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Sample records for acquire distinct activation

  1. Genetic Determinism and the Innate-Acquired Distinction in Medicine.

    Science.gov (United States)

    Kronfeldner, Maria E

    2009-06-01

    This article illustrates in which sense genetic determinism is still part of the contemporary interactionist consensus in medicine. Three dimensions of this consensus are discussed: kinds of causes, a continuum of traits ranging from monogenetic diseases to car accidents, and different kinds of determination due to different norms of reaction. On this basis, this article explicates in which sense the interactionist consensus presupposes the innate-acquired distinction. After a descriptive Part 1, Part 2 reviews why the innate-acquired distinction is under attack in contemporary philosophy of biology. Three arguments are then presented to provide a limited and pragmatic defense of the distinction: an epistemic, a conceptual, and a historical argument. If interpreted in a certain manner, and if the pragmatic goals of prevention and treatment (ideally specifying what medicine and health care is all about) are taken into account, then the innate-acquired distinction can be a useful epistemic tool. It can help, first, to understand that genetic determination does not mean fatalism, and, second, to maintain a system of checks and balances in the continuing nature-nurture debates.

  2. Microglia acquire distinct activation profiles depending on the degree of alpha-synuclein neuropathology in a rAAV based model of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Vanesa Sanchez-Guajardo

    Full Text Available Post-mortem analysis of brains from Parkinson's disease (PD patients strongly supports microglia activation and adaptive immunity as factors contributing to disease progression. Such responses may be triggered by alpha-synuclein (alpha-syn, which is known to be the main constituent of the aggregated proteins found in Lewy bodies in the brains of PD patients. To investigate this we used a recombinant viral vector to express human alpha-syn in rat midbrain at levels that induced neuronal pathology either in the absence or the presence of dopaminergic cell death, thereby mimicking early or late stages of the disease. Microglia activation was assessed by stereological quantification of Mac1+ cells, as well as the expression patterns of CD68 and MCH II. In our study, when alpha-syn induced neuronal pathology but not cell death, a fast transient increase in microglia cell numbers resulted in the long-term induction of MHC II+ microglia, denoting antigen-presenting ability. On the other hand, when alpha-syn induced both neuronal pathology and cell death, there was a delayed increase in microglia cell numbers, which correlated with long-lasting CD68 expression and a morphology reminiscent of peripheral macrophages. In addition T-lymphocyte infiltration, as judged by the presence of CD4+ and CD8+ cells, showed distinct kinetics depending on the degree of neurodegeneration, and was significantly higher when cell death occurred. We have thus for the first time shown that the microglial response differs depending on whether alpha-syn expression results on cell death or not, suggesting that microglia may play different roles during disease progression. Furthermore, our data suggest that the microglial response is modulated by early events related to alpha-syn expression in substantia nigra and persists at the long term.

  3. The electrodiagnostic distinctions between chronic familial and acquired demyelinative neuropathies.

    Science.gov (United States)

    Lewis, R A; Sumner, A J

    1982-06-01

    We compared the electrodiagnostic studies of 40 patients with chronic acquired demyelinative neuropathy and 18 patients with familial demyelinative neuropathy. Patients with acquired neuropathy had differential slowing of conduction velocity when distal latencies were compared with more proximal conduction velocities in the same nerve, when equivalent segments of different nerves were compared, and when dispersion of compound motor action potentials was examined. Conduction block was noted in some patients. Patients with familial disease had uniform conduction slowly of all nerve segments, and conduction block was not seen. Chronic acquired demyelinative neuropathy is characterized by multifocal slowing of nerve conduction, whereas familial demyelinative neuropathy is characterized by uniform conduction slowing.

  4. Evidence for distinct modes of solar activity

    CERN Document Server

    Usoskin, I G; Gallet, Y; Roth, R; Licht, A; Joos, F; Kovaltsov, G A; Thebault, E; Khokhlov, A

    2014-01-01

    Aims. The Sun shows strong variability in its magnetic activity, from Grand minima to Grand maxima, but the nature of the variability is not fully understood, mostly because of the insufficient length of the directly observed solar activity records and of uncertainties related to long-term reconstructions. Here we present a new adjustment-free reconstruction of solar activity over three millennia and study its different modes. Methods. We present a new adjustment-free, physical reconstruction of solar activity over the past three millennia, using the latest verified carbon cycle, 14C production, and archeomagnetic field models. This great improvement allowed us to study different modes of solar activity at an unprecedented level of details. Results. The distribution of solar activity is clearly bi-modal, implying the existence of distinct modes of activity. The main regular activity mode corresponds to moderate activity that varies in a relatively narrow band between sunspot numbers about 20 and 67. The exist...

  5. Soft tissue sarcoma subtypes exhibit distinct patterns of acquired uniparental disomy

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    Tuna Musaffe

    2012-12-01

    Full Text Available Abstract Background Soft tissue sarcomas (STS are heterogeneous mesenchymal tumors with diverse subtypes. STS can be classified into two main categories according to the type of genomic alteration: recurrent translocation driven STS, and non-recurrent translocations. However, little has known about acquired uniparental disomy in STS. Methods In this study, we analyzed SNP microarray data to determine the frequency and distribution patterns of acquired uniparental disomy (aUPD in major soft tissue sarcoma (STS subtypes using CNAG and R softwares. Results We identified recurrent aUPD regions specific to alveolar rhabdomyosarcoma with the most frequent at 11p15.4, gastrointestinal stromal tumor at 1p36.11-p35.3, leiomyosarcoma at 17p13.3-p13.1, myxofibrosarcoma at 1p35.1-p34.2 and 16q23.3-q24.1, and pleomorphic liposarcoma at 13q13.2-q13.3 and 13q14.11-q14.2. In contrast, specific recurrent aUPD regions were not identified in dedifferentiated liposarcoma, Ewing sarcoma, myxoid/round cell liposarcoma, and synovial sarcoma. Strikingly total, centromeric and segmental aUPD regions are more frequent in STS that do not exhibit recurrent translocation events. Conclusions Our study yields a detailed map of aUPD across 9 diverse STS subtypes and suggests the potential location of several novel tumor suppressor genes and oncogenes.

  6. Multinational Exploration of Acquired R&D Activities

    DEFF Research Database (Denmark)

    Gammelgaard, Jens

    2004-01-01

    This paper presents the results of a survey of 54 Danish multinational corporations that haveacquired activities abroad. The role of the acquired R&D units was the focus of the survey,particularly with respect to the schism between basic and applied R&D, and the schismbetween autonomous and network...... a combination of basic andnetwork-oriented R&D activities when focusing on capability development.Keywords: Acquisition; Research and Development (R&D), Basic R&D, Applied R&D,Autonomy, Network, Capabilities....

  7. Different activation signals induce distinct mast cell degranulation strategies

    Science.gov (United States)

    Sibilano, Riccardo; Marichal, Thomas; Reber, Laurent L.; Cenac, Nicolas; McNeil, Benjamin D.; Dong, Xinzhong; Hernandez, Joseph D.; Sagi-Eisenberg, Ronit; Hammel, Ilan; Roers, Axel; Valitutti, Salvatore; Tsai, Mindy

    2016-01-01

    Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-β during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P–dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation. PMID:27643442

  8. Chlamydia trachomatis co-opts GBF1 and CERT to acquire host sphingomyelin for distinct roles during intracellular development.

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    Cherilyn A Elwell

    2011-09-01

    Full Text Available The strain designated Chlamydia trachomatis serovar that was used for experiments in this paper is Chlamydia muridarum, a species closely related to C. trachomatis (and formerly termed the Mouse Pneumonitis strain of C. trachomatis. [corrected]. The obligate intracellular pathogen Chlamydia trachomatis replicates within a membrane-bound inclusion that acquires host sphingomyelin (SM, a process that is essential for replication as well as inclusion biogenesis. Previous studies demonstrate that SM is acquired by a Brefeldin A (BFA-sensitive vesicular trafficking pathway, although paradoxically, this pathway is dispensable for bacterial replication. This finding suggests that other lipid transport mechanisms are involved in the acquisition of host SM. In this work, we interrogated the role of specific components of BFA-sensitive and BFA-insensitive lipid trafficking pathways to define their contribution in SM acquisition during infection. We found that C. trachomatis hijacks components of both vesicular and non-vesicular lipid trafficking pathways for SM acquisition but that the SM obtained from these separate pathways is being utilized by the pathogen in different ways. We show that C. trachomatis selectively co-opts only one of the three known BFA targets, GBF1, a regulator of Arf1-dependent vesicular trafficking within the early secretory pathway for vesicle-mediated SM acquisition. The Arf1/GBF1-dependent pathway of SM acquisition is essential for inclusion membrane growth and stability but is not required for bacterial replication. In contrast, we show that C. trachomatis co-opts CERT, a lipid transfer protein that is a key component in non-vesicular ER to trans-Golgi trafficking of ceramide (the precursor for SM, for C. trachomatis replication. We demonstrate that C. trachomatis recruits CERT, its ER binding partner, VAP-A, and SM synthases, SMS1 and SMS2, to the inclusion and propose that these proteins establish an on-site SM biosynthetic

  9. Welfare effects of deterrence-motivated activation policy: the case of distinct activation-disutility

    DEFF Research Database (Denmark)

    Rasmussen, Martin

    . We consider a distinct disutility for participating in activation programmes. One motivation for this approach is that the choice of concrete activation programmes may affect how people are exposed to activation-disutility. We describe a principle for the choice of optimal activation programmes......, but find it hard to give real-world examples that meet the principle....

  10. Frontal theta activity reflects distinct aspects of mental fatigue.

    Science.gov (United States)

    Wascher, Edmund; Rasch, Björn; Sänger, Jessica; Hoffmann, Sven; Schneider, Daniel; Rinkenauer, Gerhard; Heuer, Herbert; Gutberlet, Ingmar

    2014-02-01

    Longer lasting performance in cognitively demanding tasks leads to an exhaustion of cognitive resources and to a state commonly described as mental fatigue. More specifically, the allocation and focusing of attention become less efficient with time on task. Additionally, the selection of even simple responses becomes more error prone. With respect to the recorded EEG, mental fatigue has been reported to be associated with an increase in frontal theta and frontal and occipital alpha activity. The present study focused on the time course of changes in behavior and in the EEG to characterize fatigue-related processes. Participants performed a spatial stimulus-response-compatibility task in eight blocks for an overall duration of 4h. Error rates increased continuously with time on task. Total alpha power was larger at the end compared to the beginning of the experiment. However, alpha power increased rapidly and reached its maximal amplitude already after 1h, whereas frontal theta showed a continuous increase with time on task, possibly related to increased effort to keep the performance level high. Time frequency analyses revealed power changes in the theta band induced by task relevant information that might be assigned to a drain of executive control capacities. Thus, frontal theta turned out to be a reliable marker of distinct changes in cognitive processing with increasing fatigue.

  11. Physical Activity and Self-Perceptions among Hong Kong Chinese with an Acquired Physical Disability

    Science.gov (United States)

    Sit, Cindy H. P.; Lau, Caren H. L.; Vertinsky, Patricia

    2009-01-01

    This study investigated the association between physical activity and self-perceptions such as body image, physical self-concept, and self-esteem among persons with an acquired physical disability in a non-Western population. Other personal variables such as gender and time of onset of disability were also examined. A convenience sample of 66 Hong…

  12. Perceptions of physical activity and walking in an early stage after stroke or acquired brain injury

    Science.gov (United States)

    2017-01-01

    Background Physical activity has been established as being highly beneficial for health after stroke. There are considerable global efforts to find rehabilitation programs that encourage increased physical activity for persons with stroke. However, many persons with stroke or acquired brain injury do not reach recommended levels of physical activity and increased knowledge about why is needed. We aimed to explore views and experiences of physical activity and walking among persons with stroke or acquired brain injury. Method A qualitative study was conducted, among persons with stroke (n = 8) or acquired brain injury (n = 2) from a rehabilitation unit at Sahlgrenska University Hospital in Sweden. Semi-structured in-depth interviews were held about perceptions and experiences of walking and physical activity in general. Data were analyzed using qualitative content analysis, with categories that were determined inductively. Results Physical activity in general and walking ability more specifically were considered very important by the participants. However, physical activity was, regardless of exercising habits pre-injury, associated with different kinds of negative feelings and experiences. Commonly reported internal barriers in the current study were; fatigue, fear of falling or getting hurt in traffic, lack of motivation and depression. Reported external barriers were mostly related to walking, for example; bad weather, uneven ground, lack of company or noisy or too busy surroundings. Conclusion Persons with stroke or acquired brain injury found it difficult to engage in and sustain an eligible level of physical activity. Understanding individual concerns about motivators and barriers surrounding physical activity may facilitate the work of forming tailor-made rehabilitation for these groups, so that the levels of physical activity and walking can increase. PMID:28273158

  13. 76 FR 36538 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2011-06-22

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are...) to engage de novo, or to acquire or control voting securities or assets of a company, including the... Northern Trust Company and Northern Trust Corporation, both located in Chicago, Illinois; to acquire...

  14. Distinct patterns of brain activity characterise lexical activation and competition in spoken word production.

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    Vitória Piai

    Full Text Available According to a prominent theory of language production, concepts activate multiple associated words in memory, which enter into competition for selection. However, only a few electrophysiological studies have identified brain responses reflecting competition. Here, we report a magnetoencephalography study in which the activation of competing words was manipulated by presenting pictures (e.g., dog with distractor words. The distractor and picture name were semantically related (cat, unrelated (pin, or identical (dog. Related distractors are stronger competitors to the picture name because they receive additional activation from the picture relative to other distractors. Picture naming times were longer with related than unrelated and identical distractors. Phase-locked and non-phase-locked activity were distinct but temporally related. Phase-locked activity in left temporal cortex, peaking at 400 ms, was larger on unrelated than related and identical trials, suggesting differential activation of alternative words by the picture-word stimuli. Non-phase-locked activity between roughly 350-650 ms (4-10 Hz in left superior frontal gyrus was larger on related than unrelated and identical trials, suggesting differential resolution of the competition among the alternatives, as reflected in the naming times. These findings characterise distinct patterns of activity associated with lexical activation and competition, supporting the theory that words are selected by competition.

  15. Physical Activity Recognition Based on Motion in Images Acquired by a Wearable Camera.

    Science.gov (United States)

    Zhang, Hong; Li, Lu; Jia, Wenyan; Fernstrom, John D; Sclabassi, Robert J; Mao, Zhi-Hong; Sun, Mingui

    2011-06-01

    A new technique to extract and evaluate physical activity patterns from image sequences captured by a wearable camera is presented in this paper. Unlike standard activity recognition schemes, the video data captured by our device do not include the wearer him/herself. The physical activity of the wearer, such as walking or exercising, is analyzed indirectly through the camera motion extracted from the acquired video frames. Two key tasks, pixel correspondence identification and motion feature extraction, are studied to recognize activity patterns. We utilize a multiscale approach to identify pixel correspondences. When compared with the existing methods such as the Good Features detector and the Speed-up Robust Feature (SURF) detector, our technique is more accurate and computationally efficient. Once the pixel correspondences are determined which define representative motion vectors, we build a set of activity pattern features based on motion statistics in each frame. Finally, the physical activity of the person wearing a camera is determined according to the global motion distribution in the video. Our algorithms are tested using different machine learning techniques such as the K-Nearest Neighbor (KNN), Naive Bayesian and Support Vector Machine (SVM). The results show that many types of physical activities can be recognized from field acquired real-world video. Our results also indicate that, with a design of specific motion features in the input vectors, different classifiers can be used successfully with similar performances.

  16. Differential MSC activation leads to distinct mononuclear leukocyte binding mechanisms

    Science.gov (United States)

    Kota, Daniel J.; Dicarlo, Bryan; Hetz, Robert A.; Smith, Philippa; Cox, Charles S.; Olson, Scott D.

    2014-04-01

    Advances in the field of Multipotent Mesenchymal Stromal cell (MSC) biology have demonstrated that MSCs can improve disease outcome when `activated' to exert immunomodulatory effects. However, the precise mechanisms modulating MSC-immune cells interactions remain largely elusive. In here, we activated MSC based on a recent polarization paradigm, in which MSCs can be polarized towards a pro- or anti-inflammatory phenotype depending on the Toll-like receptor stimulated, to dissect the mechanisms through which MSCs physically interact with and modulate leukocytes in this context. Our data show that MSCs activated through the Toll-like receptor (TLR) 4 pathway increased VCAM-1 and ICAM-1 dependent binding of leukocytes. On the other hand, TLR3 stimulation strongly increases leukocytes affinity to MSC comparatively, through the formation of cable-like hyaluronic acid structures. In addition, TLR4 activation elicited secretion of pro-inflammatory mediators by MSCs, whereas TLR3-activated MSCs displayed a milder pro-inflammatory phenotype, similar to inactivated MSCs. However, the differently activated MSCs maintained their ability to suppress leukocyte activation at similar levels in our in vitro model, and this immunomodulatory property was shown here to be partially mediated by prostaglandin. These results reinforce the concept that alternate activation profiles control MSC responses and may impact the therapeutic use of MSCs.

  17. Different bacteriocin activities of Streptococcus mutans reflect distinct phylogenetic lineages

    DEFF Research Database (Denmark)

    Balakrishnan, M; Simmonds, RS; Kilian, Mogens;

    2002-01-01

    Bacteriocins produced by mutans streptococci are known as mutacins. In this study 16 broadly active mutacin-producing Streptococcus mutans strains from New Zealand, North America and Europe were classified into four groups (A-D) on the basis of differences in their activity in deferred antagonism...

  18. Control of programmed cell death by distinct electrical activity patterns.

    Science.gov (United States)

    Golbs, Antje; Nimmervoll, Birgit; Sun, Jyh-Jang; Sava, Irina E; Luhmann, Heiko J

    2011-05-01

    Electrical activity and sufficient supply with survival factors play a major role in the control of apoptosis in the developing cortex. Coherent high-frequency neuronal activity, which efficiently releases neurotrophins, is essential for the survival of immature neurons. We studied the influence of neuronal activity on apoptosis in the developing cortex. Dissociated cultures of the newborn mouse cerebral cortex were grown on multielectrode arrays to determine the activity patterns that promote neuronal survival. Cultures were transfected with a plasmid coding for a caspase-3-sensitive fluorescent protein allowing real-time analysis of caspase-3-dependent apoptosis in individual neurons. Elevated extracellular potassium concentrations (5 and 8 mM), application of 4-aminopyridine or the γ-aminobutyric acid-A receptor antagonist Gabazine induced a shift in the frequency distribution of activity toward high-frequency bursts. Under these conditions, a reduction or delay in caspase-3 activation and an overall increase in neuronal survival could be observed. This effect was dependent on the activity of phosphatidylinositol-3 kinase, as blockade of this enzyme abolished the survival-promoting effect of high extracellular potassium concentrations. Our data indicate that increased network activity can prevent apoptosis in developing cortical neurons.

  19. 75 FR 1384 - Notice of Proposals to Engage in Permissible Nonbanking Activities or to Acquire Companies that...

    Science.gov (United States)

    2010-01-11

    ... Notice of Proposals to Engage in Permissible Nonbanking Activities or to Acquire Companies that are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under... engage de novo, or to acquire or control voting securities or assets of a company, including...

  20. 76 FR 30941 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2011-05-27

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under...), to engage de novo, or to acquire or control voting securities or assets of a company, including...

  1. 75 FR 20849 - Notice of Proposals to Engage in Permissible Nonbanking Activities or to Acquire Companies that...

    Science.gov (United States)

    2010-04-21

    ... Notice of Proposals to Engage in Permissible Nonbanking Activities or to Acquire Companies that are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under... engage de novo, or to acquire or control voting securities or assets of a company, including...

  2. 76 FR 40366 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2011-07-08

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under...) to engage de novo, or to acquire or control voting securities or assets of a company, including...

  3. 75 FR 32780 - Notice of Proposals to Engage in Permissible Nonbanking Activities or to Acquire Companies that...

    Science.gov (United States)

    2010-06-09

    ... Notice of Proposals to Engage in Permissible Nonbanking Activities or to Acquire Companies that are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under... engage de novo, or to acquire or control voting securities or assets of a company, including...

  4. 75 FR 1621 - Notice of Proposals to Engage in Permissible Nonbanking Activities or to Acquire Companies that...

    Science.gov (United States)

    2010-01-12

    ... Notice of Proposals to Engage in Permissible Nonbanking Activities or to Acquire Companies that are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under... engage de novo, or to acquire or control voting securities or assets of a company, including...

  5. 76 FR 22705 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2011-04-22

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under... engage de novo, or to acquire or control voting securities or assets of a company, including...

  6. 76 FR 35218 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2011-06-16

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under...) to engage de novo, or to acquire or control voting securities or assets of a company, including...

  7. 76 FR 53900 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2011-08-30

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under...) to engage de novo, or to acquire or control voting securities or assets of a company, including...

  8. 75 FR 32182 - Notice of Proposals to Engage in Permissible Nonbanking Activities or to Acquire Companies that...

    Science.gov (United States)

    2010-06-07

    ... Notice of Proposals to Engage in Permissible Nonbanking Activities or to Acquire Companies that are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under... engage de novo, or to acquire or control voting securities or assets of a company, including...

  9. 76 FR 9781 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2011-02-22

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under...) to engage de novo, or to acquire or control voting securities or assets of a company, including...

  10. 76 FR 38178 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2011-06-29

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under...) to engage de novo, or to acquire or control voting securities or assets of a company, including...

  11. 75 FR 69079 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2010-11-10

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under...) to engage de novo, or to acquire or control voting securities or assets of a company, including...

  12. 76 FR 46808 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2011-08-03

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under...) to engage de novo, or to acquire or control voting securities or assets of a company, including...

  13. 76 FR 30169 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2011-05-24

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under...) to engage de novo, or to acquire or control voting securities or assets of a company, including...

  14. 75 FR 60749 - Notice of Proposals to Engage in Permissible Nonbanking Activities or to Acquire Companies that...

    Science.gov (United States)

    2010-10-01

    ... Notice of Proposals to Engage in Permissible Nonbanking Activities or to Acquire Companies that are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under...) to engage de novo, or to acquire or control voting securities or assets of a company, including...

  15. 75 FR 29760 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2010-05-27

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under... engage de novo, or to acquire or control voting securities or assets of a company, including...

  16. 76 FR 54469 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2011-09-01

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under...) to engage de novo, or to acquire or control voting securities or assets of a company, including...

  17. 76 FR 55388 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2011-09-07

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under...) to engage de novo, or to acquire or control voting securities or assets of a company, including...

  18. 75 FR 2544 - Notice of Proposals to Engage in Permissible Nonbanking Activities or to Acquire Companies that...

    Science.gov (United States)

    2010-01-15

    ... Notice of Proposals to Engage in Permissible Nonbanking Activities or to Acquire Companies that are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under... engage de novo, or to acquire or control voting securities or assets of a company, including...

  19. 75 FR 24701 - Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That...

    Science.gov (United States)

    2010-05-05

    ... Notice of Proposals To Engage in Permissible Nonbanking Activities or To Acquire Companies That Are Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under... engage de novo, or to acquire or control voting securities or assets of a company, including...

  20. Early active sun - Radiation history of distinct components in fines

    Science.gov (United States)

    Crozaz, G.; Taylor, G. J.; Walker, R. M.; Seitz, M. G.

    1974-01-01

    Plagioclase feldspars were separated from lunar soil samples and their compositions were determined by electron-microprobe analysis followed by etching and track counting in an effort to find effects of early solar activity. The feldspars were assigned on this basis to three major lithologies: mare basalts, anorthositic rocks, and KREEP rock. The results are in sharp contrast to Poupeau et al.'s (1973) observations on track densities in plagioclase crystals in the Luna 16 soil: no evidence is found for an early active sun, although the evidence does not preclude this possibility, either.

  1. Elevated erythrocyte adenosine deaminase activity in a patient with primary acquired sideroblastic anemia.

    Science.gov (United States)

    Kanno, H; Fujii, H; Tani, K; Morisaki, T; Takahashi, K; Horiuchi, N; Kizaki, M; Ogawa, T; Miwa, S

    1988-03-01

    We report a case of primary acquired sideroblastic anemia (PASA) associated with elevated erythrocyte adenosine deaminase (ADA) activity. The patient was an 85-year-old Japanese male. Analysis of the peripheral blood revealed pancytopenia, and the bone marrow findings showed marked ringed sideroblasts and chromosomal deletion (46XY, 11q-). The erythrocyte ADA activity was 17 times higher than that of normal control, the leukocyte ADA activity was within the normal range, and the plasma ADA activity was 2 times higher than the normal mean. The adenine nucleotides in the patient's erythrocytes were within normal range. According to starch gel electrophoresis, ADA isozyme of the patient was ADA 1. Western blotting showed an increased amount of ADA protein in the patient's erythrocytes. Southern blotting revealed no gene amplification or large structural change. Dot blot analysis of the reticulocyte mRNA showed no increase in the amount of ADA mRNA in the patient's reticulocytes compared with those of reticulocyte-rich controls. We considered that the mechanism of elevated ADA activity in this acquired defect was similar to that found in hereditary hemolytic anemia associated with ADA overproduction.

  2. Corticomuscular coherence analysis on hand movement distinction for active rehabilitation.

    Science.gov (United States)

    Lou, Xinxin; Xiao, Siyuan; Qi, Yu; Hu, Xiaoling; Wang, Yiwen; Zheng, Xiaoxiang

    2013-01-01

    Active rehabilitation involves patient's voluntary thoughts as the control signals of restore device to assist stroke rehabilitation. Although restoration of hand opening stands importantly in patient's daily life, it is difficult to distinguish the voluntary finger extension from thumb adduction and finger flexion using stroke patients' electroencephalography (EMG) on single muscle activity. We propose to implement corticomuscular coherence analysis on electroencephalography (EEG) and EMG signals on Extensor Digitorum to extract their intention involved in hand opening. EEG and EMG signals of 8 subjects are simultaneously collected when executing 4 hand movement tasks (finger extension, thumb adduction, finger flexion, and rest). We explore the spatial and temporal distribution of the coherence and observe statistically significant corticomuscular coherence appearing at left motor cortical area and different patterns within beta frequency range for 4 movement tasks. Linear discriminate analysis is applied on the coherence pattern to distinguish finger extension from thumb adduction, finger flexion, and rest. The classification results are greater than those by EEG only. The results indicate the possibility to detect voluntary hand opening based on coherence analysis between single muscle EMG signal and single EEG channel located in motor cortical area, which potentially helps active hand rehabilitation for stroke patients.

  3. Disease Severity and Immune Activity Relate to Distinct Interkingdom Gut Microbiome States in Ethnically Distinct Ulcerative Colitis Patients

    Directory of Open Access Journals (Sweden)

    Jordan S. Mar

    2016-08-01

    Full Text Available Significant gut microbiota heterogeneity exists among ulcerative colitis (UC patients, though the clinical implications of this variance are unknown. We hypothesized that ethnically distinct UC patients exhibit discrete gut microbiotas with unique metabolic programming that differentially influence immune activity and clinical status. Using parallel 16S rRNA and internal transcribed spacer 2 sequencing of fecal samples (UC, 30; healthy, 13, we corroborated previous observations of UC-associated bacterial diversity depletion and demonstrated significant Saccharomycetales expansion as characteristic of UC gut dysbiosis. Furthermore, we identified four distinct microbial community states (MCSs within our cohort, confirmed their existence in an independent UC cohort, and demonstrated their coassociation with both patient ethnicity and disease severity. Each MCS was uniquely enriched for specific amino acid, carbohydrate, and lipid metabolism pathways and exhibited significant luminal enrichment of the metabolic products of these pathways. Using a novel ex vivo human dendritic cell and T-cell coculture assay, we showed that exposure to fecal water from UC patients caused significant Th2 skewing in CD4+ T-cell populations compared to that of healthy participants. In addition, fecal water from patients in whom their MCS was associated with the highest level of disease severity induced the most dramatic Th2 skewing. Combined with future investigations, these observations could lead to the identification of highly resolved UC subsets based on defined microbial gradients or discrete microbial features that may be exploited for the development of novel, more effective therapies.

  4. Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy.

    Science.gov (United States)

    Kim, S-M; Kim, H; Yun, M R; Kang, H N; Pyo, K-H; Park, H J; Lee, J M; Choi, H M; Ellinghaus, P; Ocker, M; Paik, S; Kim, H R; Cho, B C

    2016-07-18

    Aberrant fibroblast growth factor receptor (FGFR) activation/expression is a common feature in lung cancer (LC). In this study, we evaluated the antitumor activity of and the mechanisms underlying acquired resistance to two potent selective FGFR inhibitors, AZD4547 and BAY116387, in LC cell lines. The antitumor activity of AZD4547 and BAY1163877 was screened in 24 LC cell lines, including 5 with FGFR1 amplification. Two cell lines containing FGFR1 amplifications, H1581 and DMS114, were sensitive to FGFR inhibitors (IC50FGFR1-amplified H1581 cells resistant to AZD4547 or BAY116387 (H1581AR and H1581BR cells, respectively) were established. Receptor tyrosine kinase (RTK) array and immunoblotting analyses showed strong overexpression and activation of Met in H1581AR/BR cells, compared with that in the parental cells. Gene set enrichment analysis against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed that cytokine-cytokine receptor interaction pathways were significantly enriched in H1581AR/BR cells, with Met contributing significantly to the core enrichment. Genomic DNA quantitative PCR and fluorescent in situ hybridization analyses showed MET amplification in H1581AR, but not in H1581BR, cells. Met amplification drives acquired resistance to AZD4547 in H1581AR cells by activating ErbB3. Combination treatment with FGFR inhibitors and an anaplastic lymphoma kinase (ALK)/Met inhibitor, crizotinib, or Met-specific short interfering RNA (siRNA) synergistically inhibited cell proliferation in both H1581AR and H1581BR cells. Conversely, ectopic expression of Met in H1581 cells conferred resistance to AZD4547 and BAY1163877. Acquired resistance to FGFR inhibitors not only altered cellular morphology, but also promoted migration and invasion of resistant clones, in part by inducing epithelial-to-mesenchymal transition. Taken together, our data suggest that Met activation is sufficient to bypass dependency on FGFR signaling. Concurrent inhibition of the Met

  5. Three-dimensional data-acquiring system fusing active projection and stereo vision

    Science.gov (United States)

    Wu, Jianbo; Zhao, Hong; Tan, Yushan

    2001-09-01

    Combining the active digitizing technique with the passive stereo vision, a novel method is proposed to acquire the 3D data from two 2D images. Based on the principle of stereo vision, and assisting the active dense structure light projecting, the system overcomes the problem of data points matching between two stereo images, which is the most important difficulty occurring in stereo vision. An algorithm based on wavelet transform is proposed here to auto-get the threshold for image segment and extract the grid points. The system described here is mainly applied to digitize the 3D objects in time. Comparing with the general digitizers, it performs the translation from 2D images to 3D data completely, and gets over some shortcomings, such as slow image acquiring and data processing speed, depending on mechanical moving, painting on the object before digitizing, and so on. The system is the same with the non-contact and fast measurement and modeling for the 3D object with freedom surface, and can be employed widely in the fields of Reverse Engineering and CAD/CAM. Experiment proves the efficiency of the new use of shape from stereo vision (SFSV) in engineering.

  6. Engagement in Play Activities as a Means for Youth in Detention to Acquire Life Skills.

    Science.gov (United States)

    Shea, Chi-Kwan; Siu, Andrew M H

    2016-09-01

    This study describes how occupational therapists in a community-based programme, Occupational Therapy Training Program (OTTP), use play activities to facilitate the acquisition of life skills by youth in detention. This pilot study explored the extent of engagement of male and female inmates aged 14 to 18 years old in structured play activities on topics such as interpersonal relationships, self-awareness, cultural celebrations and the transition to community. Retrospective analysis of data collected from surveys using the Engagement in OTTP Activities Questionnaire (EOAQ), completed by youth participants at the end of each group session, was used to measure the extent of occupational engagement. Worksheets and artworks produced by OTTP participants during those group sessions were also analysed. The participants reported very high engagement in OTTP. Engagement scores for male participants were higher than those for female participants, and male and female participants had higher engagement scores for different activities. Over 90% of the worksheets and artworks were found to be complete and relevant to the topic of the session. Play activities could be an appropriate way for occupational therapists to encourage youth in detention to acquire life skills. Demographic information and the actual number of participants are unknown because of how the existing data were collected. Future studies examining the potential gender-related preferences for specific topics deserve further investigation as well as research comparing the youth's engagement in OTTP interventions using play activities to other group interventions. Copyright © 2016 John Wiley & Sons, Ltd.

  7. Perceived difficulties using everyday technology after acquired brain injury: influence on activity and participation.

    Science.gov (United States)

    Lindén, Anita; Lexell, Jan; Lund, Maria Larsson

    2010-12-01

    Using everyday technology (ET) is a prerequisite for activities and participation at home and in the community. It is well known that persons with an acquired brain injury (ABI) can have limitations in activities of daily living but our knowledge of their difficulties using ET is not known. Thirty-six persons (27 men and 9 women, mean age 44 years, age range 26-60) with an ABI (2-10 years post injury) were interviewed, using the Everyday Technology Use Questionnaire (ETUQ), about their perceived difficulties using ET and how these difficulties influenced their everyday activities and their possibilities to participate at home and in the community. A majority (78%) of the persons reported difficulties using ET. The most common difficulties were related to the use of telecommunication and computers. Despite these difficulties, a majority still used most objects and services independently. Twenty-six participants (72%) perceived that their difficulties using ET influenced their everyday activities and their possibility to participate at home and in the community. The results indicate that rehabilitation following an ABI should consider whether clients' use of ET influences their activity and participation and adopt interventions accordingly. The results also indicate that difficulties using ET need to be considered in the design of community services to prevent societal barriers.

  8. Antibacterial Activity of Electrochemically Synthesized Colloidal Silver Nanoparticles Against Hospital-Acquired Infections

    Science.gov (United States)

    Thuc, Dao Tri; Huy, Tran Quang; Hoang, Luc Huy; Hoang, Tran Huy; Le, Anh-Tuan; Anh, Dang Duc

    2017-02-01

    This study evaluated the antibacterial activity of electrochemically synthesized colloidal silver nanoparticles (AgNPs) against hospital-acquired infections. Colloidal AgNPs were synthesized via a single process using bulk silver bars, bi-distilled water, trisodium citrate, and direct current voltage at room temperature. Colloidal AgNPs were characterized by transmission electron microscopy, field-emission scanning electron microscopy, and energy-dispersive x-ray analyses. The antibacterial activity of colloidal AgNPs against four bacterial strains isolated from clinical samples, including methicillin-resistant Staphylococcus aureus, Escherichia coli O157:H7, multidrug-resistant Pseudomonas aeruginosa, and carbapenem-resistant Klebsiella pneumonia, was evaluated by disc diffusion, minimum inhibitory concentration (MIC), and ultrathin sectioning electron microscopy. The results showed that the prepared AgNPs were 19.7 ± 4.3 nm in size, quasi-spherical, and of high purity. Zones of inhibition approximately 6-10 mm in diameter were found, corresponding to AgNPs concentrations of 50 μg/mL to 100 μg/mL. The MIC results revealed that the antibacterial activity of the prepared AgNPs was strongly dependent on the concentration and strain of the tested bacteria.

  9. Native thrombocidin-1 and unfolded thrombocidin-1 exert antimicrobial activity via distinct structural elements

    NARCIS (Netherlands)

    Kwakman, P.H.S.; Krijgsveld, J.; de Boer, L.; Nguyen, L.T.; Boszhard, L.; Vreede, J.; Dekker, H.L.; Speijer, D.; Drijfhout, J.W.; te Velde, A.A.; Crielaard, W.; Vogel, H.J.; Vandenbroucke-Grauls, C.M.J.E.; Zaat, S.A.J.

    2011-01-01

    Chemokines (chemotactic cytokines) can have direct antimicrobial activity, which is apparently related to the presence of a distinct positively charged patch on the surface. However, chemokines can retain antimicrobial activity upon linearization despite the loss of their positive patch, thus questi

  10. Interconnection between flowering time control and activation of systemic acquired resistance.

    Science.gov (United States)

    Banday, Zeeshan Z; Nandi, Ashis K

    2015-01-01

    The ability to avoid or neutralize pathogens is inherent to all higher organisms including plants. Plants recognize pathogens through receptors, and mount resistance against the intruders, with the help of well-elaborated defense arsenal. In response to some localinfections, plants develop systemic acquired resistance (SAR), which provides heightened resistance during subsequent infections. Infected tissues generate mobile signaling molecules that travel to the systemic tissues, where they epigenetically modify expression o a set of genes to initiate the manifestation of SAR in distant tissues. Immune responses are largely regulated at transcriptional level. Flowering is a developmental transition that occurs as a result of the coordinated action of large numbers of transcription factors that respond to intrinsic signals and environmental conditions. The plant hormone salicylic acid (SA) which is required for SAR activation positively regulates flowering. Certain components of chromatin remodeling complexes that are recruited for suppression of precocious flowering are also involved in suppression of SAR in healthy plants. FLOWERING LOCUS D, a putative histone demethylase positively regulates SAR manifestation and flowering transition in Arabidopsis. Similarly, incorporation of histone variant H2A.Z in nucleosomes mediated by PHOTOPERIOD-INDEPENDENT EARLY FLOWERING 1, an ortholog of yeast chromatin remodeling complex SWR1, concomitantly influences SAR and flowering time. SUMO conjugation and deconjugation mechanisms also similarly affect SAR and flowering in an SA-dependent manner. The evidences suggest a common underlying regulatory mechanism for activation of SAR and flowering in plants.

  11. Pectobacterium atrosepticum and Pectobacterium carotovorum Harbor Distinct, Independently Acquired Integrative and Conjugative Elements Encoding Coronafacic Acid that Enhance Virulence on Potato Stems.

    Science.gov (United States)

    Panda, Preetinanda; Vanga, Bhanupratap R; Lu, Ashley; Fiers, Mark; Fineran, Peter C; Butler, Ruth; Armstrong, Karen; Ronson, Clive W; Pitman, Andrew R

    2016-01-01

    Integrative and conjugative elements (ICEs) play a central role in the evolution of bacterial virulence, their transmission between bacteria often leading to the acquisition of virulence factors that alter host range or aggressiveness. Much is known about the functions of the virulence determinants that ICEs harbor, but little is understood about the cryptic effects of ICEs on their host cell. In this study, the importance of horizontally acquired island 2 (HAI2), an ICE in the genome of Pectobacterium atrosepticum SCRI1043, was studied using a strain in which the entire ICE had been removed by CRISPR-Cas-mediated genome editing. HAI2 encodes coronafacic acid, a virulence factor that enhances blackleg disease of potato stems caused by P. atrosepticum SCRI1043. As expected, deletion of HAI2 resulted in reduced blackleg symptoms in potato stems. A subsequent screen for HAI2-related ICEs in other strains of the Pectobacterium genus revealed their ubiquitous nature in P. atrosepticum. Yet, HAI2-related ICEs were only detected in the genomes of a few P. carotovorum strains. These strains were notable as blackleg causing strains belonging to two different subspecies of P. carotovorum. Sequence analysis of the ICEs in different strains of both P. atrosepticum and P. carotovorum confirmed that they were diverse and were present in different locations on the genomes of their bacterial host, suggesting that the cfa cluster was probably acquired independently on a number of occasions via chromosomal insertion of related ICEs. Excision assays also demonstrated that the ICEs in both P. atrosepticum and P. carotovorum are mobilized from the host chromosome. Thus, the future spread of these ICEs via lateral gene transfer might contribute to an increase in the prevalence of blackleg-causing strains of P. carotovorum.

  12. Pectobacterium atrosepticum and Pectobacterium carotovorum harbor distinct, independently acquired integrative and conjugative elements encoding coronafacic acid that enhance virulence on potato stems

    Directory of Open Access Journals (Sweden)

    Andrew Robert Pitman

    2016-03-01

    Full Text Available Integrative and conjugative elements (ICEs play a central role in the evolution of bacterial virulence, their transmission between bacteria often leading to the acquisition of virulence factors that alter host range or aggressiveness. Much is known about the functions of the virulence determinants that ICEs harbor, but little is understood about the cryptic effects of ICEs on their host cell. In this study, the importance of horizontally acquired island 2 (HAI2, an ICE in the genome of Pectobacterium atrosepticum SCRI1043, was studied using a strain in which the entire ICE had been removed by CRISPR-Cas-mediated genome targeting. HAI2 encodes coronafacic acid, a virulence factor that enhances blackleg disease of potato stems caused by P. atrosepticum SCRI1043. As expected, deletion of HAI2 resulted in reduced blackleg symptoms in potato stems. A subsequent screen for HAI2-related ICEs in other strains of the Pectobacterium genus revealed their ubiquitous nature in P. atrosepticum. Yet, HAI2-related ICEs were only detected in the genomes of a few P. carotovorum strains. These strains were notable as blackleg causing strains belonging to two different subspecies of P. carotovorum. Sequence analysis of the ICEs in different strains of both P. atrosepticum and P. carotovorum confirmed that they were diverse and were present in different locations on the genomes of their bacterial host, suggesting that the cfa cluster was probably acquired independently on a number of occasions via chromosomal insertion of related ICEs. Excision assays also demonstrated that the ICEs in both P. atrosepticum and P. carotovorum are mobilised from the host chromosome. Thus, the future spread of these ICEs via lateral gene transfer might contribute to an increase in the prevalence of blackleg-causing strains of P. carotovorum.

