Nevo

    2014-06-01

    Full Text Available When isolated from mammalian cell nuclei, all nuclear pre-mRNAs are packaged in multi-subunit large ribonucleoprotein complexes—supraspliceosomes—composed of four native spliceosomes interconnected by the pre-mRNA. Supraspliceosomes contain all five spliceosomal U snRNPs, together with other splicing factors, and are functional in splicing. Supraspliceosomes studied thus far represent the steady-state population of nuclear pre-mRNAs that were isolated at different stages of the splicing reaction. To analyze specific splicing complexes, here, we affinity purified Pseudomonas aeruginosa phage 7 (PP7-tagged splicing complexes assembled in vivo on Adenovirus Major Late (AdML transcripts at specific functional stages, and characterized them using molecular techniques including mass spectrometry. First, we show that these affinity purified splicing complexes assembled on PP7-tagged AdML mRNA or on PP7-tagged AdML pre-mRNA are assembled in supraspliceosomes. Second, similar to the general population of supraspliceosomes, these defined supraspliceosomes populations are assembled with all five U snRNPs at all splicing stages. This study shows that dynamic changes in base-pairing interactions of U snRNA:U snRNA and U snRNA:pre-mRNA that occur in vivo during the splicing reaction do not require changes in U snRNP composition of the supraspliceosome. Furthermore, there is no need to reassemble a native spliceosome for the splicing of each intron, and rearrangements of the interactions will suffice.

  2. Selective Assembly of Na,K-ATPase α2β2 Heterodimers in the Heart: DISTINCT FUNCTIONAL PROPERTIES AND ISOFORM-SELECTIVE INHIBITORS.

    Science.gov (United States)

    Habeck, Michael; Tokhtaeva, Elmira; Nadav, Yotam; Ben Zeev, Efrat; Ferris, Sean P; Kaufman, Randal J; Bab-Dinitz, Elizabeta; Kaplan, Jack H; Dada, Laura A; Farfel, Zvi; Tal, Daniel M; Katz, Adriana; Sachs, George; Vagin, Olga; Karlish, Steven J D

    2016-10-28

    The Na,K-ATPase α 2 subunit plays a key role in cardiac muscle contraction by regulating intracellular Ca 2+ , whereas α 1 has a more conventional role of maintaining ion homeostasis. The β subunit differentially regulates maturation, trafficking, and activity of α-β heterodimers. It is not known whether the distinct role of α 2 in the heart is related to selective assembly with a particular one of the three β isoforms. We show here by immunofluorescence and co-immunoprecipitation that α 2 is preferentially expressed with β 2 in T-tubules of cardiac myocytes, forming α 2 β 2 heterodimers. We have expressed human α 1 β 1 , α 2 β 1 , α 2 β 2 , and α 2 β 3 in Pichia pastoris, purified the complexes, and compared their functional properties. α 2 β 2 and α 2 β 3 differ significantly from both α 2 β 1 and α 1 β 1 in having a higher K 0.5 K + and lower K 0.5 Na + for activating Na,K-ATPase. These features are the result of a large reduction in binding affinity for extracellular K + and shift of the E 1 P-E 2 P conformational equilibrium toward E 1 P. A screen of perhydro-1,4-oxazepine derivatives of digoxin identified several derivatives (e.g. cyclobutyl) with strongly increased selectivity for inhibition of α 2 β 2 and α 2 β 3 over α 1 β 1 (range 22-33-fold). Molecular modeling suggests a possible basis for isoform selectivity. The preferential assembly, specific T-tubular localization, and low K + affinity of α 2 β 2 could allow an acute response to raised ambient K + concentrations in physiological conditions and explain the importance of α 2 β 2 for cardiac muscle contractility. The high sensitivity of α 2 β 2 to digoxin derivatives explains beneficial effects of cardiac glycosides for treatment of heart failure and potential of α 2 β 2 -selective digoxin derivatives for reducing cardiotoxicity. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Human T cell leukemia/lymphoma virus type I infection of a CD4+ proliferative/cytotoxic T cell clone progresses in at least two distinct phases based on changes in function and phenotype of the infected cells

    NARCIS (Netherlands)

    Yssel, H.; de Waal Malefyt, R.; Duc Dodon, M. D.; Blanchard, D.; Gazzolo, L.; de Vries, J. E.; Spits, H.

    1989-01-01

    The effect of human T cell leukemia/lymphoma virus type I (HTLV-I) infection on the function and the phenotype of a human proliferating/cytotoxic T cell clone, specific for tetanus toxin, was investigated. During the period after infection, two distinct phases were observed, based on growth

  4. Fetal cardiac function in late-onset intrauterine growth restriction vs small-for-gestational age, as defined by estimated fetal weight, cerebroplacental ratio and uterine artery Doppler.

    Science.gov (United States)

    Pérez-Cruz, M; Cruz-Lemini, M; Fernández, M T; Parra, J A; Bartrons, J; Gómez-Roig, M D; Crispi, F; Gratacós, E

    2015-10-01

    Among late-onset small fetuses, a combination of estimated fetal weight (EFW), cerebroplacental ratio (CPR) and mean uterine artery (UtA) pulsatility index (PI) can predict a subgroup of fetuses with poor perinatal outcome; however, the association of these criteria with fetal cardiac structure and function is unknown. Our aim was to determine the presence and severity of signs indicating cardiac dysfunction in small fetuses, classified as intrauterine growth-restricted (IUGR) or small-for-gestational age (SGA), according to EFW, CPR and UtA-PI. A cohort of 209 late-onset small fetuses that were delivered > 34 weeks of gestation was divided in two categories: SGA (n = 59) if EFW was between the 3(rd) and 9(th) centiles with normal CPR and UtA-PI; and IUGR (n = 150) if EFW was  95(th) centile. The small population was compared with 150 appropriately grown fetuses (controls). Fetal cardiac morphometry and function were assessed by echocardiography using two-dimensional M-mode, conventional and tissue Doppler. Compared with controls, both IUGR and SGA fetuses showed larger and more globular hearts (mean left sphericity index ± SD: controls, 1.8 ± 0.3; SGA, 1.5 ± 0.2; and IUGR, 1.6 ± 0.3; P < 0.01) and showed signs of systolic and diastolic dysfunction, including decreased tricuspid annular plane systolic excursion (mean ± SD: controls, 8.2 ± 1.1; SGA, 7.4 ± 1.2; and IUGR, 6.9 ± 1.1; P < 0.001) and increased left myocardial performance index (mean ± SD: controls, 0.45 ± 0.14; SGA, 0.51 ± 0.08; and IUGR, 0.57 ± 0.1; P < 0.001). Despite a perinatal outcome comparable to that of normal fetuses, the population of so-defined SGA fetuses showed signs of prenatal cardiac dysfunction. This supports the concept that at least a proportion of them are not 'constitutionally small' and that further research is needed. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

  5. Defining how aging Pseudotsuga and Abies compensate for multiple stresses through multi-criteria assessment of a functional-structural model

    Science.gov (United States)

    Maureen C. Kennedy; E. David Ford; Thomas M. Hinckley

    2009-01-01

    Many hypotheses have been advanced about factors that control tree longevity. We use a simulation model with multi-criteria optimization and Pareto optimality to determine branch morphologies in the Pinaceae that minimize the effect of growth limitations due to water stress while simultaneously maximizing carbohydrate gain. Two distinct branch morphologies in the...

  6. Quantum Distinction: Quantum Distinctiones!

    OpenAIRE

    Zeps, Dainis

    2009-01-01

    10 pages; How many distinctions, in Latin, quantum distinctiones. We suggest approach of anthropic principle based on anthropic reference system which should be applied equally both in theoretical physics and in mathematics. We come to principle that within reference system of life subject of mathematics (that of thinking) should be equated with subject of physics (that of nature). For this reason we enter notions of series of distinctions, quantum distinction, and argue that quantum distinct...

  7. Are there two forms of isometric muscle action? Results of the experimental study support a distinction between a holding and a pushing isometric muscle function.

    Science.gov (United States)

    Schaefer, Laura V; Bittmann, Frank N

    2017-01-01

    In isometric muscle function, there are subjectively two different modes of performance: one can either hold isometrically - thus resist an impacting force - or push isometrically - therefore work against a stable resistance. The purpose of this study is to investigate whether or not two different isometric muscle actions - the holding vs. pushing one (HIMA vs PIMA) - can be distinguished by objective parameters. Ten subjects performed two different measuring modes at 80% of MVC realized by a special pneumatic system. During HIMA the subject had to resist the defined impacting force of the pneumatic system in an isometric position, whereby the force of the cylinder works in direction of elbow flexion against the subject. During PIMA the subject worked isometrically in direction of elbow extension against a stable position of the system. The signals of pressure, force, acceleration and mechanomyography/-tendography (MMG/MTG) of the elbow extensor (MMGtri/MTGtri) and the abdominal muscle (MMGobl) were recorded and evaluated concerning the duration of maintaining the force level (force endurance) and the characteristics of MMG-/MTG-signals. Statistical group differences comparing HIMA vs. PIMA were estimated using SPSS. Significant differences between HIMA and PIMA were especially apparent regarding the force endurance: During HIMA the subjects showed a decisively shorter time of stable isometric position (19 ± 8 s) in comparison with PIMA (41 ± 24 s; p  = .005). In addition, during PIMA the longest isometric plateau amounted to 59.4% of the overall duration time of isometric measuring, during HIMA it lasted 31.6% ( p  = .000). The frequency of MMG/MTG did not show significant differences. The power in the frequency ranges of 8-15 Hz and 10-29 Hz was significantly higher in the MTGtri performing HIMA compared to PIMA (but not for the MMGs). The amplitude of MMG/MTG did not show any significant difference considering the whole measurement. However

  8. Stat5 Exerts Distinct, Vital Functions in the Cytoplasm and Nucleus of Bcr-Abl{sup +} K562 and Jak2(V617F){sup +} HEL Leukemia Cells

    Energy Technology Data Exchange (ETDEWEB)

    Weber, Axel [Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main 60596 (Germany); Borghouts, Corina [Ganymed Pharmaceuticals AG, Mainz 55131 (Germany); Brendel, Christian [Boston Children’s Hospital, Division of Hematology/Oncology, Boston, MA 02115 (United States); Moriggl, Richard [Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna 1090 (Austria); Delis, Natalia; Brill, Boris; Vafaizadeh, Vida; Groner, Bernd, E-mail: Groner@em.uni-frankfurt.de [Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main 60596 (Germany)

    2015-03-19

    Signal transducers and activators of transcription (Stats) play central roles in the conversion of extracellular signals, e.g., cytokines, hormones and growth factors, into tissue and cell type specific gene expression patterns. In normal cells, their signaling potential is strictly limited in extent and duration. The persistent activation of Stat3 or Stat5 is found in many human tumor cells and contributes to their growth and survival. Stat5 activation plays a pivotal role in nearly all hematological malignancies and occurs downstream of oncogenic kinases, e.g., Bcr-Abl in chronic myeloid leukemias (CML) and Jak2(V617F) in other myeloproliferative diseases (MPD). We defined the mechanisms through which Stat5 affects growth and survival of K562 cells, representative of Bcr-Abl positive CML, and HEL cells, representative for Jak2(V617F) positive acute erythroid leukemia. In our experiments we suppressed the protein expression levels of Stat5a and Stat5b through shRNA mediated downregulation and demonstrated the dependence of cell survival on the presence of Stat5. Alternatively, we interfered with the functional capacities of the Stat5 protein through the interaction with a Stat5 specific peptide ligand. This ligand is a Stat5 specific peptide aptamer construct which comprises a 12mer peptide integrated into a modified thioredoxin scaffold, S5-DBD-PA. The peptide sequence specifically recognizes the DNA binding domain (DBD) of Stat5. Complex formation of S5-DBD-PA with Stat5 causes a strong reduction of P-Stat5 in the nuclear fraction of Bcr-Abl-transformed K562 cells and a suppression of Stat5 target genes. Distinct Stat5 mediated survival mechanisms were detected in K562 and Jak2(V617F)-transformed HEL cells. Stat5 is activated in the nuclear and cytosolic compartments of K562 cells and the S5-DBD-PA inhibitor most likely affects the viability of Bcr-Abl{sup +} K562 cells through the inhibition of canonical Stat5 induced target gene transcription. In HEL cells

  9. Gene expression profiling of two distinct neuronal populations in the rodent spinal cord

    DEFF Research Database (Denmark)

    Ryge, Jesper; Westerdahl, Ann Charlotte; Alstøm, Preben

    2008-01-01

    Background: In the field of neuroscience microarray gene expression profiles on anatomically defined brain structures are being used increasingly to study both normal brain functions as well as pathological states. Fluorescent tracing techniques in brain tissue that identifies distinct neuronal p...

  10. Estimation of an image derived input function with MR-defined carotid arteries in FDG-PET human studies using a novel partial volume correction method

    DEFF Research Database (Denmark)

    Sari, Hasan; Erlandsson, Kjell; Law, Ian

    2017-01-01

    Kinetic analysis of18F-fluorodeoxyglucose positron emission tomography data requires an accurate knowledge the arterial input function. The gold standard method to measure the arterial input function requires collection of arterial blood samples and is an invasive method. Measuring an image deriv...... input function (p > 0.12 for grey matter and white matter). Hence, the presented image derived input function extraction method can be a practical alternative to noninvasively analyze dynamic18F-fluorodeoxyglucose data without the need for blood sampling....

  11. Validity of premature ejaculation diagnostic tool and its association with International Index of Erectile Function-15 in Chinese men with evidence-based-defined premature ejaculation

    Directory of Open Access Journals (Sweden)

    Dong-Dong Tang

    2018-01-01

    Full Text Available The premature ejaculation diagnostic tool (PEDT is a brief diagnostic measure to assess premature ejaculation (PE. However, there is insufficient evidence regarding its validity in the new evidence-based-defined PE. This study was performed to evaluate the validity of PEDT and its association with IIEF-15 in different types of evidence-based-defined PE. From June 2015 to January 2016, a total of 260 men complaining of PE and defined as lifelong PE (LPE/acquired PE (APE according to the evidence-based definition from Andrology Clinic of the First Affiliated Hospital of Anhui Medical University, along with 104 male healthy controls without PE from a medical examination center, were enrolled in this study. All individuals completed questionnaires including demographics, medical and sexual history, as well as PEDT and IIEF-15. After statistical analysis, it was found that men with PE reported higher PEDT scores (14.28 ± 3.05 and lower IIEF-15 (41.26 ± 8.20 than men without PE (PEDT: 5.32 ± 3.42, IIEF-15: 52.66 ± 6.86, P < 0.001 for both. It was suggested that a score of ≥9 indicated PE in both LPE and APE by sensitivity and specificity analyses (sensitivity: 0.875, 0.913; specificity: 0.865, 0.865, respectively. In addition, IIEF-15 were higher in men with LPE (42.64 ± 8.11 than APE (39.43 ± 7.84, P < 0.001. After adjusting for age, IIEF-15 was negatively related to PEDT in men with LPE (adjust r = −0.225, P < 0.001 and APE (adjust r = −0.378, P < 0.001. In this study, we concluded that PEDT was valid in the diagnosis of evidenced-based-defined PE. Furthermore, IIEF-15 was negatively related to PEDT in men with different types of PE.

  12. Some Generalized Lacunary statistically difference double semi-normed sequence spaces defined by Orlicz function - doi: 10.4025/actascitechnol.v35i1.15523

    Directory of Open Access Journals (Sweden)

    Ayhan Esi

    2013-01-01

    Full Text Available In this article, we have introduced the idea of statistically convergent generalized difference lacunary double sequence spaces [¯w2 (M, Δn, p,q]θ, [¯w2 (M, Δn, p,q]θ and defined over a semi norm space (X, q. Also we have study some basic properties and obtained some inclusion relations between them.  

  13. PRM1 and KAR5 function in cell-cell fusion and karyogamy to drive distinct bisexual and unisexual cycles in the Cryptococcus pathogenic species complex.

    Directory of Open Access Journals (Sweden)

    Ci Fu

    2017-11-01

    events. Taken together, our findings suggest distinct mating mechanisms for unisexual and bisexual reproduction in Cryptococcus, exemplifying distinct evolutionary trajectories within this pathogenic species complex.

  14. Defining the Interactions of Cellobiohydrolase with Substrate through Structure Function Studies: Cooperative Research and Development Final Report, CRADA Number CRD-10-409

    Energy Technology Data Exchange (ETDEWEB)

    Beckham, G. T.; Himmel, M. E.

    2013-07-01

    NREL researchers will use their expertise and skilled resources in numerical computational modeling to generate structure-function relationships for improved cellulase variant enzymes to support the development of cellulases with improved performance in biomass conversion.

  15. Survival of the most transferable at the top of Jacob's ladder: Defining and testing the ωB97M(2) double hybrid density functional

    Science.gov (United States)

    Mardirossian, Narbe; Head-Gordon, Martin

    2018-06-01

    A meta-generalized gradient approximation, range-separated double hybrid (DH) density functional with VV10 non-local correlation is presented. The final 14-parameter functional form is determined by screening trillions of candidate fits through a combination of best subset selection, forward stepwise selection, and random sample consensus (RANSAC) outlier detection. The MGCDB84 database of 4986 data points is employed in this work, containing a training set of 870 data points, a validation set of 2964 data points, and a test set of 1152 data points. Following an xDH approach, orbitals from the ωB97M-V density functional are used to compute the second-order perturbation theory correction. The resulting functional, ωB97M(2), is benchmarked against a variety of leading double hybrid density functionals, including B2PLYP-D3(BJ), B2GPPLYP-D3(BJ), ωB97X-2(TQZ), XYG3, PTPSS-D3(0), XYGJ-OS, DSD-PBEP86-D3(BJ), and DSD-PBEPBE-D3(BJ). Encouragingly, the overall performance of ωB97M(2) on nearly 5000 data points clearly surpasses that of all of the tested density functionals. As a Rung 5 density functional, ωB97M(2) completes our family of combinatorially optimized functionals, complementing B97M-V on Rung 3, and ωB97X-V and ωB97M-V on Rung 4. The results suggest that ωB97M(2) has the potential to serve as a powerful predictive tool for accurate and efficient electronic structure calculations of main-group chemistry.

  16. Using the Positive and Negative Syndrome Scale (PANSS) to Define Different Domains of Negative Symptoms: Prediction of Everyday Functioning by Impairments in Emotional Expression and Emotional Experience

    OpenAIRE

    Harvey, Philip D.; Khan, Anzalee; Keefe, Richard S. E.

    2017-01-01

    Background: Reduced emotional experience and expression are two domains of negative symptoms. The authors assessed these two domains of negative symptoms using previously developed Positive and Negative Syndrome Scale (PANSS) factors. Using an existing dataset, the authors predicted three different elements of everyday functioning (social, vocational, and everyday activities) with these two factors, as well as with performance on measures of functional capacity. Methods: A large (n=630) sampl...

  17. Rehabilitation of executive functioning with training in attention regulation applied to individually defined goals: a pilot study bridging theory, assessment, and treatment.

    Science.gov (United States)

    Novakovic-Agopian, Tatjana; Chen, Anthony J-W; Rome, Scott; Abrams, Gary; Castelli, Holli; Rossi, Annemarie; McKim, Ryan; Hills, Nancy; D'Esposito, Mark

    2011-01-01

    To assess feasibility and effects of training in goal-oriented attentional self-regulation for patients with brain injury and chronic executive dysfunction. Sixteen individuals with chronic brain injury and mild to moderate executive dysfunction. Participants were divided into 2 groups: one group completed goal-oriented attentional self-regulation training during the first 5 weeks, followed by a brief (2-hour) educational instruction session as a control midway through the second 5 weeks; the other group participated in reverse order. Neuropsychological and functional performance assessed at baseline and at weeks 5 and 10. Participants found training in goal-oriented attentional self-regulation engaging, incorporated some trained strategies into daily life, and reported subjective improvements in personal functioning. At week 5, participants who completed goals training significantly improved on tests of attention and executive function and had fewer functional task failures, while performance did not change after educational instruction. At week 10, participants who crossed over from educational instruction to goals training also significantly improved on attention and executive function tests. Participants who crossed from goals training to educational instruction maintained their week 5 gains. Training in goal-oriented attentional self-regulation is theoretically driven and feasible in a research setting. Pilot results suggest improvements in cognitive and functional domains targeted by the intervention.

  18. Selection of functional 2A sequences within foot-and-mouth disease virus; requirements for the NPGP motif with a distinct codon bias.

    Science.gov (United States)

    Kjær, Jonas; Belsham, Graham J

    2018-01-01

    Foot-and-mouth disease virus (FMDV) has a positive-sense ssRNA genome including a single, large, open reading frame. Splitting of the encoded polyprotein at the 2A/2B junction is mediated by the 2A peptide (18 residues long), which induces a nonproteolytic, cotranslational "cleavage" at its own C terminus. A conserved feature among variants of 2A is the C-terminal motif N 16 P 17 G 18 /P 19 , where P 19 is the first residue of 2B. It has been shown previously that certain amino acid substitutions can be tolerated at residues E 14 , S 15 , and N 16 within the 2A sequence of infectious FMDVs, but no variants at residues P 17 , G 18 , or P 19 have been identified. In this study, using highly degenerate primers, we analyzed if any other residues can be present at each position of the NPG/P motif within infectious FMDV. No alternative forms of this motif were found to be encoded by rescued FMDVs after two, three, or four passages. However, surprisingly, a clear codon preference for the wt nucleotide sequence encoding the NPGP motif within these viruses was observed. Indeed, the codons selected to code for P 17 and P 19 within this motif were distinct; thus the synonymous codons are not equivalent. © 2018 Kjær and Belsham; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  19. Distinct roles of autophagy-dependent and -independent functions of FIP200 revealed by generation and analysis of a mutant knock-in mouse model

    Science.gov (United States)

    Chen, Song; Wang, Chenran; Yeo, Syn; Liang, Chun-Chi; Okamoto, Takako; Sun, Shaogang; Wen, Jian; Guan, Jun-Lin

    2016-01-01

    Autophagy is an evolutionarily conserved cellular process controlled through a set of essential autophagy genes (Atgs). However, there is increasing evidence that most, if not all, Atgs also possess functions independent of their requirement in canonical autophagy, making it difficult to distinguish the contributions of autophagy-dependent or -independent functions of a particular Atg to various biological processes. To distinguish these functions for FIP200 (FAK family-interacting protein of 200 kDa), an Atg in autophagy induction, we examined FIP200 interaction with its autophagy partner, Atg13. We found that residues 582–585 (LQFL) in FIP200 are required for interaction with Atg13, and mutation of these residues to AAAA (designated the FIP200-4A mutant) abolished its canonical autophagy function in vitro. Furthermore, we created a FIP200-4A mutant knock-in mouse model and found that specifically blocking FIP200 interaction with Atg13 abolishes autophagy in vivo, providing direct support for the essential role of the ULK1/Atg13/FIP200/Atg101 complex in the process beyond previous studies relying on the complete knockout of individual components. Analysis of the new mouse model showed that nonautophagic functions of FIP200 are sufficient to fully support embryogenesis by maintaining a protective role in TNFα-induced apoptosis. However, FIP200-mediated canonical autophagy is required to support neonatal survival and tumor cell growth. These studies provide the first genetic evidence linking an Atg's autophagy and nonautophagic functions to different biological processes in vivo. PMID:27013233

  20. The physiological basis of Glottal electromagnetic micropower sensors (GEMS) and their use in defining an excitation function for the human vocal tract

    Science.gov (United States)

    Burnett, Gregory Clell

    1999-10-01

    The definition, use, and physiological basis of Glottal Electromagnetic Micropower Sensors (GEMS) is presented. These sensors are a new type of low power (excitation function for the human vocal tract. For the first time, an excitation function may be calculated in near real time using a noninvasive procedure. Several experiments and models are presented to demonstrate that the GEMS signal is representative of the motion of the subglottal posterior wall of the trachea as it vibrates in response to the pressure changes caused by the folds as they modulate the airflow supplied by the lungs. The vibrational properties of the tracheal wall are modeled using a lumped-element circuit model. Taking the output of the vocal tract to be the audio pressure captured by a microphone and the input to be the subglottal pressure, the transfer function of the vocal tract (including the nasal cavities) can be approximated every 10-30 milliseconds using an autoregressive moving-average model. Unlike the currently utilized method of transfer function approximation, this new method only involves noninvasive GEMS measurements and digital signal processing and does not demand the difficult task of obtaining precise physical measurements of the tract and subsequent estimation of the transfer function using its cross-sectional area. The ability to measure the physical motion of the trachea enables a significant number of potential applications, ranging from very accurate pitch detection to speech synthesis, speaker verification, and speech recognition.

  1. Overexpression of three TaEXPA1 homoeologous genes with distinct expression divergence in hexaploid wheat exhibit functional retention in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Zhaorong Hu

    Full Text Available Common wheat is a hexaploid species with most of the genes present as triplicate homoeologs. Expression divergences of homoeologs are frequently observed in wheat as well as in other polyploid plants. However, little is known about functional variances among homologous genes arising from polyploidy. Expansins play diverse roles in plant developmental processes related to the action of cell wall loosening. Expression of the three TaEXPA1 homoeologs varied dynamically at different stages and organs, and epigenetic modifications contribute to the expression divergence of three TaEXPA1 homoeologs during wheat development. Nevertheless, their functions remain to be clarified. We found that over expression of TaEXPA1-A, -B and -D produced similar morphological changes in transgenic Arabidopsis plants, including increased germination and growth rate during seedling and adult stages, indicating that the proteins encoded by these three wheat TaEXPA1 homoeologs have similar (or conserved functions in Arabidopsis. Collectively, our present study provided an example of a set of homoeologous genes expression divergence in different developmental stages and organs in hexaploid wheat but functional retention in transgenic Arabidopsis plants.

  2. Clinical and functional results of laparoscopic intersphincteric resection for ultralow rectal cancer: is there a distinction between the three types of hand-sewn colo-anal anastomosis?

    Science.gov (United States)

    Zhang, Bin; Zhao, Ke; Liu, Quanlong; Yin, Shuhui; Zhuo, Guangzuan; Zhao, Yujuan; Zhu, Jun; Ding, Jianhua

    2017-04-01

    The purpose of this study is to compare the clinical and functional outcomes of three types of hand-sewn colo-anal anastomosis (CAA) after laparoscopic intersphincteric resection (Lap-ISR) for patients with ultralow rectal cancer. A total of 79 consecutive patients treated by Lap-ISR for low-lying rectal cancer in an academic medical center from June 2011 to February 2016. According to the distal tumor margin and individualized anal length, the patients underwent three types of hand-sewn CAA including partial-ISR, subtotal-ISR, and total-ISR. Of the 79 patients, 35.4% required partial-ISR, 43% adopted subtotal-ISR, and 21.5% underwent total-ISR. R0 resection was achieved in 78 patients (98.7%). In addition to distal resection margin, there were no significant differences in clinicopathological parameters and postoperative complications between the three groups. The type of hand-sewn CAA did not influence the 3-year disease-free survival (DFS) or local relapse-free survival (LFS). At 24-months follow-up, in spite of higher incontinence scores in total-ISR group, there were not statistically significant differences in functional outcomes including Wexner score or Kirwan grade between the groups. Nevertheless, patients with chronic anastomotic stricture showed worse anal function than those without the complication. The type of hand-sewn CAA after Lap-ISR may not influence oncological and functional outcomes, but chronic stricture deteriorates continence status.

  3. Phenotypically and functionally distinct CD8+ lymphocyte populations in long-term drug-free tolerance and chronic rejection in human kidney graft recipients

    NARCIS (Netherlands)

    Baeten, Dominique; Louis, Stéphanie; Braud, Christophe; Braudeau, Cécile; Ballet, Caroline; Moizant, Frédéric; Pallier, Annaik; Giral, Magali; Brouard, Sophie; Soulillou, Jean-Paul

    2006-01-01

    A substantial proportion of long-term kidney graft recipients, including those with a stable renal function in the absence of immunosuppressive therapy, present a skewed T cell receptor (TCR) Vbeta chain usage, essentially in the CD8+ subset. This study analyzed in more detail phenotypical and

  4. Using the Positive and Negative Syndrome Scale (PANSS) to Define Different Domains of Negative Symptoms: Prediction of Everyday Functioning by Impairments in Emotional Expression and Emotional Experience.

    Science.gov (United States)

    Harvey, Philip D; Khan, Anzalee; Keefe, Richard S E

    2017-12-01

    Background: Reduced emotional experience and expression are two domains of negative symptoms. The authors assessed these two domains of negative symptoms using previously developed Positive and Negative Syndrome Scale (PANSS) factors. Using an existing dataset, the authors predicted three different elements of everyday functioning (social, vocational, and everyday activities) with these two factors, as well as with performance on measures of functional capacity. Methods: A large (n=630) sample of people with schizophrenia was used as the data source of this study. Using regression analyses, the authors predicted the three different aspects of everyday functioning, first with just the two Positive and Negative Syndrome Scale factors and then with a global negative symptom factor. Finally, we added neurocognitive performance and functional capacity as predictors. Results: The Positive and Negative Syndrome Scale reduced emotional experience factor accounted for 21 percent of the variance in everyday social functioning, while reduced emotional expression accounted for no variance. The total Positive and Negative Syndrome Scale negative symptom factor accounted for less variance (19%) than the reduced experience factor alone. The Positive and Negative Syndrome Scale expression factor accounted for, at most, one percent of the variance in any of the functional outcomes, with or without the addition of other predictors. Implications: Reduced emotional experience measured with the Positive and Negative Syndrome Scale, often referred to as "avolition and anhedonia," specifically predicted impairments in social outcomes. Further, reduced experience predicted social impairments better than emotional expression or the total Positive and Negative Syndrome Scale negative symptom factor. In this cross-sectional study, reduced emotional experience was specifically related with social outcomes, accounting for essentially no variance in work or everyday activities, and being the

  5. Synthesis and functions of well-defined polymer-drug conjugates as efficient nanocarriers for intravesical chemotherapy of bladder cancer(a).

    Science.gov (United States)

    Yu, Qingsong; Zhang, Jiajing; Zhang, Guan; Gan, Zhihua

    2015-04-01

    Novel poly(ethylene glycol) and poly(N-(2-hydroxypropyl)methacrylamide) block copolymer (PEG-b-PHPMA) with well-defined composition was synthesized by RAFT polymerization. Folate and doxorubicin (DOX) were quantitatively introduced into the copolymer. The influences of folate content and pH value on folate receptor (FR) mediated cell endocytosis and pH-responsive DOX release were studied. It has been demonstrated that minimum folate content is needed for the enrichment of hydrophobic folate on the hydrophilic part of polymer conjugates. The cytotoxicity of targetable polymer drug conjugates was much higher than that of non-targetable ones and free DOX. It could be concluded that the folate plays a significant role in targeting and internalization of the conjugates against bladder cancer cells. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. The bottom-up approach to defining life : deciphering the functional organization of biological cells via multi-objective representation of biological complexity from molecules to cells

    Directory of Open Access Journals (Sweden)

    Sathish ePeriyasamy

    2013-12-01

    Full Text Available In silico representation of cellular systems needs to represent the adaptive dynamics of biological cells, recognizing a cell’s multi-objective topology formed by spatially and temporally cohesive intracellular structures. The design of these models needs to address the hierarchical and concurrent nature of cellular functions and incorporate the ability to self-organise in response to transitions between healthy and pathological phases, and adapt accordingly. The functions of biological systems are constantly evolving, due to the ever changing demands of their environment. Biological systems meet these demands by pursuing objectives, aided by their constituents, giving rise to biological functions. A biological cell is organised into an objective/task hierarchy. These objective hierarchy corresponds to the nested nature of temporally cohesive structures and representing them will facilitate in studying pleiotropy and polygeny by modeling causalities propagating across multiple interconnected intracellular processes. Although biological adaptations occur in physiological, developmental and reproductive timescales, the paper is focused on adaptations that occur within physiological timescales, where the biomolecular activities contributing to functional organisation, play a key role in cellular physiology. The paper proposes a multi-scale and multi-objective modelling approach from the bottom-up by representing temporally cohesive structures for multi-tasking of intracellular processes. Further the paper characterises the properties and constraints that are consequential to the organisational and adaptive dynamics in biological cells.

  7. Defining the stenotic post-laryngectomy tracheostoma and its impact on the quality of life in laryngectomees: development and validation of a stoma function questionnaire.

    Science.gov (United States)

    Paleri, V; Wight, R G; Owen, S; Hurren, A; Stafford, F W

    2006-10-01

    The aims of this study were to identify if: (i) size of stoma contributes to quality of life (QoL) in laryngectomees; (ii) stoma size has an impact on routine stoma care and function; and (iii) an optimal stoma size exists below which patients experience stoma problems. Cross-sectional study of laryngectomees. Two tertiary care centres. Fifty-seven patients who had undergone total laryngectomy one to five years ago and using tracheo-oesophageal speech as their primary communication means. Three main measures were studied: 1 a new study specific questionnaire designed to assess problems with function and care of the end tracheosto- ma; 2 QoL as assessed by the head and neck QoL instrument; 3 a precision custom designed sizer to measure the minimum stoma diameter. The final study-specific questionnaire contained four items assessing different aspects of stomal function. From raw total scores an overall stomal score was generated. The stoma score was moderately correlated to emotion and speech domains in head and neck Quality of Life questionnaire, indicating that different concepts were being measured. The mean minimum stoma diameter was 15.9 +/- 2.9 mm. There was a significant increase in the area under the receiver operating characteristic curve beyond a threshold value of > or 15 mm; smaller sizes were associated with a poorer stoma score (Mann-Whitney test, P stoma sizer use distressing. Size of stoma significantly contributes to QoL in laryngectomees and stomas with minimum diameters of 14 mm or less are associated with adverse effects on routine stoma function. The study-specific stoma function questionnaire appears to be a useful instrument.

  8. Distinctive Steady-State Heart Rate and Blood Pressure Responses to Passive Robotic Leg Exercise and Functional Electrical Stimulation During Head-up Tilt

    OpenAIRE

    Amirehsan Sarabadani Tafreshi; Amirehsan Sarabadani Tafreshi; Robert Riener; Robert Riener; Verena Klamroth-Marganska; Verena Klamroth-Marganska

    2016-01-01

    Tilt tables enable early mobilization of patients by providing verticalization. But there is a high risk of orthostatic hypotension provoked by verticalization, especially after neurological diseases such as spinal cord injury. Robot-assisted tilt tables might be an alternative as they add passive robotic leg exercise (PE) that can be enhanced with functional electrical stimulation (FES) to the verticalization, thus reducing the risk of orthostatic hypotension. We hypothesized that the influe...

  9. Tuning Hsf1 levels drives distinct fungal morphogenetic programs with depletion impairing Hsp90 function and overexpression expanding the target space

    Science.gov (United States)

    Miao, Zhengqiang; Tan, Kaeling; Vyas, Valmik K.; Whiteway, Malcolm; Robbins, Nicole; Wong, Koon Ho; Cowen, Leah E.

    2018-01-01

    The capacity to respond to temperature fluctuations is critical for microorganisms to survive within mammalian hosts, and temperature modulates virulence traits of diverse pathogens. One key temperature-dependent virulence trait of the fungal pathogen Candida albicans is its ability to transition from yeast to filamentous growth, which is induced by environmental cues at host physiological temperature. A key regulator of temperature-dependent morphogenesis is the molecular chaperone Hsp90, which has complex functional relationships with the transcription factor Hsf1. Although Hsf1 controls global transcriptional remodeling in response to heat shock, its impact on morphogenesis remains unknown. Here, we establish an intriguing paradigm whereby overexpression or depletion of C. albicans HSF1 induces morphogenesis in the absence of external cues. HSF1 depletion compromises Hsp90 function, thereby driving filamentation. HSF1 overexpression does not impact Hsp90 function, but rather induces a dose-dependent expansion of Hsf1 direct targets that drives overexpression of positive regulators of filamentation, including Brg1 and Ume6, thereby bypassing the requirement for elevated temperature during morphogenesis. This work provides new insight into Hsf1-mediated environmentally contingent transcriptional control, implicates Hsf1 in regulation of a key virulence trait, and highlights fascinating biology whereby either overexpression or depletion of a single cellular regulator induces a profound developmental transition. PMID:29590106

  10. Tuning Hsf1 levels drives distinct fungal morphogenetic programs with depletion impairing Hsp90 function and overexpression expanding the target space.