  13. DNA-PK Mediates AKT Activation and Apoptosis Inhibition in Clinically Acquired Platinum Resistance

    Directory of Open Access Journals (Sweden)

    Euan A. Stronach

    2011-11-01

    Full Text Available Clinical resistance to chemotherapy is a frequent event in cancer treatment and is closely linked to poor outcome. High-grade serous (HGS ovarian cancer is characterized by p53 mutation and high levels of genomic instability. Treatment includes platinum-based chemotherapy and initial response rates are high; however, resistance is frequently acquired, at which point treatment options are largely palliative. Recent data indicate that platinumresistant clones exist within the sensitive primary tumor at presentation, implying resistant cell selection after treatment with platinum chemotherapy. The AKT pathway is central to cell survival and has been implicated in platinum resistance. Here, we show that platinum exposure induces an AKT-dependent, prosurvival, DNA damage response in clinically platinum-resistant but not platinum-sensitive cells. AKT relocates to the nucleus of resistant cells where it is phosphorylated specifically on S473 by DNA-dependent protein kinase (DNA-PK, and this activation inhibits cisplatin-mediated apoptosis. Inhibition of DNA-PK or AKT, but not mTORC2, restores platinum sensitivity in a panel of clinically resistant HGS ovarian cancer cell lines: we also demonstrate these effects in other tumor types. Re-sensitization is associated with prevention of AKT-mediated BAD phosphorylation. Strikingly, in patient-matched sensitive cells, we do not see enhanced apoptosis on combining cisplatin with AKT or DNA-PK inhibition. Insulin-mediated activation of AKT is unaffected by DNA-PK inhibitor treatment, suggesting that this effect is restricted to DNA damage–mediated activation of AKT and that, clinically, DNA-PK inhibition might prevent platinum-induced AKT activation without interfering with normal glucose homeostasis, an unwanted toxicity of direct AKT inhibitors.

  14. The dominant Australian community-acquired methicillin-resistant Staphylococcus aureus clone ST93-IV [2B] is highly virulent and genetically distinct.

    Directory of Open Access Journals (Sweden)

    Kyra Y L Chua

    Full Text Available Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA USA300 has spread rapidly across North America, and CA-MRSA is also increasing in Australia. However, the dominant Australian CA-MRSA strain, ST93-IV [2B] appears distantly related to USA300 despite strikingly similar clinical and epidemiological profiles. Here, we compared the virulence of a recent Australian ST93 isolate (JKD6159 to other MRSA, including USA300, and found that JKD6159 was the most virulent in a mouse skin infection model. We fully sequenced the genome of JKD6159 and confirmed that JKD6159 is a distinct clone with 7616 single nucleotide polymorphisms (SNPs distinguishing this strain from all other S. aureus genomes. Despite its high virulence there were surprisingly few virulence determinants. However, genes encoding α-hemolysin, Panton-Valentine leukocidin (PVL and α-type phenol soluble modulins were present. Genome comparisons revealed 32 additional CDS in JKD6159 but none appeared to encode new virulence factors, suggesting that this clone's enhanced pathogenicity could lie within subtler genome changes, such as SNPs within regulatory genes. To investigate the role of accessory genome elements in CA-MRSA epidemiology, we next sequenced three additional Australian non-ST93 CA-MRSA strains and compared them with JKD6159, 19 completed S. aureus genomes and 59 additional S. aureus genomes for which unassembled genome sequence data was publicly available (82 genomes in total. These comparisons showed that despite its distinctive genotype, JKD6159 and other CA-MRSA clones (including USA300 share a conserved repertoire of three notable accessory elements (SSCmecIV, PVL prophage, and pMW2. This study demonstrates that the genetically distinct ST93 CA-MRSA from Australia is highly virulent. Our comparisons of geographically and genetically diverse CA-MRSA genomes suggest that apparent convergent evolution in CA-MRSA may be better explained by the rapid

  15. Two distinct RNase activities of CRISPR-C2c2 enable guide-RNA processing and RNA detection.

    Science.gov (United States)

    East-Seletsky, Alexandra; O'Connell, Mitchell R; Knight, Spencer C; Burstein, David; Cate, Jamie H D; Tjian, Robert; Doudna, Jennifer A

    2016-10-13

    Bacterial adaptive immune systems use CRISPRs (clustered regularly interspaced short palindromic repeats) and CRISPR-associated (Cas) proteins for RNA-guided nucleic acid cleavage. Although most prokaryotic adaptive immune systems generally target DNA substrates, type III and VI CRISPR systems direct interference complexes against single-stranded RNA substrates. In type VI systems, the single-subunit C2c2 protein functions as an RNA-guided RNA endonuclease (RNase). How this enzyme acquires mature CRISPR RNAs (crRNAs) that are essential for immune surveillance and how it carries out crRNA-mediated RNA cleavage remain unclear. Here we show that bacterial C2c2 possesses a unique RNase activity responsible for CRISPR RNA maturation that is distinct from its RNA-activated single-stranded RNA degradation activity. These dual RNase functions are chemically and mechanistically different from each other and from the crRNA-processing behaviour of the evolutionarily unrelated CRISPR enzyme Cpf1 (ref. 11). The two RNase activities of C2c2 enable multiplexed processing and loading of guide RNAs that in turn allow sensitive detection of cellular transcripts.

  16. Distinct regulatory mechanisms of eukaryotic transcriptional activation by SAGA and TFIID.

    Science.gov (United States)

    Bhaumik, Sukesh R

    2011-02-01

    A growing number of human diseases are linked to abnormal gene expression which is largely controlled at the level of transcriptional initiation. The gene-specific activator promotes the initiation of transcription through its interaction with one or more components of the transcriptional initiation machinery, hence leading to stimulated transcriptional initiation or activation. However, all activator proteins do not target the same component(s) of the transcriptional initiation machinery. Rather, they can have different target specificities, and thus, can lead to distinct mechanisms of transcriptional activation. Two such distinct mechanisms of transcriptional activation in yeast are mediated by the SAGA (Spt-Ada-Gcn5-Acetyltransferase) and TFIID (Transcription factor IID) complexes, and are termed as "SAGA-dependent" and "TFIID-dependent" transcriptional activation, respectively. SAGA is the target of the activator in case of SAGA-dependent transcriptional activation, while the targeting of TFIID by the activator leads to TFIID-dependent transcriptional activation. Both the SAGA and TFIID complexes are highly conserved from yeast to human, and play crucial roles in gene activation among eukaryotes. The regulatory mechanisms of eukaryotic transcriptional activation by SAGA and TFIID are discussed here. This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough!

  17. Development of Distinction Method of Production Area of Ginsengs by Using a Neutron Activation Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Young Jin; Chung, Yong Sam; Sun, Gwang Min; Lee, Yu Na; Yoo, Sang Ho [KAERI, Daejeon (Korea, Republic of)

    2010-05-15

    Distinction of production area of Korean ginsengs has been tried by using neutron activation techniques such as an instrumental neutron activation analysis (INAA) and a prompt gamma activation analysis (PGAA). A distribution of elements has varied according to the part of plant clue to the difference of enrichment effect and influence from a soil where the plants have been grown. So correlation study between plants and soil has been an Issue. In this study, the distribution of trace elements within a Korean ginseng was investigated by using an instrumental neutron activation analysis

  18. The activity of parafusin is distinct from that of phosphoglucomutase in the unicellular eukaryote Paramecium.

    Science.gov (United States)

    Andersen, A P; Wyroba, E; Reichman, M; Zhao, H; Satir, B H

    1994-05-16

    In this paper we identified the presence of a Paramecium phosphoglucomutase enzymatic activity which is clearly distinct from that of parafusin-the exocytosis-related phosphoglycoprotein. Since the recently cloned parafusin showed homology to rabbit muscle phosphoglucomutase, we have designed a specific peptide parafusin antibody-generated to a region not present in any known sequenced phosphoglucomutases-to distinguish parafusin from the Paramecium phosphoglucomutase. Separation of these two proteins was obtained using liquid chromatography, enzymatic activity assay and immunoblotting analysis with the specific parafusin peptide antibody. Parafusin fractions incorporated [B35S]UDP-Glc but not [35S]Glc-1-P whereas Paramecium phosphoglucomutase fractions incorporated [35S]Glc-1-P but not [B35S]UDP-Glc. This indicates that these two proteins are separate entities exhibiting different properties and most likely distinct functions in the cell.

  19. Distinct DNA-based epigenetic switches trigger transcriptional activation of silent genes in human dermal fibroblasts.

    Science.gov (United States)

    Pandian, Ganesh N; Taniguchi, Junichi; Junetha, Syed; Sato, Shinsuke; Han, Le; Saha, Abhijit; AnandhaKumar, Chandran; Bando, Toshikazu; Nagase, Hiroki; Vaijayanthi, Thangavel; Taylor, Rhys D; Sugiyama, Hiroshi

    2014-01-24

    The influential role of the epigenome in orchestrating genome-wide transcriptional activation instigates the demand for the artificial genetic switches with distinct DNA sequence recognition. Recently, we developed a novel class of epigenetically active small molecules called SAHA-PIPs by conjugating selective DNA binding pyrrole-imidazole polyamides (PIPs) with the histone deacetylase inhibitor SAHA. Screening studies revealed that certain SAHA-PIPs trigger targeted transcriptional activation of pluripotency and germ cell genes in mouse and human fibroblasts, respectively. Through microarray studies and functional analysis, here we demonstrate for the first time the remarkable ability of thirty-two different SAHA-PIPs to trigger the transcriptional activation of exclusive clusters of genes and noncoding RNAs. QRT-PCR validated the microarray data, and some SAHA-PIPs activated therapeutically significant genes like KSR2. Based on the aforementioned results, we propose the potential use of SAHA-PIPs as reagents capable of targeted transcriptional activation.

  20. Distinct Developmental Functions of Prostasin (CAP1/PRSS8) Zymogen and Activated Prostasin.

    Science.gov (United States)

    Friis, Stine; Madsen, Daniel H; Bugge, Thomas H

    2016-02-01

    The membrane-anchored serine prostasin (CAP1/PRSS8) is essential for barrier acquisition of the interfollicular epidermis and for normal hair follicle development. Consequently, prostasin null mice die shortly after birth. Prostasin is found in two forms in the epidermis: a one-chain zymogen and a two-chain proteolytically active form, generated by matriptase-dependent activation site cleavage. Here we used gene editing to generate mice expressing only activation site cleavage-resistant (zymogen-locked) endogenous prostasin. Interestingly, these mutant mice displayed normal interfollicular epidermal development and postnatal survival, but had defects in whisker and pelage hair formation. These findings identify two distinct in vivo functions of epidermal prostasin: a function in the interfollicular epidermis, not requiring activation site cleavage, that can be mediated by the zymogen-locked version of prostasin and a proteolysis-dependent function of activated prostasin in hair follicles, dependent on zymogen conversion by matriptase.

  1. Insights into mechanism of glucokinase activation: observation of multiple distinct protein conformations.

    Science.gov (United States)

    Liu, Shenping; Ammirati, Mark J; Song, Xi; Knafels, John D; Zhang, Jeff; Greasley, Samantha E; Pfefferkorn, Jeffrey A; Qiu, Xiayang

    2012-04-20

    Human glucokinase (GK) is a principal regulating sensor of plasma glucose levels. Mutations that inactivate GK are linked to diabetes, and mutations that activate it are associated with hypoglycemia. Unique kinetic properties equip GK for its regulatory role: although it has weak basal affinity for glucose, positive cooperativity in its binding of glucose causes a rapid increase in catalytic activity when plasma glucose concentrations rise above euglycemic levels. In clinical trials, small molecule GK activators (GKAs) have been efficacious in lowering plasma glucose and enhancing glucose-stimulated insulin secretion, but they carry a risk of overly activating GK and causing hypoglycemia. The theoretical models proposed to date attribute the positive cooperativity of GK to the existence of distinct protein conformations that interconvert slowly and exhibit different affinities for glucose. Here we report the respective crystal structures of the catalytic complex of GK and of a GK-glucose complex in a wide open conformation. To assess conformations of GK in solution, we also carried out small angle x-ray scattering experiments. The results showed that glucose dose-dependently converts GK from an apo conformation to an active open conformation. Compared with wild type GK, activating mutants required notably lower concentrations of glucose to be converted to the active open conformation. GKAs decreased the level of glucose required for GK activation, and different compounds demonstrated distinct activation profiles. These results lead us to propose a modified mnemonic model to explain cooperativity in GK. Our findings may offer new approaches for designing GKAs with reduced hypoglycemic risk.

  2. Development of distinction method of production area of ginsengs by using a neutron activation analysis

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Youngjin; Chung, Yongsam; Sim, Chulmuu; Sun, Gwangmin; Lee, Yuna; Yoo, Sangho

    2011-01-15

    During the last 2 years of the project, we have tried to develop the technology to make a distinction of the production areas for Korean ginsengs cultivated in the various provinces in Korea and foreign countries. It will contribute to secure the health food safety for public and stability of its market. In this year, we collected ginseng samples cultivated in the northeastern province in Chinese mainland such as Liaoning province, Jilin province and Baekdu mountain within Jilin province. 10 ginseng samples were collected at each province. The elemental concentrations in the ginseng were analyzed by using a neutron activation analysis technique at the HANARO research reactor. The distinction of production area was made by using a statistical software. As a result, the Chinese Korean ginsengs were certainly differentiated from those cultivated in the famous province in Korea though there was a limitation that the number of our sample we analyzed is very small.

  3. Rac-1 and Raf-1 kinases, components of distinct signaling pathways, activate myotonic dystrophy protein kinase

    Science.gov (United States)

    Shimizu, M.; Wang, W.; Walch, E. T.; Dunne, P. W.; Epstein, H. F.

    2000-01-01

    Myotonic dystrophy protein kinase (DMPK) is a serine-threonine protein kinase encoded by the myotonic dystrophy (DM) locus on human chromosome 19q13.3. It is a close relative of other kinases that interact with members of the Rho family of small GTPases. We show here that the actin cytoskeleton-linked GTPase Rac-1 binds to DMPK, and coexpression of Rac-1 and DMPK activates its transphosphorylation activity in a GTP-sensitive manner. DMPK can also bind Raf-1 kinase, the Ras-activated molecule of the MAP kinase pathway. Purified Raf-1 kinase phosphorylates and activates DMPK. The interaction of DMPK with these distinct signals suggests that it may play a role as a nexus for cross-talk between their respective pathways and may partially explain the remarkable pleiotropy of DM.

  4. The two PPX-GppA homologues from Mycobacterium tuberculosis have distinct biochemical activities.

    Directory of Open Access Journals (Sweden)

    Mei Y Choi

    Full Text Available Inorganic polyphosphate (poly-P, guanosine pentaphosphate (pppGpp and guanosine tetraphosphate (ppGpp are ubiquitous in bacteria. These molecules play a variety of important physiological roles associated with stress resistance, persistence, and virulence. In the bacterial pathogen Mycobacterium tuberculosis, the identities of the proteins responsible for the metabolism of polyphosphate and (pppGpp remain to be fully established. M. tuberculosis encodes two PPX-GppA homologues, Rv0496 (MTB-PPX1 and Rv1026, which share significant sequence similarity with bacterial exopolyphosphatase (PPX and guanosine pentaphosphate 5'-phosphohydrolase (GPP proteins. Here we delineate the respective biochemical activities of the Rv0496 and Rv1026 proteins and benchmark these against the activities of the PPX and GPP proteins from Escherichia coli. We demonstrate that Rv0496 functions as an exopolyphosphatase, showing a distinct preference for relatively short-chain poly-P substrates. In contrast, Rv1026 has no detectable exopolyphosphatase activities. Analogous to the E. coli PPX and GPP enzymes, the exopolyphosphatase activities of Rv0496 are inhibited by pppGpp and, to a lesser extent, by ppGpp alarmones, which are produced during the bacterial stringent response. However, neither Rv0496 nor Rv1026 have the ability to hydrolyze pppGpp to ppGpp; a reaction catalyzed by E. coli PPX and GPP. Both the Rv0496 and Rv1026 proteins have modest ATPase and to a lesser extent ADPase activities. pppGpp alarmones inhibit the ATPase activities of Rv1026 and, to a lesser extent, the ATPase activities of Rv0496. We conclude that PPX-GppA family proteins may not possess all the catalytic activities implied by their name and may play distinct biochemical roles involved in polyphosphate and (pppGpp metabolic pathways.

  5. Distinct mechanisms for DNA cleavage by myoglobin with a designed heme active center.

    Science.gov (United States)

    Zhao, Yuan; Du, Ke-Jie; Gao, Shu-Qin; He, Bo; Wen, Ge-Bo; Tan, Xiangshi; Lin, Ying-Wu

    2016-03-01

    Heme proteins perform diverse biological functions, of which myoglobin (Mb) is a representative protein. In this study, the O2 carrier Mb was shown to cleave double stranded DNA upon aerobic dithiothreitol-induced reduction, which is fine-tuned by an additional distal histidine, His29 or His43, engineered in the heme active center. Spectroscopic (UV-vis and EPR) and inhibition studies suggested that free radicals including singlet oxygen and hydroxyl radical are responsible for efficient DNA cleavage via an oxidative cleavage mechanism. On the other hand, L29E Mb, with a distinct heme active center involving three water molecules in the met form, was found to exhibit an excellent DNA cleavage activity that was not depending on O2. Inhibition and ligation studies demonstrated for the first time that L29E Mb cleaves double stranded DNA into both the nicked circular and linear forms via a hydrolytic cleavage mechanism, which resembles native endonucleases. This study provides valuable insights into the distinct mechanisms for DNA cleavage by heme proteins, and lays down a base for creating artificial DNA endonucleases by rational design of heme proteins. Moreover, this study suggests that the diverse functions of heme proteins can be fine-tuned by rational design of the heme active center with a hydrogen-bonding network.

  6. A Systematic Approach to Identify Markers of Distinctly Activated Human Macrophages

    Directory of Open Access Journals (Sweden)

    Bayan eSudan

    2015-05-01

    Full Text Available Polarization has been a useful concept for describing activated macrophage phenotypes and gene expression profiles. However, macrophage activation status within tumors and other settings are often inferred based on only a few markers. Complicating matters for relevance to human biology, many of the best studied macrophage activation markers have been best characterized in mice and sometimes are not similarly regulated in human macrophages. To identify novel markers of activated human macrophages, gene expression profiles for human macrophages of a single donor subjected to 33 distinct activating conditions were obtained and a set of putative activation markers were subsequently evaluated in macrophages from multiple donors using integrated fluidic circuit (IFC-based RT-PCR. Using unsupervised hierarchical clustering of the microarray screen, highly-altered transcripts (>4-fold change in expression sorted the macrophage transcription profiles into two major and 13 minor clusters. Among the 1874 highly-altered transcripts, over 100 were uniquely altered in one major or two related minor clusters. IFC PCR-derived data confirmed the microarray results and to show the kinetics of expression of potential macrophage activation markers. Transcripts encoding chemokines, cytokines, and cell surface were prominent in our analyses. The activation markers identified by this study could be used to better characterize tumor-associated macrophages from biopsies as well as other macrophage populations collected from human clinical samples.

  7. Physical activity versus cardiorespiratory fitness: two (partly) distinct components of cardiovascular health?

    Science.gov (United States)

    DeFina, Laura F; Haskell, William L; Willis, Benjamin L; Barlow, Carolyn E; Finley, Carrie E; Levine, Benjamin D; Cooper, Kenneth H

    2015-01-01

    Physical activity (PA) and cardiorespiratory fitness (CRF) both have inverse relationships to cardiovascular (CV) morbidity and mortality. Recent position papers and guidelines have identified the important role of both of these factors in CV health. The benefits of PA and CRF in the prevention of CV disease and risk factors are reviewed. In addition, assessment methodology and utilization in the research and clinical arenas are discussed. Finally, the benefits, methodology, and utilization are compared and contrasted to better understand the two (partly) distinct components and their impact on CV health.

  8. Two distinct DNA ligase activities in mitotic extracts of the yeast Saccharomyces cerevisiae.

    OpenAIRE

    Ramos, W; Tappe, N; Talamantez, J; Friedberg, E C; Tomkinson, A E

    1997-01-01

    Four biochemically distinct DNA ligases have been identified in mammalian cells. One of these enzymes, DNA ligase I, is functionally homologous to the DNA ligase encoded by the Saccharomyces cerevisiae CDC9 gene. Cdc9 DNA ligase has been assumed to be the only species of DNA ligase in this organism. In the present study we have identified a second DNA ligase activity in mitotic extracts of S. cerevisiae with chromatographic properties different from Cdc9 DNA ligase, which is the major DNA joi...

  9. Distinct developmental defense activations in barley embryos identified by transcriptome profiling

    DEFF Research Database (Denmark)

    Nielsen, ME; Lok, F; Nielsen, Henrik Bjørn

    2006-01-01

    analyses of > 22,000 genes, which together with measurements of jasmonic acid and salicylic acid during embryo development provide new information on the initiation in the developing barley embryo of at least two distinct types of developmental defense activation (DDA). Early DDA is characterized by the up......-regulation of several PR genes is notable. Throughout barley embryo development, there are no indications of an increased biosynthesis of either jasmonic acid or salicylic acid. Collectively, the results help explain how the proposed DDA enables protection of the developing barley embryo and grain for purposes...

  10. Distinct Patterns of Brain Activity Characterise Lexical Activation and Competition in Spoken Word Production

    NARCIS (Netherlands)

    Piai, V.; Roelofs, A.P.A.; Jensen, O.; Schoffelen, J.M.; Bonnefond, M.

    2014-01-01

    According to a prominent theory of language production, concepts activate multiple associated words in memory, which enter into competition for selection. However, only a few electrophysiological studies have identified brain responses reflecting competition. Here, we report a magnetoencephalography

  11. Activated Ras alters lens and corneal development through induction of distinct downstream targets

    Directory of Open Access Journals (Sweden)

    Reneker Lixing

    2010-01-01

    Full Text Available Abstract Background Mammalian Ras genes regulate diverse cellular processes including proliferation and differentiation and are frequently mutated in human cancers. Tumor development in response to Ras activation varies between different tissues and the molecular basis for these variations are poorly understood. The murine lens and cornea have a common embryonic origin and arise from adjacent regions of the surface ectoderm. Activation of the fibroblast growth factor (FGF signaling pathway induces the corneal epithelial cells to proliferate and the lens epithelial cells to exit the cell cycle. The molecular mechanisms that regulate the differential responses of these two related tissues have not been defined. We have generated transgenic mice that express a constitutively active version of human H-Ras in their lenses and corneas. Results Ras transgenic lenses and corneal epithelial cells showed increased proliferation with concomitant increases in cyclin D1 and D2 expression. This initial increase in proliferation is sustained in the cornea but not in the lens epithelial cells. Coincidentally, cdk inhibitors p27Kip1 and p57Kip2 were upregulated in the Ras transgenic lenses but not in the corneas. Phospho-Erk1 and Erk2 levels were elevated in the lens but not in the cornea and Spry 1 and Spry 2, negative regulators of Ras-Raf-Erk signaling, were upregulated more in the corneal than in the lens epithelial cells. Both lens and corneal differentiation programs were sensitive to Ras activation. Ras transgenic embryos showed a distinctive alteration in the architecture of the lens pit. Ras activation, though sufficient for upregulation of Prox1, a transcription factor critical for cell cycle exit and initiation of fiber differentiation, is not sufficient for induction of terminal fiber differentiation. Expression of Keratin 12, a marker of corneal epithelial differentiation, was reduced in the Ras transgenic corneas. Conclusions Collectively, these

  12. Unusual Initial Manifestation of Acquired Hemophilia A: A Normal Activated Partial Thromboplastin Time, Intramuscular Hematoma and Cerebral Hemorrhage

    Science.gov (United States)

    Tsuyama, Nobuaki; Ichiba, Toshihisa; Naito, Hiroshi

    2016-01-01

    We herein present a case of acquired hemophilia A with a normal activated partial thromboplastin (aPTT), intramuscular hematoma and cerebral hemorrhage occurring in a 73-year-old man. The patient visited our emergency department with gait disturbance, pain and swelling in his right leg. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed intramuscular hematoma and intracranial hemorrhage. The results of initial coagulation studies were normal, but repeated coagulation studies revealed an isolated prolongation of the aPTT. Additional laboratory tests confirmed the diagnosis of acquired hemophilia A. If the initial aPTT is normal, we should therefore repeat the aPTT and also perform other coagulation studies including a mixing study, factor VIII level and inhibitor, to investigate the underlying diseases in elderly patients with spontaneous hemorrhaging of unknown etiology. PMID:27853081

  13. Distinct neural activity associated with focused-attention meditation and loving-kindness meditation.

    Directory of Open Access Journals (Sweden)

    Tatia M C Lee

    Full Text Available This study examined the dissociable neural effects of ānāpānasati (focused-attention meditation, FAM and mettā (loving-kindness meditation, LKM on BOLD signals during cognitive (continuous performance test, CPT and affective (emotion-processing task, EPT, in which participants viewed affective pictures processing. Twenty-two male Chinese expert meditators (11 FAM experts, 11 LKM experts and 22 male Chinese novice meditators (11 FAM novices, 11 LKM novices had their brain activity monitored by a 3T MRI scanner while performing the cognitive and affective tasks in both meditation and baseline states. We examined the interaction between state (meditation vs. baseline and expertise (expert vs. novice separately during LKM and FAM, using a conjunction approach to reveal common regions sensitive to the expert meditative state. Additionally, exclusive masking techniques revealed distinct interactions between state and group during LKM and FAM. Specifically, we demonstrated that the practice of FAM was associated with expertise-related behavioral improvements and neural activation differences in attention task performance. However, the effect of state LKM meditation did not carry over to attention task performance. On the other hand, both FAM and LKM practice appeared to affect the neural responses to affective pictures. For viewing sad faces, the regions activated for FAM practitioners were consistent with attention-related processing; whereas responses of LKM experts to sad pictures were more in line with differentiating emotional contagion from compassion/emotional regulation processes. Our findings provide the first report of distinct neural activity associated with forms of meditation during sustained attention and emotion processing.

  14. Distinct neural activity associated with focused-attention meditation and loving-kindness meditation.

    Science.gov (United States)

    Lee, Tatia M C; Leung, Mei-Kei; Hou, Wai-Kai; Tang, Joey C Y; Yin, Jing; So, Kwok-Fai; Lee, Chack-Fan; Chan, Chetwyn C H

    2012-01-01

    This study examined the dissociable neural effects of ānāpānasati (focused-attention meditation, FAM) and mettā (loving-kindness meditation, LKM) on BOLD signals during cognitive (continuous performance test, CPT) and affective (emotion-processing task, EPT, in which participants viewed affective pictures) processing. Twenty-two male Chinese expert meditators (11 FAM experts, 11 LKM experts) and 22 male Chinese novice meditators (11 FAM novices, 11 LKM novices) had their brain activity monitored by a 3T MRI scanner while performing the cognitive and affective tasks in both meditation and baseline states. We examined the interaction between state (meditation vs. baseline) and expertise (expert vs. novice) separately during LKM and FAM, using a conjunction approach to reveal common regions sensitive to the expert meditative state. Additionally, exclusive masking techniques revealed distinct interactions between state and group during LKM and FAM. Specifically, we demonstrated that the practice of FAM was associated with expertise-related behavioral improvements and neural activation differences in attention task performance. However, the effect of state LKM meditation did not carry over to attention task performance. On the other hand, both FAM and LKM practice appeared to affect the neural responses to affective pictures. For viewing sad faces, the regions activated for FAM practitioners were consistent with attention-related processing; whereas responses of LKM experts to sad pictures were more in line with differentiating emotional contagion from compassion/emotional regulation processes. Our findings provide the first report of distinct neural activity associated with forms of meditation during sustained attention and emotion processing.

  15. The Metastasis-associated Proteins 1 and 2 Form Distinct Protein Complexes with Histone Deacetylase Activity

    Institute of Scientific and Technical Information of China (English)

    Ya-LiYao; Wcn-MingYang

    2005-01-01

    The metastasis-associated protein MTA1 has been shown to express differentially to high levels in metastatic cells. MTA2, which is homologous to MTA1, is a component of the NURD ATP-dependcnt chromatin remodeling and histone deacetylase complex. Here we report evidence that although both human MTA1 and MTA2 repress transcription specifically, are located in the nucleus, and contain associated histone deacetylase activity, they exist in two biochemically distinct protein complexes and may perform different functions pertaining to tumor metastasis. Specifically, both MTA1 and MTA2 complexes exert histone deacetylase activity. However, the MTA1 complex contained HDAC1/2, RbAp46/48, and MBD3, but not Sin3 or Mi2, two important components of the MTA2 complex. Moreover, the MTA2 complex is similar to the HDAC1 complex, suggesting a housekeeping role of the MTA2 complex. The MTA1 complex could be further separated, resulting in acore MTA1-HDAC complex, showing that the histone deacetylase activity and transcriptional repression activity were integral properties of the MTA1 complex. Finally, MTA1, unlike MTA2, did not interact with the pleotropic transcription factor YY1 or the immunophilin FKBP25. We suggest that MTA1 associates with adifferent set of transcription factors from MTA2 and that this property may contribute to the metastatic potential of cells overexpressing MTA1. We also report the finding of human MTA3, which is highly homologous toboth MTA1 and MTA2. However, MTA3 does not repress transcription to a significant level and appears to have a diffused pattern of subcellular localization, suggesting a biological role distinct from that of the other two MTA proteins.

  16. Variety of DNA Replication Activity Among Cyanobacteria Correlates with Distinct Respiration Activity in the Dark.

    Science.gov (United States)

    Ohbayashi, Ryudo; Yamamoto, Jun-Ya; Watanabe, Satoru; Kanesaki, Yu; Chibazakura, Taku; Miyagishima, Shin-Ya; Yoshikawa, Hirofumi

    2016-11-10

    Cyanobacteria exhibit light-dependent cell growth since most of their cellular energy is obtained by photosynthesis. In Synechococcus elongatus PCC 7942, one of the model cyanobacteria, DNA replication depends on photosynthetic electron transport. However, the critical signal for the regulatory mechanism of DNA replication has not been identified. In addition, conservation of this regulatory mechanism has not been investigated among cyanobacteria. To understand this regulatory signal and its dependence on light, we examined the regulation of DNA replication under both light and dark conditions among three model cyanobacteria, S. elongatus PCC 7942, Synechocystis sp. PCC 6803 and Anabaena sp. PCC 7120. Interestingly, DNA replication activity in Synechocystis and Anabaena was retained when cells were transferred to the dark, although it was drastically decreased in S. elongatus. Glycogen metabolism and respiration were higher in Synechocystis and Anabaena than in S. elongatus in the dark. Moreover, DNA replication activity in Synechocystis and Anabaena was reduced to the same level as that in S. elongatus by inhibition of respiratory electron transport after transfer to the dark. These results demonstrate that there is disparity in DNA replication occurring in the dark among cyanobacteria, which is caused by the difference in activity of respiratory electron transport.

  17. Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes.

    Science.gov (United States)

    Dawe, G Brent; Musgaard, Maria; Aurousseau, Mark R P; Nayeem, Naushaba; Green, Tim; Biggin, Philip C; Bowie, Derek

    2016-03-16

    Neurotransmitter-gated ion channels adopt different gating modes to fine-tune signaling at central synapses. At glutamatergic synapses, high and low activity of AMPA receptors (AMPARs) is observed when pore-forming subunits coassemble with or without auxiliary subunits, respectively. Whether a common structural pathway accounts for these different gating modes is unclear. Here, we identify two structural motifs that determine the time course of AMPAR channel activation. A network of electrostatic interactions at the apex of the AMPAR ligand-binding domain (LBD) is essential for gating by pore-forming subunits, whereas a conserved motif on the lower, D2 lobe of the LBD prolongs channel activity when auxiliary subunits are present. Accordingly, channel activity is almost entirely abolished by elimination of the electrostatic network but restored via auxiliary protein interactions at the D2 lobe. In summary, we propose that activation of native AMPAR complexes is coordinated by distinct structural pathways, favored by the association/dissociation of auxiliary subunits.

  18. Acquired Activated Protein C Resistance, Thrombophilia and Adverse Pregnancy Outcomes: A Study Performed in an Irish Cohort of Pregnant Women

    Directory of Open Access Journals (Sweden)

    Sara Sedano-Balbás

    2011-01-01

    Full Text Available The combination of thrombophilia and pregnancy increases the risk of thrombosis and the potential for adverse outcomes during pregnancy. The most significant common inherited risk factor for thrombophilia is activated protein C resistance (APCR, a poor anticoagulant response of APC in haemostasis, which is mainly caused by an inherited single-nucleotide polymorphism (SNP, factor V G1691A (FV Leiden (FVL, referred as inherited APCR. Changes in the levels of coagulation factors: FV, FVIII, and FIX, and anticoagulant factors: protein S (PS and protein C (PC can alter APC function causing acquired APCR. Prothrombin G20210A and methylenetetrahydrofolate reductase (MTHFR C677T are prothrombotic SNPs which in association with APCR can also increase the risk of thrombosis amongst Caucasians. In this study, a correlation between an acquired APCR phenotype and increased levels of factors V, VIII, and IX was demonstrated. Thrombophilic mutations amongst our acquired APCR pregnant women cohort are relatively common but do not appear to exert a severe undue adverse effect on pregnancy.

  19. Further evidence for a human B cell activating factor distinct from IL-4.

    Science.gov (United States)

    Diu, A; Février, M; Mollier, P; Charron, D; Banchereau, J; Reinherz, E L; Thèze, J

    1990-01-01

    Supernatants from activated human T cell clones were previously shown to contain B cell-activating factor (BCAF), an activity which results in polyclonal resting B cell stimulation. In the present study, we investigate the relationship between this activity and human interleukin-4 which was also shown to act on resting B cells. The supernatant of the T cell clone TT9 contains IL-4 but anti-IL-4 antiserum does not affect the response of B cells as measured by thymidine uptake or cell volume increase. Furthermore, IL-4 induces Fc epsilon-receptor (CD23) expression on 30% of unstimulated human B cells, whereas BCAF-containing supernatants from clone P2, that do not contain detectable amounts of IL-4, promote B cell proliferation without inducing CD23 expression. Our results therefore establish that IL-4 and BCAF are distinct activities and suggest that they trigger different activation pathways in human B cells. In addition, culture of B cells with T cell supernatants for 72 hr induces a three- to fourfold increase in the expression of HLA-DR, -DP, and -DQ antigens in 50% of B cells. The addition of inhibiting concentrations of anti-IFN-gamma, LT, or IL-4 antisera to the cultures does not change these results. Finally, 30% of B cells cultured with T cell supernatants leave the G1 phase of the cell cycle and 20% reach mitosis. Taken together, our findings further support the existence of a B cell-activating factor responsible for the activation of resting human B cells.

  20. SH3 Domains Differentially Stimulate Distinct Dynamin I Assembly Modes and G Domain Activity.

    Directory of Open Access Journals (Sweden)

    Sai Krishnan

    Full Text Available Dynamin I is a highly regulated GTPase enzyme enriched in nerve terminals which mediates vesicle fission during synaptic vesicle endocytosis. One regulatory mechanism involves its interactions with proteins containing Src homology 3 (SH3 domains. At least 30 SH3 domain-containing proteins bind dynamin at its proline-rich domain (PRD. Those that stimulate dynamin activity act by promoting its oligomerisation. We undertook a systematic parallel screening of 13 glutathione-S-transferase (GST-tagged endocytosis-related SH3 domains on dynamin binding, GTPase activity and oligomerisation. No correlation was found between dynamin binding and their potency to stimulate GTPase activity. There was limited correlation between the extent of their ability to stimulate dynamin activity and the level of oligomerisation, indicating an as yet uncharacterised allosteric coupling of the PRD and G domain. We examined the two variants, dynamin Iab and Ibb, which differ in the alternately splice middle domain α2 helix. They responded differently to the panel of SH3s, with the extent of stimulation between the splice variants varying greatly between the SH3s. This study reveals that SH3 binding can act as a heterotropic allosteric regulator of the G domain via the middle domain α2 helix, suggesting an involvement of this helix in communicating the PRD-mediated allostery. This indicates that SH3 binding both stabilises multiple conformations of the tetrameric building block of dynamin, and promotes assembly of dynamin-SH3 complexes with distinct rates of GTP hydrolysis.

  1. The meaning of Photosynthesis acquired by Primary School Kids from an investigative activity using multimodal representation

    Directory of Open Access Journals (Sweden)

    Andréia de Freitas Zompero

    2011-08-01

    Full Text Available This paper is the result of a research which analyses the meanings of Photosynthesis elaborated by students in the fifth grade of Primary School. The content was developed through an investigative activity using the representational multimodality in the text format, image, besides dialogic interaction through oral way between students and the teacher. The meanings, produced in each activity, were analysed based on the Meaningful Learning aspect. It was possible to verify that the activities provided differentiation and enrichment of the initial meanings which were established in the cognitive students’ structure.

  2. Activation of kinetically distinct synaptic conductances on inhibitory interneurons by electrotonically overlapping afferents.

    Science.gov (United States)

    Walker, Harrison C; Lawrence, J Josh; McBain, Chris J

    2002-07-03

    Mossy fiber (MF) and CA3 collateral (CL) axons activate common interneurons via synapses comprised of different AMPA receptors to provide feedforward and feedback inhibitory control of the CA3 hippocampal network. Because synapses potentially occur over variable electrotonic distances that distort somatically recorded synaptic currents, it is not known whether the underlying afferent-specific synaptic conductances are associated with different time courses. Using a somatic voltage jump technique to alter the driving force at the site of the synapse, we demonstrate that MF and CL synapses overlap in electrotonic location yet differ in conductance time course. Thus, afferent-specific conductance time courses allow single interneurons to differentially integrate feedforward and feedback information without the need to segregate distinct AMPA receptor subunits to different electrotonic domains.

  3. Differential Activation of Human Monocytes and Lymphocytes by Distinct Strains of Trypanosoma cruzi

    Science.gov (United States)

    Magalhães, Luísa M. D.; Viana, Agostinho; Chiari, Egler; Galvão, Lúcia M. C.; Gollob, Kenneth J.; Dutra, Walderez O.

    2015-01-01

    Background Trypanosoma cruzi strains are currently classified into six discrete typing units (DTUs) named TcI to VI. It is known that these DTUs have different geographical distribution, as well as biological features. TcI and TcII are major DTUs found in patients from northern and southern Latin America, respectively. Our hypothesis is that upon infection of human peripheral blood cells, Y strain (Tc II) and Col cl1.7 (Tc I), cause distinct immunological changes, which might influence the clinical course of Chagas disease. Methodology/Principal Findings We evaluated the infectivity of CFSE-stained trypomastigotes of Col cl1.7 and Y strain in human monocytes for 15 and 72 hours, and determined the immunological profile of lymphocytes and monocytes exposed to the different isolates using multiparameter flow cytometry. Our results showed a similar percentage and intensity of monocyte infection by Y and Col cl1.7. We also observed an increased expression of CD80 and CD86 by monocytes infected with Col cl1.7, but not Y strain. IL-10 was significantly higher in monocytes infected with Col cl1.7, as compared to Y strain. Moreover, infection with Col cl1.7, but not Y strain, led to an increased expression of IL-17 by CD8+ T cells. On the other hand, we observed a positive correlation between the expression of TNF-alpha and granzyme A only after infection with Y strain. Conclusion/Significance Our study shows that while Col cl1.7 induces higher monocyte activation and, at the same time, production of IL-10, infection with Y strain leads to a lower monocyte activation but higher inflammatory profile. These results show that TcI and TcII have a distinct immunological impact on human cells during early infection, which might influence disease progression. PMID:26147698

  4. Cocoa procyanidins with different degrees of polymerization possess distinct activities in models of colonic inflammation.

    Science.gov (United States)

    Bitzer, Zachary T; Glisan, Shannon L; Dorenkott, Melanie R; Goodrich, Katheryn M; Ye, Liyun; O'Keefe, Sean F; Lambert, Joshua D; Neilson, Andrew P

    2015-08-01

    Procyanidins are available in the diet from sources such as cocoa and grapes. Procyanidins are unique in that they are comprised of repeating monomeric units and can exist in various degrees of polymerization. The degree of polymerization plays a role in determining the biological activities of procyanidins. However, generalizations cannot be made regarding the correlation between procyanidin structure and bioactivity because the size-activity relationship appears to be system dependent. Our aim was to screen fractions of procyanidins with differing degrees of polymerization in vitro for anti-inflammatory activities in models of colonic inflammation. Monomeric, oligomeric and polymeric cocoa procyanidin fractions were screened using cell models of disrupted membrane integrity and inflammation in human colon cells. High-molecular-weight polymeric procyanidins were the most effective at preserving membrane integrity and reducing secretion of interleukin-8 in response to inflammatory stimuli. Conversely, oligomeric procyanidins appeared to be the least effective. These results suggest that polymeric cocoa procyanidins may be the most effective for preventing loss of gut barrier function and epithelial inflammation, which are critical steps in the pathogenesis of metabolic endotoxemia, inflammatory bowel disease and colon cancer. Therefore, further investigations of the potential health-protective benefits of cocoa procyanidins with distinct degrees of polymerization, particularly high-molecular-weight procyanidins, are warranted.

  5. Distinct activities of Bartonella henselae type IV secretion effector proteins modulate capillary-like sprout formation.