    Directory of Open Access Journals (Sweden)

    Amanda O Veri

    2018-03-01

    Full Text Available The capacity to respond to temperature fluctuations is critical for microorganisms to survive within mammalian hosts, and temperature modulates virulence traits of diverse pathogens. One key temperature-dependent virulence trait of the fungal pathogen Candida albicans is its ability to transition from yeast to filamentous growth, which is induced by environmental cues at host physiological temperature. A key regulator of temperature-dependent morphogenesis is the molecular chaperone Hsp90, which has complex functional relationships with the transcription factor Hsf1. Although Hsf1 controls global transcriptional remodeling in response to heat shock, its impact on morphogenesis remains unknown. Here, we establish an intriguing paradigm whereby overexpression or depletion of C. albicans HSF1 induces morphogenesis in the absence of external cues. HSF1 depletion compromises Hsp90 function, thereby driving filamentation. HSF1 overexpression does not impact Hsp90 function, but rather induces a dose-dependent expansion of Hsf1 direct targets that drives overexpression of positive regulators of filamentation, including Brg1 and Ume6, thereby bypassing the requirement for elevated temperature during morphogenesis. This work provides new insight into Hsf1-mediated environmentally contingent transcriptional control, implicates Hsf1 in regulation of a key virulence trait, and highlights fascinating biology whereby either overexpression or depletion of a single cellular regulator induces a profound developmental transition.

  11. Tuning Hsf1 levels drives distinct fungal morphogenetic programs with depletion impairing Hsp90 function and overexpression expanding the target space.

    Science.gov (United States)

    Veri, Amanda O; Miao, Zhengqiang; Shapiro, Rebecca S; Tebbji, Faiza; O'Meara, Teresa R; Kim, Sang Hu; Colazo, Juan; Tan, Kaeling; Vyas, Valmik K; Whiteway, Malcolm; Robbins, Nicole; Wong, Koon Ho; Cowen, Leah E

    2018-03-01

    The capacity to respond to temperature fluctuations is critical for microorganisms to survive within mammalian hosts, and temperature modulates virulence traits of diverse pathogens. One key temperature-dependent virulence trait of the fungal pathogen Candida albicans is its ability to transition from yeast to filamentous growth, which is induced by environmental cues at host physiological temperature. A key regulator of temperature-dependent morphogenesis is the molecular chaperone Hsp90, which has complex functional relationships with the transcription factor Hsf1. Although Hsf1 controls global transcriptional remodeling in response to heat shock, its impact on morphogenesis remains unknown. Here, we establish an intriguing paradigm whereby overexpression or depletion of C. albicans HSF1 induces morphogenesis in the absence of external cues. HSF1 depletion compromises Hsp90 function, thereby driving filamentation. HSF1 overexpression does not impact Hsp90 function, but rather induces a dose-dependent expansion of Hsf1 direct targets that drives overexpression of positive regulators of filamentation, including Brg1 and Ume6, thereby bypassing the requirement for elevated temperature during morphogenesis. This work provides new insight into Hsf1-mediated environmentally contingent transcriptional control, implicates Hsf1 in regulation of a key virulence trait, and highlights fascinating biology whereby either overexpression or depletion of a single cellular regulator induces a profound developmental transition.

  12. The IG-DMR and the MEG3-DMR at human chromosome 14q32.2: hierarchical interaction and distinct functional properties as imprinting control centers.

    Directory of Open Access Journals (Sweden)

    Masayo Kagami

    2010-06-01

    Full Text Available Human chromosome 14q32.2 harbors the germline-derived primary DLK1-MEG3 intergenic differentially methylated region (IG-DMR and the postfertilization-derived secondary MEG3-DMR, together with multiple imprinted genes. Although previous studies in cases with microdeletions and epimutations affecting both DMRs and paternal/maternal uniparental disomy 14-like phenotypes argue for a critical regulatory function of the two DMRs for the 14q32.2 imprinted region, the precise role of the individual DMR remains to be clarified. We studied an infant with upd(14pat body and placental phenotypes and a heterozygous microdeletion involving the IG-DMR alone (patient 1 and a neonate with upd(14pat body, but no placental phenotype and a heterozygous microdeletion involving the MEG3-DMR alone (patient 2. The results generated from the analysis of these two patients imply that the IG-DMR and the MEG3-DMR function as imprinting control centers in the placenta and the body, respectively, with a hierarchical interaction for the methylation pattern in the body governed by the IG-DMR. To our knowledge, this is the first study demonstrating an essential long-range imprinting regulatory function for the secondary DMR.

  13. Distinct spatiotemporal expression of serine proteases Prss23 and Prss35 in periimplantation mouse uterus and dispensable function of Prss35 in fertility.

    Directory of Open Access Journals (Sweden)

    Honglu Diao

    Full Text Available PRSS23 and PRSS35 are homologous proteases originally identified in mouse ovaries. In the periimplantation mouse uterus, Prss23 was highly expressed in the preimplantation gestation day 3.5 (D3.5 uterine luminal epithelium (LE. It disappeared from the postimplantation LE and reappeared in the stromal compartment next to the myometrium on D6.5. It was undetectable in the embryo from D4.5 to D6.5 but highly expressed in the embryo on D7.5. Prss35 became detectable in the uterine stromal compartment surrounding the embryo on D4.5 and shifted towards the mesometrial side of the stromal compartment next to the embryo from D5.5 to D7.5. In the ovariectomized uterus, Prss23 was moderately and Prss35 was dramatically downregulated by progesterone and 17β-estradiol. Based on the expression of Prss35 in granulosa cells and corpus luteum of the ovary and the early pregnant uterus, we hypothesized that PRSS35 might play a role in female reproduction, especially in oocyte development, ovulation, implantation, and decidualization. This hypothesis was tested in Prss35((-/- mice, which proved otherwise. Between wild type (WT and Prss35((-/- mice, superovulation of immature females produced comparable numbers of cumulus-oocyte complexes; there were comparable numbers of implantation sites detected on D4.5 and D7.5; there were no obvious differences in the expression of implantation and decidualization marker genes in D4.5 or D7.5 uteri. Comparable mRNA expression levels of a few known protease-related genes in the WT and Prss35((-/- D4.5 uteri indicated no compensatory upregulation. Comparable litter sizes from WT × WT and Prss35((-/-× Prss35((-/- crosses suggested that Prss35 gene was unessential for fertility and embryo development. Prss35 gene has been linked to cleft lip/palate in humans. However, no obvious such defects were observed in Prss35((-/- mice. This study demonstrates the distinct expression of Prss23 and Prss35 in the periimplantation uterus

  14. 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 exert distinct effects on human skeletal muscle function and gene expression.

    Directory of Open Access Journals (Sweden)

    Zaki K Hassan-Smith

    Full Text Available Age-associated decline in muscle function represents a significant public health burden. Vitamin D-deficiency is also prevalent in aging subjects, and has been linked to loss of muscle mass and strength (sarcopenia, but the precise role of specific vitamin D metabolites in determining muscle phenotype and function is still unclear. To address this we quantified serum concentrations of multiple vitamin D metabolites, and assessed the impact of these metabolites on body composition/muscle function parameters, and muscle biopsy gene expression in a retrospective study of a cohort of healthy volunteers. Active serum 1,25-dihydroxyvitamin D3 (1α,25(OH2D3, but not inactive 25-hydroxyvitamin D3 (25OHD3, correlated positively with measures of lower limb strength including power (rho = 0.42, p = 0.02, velocity (Vmax, rho = 0.40, p = 0.02 and jump height (rho = 0.36, p = 0.04. Lean mass correlated positively with 1α,25(OH2D3 (rho = 0.47, p = 0.02, in women. Serum 25OHD3 and inactive 24,25-dihydroxyvitamin D3 (24,25(OH2D3 had an inverse relationship with body fat (rho = -0.30, p = 0.02 and rho = -0.33, p = 0.01, respectively. Serum 25OHD3 and 24,25(OH2D3 were also correlated with urinary steroid metabolites, suggesting a link with glucocorticoid metabolism. PCR array analysis of 92 muscle genes identified vitamin D receptor (VDR mRNA in all muscle biopsies, with this expression being negatively correlated with serum 25OHD3, and Vmax, and positively correlated with fat mass. Of the other 91 muscle genes analysed by PCR array, 24 were positively correlated with 25OHD3, but only 4 were correlated with active 1α,25(OH2D3. These data show that although 25OHD3 has potent actions on muscle gene expression, the circulating concentrations of this metabolite are more closely linked to body fat mass, suggesting that 25OHD3 can influence muscle function via indirect effects on adipose tissue. By contrast, serum 1α,25(OH2D3 has limited effects on muscle gene

  15. Novel consortium of Klebsiella variicola and Lactobacillus species enhances the functional potential of fermented dairy products by increasing the availability of branched-chain amino acids and the amount of distinctive volatiles.

    Science.gov (United States)

    Rosales-Bravo, H; Morales-Torres, H C; Vázquez-Martínez, J; Molina-Torres, J; Olalde-Portugal, V; Partida-Martínez, L P

    2017-11-01

    Identify novel bacterial taxa that could increase the availability of branched-chain amino acids and the amount of distinctive volatiles during skim milk fermentation. We recovered 344 bacterial isolates from stool samples of healthy and breastfed infants. Five were selected based on their ability to produce branched-chain amino acids. Three strains were identified as Escherichia coli, one as Klebsiella pneumoniae and other as Klebsiella variicola by molecular and biochemical methods. HPLC and solid-phase microextraction with GC-MS were used for the determination of free amino acids and volatile compounds respectively. The consortium formed by K. variicola and four Lactobacillus species showed the highest production of Leu and Ile in skim milk fermentation. In addition, the production of volatile compounds, such as acetoin, ethanol, 2-nonanone, and acetic, hexanoic and octanoic acids, increased in comparison to commercial yogurt, Emmental and Gouda cheese. Also, distinctive volatiles, such as 2,3-butanediol, 4-methyl-2- hexanone and octanol, were identified. The use of K. variicola in combination with probiotic Lactobacillus species enhances the availability of Leu and Ile and the amount of distinctive volatiles during skim milk fermentation. The identified consortium increases the functional potential of fermented dairy products. © 2017 The Society for Applied Microbiology.

  16. Upper Limb Evaluation in Duchenne Muscular Dystrophy: Fat-Water Quantification by MRI, Muscle Force and Function Define Endpoints for Clinical Trials.

    Science.gov (United States)

    Ricotti, Valeria; Evans, Matthew R B; Sinclair, Christopher D J; Butler, Jordan W; Ridout, Deborah A; Hogrel, Jean-Yves; Emira, Ahmed; Morrow, Jasper M; Reilly, Mary M; Hanna, Michael G; Janiczek, Robert L; Matthews, Paul M; Yousry, Tarek A; Muntoni, Francesco; Thornton, John S

    2016-01-01

    A number of promising experimental therapies for Duchenne muscular dystrophy (DMD) are emerging. Clinical trials currently rely on invasive biopsies or motivation-dependent functional tests to assess outcome. Quantitative muscle magnetic resonance imaging (MRI) could offer a valuable alternative and permit inclusion of non-ambulant DMD subjects. The aims of our study were to explore the responsiveness of upper-limb MRI muscle-fat measurement as a non-invasive objective endpoint for clinical trials in non-ambulant DMD, and to investigate the relationship of these MRI measures to those of muscle force and function. 15 non-ambulant DMD boys (mean age 13.3 y) and 10 age-gender matched healthy controls (mean age 14.6 y) were recruited. 3-Tesla MRI fat-water quantification was used to measure forearm muscle fat transformation in non-ambulant DMD boys compared with healthy controls. DMD boys were assessed at 4 time-points over 12 months, using 3-point Dixon MRI to measure muscle fat-fraction (f.f.). Images from ten forearm muscles were segmented and mean f.f. and cross-sectional area recorded. DMD subjects also underwent comprehensive upper limb function and force evaluation. Overall mean baseline forearm f.f. was higher in DMD than in healthy controls (pmuscle f.f. as a biomarker to monitor disease progression in the upper limb in non-ambulant DMD, with sensitivity adequate to detect group-level change over time intervals practical for use in clinical trials. Clinical validity is supported by the association of the progressive fat transformation of muscle with loss of muscle force and function.

  17. Experimental study of the leakage rate through cracked reinforced concrete wall elements for defining the functional failure criteria of containment buildings

    International Nuclear Information System (INIS)

    Choun, Young Sun; Cho, Nam So

    2004-01-01

    Containment buildings in nuclear power plants should maintain their structural safety as well as their functional integrity during an operation period. To maintain the functional integrity, the wall and dome of the containment buildings have to maintain their air tightness under extreme loading conditions such as earthquakes, missile impact, and severe accidents. For evaluating the functional failure of containments, it is important to predict the leak amount through cracked concrete walls. The leakage through concrete cracks has been studied since 1972. Buss examined the flow rate of air through a pre-existing crack in a slab under air pressure. Rizkalla el al. initiated an experimental study for the leakage of prestressed concrete building segments under uniaxial and biaxial loadings to simulate the loading condition of containment buildings under an internal pressure. Recently, Salmon el al. initiated an experimental program for determining the leak rates in typical reinforced concrete shear walls subjected to beyond design basis earthquakes. This study investigates the cracking behavior of reinforced concrete containment wall elements under a uniaxial tension and addresses the outline of the leakage test for unlined containment wall elements

  18. Upper Limb Evaluation in Duchenne Muscular Dystrophy: Fat-Water Quantification by MRI, Muscle Force and Function Define Endpoints for Clinical Trials.

    Directory of Open Access Journals (Sweden)

    Valeria Ricotti

    Full Text Available A number of promising experimental therapies for Duchenne muscular dystrophy (DMD are emerging. Clinical trials currently rely on invasive biopsies or motivation-dependent functional tests to assess outcome. Quantitative muscle magnetic resonance imaging (MRI could offer a valuable alternative and permit inclusion of non-ambulant DMD subjects. The aims of our study were to explore the responsiveness of upper-limb MRI muscle-fat measurement as a non-invasive objective endpoint for clinical trials in non-ambulant DMD, and to investigate the relationship of these MRI measures to those of muscle force and function.15 non-ambulant DMD boys (mean age 13.3 y and 10 age-gender matched healthy controls (mean age 14.6 y were recruited. 3-Tesla MRI fat-water quantification was used to measure forearm muscle fat transformation in non-ambulant DMD boys compared with healthy controls. DMD boys were assessed at 4 time-points over 12 months, using 3-point Dixon MRI to measure muscle fat-fraction (f.f.. Images from ten forearm muscles were segmented and mean f.f. and cross-sectional area recorded. DMD subjects also underwent comprehensive upper limb function and force evaluation.Overall mean baseline forearm f.f. was higher in DMD than in healthy controls (p<0.001. A progressive f.f. increase was observed in DMD over 12 months, reaching significance from 6 months (p<0.001, n = 7, accompanied by a significant loss in pinch strength at 6 months (p<0.001, n = 9 and a loss of upper limb function and grip force observed over 12 months (p<0.001, n = 8.These results support the use of MRI muscle f.f. as a biomarker to monitor disease progression in the upper limb in non-ambulant DMD, with sensitivity adequate to detect group-level change over time intervals practical for use in clinical trials. Clinical validity is supported by the association of the progressive fat transformation of muscle with loss of muscle force and function.

  19. Associations of electrocardiographic P-wave characteristics with left atrial function, and diffuse left ventricular fibrosis defined by cardiac magnetic resonance: The PRIMERI Study.

    Science.gov (United States)

    Tiffany Win, Theingi; Ambale Venkatesh, Bharath; Volpe, Gustavo J; Mewton, Nathan; Rizzi, Patricia; Sharma, Ravi K; Strauss, David G; Lima, Joao A; Tereshchenko, Larisa G

    2015-01-01

    Abnormal P-terminal force in lead V1 (PTFV1) is associated with an increased risk of heart failure, stroke, atrial fibrillation, and death. Our goal was to explore associations of left ventricular (LV) diffuse fibrosis with left atrial (LA) function and electrocardiographic (ECG) measures of LA electrical activity. Patients without atrial fibrillation (n = 91; mean age 59.5 years; 61.5% men; 65.9% white) with structural heart disease (spatial QRS-T angle ≥105° and/or Selvester QRS score ≥5 on ECG) but LV ejection fraction >35% underwent clinical evaluation, cardiac magnetic resonance, and resting ECG. LA function indices were obtained by multimodality tissue tracking using 2- and 4-chamber long-axis images. T1 mapping and late gadolinium enhancement were used to assess diffuse LV fibrosis and presence of scar. P-prime in V1 amplitude (PPaV1) and duration (PPdV1), averaged P-wave-duration, PR interval, and P-wave axis were automatically measured using 12 SLTM algorithm. PTFV1 was calculated as a product of PPaV1 and PPdV1. In linear regression after adjustment for demographic characteristics, body mass index, maximum LA volume index, presence of scar, and LV mass index, each decile increase in LV interstitial fibrosis was associated with 0.76 mV*ms increase in negative abnormal PTFV1 (95% confidence interval [CI] -1.42 to -0.09; P = .025), 15.3 ms prolongation of PPdV1 (95% CI 6.9 to 23.8; P = .001) and 5.4 ms prolongation of averaged P-duration (95% CI 0.9-10.0; P = .020). LV fibrosis did not affect LA function. PPaV1 and PTFV1 were associated with an increase in LA volumes and decrease in LA emptying fraction and LA reservoir function. LV interstitial fibrosis is associated with abnormal PTFV1, prolonged PPdV1, and P-duration, but does not affect LA function. Copyright © 2015 Heart Rhythm Society. All rights reserved.

  20. Redundant and distinct functions of the ABA response loci ABA-INSENSITIVE(ABI)5 and ABRE-BINDING FACTOR (ABF)3.

    Science.gov (United States)

    Finkelstein, Ruth; Gampala, Srinivas S L; Lynch, Tim J; Thomas, Terry L; Rock, Christopher D

    2005-09-01

    Abscisic acid-responsive gene expression is regulated by numerous transcription factors, including a subgroup of basic leucine zipper factors that bind to the conserved cis-acting sequences known as ABA-responsive elements. Although one of these factors, ABA-insensitive 5 (ABI5), was identified genetically, the paucity of genetic data for the other family members has left it unclear whether they perform unique functions or act redundantly to ABI5 or each other. To test for potential redundancy with ABI5, we identified the family members with most similar effects and interactions in transient expression systems (ABF3 and ABF1), then characterized loss-of-function lines for those loci. The abf1 and abf3 monogenic mutant lines had at most minimal effects on germination or seed-specific gene expression, but the enhanced ABA- and stress-resistance of abf3 abi5 double mutants revealed redundant action of these genes in multiple stress responses of seeds and seedlings. Although ABI5, ABF3, and ABF1 have some overlapping effects, they appear to antagonistically regulate each other's expression at specific stages. Consequently, loss of any one factor may be partially compensated by increased expression of other family members.

  1. Can play be defined?

    DEFF Research Database (Denmark)

    Eichberg, Henning

    2015-01-01

    Can play be defined? There is reason to raise critical questions about the established academic demand that at phenomenon – also in humanist studies – should first of all be defined, i.e. de-lineated and by neat lines limited to a “little box” that can be handled. The following chapter develops....... Human beings can very well understand play – or whatever phenomenon in human life – without defining it....

  2. Differences in Contractile Function of Myofibrils within Human Embryonic Stem Cell-Derived Cardiomyocytes vs. Adult Ventricular Myofibrils Are Related to Distinct Sarcomeric Protein Isoforms

    Directory of Open Access Journals (Sweden)

    Bogdan Iorga

    2018-01-01

    Full Text Available Characterizing the contractile function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs is key for advancing their utility for cellular disease models, promoting cell based heart repair, or developing novel pharmacological interventions targeting cardiac diseases. The aim of the present study was to understand whether steady-state and kinetic force parameters of β-myosin heavy chain (βMyHC isoform-expressing myofibrils within human embryonic stem cell-derived cardiomyocytes (hESC-CMs differentiated in vitro resemble those of human ventricular myofibrils (hvMFs isolated from adult donor hearts. Contractile parameters were determined using the same micromechanical method and experimental conditions for both types of myofibrils. We identified isoforms and phosphorylation of main sarcomeric proteins involved in the modulation of force generation of both, chemically demembranated hESC-CMs (d-hESC-CMs and hvMFs. Our results indicate that at saturating Ca2+ concentration, both human-derived contractile systems developed forces with similar rate constants (0.66 and 0.68 s−1, reaching maximum isometric force that was significantly smaller for d-hESC-CMs (42 kPa than for hvMFs (94 kPa. At submaximal Ca2+-activation, where intact cardiomyocytes normally operate, contractile parameters of d-hESC-CMs and hvMFs exhibited differences. Ca2+ sensitivity of force was higher for d-hESC-CMs (pCa50 = 6.04 than for hvMFs (pCa50 = 5.80. At half-maximum activation, the rate constant for force redevelopment was significantly faster for d-hESC-CMs (0.51 s−1 than for hvMFs (0.28 s−1. During myofibril relaxation, kinetics of the slow force decay phase were significantly faster for d-hESC-CMs (0.26 s−1 than for hvMFs (0.21 s−1, while kinetics of the fast force decay were similar and ~20x faster. Protein analysis revealed that hESC-CMs had essentially no cardiac troponin-I, and partially non-ventricular isoforms of some other sarcomeric proteins

  3. Symbiotic specificity, association patterns, and function determine community responses to global changes: defining critical research areas for coral-Symbiodinium symbioses.

    Science.gov (United States)

    Fabina, Nicholas S; Putnam, Hollie M; Franklin, Erik C; Stat, Michael; Gates, Ruth D

    2013-11-01

    Climate change-driven stressors threaten the persistence of coral reefs worldwide. Symbiotic relationships between scleractinian corals and photosynthetic endosymbionts (genus Symbiodinium) are the foundation of reef ecosystems, and these associations are differentially impacted by stress. Here, we couple empirical data from the coral reefs of Moorea, French Polynesia, and a network theoretic modeling approach to evaluate how patterns in coral-Symbiodinium associations influence community stability under climate change. To introduce the effect of climate perturbations, we simulate local 'extinctions' that represent either the loss of coral species or the ability to engage in symbiotic interactions. Community stability is measured by determining the duration and number of species that persist through the simulated extinctions. Our results suggest that four factors greatly increase coral-Symbiodinium community stability in response to global changes: (i) the survival of generalist hosts and symbionts maximizes potential symbiotic unions; (ii) elevated symbiont diversity provides redundant or complementary symbiotic functions; (iii) compatible symbiotic assemblages create the potential for local recolonization; and (iv) the persistence of certain traits associate with symbiotic diversity and redundancy. Symbiodinium may facilitate coral persistence through novel environmental regimes, but this capacity is mediated by symbiotic specificity, association patterns, and the functional performance of the symbionts. Our model-based approach identifies general trends and testable hypotheses in coral-Symbiodinium community responses. Future studies should consider similar methods when community size and/or environmental complexity preclude experimental approaches. © 2013 John Wiley & Sons Ltd.

  4. Cerebral blood flow with [15O]water PET studies using an image-derived input function and MR-defined carotid centerlines

    Science.gov (United States)

    Fung, Edward K.; Carson, Richard E.

    2013-03-01

    Full quantitative analysis of brain PET data requires knowledge of the arterial input function into the brain. Such data are normally acquired by arterial sampling with corrections for delay and dispersion to account for the distant sampling site. Several attempts have been made to extract an image-derived input function (IDIF) directly from the internal carotid arteries that supply the brain and are often visible in brain PET images. We have devised a method of delineating the internal carotids in co-registered magnetic resonance (MR) images using the level-set method and applying the segmentations to PET images using a novel centerline approach. Centerlines of the segmented carotids were modeled as cubic splines and re-registered in PET images summed over the early portion of the scan. Using information from the anatomical center of the vessel should minimize partial volume and spillover effects. Centerline time-activity curves were taken as the mean of the values for points along the centerline interpolated from neighboring voxels. A scale factor correction was derived from calculation of cerebral blood flow (CBF) using gold standard arterial blood measurements. We have applied the method to human subject data from multiple injections of [15O]water on the HRRT. The method was assessed by calculating the area under the curve (AUC) of the IDIF and the CBF, and comparing these to values computed using the gold standard arterial input curve. The average ratio of IDIF to arterial AUC (apparent recovery coefficient: aRC) across 9 subjects with multiple (n = 69) injections was 0.49 ± 0.09 at 0-30 s post tracer arrival, 0.45 ± 0.09 at 30-60 s, and 0.46 ± 0.09 at 60-90 s. Gray and white matter CBF values were 61.4 ± 11.0 and 15.6 ± 3.0 mL/min/100 g tissue using sampled blood data. Using IDIF centerlines scaled by the average aRC over each subjects’ injections, gray and white matter CBF values were 61.3 ± 13.5 and 15.5 ± 3.4 mL/min/100 g tissue. Using global

  5. Nanostructured self-assembling peptides as a defined extracellular matrix for long-term functional maintenance of primary hepatocytes in a bioartificial liver modular device

    Directory of Open Access Journals (Sweden)

    Giri S

    2013-04-01

    Full Text Available Shibashish Giri,1 Ulf-Dietrich Braumann,2,3 Priya Giri,1,3 Ali Acikgöz,1,4 Patrick Scheibe,3,5 Karen Nieber,6 Augustinus Bader1 1Department of Cell Techniques and Applied Stem Cell Biology, Center for Biotechnology and Biomedicine (BBZ, 2Institute for Medical Informatics, Statistics, and Epidemiology (IMISE, University of Leipzig, Leipzig, Germany; 3Interdisciplinary Center for Bioinformatics (IZBI, University of Leipzig, Leipzig, Germany; 4Klinikum St Georg, Leipzig, Germany; 5Translational Center for Regenerative Medicine (TRM Leipzig, 6Department of Pharmacology for Natural Sciences, Institute of Pharmacy, University of Leipzig, Leipzig, Germany Abstract: Much effort has been directed towards the optimization of the capture of in vivo hepatocytes from their microenvironment. Some methods of capture include an ex vivo cellular model in a bioreactor based liver module, a micropatterned module, a microfluidic 3D chip, coated plates, and other innovative approaches for the functional maintenance of primary hepatocytes. However, none of the above methods meet US Food and Drug Administration (FDA guidelines, which recommend and encourage that the duration of a toxicity assay of a drug should be a minimum of 14 days, to a maximum of 90 days for a general toxicity assay. Existing innovative reports have used undefined extracellular matrices like matrigel, rigid collagen, or serum supplementations, which are often problematic, unacceptable in preclinical and clinical applications, and can even interfere with experimental outcomes. We have overcome these challenges by using integrated nanostructured self-assembling peptides and a special combination of growth factors and cytokines to establish a proof of concept to mimic the in vivo hepatocyte microenvironment pattern in vitro for predicting the in vivo drug hepatotoxicity in a scalable bioartificial liver module. Hepatocyte functionality (albumin, urea was measured at days 10, 30, 60, and 90 and we

  6. Analysis of meiosis in SUN1 deficient mice reveals a distinct role of SUN2 in mammalian meiotic LINC complex formation and function.

    Directory of Open Access Journals (Sweden)

    Jana Link

    2014-02-01

    Full Text Available LINC complexes are evolutionarily conserved nuclear envelope bridges, composed of SUN (Sad-1/UNC-84 and KASH (Klarsicht/ANC-1/Syne/homology domain proteins. They are crucial for nuclear positioning and nuclear shape determination, and also mediate nuclear envelope (NE attachment of meiotic telomeres, essential for driving homolog synapsis and recombination. In mice, SUN1 and SUN2 are the only SUN domain proteins expressed during meiosis, sharing their localization with meiosis-specific KASH5. Recent studies have shown that loss of SUN1 severely interferes with meiotic processes. Absence of SUN1 provokes defective telomere attachment and causes infertility. Here, we report that meiotic telomere attachment is not entirely lost in mice deficient for SUN1, but numerous telomeres are still attached to the NE through SUN2/KASH5-LINC complexes. In Sun1(-/- meiocytes attached telomeres retained the capacity to form bouquet-like clusters. Furthermore, we could detect significant numbers of late meiotic recombination events in Sun1(-/- mice. Together, this indicates that even in the absence of SUN1 telomere attachment and their movement within the nuclear envelope per se can be functional.

  7. Distribution and function of carbamate hydrolase genes cehA and mcd in soils: the distinct role of soil pH.

    Science.gov (United States)

    Rousidou, Constantina; Karaiskos, Dionysis; Myti, Despoina; Karanasios, Evangelos; Karas, Panagiotis A; Tourna, Maria; Tzortzakakis, Emmanuel A; Karpouzas, Dimitrios G

    2017-01-01

    Synthetic carbamates constitute a significant pesticide group with oxamyl being a leading compound in the nematicide market. Oxamyl degradation in soil is mainly microbially mediated. However, the distribution and function of carbamate hydrolase genes (cehA, mcd, cahA) associated with the soil biodegradation of carbamates is not yet clear. We studied oxamyl degradation in 16 soils from a potato monoculture area in Greece where oxamyl is regularly used. Oxamyl showed low persistence (DT50 2.4-26.7 days). q-PCR detected the cehA and mcd genes in 10 and three soils, respectively. The abundance of the cehA gene was positively correlated with pH, while both cehA abundance and pH were negatively correlated with oxamyl DT50. Amongst the carbamates used in the study region, oxamyl stimulated the abundance and expression only of the cehA gene, while carbofuran stimulated the abundance and expression of both genes. The cehA gene was also detected in pristine soils upon repeated treatments with oxamyl and carbofuran and only in soils with pH ≥7.2, where the most rapid degradation of oxamyl was observed. These results have major implications regarding the maintenance of carbamate hydrolase genes in soils, have practical implications regarding the agricultural use of carbamates, and provide insights into the evolution of cehA. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  8. Molecular mechanisms of protein-cholesterol interactions in plasma membranes: Functional distinction between topological (tilted) and consensus (CARC/CRAC) domains.

    Science.gov (United States)

    Fantini, Jacques; Di Scala, Coralie; Baier, Carlos J; Barrantes, Francisco J

    2016-09-01

    The molecular mechanisms that control the multiple possible modes of protein association with membrane cholesterol are remarkably convergent. These mechanisms, which include hydrogen bonding, CH-π stacking and dispersion forces, are used by a wide variety of extracellular proteins (e.g. microbial or amyloid) and membrane receptors. Virus fusion peptides penetrate the membrane of host cells with a tilted orientation that is compatible with a transient interaction with cholesterol; this tilted orientation is also characteristic of the process of insertion of amyloid proteins that subsequently form oligomeric pores in the plasma membrane of brain cells. Membrane receptors that are associated with cholesterol generally display linear consensus binding motifs (CARC and CRAC) characterized by a triad of basic (Lys/Arg), aromatic (Tyr/phe) and aliphatic (Leu/Val) amino acid residues. In some cases, the presence of both CARC and CRAC within the same membrane-spanning domain allows the simultaneous binding of two cholesterol molecules, one in each membrane leaflet. In this review the molecular basis and the functional significance of the different modes of protein-cholesterol interactions in plasma membranes are discussed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Burn patients' return to daily activities and participation as defined by the International Classification of Functioning, Disability and Health: A systematic review.

    Science.gov (United States)

    Osborne, Candice L; Meyer, Walter J; Ottenbacher, Kenneth J; Arcari, Christine M

    2017-06-01

    The World Health Organization's International Classification of Functioning, Disability and Health (ICF) is a universal classification system of health and health-related domains. The ICF has been successfully applied to a wide range of health conditions and diseases; however, its application in the field of burn recovery has been minimal. This systematic review uses the domains of the ICF component 'activities and participation' to explore: (1) the extent to which return to daily activities and community participation after burn has been examined in the pediatric population, (2) the most common assessments used to determine activity and participation outcomes, and (3) what activity and participation areas are most affected in the pediatric burn population after discharge from acute care. Results determined that it is difficult to draw overarching conclusions in the area of return to 'activities and participation' for children with burn based on the paucity of current evidence. Of the studies conducted, few examined the same subtopics or used similar measurements. This suggests a need for more robust studies in this area in order to inform and improve burn rehabilitation practices to meet the potential needs of burn patients beyond an acute care setting. Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.

  10. Distinct and overlapping effector functions of expanded human CD4+, CD8α+ and CD4-CD8α- invariant natural killer T cells.

    Directory of Open Access Journals (Sweden)

    Vincent O'Reilly

    Full Text Available CD1d-restricted invariant natural killer T (iNKT cells have diverse immune stimulatory/regulatory activities through their ability to release cytokines and to kill or transactivate other cells. Activation of iNKT cells can protect against multiple diseases in mice but clinical trials in humans have had limited impact. Clinical studies to date have targeted polyclonal mixtures of iNKT cells and we proposed that their subset compositions will influence therapeutic outcomes. We sorted and expanded iNKT cells from healthy donors and compared the phenotypes, cytotoxic activities and cytokine profiles of the CD4(+, CD8α(+ and CD4(-CD8α(- double-negative (DN subsets. CD4(+ iNKT cells expanded more readily than CD8α(+ and DN iNKT cells upon mitogen stimulation. CD8α(+ and DN iNKT cells most frequently expressed CD56, CD161 and NKG2D and most potently killed CD1d(+ cell lines and primary leukemia cells. All iNKT subsets released Th1 (IFN-γ and TNF-α and Th2 (IL-4, IL-5 and IL-13 cytokines. Relative amounts followed a CD8α>DN>CD4 pattern for Th1 and CD4>DN>CD8α for Th2. All iNKT subsets could simultaneously produce IFN-γ and IL-4, but single-positivity for IFN-γ or IL-4 was strikingly rare in CD4(+ and CD8α(+ fractions, respectively. Only CD4(+ iNKT cells produced IL-9 and IL-10; DN cells released IL-17; and none produced IL-22. All iNKT subsets upregulated CD40L upon glycolipid stimulation and induced IL-10 and IL-12 secretion by dendritic cells. Thus, subset composition of iNKT cells is a major determinant of function. Use of enriched CD8α(+, DN or CD4(+ iNKT cells may optimally harness the immunoregulatory properties of iNKT cells for treatment of disease.

  11. Distinctive Steady-State Heart Rate and Blood Pressure Responses to Passive Robotic Leg Exercise and Functional Electrical Stimulation during Head-Up Tilt.

    Science.gov (United States)

    Sarabadani Tafreshi, Amirehsan; Riener, Robert; Klamroth-Marganska, Verena

    2016-01-01

    Introduction: Tilt tables enable early mobilization of patients by providing verticalization. But there is a high risk of orthostatic hypotension provoked by verticalization, especially after neurological diseases such as spinal cord injury. Robot-assisted tilt tables might be an alternative as they add passive robotic leg exercise (PE) that can be enhanced with functional electrical stimulation (FES) to the verticalization, thus reducing the risk of orthostatic hypotension. We hypothesized that the influence of PE on the cardiovascular system during verticalization (i.e., head-up tilt) depends on the verticalization angle, and FES strengthens the PE influence. To test our hypotheses, we investigated the PE effects on the cardiovascular parameters heart rate (HR), and systolic and diastolic blood pressures (sBP, dBP) at different angles of verticalization in a healthy population. Methods: Ten healthy subjects on a robot-assisted tilt table underwent four different study protocols while HR, sBP, and dBP were measured: (1) head-up tilt to 60° and 71° without PE; (2) PE at 20°, 40°, and 60° of head-up tilt; (3) PE while constant FES intensity was applied to the leg muscles, at 20°, 40°, and 60° of head-up tilt; (4) PE with variation of the applied FES intensity at 0°, 20°, 40°, and 60° of head-up tilt. Linear mixed models were used to model changes in HR, sBP, and dBP responses. Results: The models show that: (1) head-up tilt alone resulted in statistically significant increases in HR and dBP, but no change in sBP. (2) PE during head-up tilt resulted in statistically significant changes in HR, sBP, and dBP, but not at each angle and not always in the same direction (i.e., increase or decrease of cardiovascular parameters). Neither adding (3) FES at constant intensity to PE nor (4) variation of FES intensity during PE had any statistically significant effects on the cardiovascular parameters. Conclusion: The effect of PE on the cardiovascular system during

  12. Distinctive Steady-State Heart Rate and Blood Pressure Responses to Passive Robotic Leg Exercise and Functional Electrical Stimulation During Head-up Tilt

    Directory of Open Access Journals (Sweden)

    Amirehsan Sarabadani Tafreshi

    2016-12-01

    Full Text Available Tilt tables enable early mobilization of patients by providing verticalization. But there is a high risk of orthostatic hypotension provoked by verticalization, especially after neurological diseases such as spinal cord injury. Robot-assisted tilt tables might be an alternative as they add passive robotic leg exercise (PE that can be enhanced with functional electrical stimulation (FES to the verticalization, thus reducing the risk of orthostatic hypotension. We hypothesized that the influence of PE on the cardiovascular system during verticalization depends on the verticalization angle, and FES strengthens the PE influence. To test our hypotheses, we investigated the PE effects on the cardiovascular parameters heart rate (HR, and systolic and diastolic blood pressures (sBP, dBP at different angles of verticalization in a healthy population. Ten healthy subjects on a robot-assisted tilt table underwent four different study protocols while HR, sBP and dBP were measured: (1 head-up tilt to 60° and 71° without PE; (2 PE at 20°, 40°, and 60° of head-up tilt; (3 PE while constant FES intensity was applied to the leg muscles, at 20°, 40°, and 60° of head-up tilt; (4 PE with variation of the applied FES intensity at 0°, 20°, 40°, and 60° of head-up tilt. Linear mixed models were used to model changes in HR, sBP, and dBP responses. The models show that: (1 head-up tilt alone resulted in statistically significant increases in HR and dBP, but no change in sBP. (2 PE during head-up tilt resulted in statistically significant changes in HR, sBP, and dBP, but not at each angle and not always in the same direction (i.e., increase or decrease of cardiovascular parameters. Neither adding (3 FES at constant intensity to PE nor (4 variation of FES intensity during PE had any statistically significant effects on the cardiovascular parameters.The effect of PE on the cardiovascular system during head-up tilt is strongly dependent on the verticalization

  13. Flt3 ligand-eGFP-reporter expression characterizes functionally distinct subpopulations of CD150+ long-term repopulating murine hematopoietic stem cells.