    Science.gov (United States)

    Scheidegger, F; Ellner, Y; Guye, P; Rhomberg, T A; Weber, H; Augustin, H G; Dehio, C

    2009-07-01

    The zoonotic pathogen Bartonella henselae (Bh) can lead to vasoproliferative tumour lesions in the skin and inner organs known as bacillary angiomatosis and bacillary peliosis. The knowledge on the molecular and cellular mechanisms involved in this pathogen-triggered angiogenic process is confined by the lack of a suitable animal model and a physiologically relevant cell culture model of angiogenesis. Here we employed a three-dimensional in vitro angiogenesis assay of collagen gel-embedded endothelial cell (EC) spheroids to study the angiogenic properties of Bh. Spheroids generated from Bh-infected ECs displayed a high capacity to form sprouts, which represent capillary-like projections into the collagen gel. The VirB/VirD4 type IV secretion system and a subset of its translocated Bartonella effector proteins (Beps) were found to profoundly modulate this Bh-induced sprouting activity. BepA, known to protect ECs from apoptosis, strongly promoted sprout formation. In contrast, BepG, triggering cytoskeletal rearrangements, potently inhibited sprouting. Hence, the here established in vitro model of Bartonella- induced angiogenesis revealed distinct and opposing activities of type IV secretion system effector proteins, which together with a VirB/VirD4-independent effect may control the angiogenic activity of Bh during chronic infection of the vasculature.

  6. Cholesterol-mediated activation of P-glycoprotein: distinct effects on basal and drug-induced ATPase activities.

    Science.gov (United States)

    Belli, Sara; Elsener, Priska M; Wunderli-Allenspach, Heidi; Krämer, Stefanie D

    2009-05-01

    Cholesterol promotes basal and verapamil-induced ATPase activity of P-glycoprotein (P-gp). We investigated whether these effects are related to each other and to the impact of the sterol on bilayer fluidity and verapamil membrane affinity. P-gp was reconstituted in egg-phosphatidylcholine (PhC) liposomes with or without cholesterol, 1,2-dipalmitoyl-phosphatidylcholine (DPPC), alpha-tocopherol (alpha-Toc) or 2,2,5,7,8-pentamethyl-6-chromanol (PMC). Basal and verapamil-induced ATPase activities were studied with an enzymatic assay. Membrane fluidity was characterized with diphenyl-hexatriene anisotropy measurements and membrane affinity by equilibrium dialysis. DPPC (70% mol/mol) decreased the fluidity of PhC bilayers to the same level as 20% cholesterol. PMC (20%) and alpha-Toc (20%) decreased the fluidity to lesser extents. alpha-Toc and PMC, but not DPPC increased the verapamil membrane affinity. While 20% cholesterol strikingly enhanced the basal ATPase activity, none of the other constituents had a similar effect. In contrast, verapamil stimulation of P-gp ATPase activity was not only enabled by cholesterol but also by alpha-Toc and DPPC. PMC had no effect. In conclusion, cholesterol exerts distinct effects on basal and verapamil-induced ATPase activity. The influence on basal ATPase activity is sterol-specific while its effect on verapamil-induced ATPase activity is unspecific and not related to its influence on membrane fluidity and on verapamil membrane affinity.

  7. Garenoxacin activity against isolates form patients hospitalized with community-acquired pneumonia and multidrug-resistant Streptococcus pneumoniae.

    Science.gov (United States)

    Jones, Ronald N; Sader, Helio S; Stilwell, Matthew G; Fritsche, Thomas R

    2007-05-01

    Community-acquired pneumonia (CAP) continues to cause significant morbidity worldwide, and the principal bacterial pathogens (Streptococcus pneumoniae and Haemophilus influenzae) have acquired numerous resistance mechanisms over the last few decades. CAP treatment guidelines have suggested the use of broader spectrum agents, such as antipneumococcal fluoroquinolones as the therapy for at-risk patient population. In this report, we studied 3087 CAP isolates from the SENTRY Antimicrobial Surveillance Program (1999-2005) worldwide and all respiratory tract infection (RTI) isolate population of pneumococci (14665 strains) grouped by antibiogram patterns against a new des-F(6)-quinolone, garenoxacin. Results indicated that garenoxacin was highly active against CAP isolates of S. pneumoniae (MIC(90), 0.06 microg/mL) and H. influenzae (MIC(90), 99.9% of strains were inhibited at pneumoniae strains to penicillin or erythromycin; however, coresistances were high among the beta-lactams (penicillins and cephalosporins), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole. Analysis of S. pneumoniae isolates with various antimicrobial resistance patterns to 6 drug classes demonstrated that garenoxacin was active against >99.9% (MIC, pneumoniae that have created therapeutic dilemmas for all RTI presentations. Garenoxacin appears to be a welcome addition to the CAP treatment options, particularly for the emerging MDR pneumococci strains.

  8. Loss of activating EGFR mutant gene contributes to acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Keisuke Tabara

    Full Text Available Non-small-cell lung cancer harboring epidermal growth factor receptor (EGFR mutations attains a meaningful response to EGFR-tyrosine kinase inhibitors (TKIs. However, acquired resistance to EGFR-TKIs could affect long-term outcome in almost all patients. To identify the potential mechanisms of resistance, we established cell lines resistant to EGFR-TKIs from the human lung cancer cell lines PC9 and11-18, which harbored activating EGFR mutations. One erlotinib-resistant cell line from PC9 and two erlotinib-resistant cell lines and two gefitinib-resistant cell lines from 11-18 were independently established. Almost complete loss of mutant delE746-A750 EGFR gene was observed in the erlotinib-resistant cells isolated from PC9, and partial loss of the mutant L858R EGFR gene copy was specifically observed in the erlotinib- and gefitinib-resistant cells from 11-18. However, constitutive activation of EGFR downstream signaling, PI3K/Akt, was observed even after loss of the mutated EGFR gene in all resistant cell lines even in the presence of the drug. In the erlotinib-resistant cells from PC9, constitutive PI3K/Akt activation was effectively inhibited by lapatinib (a dual TKI of EGFR and HER2 or BIBW2992 (pan-TKI of EGFR family proteins. Furthermore, erlotinib with either HER2 or HER3 knockdown by their cognate siRNAs also inhibited PI3K/Akt activation. Transfection of activating mutant EGFR complementary DNA restored drug sensitivity in the erlotinib-resistant cell line. Our study indicates that loss of addiction to mutant EGFR resulted in gain of addiction to both HER2/HER3 and PI3K/Akt signaling to acquire EGFR-TKI resistance.

  9. Antiarrhythmic properties of a rapid delayed-rectifier current activator in rabbit models of acquired long QT syndrome

    DEFF Research Database (Denmark)

    Diness, Thomas G; Yeh, Yung-Hsin; Qi, Xiao Yan;

    2008-01-01

    effect of a novel compound (NS1643) that activates the rapid delayed-rectifier K+ current, I(Kr), in two rabbit models of acquired LQTS. METHODS AND RESULTS: We used two clinically relevant in vivo rabbit models of TdP in which we infused NS1643 or vehicle: (i) three-week atrioventricular block...... with ventricular bradypacing; (ii) dofetilide-induced I(Kr) inhibition in methoxamine-sensitized rabbits. In addition, we studied effects on ionic currents in cardiomyocytes with I(Kr) suppressed by bradycardia remodelling or dofetilide exposure. Bradypaced rabbits developed QT interval prolongation, spontaneous...... ventricular ectopy, and TdP. Infusion of NS1643 completely suppressed arrhythmic activity and shortened the QT interval; vehicle had no effect. NS1643 also suppressed ventricular tachyarrhythmias caused by infusion of dofetilide to methoxamine-sensitized rabbits, and reversed dofetilide-induced QT...

  10. Telomerase activity and telomere length in human tumor cells with acquired resistance to anticancer agents.

    Science.gov (United States)

    Smith, V; Dai, F; Spitz, M; Peters, G J; Fiebig, H H; Hussain, A; Burger, A M

    2009-11-01

    Telomeres and telomerase are targets for anticancer drug development and specific inhibitors are currently under clinical investigation. However, it has been reported that standard cytotoxic agents can affect telomere length and telomerase activity suggesting that they also have of a role in drug resistance. in this study, telomere lengths and telomerase activity as well as drug efflux pump expression, glutathione (GSH) levels and polyadenosine-ribose polymerase (PARP) cleavage were assessed in a panel of human tumor cell lines made resistant to vindesine, gemcitabine and cisplatin. these included two lung cancer cell lines resistant to vindesine (LXFL 529L/Vind, LXFA 526L/Vind), a renal cancer cell line (RXF944L/Gem) and an ovarian cancer cell line (AG6000) resistant to gemcitabine, and one resistant to cisplatin (ADDP). The resistant clones were compared to their parental lines and evaluated for cross resistance to other cytotoxic agents. Several drug specific resistance patterns were found, and various complex patterns of cross resistance emerged from some cell lines, but these mechanisms of resistance could not be related to drug efflux pump expression, GSH levels or pARp cleavage. However, all displayed changes in telomerase activity and/or telomere length. Our studies present evidence that telomere maintenance should be taken into consideration in efforts not only to overcome drug resistance, but also to optimize the use of telomere-based therapeutics.

  11. Does the reading of different orthographies produce distinct brain activity patterns? An ERP study.

    Directory of Open Access Journals (Sweden)

    Irit Bar-Kochva

    Full Text Available Orthographies vary in the degree of transparency of spelling-sound correspondence. These range from shallow orthographies with transparent grapheme-phoneme relations, to deep orthographies, in which these relations are opaque. Only a few studies have examined whether orthographic depth is reflected in brain activity. In these studies a between-language design was applied, making it difficult to isolate the aspect of orthographic depth. In the present work this question was examined using a within-subject-and-language investigation. The participants were speakers of Hebrew, as they are skilled in reading two forms of script transcribing the same oral language. One form is the shallow pointed script (with diacritics, and the other is the deep unpointed script (without diacritics. Event-related potentials (ERPs were recorded while skilled readers carried out a lexical decision task in the two forms of script. A visual non-orthographic task controlled for the visual difference between the scripts (resulting from the addition of diacritics to the pointed script only. At an early visual-perceptual stage of processing (~165 ms after target onset, the pointed script evoked larger amplitudes with longer latencies than the unpointed script at occipital-temporal sites. However, these effects were not restricted to orthographic processing, and may therefore have reflected, at least in part, the visual load imposed by the diacritics. Nevertheless, the results implied that distinct orthographic processing may have also contributed to these effects. At later stages (~340 ms after target onset the unpointed script elicited larger amplitudes than the pointed one with earlier latencies. As this latency has been linked to orthographic-linguistic processing and to the classification of stimuli, it is suggested that these differences are associated with distinct lexical processing of a shallow and a deep orthography.

  12. Human activities cause distinct dissolved organic matter composition across freshwater ecosystems

    Science.gov (United States)

    Williams, Clayton J.; Frost, Paul C.; Morales-Williams, Ana M.; Larson, James H.; Richardson, William B.; Chiandet, Aisha S.; Xenopoulos, Marguerite A.

    2016-01-01

    Dissolved organic matter (DOM) composition in freshwater ecosystems is influenced by interactions between physical, chemical, and biological processes that are controlled, at one level, by watershed landscape, hydrology, and their connections. Against this environmental template, humans may strongly influence DOM composition. Yet, we lack a comprehensive understanding of DOM composition variation across freshwater ecosystems differentially affected by human activity. Using optical properties, we described DOM variation across five ecosystem groups of the Laurentian Great Lakes Region: large lakes, Kawartha Lakes, Experimental Lakes Area, urban stormwater ponds, and rivers (n = 184 sites). We determined how between ecosystem variation in DOM composition related to watershed size, land use and cover, water quality measures (conductivity, dissolved organic carbon (DOC), nutrient concentration, chlorophyll a), and human population density. The five freshwater ecosystem groups had distinctive DOM composition from each other. These significant differences were not explained completely through differences in watershed size nor spatial autocorrelation. Instead, multivariate partial least squares regression showed that DOM composition was related to differences in human impact across freshwater ecosystems. In particular, urban/developed watersheds with higher human population densities had a unique DOM composition with a clear anthropogenic influence that was distinct from DOM composition in natural land cover and/or agricultural watersheds. This nonagricultural, human developed impact on aquatic DOM was most evident through increased levels of a microbial, humic-like parallel factor analysis component (C6). Lotic and lentic ecosystems with low human population densities had DOM compositions more typical of clear water to humic-rich freshwater ecosystems but C6 was only present at trace to background levels. Consequently, humans are strongly altering the quality of DOM in

  13. Acquired blepharoptosis

    NARCIS (Netherlands)

    Oosterhuis, HJGH

    1996-01-01

    A review is given of the aetiology and possible treatment of acquired (non-congenital) blepharoptosis, which is a common but not specific sign of neurological disease: The diagnostic categories of upper eyelid drooping are scheduled as (a) pseudo-ptosis due to a local process or overactivity of eye

  14. Both phototropin 1 and 2 localize on the chloroplast outer membrane with distinct localization activity.

    Science.gov (United States)

    Kong, Sam-Geun; Suetsugu, Noriyuki; Kikuchi, Shingo; Nakai, Masato; Nagatani, Akira; Wada, Masamitsu

    2013-01-01

    Chloroplasts change their position to adapt cellular activities to fluctuating environmental light conditions. Phototropins (phot1 and phot2 in Arabidopsis) are plant-specific blue light photoreceptors that perceive changes in light intensity and direction, and mediate actin-based chloroplast photorelocation movements. Both phot1 and phot2 regulate the chloroplast accumulation response, while phot2 is mostly responsible for the regulation of the avoidance response. Although it has been widely accepted that distinct intracellular localizations of phototropins are implicated in the specificity, the mechanism underlying the phot2-specific avoidance response has remained elusive. In this study, we examined the relationship of the phot2 localization pattern to the chloroplast photorelocation movement. First, the fusion of a nuclear localization signal with phot2, which effectively reduced the amount of phot2 in the cytoplasm, retained the activity for both the accumulation and avoidance responses, indicating that membrane-localized phot2 but not cytoplasmic phot2 is functional to mediate the responses. Importantly, some fractions of phot2, and of phot1 to a lesser extent, were localized on the chloroplast outer membrane. Moreover, the deletion of the C-terminal region of phot2, which was previously shown to be defective in blue light-induced Golgi localization and avoidance response, affected the localization pattern on the chloroplast outer membrane. Taken together, these results suggest that dynamic phot2 trafficking from the plasma membrane to the Golgi apparatus and the chloroplast outer membrane might be involved in the avoidance response.

  15. In Vitro Activity of ASP2397 against Aspergillus Isolates with or without Acquired Azole Resistance Mechanisms.

    Science.gov (United States)

    Arendrup, Maiken Cavling; Jensen, Rasmus Hare; Cuenca-Estrella, Manuel

    2015-11-09

    ASP2397 is a new compound with a novel and as-yet-unknown target different from that of licensed antifungal agents. It has activity against Aspergillus and Candida glabrata. We compared its in vitro activity against wild-type and azole-resistant A. fumigatus and A. terreus isolates with that of amphotericin B, itraconazole, posaconazole, and voriconazole. Thirty-four isolates, including 4 wild-type A. fumigatus isolates, 24 A. fumigatus isolates with alterations in CYP51A TR/L98H (5 isolates), M220 (9 isolates), G54 (9 isolates), and HapE (1 isolate), and A. terreus isolates (2 wild-type isolates and 1 isolate with an M217I CYP51A alteration), were analyzed. EUCAST E.Def 9.2 and CLSI M38-A2 MIC susceptibility testing was performed. ASP2397 MIC50 values (in milligrams per liter, with MIC ranges in parentheses) determined by EUCAST and CLSI were 0.5 (0.25 to 1) and 0.25 (0.06 to 0.25) against A. fumigatus CYP51A wild-type isolates and were similarly 0.5 (0.125 to >4) and 0.125 (0.06 to >4) against azole-resistant A. fumigatus isolates, respectively. These values were comparable to those for amphotericin B, which were 0.25 (0.125 to 0.5) and 0.25 (0.125 to 0.25) against wild-type isolates and 0.25 (0.125 to 1) and 0.25 (0.125 to 1) against isolates with azole resistance mechanisms, respectively. In contrast, MICs for the azole compounds were elevated and highest for itraconazole: >4 (1 to >4) and 4 (0.5 to >4) against isolates with azole resistance mechanisms compared to 0.125 (0.125 to 0.25) and 0.125 (0.06 to 0.25) against wild-type isolates, respectively. ASP2397 was active against A. terreus CYP51A wild-type isolates (MIC 0.5 to 1), whereas MICs of both azole and ASP2397 were elevated for the mutant isolate. ASP2397 displayed in vitro activity against A. fumigatus and A. terreus isolates which was independent of the presence or absence of azole target gene resistance mutations in A. fumigatus. The findings are promising at a time when azole-resistant A. fumigatus

  16. Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3-dependent cancer cells.

    Science.gov (United States)

    Wang, J; Mikse, O; Liao, R G; Li, Y; Tan, L; Janne, P A; Gray, N S; Wong, K-k; Hammerman, P S

    2015-04-23

    Somatic alterations of fibroblast growth factor receptors (FGFRs) have been described in a wide range of malignancies. A number of anti-FGFR therapies are currently under investigation in clinical trials for subjects with FGFR gene amplifications, mutations and translocations. Here, we develop cell line models of acquired resistance to FGFR inhibition by exposure of cell lines harboring FGFR3 gene amplification and translocation to the selective FGFR inhibitor BGJ398 and multitargeted FGFR inhibitor ponatinib. We show that the acquisition of resistance is rapid, reversible and characterized by an epithelial to mesenchymal transition and a switch from dependency on FGFR3 to ERBB family members. Acquired resistance was associated with demonstrable changes in gene expression including increased production of ERBB2/3 ligands, which were sufficient to drive resistance in the setting of FGFR3 dependency but not dependency on other FGFR family members. These data support the concept that activation of ERBB family members is sufficient to bypass dependency on FGFR3 and suggest that concurrent inhibition of these two pathways may be desirable when targeting FGFR3-dependent cancers.

  17. lin-28 controls the succession of cell fate choices via two distinct activities.

    Directory of Open Access Journals (Sweden)

    Bhaskar Vadla

    Full Text Available lin-28 is a conserved regulator of cell fate succession in animals. In Caenorhabditis elegans, it is a component of the heterochronic gene pathway that governs larval developmental timing, while its vertebrate homologs promote pluripotency and control differentiation in diverse tissues. The RNA binding protein encoded by lin-28 can directly inhibit let-7 microRNA processing by a novel mechanism that is conserved from worms to humans. We found that C. elegans LIN-28 protein can interact with four distinct let-7 family pre-microRNAs, but in vivo inhibits the premature accumulation of only let-7. Surprisingly, however, lin-28 does not require let-7 or its relatives for its characteristic promotion of second larval stage cell fates. In other words, we find that the premature accumulation of mature let-7 does not account for lin-28's precocious phenotype. To explain let-7's role in lin-28 activity, we provide evidence that lin-28 acts in two steps: first, the let-7-independent positive regulation of hbl-1 through its 3'UTR to control L2 stage-specific cell fates; and second, a let-7-dependent step that controls subsequent fates via repression of lin-41. Our evidence also indicates that let-7 functions one stage earlier in C. elegans development than previously thought. Importantly, lin-28's two-step mechanism resembles that of the heterochronic gene lin-14, and the overlap of their activities suggests a clockwork mechanism for developmental timing. Furthermore, this model explains the previous observation that mammalian Lin28 has two genetically separable activities. Thus, lin-28's two-step mechanism may be an essential feature of its evolutionarily conserved role in cell fate succession.

  18. Distinct regions that control ion selectivity and calcium-dependent activation in the bestrophin ion channel.

    Science.gov (United States)

    Vaisey, George; Miller, Alexandria N; Long, Stephen B

    2016-11-22

    Cytoplasmic calcium (Ca(2+)) activates the bestrophin anion channel, allowing chloride ions to flow down their electrochemical gradient. Mutations in bestrophin 1 (BEST1) cause macular degenerative disorders. Previously, we determined an X-ray structure of chicken BEST1 that revealed the architecture of the channel. Here, we present electrophysiological studies of purified wild-type and mutant BEST1 channels and an X-ray structure of a Ca(2+)-independent mutant. From these experiments, we identify regions of BEST1 responsible for Ca(2+) activation and ion selectivity. A "Ca(2+) clasp" within the channel's intracellular region acts as a sensor of cytoplasmic Ca(2+). Alanine substitutions within a hydrophobic "neck" of the pore, which widen it, cause the channel to be constitutively active, irrespective of Ca(2+). We conclude that the primary function of the neck is as a "gate" that controls chloride permeation in a Ca(2+)-dependent manner. In contrast to what others have proposed, we find that the neck is not a major contributor to the channel's ion selectivity. We find that mutation of a cytosolic "aperture" of the pore does not perturb the Ca(2+) dependence of the channel or its preference for anions over cations, but its mutation dramatically alters relative permeabilities among anions. The data suggest that the aperture functions as a size-selective filter that permits the passage of small entities such as partially dehydrated chloride ions while excluding larger molecules such as amino acids. Thus, unlike ion channels that have a single "selectivity filter," in bestrophin, distinct regions of the pore govern anion-vs.-cation selectivity and the relative permeabilities among anions.

  19. Acquired Methemoglobinaemia

    Directory of Open Access Journals (Sweden)

    Adil Al-Lawati

    2012-05-01

    Full Text Available Acquired methemoglobinaemia is a relatively rare condition and, therefore infrequently encountered in acute medical practice. Suspicion of the condition may be triggered when the measured PaO2 is ‘out of keeping’ with the oxygen saturations that are discovered with pulse oximetry. We describe two separate cases of acquired methemoglobinaemia secondary to the recreational use of alkyl nitrites (’poppers’. The patients presented at separate times to two different teaching hospitals in London, UK. The similarity of these cases has led the authors to conclude that a raised awareness of this potentially fatal condition, and its association with a widely-available recreational drug, is necessary to ensure a correct and timely diagnosis.

  20. Cryptosporidiosis in the acquired immune deficiency syndrome.

    Science.gov (United States)

    Cooper, D A; Wodak, A; Marriot, D J; Harkness, J L; Ralston, M; Hill, A; Penny, R

    1984-10-01

    Cryptosporidiosis was found in a patient with the acquired immune deficiency syndrome. The microbiological and morphological features of this newly recognized opportunistic infection are distinctive and diagnostic.

  1. Acquired Techniques

    DEFF Research Database (Denmark)

    Lunde Nielsen, Espen; Halse, Karianne

    2013-01-01

    Acquired Techniques - a Leap into the Archive, at Aarhus School of Architecture. In collaboration with Karianne Halse, James Martin and Mika K. Friis. Following the footsteps of past travelers this is a journey into tools and techniques of the architectural process. The workshop will focus upon...... architectural production as a conglomerate of various analogue and digital methods, and provide the basics, the tips/tricks - and how the tool themselves becomes operational for spatial/thematic investigations. Eventually, this will become a city, exhibition and phamplet inhabited by the (by...

  2. Simultaneous reconstruction of emission activity and attenuation coefficient distribution from TOF data, acquired with external transmission source.

    Science.gov (United States)

    Panin, V Y; Aykac, M; Casey, M E

    2013-06-07

    The simultaneous PET data reconstruction of emission activity and attenuation coefficient distribution is presented, where the attenuation image is constrained by exploiting an external transmission source. Data are acquired in time-of-flight (TOF) mode, allowing in principle for separation of emission and transmission data. Nevertheless, here all data are reconstructed at once, eliminating the need to trace the position of the transmission source in sinogram space. Contamination of emission data by the transmission source and vice versa is naturally modeled. Attenuated emission activity data also provide additional information about object attenuation coefficient values. The algorithm alternates between attenuation and emission activity image updates. We also proposed a method of estimation of spatial scatter distribution from the transmission source by incorporating knowledge about the expected range of attenuation map values. The reconstruction of experimental data from the Siemens mCT scanner suggests that simultaneous reconstruction improves attenuation map image quality, as compared to when data are separated. In the presented example, the attenuation map image noise was reduced and non-uniformity artifacts that occurred due to scatter estimation were suppressed. On the other hand, the use of transmission data stabilizes attenuation coefficient distribution reconstruction from TOF emission data alone. The example of improving emission images by refining a CT-based patient attenuation map is presented, revealing potential benefits of simultaneous CT and PET data reconstruction.

  3. Dysregulated miR34a/diacylglycerol kinase ζ interaction enhances T-cell activation in acquired aplastic anemia.

    Science.gov (United States)

    Sun, Yuan-Xin; Li, Hui; Feng, Qi; Li, Xin; Yu, Ying-Yi; Zhou, Li-Wei; Gao, Yan; Li, Guo-Sheng; Ren, Juan; Ma, Chun-Hong; Gao, Cheng-Jiang; Peng, Jun

    2017-01-24

    Acquired aplastic anemia is an idiopathic paradigm of human bone marrow failure syndrome, which involves active destruction of hematopoietic stem cells and progenitors by cytotoxic T cells in the bone marrow. Aberrant expression of microRNAs in T cells has been shown to lead to development of certain autoimmune diseases. In the present study, we performed a microarray analysis of miRNA expression in bone marrow CD3+ T cells from patients with aplastic anemia and healthy controls. Overexpression of miR34a and underexpression of its target gene diacylglycerol kinase (DGK) ζ in bone marrow mononuclear cells were validated in 41 patients and associated with the severity of aplastic anemia. Further, the level of miR34a was higher in naïve T cells from patients than from controls. The role of miR34a and DGKζ in aplastic anemia was investigated in a murine model of immune-mediated bone marrow failure using miR34a-/- mice. After T-cell receptor stimulation in vitro, lymph node T cells from miR34a-/- mice demonstrated reduced activation and proliferation accompanied with a less profound down-regulation of DGKζ expression and decreased ERK phosphorylation compared to those from wild-type C57BL6 control mice. Infusion of 5 × 106 miR34a-/- lymph node T cells into sublethally irradiated CB6F1 recipients led to increased Lin-Sca1+CD117+ cells and less vigorous expansion of CD8+ T cells than injection of same number of wild-type lymph node cells. Our study demonstrates that the miR34a/DGKζ dysregulation enhances T-cell activation in aplastic anemia and targeting miR34a may represent a novel molecular therapeutic approach for patients with aplastic anemia.

  4. Bovine NK cells acquire cytotoxic activity and produce IFN-gamma after stimulation by Mycobacterium bovis BCG- or Babesia bovis-exposed splenic dendritic cells

    Science.gov (United States)

    Early interactions of innate immune cell populations such as DC, monocytes/macrophages and NK cells, can affect the ability of the acquired immune response to control infection of intracellular microorganisms. In this study, we investigated the activation of bovine NK cells by CD13+ splenic DC or CD...

  5. Distinct Developmental Functions of Prostasin (CAP1/PRSS8) Zymogen and Activated Prostasin

    DEFF Research Database (Denmark)

    Friis, Stine; Madsen, Daniel H.; Bugge, Thomas H.

    2016-01-01

    and a two-chain proteolytically active form, generated by matriptase-dependent activation site cleavage. Here we used gene editing to generate mice expressing only activation site cleavage-resistant (zymogen-locked) endogenous prostasin. Interestingly, these mutant mice displayed normal interfollicular...

  6. Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib

    NARCIS (Netherlands)

    Janjigian, Y Y; Groen, H J; Horn, L; Smit, E F; Fu, Y; Wang, F; Shahidi, M; Denis, L J; Pao, W; Miller, V A

    2011-01-01

    7525^ Background: Despite initial responses to reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, (erlotinib or gefitinib), all non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations experience disease progression. This "acquired resistance" (AR) is a

  7. Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib

    NARCIS (Netherlands)

    Janjigian, Y. Y.; Groen, H. J.; Horn, L.; Smit, E. F.; Fu, Y.; Wang, F.; Shahidi, M.; Denis, L. J.; Pao, W.; Miller, V. A.

    2011-01-01

    Background: Despite initial responses to reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, (erlotinib or gefitinib), all non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations experience disease progression. This “acquired resistance” (AR) is associa

  8. Modification of Pulsed Electric Field Conditions Results in Distinct Activation Profiles of Platelet-Rich Plasma

    Science.gov (United States)

    Frelinger, Andrew L.; Gerrits, Anja J.; Garner, Allen L.; Torres, Andrew S.; Caiafa, Antonio; Morton, Christine A.; Berny-Lang, Michelle A.; Carmichael, Sabrina L.; Neculaes, V. Bogdan; Michelson, Alan D.

    2016-01-01

    Background Activated autologous platelet-rich plasma (PRP) used in therapeutic wound healing applications is poorly characterized and standardized. Using pulsed electric fields (PEF) to activate platelets may reduce variability and eliminate complications associated with the use of bovine thrombin. We previously reported that exposing PRP to sub-microsecond duration, high electric field (SMHEF) pulses generates a greater number of platelet-derived microparticles, increased expression of prothrombotic platelet surfaces, and differential release of growth factors compared to thrombin. Moreover, the platelet releasate produced by SMHEF pulses induced greater cell proliferation than plasma. Aims To determine whether sub-microsecond duration, low electric field (SMLEF) bipolar pulses results in differential activation of PRP compared to SMHEF, with respect to profiles of activation markers, growth factor release, and cell proliferation capacity. Methods PRP activation by SMLEF bipolar pulses was compared to SMHEF pulses and bovine thrombin. PRP was prepared using the Harvest SmartPreP2 System from acid citrate dextrose anticoagulated healthy donor blood. PEF activation by either SMHEF or SMLEF pulses was performed using a standard electroporation cuvette preloaded with CaCl2 and a prototype instrument designed to take into account the electrical properties of PRP. Flow cytometry was used to assess platelet surface P-selectin expression, and annexin V binding. Platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), endothelial growth factor (EGF) and platelet factor 4 (PF4), and were measured by ELISA. The ability of supernatants to stimulate proliferation of human epithelial cells in culture was also evaluated. Controls included vehicle-treated, unactivated PRP and PRP with 10 mM CaCl2 activated with 1 U/mL bovine thrombin. Results PRP activated with SMLEF bipolar pulses or thrombin had similar light scatter profiles, consistent with the

  9. Distinct Kinetics Features of LFA-1 and Mac-1 in Neutrophil Activation

    Institute of Scientific and Technical Information of China (English)

    LI Ning; MAO De-bin; GONG Yi-xin; LV Shou-qin; ZHANG Yan; LONG Mian

    2015-01-01

    LFA-1 and Mac-1, two β2 integrin members constitutively expressed on neutrophils, mediate leukocyte recruitment cascade by binding to the same ligand of ICAM-1The slow rolling and firm adhesion of leukocytes rely on LFA-1 while the cell crawling is dependent on Mac-1We hypothesized that their distinct roles are likely attributed to the differences in the binding kinetics or in the diverse responses of outside-in and inside-out signalingIn this study, we compared the ICAM-1 binding features between soluble or membrane-expressed LFA-1 and Mac-1 with different affinity conformation using optical trap techniqueOur data indicated that the affinity up-regulation from wide type (WT) to high affinity (HA) is off-rate dependent for LFA-1 but on-rate dependent for Mac-1The structural bases of this new finding were found to be consistent with our previous simulationsThese results furthered our understanding in their function differences under shear flow.

  10. New Isorhamnetin Derivatives from Salsola imbricata Forssk. Leaves with Distinct Anti-inflammatory Activity

    OpenAIRE

    Osman, Samir M.; El Kashak, Walaa A.; Michael Wink; El Raey, Mohamed A.

    2016-01-01

    Background: Salsola imbricata Forssk. is a shrub widely growing in Egypt, used as a camel food, traditionally, used as anti-inflammatory agent. Literature survey showed no report about the anti-inflammatory activity of S. imbricata. Aim of the Study: This work was designed to study the phenolic constituents and to provide evidence for the traditional use of S. imbricata as an anti-inflammatory agent. Materials and Methods: The in vitro anti-inflammatory activity of the total aqueous methanol ...

  11. Pregnane X receptor activation and silencing promote steatosis of human hepatic cells by distinct lipogenic mechanisms.

    Science.gov (United States)

    Bitter, Andreas; Rümmele, Petra; Klein, Kathrin; Kandel, Benjamin A; Rieger, Jessica K; Nüssler, Andreas K; Zanger, Ulrich M; Trauner, Michael; Schwab, Matthias; Burk, Oliver

    2015-11-01

    In addition to its well-characterized role in the regulation of drug metabolism and transport by xenobiotics, pregnane X receptor (PXR) critically impacts on lipid homeostasis. In mice, both ligand-dependent activation and knockout of PXR were previously shown to promote hepatic steatosis. To elucidate the respective pathways in human liver, we generated clones of human hepatoma HepG2 cells exhibiting different PXR protein levels, and analyzed effects of PXR activation and knockdown on steatosis and expression of lipogenic genes. Ligand-dependent activation as well as knockdown of PXR resulted in increased steatosis in HepG2 cells. Activation of PXR induced the sterol regulatory element-binding protein (SREBP) 1-dependent lipogenic pathway via PXR-dependent induction of SREBP1a, which was confirmed in primary human hepatocytes. Inhibiting SREBP1 activity by blocking the cleavage-dependent maturation of SREBP1 protein impaired the induction of lipogenic SREBP1 target genes and triglyceride accumulation by PXR activation. On the other hand, PXR knockdown resulted in up-regulation of aldo-keto reductase (AKR) 1B10, which enhanced the acetyl-CoA carboxylase (ACC)-catalyzed reaction step of de novo lipogenesis. In a cohort of human liver samples histologically classified for non-alcoholic fatty liver disease, AKR1B10, SREBP1a and SREBP1 lipogenic target genes proved to be up-regulated in steatohepatitis, while PXR protein was reduced. In summary, our data suggest that activation and knockdown of PXR in human hepatic cells promote de novo lipogenesis and steatosis by induction of the SREBP1 pathway and AKR1B10-mediated increase of ACC activity, respectively, thus providing mechanistic explanations for a putative dual role of PXR in the pathogenesis of steatohepatitis.

  12. An Acidic Thermostable Recombinant Aspergillus nidulans Endoglucanase Is Active towards Distinct Agriculture Residues

    Directory of Open Access Journals (Sweden)

    Eveline Queiroz de Pinho Tavares

    2013-01-01

    Full Text Available Aspergillus nidulans is poorly exploited as a source of enzymes for lignocellulosic residues degradation for biotechnological purposes. This work describes the A. nidulans Endoglucanase A heterologous expression in Pichia pastoris, the purification and biochemical characterization of the recombinant enzyme. Active recombinant endoglucanase A (rEG A was efficiently secreted as a 35 kDa protein which was purified through a two-step chromatography procedure. The highest enzyme activity was detected at 50°C/pH 4. rEG A retained 100% of activity when incubated at 45 and 55°C for 72 h. Purified rEG A kinetic parameters towards CMC were determined as Km=27.5±4.33 mg/mL, Vmax=1.185±0.11 mmol/min, and 55.8 IU (international units/mg specific activity. Recombinant P. pastoris supernatant presented hydrolytic activity towards lignocellulosic residues such as banana stalk, sugarcane bagasse, soybean residues, and corn straw. These data indicate that rEG A is suitable for plant biomass conversion into products of commercial importance, such as second-generation fuel ethanol.

  13. Arabidopsis Profilin Isoforms, PRF1 and PRF2Show Distinctive Binding Activities and Subcellular Distributions

    Institute of Scientific and Technical Information of China (English)

    Feng Wang; Yanping Jing; Zhen Wang; Tonglin Mao; Jozef (S)amaj; Ming Yuan; Haiyun Ren

    2009-01-01

    Profilin is an actin-binding protein that shows complex effects on the dynamics of the actin cytoskeleton. There are five profilin isoforms in Arabidopsis thaliana L. However, it is still an open question whether these isoforms are functionally different. In the present study, two profilin isoforms from Arabidopsis, PRF1 and PRF2 were fused with green fluorescent protein (GFP) tag and expressed in Escherichia coli and A. thaliana in order to compare their biochemical properties in vitro and their cellular distributions in vivo. Biochemical analysis revealed that fusion proteins of GFP-PRF1 and GFP-PRF2 can bind to poly-L-proline and G-actin showing remarkable differences. GFP-PRF1 has much higher affinities for both poly-L-proline and G-actin compared with GFP-PRF2. Observations of living cells in stable transgsnic A. thaliana lines revealed that 35S::GFP-PRF1 formed a filamentous network, while 35S::GFP-PRF2 formed polygonal meshes. Results from the treatment with latrunculin A and a subsequent recovery experiment indicated that filamentous alignment of GFP-PRF1 was likely associated with actin filaments. However, GFP-PRF2 localized to polygonal meshes resembling the endoplasmic reticulum. Our results provide evidence that Arabidopsis profllin isoforms PRF1 and PRF2 have different biochemical affinities for poly-L-proline and G-actin, and show distinctive Iocalizations in living cells. These data suggest that PRF1 and PRF2 are functionally different isoforms.

  14. Distinctive role of activated tumor-associated macrophages in photosensitizer accumulation

    Science.gov (United States)

    Korbelik, Mladen; Krosl, Gorazd

    1995-05-01

    Cells dissociated from tumors (carcinomas and sarcomas) growing subcutaneously in mice that have been administered Photofrin or other photosensitizers were analyzed by flow cytometry. Monoclonal antibodies were used for identification of major cellular populations contained in these tumors. The results demonstrate that a subpopulation of tumor-associated macrophages (TAMs) is unique among tumor cell populations in that it excels in the accumulation of very high levels of photosensitizers. These macrophages showed an increased expression of interleukin 2 receptor, which is indicative of their activated state. since macrophages were reported to concentrate in the periphery of human neoplasms, it is suggested that activates TAMs are the determinants of tumor-localized photosensitizer fluorescence.

  15. Distinct neural pathways mediate alpha7 nicotinic acetylcholine receptor-dependent activation of the forebrain

    DEFF Research Database (Denmark)

    Thomsen, Morten S; Hay-Schmidt, Anders; Hansen, Henrik H;

    2010-01-01

    alpha(7) nicotinic acetylcholine receptor (nAChR) agonists are candidates for the treatment of cognitive deficits in schizophrenia. Selective alpha(7) nAChR agonists, such as SSR180711, activate neurons in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (ACCshell) in rats, regions...

  16. Anterior asymetrical alpha activity predicts Iowa gambling performance: distinctly but reversed.

    Science.gov (United States)

    Schutter, Dennis J L G; de Haan, Edward H F; van Honk, Jack

    2004-01-01

    Animal research indicates that the prefrontal cortex (PFC) plays a crucial role in decision making. In concordance, deficits in decision making have been observed in human patients with damage to the PFC. Contemporary accounts of decision making suggest that emotion guides the process of decision making by ways of providing for reward-punishment contingencies. A task capable of assessing the influence of reward and punishment on decision making is the Iowa gambling task. In this task decisions become motivated by inherent punishment and reward schedules. Insensitivity for punishment together with a strong reward dependency results in risk taking, which is in the gambling task the disadvantageous strategy. Interestingly, the processing of punishment and reward is argued to be lateralized over the right and left PFC, respectively. Here we investigated whether more relative left compared to right-sided frontal brain activity (left-sided dominance) quantified as reduced alpha (8-12 Hz) activity in the electroencephalogram (EEG) would lead to a more risky, disadvantageous pattern of decision making. Contrary to what was expected, relatively more right compared to left frontal brain activity was strongly associated with the disadvantageous strategy. The results are discussed in terms of recent theoretical accounts which argue that the functional interpretation of baseline frontal alpha activity depends on the mental operation involved and does not necessarily imply inactivity.

  17. Comparison of mitochondrial and nucleolar RNase MRP reveals identical RNA components with distinct enzymatic activities and protein components.

    Science.gov (United States)

    Lu, Qiaosheng; Wierzbicki, Sara; Krasilnikov, Andrey S; Schmitt, Mark E

    2010-03-01

    RNase MRP is a ribonucleoprotein endoribonuclease found in three cellular locations where distinct substrates are processed: the mitochondria, the nucleolus, and the cytoplasm. Cytoplasmic RNase MRP is the nucleolar enzyme that is transiently relocalized during mitosis. Nucleolar RNase MRP (NuMRP) was purified to homogeneity, and we extensively purified the mitochondrial RNase MRP (MtMRP) to a single RNA component identical to the NuMRP RNA. Although the protein components of the NuMRP were identified by mass spectrometry successfully, none of the known NuMRP proteins were found in the MtMRP preparation. Only trace amounts of the core NuMRP protein, Pop4, were detected in MtMRP by Western blot. In vitro activity of the two enzymes was compared. MtMRP cleaved only mitochondrial ORI5 substrate, while NuMRP cleaved all three substrates. However, the NuMRP enzyme cleaved the ORI5 substrate at sites different than the MtMRP enzyme. In addition, enzymatic differences in preferred ionic strength confirm these enzymes as distinct entities. Magnesium was found to be essential to both enzymes. We tested a number of reported inhibitors including puromycin, pentamidine, lithium, and pAp. Puromycin inhibition suggested that it binds directly to the MRP RNA, reaffirming the role of the RNA component in catalysis. In conclusion, our study confirms that the NuMRP and MtMRP enzymes are distinct entities with differing activities and protein components but a common RNA subunit, suggesting that the RNA must be playing a crucial role in catalytic activity.