    Science.gov (United States)

    Tornack, Julia; Kawano, Yohei; Garbi, Natalio; Hämmerling, Günter J; Melchers, Fritz; Tsuneto, Motokazu

    2017-09-01

    The pool of hematopoietic stem cells (HSCs) in the bone marrow is a mixture of resting, proliferating, and differentiating cells. Long-term repopulating HSCs (LT-HSC) are routinely enriched as Lin - Sca1 + c-Kit + CD34 - Flt3 - CD150 + CD48 - cells. The Flt3 ligand (Flt3L) and its receptor Flt3 are important regulators of HSC maintenance, expansion and differentiation. Using Flt3L-eGFP reporter mice, we show that endogenous Flt3L-eGFP-reporter RNA expression correlates with eGFP-protein expression. This Flt3L-eGFP-reporter expression distinguishes two LT-HSC populations with differences in gene expressions and reconstituting potential. Thus, Flt3L-eGFP-reporter low cells are identified as predominantly resting HSCs with long-term repopulating capacities. In contrast, Flt3L-eGFP-reporter high cells are in majority proliferating HSCs with only short-term repopulating capacities. Flt3L-eGFP-reporter low cells express hypoxia, autophagy-inducing, and the LT-HSC-associated genes HoxB5 and Fgd5, while Flt3L-eGFP-reporter high HSCs upregulate genes involved in HSC differentiation. Flt3L-eGFP-reporter low cells develop to Flt3L-eGFP-reporter high cells in vitro, although Flt3L-eGFP-reporter high cells remain Flt3L-eGFP-reporter high . CD150 + Flt3L-eGFP-reporter low cells express either endothelial protein C receptor (EPCR) or CD41, while Flt3L-eGFP-reporter high cells do express EPCR but not CD41. Thus, FACS-enrichment of Flt3/ Flt3L-eGFP-reporter negative, Lin - CD150 + CD48 - EPCR + CD41 + HSCs allows a further 5-fold enrichment of functional LT-HSCs. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Niemann-Pick C1 (NPC1/NPC1-like1 Chimeras Define Sequences Critical for NPC1’s Function as a Filovirus Entry Receptor

    Directory of Open Access Journals (Sweden)

    Esther Ndungo

    2012-10-01

    Full Text Available We recently demonstrated that Niemann-Pick C1 (NPC1, a ubiquitous 13-pass cellular membrane protein involved in lysosomal cholesterol transport, is a critical entry receptor for filoviruses. Here we show that Niemann-Pick C1-like1 (NPC1L1, an NPC1 paralog and hepatitis C virus entry factor, lacks filovirus receptor activity. We exploited the structural similarity between NPC1 and NPC1L1 to construct and analyze a panel of chimeras in which NPC1L1 sequences were replaced with cognate sequences from NPC1. Only one chimera, NPC1L1 containing the second luminal domain (C of NPC1 in place of its own, bound to the viral glycoprotein, GP. This engineered protein mediated authentic filovirus infection nearly as well as wild-type NPC1, and more efficiently than did a minimal NPC1 domain C-based receptor recently described by us. A reciprocal chimera, NPC1 containing NPC1L1’s domain C, was completely inactive. Remarkably, an intra-domain NPC1L1-NPC1 chimera bearing only a ~130-amino acid N–terminal region of NPC1 domain C could confer substantial viral receptor activity on NPC1L1. Taken together, these findings account for the failure of NPC1L1 to serve as a filovirus receptor, highlight the central role of the luminal domain C of NPC1 in filovirus entry, and reveal the direct involvement of N–terminal domain C sequences in NPC1’s function as a filovirus receptor.

  15. Defining predictive values using three different platelet function tests for CYP2C19 phenotype status on maintenance dual antiplatelet therapy after PCI.

    Science.gov (United States)

    Zhang, Hong-Zhe; Kim, Moo Hyun; Han, Jin-Yeong; Jeong, Young-Hoon

    2014-01-01

    Published data suggests that the presence of CYP2C19*2 or *3 loss of function (LOF) alleles is indicative of increased platelet aggregation and a higher risk of adverse cardiovascular events after clopidogrel administration. We sought to determine cut-off values using three different assays for prediction of the CYP2C19 phenotype in Korean percutaneous coronary intervention (PCI) patients. We enrolled 244 patients with drug-eluting stent implantation who were receiving clopidogrel and aspirin maintenance therapy for one month or more. Platelet reactivity was assessed with light transmittance aggregometry (LTA), multiple electrode aggregometry (MEA) and the VerifyNow P2Y12 assay (VN). The CYP2C19 genotype was analyzed by polymerase chain reaction (PCR) and snapshot method. The frequency of CYP2C19 LOF allele carriers was 58.6%. The cut-off values from LTA, MEA and VerifyNow for the identification of LOF allele carriers were as follows: 10 µM ADP-induced LTA ≥ 48 %, VN>242 PRU and MEA ≥ 37 U. Between the three tests, correlation was higher between LTA vs. VN assays (r=0.69) and LTA vs. MEA (r=0.56), with moderate agreement (κ=0.46 and κ=0.46), but between VN assay and MEA, both devices using whole blood showed a lower correlation (r=0.42) and agreement (κ=0.3). Our results provide guidance regarding cut-off levels for LTA, VerifyNow and MEA assays to detect the CYP2C19 LOF allele in patients during dual antiplatelet maintenance therapy.

  16. Defining a periodontitis case

    DEFF Research Database (Denmark)

    Baelum, Vibeke; Lopez, Rodrigo

    2012-01-01

    . Conclusions The results indicate that it should be feasible for the periodontal community to reach an agreement over the distinction between a case and a non-case. The classification system proposed by van der Velden is better suited for providing clinicians with a clear image of the case....

  17. Defining Overweight and Obesity

    Science.gov (United States)

    ... Micronutrient Malnutrition State and Local Programs Defining Adult Overweight and Obesity Recommend on Facebook Tweet Share Compartir ... weight for a given height is described as overweight or obese. Body Mass Index, or BMI, is ...

  18. Drinking Levels Defined

    Science.gov (United States)

    ... of Alcohol Consumption Alcohol's Effects on the Body Alcohol Use Disorder Fetal Alcohol Exposure Support & Treatment Alcohol Policy Special ... Definition of Drinking at Low Risk for Developing Alcohol Use Disorder (AUD): For women, low-risk drinking is defined ...

  19. Defining Documentary Film

    DEFF Research Database (Denmark)

    Juel, Henrik

    2006-01-01

    A discussion of various attemts at defining documentary film regarding form, content, truth, stile, genre or reception - and a propoposal of a positive list of essential, but non-exclusive characteristica of documentary film......A discussion of various attemts at defining documentary film regarding form, content, truth, stile, genre or reception - and a propoposal of a positive list of essential, but non-exclusive characteristica of documentary film...

  20. Definably compact groups definable in real closed fields. I

    OpenAIRE

    Barriga, Eliana

    2017-01-01

    We study definably compact definably connected groups definable in a sufficiently saturated real closed field $R$. We introduce the notion of group-generic point for $\\bigvee$-definable groups and show the existence of group-generic points for definably compact groups definable in a sufficiently saturated o-minimal expansion of a real closed field. We use this notion along with some properties of generic sets to prove that for every definably compact definably connected group $G$ definable in...

  1. Defining Game Mechanics

    DEFF Research Database (Denmark)

    Sicart (Vila), Miguel Angel

    2008-01-01

    This article defins game mechanics in relation to rules and challenges. Game mechanics are methods invoked by agents for interacting with the game world. I apply this definition to a comparative analysis of the games Rez, Every Extend Extra and Shadow of the Colossus that will show the relevance...... of a formal definition of game mechanics. Udgivelsesdato: Dec 2008...

  2. Modal Logics and Definability

    OpenAIRE

    Kuusisto, Antti

    2013-01-01

    In recent years, research into the mathematical foundations of modal logic has become increasingly popular. One of the main reasons for this is the fact that modal logic seems to adapt well to the requirements of a wide range of different fields of application. This paper is a summary of some of the author’s contributions to the understanding of modal definability theory.

  3. Software Defined Cyberinfrastructure

    Energy Technology Data Exchange (ETDEWEB)

    Foster, Ian; Blaiszik, Ben; Chard, Kyle; Chard, Ryan

    2017-07-17

    Within and across thousands of science labs, researchers and students struggle to manage data produced in experiments, simulations, and analyses. Largely manual research data lifecycle management processes mean that much time is wasted, research results are often irreproducible, and data sharing and reuse remain rare. In response, we propose a new approach to data lifecycle management in which researchers are empowered to define the actions to be performed at individual storage systems when data are created or modified: actions such as analysis, transformation, copying, and publication. We term this approach software-defined cyberinfrastructure because users can implement powerful data management policies by deploying rules to local storage systems, much as software-defined networking allows users to configure networks by deploying rules to switches.We argue that this approach can enable a new class of responsive distributed storage infrastructure that will accelerate research innovation by allowing any researcher to associate data workflows with data sources, whether local or remote, for such purposes as data ingest, characterization, indexing, and sharing. We report on early experiments with this approach in the context of experimental science, in which a simple if-trigger-then-action (IFTA) notation is used to define rules.

  4. Defining Abnormally Low Tenders

    DEFF Research Database (Denmark)

    Ølykke, Grith Skovgaard; Nyström, Johan

    2017-01-01

    The concept of an abnormally low tender is not defined in EU public procurement law. This article takes an interdisciplinary law and economics approach to examine a dataset consisting of Swedish and Danish judgments and verdicts concerning the concept of an abnormally low tender. The purpose...

  5. Software Defined Coded Networking

    DEFF Research Database (Denmark)

    Di Paola, Carla; Roetter, Daniel Enrique Lucani; Palazzo, Sergio

    2017-01-01

    the quality of each link and even across neighbouring links and using simulations to show that an additional reduction of packet transmission in the order of 40% is possible. Second, to advocate for the use of network coding (NC) jointly with software defined networking (SDN) providing an implementation...

  6. Defining depth of anesthesia.

    Science.gov (United States)

    Shafer, S L; Stanski, D R

    2008-01-01

    In this chapter, drawn largely from the synthesis of material that we first presented in the sixth edition of Miller's Anesthesia, Chap 31 (Stanski and Shafer 2005; used by permission of the publisher), we have defined anesthetic depth as the probability of non-response to stimulation, calibrated against the strength of the stimulus, the difficulty of suppressing the response, and the drug-induced probability of non-responsiveness at defined effect site concentrations. This definition requires measurement of multiple different stimuli and responses at well-defined drug concentrations. There is no one stimulus and response measurement that will capture depth of anesthesia in a clinically or scientifically meaningful manner. The "clinical art" of anesthesia requires calibration of these observations of stimuli and responses (verbal responses, movement, tachycardia) against the dose and concentration of anesthetic drugs used to reduce the probability of response, constantly adjusting the administered dose to achieve the desired anesthetic depth. In our definition of "depth of anesthesia" we define the need for two components to create the anesthetic state: hypnosis created with drugs such as propofol or the inhalational anesthetics and analgesia created with the opioids or nitrous oxide. We demonstrate the scientific evidence that profound degrees of hypnosis in the absence of analgesia will not prevent the hemodynamic responses to profoundly noxious stimuli. Also, profound degrees of analgesia do not guarantee unconsciousness. However, the combination of hypnosis and analgesia suppresses hemodynamic response to noxious stimuli and guarantees unconsciousness.

  7. Defining and classifying syncope

    NARCIS (Netherlands)

    Thijs, Roland D.; Wieling, Wouter; Kaufmann, Horacio; van Dijk, Gert

    2004-01-01

    There is no widely adopted definition or classification of syncope and related disorders. This lack of uniformity harms patient care, research, and medical education. In this article, syncope is defined as a form of transient loss of consciousness (TLOC) due to cerebral hypoperfusion. Differences

  8. Human chimera-type galectin-3: defining the critical tail length for high-affinity glycoprotein/cell surface binding and functional competition with galectin-1 in neuroblastoma cell growth regulation.

    Science.gov (United States)

    Kopitz, Jürgen; Vértesy, Sabine; André, Sabine; Fiedler, Sabine; Schnölzer, Martina; Gabius, Hans-Joachim

    2014-09-01

    Many human proteins have a modular design with receptor and structural domains. Using adhesion/growth-regulatory galectin-3 as model, we describe an interdisciplinary strategy to define the functional significance of its tail established by nine non-triple helical collagen-like repeats (I-IX) and the N-terminal peptide. Genetic engineering with sophisticated mass spectrometric product analysis provided the tools for biotesting, i.e. eight protein variants with different degrees of tail truncation. Evidently,various aspects of galectin-3 activity (cis binding and cell bridging) are affected by tail shortening in a different manner. Thus, this combined approach reveals an unsuspected complexity of structure-function relationship, encouraging further application beyond this chimera-type galectin. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  9. Two Distinct Scene-Processing Networks Connecting Vision and Memory.

    Science.gov (United States)

    Baldassano, Christopher; Esteva, Andre; Fei-Fei, Li; Beck, Diane M

    2016-01-01

    A number of regions in the human brain are known to be involved in processing natural scenes, but the field has lacked a unifying framework for understanding how these different regions are organized and interact. We provide evidence from functional connectivity and meta-analyses for a new organizational principle, in which scene processing relies upon two distinct networks that split the classically defined parahippocampal place area (PPA). The first network of strongly connected regions consists of the occipital place area/transverse occipital sulcus and posterior PPA, which contain retinotopic maps and are not strongly coupled to the hippocampus at rest. The second network consists of the caudal inferior parietal lobule, retrosplenial complex, and anterior PPA, which connect to the hippocampus (especially anterior hippocampus), and are implicated in both visual and nonvisual tasks, including episodic memory and navigation. We propose that these two distinct networks capture the primary functional division among scene-processing regions, between those that process visual features from the current view of a scene and those that connect information from a current scene view with a much broader temporal and spatial context. This new framework for understanding the neural substrates of scene-processing bridges results from many lines of research, and makes specific functional predictions.

  10. Participation and social participation: are they distinct concepts?

    Science.gov (United States)

    Piškur, Barbara; Daniëls, Ramon; Jongmans, Marian J; Ketelaar, Marjolijn; Smeets, Rob J E M; Norton, Meghan; Beurskens, Anna J H M

    2014-03-01

    The concept of participation has been extensively used in health and social care literature since the World Health Organization introduced its description in the International Classification of Functioning, Disability and Health (ICF) in 2001. More recently, the concept of social participation is frequently used in research articles and policy reports. However, in the ICF, no specific definition exists for social participation, and an explanation of differences between the concepts is not available. The central question in this discussion article is whether participation, as defined by the ICF, and social participation are distinct concepts. This article illustrates the concepts of participation and social participation, presents a critical discussion of their definitions, followed by implications for rehabilitation and possible future directions. A clear definition for participation or social participation does not yet exist. Definitions for social participation differ from each other and are not sufficiently distinct from the ICF definition of participation. Although the ICF is regarded an important conceptual framework, it is criticised for not being comprehensive. The relevance of societal involvement of clients is evident for rehabilitation, but the current ICF definition of participation does not sufficiently capture societal involvement. Changing the ICF's definition of participation towards social roles would overcome a number of its shortcomings. Societal involvement would then be understood in the light of social roles. Consequently, there would be no need to make a distinction between social participation and participation.

  11. Touch communicates distinct emotions.

    Science.gov (United States)

    Hertenstein, Matthew J; Keltner, Dacher; App, Betsy; Bulleit, Brittany A; Jaskolka, Ariane R

    2006-08-01

    The study of emotional signaling has focused almost exclusively on the face and voice. In 2 studies, the authors investigated whether people can identify emotions from the experience of being touched by a stranger on the arm (without seeing the touch). In the 3rd study, they investigated whether observers can identify emotions from watching someone being touched on the arm. Two kinds of evidence suggest that humans can communicate numerous emotions with touch. First, participants in the United States (Study 1) and Spain (Study 2) could decode anger, fear, disgust, love, gratitude, and sympathy via touch at much-better-than-chance levels. Second, fine-grained coding documented specific touch behaviors associated with different emotions. In Study 3, the authors provide evidence that participants can accurately decode distinct emotions by merely watching others communicate via touch. The findings are discussed in terms of their contributions to affective science and the evolution of altruism and cooperation. (c) 2006 APA, all rights reserved

  12. The N- and C-terminal carbohydrate recognition domains of Haemonchus contortus galectin bind to distinct receptors of goat PBMC and contribute differently to its immunomodulatory functions in host-parasite interactions.

    Science.gov (United States)

    Lu, MingMin; Tian, XiaoWei; Yang, XinChao; Yuan, Cheng; Ehsan, Muhammad; Liu, XinChao; Yan, RuoFeng; Xu, LiXin; Song, XiaoKai; Li, XiangRui

    2017-09-05

    Hco-gal-m is a tandem-repeat galectin isolated from the adult worm of Haemonchus contortus. A growing body of studies have demonstrated that Hco-gal-m could exert its immunomodulatory effects on host peripheral blood mononuclear cells (PBMC) to facilitate the immune evasion. Our previous work revealed that C-terminal and N-terminal carbohydrate recognition domains (CRD) of Hco-gal-m had different sugar binding abilities. However, whether different domains of Hco-gal-m account differently for its multiple immunomodulatory functions in the host-parasite interaction remains to be elucidated. We found that the N-terminal CRD of Hco-gal-m (MNh) and the C-terminal CRD (MCh) could bind to goat peripheral blood mononuclear cells by distinct receptors: transmembrane protein 63A (TMEM63A) was a binding receptor of MNh, while transmembrane protein 147 (TMEM147) was a binding receptor of MCh. In addition, MCh was much more potent than MNh in inhibiting cell proliferation and inducing apoptosis, while MNh was much more effective in inhibiting NO production. Moreover, MNh could suppress the transcription of interferon-γ (IFN-γ), but MCh not. Our data suggested that these two CRDs of Hco-gal-m bind to distinct receptors and contributed differently to its ability to downregulate host immune response. These results will improve our understanding of galectins from parasitic nematodes contributing to the mechanism of parasitic immune evasion and continue to illustrate the diverse range of biological activities attributable to the galectin family.

  13. Education and Training: Is There Any Longer a Useful Distinction?

    Science.gov (United States)

    Hager, Paul; Laurent, John

    1990-01-01

    Although education and training were distinct concepts when Taylorism dominated the workplace, it is no longer appropriate to separate them. Today's highly competitive environment requires the education of a flexible, multiskilled workforce, not training for narrowly defined employment tasks. (SK)

  14. Identifying the distinct features of geometric structures for hole trapping to generate radicals on rutile TiO₂(110) in photooxidation using density functional theory calculations with hybrid functional.

    Science.gov (United States)

    Wang, Dong; Wang, Haifeng; Hu, P

    2015-01-21

    Using density functional theory calculations with HSE 06 functional, we obtained the structures of spin-polarized radicals on rutile TiO2(110), which is crucial to understand the photooxidation at the atomic level, and further calculate the thermodynamic stabilities of these radicals. By analyzing the results, we identify the structural features for hole trapping in the system, and reveal the mutual effects among the geometric structures, the energy levels of trapped hole states and their hole trapping capacities. Furthermore, the results from HSE 06 functional are compared to those from DFT + U and the stability trend of radicals against the number of slabs is tested. The effect of trapped holes on two important steps of the oxygen evolution reaction, i.e. water dissociation and the oxygen removal, is investigated and discussed.

  15. Definable davies' theorem

    DEFF Research Database (Denmark)

    Törnquist, Asger Dag; Weiss, W.

    2009-01-01

    We prove the following descriptive set-theoretic analogue of a theorem of R. 0. Davies: Every σ function f:ℝ × ℝ → ℝ can be represented as a sum of rectangular Σ functions if and only if all reals are constructible.......We prove the following descriptive set-theoretic analogue of a theorem of R. 0. Davies: Every σ function f:ℝ × ℝ → ℝ can be represented as a sum of rectangular Σ functions if and only if all reals are constructible....

  16. Defining local food

    DEFF Research Database (Denmark)

    Eriksen, Safania Normann

    2013-01-01

    Despite evolving local food research, there is no consistent definition of “local food.” Various understandings are utilized, which have resulted in a diverse landscape of meaning. The main purpose of this paper is to examine how researchers within the local food systems literature define local...... food, and how these definitions can be used as a starting point to identify a new taxonomy of local food based on three domains of proximity....

  17. Intergroup Leadership Across Distinct Subgroups and Identities.

    Science.gov (United States)

    Rast, David E; Hogg, Michael A; van Knippenberg, Daan

    2018-03-01

    Resolving intergroup conflict is a significant and often arduous leadership challenge, yet existing theory and research rarely, if ever, discuss or examine this situation. Leaders confront a significant challenge when they provide leadership across deep divisions between distinct subgroups defined by self-contained identities-The challenge is to avoid provoking subgroup identity distinctiveness threat. Drawing on intergroup leadership theory, three studies were conducted to test the core hypothesis that, where identity threat exists, leaders promoting an intergroup relational identity will be better evaluated and are more effective than leaders promoting a collective identity; in the absence of threat, leaders promoting a collective identity will prevail. Studies 1 and 2 ( N = 170; N = 120) supported this general proposition. Study 3 ( N = 136) extended these findings, showing that leaders promoting an intergroup relational identity, but not a collective identity, improved intergroup attitudes when participants experienced an identity distinctiveness threat.

  18. A distinction of two discourses concerning wellbeing

    DEFF Research Database (Denmark)

    Wistoft, Karen; Qvortrup, Lars

    2017-01-01

    and behavioral mental health interventions, while the latter defines wellbeing in positive terms with a focus on wellbeing as the result of learning and with pedagogical interventions that only indirectly can support the individual’s learning activity. The former sees wellbeing as the result of a “wellbeing cure......The article concerns the current discourses concerning well-being with the point that it is important to make a distinction between a healthcare oriented discourse and a learning oriented discourse. The former defines wellbeing in negative terms and looks at causally oriented aspects of wellbeing......”, while the latter sees wellbeing as the result of wellbeing learning processes....

  19. Defining and Distinguishing Traditional and Religious Terrorism

    OpenAIRE

    Gregg, Heather S.

    2014-01-01

    The article of record may be found at: http://dx.doi.org/10.1080/23296151.2016.1239978 thus offering few if any policy options for counterterrorism measures. This assumption about religious terrorism stems from two challenges in the literature: disproportionate attention to apocalyptic terrorism, and a lack of distinction between religious terrorism and its secular counterpart. This article, therefore, aims to do four things: define and differentiate religiously motivated terrorism from tr...

  20. Network Coded Software Defined Networking

    DEFF Research Database (Denmark)

    Krigslund, Jeppe; Hansen, Jonas; Roetter, Daniel Enrique Lucani

    2015-01-01

    Software Defined Networking (SDN) and Network Coding (NC) are two key concepts in networking that have garnered a large attention in recent years. On the one hand, SDN's potential to virtualize services in the Internet allows a large flexibility not only for routing data, but also to manage....... This paper advocates for the use of SDN to bring about future Internet and 5G network services by incorporating network coding (NC) functionalities. The inherent flexibility of both SDN and NC provides a fertile ground to envision more efficient, robust, and secure networking designs, that may also...

  1. Network Coded Software Defined Networking

    DEFF Research Database (Denmark)

    Hansen, Jonas; Roetter, Daniel Enrique Lucani; Krigslund, Jeppe

    2015-01-01

    Software defined networking has garnered large attention due to its potential to virtualize services in the Internet, introducing flexibility in the buffering, scheduling, processing, and routing of data in network routers. SDN breaks the deadlock that has kept Internet network protocols stagnant...... for decades, while applications and physical links have evolved. This article advocates for the use of SDN to bring about 5G network services by incorporating network coding (NC) functionalities. The latter constitutes a major leap forward compared to the state-of-the- art store and forward Internet paradigm...

  2. Defined contribution health benefits.

    Science.gov (United States)

    Fronstin, P

    2001-03-01

    This Issue Brief discusses the emerging issue of "defined contribution" (DC) health benefits. The term "defined contribution" is used to describe a wide variety of approaches to the provision of health benefits, all of which have in common a shift in the responsibility for payment and selection of health care services from employers to employees. DC health benefits often are mentioned in the context of enabling employers to control their outlay for health benefits by avoiding increases in health care costs. DC health benefits may also shift responsibility for choosing a health plan and the associated risks of choosing a plan from employers to employees. There are three primary reasons why some employers currently are considering some sort of DC approach. First, they are once again looking for ways to keep their health care cost increases in line with overall inflation. Second, some employers are concerned that the public "backlash" against managed care will result in new legislation, regulations, and litigation that will further increase their health care costs if they do not distance themselves from health care decisions. Third, employers have modified not only most employee benefit plans, but labor market practices in general, by giving workers more choice, control, and flexibility. DC-type health benefits have existed as cafeteria plans since the 1980s. A cafeteria plan gives each employee the opportunity to determine the allocation of his or her total compensation (within employer-defined limits) among various employee benefits (primarily retirement or health). Most types of DC health benefits currently being discussed could be provided within the existing employment-based health insurance system, with or without the use of cafeteria plans. They could also allow employees to purchase health insurance directly from insurers, or they could drive new technologies and new forms of risk pooling through which health care services are provided and financed. DC health

  3. Organization of Valence-Encoding and Projection-Defined Neurons in the Basolateral Amygdala

    Directory of Open Access Journals (Sweden)

    Anna Beyeler

    2018-01-01

    Full Text Available The basolateral amygdala (BLA mediates associative learning for both fear and reward. Accumulating evidence supports the notion that different BLA projections distinctly alter motivated behavior, including projections to the nucleus accumbens (NAc, medial aspect of the central amygdala (CeM, and ventral hippocampus (vHPC. Although there is consensus regarding the existence of distinct subsets of BLA neurons encoding positive or negative valence, controversy remains regarding the anatomical arrangement of these populations. First, we map the location of more than 1,000 neurons distributed across the BLA and recorded during a Pavlovian discrimination task. Next, we determine the location of projection-defined neurons labeled with retrograde tracers and use CLARITY to reveal the axonal path in 3-dimensional space. Finally, we examine the local influence of each projection-defined populations within the BLA. Understanding the functional and topographical organization of circuits underlying valence assignment could reveal fundamental principles about emotional processing.

  4. On Defining Mass

    Science.gov (United States)

    Hecht, Eugene

    2011-01-01

    Though central to any pedagogical development of physics, the concept of mass is still not well understood. Properly defining mass has proven to be far more daunting than contemporary textbooks would have us believe. And yet today the origin of mass is one of the most aggressively pursued areas of research in all of physics. Much of the excitement surrounding the Large Hadron Collider at CERN is associated with discovering the mechanism responsible for the masses of the elementary particles. This paper will first briefly examine the leading definitions, pointing out their shortcomings. Then, utilizing relativity theory, it will propose—for consideration by the community of physicists—a conceptual definition of mass predicated on the more fundamental concept of energy, more fundamental in that everything that has mass has energy, yet not everything that has energy has mass.

  5. Implementing Software Defined Radio

    CERN Document Server

    Grayver, Eugene

    2013-01-01

    Software Defined Radio makes wireless communications easier, more efficient, and more reliable. This book bridges the gap between academic research and practical implementation. When beginning a project, practicing engineers, technical managers, and graduate students can save countless hours by considering the concepts presented in these pages. The author covers the myriad options and trade-offs available when selecting an appropriate hardware architecture. As demonstrated here, the choice between hardware- and software-centric architecture can mean the difference between meeting an aggressive schedule and bogging down in endless design iterations. Because of the author’s experience overseeing dozens of failed and successful developments, he is able to present many real-life examples. Some of the key concepts covered are: Choosing the right architecture for the market – laboratory, military, or commercial Hardware platforms – FPGAs, GPPs, specialized and hybrid devices Standardization efforts to ens...

  6. Defining cyber warfare

    Directory of Open Access Journals (Sweden)

    Dragan D. Mladenović

    2012-04-01

    Full Text Available Cyber conflicts represent a new kind of warfare that is technologically developing very rapidly. Such development results in more frequent and more intensive cyber attacks undertaken by states against adversary targets, with a wide range of diverse operations, from information operations to physical destruction of targets. Nevertheless, cyber warfare is waged through the application of the same means, techniques and methods as those used in cyber criminal, terrorism and intelligence activities. Moreover, it has a very specific nature that enables states to covertly initiate attacks against their adversaries. The starting point in defining doctrines, procedures and standards in the area of cyber warfare is determining its true nature. In this paper, a contribution to this effort was made through the analysis of the existing state doctrines and international practice in the area of cyber warfare towards the determination of its nationally acceptable definition.

  7. Defining the mobilome.

    Science.gov (United States)

    Siefert, Janet L

    2009-01-01

    This chapter defines the agents that provide for the movement of genetic material which fuels the adaptive potential of life on our planet. The chapter has been structured to be broadly comprehensive, arbitrarily categorizing the mobilome into four classes: (1) transposons, (2) plasmids, (3) bacteriophage, and (4) self-splicing molecular parasites.Our increasing understanding of the mobilome is as dynamic as the mobilome itself. With continuing discovery, it is clear that nature has not confined these genomic agents of change to neat categories, but rather the classification categories overlap and intertwine. Massive sequencing efforts and their published analyses are continuing to refine our understanding of the extent of the mobilome. This chapter provides a framework to describe our current understanding of the mobilome and a foundation on which appreciation of its impact on genome evolution can be understood.

  8. Software Defined Networking

    DEFF Research Database (Denmark)

    Caba, Cosmin Marius

    Network Service Providers (NSP) often choose to overprovision their networks instead of deploying proper Quality of Services (QoS) mechanisms that allow for traffic differentiation and predictable quality. This tendency of overprovisioning is not sustainable for the simple reason that network...... resources are limited. Hence, to counteract this trend, current QoS mechanisms must become simpler to deploy and operate, in order to motivate NSPs to employ QoS techniques instead of overprovisioning. Software Defined Networking (SDN) represents a paradigm shift in the way telecommunication and data...... generic perspective (e.g. service provisioning speed, resources availability). As a result, new mechanisms for providing QoS are proposed, solutions for SDN-specific QoS challenges are designed and tested, and new network management concepts are prototyped, all aiming to improve QoS for network services...

  9. Defining the Anthropocene

    Science.gov (United States)

    Lewis, Simon; Maslin, Mark

    2016-04-01

    Time is divided by geologists according to marked shifts in Earth's state. Recent global environmental changes suggest that Earth may have entered a new human-dominated geological epoch, the Anthropocene. Should the Anthropocene - the idea that human activity is a force acting upon the Earth system in ways that mean that Earth will be altered for millions of years - be defined as a geological time-unit at the level of an Epoch? Here we appraise the data to assess such claims, first in terms of changes to the Earth system, with particular focus on very long-lived impacts, as Epochs typically last millions of years. Can Earth really be said to be in transition from one state to another? Secondly, we then consider the formal criteria used to define geological time-units and move forward through time examining whether currently available evidence passes typical geological time-unit evidence thresholds. We suggest two time periods likely fit the criteria (1) the aftermath of the interlinking of the Old and New Worlds, which moved species across continents and ocean basins worldwide, a geologically unprecedented and permanent change, which is also the globally synchronous coolest part of the Little Ice Age (in Earth system terms), and the beginning of global trade and a new socio-economic "world system" (in historical terms), marked as a golden spike by a temporary drop in atmospheric CO2, centred on 1610 CE; and (2) the aftermath of the Second World War, when many global environmental changes accelerated and novel long-lived materials were increasingly manufactured, known as the Great Acceleration (in Earth system terms) and the beginning of the Cold War (in historical terms), marked as a golden spike by the peak in radionuclide fallout in 1964. We finish by noting that the Anthropocene debate is politically loaded, thus transparency in the presentation of evidence is essential if a formal definition of the Anthropocene is to avoid becoming a debate about bias. The

  10. Teleology and Defining Sex.

    Science.gov (United States)

    Gamble, Nathan K; Pruski, Michal

    2018-07-01

    Disorders of sexual differentiation lead to what is often referred to as an intersex state. This state has medical, as well as some legal, recognition. Nevertheless, the question remains whether intersex persons occupy a state in between maleness and femaleness or whether they are truly men or women. To answer this question, another important conundrum needs to be first solved: what defines sex? The answer seems rather simple to most people, yet when morphology does not coincide with haplotypes, and genetics might not correlate with physiology the issue becomes more complex. This paper tackles both issues by establishing where the essence of sex is located and by superimposing that framework onto the issue of the intersex. This is achieved through giving due consideration to the biology of sexual development, as well as through the use of a teleological framework of the meaning of sex. Using a range of examples, the paper establishes that sex cannot be pinpointed to one biological variable but is rather determined by how the totality of one's biology is oriented towards biological reproduction. A brief consideration is also given to the way this situation could be comprehended from a Christian understanding of sex and suffering.

  11. Short- and Long-Term Quality of Life and Bowel Function in Patients With MRI-Defined, High-Risk, Locally Advanced Rectal Cancer Treated With an Intensified Neoadjuvant Strategy in the Randomized Phase 2 EXPERT-C Trial

    International Nuclear Information System (INIS)

    Sclafani, Francesco; Peckitt, Clare; Cunningham, David; Tait, Diana; Giralt, Jordi; Glimelius, Bengt; Keränen, Susana Roselló; Bateman, Andrew; Hickish, Tamas; Tabernero, Josep; Thomas, Janet; Brown, Gina; Oates, Jacqueline; Chau, Ian

    2015-01-01

    Objective: Intensified preoperative treatments have been increasingly investigated in locally advanced rectal cancer (LARC), but limited data are available for the impact of these regimens on quality of life (QoL) and bowel function (BF). We assessed these outcome measures in EXPERT-C, a randomized phase 2 trial of neoadjuvant capecitabine combined with oxaliplatin (CAPOX), followed by chemoradiation therapy (CRT), total mesorectal excision, and adjuvant CAPOX with or without cetuximab in magnetic resonance imaging-defined, high-risk LARC. Methods and Materials: QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR29 questionnaires. Bowel incontinence was assessed using the modified Fecal Incontinence Severity Index questionnaire. Results: Compared to baseline, QoL scores during preoperative treatment were better for symptoms associated with the primary tumor in the rectum (blood and mucus in stool, constipation, diarrhea, stool frequency, buttock pain) but worse for global health status, role functioning, and symptoms related to the specific safety profile of each treatment modality. During follow-up, improved emotional functioning and lessened anxiety and insomnia were observed, but deterioration of body image, increased urinary incontinence, less sexual interest (men), and increased impotence and dyspareunia were observed. Cetuximab was associated with a deterioration of global health status during neoadjuvant chemotherapy but did not have any long-term detrimental effect. An improvement in bowel continence was observed after preoperative treatment and 3 years after sphincter-sparing surgery. Conclusions: Intensifying neoadjuvant treatment by administering induction systemic chemotherapy before chemoradiation therapy improves tumor-related symptoms and does not appear to have a significantly detrimental effect on QoL and BF, in both the short and the long term

  12. Short- and Long-Term Quality of Life and Bowel Function in Patients With MRI-Defined, High-Risk, Locally Advanced Rectal Cancer Treated With an Intensified Neoadjuvant Strategy in the Randomized Phase 2 EXPERT-C Trial

    Energy Technology Data Exchange (ETDEWEB)

    Sclafani, Francesco; Peckitt, Clare [The Royal Marsden NHS Foundation Trust, London (United Kingdom); Cunningham, David, E-mail: david.cunningham@rmh.nhs.uk [The Royal Marsden NHS Foundation Trust, London (United Kingdom); Tait, Diana [The Royal Marsden NHS Foundation Trust, London (United Kingdom); Giralt, Jordi [Vall d' Hebron University Hospital, Universitat Autònoma de Barcelona, Department of Medical Oncology, Barcelona (Spain); Glimelius, Bengt [University of Uppsala, Uppsala (Sweden); Keränen, Susana Roselló [Biomedical Research Institute INCLIVA, Department of Hematology and Medical Oncology, University of Valencia (Spain); Bateman, Andrew [Southampton General Hospital, Cancer Sciences Unit, University of Southampton (United Kingdom); Hickish, Tamas [Poole Hospital NHS Foundation Trust, Department of Medical Oncology, Bournemouth University (United Kingdom); Tabernero, Josep [Vall d' Hebron University Hospital, Universitat Autònoma de Barcelona, Department of Medical Oncology, Barcelona (Spain); Thomas, Janet; Brown, Gina; Oates, Jacqueline; Chau, Ian [The Royal Marsden NHS Foundation Trust, London (United Kingdom)

    2015-10-01

    Objective: Intensified preoperative treatments have been increasingly investigated in locally advanced rectal cancer (LARC), but limited data are available for the impact of these regimens on quality of life (QoL) and bowel function (BF). We assessed these outcome measures in EXPERT-C, a randomized phase 2 trial of neoadjuvant capecitabine combined with oxaliplatin (CAPOX), followed by chemoradiation therapy (CRT), total mesorectal excision, and adjuvant CAPOX with or without cetuximab in magnetic resonance imaging-defined, high-risk LARC. Methods and Materials: QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR29 questionnaires. Bowel incontinence was assessed using the modified Fecal Incontinence Severity Index questionnaire. Results: Compared to baseline, QoL scores during preoperative treatment were better for symptoms associated with the primary tumor in the rectum (blood and mucus in stool, constipation, diarrhea, stool frequency, buttock pain) but worse for global health status, role functioning, and symptoms related to the specific safety profile of each treatment modality. During follow-up, improved emotional functioning and lessened anxiety and insomnia were observed, but deterioration of body image, increased urinary incontinence, less sexual interest (men), and increased impotence and dyspareunia were observed. Cetuximab was associated with a deterioration of global health status during neoadjuvant chemotherapy but did not have any long-term detrimental effect. An improvement in bowel continence was observed after preoperative treatment and 3 years after sphincter-sparing surgery. Conclusions: Intensifying neoadjuvant treatment by administering induction systemic chemotherapy before chemoradiation therapy improves tumor-related symptoms and does not appear to have a significantly detrimental effect on QoL and BF, in both the short and the long term.