  18. Distinct BOLD activation profiles following central and peripheral oxytocin administration in awake rats

    Directory of Open Access Journals (Sweden)

    Craig F Ferris

    2015-09-01

    Full Text Available A growing body of literature has suggested that intranasal oxytocin (OT or other systemic routes of administration can alter prosocial behavior, presumably by directly activating OT sensitive neural circuits in the brain. Yet there is no clear evidence that OT given peripherally can cross the blood-brain-barrier at levels sufficient to engage the OT receptor. To address this issue we examined changes in blood oxygen level dependent (BOLD signal intensity in response to peripheral OT injections (0.1, 0.5 or 2.5 mg/kg during functional magnetic resonance (fMRI in awake rats imaged at 7.0 tesla. These data were compared to OT (1ug/5 µl given directly to the brain via the lateral cerebroventricle. Using a 3D annotated MRI atlas of the rat brain segmented into 171 brain areas and computational analysis we reconstructed the distributed integrated neural circuits identified with BOLD fMRI following central and peripheral OT. Both routes of administration caused significant changes in BOLD signal within the first 10 min of administration. As expected, central OT activated a majority of brain areas known to express a high density of OT receptors e.g., lateral septum, subiculum, shell of the accumbens, bed nucleus of the stria terminalis. This profile of activation was not matched by peripheral OT. The change in BOLD signal to peripheral OT did not show any discernible dose-response. Interestingly, peripheral OT affected all subdivisions of the olfactory bulb, in addition to the cerebellum and several brainstem areas relevant to the autonomic nervous system, including the solitary tract nucleus. The results from this imaging study do not support a direct central action of peripheral OT on the brain. Instead, the patterns of brain activity suggest that peripheral OT may interact at the level of the olfactory bulb and through sensory afferents from the autonomic nervous system to influence brain activity.

  19. Distinct patterns of constitutive phosphodiesterase activity in mouse sinoatrial node and atrial myocardium.

    Directory of Open Access Journals (Sweden)

    Rui Hua

    Full Text Available Phosphodiesterases (PDEs are critical regulators of cyclic nucleotides in the heart. In ventricular myocytes, the L-type Ca(2+ current (I(Ca,L is a major target of regulation by PDEs, particularly members of the PDE2, PDE3 and PDE4 families. Conversely, much less is known about the roles of PDE2, PDE3 and PDE4 in the regulation of action potential (AP properties and I(Ca,L in the sinoatrial node (SAN and the atrial myocardium, especially in mice. Thus, the purpose of our study was to measure the effects of global PDE inhibition with Isobutyl-1-methylxanthine (IBMX and selective inhibitors of PDE2, PDE3 and PDE4 on AP properties in isolated mouse SAN and right atrial myocytes. We also measured the effects of these inhibitors on I(Ca,L in SAN and atrial myocytes in comparison to ventricular myocytes. Our data demonstrate that IBMX markedly increases spontaneous AP frequency in SAN myocytes and AP duration in atrial myocytes. Spontaneous AP firing in SAN myocytes was also increased by the PDE2 inhibitor erythro-9-[2-hydroxy-3-nonyl] adenine (EHNA, the PDE3 inhibitor milrinone (Mil and the PDE4 inhibitor rolipram (Rol. In contrast, atrial AP duration was increased by EHNA and Rol, but not by Mil. IBMX also potently, and similarly, increased I(Ca,L in SAN, atrial and ventricular myocytes; however, important differences emerged in terms of which inhibitors could modulate I(Ca,L in each myocyte type. Consistent with our AP measurements, EHNA, Mil and Rol each increased I(Ca,L in SAN myocytes. Also, EHNA and Rol, but not Mil, increased atrial I(Ca,L. In complete contrast, no selective PDE inhibitors increased I(Ca,L in ventricular myocytes when given alone. Thus, our data show that the effects of selective PDE2, PDE3 and PDE4 inhibitors are distinct in the different regions of the myocardium indicating important differences in how each PDE family constitutively regulates ion channel function in the SAN, atrial and ventricular myocardium.

  20. Mycobacterial secretion systems ESX-1 and ESX-5 play distinct roles in host cell death and inflammasome activation

    KAUST Repository

    Abdallah, Abdallah

    2011-09-28

    During infection of humans and animals, pathogenic mycobacteria manipulate the host cell causing severe diseases such as tuberculosis and leprosy. To understand the basis of mycobacterial pathogenicity, it is crucial to identify the molecular virulence mechanisms. In this study, we address the contribution of ESX-1 and ESX-5 - two homologous type VII secretion systems of mycobacteria that secrete distinct sets of immune modulators - during the macrophage infection cycle. Using wild-type, ESX-1- and ESX-5-deficient mycobacterial strains, we demonstrate that these secretion systems differentially affect subcellular localization and macrophage cell responses. We show that in contrast to ESX-1, the effector proteins secreted by ESX-5 are not required for the translocation of Mycobacterium tuberculosis or Mycobacterium marinum to the cytosol of host cells. However, the M. marinum ESX-5 mutant does not induce inflammasome activation and IL-1b activation. The ESX-5 system also induces a caspase-independent cell death after translocation has taken place. Importantly, by means of inhibitory agents and small interfering RNA experiments, we reveal that cathepsin B is involved in both the induction of cell death and inflammasome activation upon infection with wild-type mycobacteria. These results reveal distinct roles for two different type VII secretion systems during infection and shed light on how virulent mycobacteria manipulate the host cell in various ways to replicate and spread. Copyright © 2011 by The American Association of Immunologists, Inc.

  1. P2X7R activation drives distinct IL-1 responses in dendritic cells compared to macrophages

    OpenAIRE

    Englezou, Pavlos C.; Rothwell, Simon W.; Ainscough, Joseph S.; Brough, David; Landsiedel, Robert; Verkhratsky, Alexei; Kimber, Ian; Dearman, Rebecca J

    2015-01-01

    The P2X7R is a functionally distinct member of the P2X family of non-selective cation channels associated with rapid activation of the inflammasome complex and signalling interleukin (IL)-1β release in macrophages. The main focus of this investigation was to compare P2X7R-driven IL-1 production by primary murine bone marrow derived dendritic cells (BMDC) and macrophages (BMM). P2X7R expression in murine BMDC and BMM at both transcriptional (P2X7A variant) and protein levels was demonstrated....

  2. Identification and quantification of aroma-active components that contribute to the distinct malty flavor of buckwheat honey.

    Science.gov (United States)

    Zhou, Qiaoxuan; Wintersteen, Carol L; Cadwallader, Keith R

    2002-03-27

    Characteristic aroma components of buckwheat honey were studied by combined sensory and instrumental techniques. Relative aroma intensity of individual volatile components was evaluated by aroma extract dilution analysis (AEDA) of solvent extracts and by gas chromatography-olfactometry (GCO) of decreasing headspace samples (GCO-H). Results indicated that 3-methylbutanal, 3-hydroxy-4,5-dimethyl-2(5H)-furanone (sotolon), and (E)-beta-damascenone were the most potent odorants in buckwheat honey, with 3-methylbutanal being primarily responsible for the distinct malty aroma. Other important aroma-active compounds included methylpropanal, 2,3-butanedione, phenylacetaldehyde, 3-methylbutyric acid, maltol, vanillin, methional, coumarin, and p-cresol.

  3. Distinct promoter activation mechanisms modulate noise-driven HIV gene expression

    Science.gov (United States)

    Chavali, Arvind K.; Wong, Victor C.; Miller-Jensen, Kathryn

    2015-12-01

    Latent human immunodeficiency virus (HIV) infections occur when the virus occupies a transcriptionally silent but reversible state, presenting a major obstacle to cure. There is experimental evidence that random fluctuations in gene expression, when coupled to the strong positive feedback encoded by the HIV genetic circuit, act as a ‘molecular switch’ controlling cell fate, i.e., viral replication versus latency. Here, we implemented a stochastic computational modeling approach to explore how different promoter activation mechanisms in the presence of positive feedback would affect noise-driven activation from latency. We modeled the HIV promoter as existing in one, two, or three states that are representative of increasingly complex mechanisms of promoter repression underlying latency. We demonstrate that two-state and three-state models are associated with greater variability in noisy activation behaviors, and we find that Fano factor (defined as variance over mean) proves to be a useful noise metric to compare variability across model structures and parameter values. Finally, we show how three-state promoter models can be used to qualitatively describe complex reactivation phenotypes in response to therapeutic perturbations that we observe experimentally. Ultimately, our analysis suggests that multi-state models more accurately reflect observed heterogeneous reactivation and may be better suited to evaluate how noise affects viral clearance.

  4. Bidirectional Transcription Arises from Two Distinct Hubs of Transcription Factor Binding and Active Chromatin.

    Science.gov (United States)

    Scruggs, Benjamin S; Gilchrist, Daniel A; Nechaev, Sergei; Muse, Ginger W; Burkholder, Adam; Fargo, David C; Adelman, Karen

    2015-06-18

    Anti-sense transcription originating upstream of mammalian protein-coding genes is a well-documented phenomenon, but remarkably little is known about the regulation or function of anti-sense promoters and the non-coding RNAs they generate. Here we define at nucleotide resolution the divergent transcription start sites (TSSs) near mouse mRNA genes. We find that coupled sense and anti-sense TSSs precisely define the boundaries of a nucleosome-depleted region (NDR) that is highly enriched in transcription factor (TF) motifs. Notably, as the distance between sense and anti-sense TSSs increases, so does the size of the NDR, the level of signal-dependent TF binding, and gene activation. We further discover a group of anti-sense TSSs in macrophages with an enhancer-like chromatin signature. Interestingly, this signature identifies divergent promoters that are activated during immune challenge. We propose that anti-sense promoters serve as platforms for TF binding and establishment of active chromatin to further regulate or enhance sense-strand mRNA expression.

  5. Adenovirus Activates Complement by Distinctly Different Mechanisms In Vitro and In Vivo: Indirect Complement Activation by Virions In Vivo▿

    OpenAIRE

    Tian, Jie; Xu, Zhili; Jeffrey S Smith; Hofherr, Sean E.; Barry, Michael A.; Byrnes, Andrew P.

    2009-01-01

    Understanding innate immunity is key to improving the safety of adenovirus (Ad) vectors for systemic gene therapy. Ad has been shown to activate complement in vitro, but activation of complement after Ad injection in vivo has not been directly measured. Using complement protein C3a as a marker of complement activation, we show that types 2 and 5 human Ads cause rapid complement activation after intravenous injection in mice. Unexpectedly, the mechanisms in vivo were different than those in vi...

  6. Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation.

    Science.gov (United States)

    Ngo, Huu B; Lovely, Geoffrey A; Phillips, Rob; Chan, David C

    2014-01-01

    TFAM (transcription factor A, mitochondrial) is a DNA-binding protein that activates transcription at the two major promoters of mitochondrial DNA (mtDNA)--the light strand promoter (LSP) and the heavy strand promoter 1 (HSP1). Equally important, it coats and packages the mitochondrial genome. TFAM has been shown to impose a U-turn on LSP DNA; however, whether this distortion is relevant at other sites is unknown. Here we present crystal structures of TFAM bound to HSP1 and to nonspecific DNA. In both, TFAM similarly distorts the DNA into a U-turn. Yet, TFAM binds to HSP1 in the opposite orientation from LSP explaining why transcription from LSP requires DNA bending, whereas transcription at HSP1 does not. Moreover, the crystal structures reveal dimerization of DNA-bound TFAM. This dimerization is dispensable for DNA bending and transcriptional activation but is important in DNA compaction. We propose that TFAM dimerization enhances mitochondrial DNA compaction by promoting looping of the DNA.

  7. Distinct resting-state brain activity in patients with functional constipation.

    Science.gov (United States)

    Zhu, Qiang; Cai, Weiwei; Zheng, Jianyong; Li, Guanya; Meng, Qianqian; Liu, Qiaoyun; Zhao, Jizheng; von Deneen, Karen M; Wang, Yuanyuan; Cui, Guangbin; Duan, Shijun; Han, Yu; Wang, Huaning; Tian, Jie; Zhang, Yi; Nie, Yongzhan

    2016-10-01

    Functional constipation (FC) is a common functional gastrointestinal disorder (FGID) with a higher prevalence in clinical practice. The primary brain regions involved in emotional arousal regulation, somatic, sensory and motor control processing have been identified with neuroimaging in FGID. It remains unclear how these factors interact to influence the baseline brain activity of patients with FC. In the current study, we combined resting-state fMRI (RS-fMRI) with Granger causality analysis (GCA) to investigate the causal interactions of the brain areas in 14 patients with FC and in 26 healthy controls (HC). Our data showed significant differences in baseline brain activities in a number of major brain regions implicated in emotional process modulation (i.e. dorsal anterior cingulate cortex-dACC, anterior insula-aINS, orbitofrontal cortex-OFC, hippocampus-HIPP), somatic and sensory processing, and motor control (i.e., supplementary motor area-SMA, precentral gyrus-PreCen) (Ppropel limbic regions at the aINS and HIPP to induce abnormal emotional processing regulating visceral responses; and weaker effective connectivity from the SMA and PreCen, which are regions involved with somatic, sensory and motor control, propel the aINS and HIPP, suggesting abnormalities of sensory and behavioral responses. Such information of basal level functional abnormalities expands our current understanding of neural mechanisms underlying functional constipation.

  8. Distinct patterns of brain activity in progressive supranuclear palsy and Parkinson's disease.

    Science.gov (United States)

    Burciu, Roxana G; Ofori, Edward; Shukla, Priyank; Planetta, Peggy J; Snyder, Amy F; Li, Hong; Hass, Chris J; Okun, Michael S; McFarland, Nikolaus R; Vaillancourt, David E

    2015-08-01

    The basal ganglia-thalamo-cortical and cerebello-thalamo-cortical circuits are important for motor control. Whether their functioning is affected in a similar or different way by progressive supranuclear palsy (PSP) and Parkinson's disease (PD) is not clear. A functional magnetic resonance imaging (fMRI) force production paradigm and voxel-based morphometry were used to assess differences in brain activity and macrostructural volumes between PSP, PD, and healthy age-matched controls. We found that PSP and PD share reduced functional activity of the basal ganglia and cortical motor areas, but this is more pronounced in PSP than in PD. In PSP the frontal regions are underactive, whereas the posterior parietal and occipital regions are overactive as compared with controls and PD. Furthermore, lobules I through IV, V, and VI of the cerebellum are hypoactive in PSP and PD, whereas Crus I and lobule IX are hyperactive in PSP only. Reductions in gray and white matter volume are specific to PSP. Finally, the functional status of the caudate as well as the volume of the superior frontal gyrus predict clinical gait and posture measures in PSP. PSP and PD share hypoactivity of the basal ganglia, motor cortex, and anterior cerebellum. These patients also display a unique pattern, such that anterior regions of the cortex are hypoactive and posterior regions of the cortex and cerebellum are hyperactive. Together, these findings suggest that specific structures within the basal ganglia, cortex, and cerebellum are affected differently in PSP relative to PD.

  9. ϒ-secretase and LARG mediate distinct RGMa activities to control appropriate layer targeting within the optic tectum.

    Science.gov (United States)

    Banerjee, P; Harada, H; Tassew, N G; Charish, J; Goldschneider, D; Wallace, V A; Sugita, S; Mehlen, P; Monnier, P P

    2016-03-01

    While a great deal of progress has been made in understanding the molecular mechanisms that regulate retino-tectal mapping, the determinants that target retinal projections to specific layers of the optic tectum remain elusive. Here we show that two independent RGMa-peptides, C- and N-RGMa, activate two distinct intracellular pathways to regulate axonal growth. C-RGMa utilizes a Leukemia-associated RhoGEF (LARG)/Rho/Rock pathway to inhibit axonal growth. N-RGMa on the other hand relies on ϒ-secretase cleavage of the intracellular portion of Neogenin to generate an intracellular domain (NeICD) that uses LIM-only protein 4 (LMO4) to block growth. In the developing tectum (E18), overexpression of C-RGMa and dominant-negative LARG (LARG-PDZ) induced overshoots in the superficial tectal layer but not in deeper tectal layers. In younger embryos (E12), C-RGMa and LARG-PDZ prevented ectopic projections toward deeper tectal layers, indicating that C-RGMa may act as a barrier to descending axons. In contrast both N-RGMa and NeICD overexpression resulted in aberrant axonal-paths, all of which suggests that it is a repulsive guidance molecule. Thus, two RGMa fragments activate distinct pathways resulting in different axonal responses. These data reveal how retinal projections are targeted to the appropriate layer in their target tissue.

  10. Imaging Surrogates of Disease Activity in Neuromyelitis Optica Allow Distinction from Multiple Sclerosis.

    Science.gov (United States)

    Matthews, Lucy; Kolind, Shannon; Brazier, Alix; Leite, Maria Isabel; Brooks, Jonathan; Traboulsee, Anthony; Jenkinson, Mark; Johansen-Berg, Heidi; Palace, Jacqueline

    2015-01-01

    Inflammatory demyelinating lesions of the central nervous system are a common feature of both neuromyelitis optica and multiple sclerosis. Despite this similarity, it is evident clinically that the accumulation of disability in patients with neuromyelitis optica is relapse related and that a progressive phase is very uncommon. This poses the question whether there is any pathological evidence of disease activity or neurodegeneration in neuromyelitis optica between relapses. To investigate this we conducted a longitudinal advanced MRI study of the brain and spinal cord in neuromyelitis optica patients, comparing to patients with multiple sclerosis and controls. We found both cross-sectional and longitudinal evidence of diffusely distributed neurodegenerative surrogates in the multiple sclerosis group (including thalamic atrophy, cervical cord atrophy and progressive widespread diffusion and myelin water imaging abnormalities in the normal appearing white matter) but not in those with neuromyelitis optica, where localised abnormalities in the optic radiations of those with severe visual impairment were noted. In addition, between relapses, there were no new silent brain lesions in the neuromyelitis optica group. These findings indicate that global central nervous system neurodegeneration is not a feature of neuromyelitis optica. The work also questions the theory that neurodegeneration in multiple sclerosis is a chronic sequela to prior inflammatory and demyelinating pathology, as this has not been found to be the case in neuromyelitis optica where the lesions are often more destructive.

  11. Imaging Surrogates of Disease Activity in Neuromyelitis Optica Allow Distinction from Multiple Sclerosis.

    Directory of Open Access Journals (Sweden)

    Lucy Matthews

    Full Text Available Inflammatory demyelinating lesions of the central nervous system are a common feature of both neuromyelitis optica and multiple sclerosis. Despite this similarity, it is evident clinically that the accumulation of disability in patients with neuromyelitis optica is relapse related and that a progressive phase is very uncommon. This poses the question whether there is any pathological evidence of disease activity or neurodegeneration in neuromyelitis optica between relapses. To investigate this we conducted a longitudinal advanced MRI study of the brain and spinal cord in neuromyelitis optica patients, comparing to patients with multiple sclerosis and controls. We found both cross-sectional and longitudinal evidence of diffusely distributed neurodegenerative surrogates in the multiple sclerosis group (including thalamic atrophy, cervical cord atrophy and progressive widespread diffusion and myelin water imaging abnormalities in the normal appearing white matter but not in those with neuromyelitis optica, where localised abnormalities in the optic radiations of those with severe visual impairment were noted. In addition, between relapses, there were no new silent brain lesions in the neuromyelitis optica group. These findings indicate that global central nervous system neurodegeneration is not a feature of neuromyelitis optica. The work also questions the theory that neurodegeneration in multiple sclerosis is a chronic sequela to prior inflammatory and demyelinating pathology, as this has not been found to be the case in neuromyelitis optica where the lesions are often more destructive.

  12. Motivational states activate distinct hippocampal representations to guide goal-directed behaviors.

    Science.gov (United States)

    Kennedy, Pamela J; Shapiro, Matthew L

    2009-06-30

    Adaptive behaviors are guided by motivation and memory. Motivational states specify goals, and memory can inform motivated behavior by providing detailed records of past experiences when goals were obtained. These 2 fundamental processes interact to guide animals to biologically relevant targets, but the neuronal mechanisms that integrate them remain unknown. To investigate these mechanisms, we recorded unit activity from the same population of hippocampal neurons as rats performed identical tasks while either food or water deprived. We compared the influence of motivational state (hunger and thirst), memory demand, and spatial behavior in 2 tasks: hippocampus-dependent contextual memory retrieval and hippocampus-independent random foraging. We found that: (i) hippocampal coding was most strongly influenced by motivational state during contextual memory retrieval, when motivational cues were required to select among remembered, goal-directed actions in the same places; (ii) the same neuronal populations were relatively unaffected by motivational state during random foraging, when hunger and thirst were incidental to behavior, and signals derived from deprivation states thus informed, but did not determine, hippocampal coding; and (iii) "prospective coding" in the contextual retrieval task was not influenced by allocentric spatial trajectory, but rather by the animal's deprivation state and the associated, non-spatial target, suggesting that hippocampal coding includes a wide range of predictive associations. The results show that beyond coding spatiotemporal context, hippocampal representations encode the relationships between internal states, the external environment, and action to provide a mechanism by which motivation and memory are coordinated to guide behavior.

  13. Distinct vasodilation, without reflex neurohormonal activation, induced by barnidipine in hypertensive patients.

    Science.gov (United States)

    Argenziano, L; Izzo, R; Iovino, G; De Luca, N; Parrella, L; Morisco, C; Trimarco, B

    1998-01-01

    Barnidipine is a new 1,4-dihydropyridine calcium antagonist with a strong and long-lasting vasodilatory effect. In order to assess the haemodynamic profile of the antihypertensive effect of barnidipine, a randomized, double-blind study of barnidipine vs nitrendipine was performed in 24 patients with mild to moderate essential hypertension. Following an initial 4-week placebo period, patients whose sitting diastolic blood pressure (SiDBP) was between 95 and 114 mm Hg, and whose sitting systolic blood pressure was between 150 and 219 mm Hg, were randomized (2:1 ratio) to receive either barnidipine (10 mg) or nitrendipine (10 mg) once daily, for a 6-week double-blind period. Subsequently, patients with an SiDBP of less than 90 mm Hg continued for a second 6-week period with the same monotherapy, while patients with an SiDBP of 90 mm Hg or above received double the dose of antihypertensive treatment for the next 6 weeks. Two-dimensional M- and B-mode echocardiography with Doppler flowmetry was performed at the end of both the placebo and active treatment phases. Barnidipine and nitrendipine reduced blood pressure by the same degree (barnidipine: from 165 +/- 2/100 +/- 1 to 145 +/- 2/89 +/- 1 mm Hg, p barnidipine was a significant decrease in plasma noradrenaline observed, both when the patients were in the supine position (from 298 +/- 27 to 214 +/- 21 pg/ml, p < 0.05) and when they were upright (from 472 +/- 37 to 348 +/- 38 pg/ml, p < 0.05).

  14. Hypoxia-Inducible Factor 3 Is an Oxygen-Dependent Transcription Activator and Regulates a Distinct Transcriptional Response to Hypoxia

    Directory of Open Access Journals (Sweden)

    Peng Zhang

    2014-03-01

    Full Text Available Hypoxia-inducible factors (HIFs play key roles in the cellular response to hypoxia. It is widely accepted that whereas HIF-1 and HIF-2 function as transcriptional activators, HIF-3 inhibits HIF-1/2α action. Contrary to this idea, we show that zebrafish Hif-3α has strong transactivation activity. Hif-3α is degraded under normoxia. Mutation of P393, P493, and L503 inhibits this oxygen-dependent degradation. Transcriptomics and chromatin immunoprecipitation analyses identify genes that are regulated by Hif-3α, Hif-1α, or both. Under hypoxia or when overexpressed, Hif-3α binds to its target gene promoters and upregulates their expression. Dominant-negative inhibition and knockdown of Hif-3α abolish hypoxia-induced Hif-3α-promoter binding and gene expression. Hif-3α not only mediates hypoxia-induced growth and developmental retardation but also possesses hypoxia-independent activities. Importantly, transactivation activity is conserved and human HIF-3α upregulates similar genes in human cells. These findings suggest that Hif-3 is an oxygen-dependent transcription factor and activates a distinct transcriptional response to hypoxia.

  15. Src kinases and ERK activate distinct responses to Stitcher receptor tyrosine kinase signaling during wound healing in Drosophila.

    Science.gov (United States)

    Tsarouhas, Vasilios; Yao, Liqun; Samakovlis, Christos

    2014-04-15

    Metazoans have evolved efficient mechanisms for epidermal repair and survival following injury. Several cellular responses and key signaling molecules that are involved in wound healing have been identified in Drosophila, but the coordination of cytoskeletal rearrangements and the activation of gene expression during barrier repair are poorly understood. The Ret-like receptor tyrosine kinase (RTK) Stitcher (Stit, also known as Cad96Ca) regulates both re-epithelialization and transcriptional activation by Grainy head (Grh) to induce restoration of the extracellular barrier. Here, we describe the immediate downstream effectors of Stit signaling in vivo. Drk (Downstream of receptor kinase) and Src family tyrosine kinases bind to the same docking site in the Stit intracellular domain. Drk is required for the full activation of transcriptional responses but is dispensable for re-epithelialization. By contrast, Src family kinases (SFKs) control both the assembly of a contractile actin ring at the wound periphery and Grh-dependent activation of barrier-repair genes. Our analysis identifies distinct pathways mediating injury responses and reveals an RTK-dependent activation mode for Src kinases and their central functions during epidermal wound healing in vivo.

  16. The cyanobacterial Fluorescence Recovery Protein has two distinct activities: Orange Carotenoid Protein amino acids involved in FRP interaction.

    Science.gov (United States)

    Thurotte, Adrien; Bourcier de Carbon, Céline; Wilson, Adjélé; Talbot, Léa; Cot, Sandrine; López-Igual, Rocio; Kirilovsky, Diana

    2017-04-01

    To deal with fluctuating light condition, cyanobacteria have developed a photoprotective mechanism which, under high light conditions, decreases the energy arriving at the photochemical centers. It relies on a photoswitch, the Orange Carotenoid Protein (OCP). Once photoactivated, OCP binds to the light harvesting antenna, the phycobilisome (PBS), and triggers the thermal dissipation of the excess energy absorbed. Deactivation of the photoprotective mechanism requires the intervention of a third partner, the Fluorescence Recovery Protein (FRP). FRP by interacting with the photoactivated OCP accelerates its conversion to the non-active form and its detachment from the phycobilisome. We have studied the interaction of FRP with free and phycobilisome-bound OCP. Several OCP variants were constructed and characterized. In this article we show that OCP amino acid F299 is essential and D220 important for OCP deactivation mediated by FRP. Mutations of these amino acids did not affect FRP activity as helper to detach OCP from phycobilisomes. In addition, while mutated R60L FRP is inactive on OCP deactivation, its activity on the detachment of the OCP from the phycobilisomes is not affected. Thus, our results demonstrate that FRP has two distinct activities: it accelerates OCP detachment from phycobilisomes and then it helps deactivation of the OCP. They also suggest that different OCP and FRP amino acids could be involved in these two activities.

  17. Contrasting extracellular enzyme activities of particle-associated bacteria from distinct provinces of the North Atlantic Ocean

    Directory of Open Access Journals (Sweden)

    Carol eArnosti

    2012-12-01

    Full Text Available Microbial communities play a key role in the marine carbon cycle, processing much of phytoplankton-derived organic matter. The composition of these communities varies by depth, season, and location in the ocean; the functional consequences of these compositional variations for the carbon cycle are only beginning to be explored. We measured the abilities of microbial communities in the large particle fraction (retained by a 10 μm pore size cartridge filter to enzymatically hydrolyze high molecular weight substrates, and therefore initiate carbon remineralization in four distinct oceanic provinces: the boreal polar (BPLR, the Arctic oceanic (ARCT, the North Atlantic drift (NADR, and the North Atlantic subtropical (NAST provinces. Since we expected the large particle fraction to include phytoplankton cells, we measured the hydrolysis of polysaccharide substrates (laminarin, fucoidan, xylan, and chondroitin sulfate expected to be associated with phytoplankton. Hydrolysis rates and patterns clustered into two groups, the BPLR/ARCT and the NADR/NAST. All four substrates were hydrolyzed by the BPLR/ARCT communities; hydrolysis rates of individual substrate varied by factors of ca. 1 to 4. In contrast, chondroitin was not hydrolyzed in the NADR/NAST, and hydrolytic activity was dominated by laminarinase. FISH (fluorescence in situ hybridization of the large-particle fraction post-incubation showed a substantial contribution (15-26% of CF319a-positive cells (Bacteroidetes to total DAPI-stainable cells. Concurrent studies of microbial community composition and of fosmids from these same stations also demonstrated similarities between BPLR and ARCT stations, which were distinct from the NADR/NAST stations. Together, these data support a picture of compositionally as well as functionally distinct communities across these oceanic provinces.

  18. Acquired platelet function defect

    Science.gov (United States)

    Acquired qualitative platelet disorders; Acquired disorders of platelet function ... blood clotting. Disorders that can cause problems in platelet function include: Idiopathic thrombocytopenic purpura Chronic myelogenous leukemia Multiple ...

  19. P2X7R activation drives distinct IL-1 responses in dendritic cells compared to macrophages.

    Science.gov (United States)

    Englezou, Pavlos C; Rothwell, Simon W; Ainscough, Joseph S; Brough, David; Landsiedel, Robert; Verkhratsky, Alexei; Kimber, Ian; Dearman, Rebecca J

    2015-08-01

    The P2X(7)R is a functionally distinct member of the P2X family of non-selective cation channels associated with rapid activation of the inflammasome complex and signalling interleukin (IL)-1β release in macrophages. The main focus of this investigation was to compare P2X(7)R-driven IL-1 production by primary murine bone marrow derived dendritic cells (BMDC) and macrophages (BMM). P2X(7)R expression in murine BMDC and BMM at both transcriptional (P2X(7)A variant) and protein levels was demonstrated. Priming with lipopolysaccharide (LPS) and receptor activation with adenosine triphosphate (ATP) resulted in markedly enhanced IL-1 (α and β) secretion in BMDC compared with BMM. In both cell types IL-1 production was profoundly inhibited with a P2X(7)R-specific inhibitor (A-740003) demonstrating that this release is predominantly a P2X(7)R-dependent process. These data also suggest that P2X(7)R and caspase-1 activation drive IL-1α release from BMDC. Both cell types expressed constitutively the gain-of-function P2X(7)K as well as the full P2X(7)A variant at equivalent levels. LPS priming reduced significantly levels of P2X(7)A but not P2X(7)K transcripts in both BMDC and BMM. P2X(7)R-induced pore formation, assessed by YO-PRO-1 dye uptake, was greater in BMDC, and these cells were protected from cell death. These data demonstrate that DC and macrophages display distinct patterns of cytokine regulation, particularly with respect to IL-1, as a consequence of cell-type specific differences in the physicochemical properties of the P2X(7)R. Understanding the cell-specific regulation of these cytokines is essential for manipulating such responses in health and disease.

  20. Two distinct domains of Flo8 activator mediates its role in transcriptional activation and the physical interaction with Mss11.

    Science.gov (United States)

    Kim, Hye Young; Lee, Sung Bae; Kang, Hyen Sam; Oh, Goo Taeg; Kim, TaeSoo

    2014-06-27

    Flo8 is a transcriptional activator essential for the inducible expression of a set of target genes such as STA1, FLO11, and FLO1 encoding an extracellular glucoamylase and two cell surface proteins, respectively. However, the molecular mechanism of Flo8-mediated transcriptional activation remains largely elusive. By generating serial deletion constructs, we revealed here that a novel transcriptional activation domain on its extreme C-terminal region plays a crucial role in activating transcription. On the other hand, the N-terminal LisH motif of Flo8 appears to be required for its physical interaction with another transcriptional activator, Mss11, for their cooperative transcriptional regulation of the shared targets. Additionally, GST pull-down experiments uncovered that Flo8 and Mss11 can directly form either a heterodimer or a homodimer capable of binding to DNA, and we also showed that this formed complex of two activators interacts functionally and physically with the Swi/Snf complex. Collectively, our findings provide valuable clues for understanding the molecular mechanism of Flo8-mediated transcriptional control of multiple targets.

  1. Differential sensitivity of myosin-heavy-chain-typed fibers to distinct aggregates of nerve-mediated activation.

    Science.gov (United States)

    Dunn, S E; Michel, R N

    1999-02-01

    We studied the regulatory effects of nerve-mediated activity on the early expression of embryonic and adult myosin heavy chains (MHC) within inactive though still innervated rat plantaris and soleus muscle fibers. To this end, we stimulated motor nerves that were quiescent following treatment with tetrodotoxin (TTX) with paradigms designed to partition the influence of neural activation frequency and assessed the selective expression and accumulation of MHCs within muscle fibers using an array of specific antibodies. We show rapid de novo expression of IIx MHC within select soleus fibers in response to high-frequency activation for more than 0.01% of daily time. High-frequency aggregates were also the most effective in preventing the TTX-induced reexpression of embryonic MHCs within specific fibers. Only configurations that included high-frequency trains for more than 0.01% of daily time or combined with 10 Hz stimulation preserved the size of select fibers, used as a measure of the net cellular content of MHC. The effectiveness of this preservation varied according to the muscle type and MHC expressed, and, in a subset of fibers, was influenced by contractile loading status. Our results demonstrate that distinct subsets of MHC-typed fibers are differentially sensitive to the neural activation cues mediating the cellular expression of these proteins.

  2. Methanopyrus kandleri topoisomerase V contains three distinct AP lyase active sites in addition to the topoisomerase active site.

    Science.gov (United States)

    Rajan, Rakhi; Osterman, Amy; Mondragón, Alfonso

    2016-04-20

    Topoisomerase V (Topo-V) is the only topoisomerase with both topoisomerase and DNA repair activities. The topoisomerase activity is conferred by a small alpha-helical domain, whereas the AP lyase activity is found in a region formed by 12 tandem helix-hairpin-helix ((HhH)2) domains. Although it was known that Topo-V has multiple repair sites, only one had been mapped. Here, we show that Topo-V has three AP lyase sites. The atomic structure and Small Angle X-ray Scattering studies of a 97 kDa fragment spanning the topoisomerase and 10 (HhH)2 domains reveal that the (HhH)2 domains extend away from the topoisomerase domain. A combination of biochemical and structural observations allow the mapping of the second repair site to the junction of the 9th and 10th (HhH)2 domains. The second site is structurally similar to the first one and to the sites found in other AP lyases. The 3rd AP lyase site is located in the 12th (HhH)2 domain. The results show that Topo-V is an unusual protein: it is the only known protein with more than one (HhH)2 domain, the only known topoisomerase with dual activities and is also unique by having three AP lyase repair sites in the same polypeptide.

  3. EFFECTS OF DISTINCT PHYSICAL ACTIVITY AND MEDITATION PROGRAMS ON QUALITY OF LIFE AND DEPRESSION LEVELS IN ACTIVE ELDERLY WOMEN

    OpenAIRE

    J. Corrêa; Cunha, F.A.; T. H. Pires; Giani T.; FERREIRA, M. de A.; Dantas, E.

    2010-01-01

     

    ABSTRACT

    Sedentary aging can evolve to depression which interferes both qualitatively and quantitatively on elderly’s quality of life. The present study compared quality of life and depression levels between sedentary and active elderly women. For this, a correlational ex post facto study was employed, the sample...

  4. Distinct licensing of IL-18 and IL-1β secretion in response to NLRP3 inflammasome activation.

    Directory of Open Access Journals (Sweden)

    Rebecca L Schmidt

    Full Text Available Inflammasome activation permits processing of interleukins (IL-1β and 18 and elicits cell death (pyroptosis. Whether these responses are independently licensed or are "hard-wired" consequences of caspase-1 (casp1 activity has not been clear. Here, we show that that each of these responses is independently regulated following activation of NLRP3 inflammasomes by a "non-canonical" stimulus, the secreted Listeria monocytogenes (Lm p60 protein. Primed murine dendritic cells (DCs responded to p60 stimulation with reactive oxygen species (ROS production and secretion of IL-1β and IL-18 but not pyroptosis. Inhibitors of ROS production inhibited secretion of IL-1β, but did not impair IL-18 secretion. Furthermore, DCs from caspase-11 (casp11-deficient 129S6 mice failed to secrete IL-1β in response to p60 but were fully responsive for IL-18 secretion. These findings reveal that there are distinct licensing requirements for processing of IL-18 versus IL-1β by NLRP3 inflammasomes.

  5. Recursive Distinctioning

    CERN Document Server

    Isaacson, Joel

    2016-01-01

    Recursive distinctioning (RD) is a name coined by Joel Isaacson in his original patent document describing how fundamental patterns of process arise from the systematic application of operations of distinction and description upon themselves. Recursive distinctioning means just what it says. A pattern of distinctions is given in a space based on a graphical structure (such as a line of print or a planar lattice or given graph). Each node of the graph is occupied by a letter from some arbitrary alphabet. A specialized alphabet is given that can indicate distinctions about neighbors of a given node. The neighbors of a node are all nodes that are connected to the given node by edges in the graph. The letters in the specialized alphabet (call it SA) are used to describe the states of the letters in the given graph and at each stage in the recursion, letters in SA are written at all nodes in the graph, describing its previous state. The recursive structure that results from the iteration of descriptions is called ...

  6. Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling.

    Science.gov (United States)

    Yeh, Yuh-Ying; Ozer, Hatice Gulcin; Lehman, Amy M; Maddocks, Kami; Yu, Lianbo; Johnson, Amy J; Byrd, John C

    2015-05-21

    Multiple studies show that chronic lymphocytic leukemia (CLL) cells are heavily dependent on their microenvironment for survival. Communication between CLL cells and the microenvironment is mediated through direct cell contact, soluble factors, and extracellular vesicles. Exosomes are small particles enclosed with lipids, proteins, and small RNAs that can convey biological materials to surrounding cells. Our data herein demonstrate that CLL cells release significant amounts of exosomes in plasma that exhibit abundant CD37, CD9, and CD63 expression. Our work also pinpoints the regulation of B-cell receptor (BCR) signaling in the release of CLL exosomes: BCR activation by α-immunoglobulin (Ig)M induces exosome secretion, whereas BCR inactivation via ibrutinib impedes α-IgM-stimulated exosome release. Moreover, analysis of serial plasma samples collected from CLL patients on an ibrutinib clinical trial revealed that exosome plasma concentration was significantly decreased following ibrutinib therapy. Furthermore, microRNA (miR) profiling of plasma-derived exosomes identified a distinct exosome microRNA signature, including miR-29 family, miR-150, miR-155, and miR-223 that have been associated with CLL disease. Interestingly, expression of exosome miR-150 and miR-155 increases with BCR activation. In all, this study successfully characterized CLL exosomes, demonstrated the control of BCR signaling in the release of CLL exosomes, and uncovered a disease-relevant exosome microRNA profile.

  7. Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor-1 in colon cancer liver metastases

    DEFF Research Database (Denmark)

    Illemann, Martin; Bird, Nigel; Majeed, Ali;

    2009-01-01

    Metastatic growth and invasion by colon cancer cells in the liver requires the ability of the cancer cells to interact with the new tissue environment. Plasmin(ogen) is activated on cell surfaces by urokinase-type PA (uPA), and is regulated by uPAR and plasminogen activator inhibitor-1 (PAI-1......). To compare the expression patterns of uPA, uPAR and PAI-1 in colon cancer with that in their liver metastases, we analysed matched samples from 14 patients. In all 14 primary colon cancers, we found upregulation of uPAR, uPA mRNA and PAI-1 in primarily stromal cells at the invasive front. In 5 of the 14......, whereas 8 of the remaining 9 showed direct contact between the cancer cells and the liver parenchyma. We conclude that there are 2 distinct patterns of expression of uPAR, uPA and PAI-1 in colon cancer liver metastases and that these correlate closely with 2 morphological growth patterns. These findings...

  8. Common and distinct DNA-binding and regulatory activities of the BEN-solo transcription factor family.

    Science.gov (United States)

    Dai, Qi; Ren, Aiming; Westholm, Jakub O; Duan, Hong; Patel, Dinshaw J; Lai, Eric C

    2015-01-01

    Recently, the BEN (BANP, E5R, and NAC1) domain was recognized as a new class of conserved DNA-binding domain. The fly genome encodes three proteins that bear only a single BEN domain ("BEN-solo" factors); namely, Insensitive (Insv), Bsg25A (Elba1), and CG9883 (Elba2). Insv homodimers preferentially bind CCAATTGG palindromes throughout the genome to mediate transcriptional repression, whereas Bsg25A and Elba2 heterotrimerize with their obligate adaptor, Elba3 (i.e., the ELBA complex), to recognize a CCAATAAG motif in the Fab-7 insulator. While these data suggest distinct DNA-binding properties of BEN-solo proteins, we performed reporter assays that indicate that both Bsg25A and Elba2 can individually recognize Insv consensus sites efficiently. We confirmed this by solving the structure of Bsg25A complexed to the Insv site, which showed that key aspects of the BEN:DNA recognition strategy are similar between these proteins. We next show that both Insv and ELBA proteins are competent to mediate transcriptional repression via Insv consensus sequences but that the ELBA complex appears to be selective for the ELBA site. Reciprocally, genome-wide analysis reveals that Insv exhibits significant cobinding to class I insulator elements, indicating that it may also contribute to insulator function. Indeed, we observed abundant Insv binding within the Hox complexes with substantial overlaps with class I insulators, many of which bear Insv consensus sites. Moreover, Insv coimmunoprecipitates with the class I insulator factor CP190. Finally, we observed that Insv harbors exclusive activity among fly BEN-solo factors with respect to regulation of Notch-mediated cell fate choices in the peripheral nervous system. This in vivo activity is recapitulated by BEND6, a mammalian BEN-solo factor that conserves the Notch corepressor function of Insv but not its capacity to bind Insv consensus sites. Altogether, our data define an array of common and distinct biochemical and functional

  9. Apolipoprotein E inhibits toll-like receptor (TLR)-3- and TLR-4-mediated macrophage activation through distinct mechanisms.

    Science.gov (United States)

    Zhu, Yanjuan; Kodvawala, Ahmer; Hui, David Y

    2010-04-28

    Previous studies have shown that apoE (apolipoprotein E) expression in macrophages suppresses inflammatory responses; however, whether endogenously synthesized apoE acts intracellularly or after its secretion in suppressing macrophage inflammation remains unclear. The present study used the murine monocyte macrophage cell line RAW 264.7 to examine the influence of exogenous apoE on macrophage inflammatory responses induced by TLR (Toll-like receptor)-4 and TLR-3 agonists LPS (lipopolysaccharide) and poly(I-C) respectively. Results showed that exogenously added apoE suppressed the LPS and poly(I-C) induction of IL (interleukin)-6, IL-1beta and TNF-alpha (tumour necrosis factor-alpha) secretion by RAW 264.7 cells. The mechanism was related to apoE suppression of TLR-agonist-induced phosphorylation of JNK (c-Jun N-terminal kinase) and c-Jun. A peptide containing the tandem repeat sequence of the receptor-binding domain of apoE, apoE-(141-155)2, was similarly effective in inhibiting LPS- and poly(I-C)-induced macrophage inflammatory responses. Reductive methylation of lysine residues in apoE, which abolished its receptor-binding capability without affecting its ability to interact with HSPGs (heparin sulfate proteoglycans), inhibited the ability of apoE to suppress macrophage responses to LPS, but had no effect on apoE suppression of poly(I-C)-induced macrophage activation. The ability of apoE to suppress poly(I-C)-induced pro-inflammatory cytokine production was abolished by heparinase treatment of RAW 264.7 cells to remove cell-surface HSPGs. Taken together, these results indicate that exogenous apoE inhibits macrophage inflammatory responses to TLR-4 and TLR-3 agonists through distinct mechanisms related to receptor and HSPG binding respectively, and that these inhibitory effects converged on suppression of JNK and c-Jun activation which are necessary for macrophage activation.

  10. Different Phases of Long-Term Memory Require Distinct Temporal Patterns of PKA Activity after Single-Trial Classical Conditioning

    Science.gov (United States)

    Michel, Maximilian; Kemenes, Ildiko; Muller, Uli; Kemenes, Gyorgy

    2008-01-01

    The cAMP-dependent protein kinase (PKA) is known to play a critical role in both transcription-independent short-term or intermediate-term memory and transcription-dependent long-term memory (LTM). Although distinct phases of LTM already have been demonstrated in some systems, it is not known whether these phases require distinct temporal patterns…

  11. Alterations in ROS activity and lysosomal pH account for distinct patterns of macroautophagy in LINCL and JNCL fibroblasts.

    Directory of Open Access Journals (Sweden)

    José Manuel Vidal-Donet

    Full Text Available Neuronal ceroid lipofuscinoses (NCL are lysosomal storage disorders characterized by the accumulation of lipofuscin within lysosomes. Late infantile (LINCL and juvenile (JNCL are their most common forms and are caused by loss-of-function mutations in tripeptidyl peptidase 1 (TPP1, a lysosomal endopeptidase, and CLN3 protein (CLN3p, whose location and function is still controversial. LINCL patients suffer more severely from NCL consequences than JNCL patients, in spite of having in common an abnormal accumulation of material with a similar composition in the lysosomes. To identify distinctive characteristics that could explain the differences in the severity of LINCL and JNCL pathologies, we compared the protein degradation mechanisms in patientś fibroblasts. Pulse-chase experiments show a significant decrease in protein degradation by macroautophagy in fibroblasts bearing TPP1 (CLN2 and CLN3p (CLN3 mutations. In CLN2 fibroblasts, LC3-II levels and other procedures indicate an impaired formation of autophagosomes, which confirms the pulse-chase experiments. This defect is linked to an accumulation of reactive oxygen species (ROS, an upregulation of the Akt-mTOR signalling pathway and increased activities of the p38α and ERK1/2 MAPKs. In CLN3 fibroblasts, LC3-II analysis indicates impairment in autophagosome maturation and there is also a defect in fluid phase endocytosis, two alterations that can be related to an observed increase of 0.5 units in lysosomal pH. CLN3 fibroblasts also accumulate ROS but to a lower extent than CLN2. TPP1 activity is completely abrogated in CLN2 and partially diminished in CLN3 fibroblasts. TPP1 cleaves small hydrophobic proteins like subunit c of mitochondrial ATP synthase and the lack or a lower activity of this enzyme can contribute to lipofuscin accumulation. These alterations in TPP1 activity lead to an increased ROS production, especially in CLN2 in which it is aggravated by a decrease in catalase activity

  12. Sequential activation and distinct functions for distal and proximal modules within the IgH 3′ regulatory region

    Science.gov (United States)

    Garot, Armand; Marquet, Marie; Saintamand, Alexis; Bender, Sébastien; Le Noir, Sandrine; Rouaud, Pauline; Carrion, Claire; Oruc, Zéliha; Bébin, Anne-Gaëlle; Moreau, Jeanne; Lebrigand, Kevin; Denizot, Yves; Alt, Frederick W.; Cogné, Michel; Pinaud, Eric

    2016-01-01

    As a master regulator of functional Ig heavy chain (IgH) expression, the IgH 3′ regulatory region (3′RR) controls multiple transcription events at various stages of B-cell ontogeny, from newly formed B cells until the ultimate plasma cell stage. The IgH 3′RR plays a pivotal role in early B-cell receptor expression, germ-line transcription preceding class switch recombination, interactions between targeted switch (S) regions, variable region transcription before somatic hypermutation, and antibody heavy chain production, but the functional ranking of its different elements is still inaccurate, especially that of its evolutionarily conserved quasi-palindromic structure. By comparing relevant previous knockout (KO) mouse models (3′RR KO and hs3b-4 KO) to a novel mutant devoid of the 3′RR quasi-palindromic region (3′PAL KO), we pinpointed common features and differences that specify two distinct regulatory entities acting sequentially during B-cell ontogeny. Independently of exogenous antigens, the 3′RR distal part, including hs4, fine-tuned B-cell receptor expression in newly formed and naïve B-cell subsets. At mature stages, the 3′RR portion including the quasi-palindrome dictated antigen-dependent locus remodeling (global somatic hypermutation and class switch recombination to major isotypes) in activated B cells and antibody production in plasma cells. PMID:26831080

  13. Evaluation of fatigue cracks using nonlinearities of acousto-ultrasonic waves acquired by an active sensor network

    Science.gov (United States)

    Zhou, Chao; Hong, Ming; Su, Zhongqing; Wang, Qiang; Cheng, Li

    2013-01-01

    There has been increasing interest in using the nonlinear features of acousto-ultrasonic (AU) waves to detect damage onset (e.g., micro-fatigue cracks) due to their high sensitivity to damage with small dimensions. However, most existing approaches are able to infer the existence of fatigue damage qualitatively, but fail to further ascertain its location and severity. A damage characterization approach, in conjunction with the use of an active piezoelectric sensor network, was established, capable of evaluating fatigue cracks in a quantitative manner (including the co-presence of multiple fatigue cracks, and their individual locations and severities). Fundamental investigations, using both experiment and enhanced finite element analysis dedicated to the simulation of nonlinear AU waves, were carried out to link the accumulation of nonlinearities extracted from high-order AU waves to the characteristic parameters of a fatigue crack. A probability-based diagnostic imaging algorithm was developed, facilitating an intuitive presentation of identification results in images. The approach was verified experimentally by evaluating multi-fatigue cracks near rivet holes of a fatigued aluminum plate, showing satisfactory precision in characterizing real, barely visible fatigue cracks. Compared with existing methods, this approach innovatively (i) uses permanently integrated active sensor networks, conducive to automatic and online health monitoring; (ii) characterizes fatigue cracks at a quantitative level; (iii) allows detection of multiple fatigue cracks; and (iv) visualizes identification results in intuitive images.

  14. Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Rahman, Sunniyat; Magnussen, Michael; León, Theresa E; Farah, Nadine; Li, Zhaodong; Abraham, Brian J; Alapi, Krisztina Z; Mitchell, Rachel J; Naughton, Tom; Fielding, Adele K; Pizzey, Arnold; Bustraan, Sophia; Allen, Christopher; Popa, Teodora; Pike-Overzet, Karin; Garcia-Perez, Laura; Gale, Rosemary E; Linch, David C; Staal, Frank J T; Young, Richard A; Look, A Thomas; Mansour, Marc R

    2017-03-07

    Somatic mutations within non-coding genomic regions that aberrantly activate oncogenes have remained poorly characterized. Here we describe recurrent activating intronic mutations of LMO2, a prominent oncogene in T-cell acute lymphoblastic leukemia (T-ALL). Heterozygous mutations were identified in PF-382 and DU.528 T-ALL cell lines, in addition to 3.7% (6/160) of pediatric and 5.5% (9/163) of adult T-ALL patient samples. The majority of indels harbour putative de novo MYB, ETS1 or RUNX1 consensus binding sites. Analysis of 5'-capped RNA transcripts in mutant cell lines identified the usage of an intermediate promoter site, with consequential monoallelic LMO2 overexpression. CRISPR/Cas9-mediated disruption of the mutant allele in PF-382 cells markedly downregulated LMO2 expression, establishing clear causality between the mutation and oncogene dysregulation. Furthermore, the spectrum of CRISPR/Cas9-derived mutations provide important insights into the interconnected contributions of functional transcription factor binding. Finally, these mutations occur in the same intron as retroviral integration sites in gene therapy induced T-ALL, suggesting that such events occur at preferential sites in the non-coding genome.

  15. HIF-1alpha and HIF-2alpha are differentially activated in distinct cell populations in retinal ischaemia.

    Directory of Open Access Journals (Sweden)

    Freya M Mowat

    Full Text Available BACKGROUND: Hypoxia plays a key role in ischaemic and neovascular disorders of the retina. Cellular responses to oxygen are mediated by hypoxia-inducible transcription factors (HIFs that are stabilised in hypoxia and induce the expression of a diverse range of genes. The purpose of this study was to define the cellular specificities of HIF-1alpha and HIF-2alpha in retinal ischaemia, and to determine their correlation with the pattern of retinal hypoxia and the expression profiles of induced molecular mediators. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the tissue distribution of retinal hypoxia during oxygen-induced retinopathy (OIR in mice using the bio-reductive drug pimonidazole. We measured the levels of HIF-1alpha and HIF-2alpha proteins by Western blotting and determined their cellular distribution by immunohistochemistry during the development of OIR. We measured the temporal expression profiles of two downstream mediators, vascular endothelial growth factor (VEGF and erythropoietin (Epo by ELISA. Pimonidazole labelling was evident specifically in the inner retina. Labelling peaked at 2 hours after the onset of hypoxia and gradually declined thereafter. Marked binding to Müller glia was evident during the early hypoxic stages of OIR. Both HIF-1alpha and HIF-2alpha protein levels were significantly increased during retinal hypoxia but were evident in distinct cellular distributions; HIF-1alpha stabilisation was evident in neuronal cells throughout the inner retinal layers whereas HIF-2alpha was restricted to Müller glia and astrocytes. Hypoxia and HIF-alpha stabilisation in the retina were closely followed by upregulated expression of the downstream mediators VEGF and EPO. CONCLUSIONS/SIGNIFICANCE: Both HIF-1alpha and HIF-2alpha are activated in close correlation with retinal hypoxia but have contrasting cell specificities, consistent with differential roles in retinal ischaemia. Our findings suggest that HIF-2alpha activation

  16. Tumors initiated by constitutive Cdk2 activation exhibit transforming growth factor beta resistance and acquire paracrine mitogenic stimulation during progression

    DEFF Research Database (Denmark)

    Corsino, P.; Davis, B.; Law, M.;

    2007-01-01

    mediate some of the transforming effects that result from cyclin D1 overexpression in human breast cancers. MMTV-DIK2 cancer cells express the hepatocyte growth factor (HGF) receptor, c-Met. MMTV-D1K2 cancer cells also secrete transforming growth factor beta (TGF beta), but are relatively resistant to TGF......Cyclin D1/cyclin-dependent kinase 2 (Cdk2) complexes are present at high frequency in human breast cancer cell lines, but the significance of this observation is unknown. This report shows that expression of a cyclin D1-Cdk2 fusion protein under the control of the mouse mammary tumor virus (MMITV...... beta antiproliferative effects. Fibroblasts derived from MMTV-DIK2 tumors secrete factors that stimulate the proliferation of MMTV-D1K2 cancer cells, stimulate c-Met tyrosine phosphorylation, and stimulate the phosphorylation of the downstream signaling intermediates p70(s6k) and Akt on activating...

  17. [Analysis of the effect of physical group activities in patients with acquired brain injury in the subacute phase].

    Science.gov (United States)

    García-Hernández, Juan José; Mediavilla-Saldaña, Lázaro; Pérez-Rodríguez, Pérez-Rodríguez; Pérez-Tejero, Javier; González-Alted, Carlos

    2013-07-16

    Introduccion. El daño cerebral adquirido (DCA) hace referencia a cualquier tipo de lesion no degenerativa que se produce en el cerebro. Las actividades fisicas grupales (AFG) se presentan como un tratamiento efectivo para la mejora de la capacidad funcional. Objetivo. Analizar la eficacia de un programa de AFG en personas con DCA en fase subaguda para su integracion fisica en la comunidad. Pacientes y metodos. Treinta y tres pacientes con DCA, con una edad de 33,18 ± 10,39 años, participaron en un programa de AFG (talleres de circuito, equilibrio simple, equilibrio dual, desplazamiento dual y actividades fisico-deportivas) de 10 semanas. Al comenzar y concluir el programa se evaluaron las variables de velocidad (prueba de velocidad de la marcha en 10 metros), resistencia (prueba de marcha de seis minutos), equilibrio dinamico (Step Test), capacidad funcional (Timed Up and Go), escala de percepcion de seguridad (Activities-specific Balance Confidence Scale) y Physical Activity and Disability Survey (PADS), el promedio por hora de la intensidad de la actividad y el numero de pasos fuera del centro de rehabilitacion (usando monitores de actividad fisica). La prueba t para muestras relacionadas se utilizo para evaluar las diferencias en las variables. Resultados. Se hallaron diferencias significativas (p <= 0,05) en las variables de velocidad, resistencia, equilibrio, capacidad funcional, percepcion de seguridad, percepcion de realizacion de actividad general (pregunta 3 del PADS) y numero de pasos. Conclusion. Los programas de AFG mejoran las capacidades fisicas, percepcion de seguridad, realizacion de actividad en general y numero de pasos, lo que puede conllevar una mayor participacion en la comunidad.

  18. Primary murine CD4+ T cells fail to acquire the ability to produce effector cytokines when active Ras is present during Th1/Th2 differentiation.

    Directory of Open Access Journals (Sweden)

    Sujit V Janardhan

    Full Text Available Constitutive Ras signaling has been shown to augment IL-2 production, reverse anergy, and functionally replace many aspects of CD28 co-stimulation in CD4+ T cells. These data raise the possibility that introduction of active Ras into primary T cells might result in improved functionality in pathologic situations of T cell dysfunction, such as cancer or chronic viral infection. To test the biologic effects of active Ras in primary T cells, CD4+ T cells from Coxsackie-Adenovirus Receptor Transgenic mice were transduced with an adenovirus encoding active Ras. As expected, active Ras augmented IL-2 production in naive CD4+ T cells. However, when cells were cultured for 4 days under conditions to promote effector cell differentiation, active Ras inhibited the ability of CD4+ T cells to acquire a Th1 or Th2 effector cytokine profile. This differentiation defect was not due to deficient STAT4 or STAT6 activation by IL-12 or IL-4, respectively, nor was it associated with deficient induction of T-bet and GATA-3 expression. Impaired effector cytokine production in active Ras-transduced cells was associated with deficient demethylation of the IL-4 gene locus. Our results indicate that, despite augmenting acute activation of naïve T cells, constitutive Ras signaling inhibits the ability of CD4+ T cells to properly differentiate into Th1/Th2 effector cytokine-producing cells, in part by interfering with epigenetic modification of effector gene loci. Alternative strategies to potentiate Ras pathway signaling in T cells in a more regulated fashion should be considered as a therapeutic approach to improve immune responses in vivo.

  19. Co-existence of clonal expanded autologous and transplacental-acquired maternal T cells in recombination activating gene-deficient severe combined immunodeficiency

    Science.gov (United States)

    Lev, A; Simon, A J; Ben-Ari, J; Takagi, D; Stauber, T; Trakhtenbrot, L; Rosenthal, E; Rechavi, G; Amariglio, N; Somech, R

    2014-01-01

    It is commonly accepted that the presence of high amounts of maternal T cells excludes Omenn syndrome (OS) in severe combined immunodeficiency (SCID). We report a SCID patient with a novel mutation in the recombination activating gene (RAG)1 gene (4-BP DEL.1406 TTGC) who presented with immunodeficiency and OS. Several assays, including representatives of specific T cell receptors (TCR), Vβ families and TCR-γ rearrangements, were performed in order to understand more clearly the nature and origin of the patient's T cells. The patient had oligoclonal T cells which, based on the patient–mother human leucocyte antigen (HLA)-B50 mismatch, were either autologous or of maternal origin. These cell populations were different in their numbers of regulatory T cells (Treg) and the diversity of TCR repertoires. This is the first description of the co-existence of large amounts of clonal expanded autologous and transplacental-acquired maternal T cells in RAG1-deficient SCID. PMID:24666246

  20. Co-existence of clonal expanded autologous and transplacental-acquired maternal T cells in recombination activating gene-deficient severe combined immunodeficiency.

    Science.gov (United States)

    Lev, A; Simon, A J; Ben-Ari, J; Takagi, D; Stauber, T; Trakhtenbrot, L; Rosenthal, E; Rechavi, G; Amariglio, N; Somech, R

    2014-06-01

    It is commonly accepted that the presence of high amounts of maternal T cells excludes Omenn syndrome (OS) in severe combined immunodeficiency (SCID). We report a SCID patient with a novel mutation in the recombination activating gene (RAG)1 gene (4-BP DEL.1406 TTGC) who presented with immunodeficiency and OS. Several assays, including representatives of specific T cell receptors (TCR), Vβ families and TCR-γ rearrangements, were performed in order to understand more clearly the nature and origin of the patient's T cells. The patient had oligoclonal T cells which, based on the patient-mother human leucocyte antigen (HLA)-B50 mismatch, were either autologous or of maternal origin. These cell populations were different in their numbers of regulatory T cells (T(reg)) and the diversity of TCR repertoires. This is the first description of the co-existence of large amounts of clonal expanded autologous and transplacental-acquired maternal T cells in RAG1-deficient SCID.

  1. Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice.

    Science.gov (United States)

    Gomes, Felipe V; Del Bel, Elaine A; Guimarães, Francisco S

    2013-10-01

    Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa plant that produces antipsychotic effects in rodents and humans. It also reverses L-dopa-induced psychotic symptoms and improves motor function in Parkinson's patients. This latter effect raised the possibility that CBD could have beneficial effects on motor related striatal disorders. To investigate this possibility we evaluated if CBD would prevent catalepsy induced by drugs with distinct pharmacological mechanisms. The catalepsy test is largely used to investigate impairments of motor function caused by interference on striatal function. Male Swiss mice received acute pretreatment with CBD (5, 15, 30 or 60mg/kg, ip) 30min prior to the D2 receptor antagonist haloperidol (0.6mg/kg), the non-selective nitric oxide synthase (NOS) inhibitor L-nitro-N-arginine (L-NOARG, 80mg/kg) or the CB1 receptor agonist WIN55,212-2 (5mg/kg). The mice were tested 1, 2 or 4h after haloperidol, L-NOARG or WIN55,212-2 injection. These drugs significantly increased catalepsy time and this effect was attenuated dose-dependently by CBD. CBD, by itself, did not induce catalepsy. In a second set of experiments the mechanism of CBD effects was investigated. Thirty minutes before CBD (30mg/kg) the animals received the 5-HT1A receptor antagonist WAY100635 (0.1mg/kg). The anticataleptic effect of CBD was prevented by WAY100635. These findings indicate that CBD can attenuate catalepsy caused by different mechanisms (D2 blockade, NOS inhibition and CB1 agonism) via 5-HT1A receptor activation, suggesting that it could be useful in the treatment of striatal disorders.

  2. An enriched rearing environment calms adult male rat sexual activity: implication for distinct serotonergic and hormonal responses to females.

    Directory of Open Access Journals (Sweden)

    Susumu Urakawa

    Full Text Available Early life events induce alterations in neural function in adulthood. Although rearing in an enriched environment (EE has a great impact on behavioral development, the effects of enriched rearing on sociosexual behavior remain unclear. In this study, we investigated the effects of rearing in an EE on male copulatory behavior and its underlying neurobiological mechanisms in Wistar-Imamichi rats. Three-week-old, recently weaned rats were continuously subjected to a standard environment (SE or an EE comprised of a large cage with several objects, such as toys, tunnels, ladders, and a running wheel. After 6 weeks, rats reared in an EE (EE rats showed decreased sexual activity compared with rats reared in a SE (SE rats. This included a lower number of ejaculations and longer latencies in three consecutive copulatory tests. In addition, EE rats showed decreased emotional responsiveness and less locomotor behavior in an open field. In a runway test, on the other hand, sexual motivation toward receptive females in EE males was comparable to that of SE males. Furthermore, following exposure to a female, increases in serotonin levels in the nucleus accumbens and the striatum were significantly suppressed in EE males, whereas dopaminergic responses were similar between the groups. Female-exposure-induced increases in the levels of plasma corticosterone and testosterone were also suppressed in EE rats compared to SE rats. These data suggest that rearing in an EE decreases male copulatory behavior, and serotonin and hormonal regulating systems may regulate the differences in sociosexual interactions that result from distinct rearing environments.

  3. Medawar's legacy to cellular immunology and clinical transplantation: a commentary on Billingham, Brent and Medawar (1956) 'Quantitative studies on tissue transplantation immunity. III. Actively acquired tolerance'.

    Science.gov (United States)

    Simpson, Elizabeth

    2015-04-19

    'Quantitative studies on tissue transplantation immunity. III. Actively acquired tolerance', published in Philosophical Transactions B in 1956 by Peter Medawar and his colleagues, PhD graduate Leslie Brent and postdoctoral fellow Rupert Billingham, is a full description of the concept of acquired transplantation tolerance. Their 1953 Nature paper (Billingham RE et al. 1953 Nature 172, 603-606. (doi:10.1038/172603a0)) had provided initial evidence with experimental results from a small number of neonatal mice, with mention of similar findings in chicks. The Philosophical Transactions B 1956 paper is clothed with an astonishing amount of further experimental detail. It is written in Peter Medawar's landmark style: witty, perceptive and full of images that can be recalled even when details of the supporting information have faded. Those images are provided not just by a series of 20 colour plates showing skin graft recipient mice, rats, rabbits, chickens and duck, bearing fur or plumage of donor origin, but by his choice of metaphor, simile and analogy to express the questions being addressed and the interpretation of their results, along with those of relevant published data and his prescient ideas of what the results might portend. This work influenced both immunology researchers and clinicians and helped to lay the foundations for successful transplantation programmes. It led to the award of a Nobel prize in 1960 to Medawar, and subsequently to several scientists who advanced these areas. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.

  4. Generation, characterization and in vivo biological activity of two distinct monoclonal anti-PEG IgMs

    Energy Technology Data Exchange (ETDEWEB)

    Hashimoto, Yosuke; Shimizu, Taro; Mima, Yu [Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505 (Japan); Abu Lila, Amr S. [Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505 (Japan); Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Sharqia Governorate, Zagazig 44519 (Egypt); Ishida, Tatsuhiro, E-mail: ishida@tokushima-u.ac.jp [Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505 (Japan); Kiwada, Hiroshi [Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505 (Japan)

    2014-05-15

    PEGylation, the attachment of polyethylene glycol (PEG) to nanocarriers and proteins, is a widely accepted approach to improving the in vivo efficacy of the non-PEGylated products. However, both PEGylated liposomes and PEGylated proteins reportedly trigger the production of specific antibodies, mainly IgM, against the PEG moiety, which possibly leads to a reduction in safety and therapeutic efficacy of the PEGylated products. In the present study, two monoclonal anti-PEG IgMs — HIK-M09 via immunization with an intravenous injection of PEGylated liposomes (SLs) and HIK-M11 via immunization with a subcutaneous administration of PEGylated ovalbumin (PEG-OVA) were successfully generated. The generated IgMs showed efficient reactivity to mPEG{sub 2000} conjugated to 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine (DSPE), PEGylated liposome (SL) and PEG-OVA. It appears that HIK-M09 recognizes ethoxy (OCH{sub 2}CH{sub 2}) repeat units along with a terminal motif of PEG, while HIK-M11 recognizes only ethoxy repeat units of PEG. Such unique properties allow HIK-M09 to bind with dense PEG. In addition, their impact on the in vivo clearance of the PEGylated products was investigated. It was found that the generated ant-PEG IgMs induced a clearance of SL as they were intravenously administered with SL. Interestingly, the HIK-M11, generated by PEG-OVA, induced the clearance of both SL and PEG-OVA, while the HIK-M09, generated by SL, induced the clearance of SL only. We here revealed that the presence of serum anti-PEG IgM and the subsequent binding of anti-PEG IgM to the PEGylated products are not necessarily related to the enhanced clearance of the products. It appears that subsequent complement activation following anti-PEG IgM binding is the most important step in dictating the in vivo fate of PEGylated products. This study may have implications for the design, development and clinical application of PEGylated products and therapeutics. - Highlights: • Two monoclonal

  5. Bacillus cereus AR156 activates PAMP-triggered immunity and induces a systemic acquired resistance through a NPR1-and SA-dependent signaling pathway.

    Science.gov (United States)

    Niu, Dongdong; Wang, Xiujuan; Wang, Yanru; Song, Xiaoou; Wang, Jiansheng; Guo, Jianhua; Zhao, Hongwei

    2016-01-01

    Induced resistance responses play a potent role in plant defense system against pathogen attack. Bacillus cereus AR156 is a plant growth promoting rhizobacterium (PGPR) that installs induced systemic resistance (ISR) to Pseudomonas syringae pv. tomato (Pst) in Arabidopsis. Here, we show that AR156 leaf infiltration enhances disease resistance in Arabidopsis through the activation of a systemic acquired resistance (SAR). PR1 protein expression and reactive oxygen species (ROS) burst are strongly induced in plants treated with AR156 and inoculated with Pst than that in plants inoculated with Pst only. Moreover, AR156 can trigger SAR in jar1 or ein2 mutants, but not in the NahG transgenic and NPR1 mutant plants. Our results indicate that AR156-induced SAR depends on SA-signaling pathway and NPR1, but not JA and ET. Also, AR156-treated plants are able to rapidly activate MAPK signaling and FRK1 gene expression, which are involved in pathogen associated molecular pattern (PAMP)-triggered immunity (PTI). Altogether, our results indicate that AR156 can induce SAR by the SA-signaling pathways in an NPR1-dependent manner and involves multiple PTI components.

  6. Immunomodulation in community-acquired pneumonia

    NARCIS (Netherlands)

    Remmelts, H.H.F.

    2013-01-01

    Community-acquired pneumonia (CAP) is a common disease with considerable morbidity and mortality, despite effective antibiotic treatment. In this thesis, we showed that the major causative microorganisms in CAP trigger distinct inflammatory response profiles in the host. While an inflammatory respon

  7. Acquired inflammatory demyelinating neuropathies.

    Science.gov (United States)

    Ensrud, E R; Krivickas, L S

    2001-05-01

    The acquired demyelinating neuropathies can be divided into those with an acute onset and course and those with a more chronic course. The acute neuropathies present as Guillain-Barré syndrome and include acute inflammatory demyelinating polyradiculoneuropathy (AIDP), Miller Fisher syndrome, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), and acute pandysautonomia. The chronic neuropathies are collectively known as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and include MADSAM (multifocal acquired demyelinating sensory and motor neuropathy, also know as Lewis-Sumner syndrome) and DADS (distal acquired demyelinating symmetric neuropathy) as variants. The clinical features, pathology, pathogenesis, diagnosis, treatment, rehabilitation, and prognosis of these neuropathies are discussed.

  8. A study of National Lightning Detection Network responses to natural lightning based on ground truth data acquired at LOG with emphasis on cloud discharge activity

    Science.gov (United States)

    Zhu, Y.; Rakov, V. A.; Tran, M. D.; Nag, A.

    2016-12-01

    The U.S. National Lightning Detection Network (NLDN) detection efficiency (DE) and classification accuracy (CA) for cloud discharge (IC) activity (identified here by a sequence of non-return-stroke-type electric field pulses not accompanied by channels to ground) were evaluated using optical and electric field data acquired at the LOG (Lightning Observatory in Gainesville), Florida. Our ground truth "IC events" include 26 "isolated IC events" (complete IC flashes), 58 "IC events before first return stroke," and 69 "IC events after first return stroke." For the total of 153 IC events, 33% were detected by the NLDN, and the classification accuracy was 86%. For complete IC flashes, the detection efficiency and classification accuracy were 73% and 95%, respectively, and the average number of NLDN-reported cloud pulses was 2.9 per detected event. For 24 preliminary breakdown pulse trains in CG flashes, the detection efficiency and classification accuracy were 46% and 82%, respectively. We have additionally estimated the DE and CA for return strokes in CG flashes. Irrespective of stroke order and polarity, the DE was 92% (339/367), and the CA was also 92% (312/339). The DEs for negative first and subsequent strokes were 98% and 90%, respectively.

  9. Hospital-acquired pneumonia

    Science.gov (United States)

    ... tends to be more serious than other lung infections because: People in the hospital are often very sick and cannot fight off ... prevent pneumonia. Most hospitals have programs to prevent hospital-acquired infections.

  10. Acquired color vision deficiency.

    Science.gov (United States)

    Simunovic, Matthew P

    2016-01-01

    Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from diseases of the ocular media through to pathology of the visual cortex. Traditionally, acquired color vision deficiency is considered a separate entity from congenital color vision deficiency, although emerging clinical and molecular genetic data would suggest a degree of overlap. We review the pathophysiology of acquired color vision deficiency, the data on its prevalence, theories for the preponderance of acquired S-mechanism (or tritan) deficiency, and discuss tests of color vision. We also briefly review the types of color vision deficiencies encountered in ocular disease, with an emphasis placed on larger or more detailed clinical investigations.

  11. Activation of the cannabinoid type-1 receptor mediates the anticonvulsant properties of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy and status epilepticus.

    Science.gov (United States)

    Blair, Robert E; Deshpande, Laxmikant S; Sombati, Sompong; Falenski, Katherine W; Martin, Billy R; DeLorenzo, Robert J

    2006-06-01

    Cannabinoids have been shown to have anticonvulsant properties, but no studies have evaluated the effects of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy (AE) and status epilepticus (SE). This study investigated the anticonvulsant properties of the cannabinoid receptor agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolol[1,2,3 de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone (WIN 55,212-2) in primary hippocampal neuronal culture models of both AE and SE. WIN 55,212-2 produced dose-dependent anticonvulsant effects against both spontaneous recurrent epileptiform discharges (SRED) (EC50 = 0.85 microM) and SE (EC50 = 1.51 microM), with total suppression of seizure activity at 3 microM and of SE activity at 5 microM. The anticonvulsant properties of WIN 55,212-2 in these preparations were both stereospecific and blocked by the cannabinoid type-1 (CB1) receptor antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A; 1 microM), showing a CB1 receptor-dependent pathway. The inhibitory effect of WIN 55,212-2 against low Mg2+-induced SE is the first observation in this model of total suppression of SE by a selective pharmacological agent. The clinically used anticonvulsants phenytoin and phenobarbital were not able to abolish low Mg2+-induced SE at concentrations up to 150 microM. The results from this study show CB1 receptor-mediated anticonvulsant effects of the cannabimimetic WIN 55,212-2 against both SRED and low Mg2+-induced SE in primary hippocampal neuronal cultures and show that these in vitro models of AE and SE may represent powerful tools to investigate the molecular mechanisms mediating the effects of cannabinoids on neuronal excitability.

  12. Laboratory-acquired brucellosis

    DEFF Research Database (Denmark)

    Fabiansen, C.; Knudsen, J.D.; Lebech, A.M.

    2008-01-01

    Brucellosis is a rare disease in Denmark. We describe one case of laboratory-acquired brucellosis from an index patient to a laboratory technician following exposure to an infected blood culture in a clinical microbiology laboratory Udgivelsesdato: 2008/6/9......Brucellosis is a rare disease in Denmark. We describe one case of laboratory-acquired brucellosis from an index patient to a laboratory technician following exposure to an infected blood culture in a clinical microbiology laboratory Udgivelsesdato: 2008/6/9...

  13. Light-independent and light-dependent protochlorophyllide-reducing activities and two distinct NADPH-protochlorophyllide oxidoreductase polypeptides in mountain pine (Pinus mugo).

    Science.gov (United States)

    Forreiter, C; Apel, K

    1993-01-01

    Lower plants and gymnosperms synthesize chlorophyll and develop photosynthetically competent chloroplasts even when grown in the dark. In cell-free extracts of pine (Pinus mugo, Turra, ssp. mugo) seedlings, light-independent and light-dependent protochlorophyllide-reducing activities are present. Two distinct NADPH-protochlorophyllide-oxidoreductase (POR) polypeptides can be detected immunologically with an antiserum raised against the POR of barley. The subcellular localization and amounts of the two POR polypeptides are differentially affected by light: one of them is predominantly present in prolamellar bodies of etiochloroplasts and its abundance rapidly declines once the pine seedlings are exposed to light; the other is found in thylakoid membranes and its amount does not change during illumination of dark-grown seedlings. Two types of cDNA sequences are identified that encode two distinct POR polypeptides in pine. The relevance of these POR polypeptides for the two chlorophyll biosynthetic pathways active in gymnosperms is discussed.

  14. Factors affecting the myocardial activity acquired during exercise SPECT with a high-sensitivity cardiac CZT camera as compared with conventional Anger camera

    Energy Technology Data Exchange (ETDEWEB)

    Verger, Antoine; Karcher, Gilles [CHU-Nancy, Department of Nuclear Medicine, Nancy (France); INSERM U947 and Universite de Lorraine, Nancy (France); Nancyclotep experimental imaging platform, Nancy (France); Imbert, Laetitia [CHU-Nancy, Department of Nuclear Medicine, Nancy (France); Nancyclotep experimental imaging platform, Nancy (France); Centre Alexis Vautrin, Department of Radiotherapy, Vandoeuvre (France); Yagdigul, Yalcine; Roch, Veronique [CHU-Nancy, Department of Nuclear Medicine, Nancy (France); Nancyclotep experimental imaging platform, Nancy (France); Fay, Renaud [INSERM, Centre d' Investigation Clinique CIC-P 9501, Nancy (France); Djaballah, Wassila [CHU-Nancy, Department of Nuclear Medicine, Nancy (France); INSERM U947 and Universite de Lorraine, Nancy (France); Rouzet, Francois; Le Guludec, Dominique [AP-HP, Hopital Bichat, Department of Nuclear Medicine, Paris (France); INSERM U 773 and Denis Diderot University, Paris (France); Fourquet, Nicolas [Clinique Pasteur, Toulouse (France); Poussier, Sylvain [INSERM U947 and Universite de Lorraine, Nancy (France); Nancyclotep experimental imaging platform, Nancy (France); Marie, Pierre-Yves [CHU-Nancy, Department of Nuclear Medicine, Nancy (France); Nancyclotep experimental imaging platform, Nancy (France); INSERM U1116 and Universite de Lorraine, Nancy (France); CHU-Nancy, Allee du Morvan, Medecine Nucleaire, Hopital de Brabois, Vandoeuvre-les-Nancy (France)

    2014-03-15

    Injected doses are difficult to optimize for exercise SPECT since they depend on the myocardial fraction of injected activity (MFI) that is detected by the camera. The aim of this study was to analyse the factors affecting MFI determined using a cardiac CZT camera as compared with those determined using conventional Anger cameras. Factors affecting MFI were determined and compared in patients who had consecutive exercise SPECT acquisitions with {sup 201}Tl (84 patients) or {sup 99m}Tc-sestamibi (87 patients) with an Anger or a CZT camera. A predictive model was validated in a group of patients routinely referred for {sup 201}Tl (78 patients) or {sup 99m}Tc-sestamibi (80 patients) exercise CZT SPECT. The predictive model involved: (1) camera type, adjusted mean MFI being ninefold higher for CZT than for Anger SPECT, (2) tracer type, adjusted mean MFI being twofold higher for {sup 201}Tl than for {sup 99m}Tc-sestamibi, and (3) logarithm of body weight. The CZT SPECT model led to a +1 ± 26 % error in the prediction of the actual MFI from the validation group. The mean MFI values estimated for CZT SPECT were more than twofold higher in patients with a body weight of 60 kg than in patients with a body weight of 120 kg (15.9 and 6.8 ppm for {sup 99m}Tc-sestamibi and 30.5 and 13.1ppm for {sup 201}Tl, respectively), and for a 14-min acquisition of up to one million myocardial counts, the corresponding injected activities were only 80 and 186 MBq for {sup 99m}Tc-sestamibi and 39 and 91 MBq for {sup 201}Tl, respectively. Myocardial activities acquired during exercise CZT SPECT are strongly influenced by body weight and tracer type, and are dramatically higher than those obtained using an Anger camera, allowing very low-dose protocols to be planned, especially for {sup 99m}Tc-sestamibi and in non-obese subjects. (orig.)

  15. Mast cell degranulation distinctly activates trigemino-cervical and lumbosacral pain pathways and elicits widespread tactile pain hypersensitivity.

    Science.gov (United States)

    Levy, Dan; Kainz, Vanessa; Burstein, Rami; Strassman, Andrew M

    2012-02-01

    Mast cells (MCs) are tissue resident immune cells that participate in a variety of allergic and other inflammatory conditions. In most tissues, MCs are found in close proximity to nerve endings of primary afferent neurons that signal pain (i.e. nociceptors). Activation of MCs causes the release of a plethora of mediators that can activate these nociceptors and promote pain. Although MCs are ubiquitous, conditions associated with systemic MC activation give rise primarily to two major types of pain, headache and visceral pain. In this study we therefore examined the extent to which systemic MC degranulation induced by intraperitoneal administration of the MC secretagogue compound 48/80 activates pain pathways that originate in different parts of the body and studied whether this action can lead to development of behavioral pain hypersensitivity. Using c-fos expression as a marker of central nervous system neural activation, we found that intraperitoneal administration of 48/80 leads to the activation of dorsal horn neurons at two specific levels of the spinal cord; one responsible for processing cranial pain, at the medullary/C2 level, and one that processes pelvic visceral pain, at the caudal lumbar/rostral sacral level (L6-S2). Using behavioral sensory testing, we found that this nociceptive activation is associated with development of widespread tactile pain hypersensitivity within and outside the body regions corresponding to the activated spinal levels. Our data provide a neural basis for understanding the primacy of headache and visceral pain in conditions that involve systemic MC degranulation. Our data further suggest that MC activation may lead to widespread tactile pain hypersensitivity.

  16. Subterranean, herbivore-induced plant volatile increases biological control activity of multiple beneficial nematode species in distinct habitats.

    Directory of Open Access Journals (Sweden)

    Jared G Ali

    Full Text Available While the role of herbivore-induced volatiles in plant-herbivore-natural enemy interactions is well documented aboveground, new evidence suggests that belowground volatile emissions can protect plants by attracting entomopathogenic nematodes (EPNs. However, due to methodological limitations, no study has previously detected belowground herbivore-induced volatiles in the field or quantified their impact on attraction of diverse EPN species. Here we show how a belowground herbivore-induced volatile can enhance mortality of agriculturally significant root pests. First, in real time, we identified pregeijerene (1,5-dimethylcyclodeca-1,5,7-triene from citrus roots 9-12 hours after initiation of larval Diaprepes abbreviatus feeding. This compound was also detected in the root zone of mature citrus trees in the field. Application of collected volatiles from weevil-damaged citrus roots attracted native EPNs and increased mortality of beetle larvae (D. abbreviatus compared to controls in a citrus orchard. In addition, field applications of isolated pregeijerene caused similar results. Quantitative real-time PCR revealed that pregeijerene increased pest mortality by attracting four species of naturally occurring EPNs in the field. Finally, we tested the generality of this root-zone signal by application of pregeijerene in blueberry fields; mortality of larvae (Galleria mellonella and Anomala orientalis again increased by attracting naturally occurring populations of an EPN. Thus, this specific belowground signal attracts natural enemies of widespread root pests in distinct agricultural systems and may have broad potential in biological control of root pests.

  17. Secretion by stimulated murine macrophages of a heparin-binding fibroblast growth activity, distinct from basic FGE and IL-1

    Energy Technology Data Exchange (ETDEWEB)

    Rappolee, D.A.; Banda, M.J.; Werb, Z.

    1986-03-01

    Wound healing requires granulation and formation of neovascularization tissue. These two events require increases in fibroblasts, vascular endothelial, and smooth muscle cells. Macrophages may produce several growth factors which participate in these would healing events. To test this hypothesis they have partially purified a fibroblast growth promoting activity from a murine macrophage cell line (P388 Dl). The activity causes growth in Balb/c and Swiss 3T3 cells as measured by thymidine uptake, nuclear labeling and increase in cell number. PDGF, Basic FGF, and EGF are also mitogenic by thymidine uptake, but purified human IL-1 and recombinant murine IL-1 are not. The activity is pH 2.5-, freeze/thaw-, and dialysis/lyphilyzation-stable. The activity elutes from heparin-Sepharose at 2.0M, but not 0.15m, 0.5M, or 3.0M NaCl. Basic FGF elutes from the same heparin-Sepharose batch at 3.0M, but not at the other three NaCl concentrations. The growth activity is secreted by viable murine macrophage line cells (P388D1, WEHI-3, RAW 264.7) at a 48 hour peak after activating (LPS) or phagocytic stimuli. Unstimulated P388D1 caused growth 1.7 times control whereas stimulation increases the growth 5.1 to 7.1 times control. The optimal activity concentration fails to complement insulin in an assay in which optimal basic FGF concentration complements insulin. These data suggest that the activity may contain a progression factor.