  13. Defining an emerging disease.

    Science.gov (United States)

    Moutou, F; Pastoret, P-P

    2015-04-01

    Defining an emerging disease is not straightforward, as there are several different types of disease emergence. For example, there can be a 'real' emergence of a brand new disease, such as the emergence of bovine spongiform encephalopathy in the 1980s, or a geographic emergence in an area not previously affected, such as the emergence of bluetongue in northern Europe in 2006. In addition, disease can emerge in species formerly not considered affected, e.g. the emergence of bovine tuberculosis in wildlife species since 2000 in France. There can also be an unexpected increase of disease incidence in a known area and a known species, or there may simply be an increase in our knowledge or awareness of a particular disease. What all these emerging diseases have in common is that human activity frequently has a role to play in their emergence. For example, bovine spongiform encephalopathy very probably emerged as a result of changes in the manufacturing of meat-and-bone meal, bluetongue was able to spread to cooler climes as a result of uncontrolled trade in animals, and a relaxation of screening and surveillance for bovine tuberculosis enabled the disease to re-emerge in areas that had been able to drastically reduce the number of cases. Globalisation and population growth will continue to affect the epidemiology of diseases in years to come and ecosystems will continue to evolve. Furthermore, new technologies such as metagenomics and high-throughput sequencing are identifying new microorganisms all the time. Change is the one constant, and diseases will continue to emerge, and we must consider the causes and different types of emergence as we deal with these diseases in the future.

  14. Distinct signaling pathways leading to the induction of human β-defensin 2 by stimulating an electrolyticaly-generated acid functional water and double strand RNA in oral epithelial cells.

    Science.gov (United States)

    Gojoubori, Takahiro; Nishio, Yukina; Asano, Masatake; Nishida, Tetsuya; Komiyama, Kazuo; Ito, Koichi

    2014-04-01

    Defensins, a major family of cationic antimicrobial peptides, play important roles in innate immunity. In the present study, we investigated whether double-stranded RNA (dsRNA), a by-product of RNA virus replication, can induce human β-defensins-2 (hBD-2) expression in oral epithelial cells (OECs). We also examined the hBD-2-inducible activity of acid-electrolyzed functional water (FW). The results indicated that both dsRNA- and FW-induced hBD-2 expression in OECs. The induction efficiency was much higher for FW than for dsRNA. FW-induced production of hBD-2 was clearly observed by immunofluorescence staining. A luciferase assay was performed with 1.2 kb of the 5'-untranslated region (5'-UTR) of the hBD-2 gene. The results indicated that the nuclear factor-kappa B (NF-κB)-binding site proximal to the translation initiation site was indispensable for dsRNA-stimulated hBD-2 expression, but not in the case of FW. Moreover, FW-stimulated hBD-2 expression did not depend on NF-κB activity; instead, FW inhibited NF-κB activity. Pretreatment of the cells with specific inhibitors against NF-κB further confirmed NF-κB-independent hBD-2 induction by FW. In analogy to the results for intestinal epithelial cells (IECs), the dsRNA signal, but not FW, was sensed by toll-like receptor 3 (TLR3) in OECs. These results suggested that hBD-2 expression induced by dsRNA and FW is regulated by distinct mechanisms in OECs.

  15. Defining the cortical visual systems: "what", "where", and "how"

    Science.gov (United States)

    Creem, S. H.; Proffitt, D. R.; Kaiser, M. K. (Principal Investigator)

    2001-01-01

    The visual system historically has been defined as consisting of at least two broad subsystems subserving object and spatial vision. These visual processing streams have been organized both structurally as two distinct pathways in the brain, and functionally for the types of tasks that they mediate. The classic definition by Ungerleider and Mishkin labeled a ventral "what" stream to process object information and a dorsal "where" stream to process spatial information. More recently, Goodale and Milner redefined the two visual systems with a focus on the different ways in which visual information is transformed for different goals. They relabeled the dorsal stream as a "how" system for transforming visual information using an egocentric frame of reference in preparation for direct action. This paper reviews recent research from psychophysics, neurophysiology, neuropsychology and neuroimaging to define the roles of the ventral and dorsal visual processing streams. We discuss a possible solution that allows for both "where" and "how" systems that are functionally and structurally organized within the posterior parietal lobe.

  16. Common and distinct neural correlates of facial emotion processing in social anxiety disorder and Williams syndrome: A systematic review and voxel-based meta-analysis of functional resonance imaging studies.

    Science.gov (United States)

    Binelli, C; Subirà, S; Batalla, A; Muñiz, A; Sugranyés, G; Crippa, J A; Farré, M; Pérez-Jurado, L; Martín-Santos, R

    2014-11-01

    Social Anxiety Disorder (SAD) and Williams-Beuren Syndrome (WS) are two conditions which seem to be at opposite ends in the continuum of social fear but show compromised abilities in some overlapping areas, including some social interactions, gaze contact and processing of facial emotional cues. The increase in the number of neuroimaging studies has greatly expanded our knowledge of the neural bases of facial emotion processing in both conditions. However, to date, SAD and WS have not been compared. We conducted a systematic review of functional magnetic resonance imaging (fMRI) studies comparing SAD and WS cases to healthy control participants (HC) using facial emotion processing paradigms. Two researchers conducted comprehensive PubMed/Medline searches to identify all fMRI studies of facial emotion processing in SAD and WS. The following search key-words were used: "emotion processing"; "facial emotion"; "social anxiety"; "social phobia"; "Williams syndrome"; "neuroimaging"; "functional magnetic resonance"; "fMRI" and their combinations, as well as terms specifying individual facial emotions. We extracted spatial coordinates from each study and conducted two separate voxel-wise activation likelihood estimation meta-analyses, one for SAD and one for WS. Twenty-two studies met the inclusion criteria: 17 studies of SAD and five of WS. We found evidence for both common and distinct patterns of neural activation. Limbic engagement was common to SAD and WS during facial emotion processing, although we observed opposite patterns of activation for each disorder. Compared to HC, SAD cases showed hyperactivation of the amygdala, the parahippocampal gyrus and the globus pallidus. Compared to controls, participants with WS showed hypoactivation of these regions. Differential activation in a number of regions specific to either condition was also identified: SAD cases exhibited greater activation of the insula, putamen, the superior temporal gyrus, medial frontal regions and

  17. Definably compact groups definable in real closed fields.II

    OpenAIRE

    Barriga, Eliana

    2017-01-01

    We continue the analysis of definably compact groups definable in a real closed field $\\mathcal{R}$. In [3], we proved that for every definably compact definably connected semialgebraic group $G$ over $\\mathcal{R}$ there are a connected $R$-algebraic group $H$, a definable injective map $\\phi$ from a generic definable neighborhood of the identity of $G$ into the group $H\\left(R\\right)$ of $R$-points of $H$ such that $\\phi$ acts as a group homomorphism inside its domain. The above result and o...

  18. Counselor Identity: Conformity or Distinction?

    Science.gov (United States)

    McLaughlin, Jerry E.; Boettcher, Kathryn

    2009-01-01

    The authors explore 3 debates in other disciplines similar to counseling's identity debate in order to learn about common themes and outcomes. Conformity, distinction, and cohesion emerged as common themes. They conclude that counselors should retain their distinctive, humanistic approach rather than conforming to the dominant, medical approach.

  19. Phenotypes in defined genotypes including siblings with Usher syndrome.

    Science.gov (United States)

    Malm, Eva; Ponjavic, Vesna; Möller, Claes; Kimberling, William J; Andréasson, Sten

    2011-06-01

    To characterize visual function in defined genotypes including siblings with Usher syndrome. Thirteen patients with phenotypically different subtypes of Usher syndrome, including 3 families with affected siblings, were selected. Genetic analysis and ophthalmological examinations including visual fields, full-field electroretinography (ERG), multifocal electroretinography (mf ERG), and optical coherence tomography (OCT) were assessed. The patients' degree of visual handicap was evaluated by a questionnaire (ADL). Twelve of thirteen patients were genotyped as Usher 1B, 1D, 1F, 2A, 2C or 3A. In 12 of 13 patients examined with ERG the 30 Hz flickering light response revealed remaining cone function. In 3 of the patients with Usher type 1 mf ERG demonstrated a specific pattern, with a sharp distinction between the area with reduced function and the central area with remaining macular function and normal peak time. OCT demonstrated loss of foveal depression with distortion of the foveal architecture in the macula in all patients. The foveal thickness ranged from 159 to 384 µm and was not correlated to retinal function. Three siblings shared the same mutation for Usher 2C but in contrast to previous reports regarding this genotype, 1 of them diverged in phenotype with substantially normal visual fields, almost normal OCT and mf ERG findings, and only moderately reduced rod and cone function according to ERG. Evaluation of visual function comprising both the severity of the rod cone degeneration and the function in the macular region confirm phenotypical heterogeneity within siblings and between different genotypes of Usher syndrome.

  20. Unified thalamic model generates multiple distinct oscillations with state-dependent entrainment by stimulation.

    Directory of Open Access Journals (Sweden)

    Guoshi Li

    2017-10-01

    Full Text Available The thalamus plays a critical role in the genesis of thalamocortical oscillations, yet the underlying mechanisms remain elusive. To understand whether the isolated thalamus can generate multiple distinct oscillations, we developed a biophysical thalamic model to test the hypothesis that generation of and transition between distinct thalamic oscillations can be explained as a function of neuromodulation by acetylcholine (ACh and norepinephrine (NE and afferent synaptic excitation. Indeed, the model exhibited four distinct thalamic rhythms (delta, sleep spindle, alpha and gamma oscillations that span the physiological states corresponding to different arousal levels from deep sleep to focused attention. Our simulation results indicate that generation of these distinct thalamic oscillations is a result of both intrinsic oscillatory cellular properties and specific network connectivity patterns. We then systematically varied the ACh/NE and input levels to generate a complete map of the different oscillatory states and their transitions. Lastly, we applied periodic stimulation to the thalamic network and found that entrainment of thalamic oscillations is highly state-dependent. Our results support the hypothesis that ACh/NE modulation and afferent excitation define thalamic oscillatory states and their response to brain stimulation. Our model proposes a broader and more central role of the thalamus in the genesis of multiple distinct thalamo-cortical rhythms than previously assumed.

  1. Distinction

    OpenAIRE

    2010-01-01

    Pr Serge Haroche La Médaille d’or 2009 du CNRS est décernée au Pr Serge Haroche, titulaire de la chaire de Physique quantique depuis 2001. Serge Haroche est spécialiste de physique atomique et d’optique quantique. Il est l’un des fondateurs de l’électrodynamique quantique en cavité, domaine qui permet, par des expériences conceptuellement simples, d’éclairer les fondements de la théorie quantique et de réaliser des prototypes de systèmes de traitement quantique de l’information. Serge Haroche...

  2. Interaction proteomics analysis of polycomb proteins defines distinct PRC1 complexes in mammalian cells

    DEFF Research Database (Denmark)

    Vandamme, Julien; Völkel, Pamela; Rosnoblet, Claire

    2011-01-01

    Polycomb group (PcG) proteins maintain transcriptional repression of hundreds of genes involved in development, signaling or cancer using chromatin-based epigenetic mechanisms. Biochemical studies in Drosophila have revealed that PcG proteins associate in at least two classes of protein complexes...... known as Polycomb repressive complexes 1 and 2 (PRC1 and PRC2). Drosophila core PRC1 is composed of four subunits, Polycomb (Pc), Sex combs extra (Sce), Polyhomeotic (Ph), and Posterior sex combs (Psc). Each of these proteins has multiple orthologs in vertebrates classified respectively as the CBX, RING...... in order to identify interacting partners of CBX family proteins under the same experimental conditions. Our analysis identified with high confidence about 20 proteins co-eluted with CBX2 and CBX7 tagged proteins, about 40 with CBX4, and around 60 with CBX6 and CBX8. We provide evidences that the CBX...

  3. deep-orange and carnation define distinct stages in late endosomal biogenesis in Drosophila melanogaster

    OpenAIRE

    Sriram, V.; Krishnan, K.S.; Mayor, Satyajit

    2003-01-01

    Endosomal degradation is severely impaired in primary hemocytes from larvae of eye color mutants of Drosophila. Using high resolution imaging and immunofluorescence microscopy in these cells, products of eye color genes, deep-orange (dor) and carnation (car), are localized to large multivesicular Rab7-positive late endosomes containing Golgi-derived enzymes. These structures mature into small sized Dor-negative, Car-positive structures, which subsequently fuse to form tubular lysosomes. Defec...

  4. Defining distinct negative beliefs about uncertainty: validating the factor structure of the Intolerance of Uncertainty Scale.

    Science.gov (United States)

    Sexton, Kathryn A; Dugas, Michel J

    2009-06-01

    This study examined the factor structure of the English version of the Intolerance of Uncertainty Scale (IUS; French version: M. H. Freeston, J. Rhéaume, H. Letarte, M. J. Dugas, & R. Ladouceur, 1994; English version: K. Buhr & M. J. Dugas, 2002) using a substantially larger sample than has been used in previous studies. Nonclinical undergraduate students and adults from the community (M age = 23.74 years, SD = 6.36; 73.0% female and 27.0% male) who participated in 16 studies in the Anxiety Disorders Laboratory at Concordia University in Montreal, Canada were randomly assigned to 2 datasets. Exploratory factor analysis with the 1st sample (n = 1,230) identified 2 factors: the beliefs that "uncertainty has negative behavioral and self-referent implications" and that "uncertainty is unfair and spoils everything." This 2-factor structure provided a good fit to the data (Bentler-Bonett normed fit index = .96, comparative fit index = .97, standardized root-mean residual = .05, root-mean-square error of approximation = .07) upon confirmatory factor analysis with the 2nd sample (n = 1,221). Both factors showed similarly high correlations with pathological worry, and Factor 1 showed stronger correlations with generalized anxiety disorder analogue status, trait anxiety, somatic anxiety, and depressive symptomatology. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

  5. A Novel Algorithm for the Generation of Distinct Kinematic Chain

    Science.gov (United States)

    Medapati, Sreenivasa Reddy; Kuchibhotla, Mallikarjuna Rao; Annambhotla, Balaji Srinivasa Rao

    2016-07-01

    Generation of distinct kinematic chains is an important topic in the design of mechanisms for various industrial applications i.e., robotic manipulator, tractor, crane etc. Many researchers have intently focused on this area and explained various processes of generating distinct kinematic chains which are laborious and complex. It is desirable to enumerate the kinematic chains systematically to know the inherent characteristics of a chain related to its structure so that all the distinct chains can be analyzed in depth, prior to the selection of a chain for a purpose. This paper proposes a novel and simple method with set of rules defined to eliminate isomorphic kinematic chains generating distinct kinematic chains. Also, this method simplifies the process of generating distinct kinematic chains even at higher levels i.e., 10-link, 11-link with single and multiple degree of freedom.

  6. The Distinction Between Curative and Assistive Technology.

    Science.gov (United States)

    Stramondo, Joseph A

    2018-05-01

    Disability activists have sometimes claimed their disability has actually increased their well-being. Some even say they would reject a cure to keep these gains. Yet, these same activists often simultaneously propose improvements to the quality and accessibility of assistive technology. However, for any argument favoring assistive over curative technology (or vice versa) to work, there must be a coherent distinction between the two. This line is already vague and will become even less clear with the emergence of novel technologies. This paper asks and tries to answer the question: what is it about the paradigmatic examples of curative and assistive technologies that make them paradigmatic and how can these defining features help us clarify the hard cases? This analysis will begin with an argument that, while the common views of this distinction adequately explain the paradigmatic cases, they fail to accurately pick out the relevant features of those technologies that make them paradigmatic and to provide adequate guidance for parsing the hard cases. Instead, it will be claimed that these categories of curative or assistive technologies are defined by the role the technologies play in establishing a person's relational narrative identity as a member of one of two social groups: disabled people or non-disabled people.