  18. The metabolically active subpopulation in Pseudomonas aeruginosa biofilms survives exposure to membrane-targeting antimicrobials via distinct molecular mechanisms

    DEFF Research Database (Denmark)

    Chiang, Wen-Chi; Pamp, Sünje Johanna; Nilsson, Martin

    2012-01-01

    Biofilms are reported to be inherently refractory toward antimicrobial attack and, therefore, cause problems in industrial and medical settings. Pseudomonas aeruginosa biofilms contain subpopulations that exhibit high metabolic activity and subpopulations that exhibit low metabolic activity. We......-targeting compounds colistin, EDTA, SDS, and chlorhexidine resulted in the same spatial distribution of live and dead bacteria, we investigated whether tolerance to these compounds originated from the same molecular mechanisms. Development of colistin-tolerant subpopulations was found to depend on the pmr genes...

  19. Acquired cutis laxa

    Directory of Open Access Journals (Sweden)

    Musaliar S

    2003-03-01

    Full Text Available A 13-yeat-old male patient born of non consanguineous marriage with history of recurrent urticaria and angioedema for the past 2 years presented with wrinkling and laxity of the skin over the face, axilla and abdomen. Histopathology was consistent with cutis laxa. We are reporting a rare case of acquired cutis laxa due to recurrent urticaria.

  20. Acquired cutis laxa

    Directory of Open Access Journals (Sweden)

    Musaliar S

    2003-01-01

    Full Text Available A 13-yeat-old male patient born of non consanguineous marriage with history of recurrent urticaria and angioedema for the past 2 years presented with wrinkling and laxity of the skin over the face, axilla and abdomen. Histopathology was consistent with cutis laxa. We are reporting a rare case of acquired cutis laxa due to recurrent urticaria.

  1. Distinct Neural Activities in Premotor Cortex during Natural Vocal Behaviors in a New World Primate, the Common Marmoset (Callithrix jacchus).

    Science.gov (United States)

    Roy, Sabyasachi; Zhao, Lingyun; Wang, Xiaoqin

    2016-11-30

    Although evidence from human studies has long indicated the crucial role of the frontal cortex in speech production, it has remained uncertain whether the frontal cortex in nonhuman primates plays a similar role in vocal communication. Previous studies of prefrontal and premotor cortices of macaque monkeys have found neural signals associated with cue- and reward-conditioned vocal production, but not with self-initiated or spontaneous vocalizations (Coudé et al., 2011; Hage and Nieder, 2013), which casts doubt on the role of the frontal cortex of the Old World monkeys in vocal communication. A recent study of marmoset frontal cortex observed modulated neural activities associated with self-initiated vocal production (Miller et al., 2015), but it did not delineate whether these neural activities were specifically attributed to vocal production or if they may result from other nonvocal motor activity such as orofacial motor movement. In the present study, we attempted to resolve these issues and examined single neuron activities in premotor cortex during natural vocal exchanges in the common marmoset (Callithrix jacchus), a highly vocal New World primate. Neural activation and suppression were observed both before and during self-initiated vocal production. Furthermore, by comparing neural activities between self-initiated vocal production and nonvocal orofacial motor movement, we identified a subpopulation of neurons in marmoset premotor cortex that was activated or suppressed by vocal production, but not by orofacial movement. These findings provide clear evidence of the premotor cortex's involvement in self-initiated vocal production in natural vocal behaviors of a New World primate.

  2. Distinct Polymer Architecture Mediates Switching of Complement Activation Pathways at the Nanosphere-Serum Interface: Implications for Stealth Nanoparticle Engineering

    DEFF Research Database (Denmark)

    Hamad, I.; Al-Hanbali, O.; Hunter, A.C.;

    2010-01-01

    Nanoparticles with surface projected polyethyleneoxide (PEO) chains in 'mushroom-brush' and "brush" configurations display stealth properties in systemic circulation and have numerous applications in site specific targeting for controlled drug delivery and release as well as diagnostic Imaging. W...... engineering and design of immunologically safer stealth and targetable nanosystems with polymers for use in clinical medicine.......Nanoparticles with surface projected polyethyleneoxide (PEO) chains in 'mushroom-brush' and "brush" configurations display stealth properties in systemic circulation and have numerous applications in site specific targeting for controlled drug delivery and release as well as diagnostic Imaging. We...... switches complement activation from C1q dependent classical to lectin pathway but also reduces the level of generated complement activation, products C4d, Bb, C5a, and SC5b-9. Also changes In adsorbed polymer configuration trigger alternative pathway activation differently and through different initiators...

  3. Treatment of bleeding in acquired hemophilia A with the proper administration of recombinant activated factor VII: single-center study of 7 cases

    Science.gov (United States)

    Saito, Makoto; Kanaya, Minoru; Izumiyama, Koh; Mori, Akio; Irie, Tatsuro; Tanaka, Masanori; Morioka, Masanobu; Ieko, Masahiro

    2016-01-01

    Recombinant activated factor VII (rFVIIa) is the bypassing agent used in the first-line hemostatic therapy for acquired hemophilia A (AHA); however, the occurrence of thrombotic complications in rFVIIa-treated AHA patients was recently reported to be 2.9–6.5%. Therefore, the investigation of the proper administration of rFVIIa for AHA is needed. In the present study, we retrospectively investigated the clinical features of AHA with regards to the use of rFVIIa (presence or absence of use and total amount) in 7 AHA patients encountered in our department for 7 years between January 2008 and December 2014. Ages were 63–89 years old (median: 79 years old), and there were 5 male and 2 female patients. The coexistence of cardiovascular risk factors and arteriosclerotic diseases, such as hypertension, diabetes mellitus, and cerebral infarction were present in 6 patients. Anemia progressed to less than 7 g/dL of hemoglobin and required red blood cell transfusion in 5 patients, showing “severe” hemorrhage. Factor VIII inhibitors were removed by immunological treatments in 6 patients. As a hemostatic therapy, rFVIIa was used in 4 patients. rFVIIa was not administered or was administered at a very low dose (20 mg) to 3 and 1 patient, respectively, and bleeding stopped as inhibitor titers decreased and disappeared in these patients. Inhibitors did not disappear in 1 patient and the control of hemostasis became poor and was accompanied by intestinal hemorrhage. Although a large amount of rFVIIa (265 mg in total) was administered, the patient bled to death. Therefore, bleeding may be stopped without the administration of rFVIIa in some AHA cases, while the dose of rFVIIa is not necessarily related to hemostatic effects in other cases. Since the main aim of AHA treatments is the removal of inhibitors, caution is needed to ensure that more than the necessary amount of rFVIIa is not administered. PMID:27843336

  4. Serotonin 2C receptor activates a distinct population of arcuate pro-opiomelanocortin neurons via TRPC channels

    Science.gov (United States)

    Serotonin 2C receptors (5-HT2CRs) expressed by pro-opiomelanocortin (POMC) neurons of hypothalamic arcuate nucleus regulate food intake, energy homeostasis ,and glucose metabolism. However, the cellular mechanisms underlying the effects of 5-HT to regulate POMC neuronal activity via 5-HT2CRs have no...

  5. DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization

    DEFF Research Database (Denmark)

    Reinhardt, H Christian; Hasskamp, Pia; Schmedding, Ingolf

    2010-01-01

    Following genotoxic stress, cells activate a complex kinase-based signaling network to arrest the cell cycle and initiate DNA repair. p53-defective tumor cells rewire their checkpoint response and become dependent on the p38/MK2 pathway for survival after DNA damage, despite a functional ATR-Chk1...

  6. DNA Damage Activates a Spatially Distinct Late Cytoplasmic Cell-Cycle Checkpoint Network Controlled by MK2-Mediated RNA Stabilization

    NARCIS (Netherlands)

    Reinhardt, H. Christian; Hasskamp, Pia; Schmedding, Ingolf; Morandell, Sandra; van Vugt, Marcel A. T. M.; Wang, XiaoZhe; Linding, Rune; Ong, Shao-En; Weaver, David; Carr, Steven A.; Yaffe, Michael B.

    2010-01-01

    Following genotoxic stress, cells activate a complex kinase-based signaling network to arrest the cell cycle and initiate DNA repair. p53-defective tumor cells rewire their checkpoint response and become dependent on the p38/MK2 pathway for survival after DNA damage, despite a functional ATR-Chk1 pa

  7. MMTV-Wnt1 and -DeltaN89beta-catenin induce canonical signaling in distinct progenitors and differentially activate Hedgehog signaling within mammary tumors.

    Directory of Open Access Journals (Sweden)

    Brigitte Teissedre

    Full Text Available Canonical Wnt/beta-catenin signaling regulates stem/progenitor cells and, when perturbed, induces many human cancers. A significant proportion of human breast cancer is associated with loss of secreted Wnt antagonists and mice expressing MMTV-Wnt1 and MMTV-DeltaN89beta-catenin develop mammary adenocarcinomas. Many studies have assumed these mouse models of breast cancer to be equivalent. Here we show that MMTV-Wnt1 and MMTV-DeltaN89beta-catenin transgenes induce tumors with different phenotypes. Using axin2/conductin reporter genes we show that MMTV-Wnt1 and MMTV-DeltaN89beta-catenin activate canonical Wnt signaling within distinct cell-types. DeltaN89beta-catenin activated signaling within a luminal subpopulation scattered along ducts that exhibited a K18(+ER(-PR(-CD24(highCD49f(low profile and progenitor properties. In contrast, MMTV-Wnt1 induced canonical signaling in K14(+ basal cells with CD24/CD49f profiles characteristic of two distinct stem/progenitor cell-types. MMTV-Wnt1 produced additional profound effects on multiple cell-types that correlated with focal activation of the Hedgehog pathway. We document that large melanocytic nevi are a hitherto unreported hallmark of early hyperplastic Wnt1 glands. These nevi formed along the primary mammary ducts and were associated with Hedgehog pathway activity within a subset of melanocytes and surrounding stroma. Hh pathway activity also occurred within tumor-associated stromal and K14(+/p63(+ subpopulations in a manner correlated with Wnt1 tumor onset. These data show MMTV-Wnt1 and MMTV-DeltaN89beta-catenin induce canonical signaling in distinct progenitors and that Hedgehog pathway activation is linked to melanocytic nevi and mammary tumor onset arising from excess Wnt1 ligand. They further suggest that Hedgehog pathway activation maybe a critical component and useful indicator of breast tumors arising from unopposed Wnt1 ligand.

  8. Distinct and cooperative activities of HESO1 and URT1 nucleotidyl transferases in microRNA turnover in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Bin Tu

    2015-04-01

    Full Text Available 3' uridylation is increasingly recognized as a conserved RNA modification process associated with RNA turnover in eukaryotes. 2'-O-methylation on the 3' terminal ribose protects micro(miRNAs from 3' truncation and 3' uridylation in Arabidopsis. Previously, we identified HESO1 as the nucleotidyl transferase that uridylates most unmethylated miRNAs in vivo, but substantial 3' tailing of miRNAs still remains in heso1 loss-of-function mutants. In this study, we found that among nine other potential nucleotidyl transferases, UTP:RNA uridylyltransferase 1 (URT1 is the single most predominant nucleotidyl transferase that tails miRNAs. URT1 and HESO1 prefer substrates with different 3' end nucleotides in vitro and act cooperatively to tail different forms of the same miRNAs in vivo. Moreover, both HESO1 and URT1 exhibit nucleotidyl transferase activity on AGO1-bound miRNAs. Although these enzymes are able to add long tails to AGO1-bound miRNAs, the tailed miRNAs remain associated with AGO1. Moreover, tailing of AGO1-bound miRNA165/6 drastically reduces the slicing activity of AGO1-miR165/6, suggesting that tailing reduces miRNA activity. However, monouridylation of miR171a by URT1 endows the miRNA the ability to trigger the biogenesis of secondary siRNAs. Therefore, 3' tailing could affect the activities of miRNAs in addition to leading to miRNA degradation.

  9. Enzyme kinetics and distinct modulation of the protein kinase N family of kinases by lipid activators and small molecule inhibitors

    OpenAIRE

    Falk, Matthew D.; Liu, Wei; Bolaños, Ben; Unsal-Kacmaz, Keziban; Klippel, Anke; Grant, Stephan; Brooun, Alexei; Timofeevski, Sergei

    2014-01-01

    The PKN (protein kinase N) family of Ser/Thr protein kinases regulates a diverse set of cellular functions, such as cell migration and cytoskeletal organization. Inhibition of tumour PKN activity has been explored as an oncology therapeutic approach, with a PKN3-targeted RNAi (RNA interference)-derived therapeutic agent in Phase I clinical trials. To better understand this important family of kinases, we performed detailed enzymatic characterization, determining the kinetic mechanism and lipi...

  10. Distinct immunological activation profiles of dSLIM® and ProMune® depend on their different structural context

    Science.gov (United States)

    Schneider, Jacqueline; Schneider, Lisa; Gollinge, Nadine; Jänsch, Stefanie; Schroff, Matthias; Wittig, Burghardt; Kleuss, Christiane

    2016-01-01

    Abstract Introduction DNA‐based TLR9 agonists are potent activators of the immune system. ProMune® and dSLIM® belong to different families of TLR9 agonists and both have been established as cancer immunotherapeutics in clinical proof‐of‐concept studies. Unfortunately, ProMune® failed in pivotal oncological trials. dSLIM®, the active ingredient of Lefitolimod (MGN1703), successfully finished a double‐blinded, placebo‐controlled phase II study in patients with advanced colorectal cancer, exhibiting improved progression‐free survival and durable disease control. Methods To explain the different systemic efficacies of dSLIM® and ProMune®, both TLR9 agonists and chimeric molecules thereof are analyzed side‐by‐side in a panel of in vitro assays for immune activation. Results and conclusions Indeed, dSLIM® exposure results in an IFN‐α dependent broad activation of immune cells whereas ProMune® strongly stimulates B cells. Moreover, all functional effects of dSLIM® strictly depend on the presence of CG‐motifs within its dumbbell‐shaped, covalently closed structural context. Conversely, several immunological effects of ProMune® like IL‐8 secretion are independent of CG‐motifs and could be ascribed to the phosphorothioate‐modifications of its DNA backbone, which may have caused the side effects of ProMune® in clinical trials. Finally, we showed that the implementation of ProMune® (ODN2006) base sequence into the characteristic dSLIM® dumbbell form resulted in dSLIM2006 with all beneficial effects for immunostimulation combined from both TLR9 classes without any CG‐independent effects. PMID:27980779

  11. Distinct spatial activation of intrinsic and extrinsic apoptosis pathways in natural scrapie: association with prion-related lesions

    Science.gov (United States)

    Serrano, Carmen; Lyahyai, Jaber; Bolea, Rosa; Varona, Luis; Monleón, Eva; Badiola, Juan J.; Zaragoza, Pilar; Martín-Burriel, Inmaculada

    2009-01-01

    Neurodegeneration and gliosis are the main neuropathological features of prion diseases. However, the molecular mechanisms involved in these processes remain unclear. Several studies have demonstrated changes in the expression of apoptotic factors and inflammatory cytokines in animals with experimental infection. Here we present the expression profiles of 15 genes implicated in the intrinsic and extrinsic apoptotic pathways in the central nervous systems of sheep naturally infected with scrapie. Expression changes obtained by real-time RT-PCR were also compared with the extent of classical scrapie lesions, such as prion deposition, neuronal vacuolisation, spongiosis, and astrogliosis as well as with the activation of caspase-3, using a stepwise regression. The results suggest that the factors assessed participate in apoptotic or inflammatory functions, depending on the affected area. The mitochondrial apoptosis pathway was associated with prion deposition in the prefrontal cortex (the less affected area), and with activation of caspase-3-mediated cell death via over-expression of BAK. In addition to its known association with astroglial activation, the extrinsic apoptosis pathway was also related to cell death and neuronal vacuolisation. PMID:19401142

  12. Different synchronization characteristics of distinct types of traveling waves in a model of active medium with periodic boundary conditions

    Science.gov (United States)

    Shepelev, Igor A.; Slepnev, Andrei V.; Vadivasova, Tatiana E.

    2016-09-01

    The model of a one-dimensional active medium, which cells are the FitzHugh-Nagumo oscillators, is studied for periodical boundary conditions. The medium possesses three different regimes in dependence on the parameter values. The regimes correspond to the self-sustained oscillations, excitable dynamics or bistability of the medium cells. Periodic boundary conditions provide the existence of traveling wave modes in all mentioned cases without any deterministic or stochastic excitation. The spatial waveforms and the character of oscillations in time can be similar in the different cases, but the properties of wave modes depend considerably on the medium regime. So, the dispersion characteristics and the synchronization phenomena are essentially different for bistable and excitable media on the one hand, and for the self-sustained oscillatory medium on the other hand. The local and distributed periodic influence on the medium are studied. The phenomenon of the traveling wave frequency locking is observed for all three regimes of the active medium. The comparison of synchronization effects in self-oscillatory, excitable and bistable regimes of the active medium is carried out.

  13. Acquired methemoglobinemia in infants

    Directory of Open Access Journals (Sweden)

    Mehmet Mutlu

    2011-06-01

    Full Text Available Objective: This study aimed to determine the etiologic factors of acquired methemoglobinemia in infants younger than three months in our region. Material and Methods: This study was carried out retrospectively in infants with methemoglobinemia admitted to Karadeniz Technical University, Pediatric Clinic, during the period 2000-2009. Infants with methemoglobinemia were identified according to the medical records or ICD-10 code. Results: Nine infants with acquired methemoglobinemia (8 male, 1 female were included in the study. Seven cases were associated with the use of prilocaine for circumcision, one case with the use of prilocaine-lidocaine for local pain therapy, and one case with neonatal sepsis caused by Staphylococcus aureus.Conclusion: Prilocaine should not be used in infants less than three months of age because of the risk of methemoglobinemia. Ascorbic acid is an effective therapy if methylene blue is not obtained. It should not be forgotten that sepsis caused by S. aureus may cause methemoglobinemia in infants.

  14. Acquired hypertrichosis lanuginosa

    Directory of Open Access Journals (Sweden)

    Kumar Pramod

    1993-01-01

    Full Text Available Acquired hypertirichosis lanuginose developed rapidly in a patient with no detectable malignancy. Soft, fine, downy hair growth was noticed on the face, ears, limbs and trunk. Bilaterally symmetrical vitiliginous macules were present on the ear and preauricular region. This case is reported because of its rarity, absence of any detectable malignancy and development of vitiligo, which to our knowledge has not been reported earlier.

  15. UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase. Identification and separation of two distinct transferase activities

    DEFF Research Database (Denmark)

    Sørensen, T; White, T; Wandall, H H;

    1995-01-01

    Using a defined acceptor substrate peptide as an affinity chromatography ligand we have developed a purification scheme for a unique human polypeptide, UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase (GalNAc-transferase) (White, T., Bennett, E.P., Takio, K., Sørensen, T., Bonding, N......., and Clausen, H. (1995) J. Biol. Chem. 270, 24156-24165). Here we report detailed studies of the acceptor substrate specificity of GalNAc-transferase purified by this scheme as well as the Gal-NAc-transferase activity, which, upon repeated affinity chromatography, evaded purification by this affinity ligand...

  16. Distinct activation phenotype of a highly conserved novel HLA-B57-restricted epitope during dengue virus infection.

    Science.gov (United States)

    Townsley, Elizabeth; Woda, Marcia; Thomas, Stephen J; Kalayanarooj, Siripen; Gibbons, Robert V; Nisalak, Ananda; Srikiatkhachorn, Anon; Green, Sharone; Stephens, Henry A F; Rothman, Alan L; Mathew, Anuja

    2014-01-01

    Variation in the sequence of T-cell epitopes between dengue virus (DENV) serotypes is believed to alter memory T-cell responses during second heterologous infections. We identified a highly conserved, novel, HLA-B57-restricted epitope on the DENV NS1 protein. We predicted higher frequencies of B57-NS1(26-34) -specific CD8(+) T cells in peripheral blood mononuclear cells from individuals undergoing secondary rather than primary DENV infection. However, high tetramer-positive T-cell frequencies during acute infection were seen in only one of nine subjects with secondary infection. B57-NS1(26-34) -specific and other DENV epitope-specific CD8(+) T cells, as well as total CD8(+) T cells, expressed an activated phenotype (CD69(+) and/or CD38(+)) during acute infection. In contrast, expression of CD71 was largely limited to DENV epitope-specific CD8(+) T cells. In vitro stimulation of cell lines indicated that CD71 expression was differentially sensitive to stimulation by homologous and heterologous variant peptides. CD71 may represent a useful marker of antigen-specific T-cell activation.

  17. Distinct structures of the α-fucose branches in fucosylated chondroitin sulfates do not affect their anticoagulant activity.

    Science.gov (United States)

    Santos, Gustavo R C; Glauser, Bianca F; Parreiras, Luane A; Vilanova, Eduardo; Mourão, Paulo A S

    2015-10-01

    Fucosylated chondroitin sulfate (FCS) is a glycosaminoglycan found in sea cucumbers. It has a backbone like that of mammalian chondroitin sulfate (4-β-d-GlcA-1→3-β-d-GalNAc-1)n but substituted at the 3rd position of the β-d-glururonic acid residues with α-fucose branches. The structure of these branches varies among FCSs extracted from different species of sea cucumbers, as revealed by solution NMR spectroscopy. Some species (Isostichopus badionotus and Patalus mollis) contain branches formed by single α-fucose residues but with variable sulfation patterns (2,4-, 3,4- and 4-sulfation). FCS from Ludwigothurea grisea is distinguished because it contains preponderant branches formed by disaccharide units containing non-sulfated and 3-sulfated α-fucose units at the reducing and non-reducing ends, respectively. Despite the structural variability on their α-fucose branches, these FCSs have similar anticoagulant action on assays using purified reagents. They have serpin-dependent and serpin-independent effects. Pharmacological assays using experimental animals showed that the three types of FCSs have similar antithrombotic effect and bleeding tendency. They also activate factor XII on the same range of concentration. Based on these observations, we proposed that only few sulfated α-fucose branches along the FCS chain are enough to assure the binding of this glycosaminoglycan to proteins of the coagulation system. Substitution with additional sulfated α-fucose does not increase further the activity. Overall, the use of FCSs with marked variability on their branches of α-fucose allowed us to establish correlations between structures vs biological effects of these glycosaminoglycans on a more refined basis. It opens new avenues for therapeutic intervention using FCSs.

  18. A ternary classification using machine learning methods of distinct estrogen receptor activities within a large collection of environmental chemicals.

    Science.gov (United States)

    Zhang, Quan; Yan, Lu; Wu, Yan; Ji, Li; Chen, Yuanchen; Zhao, Meirong; Dong, Xiaowu

    2017-02-15

    Endocrine-disrupting chemicals (EDCs), which can threaten ecological safety and be harmful to human beings, have been cause for wide concern. There is a high demand for efficient methodologies for evaluating potential EDCs in the environment. Herein an evaluation platform was developed using novel and statistically robust ternary models via different machine learning models (i.e., linear discriminant analysis, classification and regression tree, and support vector machines). The platform is aimed at effectively classifying chemicals with agonistic, antagonistic, or no estrogen receptor (ER) activities. A total of 440 chemicals from the literature were selected to derive and optimize the three-class model. One hundred and nine new chemicals appeared on the 2014 EPA list for EDC screening, which were used to assess the predictive performances by comparing the E-screen results with the predicted results of the classification models. The best model was obtained using support vector machines (SVM) which recognized agonists and antagonists with accuracies of 76.6% and 75.0%, respectively, on the test set (with an overall predictive accuracy of 75.2%), and achieved a 10-fold cross-validation (CV) of 73.4%. The external predicted accuracy validated by the E-screen assay was 87.5%, which demonstrated the application value for a virtual alert for EDCs with ER agonistic or antagonistic activities. It was demonstrated that the ternary computational model could be used as a faster and less expensive method to identify EDCs that act through nuclear receptors, and to classify these chemicals into different mechanism groups.

  19. Distinct summer and winter bacterial communities in the active layer of Svalbard permafrost revealed by DNA- and RNA-based analyses

    DEFF Research Database (Denmark)

    Schostag, Morten; Stibal, Marek; Jacobsen, Carsten S.;

    2015-01-01

    organic matter on the bacterial communities. The copy number of 16S rRNA genes and transcripts revealed no distinct seasonal changes indicating potential bacterial activity during winter despite soil temperatures well below -10ºC. Multivariate statistical analysis of the bacterial diversity data (DNA......N) by co-extracting DNA and RNA from 12 soil cores collected monthly over a year. PCR amplicons of 16S rRNA genes (DNA) and reverse transcribed transcripts (cDNA) were quantified and sequenced to test for the effect of low winter temperature and seasonal variation in concentration of easily degradable...... was significantly correlated with pH and dissolved organic carbon, while the potentially active (RNA-based) community structure was not significantly correlated with any of the measured soil parameters. A large fraction of the 16S rRNA transcripts was assigned to nitrogen-fixing bacteria (up to 24% in June...

  20. Activating FLT3 mutants show distinct gain-of-function phenotypes in vitro and a characteristic signaling pathway profile associated with prognosis in acute myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Hanna Janke

    Full Text Available About 30% of patients with acute myeloid leukemia (AML harbour mutations of the receptor tyrosine kinase FLT3, mostly internal tandem duplications (ITD and point mutations of the second tyrosine kinase domain (TKD. It was the aim of this study to comprehensively analyze clinical and functional properties of various FLT3 mutants. In 672 normal karyotype AML patients FLT3-ITD, but not FLT3-TKD mutations were associated with a worse relapse free and overall survival in multivariate analysis. In paired diagnosis-relapse samples FLT3-ITD showed higher stability (70% compared to FLT3-TKD (30%. In vitro, FLT3-ITD induced a strong activating phenotype in Ba/F3 cells. In contrast, FLT3-TKD mutations and other point mutations--including two novel mutations--showed a weaker but clear gain-of-function phenotype with gradual increase in proliferation and protection from apoptosis. The pro-proliferative capacity of the investigated FLT3 mutants was associated with cell surface expression and tyrosine 591 phosphorylation of the FLT3 receptor. Western blot experiments revealed STAT5 activation only in FLT3-ITD positive cell lines, in contrast to FLT3-non-ITD mutants, which displayed an enhanced signal of AKT and MAPK activation. Gene expression analysis revealed distinct difference between FLT3-ITD and FLT3-TKD for STAT5 target gene expression as well as deregulation of SOCS2, ENPP2, PRUNE2 and ART3. FLT3-ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. Although poor prognosis in AML is only associated with FLT3-ITD, all activating FLT3 mutations can contribute to leukemogenesis and are thus potential targets for therapeutic interventions.

  1. Distinct symmetry and limited peptide refolding activity of the thermosomes from the acidothermophilic archaea Acidianus tengchongensis S5{sup T}

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Li [The State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China); Hu, Zhong-jun [National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101 (China); Luo, Yuan-ming [The State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China); Huo, Yan-wu [National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101 (China); Ma, Qing [The State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China); The College of Life Sciences, Beijing Normal University, Beijing 100875 (China); He, Yong-zhi; Zhang, Yu-ying [The State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China); Sun, Fei, E-mail: feisun@ibp.ac.cn [National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101 (China); Dong, Zhi-yang, E-mail: dongzy@sun.im.ac.cn [The State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China)

    2010-03-05

    Recombinant thermosomes from the Acidianus tengchongensis strain S5{sup T} were purified to homogeneity and assembled in vitro into homo-oligomers (rATcpn{alpha} or rATcpn{beta}) and hetero-oligomers (rATcpn{alpha}{beta}). The symmetries of these complexes were determined by electron microscopy and image analysis. The rATcpn{alpha} homo-oligomer was shown to possess 8-fold symmetry while both rATcpn{beta} and rATcpn{alpha}{beta} oligomers adopted 9-fold symmetry. rATcpn{alpha}{beta} oligomers were shown to contain the {alpha} and {beta} subunits in a 1:2 ratio. All of the complexes prevented the irreversible inactivation of yeast alcohol dehydrogenase at 55 {sup o}C and completely prevented the formation of aggregates during thermal inactivation of citrate synthase at 45 {sup o}C. All rATcpn complexes showed trace ATP hydrolysis activity. Furthermore, rATcpn{beta} sequestered fully chemically denatured substrates (GFP and thermophilic malic dehydrogenase) in vitro without refolding them in an ATP-dependent manner. This property is similar to previously reported properties of chaperonins from Sulfolobus tokodaii and Sulfolobus acidocaldarius. These features are consistent with the slow growth rates of these species of archaea in their native environment.

  2. Enzyme kinetics and distinct modulation of the protein kinase N family of kinases by lipid activators and small molecule inhibitors

    Science.gov (United States)

    Falk, Matthew D.; Liu, Wei; Bolaños, Ben; Unsal-Kacmaz, Keziban; Klippel, Anke; Grant, Stephan; Brooun, Alexei; Timofeevski, Sergei

    2014-01-01

    The PKN (protein kinase N) family of Ser/Thr protein kinases regulates a diverse set of cellular functions, such as cell migration and cytoskeletal organization. Inhibition of tumour PKN activity has been explored as an oncology therapeutic approach, with a PKN3-targeted RNAi (RNA interference)-derived therapeutic agent in Phase I clinical trials. To better understand this important family of kinases, we performed detailed enzymatic characterization, determining the kinetic mechanism and lipid sensitivity of each PKN isoform using full-length enzymes and synthetic peptide substrate. Steady-state kinetic analysis revealed that PKN1–3 follows a sequential ordered Bi–Bi kinetic mechanism, where peptide substrate binding is preceded by ATP binding. This kinetic mechanism was confirmed by additional kinetic studies for product inhibition and affinity of small molecule inhibitors. The known lipid effector, arachidonic acid, increased the catalytic efficiency of each isoform, mainly through an increase in kcat for PKN1 and PKN2, and a decrease in peptide KM for PKN3. In addition, a number of PKN inhibitors with various degrees of isoform selectivity, including potent (Ki<10 nM) and selective PKN3 inhibitors, were identified by testing commercial libraries of small molecule kinase inhibitors. This study provides a kinetic framework and useful chemical probes for understanding PKN biology and the discovery of isoform-selective PKN-targeted inhibitors. PMID:27919031

  3. Distinct muscle apoptotic pathways are activated in muscles with different fiber types a rat model of critical illness myopathy

    Science.gov (United States)

    Barnes, Benjamin T.; Confides, Amy L.; Rich, Mark M.; Dupont-Versteegden, Esther E.

    2015-01-01

    Critical illness myopathy (CIM) is associated with severe muscle atrophy and fatigue in affected patients. Apoptotic signaling is involved in atrophy and is elevated in muscles from patients with CIM. In this study we investigated underlying mechanisms of apoptosis-related pathways in muscles with different fiber type composition in a rat model of CIM using denervation and glucocorticoid administration (denervation and steroid-induced myopathy, DSIM). Soleus and tibialis anterior (TA) muscles showed severe muscle atrophy (40–60% of control muscle weight) and significant apoptosis in interstitial as well as myofiber nuclei that was similar between the two muscles with DSIM. Caspase-3 and −8 activities, but not caspase-9 and −12, were elevated in TA and not in soleus muscle, while the caspase-independent proteins endonuclease G (EndoG) and apoptosis inducing factor (AIF) were not changed in abundance nor differentially localized in either muscle. Anti-apoptotic proteins HSP70, −27, and apoptosis repressor with a caspase recruitment domain (ARC) were elevated in soleus compared to TA muscle and ARC was significantly decreased with induction of DSIM in soleus. Results indicate that apoptosis is a significant process associated with DSIM in both soleus and TA muscles, and that apoptosis-associated processes are differentially regulated in muscles of different function and fiber type undergoing atrophy due to DSIM. We conclude that interventions combating apoptosis with CIM may need to be directed towards inhibiting caspase-dependent as well as -independent mechanisms to be able to affect muscles of all fiber types. PMID:25740800

  4. Distinct muscle apoptotic pathways are activated in muscles with different fiber types in a rat model of critical illness myopathy.

    Science.gov (United States)

    Barnes, Benjamin T; Confides, Amy L; Rich, Mark M; Dupont-Versteegden, Esther E

    2015-06-01

    Critical illness myopathy (CIM) is associated with severe muscle atrophy and fatigue in affected patients. Apoptotic signaling is involved in atrophy and is elevated in muscles from patients with CIM. In this study we investigated underlying mechanisms of apoptosis-related pathways in muscles with different fiber type composition in a rat model of CIM using denervation and glucocorticoid administration (denervation and steroid-induced myopathy, DSIM). Soleus and tibialis anterior (TA) muscles showed severe muscle atrophy (40-60% of control muscle weight) and significant apoptosis in interstitial as well as myofiber nuclei that was similar between the two muscles with DSIM. Caspase-3 and -8 activities, but not caspase-9 and -12, were elevated in TA and not in soleus muscle, while the caspase-independent proteins endonuclease G (EndoG) and apoptosis inducing factor (AIF) were not changed in abundance nor differentially localized in either muscle. Anti-apoptotic proteins HSP70, -27, and apoptosis repressor with a caspase recruitment domain (ARC) were elevated in soleus compared to TA muscle and ARC was significantly decreased with induction of DSIM in soleus. Results indicate that apoptosis is a significant process associated with DSIM in both soleus and TA muscles, and that apoptosis-associated processes are differentially regulated in muscles of different function and fiber type undergoing atrophy due to DSIM. We conclude that interventions combating apoptosis with CIM may need to be directed towards inhibiting caspase-dependent as well as -independent mechanisms to be able to affect muscles of all fiber types.

  5. 获得性再生障碍性贫血患者端粒-端粒酶活性的变化及其意义%Changes of telomere-telomerase activity in patients with acquired aplastic anemia

    Institute of Scientific and Technical Information of China (English)

    宋佳音; 王耀春; 肖扬

    2013-01-01

    Summary To summarize (he research progress of iclomcrc length and telomerase activity in acquired aplastic anemia(Aaa). A full text database system based on PUBMED and CNK1 was adopted for searching relevant literature from 1996 to 2012 with the key words of "telomere.telomerase and acquired aplastic anemia". Criterion for data selection-The literature about advances of telomere, telomerase and acquired aplastic anemia was selected for a-nalysis. According to the standard.236 articles were analyzed. Acquired aplastic anemia is hone marrow failure syndromes that mainly results from immune-mediated destruction of hematopoiesis. About one-third of patients with Aaa have short telomeres in peripheral white blood cells.some of which have heterozygous mutations in genes encoding the telomerase components of TERT or TERC Clinical observation found that most Aaa patients with telomere shortening were insensitive to immunosuppressive therapy;the disease duration increased and the prognosis was poor. Short telomeres may cause malignant clonal diseases in the advanced .stage.such as MDS.AML. Treatment plan for these Aaa patients with shortening telomere should he adjusted. They must undergo haematopoietic stem cell transplant ( HSCT) as soon as possible,and family donors with relevant mutations must he avoided. The Aaa patients with telomere related abnormality are different from other patients regarding pathological mechanism,disease progress, treatment and prognosis. Only a small proportion of these eases could be explained by TERT or TERC mutation. Other mutation or causes may remain unknown .

  6. Acquired von Willebrand Syndrome

    Institute of Scientific and Technical Information of China (English)

    郭涛

    2005-01-01

    @@ Acquired von Willebrand syndrome (AvWS) is kind of bleeding disorder with laboratory findings similar to those in congenital yon Willebrand disease (vWD).AvWS doesn's have any personal or family history of bleeding, but is associated with certain diseases or abnormal conditions or drugs. Although AvWS is being stated as a rare disease, it has gained more and more attention during the past years. Not because of the severity of the disease, but it is more common than we thought and most patients don' t have a proper diagnosis.

  7. Acquired hyperostosis syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Dihlmann, W.; Hering, L.; Bargon, G.W.

    1988-10-01

    Sterno-costo-clavicular hyperostosis (SCCH) is the most common manifestation of a syndrome, consisting of increased bone metabolism, mostly new bone formation and heterotopic ossification of fibrous tissue, which we have characterised as the acquired hyperostosis syndrome. In part I we discuss the terminology, radiological appearances, scintigraphy, clinical and laboratory findings, bacteriology, histology, nosology, complications, treatment and differential diagnosis of SCCH. Chronic recurrent multifocal osteomyelitis (CRMO) is regarded as a phaenotype of SCCH, depending on the age. CRMO occurs in children, adolescents and young adults, SCCH predominantly in middleaged and elderly adults.

  8. "Ready to Acquire"

    DEFF Research Database (Denmark)

    Yetton, Philip; Henningsson, Stefan; Bjørn-Andersen, Niels

    2013-01-01

    This article describes the experiences of Danisco (a global food ingredients company) as it followed a growth-by-acquisition business strategy, focusing on how a new CIO built the IT resources to ensure the IT organization was "ready to acquire." We illustrate how these IT capabilities expedited...... the IT integration following two acquisitions, one of which involved Danisco expanding the scale of its business and the other extending the scope. Based on insights gained from Danisco, we provide lessons for CIOs to realize business benefits when managing post-acquisition IT integration....

  9. 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 controlof anti...Distinct functions of IRF-3 and IRF-7 in IFN-alpha gene regulation and controlof anti... IFN-alpha gene regulation and controlof anti-tumor activity in primary macrophages. Authors Solis M, Goubau

  10. The RafC1 cysteine-rich domain contains multiple distinct regulatory epitopes which control Ras-dependent Raf activation.

    Science.gov (United States)

    Daub, M; Jöckel, J; Quack, T; Weber, C K; Schmitz, F; Rapp, U R; Wittinghofer, A; Block, C

    1998-11-01

    Activation of c-Raf-1 (referred to as Raf) by Ras is a pivotal step in mitogenic signaling. Raf activation is initiated by binding of Ras to the regulatory N terminus of Raf. While Ras binding to residues 51 to 131 is well understood, the role of the RafC1 cysteine-rich domain comprising residues 139 to 184 has remained elusive. To resolve the function of the RafC1 domain, we have performed an exhaustive surface scanning mutagenesis. In our study, we defined a high-resolution map of multiple distinct functional epitopes within RafC1 that are required for both negative control of the kinase and the positive function of the protein. Activating mutations in three different epitopes enhanced Ras-dependent Raf activation, while only some of these mutations markedly increased Raf basal activity. One contiguous inhibitory epitope consisting of S177, T182, and M183 clearly contributed to Ras-Raf binding energy and represents the putative Ras binding site of the RafC1 domain. The effects of all RafC1 mutations on Ras binding and Raf activation were independent of Ras lipid modification. The inhibitory mutation L160A is localized to a position analogous to the phorbol ester binding site in the protein kinase C C1 domain, suggesting a function in cofactor binding. Complete inhibition of Ras-dependent Raf activation was achieved by combining mutations K144A and L160A, which clearly demonstrates an absolute requirement for correct RafC1 function in Ras-dependent Raf activation.

  11. Low and high gamma oscillations in rat ventral striatum have distinct relationships to behavior, reward, and spiking activity on a learned spatial decision task

    Directory of Open Access Journals (Sweden)

    Matthijs A A Van Der Meer

    2009-06-01

    Full Text Available Local field potential (LFP oscillations in the brain reflect organization thought to be important for perception, attention, movement, and memory. In the basal ganglia, including dorsal striatum, dysfunctional LFP states are associated with Parkinson’s disease, while in healthy subjects, dorsal striatal LFPs have been linked to decision-making processes. However, LFPs in ventral striatum have been less studied. We report that in rats running a spatial decision task, prominent gamma-50 (45-55 Hz and gamma-80 (70-85 Hz oscillations in ventral striatum had distinct relationships to behavior, task events, and spiking activity. Gamma-50 power increased sharply following reward delivery and before movement initiation, while in contrast, gamma-80 power ramped up gradually to reward locations. Gamma-50 power was low and contained little structure during early learning, but rapidly developed a stable pattern, while gamma-80 power was initially high before returning to a stable level within a similar timeframe. Putative fast-spiking interneurons (FSIs showed phase, firing rate, and coherence relationships with gamma-50 and gamma-80, indicating that the observed LFP patterns are locally relevant. Furthermore, in a number of FSIs such relationships were specific to gamma-50 or gamma-80, suggesting that partially distinct FSI populations mediate the effects of gamma-50 and gamma-80.

  12. Learning-by-Being-Acquired

    DEFF Research Database (Denmark)

    Colombo, Massimo Gaetano; Moreira, Solon; Rabbiosi, Larissa

    2016-01-01

    of new teams with both inventors of the acquiring and acquired firms-and assess the impact of this integration action in the period that immediately follows the acquisition. Drawing on social identity and self-categorization theories, we argue that R&D team reorganization increases the acquired inventors......’ use of the prior stock of technological knowledge of the acquiring firm after the acquisition. Furthermore, this effect is enhanced if the focal acquired inventor has high relative innovation ability but is weakened for acquired inventors with high ingroup collaborative strength. We construct a sample...

  13. Learning-By-Being-Acquired

    DEFF Research Database (Denmark)

    Colombo, Massimo G.; Moreira, Solon; Rabbiosi, Larissa

    In this paper we study post-acquisition integration in terms of R&D team reorganization—i.e., the creation of new teams with both inventors of the acquiring and acquired firms—and assess its impact on knowledge transfer in the period that follows the acquisition. Drawing on social identity and self......-categorization theories, we argue that R&D team reorganization increases the acquired inventors’ use of the prior stock of technological knowledge of the acquiring firm after the acquisition. Furthermore, this effect is enhanced if acquired inventors have higher innovation ability relative to their acquiring peers...

  14. Developmental increase in ecto-5'-nucleotidase activity overlaps with appearance of two immunologically distinct enzyme isoforms in rat hippocampal synaptic plasma membranes.

    Science.gov (United States)

    Grkovic, Ivana; Bjelobaba, Ivana; Nedeljkovic, Nadezda; Mitrovic, Natasa; Drakulic, Dunja; Stanojlovic, Milos; Horvat, Anica

    2014-09-01

    Ecto-5'-nucleotidase (e-5NT), a glycosylphosphatidylinositol-linked membrane protein, catalyzes a conversion of AMP to adenosine, which influences nearly every aspect of brain physiology, including embryonic and postnatal brain development. The present study aimed to investigate a pattern of expression, activity and kinetic properties of e-5NT in the hippocampal formation and synaptic plasma membrane (SPM) preparations in rats at postnatal days (PDs) 7, 15, 20, 30 and 90. By combining gene expression analysis and enzyme histochemistry, we observed that e-5NT mRNA reached the adult level at PD20, while the enzyme activity continued to increase beyond this age. Further analysis revealed that hippocampal layers rich in synapses expressed the highest levels of e-5NT activity, while in layers populated with neuronal cell bodies, the enzyme activity was weak or absent. Therefore, activity and expression of e-5NT were analyzed in SPM preparations isolated from rats at different ages. The presence of two protein bands of about 65 and 68 kDa was determined by immunoblot analysis. The 65-kDa band was present at all ages, and its abundance increased from PD7 to PD20. The 68-kDa band appeared at PD15 and increased until PD30, coinciding with the increase of e-5NT activity, substrate affinity and enzymatic efficiency. Since distinct e-5NT isoforms may derive from different patterns of the enzyme protein N-glycosylation, we speculate that long-term regulation of e-5NT activity in adulthood may be effectuated at posttranslational level and without overall change in the gene and protein expression.

  15. Phenolic antioxidants in some Vigna species of legumes and their distinct inhibitory effects on α-glucosidase and pancreatic lipase activities.

    Science.gov (United States)

    Sreerama, Yadahally N; Takahashi, Yoko; Yamaki, Kohji

    2012-09-01

    Phenolic extracts of 4 Vigna species of legumes (mung bean, moth bean, and black and red varieties of adzuki beans) were evaluated for phenolic contents, antioxidant activities, and inhibitory properties against α-glucosidase and pancreatic lipase. Results showed that adzuki bean varieties contain higher phenolic indexes than mung bean and moth beans. Adzuki bean (black) variety was found to be the most active 2,2'-diphenyl-1-picrylhydrazyl and superoxide anion scavenger. However, the hydrogen peroxide scavenging and metal chelating abilities were significantly higher in adzuki bean (red) variety. Mung bean exhibited least antioxidant activities in all the methods tested. Phenolic extracts from these legumes also showed distinct variations in the inhibition of enzymes associated with hyperglycemia and hyperlipidemia. Inhibitory activities of all the extracts against lipase were found to be more potent than α-glucosidase. Although, α-glucosidase inhibitory activity was superior in the black variety of adzuki bean (IC(50,) 26.28 mg/mL), both adzuki bean varieties (black and red) along with moth bean showed strong inhibitory activities on lipase with no significant difference in their IC(50) values (7.32 to 9.85 mg/mL). These results suggest that Vigna species of legumes are potential source of antioxidant phenolics and also great sources of strong natural inhibitors for α-glucosidase and lipase activities. This information may help for effective utilization of these legumes as functional food ingredients for promoting health. Practical Application:  Vigna species of legumes are good sources of phenolic antioxidants and strong natural inhibitors of enzymes associated with diabetes and obesity. Therefore, utilization of these legumes in the development of functional foods with increased therapeutic value would be a significant step toward health promotion and wellness.

  16. Distinct summer and winter bacterial communities in the active layer of Svalbard permafrost revealed by DNA- and RNA-based analyses

    Energy Technology Data Exchange (ETDEWEB)

    Schostag, Morten; Stibal, Marek; Jacobsen, Carsten S.; Baelum, Jacob; Tas, Neslihan; Elberling, Bo; Jansson, Janet K.; Semenchuk, Phillip; Prieme, Anders

    2015-04-30

    The active layer of soil overlaying permafrost in the Arctic is subjected to dramatic annual changes in temperature and soil chemistry, which likely affect bacterial activity and community structure. We studied seasonal variations in the bacterial community of active layer soil from Svalbard (78°N) by co-extracting DNA and RNA from 12 soil cores collected monthly over a year. PCR amplicons of 16S rRNA genes (DNA) and reverse transcribed transcripts (cDNA) were quantified and sequenced to test for the effect of low winter temperature and seasonal variation in concentration of easily degradable organic matter on the bacterial communities. The copy number of 16S rRNA genes and transcripts revealed no distinct seasonal changes indicating potential bacterial activity during winter despite soil temperatures well below -10°C. Multivariate statistical analysis of the bacterial diversity data (DNA and cDNA libraries) revealed a season-based clustering of the samples, and, e.g., the relative abundance of potentially active Cyanobacteria peaked in June and Alphaproteobacteria increased over the summer and then declined from October to November. The structure of the bulk (DNA-based) community was significantly correlated with pH and dissolved organic carbon, while the potentially active (RNA-based) community structure was not significantly correlated with any of the measured soil parameters. A large fraction of the 16S rRNA transcripts was assigned to nitrogen-fixing bacteria (up to 24% in June) and phototrophic organisms (up to 48% in June) illustrating the potential importance of nitrogen fixation in otherwise nitrogen poor Arctic ecosystems and of phototrophic bacterial activity on the soil surface.

  17. ECoG high gamma activity reveals distinct cortical representations of lyrics passages, harmonic and timbre-related changes in a rock song.

    Science.gov (United States)

    Sturm, Irene; Blankertz, Benjamin; Potes, Cristhian; Schalk, Gerwin; Curio, Gabriel

    2014-01-01

    Listening to music moves our minds and moods, stirring interest in its neural underpinnings. A multitude of compositional features drives the appeal of natural music. How such original music, where a composer's opus is not manipulated for experimental purposes, engages a listener's brain has not been studied until recently. Here, we report an in-depth analysis of two electrocorticographic (ECoG) data sets obtained over the left hemisphere in ten patients during presentation of either a rock song or a read-out narrative. First, the time courses of five acoustic features (intensity, presence/absence of vocals with lyrics, spectral centroid, harmonic change, and pulse clarity) were extracted from the audio tracks and found to be correlated with each other to varying degrees. In a second step, we uncovered the specific impact of each musical feature on ECoG high-gamma power (70-170 Hz) by calculating partial correlations to remove the influence of the other four features. In the music condition, the onset and offset of vocal lyrics in ongoing instrumental music was consistently identified within the group as the dominant driver for ECoG high-gamma power changes over temporal auditory areas, while concurrently subject-individual activation spots were identified for sound intensity, timbral, and harmonic features. The distinct cortical activations to vocal speech-related content embedded in instrumental music directly demonstrate that song integrated in instrumental music represents a distinct dimension in complex music. In contrast, in the speech condition, the full sound envelope was reflected in the high gamma response rather than the onset or offset of the vocal lyrics. This demonstrates how the contributions of stimulus features that modulate the brain response differ across the two examples of a full-length natural stimulus, which suggests a context-dependent feature selection in the processing of complex auditory stimuli.

  18. ECoG high gamma activity reveals distinct cortical representations of lyrics passages, harmonic and timbre-related changes in a rock song

    Directory of Open Access Journals (Sweden)

    Irene eSturm

    2014-10-01

    Full Text Available Listening to music moves our minds and moods, stirring interest in its neural underpinnings. A multitude of compositional features drives the appeal of natural music. How such original music, where a composer's opus is not manipulated for experimental purposes, engages a listener's brain has not been studied until recently. Here, we report an in-depth analysis of two electrocorticographic (ECoG data sets obtained over the left hemisphere in ten patients during presentation of either a rock song or a read-out narrative. First, the time courses of five acoustic features (intensity, presence/absence of vocals with lyrics, spectral centroid, harmonic change, and pulse clarity were extracted from the audio tracks and found to be correlated with each other to varying degrees. In a second step, we uncovered the specific impact of each musical feature on ECoG high-gamma power (70-170 Hz by calculating partial correlations to remove the influence of the other four features. In the music condition, the onset and offset of vocal lyrics in ongoing instrumental music was consistently within the subject group identified as the dominant driver for ECoG high-gamma power changes over temporal auditory areas, while concurrently subject-individual activation spots were identified for sound intensity, timbral and harmonic features. The distinct cortical activations to vocal speech-related content embedded in instrumental music directly demonstrate that song overlaid on instrumental music represents a distinct dimension in complex music. In contrast, in the speech condition, the full sound envelope was reflected in the high gamma response rather than the onset or offset of the vocal lyrics. This demonstrates how the contributions of stimulus features that modulate the brain response differ across the two examples of a full-length natural stimulus, which suggests a context-dependent feature selection in the processing of complex auditory stimuli.

  19. Does chromatin remodeling mark systemic acquired resistance?

    NARCIS (Netherlands)

    Burg, van den H.A.; Takken, F.L.W.

    2009-01-01

    The recognition of plant pathogens activates local defense responses and triggers a long-lasting systemic acquired resistance (SAR) response. Activation of SAR requires the hormone salicylic acid (SA), which induces SA-responsive gene expression. Recent data link changes in gene expression to chroma

  20. Surgical treatment of acquired tracheocele.

    Science.gov (United States)

    Porubsky, Edward A; Gourin, Christine G

    2006-06-01

    Acquired tracheoceles are rare clinical entities that can cause a variety of chronic and recurrent aerodigestive tract symptoms. The management of acquired tracheoceles is primarily conservative, but surgical intervention may be indicated for patients with refractory symptoms. We present a case of acquired tracheocele and describe a method of successful surgical management.

  1. The viral KSHV chemokine vMIP-II inhibits the migration of Naive and activated human NK cells by antagonizing two distinct chemokine receptors.

    Directory of Open Access Journals (Sweden)

    Rachel Yamin

    2013-08-01

    Full Text Available Natural killer (NK cells are innate immune cells able to rapidly kill virus-infected and tumor cells. Two NK cell populations are found in the blood; the majority (90% expresses the CD16 receptor and also express the CD56 protein in intermediate levels (CD56(Dim CD16(Pos while the remaining 10% are CD16 negative and express CD56 in high levels (CD56(Bright CD16(Neg. NK cells also reside in some tissues and traffic to various infected organs through the usage of different chemokines and chemokine receptors. Kaposi's sarcoma-associated herpesvirus (KSHV is a human virus that has developed numerous sophisticated and versatile strategies to escape the attack of immune cells such as NK cells. Here, we investigate whether the KSHV derived cytokine (vIL-6 and chemokines (vMIP-I, vMIP-II, vMIP-III affect NK cell activity. Using transwell migration assays, KSHV infected cells, as well as fusion and recombinant proteins, we show that out of the four cytokine/chemokines encoded by KSHV, vMIP-II is the only one that binds to the majority of NK cells, affecting their migration. We demonstrate that vMIP-II binds to two different receptors, CX3CR1 and CCR5, expressed by naïve CD56(Dim CD16(Pos NK cells and activated NK cells, respectively. Furthermore, we show that the binding of vMIP-II to CX3CR1 and CCR5 blocks the binding of the natural ligands of these receptors, Fractalkine (Fck and RANTES, respectively. Finally, we show that vMIP-II inhibits the migration of naïve and activated NK cells towards Fck and RANTES. Thus, we present here a novel mechanism in which KSHV uses a unique protein that antagonizes the activity of two distinct chemokine receptors to inhibit the migration of naïve and activated NK cells.

  2. Auxin-activated NADH oxidase activity of soybean plasma membranes is distinct from the constitutive plasma membrane NADH oxidase and exhibits prion-like properties

    Science.gov (United States)

    Morre, D. James; Morre, Dorothy M.; Ternes, Philipp

    2003-01-01

    The hormone-stimulated and growth-related cell surface hydroquinone (NADH) oxidase activity of etiolated hypocotyls of soybeans oscillates with a period of about 24 min or 60 times per 24-h day. Plasma membranes of soybean hypocotyls contain two such NADH oxidase activities that have been resolved by purification on concanavalin A columns. One in the apparent molecular weight range of 14-17 kDa is stimulated by the auxin herbicide 2,4-dichlorophenoxyacetic acid (2,4-D). The other is larger and unaffected by 2,4-D. The 2,4-D-stimulated activity absolutely requires 2,4-D for activity and exhibits a period length of about 24 min. Also exhibiting 24-min oscillations is the rate of cell enlargement induced by the addition of 2,4-D or the natural auxin indole-3-acetic acid (IAA). Immediately following 2,4-D or IAA addition, a very complex pattern of oscillations is frequently observed. However, after several hours a dominant 24-min period emerges at the expense of the constitutive activity. A recruitment process analogous to that exhibited by prions is postulated to explain this behavior.

  3. Acquiring specific interpreting competence

    Directory of Open Access Journals (Sweden)

    Jana Zidar Forte

    2012-12-01

    Full Text Available In postgraduate interpreter training, the main objective of the course is to help trainees develop various competences, from linguistic, textual and cultural competence, to professional and specific interpreting competence. For simultaneous interpreting (SI, the main focus is on mastering the SI technique and strategies as well as on developing and strengthening communicative skills, which is discussed and illustrated with examples in the present paper. First, a brief overview is given of all the necessary competences of a professional interpreter with greater emphasis on specific interpreting competence for SI. In the second part of the paper, various approaches are described in terms of acquiring specific skills and strategies, specifically through a range of exercises. Besides interpreting entire speeches, practical courses should also consist of targeted exercises, which help trainees develop suitable coping strategies and mechanisms (later on almost automatisms, while at the same time "force" them to reflect on their individual learning process and interpreting performance. This provides a solid base on which trained interpreters can progress and develop their skills also after joining the professional sphere.

  4. Distinct structural and redox properties of the heme active site in bacterial dye decolorizing peroxidase-type peroxidases from two subfamilies: resonance Raman and electrochemical study.

    Science.gov (United States)

    Sezer, Murat; Santos, Ana; Kielb, Patrycja; Pinto, Tiago; Martins, Ligia O; Todorovic, Smilja

    2013-05-07

    Spectroscopic data of dye decolorizing peroxidases (DyPs) from Bacillus subtilis (BsDyP), an A subfamily member, and Pseudomonas putida (PpDyP), a B subfamily enzyme, reveal distinct heme coordination patterns of the respective active sites. In solution, both enzymes show a heterogeneous spin population, with the six-coordinated low-spin state being the most populated in the former and the five-coordinated quantum mechanically mixed-spin state in the latter. We ascribe the poor catalytic activity of BsDyP to the presence of a catalytically incompetent six-coordinated low-spin population. The spin populations of the two DyPs are sensitively dependent on the pH, temperature, and physical, i.e., solution versus crystal versus immobilized, state of the enzymes. We observe a redox potential for the Fe(2+)/Fe(3+) couple in BsDyP (-40 mV) at pH 7.6 substantially more positive than those reported for the majority of other peroxidases, including PpDyP (-260 mV). Furthermore, we evaluate the potential of the studied enzymes for biotechnological applications on the basis of electrochemical and spectroelectrochemical data.

  5. Acquired portosystemic collaterals: anatomy and imaging

    Energy Technology Data Exchange (ETDEWEB)

    Leite, Andrea Farias de Melo; Mota Junior, Americo, E-mail: andreafariasm@gmail.com [Instituto de Medicina Integral Professor Fernando Figueira de Pernambuco (IMIP), Recife, PE (Brazil); Chagas-Neto, Francisco Abaete [Universidade de Fortaleza (UNIFOR), Fortaleza, CE (Brazil); Teixeira, Sara Reis; Elias Junior, Jorge; Muglia, Valdair Francisco [Universidade de Sao Paulo (FMRP/USP), Ribeirao Preto, SP (Brazil). Faculdade de Medicina

    2016-07-15

    Portosystemic shunts are enlarged vessels that form collateral pathological pathways between the splanchnic circulation and the systemic circulation. Although their causes are multifactorial, portosystemic shunts all have one mechanism in common - increased portal venous pressure, which diverts the blood flow from the gastrointestinal tract to the systemic circulation. Congenital and acquired collateral pathways have both been described in the literature. The aim of this pictorial essay was to discuss the distinct anatomic and imaging features of portosystemic shunts, as well as to provide a robust method of differentiating between acquired portosystemic shunts and similar pathologies, through the use of illustrations and schematic drawings. Imaging of portosystemic shunts provides subclinical markers of increased portal venous pressure. Therefore, radiologists play a crucial role in the identification of portosystemic shunts. Early detection of portosystemic shunts can allow ample time to perform endovascular shunt operations, which can relieve portal hypertension and prevent acute or chronic complications in at-risk patient populations. (author)

  6. Acquired portosystemic collaterals: anatomy and imaging*

    Science.gov (United States)

    Leite, Andréa Farias de Melo; Mota Jr., Américo; Chagas-Neto, Francisco Abaeté; Teixeira, Sara Reis; Elias Junior, Jorge; Muglia, Valdair Francisco

    2016-01-01

    Portosystemic shunts are enlarged vessels that form collateral pathological pathways between the splanchnic circulation and the systemic circulation. Although their causes are multifactorial, portosystemic shunts all have one mechanism in common-increased portal venous pressure, which diverts the blood flow from the gastrointestinal tract to the systemic circulation. Congenital and acquired collateral pathways have both been described in the literature. The aim of this pictorial essay was to discuss the distinct anatomic and imaging features of portosystemic shunts, as well as to provide a robust method of differentiating between acquired portosystemic shunts and similar pathologies, through the use of illustrations and schematic drawings. Imaging of portosystemic shunts provides subclinical markers of increased portal venous pressure. Therefore, radiologists play a crucial role in the identification of portosystemic shunts. Early detection of portosystemic shunts can allow ample time to perform endovascular shunt operations, which can relieve portal hypertension and prevent acute or chronic complications in at-risk patient populations. PMID:27777479

  7. cAMP response element binding protein (CREB activates transcription via two distinct genetic elements of the human glucose-6-phosphatase gene

    Directory of Open Access Journals (Sweden)

    Stefano Luisa

    2005-01-01

    Full Text Available Abstract Background The enzyme glucose-6-phosphatase catalyzes the dephosphorylation of glucose-6-phosphatase to glucose, the final step in the gluconeogenic and glycogenolytic pathways. Expression of the glucose-6-phosphatase gene is induced by glucocorticoids and elevated levels of intracellular cAMP. The effect of cAMP in regulating glucose-6-phosphatase gene transcription was corroborated by the identification of two genetic motifs CRE1 and CRE2 in the human and murine glucose-6-phosphatase gene promoter that resemble cAMP response elements (CRE. Results The cAMP response element is a point of convergence for many extracellular and intracellular signals, including cAMP, calcium, and neurotrophins. The major CRE binding protein CREB, a member of the basic region leucine zipper (bZIP family of transcription factors, requires phosphorylation to become a biologically active transcriptional activator. Since unphosphorylated CREB is transcriptionally silent simple overexpression studies cannot be performed to test the biological role of CRE-like sequences of the glucose-6-phosphatase gene. The use of a constitutively active CREB2/CREB fusion protein allowed us to uncouple the investigation of target genes of CREB from the variety of signaling pathways that lead to an activation of CREB. Here, we show that this constitutively active CREB2/CREB fusion protein strikingly enhanced reporter gene transcription mediated by either CRE1 or CRE2 derived from the glucose-6-phosphatase gene. Likewise, reporter gene transcription was enhanced following expression of the catalytic subunit of cAMP-dependent protein kinase (PKA in the nucleus of transfected cells. In contrast, activating transcription factor 2 (ATF2, known to compete with CREB for binding to the canonical CRE sequence 5'-TGACGTCA-3', did not transactivate reporter genes containing CRE1, CRE2, or both CREs derived from the glucose-6-phosphatase gene. Conclusions Using a constitutively active CREB2

  8. Acquired Dyslexia in Japanese: Implications for Reading Theory

    OpenAIRE

    Sato, H.

    2007-01-01

    Acquired dyslexia research has been conducted mainly on English neurological patients. A limited number of dyslexia studies on non-alphabetic orthographies are available. Classical case studies for acquired dyslexia in Japanese, which has two distinctive scripts (morphographic Kanji and phonographic Kana), reported 'script-dependent' dyslexia patterns. Although recent case studies showed 'script-independent' dyslexia patterns for surface and phonological dyslexia, a 'script-independent'...

  9. 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...

  10. Hypersexual, Sexually Compulsive, or Just Highly Sexually Active? Investigating Three Distinct Groups of Gay and Bisexual Men and Their Profiles of HIV-Related Sexual Risk

    Science.gov (United States)

    Rendina, H. Jonathon; Ventuneac, Ana; Moody, Raymond L.; Grov, Christian

    2015-01-01

    Emerging research supports the notion that sexual compulsivity (SC) and hypersexual disorder (HD) among gay and bisexual men (GBM) might be conceptualized as comprising three groups—Neither SC nor HD; SC only, and Both SC and HD—that capture distinct levels of severity across the SC/HD continuum. We examined data from 370 highly sexually active GBM to assess how the three groups compare across a range of risk factors for HIV infection. Comparisons focused on psychosexual measures—temptation for condomless anal sex (CAS), self-efficacy for avoiding CAS, sexual excitation and inhibition—as well as reports of actual sexual behavior. Nearly half (48.9 %) of this highly sexually active sample was classified as Neither SC nor HD, 30 % as SC Only, and 21.1 % as Both SC and HD. While we found no significant differences between the three groups on reported number of male partners, anal sex acts, or anal sex acts with serodiscordant partners, the Both SC and HD group reported higher numbers of CAS acts and CAS acts with serodiscordant partners and also had a higher proportion of their anal sex acts without condoms compared to the SC Only group. Our findings support the validity of a three-group classification system of SC/HD severity in differentiating psychosexual and HIV-related sexual risk behavior outcomes in a sample of GBM who report similarly high levels of sexual activity. Notwithstanding the need for sex positive HIV prevention programs, interventions that attempt to help Both SC and HD men deal with distress and address their psychosexual needs specifically may derive HIV prevention benefits. PMID:25750052

  11. Hypersexual, Sexually Compulsive, or Just Highly Sexually Active? Investigating Three Distinct Groups of Gay and Bisexual Men and Their Profiles of HIV-Related Sexual Risk.

    Science.gov (United States)

    Parsons, Jeffrey T; Rendina, H Jonathon; Ventuneac, Ana; Moody, Raymond L; Grov, Christian

    2016-02-01

    Emerging research supports the notion that sexual compulsivity (SC) and hypersexual disorder (HD) among gay and bisexual men (GBM) might be conceptualized as comprising three groups-Neither SC nor HD; SC only, and Both SC and HD-that capture distinct levels of severity across the SC/HD continuum. We examined data from 370 highly sexually active GBM to assess how the three groups compare across a range of risk factors for HIV infection. Comparisons focused on psychosexual measures-temptation for condomless anal sex (CAS), self-efficacy for avoiding CAS, sexual excitation and inhibition-as well as reports of actual sexual behavior. Nearly half (48.9 %) of this highly sexually active sample was classified as Neither SC nor HD, 30 % as SC Only, and 21.1 % as Both SC and HD. While we found no significant differences between the three groups on reported number of male partners, anal sex acts, or anal sex acts with serodiscordant partners, the Both SC and HD group reported higher numbers of CAS acts and CAS acts with serodiscordant partners and also had a higher proportion of their anal sex acts without condoms compared to the SC Only group. Our findings support the validity of a three-group classification system of SC/HD severity in differentiating psychosexual and HIV-related sexual risk behavior outcomes in a sample of GBM who report similarly high levels of sexual activity. Notwithstanding the need for sex positive HIV prevention programs, interventions that attempt to help Both SC and HD men deal with distress and address their psychosexual needs specifically may derive HIV prevention benefits.

  12. The in vitro anti-viral potential of Setarud (IMOD™, a commercial herbal medicine with protective activity against acquired immune deficiency syndrome in clinical trials

    Directory of Open Access Journals (Sweden)

    Rezvan Zabihollahi

    2012-01-01

    Conclusions: Data from this study indicate that IMOD has significant anti-viral activity against HIV, HSV and MLV. Setarud could be subjected to further investigation after isolation of the constituents and determination of the toxic components.

  13. Anthranoyl-CoA monooxygenase/reductase from Azoarcus evansii possesses both FMN and FAD in two distinct and independent active sites.

    Science.gov (United States)

    Bergner, Thomas; Pavkov-Keller, Tea; Kreuzer, Katharina; Kowaliuk, Jakob; Plank, Markus; Runggatscher, Kathrin; Turrini, Nikolaus G; Zucol, Benjamin; Wallner, Silvia; Faber, Kurt; Gruber, Karl; Macheroux, Peter

    2015-08-01

    Anthranoyl-CoA monooxygenase/reductase (ACMR) participates in an unusual pathway for the degradation of aromatic compounds in Azoarcus evansii. It catalyzes the monooxygenation of anthranoyl-CoA to 5-hydroxyl-2-aminobenzoyl-CoA and the subsequent reduction to the dearomatized product 2-amino-5-oxo-cyclohex-1-ene-1-carbonyl-CoA. The two reactions occur in separate domains, termed the monooxygenase and reductase domain. Both domains were reported to utilize FAD as a cofactor for hydroxylation and reduction, respectively. We have heterologously expressed ACMR in Escherichia coli BL21 and found that the monooxygenase domain contains FAD. However, the reductase domain utilizes FMN and not FAD for the reduction of the intermediate 5-hydroxyl-2-aminobenzoyl-CoA. A homology model for the reductase domain predicted a topology similar to the Old Yellow Enzyme family, which exclusively bind FMN, in accordance with our results. Binding studies with 2-aminobenzoyl-CoA (AbCoA) and p-hydroxybenzaldehyde (pHB) as probes for the monooxygenase and reductase domain, respectively, indicated that two functionally distinct and independent active sites exist. Given the homodimeric quartenary structure of ACMR and the compact shape of the dimer as determined by small-angle X-ray scattering experiments we propose that the monooxygenase and reductase domain of opposite peptide chains are involved in the transformation of anthranoyl-CoA to 2-amino-5-oxo-cyclohex-1-ene-1-carbonyl-CoA.

  14. Urokinase-type plasminogen activator deficiency has little effect on seizure susceptibility and acquired epilepsy phenotype but reduces spontaneous exploration in mice.

    Science.gov (United States)

    Rantala, J; Kemppainen, S; Ndode-Ekane, X E; Lahtinen, L; Bolkvadze, Tamuna; Gurevicius, K; Tanila, H; Pitkänen, A

    2015-01-01

    Urokinase-type plasminogen activator (uPA), a serine protease, converts plasminogen to plasmin. Activation of plasmin leads to degradation of the extracellular matrix, which is critical for tissue recovery, angiogenesis, cell migration, and axonal and synaptic plasticity. We hypothesized that uPA deficiency would cause an abnormal neurophenotype and would lead to exacerbated epileptogenesis after brain injury. Wild-type (Wt) and uPA-/- mice underwent a battery of neurologic behavioral tests evaluating general reactivity, spontaneous exploratory activity, motor coordination, pain threshold, fear and anxiety, and memory. We placed particular emphasis on the effect of uPA deficiency on seizure susceptibility, including the response to convulsants (pentylenetetrazol, kainate, or pilocarpine) and kainate-induced epileptogenesis and epilepsy. The uPA-/- mice showed no motor or sensory impairment compared with the Wt mice. Hippocampus-dependent spatial memory also remained intact. The uPA-/- mice, however, exhibited reduced exploratory activity and an enhanced response to a tone stimulus (p<0.05 compared with the Wt mice). The urokinase-type plasminogen activator deficient mice showed no increase in spontaneous or evoked epileptiform electrographic activity. Rather, the response to pilocarpine administration was reduced compared with the Wt mice (p<0.05). Also, the epileptogenesis and the epilepsy phenotype after intrahippocampal kainate injection were similar to those in the Wt mice. Taken together, uPA deficiency led to diminished interest in the environmental surroundings and enhanced emotional reactivity to unexpected aversive stimuli. Urokinase-type plasminogen activator deficiency was not associated with enhanced seizure susceptibility or worsened poststatus epilepticus epilepsy phenotype.

  15. Distinct synaptic properties of perisomatic inhibitory cell types and their different modulation by cholinergic receptor activation in the CA3 region of the mouse hippocampus.

    Science.gov (United States)

    Szabó, Gergely G; Holderith, Noémi; Gulyás, Attila I; Freund, Tamás F; Hájos, Norbert

    2010-06-01

    Perisomatic inhibition originates from three types of GABAergic interneurons in cortical structures, including parvalbumin-containing fast-spiking basket cells (FSBCs) and axo-axonic cells (AACs), as well as cholecystokinin-expressing regular-spiking basket cells (RSBCs). These interneurons may have significant impact in various cognitive processes, and are subjects of cholinergic modulation. However, it is largely unknown how cholinergic receptor activation modulates the function of perisomatic inhibitory cells. Therefore, we performed paired recordings from anatomically identified perisomatic interneurons and pyramidal cells in the CA3 region of the mouse hippocampus. We determined the basic properties of unitary inhibitory postsynaptic currents (uIPSCs) and found that they differed among cell types, e.g. GABA released from axon endings of AACs evoked uIPSCs with the largest amplitude and with the longest decay measured at room temperature. RSBCs could also release GABA asynchronously, the magnitude of the release increasing with the discharge frequency of the presynaptic interneuron. Cholinergic receptor activation by carbachol significantly decreased the uIPSC amplitude in all three types of cell pairs, but to different extents. M2-type muscarinic receptors were responsible for the reduction in uIPSC amplitudes in FSBC- and AAC-pyramidal cell pairs, while an antagonist of CB(1) cannabinoid receptors recovered the suppression in RSBC-pyramidal cell pairs. In addition, carbachol suppressed or even eliminated the short-term depression of uIPSCs in FSBC- and AAC-pyramidal cell pairs in a frequency-dependent manner. These findings suggest that not only are the basic synaptic properties of perisomatic inhibitory cells distinct, but acetylcholine can differentially control the impact of perisomatic inhibition from different sources.

  16. Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant

    DEFF Research Database (Denmark)

    Frogne, Thomas; Benjaminsen, Rikke V; Sonne-Hansen, Katrine

    2008-01-01

    activation was observed only in the parental MCF-7 cells. The downstream kinases pAkt and pErk were increased in five of seven and in all seven resistant cell lines, respectively. Treatment with the EGFR inhibitor gefitinib preferentially inhibited growth and reduced the S phase fraction in the resistant...

  17. Maternally acquired runt disease.

    Science.gov (United States)

    Beer, A E; Billingham, R E

    1973-01-19

    Without altering the structural integrity of the placenta by irradiation or drugs, we have shown that it is possible to immunize females both adoptively and actively against the paternally inherited transplantation antigens of their fetuses. Such immunization causes a high incidence of runt disease among the litters. Although the putative chimeric status of the affected offspring has yet to be confirmed, the results of our experiments support the thesis that runt disease is caused by the activities of "unwanted" immigrant lymphocytes from the maternal circulation. Our results suggest that immunologically activated cells are more likely to cross the placenta than normal cells and that this greater mobility may not be related to the immunologic specificity of the activated cells. Two factors may have contributed to the apparent failure of numerous previous attempts to demonstrate the capacity of transplantation immunity to affect the well-being of a fetus or, more correctly, its placenta, in the way that might be expected of a homograft. (i) Investigators were preoccupied with obtaining a classic type of rejection, in utero, analogous to the rejection of an orthotopic skin homograft. The birth of consistently healthy-looking litters, interpreted as a failure of the experiment, convinced the investigators of the efficacy of nature's solution of the homograft problem and there was no reason for them to suspect its possible limitations. Observation of the litters for several weeks might have uncovered the phenomenon of maternally induced runt disease. (ii) Most investigators resorted to hyperimmunization of the mothers. This would have facilitated the synthesis of protective isoantibodies capable of interfering with the expression of the potentially harmful cellular immune response (6). Ever since the abnormalities of runt disease were first described they have repeatedly been compared to those observed in patients with certain lymphomas (17). Various theories have been

  18. Recommendations for the management of individuals with acquired valvular heart diseases who are involved in leisure-time physical activities or competitive sports.

    Science.gov (United States)

    Mellwig, Klaus Peter; van Buuren, Frank; Gohlke-Baerwolf, Christa; Bjørnstad, Hans Halvor

    2008-02-01

    Physical check-ups among athletes with valvular heart disease are of significant relevance. In athletes with mitral valve stenosis the extent of allowed physical activity is dependant on the size of the left atrium and the severity of the valve defect. Patients with mild-to-moderate mitral valve regurgitation can participate in all types of sport associated with low and moderate isometric stress and moderate dynamic stress. Patients under anticoagulation should not participate in any type of contact sport. Asymptomatic athletes with mild aortic valve stenosis can take part in all types of sport, as long as left ventricular function and size are normal, a normal response to exercise at the level performed during athletic activities is present and there are no arrhythmias. Asymptomatic athletes with moderate aortic valve stenosis should only take part in sports with low dynamic and static stress. Aortic valve regurgitation is often present due to connective tissue disease of a bicuspid valve. Athletes with mild aortic valve regurgitation, with normal end diastolic left ventricular size and systolic function can participate in all types of sport. A mitral valve prolapse is often associated with structural diseases of the myocardium and endocardium. In patients with mitral valve prolapse Holter-ECG monitoring should also be performed to detect significant arrhythmias. All athletes with known valvular heart disease, a previous history of infective endocarditis and valve surgery should receive endocarditis prophylaxis before dental, oral, respiratory, intestinal and genitourinary procedures associated with bacteraemia. Sport activities have to be avoided during active infection with fever.

  19. Optimizing the function of upstanding activities in adult patients with acquired lesions of the central nervous system by using the Bobath concept approach - A case report.

    Science.gov (United States)

    Jelica, Stjepan; Seper, Vesna; Davidović, Erna; Bujisić, Gordana

    2011-01-01

    Nonspecific medical gymnastic therapy may help patients after stroke achieve certain results in terms of efficiency but not in terms of quality of movement. The goal of treatment by Bobath concept is development of movement (effectiveness) and optimization of movement (efficiency). This article presents the case of a 62-year old patient who had experienced a stroke and has difficulties with standing up activities. It underscores the importance of not only recovery of function but also optimization of the function in such patients.

  20. Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1

    Directory of Open Access Journals (Sweden)

    Valentina Pirazzoli

    2014-05-01

    Full Text Available Patients with EGFR-mutant lung adenocarcinomas (LUADs who initially respond to first-generation tyrosine kinase inhibitors (TKIs develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.

  1. Highly Efficient F, Cu doped TiO2 anti-bacterial visible light active photocatalytic coatings to combat hospital-acquired infections

    Science.gov (United States)

    Leyland, Nigel S.; Podporska-Carroll, Joanna; Browne, John; Hinder, Steven J.; Quilty, Brid; Pillai, Suresh C.

    2016-04-01

    Bacterial infections are a major threat to the health of patients in healthcare facilities including hospitals. One of the major causes of patient morbidity is infection with Staphylococcus aureus. One of the the most dominant nosocomial bacteria, Methicillin Resistant Staphylococcus aureus (MRSA) have been reported to survive on hospital surfaces (e.g. privacy window glasses) for up to 5 months. None of the current anti-bacterial technology is efficient in eliminating Staphylococcus aureus. A novel transparent, immobilised and superhydrophilic coating of titanium dioxide, co-doped with fluorine and copper has been prepared on float glass substrates. Antibacterial activity has demonstrated (by using Staphylococcus aureus), resulting from a combination of visible light activated (VLA) photocatalysis and copper ion toxicity. Co-doping with copper and fluorine has been shown to improve the performance of the coating, relative to a purely fluorine-doped VLA photocatalyst. Reductions in bacterial population of log10 = 4.2 under visible light irradiation and log10 = 1.8 in darkness have been achieved, compared with log10 = 1.8 under visible light irradiation and no activity, for a purely fluorine-doped titania. Generation of reactive oxygen species from the photocatalytic coatings is the major factor that significantly reduces the bacterial growth on the glass surfaces.

  2. Up-regulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of fsp27 deficient mice.

    Directory of Open Access Journals (Sweden)

    Shen Yon Toh

    Full Text Available Fsp27, a member of the Cide family proteins, was shown to localize to lipid droplet and promote lipid storage in adipocytes. We aimed to understand the biological role of Fsp27 in regulating adipose tissue differentiation, insulin sensitivity and energy balance. Fsp27(-/- mice and Fsp27/lep double deficient mice were generated and we examined the adiposity, whole body metabolism, BAT and WAT morphology, insulin sensitivity, mitochondrial activity, and gene expression changes in these mouse strains. Furthermore, we isolated mouse embryonic fibroblasts (MEFs from wildtype and Fsp27(-/- mice, followed by their differentiation into adipocytes in vitro. We found that Fsp27 is expressed in both brown adipose tissue (BAT and white adipose tissue (WAT and its levels were significantly elevated in the WAT and liver of leptin-deficient ob/ob mice. Fsp27(-/- mice had increased energy expenditure, lower levels of plasma triglycerides and free fatty acids. Furthermore, Fsp27(-/-and Fsp27/lep double-deficient mice are resistant to diet-induced obesity and display increased insulin sensitivity. Moreover, white adipocytes in Fsp27(-/- mice have reduced triglycerides accumulation and smaller lipid droplets, while levels of mitochondrial proteins, mitochondrial size and activity are dramatically increased. We further demonstrated that BAT-specific genes and key metabolic controlling factors such as FoxC2, PPAR and PGC1alpha were all markedly upregulated. In contrast, factors inhibiting BAT differentiation such as Rb, p107 and RIP140 were down-regulated in the WAT of Fsp27(-/- mice. Remarkably, Fsp27(-/- MEFs differentiated in vitro show many brown adipocyte characteristics in the presence of the thyroid hormone triiodothyronine (T3. Our data thus suggest that Fsp27 acts as a novel regulator in vivo to control WAT identity, mitochondrial activity and insulin sensitivity.

  3. The OsCYP19-4 Gene Is Expressed as Multiple Alternatively Spliced Transcripts Encoding Isoforms with Distinct Cellular Localizations and PPIase Activities under Cold Stress

    Directory of Open Access Journals (Sweden)

    Areum Lee

    2016-07-01

    Full Text Available Alternative splicing (AS is an important molecular mechanism by which single genes can generate multiple mRNA isoforms. We reported previously that, in Oryza sativa, the cyclophilin 19-4 (OsCYP19-4.1 transcript was significantly upregulated in response to cold stress, and that transgenic plants were cold tolerant. Here we show that, under cold stress, OsCYP19-4 produces eight transcript variants by intron retention and exon skipping, resulting in production of four distinct protein isoforms. The OsCYP19-4 AS isoforms exhibited different cellular localizations in the epidermal cells: in contrast to OsCYP19-4.1, the OsCYP19-4.2 and OsCYP19-4.3 proteins were primarily targeted to guard and subsidiary cells, whereas OsCYP19-4.5, which consists largely of an endoplasmic reticulum (ER targeting signal, was co-localized with the RFP-BiP marker in the ER. In OsCYP19-4.2, the key residues of the PPIase domain are altered; consistent with this, recombinant OsCYP19-4.2 had significantly lower PPIase activity than OsCYP19-4.1 in vitro. Specific protein-protein interactions between OsCYP19-4.2/3 and AtRCN1 were verified in yeast two-hybrid (Y2H and bimolecular fluoresence complementation (BiFC assays, although the OsCYP19-4 isoforms could not bind each other. Based on these results, we propose that two OsCYP19-4 AS isoforms, OsCYP19-4.2 and OsCYP19-4.3, play roles linking auxin transport and cold stress via interactions with RCN1.

  4. Ikaros isoforms in human pituitary tumors: distinct localization, histone acetylation, and activation of the 5' fibroblast growth factor receptor-4 promoter.

    Science.gov (United States)

    Ezzat, Shereen; Yu, Shunjiang; Asa, Sylvia L

    2003-09-01

    Targeted expression of a human pituitary tumor derived-fibroblast growth factor receptor-4 (FGFR4) recapitulates pituitary tumorigenesis. We have shown that FGFR4 is a target for Ikaros, a zinc finger-containing transcription factor that localizes to heterochromatin regions and participates in higher order chromatin complexes and control of gene expression. We report here the expression of Ikaros and functional differences between its alternatively spliced variants in human pituitary tumors. Ik1 expression was detected in human pituitary tumors and we also identified a truncated isoform consistent with the non-DNA-binding Ik6 isoform in a subset of adenomas by reverse transcriptase-polymerase chain reaction, sequencing, and Western immunoblotting. Transfection of Ik6 in GH4 pituitary cells resulted in predominantly cytoplasmic expression as compared to Ik1, which resulted in exclusively nuclear expression as determined by immunofluorescence and immunoblotting of fractionated protein. Immunohistochemistry of primary human pituitary adenomas localized Ikaros expression to the nuclear compartment but also in the cytoplasm, the latter consistent with Ik6. Expression of Ikaros and truncated non-DNA-binding isoforms was also suggested by electromobility shift assays using nuclear proteins from primary human pituitary adenomas. Ik6 resulted in reversal of the effects of Ik1 on wild-type 5' FGFR4 promoter activity, histone acetylation, and regulation of the endogenous gene. We conclude that dominant-negative Ik6 isoforms with their distinct localization and effects on Ik1 action may contribute to the altered expression of FGFR4 and possibly other target genes in human pituitary tumors.