  7. Many-Objective Distinct Candidates Optimization using Differential Evolution

    DEFF Research Database (Denmark)

    Justesen, Peter; Ursem, Rasmus Kjær

    2010-01-01

    for each objective. The Many-Objective Distinct Candidates Optimization using Differential Evolution (MODCODE) algorithm takes a novel approach by focusing search using a user-defined number of subpopulations each returning a distinct optimal solution within the preferred region of interest. In this paper......, we present the novel MODCODE algorithm incorporating the ROD measure to measure and control candidate distinctiveness. MODCODE is tested against GDE3 on three real world centrifugal pump design problems supplied by Grundfos. Our algorithm outperforms GDE3 on all problems with respect to all...

  8. Defining asthma in genetic studies

    NARCIS (Netherlands)

    Koppelman, GH; Postma, DS; Meijer, G.

    1999-01-01

    Genetic studies have been hampered by the lack of a gold standard to diagnose asthma. The complex nature of asthma makes it more difficult to identify asthma genes. Therefore, approaches to define phenotypes, which have been successful in other genetically complex diseases, may be applied to define

  9. Wetlands Restoration Definitions and Distinctions

    Science.gov (United States)

    Ecological restoration is a valuable endeavor that has proven very difficult to define. The term indicates that degraded and destroyed natural wetland systems will be reestablished to sites where they once existed. But, what wetland ecosystems are we talki

  10. Defining and Distinguishing Secular and Religious Terrorism

    Directory of Open Access Journals (Sweden)

    Heather S. Gregg

    2014-04-01

    Full Text Available Religious terrorism is typically characterised as acts of unrestrained, irrational and indiscriminant violence, thus offering few if any policy options for counterterrorism measures. This assumption about religious terrorism stems from two challenges in the literature: disproportionate attention to apocalyptic terrorism, and a lack of distinction between religious terrorism and its secular counterpart. This article, therefore, aims to do four things: define and differentiate religiously motivated terrorism from traditional terrorism; investigate three goals of religious terrorism (fomenting the apocalypse, creating a religious government, and establishing a religiously pure state; consider the role of leadership and target selection of religious terrorists; and, finally, suggest a range of counterterrorism strategies based on these observations.

  11. Bruxism defined and graded: an international consensus.

    Science.gov (United States)

    Lobbezoo, F; Ahlberg, J; Glaros, A G; Kato, T; Koyano, K; Lavigne, G J; de Leeuw, R; Manfredini, D; Svensson, P; Winocur, E

    2013-01-01

    To date, there is no consensus about the definition and diagnostic grading of bruxism. A written consensus discussion was held among an international group of bruxism experts as to formulate a definition of bruxism and to suggest a grading system for its operationalisation. The expert group defined bruxism as a repetitive jaw-muscle activity characterised by clenching or grinding of the teeth and/or by bracing or thrusting of the mandible. Bruxism has two distinct circadian manifestations: it can occur during sleep (indicated as sleep bruxism) or during wakefulness (indicated as awake bruxism). For the operationalisation of this definition, the expert group proposes a diagnostic grading system of 'possible', 'probable' and 'definite' sleep or awake bruxism. The proposed definition and grading system are suggested for clinical and research purposes in all relevant dental and medical domains. © 2012 Blackwell Publishing Ltd.

  12. Theoretical approaches to elections defining

    OpenAIRE

    Natalya V. Lebedeva

    2011-01-01

    Theoretical approaches to elections defining develop the nature, essence and content of elections, help to determine their place and a role as one of the major national law institutions in democratic system.

  13. Theoretical approaches to elections defining

    Directory of Open Access Journals (Sweden)

    Natalya V. Lebedeva

    2011-01-01

    Full Text Available Theoretical approaches to elections defining develop the nature, essence and content of elections, help to determine their place and a role as one of the major national law institutions in democratic system.

  14. Defining Modules, Modularity and Modularization

    DEFF Research Database (Denmark)

    Miller, Thomas Dedenroth; Pedersen, Per Erik Elgård

    The paper describes the evolution of the concept of modularity in a historical perspective. The main reasons for modularity are: create variety, utilize similarities, and reduce complexity. The paper defines the terms: Module, modularity, and modularization.......The paper describes the evolution of the concept of modularity in a historical perspective. The main reasons for modularity are: create variety, utilize similarities, and reduce complexity. The paper defines the terms: Module, modularity, and modularization....

  15. On Undefined and Meaningless in Lambda Definability

    OpenAIRE

    de Vries, Fer-Jan

    2016-01-01

    We distinguish between undefined terms as used in lambda definability of partial recursive functions and meaningless terms as used in infinite lambda calculus for the infinitary terms models that generalise the Bohm model. While there are uncountable many known sets of meaningless terms, there are four known sets of undefined terms. Two of these four are sets of meaningless terms. In this paper we first present set of sufficient conditions for a set of lambda terms to se...

  16. Defining safety goals. 2. Basic Consideration on Defining Safety Goals

    International Nuclear Information System (INIS)

    Hakata, T.

    2001-01-01

    cancer and severe hereditary effects are 10 x 10 -2 /Sv and 1.3 x10 -2 /Sv, respectively. The basic safety goals can be expressed by the complementary accumulative distribution function (CCDF) of dose versus frequencies of events: Pc(C > Cp) 5 (Cp/Co) -α . The aversion factor a is here expressed by the following arbitrary equation, which gives a polynomial curve of the order of m on a logarithmic plane: α = a+b(log(Cp/Co)) m , where: Pc = CCDF frequency for Cp (/yr), Cp = dose (mSv), Co = Cp for Pc =1, a, b, m = constants. Figure 1 shows a typical tolerable risk profile (risk limit curve), which is drawn so that all the points obtained in the previous discussions are above the curve (Co=1, a=1, b=0.0772, and m = 2). Safety criteria by ANS (Ref. 2) and SHE (Ref. 3) are shown in Fig. 1 for comparison. An aversion of a factor of 2 is resulted between 1 mSv and 1 Sv. No ALARA is included, which must be considered in defining specific safety goals. The frequency of a single class of events must be lower than the CCDF profile, and a curve lower by a factor of 10 is drawn in Fig. 1. The doses referenced in the current Japanese safety guidelines and site criteria are shown in Fig. 1. The referenced doses seem reasonable, considering the conservatism in the analysis of design-basis accidents. Specific safety goals for each sort of facility can be defined based on the basic safety goals, reflecting the characteristics of the facilities and considering ALARA. The indexes of engineering terms, such as CMF and LERF, are preferable for nuclear power plants, although interpretation from dose to the engineering terms is needed. Other indexes may be used (such as frequency of criticality accidents, etc.) for facilities except for power plants. The applicability of safety goals will thus be improved. Figure 2 shows the relative risk factors (1, 1%, and 0.1%) versus the severity of radiation effects. This might indicate the adequacy of the risk factors. The absolute risk limits, which

  17. Defining Plagiarism: A Literature Review

    Directory of Open Access Journals (Sweden)

    Akbar Akbar

    2018-02-01

    Full Text Available Plagiarism has repeatedly occurred in Indonesia, resulting in focusing on such academic misbehavior as a “central issue” in Indonesian higher education. One of the issues of addressing plagiarism in higher education is that there is a confusion of defining plagiarism. It seems that Indonesian academics had different perception when defining plagiarism. This article aims at exploring the issue of plagiarism by helping define plagiarism to address confusion among Indonesian academics. This article applies literature review by firs finding relevant articles after identifying databases for literature searching. After the collection of required articles for review, the articles were synthesized before presenting the findings. This study has explored the definition of plagiarism in the context of higher education. This research found that plagiarism is defined in the relation of criminal acts. The huge numbers of discursive features used position plagiaristic acts as an illegal deed. This study also found that cultural backgrounds and exposure to plagiarism were influential in defining plagiarism.

  18. The neural signatures of distinct psychopathic traits.

    Science.gov (United States)

    Carré, Justin M; Hyde, Luke W; Neumann, Craig S; Viding, Essi; Hariri, Ahmad R

    2013-01-01

    Recent studies suggest that psychopathy may be associated with dysfunction in the neural circuitry supporting both threat- and reward-related processes. However, these studies have involved small samples and often focused on extreme groups. Thus, it is unclear to what extent current findings may generalize to psychopathic traits in the general population. Furthermore, no studies have systematically and simultaneously assessed associations between distinct psychopathy facets and both threat- and reward-related brain function in the same sample of participants. Here, we examined the relationship between threat-related amygdala reactivity and reward-related ventral striatum (VS) reactivity and variation in four facets of self-reported psychopathy in a sample of 200 young adults. Path models indicated that amygdala reactivity to fearful facial expressions is negatively associated with the interpersonal facet of psychopathy, whereas amygdala reactivity to angry facial expressions is positively associated with the lifestyle facet. Furthermore, these models revealed that differential VS reactivity to positive versus negative feedback is negatively associated with the lifestyle facet. There was suggestive evidence for gender-specific patterns of association between brain function and psychopathy facets. Our findings are the first to document differential associations between both threat- and reward-related neural processes and distinct facets of psychopathy and thus provide a more comprehensive picture of the pattern of neural vulnerabilities that may predispose to maladaptive outcomes associated with psychopathy.

  19. The Potential Use of Legitimate Force for the Preservation of Order: Defining the Inherent Role of Public Police Through Policing Functions that cannot be Carried out by Private Police

    Directory of Open Access Journals (Sweden)

    Jasmina Arnež

    2016-12-01

    Full Text Available In the UK, private policing institutions have been rapidly increasing since the 1980s, so the lines between public- and private police have been blurred. This paper explores whether there is a policing function that is inherent in public police and if so, why it occupies this position. It integrates Rousseau’s social contract theory, Bittner’s definition of police functions, Brodeur’s reasoning on force and Loader and Walker’s concept of ‘policing as public good’ to argue that the potential use of legitimate force for the preservation of order is the function intrinsic to public police. It shows why it cannot and should not be carried out by private police and outlines how it depends on police legitimacy. It concludes with an abstract rethinking of public-state-police relations to determine that this function remains in the realm of public policing.

  20. Modular Software-Defined Radio

    Directory of Open Access Journals (Sweden)

    Rhiemeier Arnd-Ragnar

    2005-01-01

    Full Text Available In view of the technical and commercial boundary conditions for software-defined radio (SDR, it is suggestive to reconsider the concept anew from an unconventional point of view. The organizational principles of signal processing (rather than the signal processing algorithms themselves are the main focus of this work on modular software-defined radio. Modularity and flexibility are just two key characteristics of the SDR environment which extend smoothly into the modeling of hardware and software. In particular, the proposed model of signal processing software includes irregular, connected, directed, acyclic graphs with random node weights and random edges. Several approaches for mapping such software to a given hardware are discussed. Taking into account previous findings as well as new results from system simulations presented here, the paper finally concludes with the utility of pipelining as a general design guideline for modular software-defined radio.

  1. Defining and Classifying Interest Groups

    DEFF Research Database (Denmark)

    Baroni, Laura; Carroll, Brendan; Chalmers, Adam

    2014-01-01

    The interest group concept is defined in many different ways in the existing literature and a range of different classification schemes are employed. This complicates comparisons between different studies and their findings. One of the important tasks faced by interest group scholars engaged...... in large-N studies is therefore to define the concept of an interest group and to determine which classification scheme to use for different group types. After reviewing the existing literature, this article sets out to compare different approaches to defining and classifying interest groups with a sample...... in the organizational attributes of specific interest group types. As expected, our comparison of coding schemes reveals a closer link between group attributes and group type in narrower classification schemes based on group organizational characteristics than those based on a behavioral definition of lobbying....

  2. ON DEFINING S-SPACES

    Directory of Open Access Journals (Sweden)

    Francesco Strati

    2013-05-01

    Full Text Available The present work is intended to be an introduction to the Superposition Theory of David Carfì. In particular I shall depict the meaning of his brand new theory, on the one hand in an informal fashion and on the other hand by giving a formal approach of the algebraic structure of the theory: the S-linear algebra. This kind of structure underpins the notion of S-spaces (or Carfì-spaces by defining both its properties and its nature. Thus I shall define the S-triple as the fundamental principle upon which the S-linear algebra is built up.

  3. Camptothecin and khat (Catha edulis Forsk. induced distinct cell death phenotypes involving modulation of c-FLIPL, Mcl-1, procaspase-8 and mitochondrial function in acute myeloid leukemia cell lines

    Directory of Open Access Journals (Sweden)

    Fossan Kjell O

    2009-11-01

    Full Text Available Abstract Background An organic extract of the recreational herb khat (Catha edulis Forsk. triggers cell death in various leukemia cell lines in vitro. The chemotherapeutics camptothecin, a plant alkaloid topoisomerase I inhibitor, was tested side-by-side with khat in a panel of acute myeloid leukemia cell lines to elucidate mechanisms of toxicity. Results Khat had a profound effect on MOLM-13 cells inducing mitochondrial damage, chromatin margination and morphological features of autophagy. The effects of khat on mitochondrial ultrastructure in MOLM-13 correlated with strongly impaired routine respiration, an effect neither found in the khat-resistant MV-4-11 cells nor in camptothecin treated cells. Enforced expression of anti-apoptotic Bcl-2 protein provided protection against camptothecin-induced cell death and partly against khat toxicity. Khat-induced cell death in MOLM-13 cells included reduced levels of anti-apoptotic Mcl-1 protein, while both khat and camptothecin induced c-FLIPL cleavage and procaspase-8 activation. Conclusion Khat activated a distinct cell death pathway in sensitive leukemic cells as compared to camptothecin, involving mitochondrial damage and morphological features of autophagy. This suggests that khat should be further explored in the search for novel experimental therapeutics.

  4. Presidential address: distinction or extinction.

    Science.gov (United States)

    Pressman, Barry D

    2008-10-01

    Despite its continuing scientific successes in imaging, radiology as a specialty is faced with a very difficult and competitive environment. Nonradiologists are more and more interested in vertically integrating imaging into their practices, while teleradiology and picture archiving and communication systems are resulting in the greater isolation of radiologists. Commoditization is a realistic and devastating threat to the survival and professionalism of the specialty. To remain viable as a specialty, radiologists must elevate their practice by subspecializing, becoming more involved with clinical care, and actively interacting with patients and referring clinicians. Distinction will prevent extinction.

  5. Impact of a systolic parameter, defined as the ratio of right brachial pre-ejection period to ejection time, on the relationship between brachial-ankle pulse wave velocity and left ventricular diastolic function.

    Science.gov (United States)

    Hsu, Po-Chao; Lin, Tsung-Hsien; Lee, Chee-Siong; Chu, Chun-Yuan; Su, Ho-Ming; Voon, Wen-Chol; Lai, Wen-Ter; Sheu, Sheng-Hsiung

    2011-04-01

    Arterial stiffness is correlated with left ventricular (LV) diastolic function as well as susceptibility to LV systolic function. Therefore, if LV systolic function is not known, the relationship between arterial stiffness and LV diastolic function is difficult to determine. A total of 260 patients were included in the study. The brachial-ankle pulse wave velocity (baPWV) and the ratio of right brachial pre-ejection period to ejection time (rbPEP/rbET) were measured using an ABI-form device. Patients were classified into four groups. Groups 1, 2, 3 and 4 were patients with rbPEP/rbET and baPWV below the median, rbPEP/rbET above but baPWV below the median, rbPET/rbET below but baPWV above the median, and rbPET/rbET and baPWV above the median, respectively. The LV ejection fractions in groups 1 and 3 were higher than those in groups 2 and 4 (Pwave velocity to Ea that were comparable to those in groups 3 and 4. In conclusion, rbPEP/rbET had an impact on the relationship between baPWV and LV diastolic function. In patients with high rbPEP/rbET but low baPWV, low baPWV may not indicate good LV diastolic function but implies that cardiac dysfunction may precede vascular dysfunction in such patients. When interpreting the relationship between baPWV and LV diastolic function, the rbPEP/rbET value obtained from the same examination should be considered.

  6. Defining and Differentiating the Makerspace

    Science.gov (United States)

    Dousay, Tonia A.

    2017-01-01

    Many resources now punctuate the maker movement landscape. However, some schools and communities still struggle to understand this burgeoning movement. How do we define these spaces and differentiate them from previous labs and shops? Through a multidimensional framework, stakeholders should consider how the structure, access, staffing, and tools…

  7. Indico CONFERENCE: Define the Programme

    CERN Multimedia

    CERN. Geneva; Ferreira, Pedro

    2017-01-01

    In this tutorial you are going to learn how to define the programme of a conference in Indico. The program of your conference is divided in different “tracks”. Tracks represent the subject matter of the conference, such as “Online Computing”, “Offline Computing”, and so on.

  8. X marks the spot : structural and functional brain mapping in a genetically defined group at high risk of autism symptoms (47,XXY), and a comparison with idiopathic autism spectrum disorder

    NARCIS (Netherlands)

    Goddard, Marcia Naomi

    2015-01-01

    Klinefelter syndrome (47,XXY) is associated with a wide range of behavioral problems, including autism symptomatology. In the current thesis, brain structure and function were assesed in boys with 47,XXY, boys with idiopathic autism spectrum disorder, and non-clinical controls, using multiple

  9. Reliability for systems of degrading components with distinct component shock sets

    International Nuclear Information System (INIS)

    Song, Sanling; Coit, David W.; Feng, Qianmei

    2014-01-01

    This paper studies reliability for multi-component systems subject to dependent competing risks of degradation wear and random shocks, with distinct shock sets. In practice, many systems are exposed to distinct and different types of shocks that can be categorized according to their sizes, function, affected components, etc. Previous research primarily focuses on simple systems with independent failure processes, systems with independent component time-to-failure, or components that share the same shock set or type of shocks. In our new model, we classify random shocks into different sets based on their sizes or function. Shocks with specific sizes or function can selectively affect one or more components in the system but not necessarily all components. Additionally the shocks from the different shock sets can arrive at different rates and have different relative magnitudes. Preventive maintenance (PM) optimization is conducted for the system with different component shock sets. Decision variables for two different maintenance scheduling problems, the PM replacement time interval, and the PM inspection time interval, are determined by minimizing a defined system cost rate. Sensitivity analysis is performed to provide insight into the behavior of the proposed maintenance policies. These models can be applied directly or customized for many complex systems that experience dependent competing failure processes with different component shock sets. A MEMS (Micro-electro mechanical systems) oscillator is a typical system subject to dependent and competing failure processes, and it is used as a numerical example to illustrate our new reliability and maintenance models

  10. Overexpressed Genes/ESTs and Character