  5. Small and intermediate conductance Ca(2+)-activated K+ channels confer distinctive patterns of distribution in human tissues and differential cellular localisation in the colon and corpus cavernosum.

    Science.gov (United States)

    Chen, Mao Xiang; Gorman, Shelby A; Benson, Bill; Singh, Kuljit; Hieble, J Paul; Michel, Martin C; Tate, Simon N; Trezise, Derek J

    2004-06-01

    The SK/IK family of small and intermediate conductance calcium-activated potassium channels contains four members, SK1, SK2, SK3 and IK1, and is important for the regulation of a variety of neuronal and non-neuronal functions. In this study we have analysed the distribution of these channels in human tissues and their cellular localisation in samples of colon and corpus cavernosum. SK1 mRNA was detected almost exclusively in neuronal tissues. SK2 mRNA distribution was restricted but more widespread than SK1, and was detected in adrenal gland, brain, prostate, bladder, liver and heart. SK3 mRNA was detected in almost every tissue examined. It was highly expressed in brain and in smooth muscle-rich tissues including the clitoris and the corpus cavernosum, and expression in the corpus cavernosum was upregulated up to 5-fold in patients undergoing sex-change operations. IK1 mRNA was present in surface-rich, secretory and inflammatory cell-rich tissues, highest in the trachea, prostate, placenta and salivary glands. In detailed immunohistochemical studies of the colon and the corpus cavernosum, SK1-like immunoreactivity was observed in the enteric neurons. SK3-like immunoreactivity was observed strongly in smooth muscle and vascular endothelium. IK1-like immunoreactivity was mainly observed in inflammatory cells and enteric neurons of the colon, but absent in corpus cavernosum. These distinctive patterns of distribution suggest that these channels are likely to have different biological functions and could be specifically targeted for a number of human diseases, such as irritable bowel syndrome, hypertension and erectile dysfunction.

  6. Evolution of Enzymatic Activities in the Enolase Superfamily: Stereochemically Distinct Mechanisms in Two Families of cis,cis-Muconate Lactonizing Enzymes

    Energy Technology Data Exchange (ETDEWEB)

    Sakai, A.; Fedorov, A; Fedorov, E; Schnoes, A; Glasner, M; Burley, S; Babbitt, P; Almo, S; Gerlt, J

    2009-01-01

    The mechanistically diverse enolase superfamily is a paradigm for elucidating Nature's strategies for divergent evolution of enzyme function. Each of the different reactions catalyzed by members of the superfamily is initiated by abstraction of the a-proton of a carboxylate substrate that is coordinated to an essential Mg2+. The muconate lactonizing enzyme (MLE) from Pseudomonas putida, a member of a family that catalyzes the syn-cycloisomerization of cis,cis-muconate to (4S)-muconolactone in the e-ketoadipate pathway, has provided critical insights into the structural bases for evolution of function within the superfamily. A second, divergent family of homologous MLEs that catalyzes anti-cycloisomerization has been identified. Structures of members of both families liganded with the common (4S)-muconolactone product (syn, Pseudomonas fluorescens, gi 70731221; anti, Mycobacterium smegmatis, gi 118470554) document that the conserved Lys at the end of the second e-strand in the (e/a)7e-barrel domain serves as the acid catalyst in both reactions. The different stereochemical courses (syn and anti) result from different structural strategies for determining substrate specificity: although the distal carboxylate group of the cis,cis-muconate substrate attacks the same face of the proximal double bond, opposite faces of the resulting enolate anion intermediate are presented to the conserved Lys acid catalyst. The discovery of two families of homologous, but stereochemically distinct, MLEs likely provides an example of 'pseudoconvergent' evolution of the same function from different homologous progenitors within the enolase superfamily, in which different spatial arrangements of active site functional groups and substrate specificity determinants support catalysis of the same reaction.

  7. Learning to Acquire

    DEFF Research Database (Denmark)

    Henningsson, Stefan

    2015-01-01

    This paper develops a knowledge-based model of information systems (IS) integration in acquisition-based growth programs. Previous research has found important differences in the acquirers’ abilities for acquisition IS integration, and that these differences play key roles in explaining the econo......This paper develops a knowledge-based model of information systems (IS) integration in acquisition-based growth programs. Previous research has found important differences in the acquirers’ abilities for acquisition IS integration, and that these differences play key roles in explaining...... Trelleborg. The analyses yield five propositions that explain the building of knowledge for acquisition IS integration by the mechanisms of routine refinement, superstitious learning, expertise building, sub-activity refinement and related expertise building. Together, the five propositions form a knowledge...

  8. A constant threat for HIV: Fc-engineering to enhance broadly neutralizing antibody activity for immunotherapy of the acquired immunodeficiency syndrome.

    Science.gov (United States)

    Nimmerjahn, Falk

    2015-08-01

    Passive immunotherapy with polyclonal or hyperimmune serum immunoglobulin G (IgG) preparations provides an efficient means of protecting immunocompromised patients from microbial infections. More recently, the use of passive immunotherapy to prevent or to treat established infections with the human immunodeficiency virus (HIV) has gained much attention, due to promising preclinical data obtained in monkey and humanized mouse in vivo model systems, demonstrating that the transfer of HIV-specific antibodies can not only prevent HIV infection, but also diminish virus load during chronic infection. Furthermore, an array of broadly neutralizing HIV-specific antibodies has become available and the importance of the IgG constant region as a critical modulator of broadly neutralizing activity has been demonstrated. The aim of this review is to summarize the most recent findings with regard to the molecular and cellular mechanisms responsible for antibody-mediated clearance of HIV infection, and to discuss how this may help to improve HIV therapy via optimizing Fcγ-receptor-dependent activities of HIV-specific antibodies.

  9. Peroxisomes in Different Skeletal Cell Types during Intramembranous and Endochondral Ossification and Their Regulation during Osteoblast Differentiation by Distinct Peroxisome Proliferator-Activated Receptors.

    Directory of Open Access Journals (Sweden)

    Guofeng Qian

    Full Text Available Ossification defects leading to craniofacial dysmorphism or rhizomelia are typical phenotypes in patients and corresponding knockout mouse models with distinct peroxisomal disorders. Despite these obvious skeletal pathologies, to date no careful analysis exists on the distribution and function of peroxisomes in skeletal tissues and their alterations during ossification. Therefore, we analyzed the peroxisomal compartment in different cell types of mouse cartilage and bone as well as in primary cultures of calvarial osteoblasts. The peroxisome number and metabolism strongly increased in chondrocytes during endochondral ossification from the reserve to the hypertrophic zone, whereas in bone, metabolically active osteoblasts contained a higher numerical abundance of this organelle than osteocytes. The high abundance of peroxisomes in these skeletal cell types is reflected by high levels of Pex11β gene expression. During culture, calvarial pre-osteoblasts differentiated into secretory osteoblasts accompanied by peroxisome proliferation and increased levels of peroxisomal genes and proteins. Since many peroxisomal genes contain a PPAR-responsive element, we analyzed the gene expression of PPARɑ/ß/ɣ in calvarial osteoblasts and MC3T3-E1 cells, revealing higher levels for PPARß than for PPARɑ and PPARɣ. Treatment with different PPAR agonists and antagonists not only changed the peroxisomal compartment and associated gene expression, but also induced complex alterations of the gene expression patterns of the other PPAR family members. Studies in M3CT3-E1 cells showed that the PPARß agonist GW0742 activated the PPRE-mediated luciferase expression and up-regulated peroxisomal gene transcription (Pex11, Pex13, Pex14, Acox1 and Cat, whereas the PPARß antagonist GSK0660 led to repression of the PPRE and a decrease of the corresponding mRNA levels. In the same way, treatment of calvarial osteoblasts with GW0742 increased in peroxisome number and

  10. Computational visual distinctness metric

    NARCIS (Netherlands)

    Martínez-Baena, J.; Toet, A.; Fdez-Vidal, X.R.; Garrido, A.; Rodríguez-Sánchez, R.

    1998-01-01

    A new computational visual distinctness metric based on principles of the early human visual system is presented. The metric is applied to quantify (1) the visual distinctness of targets in complex natural scenes and (2) the perceptual differences between compressed and uncompressed images. The new

  11. Acquired ichthyosis with hoffman's syndrome

    Directory of Open Access Journals (Sweden)

    Sathyanarayana B

    2003-01-01

    Full Text Available A middle aged man presented with features of acquired ichthyosis with Hoffman's syndrome. Laboratory tests support hypothyodism. Myoedema and hypertrophy of muscles were present. Patient was previously treated for Pellagra.

  12. Primary parotid B-cell lymphoma successfully treated with chemotherapy plus highly active antiretroviral therapy with prolonged survival and immune reconstitution in an acquired immunodeficiency syndrome patient: Case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Marcelo Corti

    2014-01-01

    Full Text Available Non-Hodgkin′s lymphoma (NHL is the second most common acquired immunodeficiency syndrome (AIDS-defining cancer. In this population, up to 70-80% of cases may present as extranodal location as the primary clinical manifestation of the neoplasm disease. Gastrointestinal tract is the most frequent location of AIDS-associated NHL. However, salivary gland involvement, including the parotid gland is a rare complication in human immunodeficiency virus (HIV-patients. Here, we describe a patient seropositive for the HIV, who developed a primary NHL of the parotid gland histologically classified as a high-grade diffuse large B-cell lymphoma. Patient was treated with a combination of chemotherapy plus highly active antiretroviral therapy with a good clinical, virological and immunological response and a prolonged survival, more than 5 years, without evidence of neoplasm relapse.

  13. Immature myeloid Gr-1+ CD11b+ cells from lipopolysaccharide-immunosuppressed mice acquire inhibitory activity in the bone marrow and migrate to lymph nodes to exert their suppressive function.

    Science.gov (United States)

    Landoni, Veronica I; Martire-Greco, Daiana; Rodriguez-Rodrigues, Nahuel; Chiarella, Paula; Schierloh, Pablo; Isturiz, Martin A; Fernández, Gabriela C

    2016-02-01

    Secondary infections due to post-sepsis immunosuppression are a major cause of death in patients with sepsis. Repetitive inoculation of increasing doses of lipopolysaccharide (LPS) into mice mimics the immunosuppression associated with sepsis. Myeloid-derived suppressor cells (MDSCs, Gr-1(+) CD11b(+)) are considered a major component of the immunosuppressive network, interfering with T-cell responses in many pathological conditions. We used LPS-immunosuppressed (IS) mice to address whether MDSCs acquired their suppressive ability in the bone marrow (BM) and whether they could migrate to lymph nodes (LNs) to exert their suppressive function. Our results showed that Gr-1(+) CD11b(+) cells of IS mice already had the potential to inhibit T-cell proliferation in the BM. Moreover, soluble factors present in the BM from IS mice were responsible for inducing this inhibitory ability in control BM cells. In addition, migration of Gr-1(+) CD11b(+) to LNs in vivo was maximal when cells obtained from the BM of IS mice were inoculated into an IS context. In this regard, we found chemoattractant activity in cell-free LN extracts (LNEs) from IS mice and an increased expression of the LN-homing chemokine receptor C-C chemokine receptor type 7 (CCR7) in IS BM Gr-1(+) CD11b(+) cells. These results indicate that Gr-1(+) CD11b(+) cells found in BM from IS mice acquire their suppressive activity in the same niche where they are generated, and migrate to LNs to exert their inhibitory role. A better understanding of MDSC generation and/or regulation of factors able to induce their inhibitory function may provide new and more effective tools for the treatment of sepsis-associated immunosuppression.

  14. 33 CFR 211.2 - Authority to acquire real estate.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Authority to acquire real estate..., DEPARTMENT OF DEFENSE REAL ESTATE ACTIVITIES OF THE CORPS OF ENGINEERS IN CONNECTION WITH CIVIL WORKS PROJECTS Real Estate; General § 211.2 Authority to acquire real estate. (a) Congressional...

  15. Earth Knowledge Acquired by Middle School Students

    Science.gov (United States)

    Ride, Sally

    2008-01-01

    Earth Knowledge Acquired by Middle School Students (EarthKAM), an education activity, allows middle school students to program a digital camera on board the International Space Station to photograph a variety of geographical targets for study in the classroom. Photos are made available on the web for viewing and study by participating schools around the world. Educators use the images for projects involving Earth Science, geography, physics, and social science.

  16. Somatically acquired structural genetic differences

    DEFF Research Database (Denmark)

    Magaard Koldby, Kristina; Nygaard, Marianne; Christensen, Kaare;

    2016-01-01

    Structural genetic variants like copy number variants (CNVs) comprise a large part of human genetic variation and may be inherited as well as somatically acquired. Recent studies have reported the presence of somatically acquired structural variants in the human genome and it has been suggested t...... with age.European Journal of Human Genetics advance online publication, 20 April 2016; doi:10.1038/ejhg.2016.34.......Structural genetic variants like copy number variants (CNVs) comprise a large part of human genetic variation and may be inherited as well as somatically acquired. Recent studies have reported the presence of somatically acquired structural variants in the human genome and it has been suggested...... that they may accumulate in elderly individuals. To further explore the presence and the age-related acquisition of somatic structural variants in the human genome, we investigated CNVs acquired over a period of 10 years in 86 elderly Danish twins as well as CNV discordances between co-twins of 18 monozygotic...

  17. Acquired resistance to dasatinib in lung cancer cell lines conferred by DDR2 gatekeeper mutation and NF1 loss.

    Science.gov (United States)

    Beauchamp, Ellen M; Woods, Brittany A; Dulak, Austin M; Tan, Li; Xu, Chunxiao; Gray, Nathanael S; Bass, Adam J; Wong, Kwok-kin; Meyerson, Matthew; Hammerman, Peter S

    2014-02-01

    The treatment of non-small cell lung cancer has evolved dramatically over the past decade with the adoption of widespread use of effective targeted therapies in patients with distinct molecular alterations. In lung squamous cell carcinoma (lung SqCC), recent studies have suggested that DDR2 mutations are a biomarker for therapeutic response to dasatinib and clinical trials are underway testing this hypothesis. Although targeted therapeutics are typically quite effective as initial therapy for patients with lung cancer, nearly all patients develop resistance with long-term exposure to targeted drugs. Here, we use DDR2-dependent lung cancer cell lines to model acquired resistance to dasatinib therapy. We perform targeted exome sequencing to identify two distinct mechanisms of acquired resistance: acquisition of the T654I gatekeeper mutation in DDR2 and loss of NF1. We show that NF1 loss activates a bypass pathway, which confers ERK dependency downstream of RAS activation. These results indicate that acquired resistance to dasatinib can occur via both second-site mutations in DDR2 and by activation of bypass pathways. These data may help to anticipate mechanisms of resistance that may be identified in upcoming clinical trials of anti-DDR2 therapy in lung cancer and suggest strategies to overcome resistance.

  18. Benefits and costs of clearer distinction between networks and sales activities; Nytte og kostnader ved klarere skille mellom nett- og omsetningsvirksomhet

    Energy Technology Data Exchange (ETDEWEB)

    2008-12-15

    There will be substantial socio-economic cost connected to an introduction to a stronger distinction between the grid company and power provider in the vertically integrated companies or companies in the same group, provided information from a variety of network companies and suppliers. Full separation will result in additional costs to society in the order of 300 to 500 million kroner per year. The rewards for society can be expected to be modest, a maximum of two million per year. It may therefore be useful to consider other measures that can help to increase companies 'net neutrality, such as measures that restrict net companies' direct contact with end customers, clearer distinction between the operator and electricity supplier in the communication that takes place and strengthen NVE regulator's role. (AG)

  19. Clinicopathological correlation of acquired hyperpigmentary disorders

    Directory of Open Access Journals (Sweden)

    Anisha B Patel

    2013-01-01

    Full Text Available Acquired pigmentary disorders are group of heterogenous entities that share single, most significant, clinical feature, that is, dyspigmentation. Asians and Indians, in particular, are mostly affected. Although the classic morphologies and common treatment options of these conditions have been reviewed in the global dermatology literature, the value of histpathological evaluation has not been thoroughly explored. The importance of accurate diagnosis is emphasized here as the underlying diseases have varying etiologies that need to be addressed in order to effectively treat the dyspigmentation. In this review, we describe and discuss the utility of histology in the diagnostic work of hyperpigmentary disorders, and how, in many cases, it can lead to targeted and more effective therapy. We focus on the most common acquired pigmentary disorders seen in Indian patients as well as a few uncommon diseases with distinctive histological traits. Facial melanoses, including mimickers of melasma, are thoroughly explored. These diseases include lichen planus pigmentosus, discoid lupus erythematosus, drug-induced melanoses, hyperpigmentation due to exogenous substances, acanthosis nigricans, and macular amyloidosis.

  20. Multiparametric flow cytometry for identification and fluorescence activated cell sorting of five distinct B-cell subpopulations in normal tonsil tissue.

    Science.gov (United States)

    Kjeldsen, Malene Krag; Perez-Andres, Martin; Schmitz, Alexander; Johansen, Preben; Boegsted, Martin; Nyegaard, Mette; Gaihede, Michael; Bukh, Anne; Johnsen, Hans E; Orfao, Alberto; Dybkaer, Karen

    2011-12-01

    The purpose of this study was to establish a procedure capable of isolating distinct B-cell subpopulations from human tonsils as a basis for subsequent molecular analyses. Overall, 5 distinct B-cell subpopulations were purified from fresh tonsils based on their fluorescence surface marker expression: naive B cells, centroblasts, centrocytes, memory B cells, and plasmablasts. The immunophenotypic identity of the subpopulations was verified by quantitative real-time reverse transcriptase-polymerase chain reaction using the proliferation marker MKI-67 and 6 B-cell-associated differentiation markers (BACH2, BCL6, PAX5, IRF4, PRDM1, and XBP1). Furthermore, within the centroblast compartment, large and small centroblasts could be distinguished and large centroblasts were shown to proliferate with a morphologic appearance of a "centroblast"-like cell but with lower gene expression of the germinal center markers BCL6 and BACH2 vs small centroblasts. This study has established a detailed and fast procedure for simultaneous sorting of up to 5 distinct maturation-associated B-cell subpopulations from human tonsils.

  1. Acquired Factor VIII Inhibitors: Three Cases

    Directory of Open Access Journals (Sweden)

    Tay Za Kyaw

    2013-03-01

    Full Text Available Acquired hemophilia A is a rare, but devastating bleeding disorder caused by spontaneous development of autoantibodies directed against coagulation factor VIII. In 40%-50% of patients it is associated with such conditions as the postpartum period, malignancy, use of medications, and autoimmune diseases; however, its cause is unknown in most cases. Acquired hemophilia A should be suspected in patients that present with a coagulation abnormality, and a negative personal and family history of bleeding. Herein we report 3 patients with acquired hemophilia A that had different underlying pathologies, clinical presentations, and therapeutic responses. Factor VIII inhibitor formation in case 1 occurred 6 months after giving birth; underlying disorders were not identified in cases 2 or 3. The bleeding phenotype in these patients’ ranged from no bleeding tendency with isolated prolongation of APTT (activated partial thromboplastin time to severe intramuscular hematoma and hemarthrosis necessitating recombinant activated factor VII infusion and blood components transfusion. Variable responses to immunosuppressive treatment were also observed.

  2. Substance, Reality, and Distinctness

    Directory of Open Access Journals (Sweden)

    Boris Hennig

    2008-04-01

    Full Text Available Descartes claims that God is a substance, and that mind and body are two different and separable substances. This paper provides some background that renders these claims intelligible. For Descartes, that something is real means it can exist in separation, and something is a substance if it does not depend on other substances for its existence. Further, separable objects are correlates of distinct ideas, for an idea is distinct (in an objective sense if its object may be easily and clearly separated from everything that is not its object. It follows that if our idea of God is our most distinct idea, as Descartes claims, then God must be a substance in the Cartesian sense of the term. Also, if we can have an idea of a thinking subject which does not in any sense refer to bodily things, and if bodily things are substances, then mind and body must be two different substances.

  3. In vitro activities of tedizolid compared with other antibiotics against Gram-positive pathogens associated with hospital-acquired pneumonia, skin and soft tissue infection and bloodstream infection collected from 26 hospitals in China.

    Science.gov (United States)

    Li, Shuguang; Guo, Yu; Zhao, Chunjiang; Chen, Hongbin; Hu, Bijie; Chu, Yunzhuo; Zhang, Zhijie; Hu, Yunjian; Liu, Zhiyong; Du, Yan; Gui, Qiaodi; Ji, Ping; Zeng, Ji; Cao, Bin; Fu, Quan; Zhang, Rong; Wang, Zhongxin; Zhuo, Chao; Feng, Xianju; Jia, Wei; Jin, Yan; Xu, Xuesong; Liao, Kang; Ni, Yuxing; Yu, Yunsong; Xu, Xiuli; Hu, Zhidong; Lei, Jin-E; Yang, Qing; Wang, Hui

    2016-10-01

    To evaluate the in vitro antimicrobial activities of tedizolid, linezolid and other comparators against clinically significant Gram-positive cocci isolates from hospital-acquired pneumonia (HAP), skin and soft tissue infection (SSTI) and bloodstream infection (BSI), 2140 nonduplicate isolates (23.7 % isolated from HAP, 46.8 % from SSTI and 29.5 % from BSI) were consecutively collected in 26 hospitals in 17 cities across China during 2014. These pathogens included 632 methicillin-resistant Staphylococcus aureus, 867 methicillin-sensitive Staphylococcusaureus, 299 coagulase-negative Staphylococcus (CoNS), 104 Enterococcus faecalis, 99 Enterococcusfaecium, 13 Streptococcus pneumoniae, 23 α-haemolytic Streptococcus and 103 β-haemolytic Streptococcus. MICs of routine clinical antibiotics were determined by broth microdilution method according to the Clinical and Laboratory Standards Institute guidelines 2015. Tedizolid, linezolid, vancomycin, daptomycin, teicoplanin and tigecycline showed high in vitro activity against Gram-positive pathogens (≥98.0 % susceptible), and tedizolid exhibited four- to eight fold greater activity than linezolid against the pathogens tested, with MIC90s of methicillin-resistant Staphylococcus aureus, α-haemolytic Streptococcus and β-haemolytic Streptococcus (0.25 vs 2 µg ml-1); methicillin-sensitive Staphylococcu saureus, E. faecalis and E. faecium (0.5 vs 2 µg ml-1); methicillin-resistant CoNS and methicillin-sensitive CoNS (0.25 vs 1 µg ml-1); and Streptococcuspneumoniae (0.125 vs 0.5 µg ml-1). Tedizolid MIC90s associated with different infections did not show significant differences, and the drug exhibited excellent activity against surveyed Gram-positive pathogens associated with HAP, SSTI and BSI, including linezolid-nonsusceptible strains. These data suggest that tedizolid could be an alternative to linezolid for the treatment of infections caused by Gram-positive organisms.

  4. Acquired aplastic anemia in children.

    Science.gov (United States)

    Hartung, Helge D; Olson, Timothy S; Bessler, Monica

    2013-12-01

    This article provides a practice-based and concise review of the etiology, diagnosis, and management of acquired aplastic anemia in children. Bone marrow transplantation, immunosuppressive therapy, and supportive care are discussed in detail. The aim is to provide the clinician with a better understanding of the disease and to offer guidelines for the management of children with this uncommon yet serious disorder.

  5. Acquired prosopagnosia: structural basis and processing impairments.

    Science.gov (United States)

    Davies-Thompson, Jodie; Pancaroglu, Raika; Barton, Jason

    2014-01-01

    Cognitive models propose a hierarchy of parallel processing stages in face perception, and functional neuroimaging shows a network of regions involved in face processing. Reflecting this, acquired prosopagnosia is not a single entity but a family of disorders with different anatomic lesions and different functional deficits. One classic distinction is between an apperceptive variant, in which there is impaired perception of facial structure, and an associative/amnestic variant, in which perception is relatively intact, with subsequent problems matching perception to facial memories, because of either disconnection or loss of those memories. These disorders also have to be distinguished from people-specific amnesia, a multimodal impairment, and prosop-anomia, in which familiarity with faces is preserved but access to names is disrupted. These different disorders can be conceived as specific deficits at different processing stages in cognitive models, and suggests that these functional stages may have distinct neuroanatomic substrates. It remains to be seen whether a similar anatomic and functional variability is present in developmental prosopagnosia.

  6. CovS Simultaneously Activates and Inhibits the CovR-Mediated Repression of Distinct Subsets of Group A Streptococcus Virulence Factor-Encoding Genes▿ †

    OpenAIRE

    Treviño, Jeanette; Perez, Nataly; Ramirez-Peña, Esmeralda; Liu, Zhuyun; Shelburne, Samuel A.; Musser, James M.; Sumby, Paul

    2009-01-01

    To colonize and cause disease at distinct anatomical sites, bacterial pathogens must tailor gene expression in a microenvironment-specific manner. The molecular mechanisms that control the ability of the human bacterial pathogen group A Streptococcus (GAS) to transition between infection sites have yet to be fully elucidated. A key regulator of GAS virulence gene expression is the CovR-CovS two-component regulatory system (also known as CsrR-CsrS). covR and covS mutant strains arise spontaneo...

  7. Antibacterial activity and PK/PD of ceftriaxone against penicillin-resistant Streptococcus pneumoniae and beta-lactamase-negative ampicillin-resistant Haemophilus influenzae isolates from patients with community-acquired pneumonia.

    Science.gov (United States)

    Ohno, Akira; Ishii, Yoshikazu; Kobayashi, Intetsu; Yamaguchi, Keizo

    2007-10-01

    The suitability of ceftriaxone for penicillin-resistant Streptococcus pneumoniae (PRSP) and ampicillin-resistant Haemophilus influenzae (especially beta-lactamase-negative ampicillin-resistant (BLNAR) H. influenzae) and the relationship between in vitro antimicrobial activities and pharmacokinetic parameters were evaluated. The values for percentage of time above the MIC (%T>MIC) for ceftriaxone, cefotiam, flomoxef, sulbactam/cefoperazone, sulbactam/ampicillin, and meropenem, using 400 S. pneumoniae isolates and 430 H. influenzae isolates from patients with community-acquired pneumonia (CAP) from more than 100 geographically diverse medical centers during January to July of 2005, were calculated by measuring the MIC for each isolate and by using patameters of pharmacokinetics. A broth microdilution method was used to determine the MIC, using the guidelines of the Clinical and Laboratory Standards Institute (CLSI). Meropenem showed the lowest MIC against penicillin-susceptible S. pneumoniae, followed by sulbactam/cefoperazone and ceftriaxone. Ceftriaxone had the best activity against penicillin-resistant S. pneumoniae and beta-lactamase-negative and beta-lactamase-producing ampicillin-resistant H. influenzae. Ceftriaxone was unique, showing a long elimination half-life and low MIC values where its serum level duration time was above the MIC for longer than other cephalosporins. Accordingly, the %T>MIC of ceftriaxone for a once-daily administration greatly exceeded the efficacy levels of those for the other antibacterial agents tested. Ceftriaxone has an excellent balance between in vitro antimicrobial activities and pharmacokinetic profiles; and therefore remains effective as a therapeutic agent against PRSP and BLNAR H. influenzae in CAP.

  8. A shared neural ensemble links distinct contextual memories encoded close in time

    Science.gov (United States)

    Cai, Denise J.; Aharoni, Daniel; Shuman, Tristan; Shobe, Justin; Biane, Jeremy; Song, Weilin; Wei, Brandon; Veshkini, Michael; La-Vu, Mimi; Lou, Jerry; Flores, Sergio E.; Kim, Isaac; Sano, Yoshitake; Zhou, Miou; Baumgaertel, Karsten; Lavi, Ayal; Kamata, Masakazu; Tuszynski, Mark; Mayford, Mark; Golshani, Peyman; Silva, Alcino J.

    2016-06-01

    Recent studies suggest that a shared neural ensemble may link distinct memories encoded close in time. According to the memory allocation hypothesis, learning triggers a temporary increase in neuronal excitability that biases the representation of a subsequent memory to the neuronal ensemble encoding the first memory, such that recall of one memory increases the likelihood of recalling the other memory. Here we show in mice that the overlap between the hippocampal CA1 ensembles activated by two distinct contexts acquired within a day is higher than when they are separated by a week. Several findings indicate that this overlap of neuronal ensembles links two contextual memories. First, fear paired with one context is transferred to a neutral context when the two contexts are acquired within a day but not across a week. Second, the first memory strengthens the second memory within a day but not across a week. Older mice, known to have lower CA1 excitability, do not show the overlap between ensembles, the transfer of fear between contexts, or the strengthening of the second memory. Finally, in aged mice, increasing cellular excitability and activating a common ensemble of CA1 neurons during two distinct context exposures rescued the deficit in linking memories. Taken together, these findings demonstrate that contextual memories encoded close in time are linked by directing storage into overlapping ensembles. Alteration of these processes by ageing could affect the temporal structure of memories, thus impairing efficient recall of related information.

  9. Nursing home-acquired pneumonia.

    Science.gov (United States)

    El Solh, Ali A

    2009-02-01

    Nursing home-acquired pneumonia (NHAP) was first described in 1978. Since then there has been much written regarding NHAP and its management despite the lack of well-designed studies in this patient population. The most characteristic features of patients with NHAP are the atypical presentation, which may lead to delay in diagnosis and therapy. The microbial etiology of pneumonia encompasses a wide spectrum that spans microbes recovered from patients with community-acquired pneumonia to organisms considered specific only to nosocomial settings. Decision to transfer a nursing home patient to an acute care facility depends on a host of factors, which include the level of staffing available at the nursing home, patients' advance directives, and complexity of treatment. The presence of risk factors for multidrug-resistant pathogens dictates approach to therapy. Prevention remains the cornerstone of reducing the incidence of disease. Despite the advance in medical services, mortality from NHAP remains high.

  10. Occupationally Acquired American Cutaneous Leishmaniasis

    Directory of Open Access Journals (Sweden)

    Maria Edileuza Felinto de Brito

    2012-01-01

    Full Text Available We report two occupationally acquired cases of American cutaneous leishmaniasis (ACL: one accidental laboratory autoinoculation by contaminated needlestick while handling an ACL lesion sample, and one acquired during field studies on bird biology. Polymerase chain reaction (PCR assays of patient lesions were positive for Leishmania, subgenus Viannia. One isolate was obtained by culture (from patient 2 biopsy samples and characterized as Leishmania (Viannia naiffi through an indirect immunofluorescence assay (IFA with species-specific monoclonal antibodies (mAbs and by multilocus enzyme electrophoresis (MLEE. Patients were successfully treated with N-methyl-glucamine. These two cases highlight the potential risks of laboratory and field work and the need to comply with strict biosafety procedures in daily routines. The swab collection method, coupled with PCR detection, has greatly improved ACL laboratory diagnosis.

  11. CNOOC Acquires Oversea Assets Successfully

    Institute of Scientific and Technical Information of China (English)

    Hu Senlin

    2006-01-01

    @@ After last year CNOOC's bidding for buy the US energy company Unocal Corp lost out to the Chevron Corporation, it conducted the crossing-border asset-acquirement again in the beginning of this year. On Jan. 9, 2006,CNOOC Ltd signed a definitive agreement with Nigeria South Atlantic Petroleum Limited (SAPETRO) to acquire a 45 % working interest in an offshore oil developing license OML 130 in Nigeria for US$2.268 billion cash. The purchase will be funded by the internal capital resources of CNOOC Ltd. In which, US$1.75 billion will pay for buying SAPETRO, and the remaining cash will be used to pay for the early operation cost.

  12. [Acquired disorders of color vision].

    Science.gov (United States)

    Lascu, Lidia; Balaş, Mihaela

    2002-01-01

    This article is a general view of acquired disorders of color vision. The revision of the best known methods and of the etiopathogenic classification is not very important in ophthalmology but on the other hand, the detection of the blue defect advertise and associated ocular pathology. There is a major interest in serious diseases as multiple sclerosis, AIDS, diabetes melitus, when the first ocular sign can be a defect in the color vision.

  13. Comparison of pharmacological activities of three distinct kappa ligands (Salvinorin A, TRK-820 and 3FLB) on kappa opioid receptors in vitro and their antipruritic and antinociceptive activities in vivo.

    Science.gov (United States)

    Wang, Yulin; Tang, Kang; Inan, Saadet; Siebert, Daniel; Holzgrabe, Ulrike; Lee, David Y W; Huang, Peng; Li, Jian-Guo; Cowan, Alan; Liu-Chen, Lee-Yuan

    2005-01-01

    Salvinorin A, TRK-820 (17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6beta-[N-methyl-trans-3-(3-furyl) acrylamido]morphinan hydrochloride), and 3FLB (diethyl 2,4-di-[3-fluorophenyl]-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane-9-one-1,5-dicarboxylate) are structurally distinctly different from U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate], the prototypic selective kappa agonist. Here, we investigated their in vitro pharmacological activities on receptors expressed in Chinese hamster ovary cells and in vivo antiscratch and antinociceptive activities in mice. All three compounds showed high selectivity for the kappa opioid receptor (KOR) over the mu opioid receptor (MOR) and delta opioid receptor (DOR) and nociceptin or orphanin FQ receptors. In the guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding assay, all three were full agonists on the KOR. The rank order of affinity and potency for the KOR was TRK-820 > U50,488H approximately salvinorin A > 3FLB. TRK-820 acted as a partial agonist on MOR and DOR, whereas salvinorin A and 3FLB showed no activities on these receptors. Salvinorin A, TRK-820, and 3FLB caused internalization of the human KOR in a dose-dependent manner. Interestingly, although salvinorin A and U50,488H had similar potencies in stimulating [(35)S]GTPgammaS binding, salvinorin A was about 40-fold less potent than U50,488H in promoting internalization. Following 4-h incubation, all three compounds induced down-regulation of the human KOR, with salvinorin A causing a lower extent of down-regulation. Although TRK-820 was potent and efficacious against compound 48/80-induced scratching, salvinorin A showed low and inconsistent effects, and 3FLB was inactive. In addition, salvinorin A and 3FLB were not active in the acetic acid abdominal constriction test. The discrepancy between in vitro and in vivo results may be due to in vivo metabolism of salvinorin A and 3FLB and

  14. Acquired plate-like osteoma cutis.

    Science.gov (United States)

    Vashi, Neelam; Chu, Julie; Patel, Rishi

    2011-10-15

    Plate-like osteoma cutis is a rare disorder that has been historically classified as a congenital syndrome. It has a possible relationship to a mutation in the gene (GNAS1) that encodes the α-subunit of the stimulatory G protein, which regulates adenyl cyclase activity. We report a case of extensive plaque-like masses on the scalp and face with no abnormalities in calcium or phosphate metabolism and no preceding inflammatory cutaneous conditions. With less than ten reported cases, to our knowledge, this is one the few cases of acquired plate-like osteoma cutis described in the literature.

  15. Activity-based anorexia reduces body weight without inducing a separate food intake microstructure or activity phenotype in female rats – mediation via an activation of distinct brain nuclei

    Directory of Open Access Journals (Sweden)

    Sophie Scharner

    2016-10-01

    Full Text Available Anorexia nervosa (AN is accompanied by severe somatic and psychosocial complications. However, the underlying pathogenesis is poorly understood, treatment is challenging and often hampered by high relapse. Therefore, more basic research is needed to better understand the disease. Since hyperactivity often plays a role in AN, we characterized an animal model to mimic AN using restricted feeding and hyperactivity. Female Sprague-Dawley rats were divided into four groups: no activity/ad libitum feeding (ad libitum, AL, n=9, activity/ad libitum feeding (activity, AC, n=9, no activity/restricted feeding (RF, n=12 and activity/restricted feeding (activity-based anorexia, ABA, n=11. During the first week all rats were fed ad libitum, ABA and AC had access to a running wheel for 24h/d. From week two ABA and RF only had access to food from 9:00-10:30 am. Body weight was assessed daily, activity and food intake monitored electronically, brain activation assessed using Fos immunohistochemistry at the end of the experiment. While during the first week no body weight differences were observed (p>0.05, after food restriction RF rats showed a body weight decrease: -13% vs. day eight (p0.05. Similarly, the daily physical activity was not different between AC and ABA (p>0.05. The investigation of Fos expression in the brain showed neuronal activation in several brain nuclei such as the supraoptic nucleus, arcuate nucleus, locus coeruleus and nucleus of the solitary tract of ABA compared to AL rats. In conclusion, ABA combining physical activity and restricted feeding likely represents a suited animal model for AN to study pathophysiological alterations and pharmacological treatment options. Nonetheless, cautious interpretation of the data is necessary since rats do not voluntarily reduce their body weight as observed in human AN.

  16. Distinct Afatinib Resistance Mechanisms Identified in Lung Adenocarcinoma Harboring an EGFR Mutation.

    Science.gov (United States)

    Yamaoka, Toshimitsu; Ohmori, Tohru; Ohba, Motoi; Arata, Satoru; Murata, Yasunori; Kusumoto, Sojiro; Ando, Koichi; Ishida, Hiroo; Ohnishi, Tsukasa; Sasaki, Yasutsuna

    2017-03-13

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are associated with significant responses in non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations. However, acquired resistance to reversible EGFR-TKIs remains a major obstacle. In particular, while the second-generation irreversible EGFR-TKI afatinib is currently used for treating NSCLC patients, the mechanisms underlying acquired afatinib resistance remain poorly understood. Here, heterogeneous mechanisms of acquired resistance were identified following long-term exposure to increasing doses of afatinib in EGFR mutant lung adenocarcinoma PC9 cells. Notably, three resistant cell lines, PC-9AFR1, PC-9AFR2, and PC-9AFR3 (AFR1, AFR2, and AFR3, respectively), employed distinct mechanisms for avoiding EGFR inhibition, with increased EGFR expression being detected in all resistant cell lines. Moreover, an activating EGFR mutation was partially lost in AFR1 and AFR2 cells. AFR1 cells exhibited afatinib resistance as a result of wild-type KRAS amplification and overexpression; however, these cells showed a progressive decrease and eventual loss of the acquired KRAS dependence, as well as resensitization to afatinib, following a drug holiday. Meanwhile, AFR2 cells exhibited increased expression of insulin-like growth factor-binding protein 3 (IGFBP3), which promoted insulin-like growth factor 1 receptor (IGF1R) activity and subsequent AKT phosphorylation, thereby indicating a potential bypass signaling pathway associated with IGFR1. Finally, AFR3 cells harbored the secondary EGFR mutation T790M. Our findings constitute the first report showing acquired wild-type KRAS overexpression and attenuation of afatinib resistance following a drug holiday.

  17. Distinct Roles for JNK and IKK Activation in Agouti-Related Peptide Neurons in the Development of Obesity and Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Eva Tsaousidou

    2014-11-01

    Full Text Available Activation of c-Jun N-terminal kinase 1 (JNK1- and inhibitor of nuclear factor kappa-B kinase 2 (IKK2-dependent signaling plays a crucial role in the development of obesity-associated insulin and leptin resistance not only in peripheral tissues but also in the CNS. Here, we demonstrate that constitutive JNK activation in agouti-related peptide (AgRP-expressing neurons of the hypothalamus is sufficient to induce weight gain and adiposity in mice as a consequence of hyperphagia. JNK activation increases spontaneous action potential firing of AgRP cells and causes both neuronal and systemic leptin resistance. Similarly, activation of IKK2 signaling in AgRP neurons also increases firing of these cells but fails to cause obesity and leptin resistance. In contrast to JNK activation, IKK2 activation blunts insulin signaling in AgRP neurons and impairs systemic glucose homeostasis. Collectively, these experiments reveal both overlapping and nonredundant effects of JNK- and IKK-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome.

  18. Pneumonia acquired in the Community

    Directory of Open Access Journals (Sweden)

    María Caridad Fragoso Marchante

    2007-06-01

    Full Text Available A bibliographical revision of the main aspects in the diagnosis and treatment of the patients suffering from pneumonia acquired in the community is carried out. Microorganisms responsible for this type of pneumonia are mention in this paper as well as the available diagnostic methods for germs isolation. Different guidelines for diagnosis and treatment of this disease published by several medical societies and scientific institutions are analyzed by means of a review of the stratification index of the patients used in each of them. Aspects related to the duration of the treatment and the possible causes associated with the unfavorable evolution are stated.

  19. Increasing maternal body mass index is associated with systemic inflammation in the mother and the activation of distinct placental inflammatory pathways.

    Science.gov (United States)

    Aye, Irving L M H; Lager, Susanne; Ramirez, Vanessa I; Gaccioli, Francesca; Dudley, Donald J; Jansson, Thomas; Powell, Theresa L

    2014-06-01

    Obese pregnant women have increased levels of proinflammatory cytokines in maternal circulation and placental tissues. However, the pathways contributing to placental inflammation in obesity are largely unknown. We tested the hypothesis that maternal body mass index (BMI) was associated with elevated proinflammatory cytokines in maternal and fetal circulations and increased activation of placental inflammatory pathways. A total of 60 women of varying pre-/early pregnancy BMI, undergoing delivery by Cesarean section at term, were studied. Maternal and fetal (cord) plasma were collected for analysis of insulin, leptin, IL-1beta, IL-6, IL-8, monocyte chemoattractant protein (MCP) 1, and TNFalpha by multiplex ELISA. Activation of the inflammatory pathways in the placenta was investigated by measuring the phosphorylated and total protein expression of p38-mitogen-activated protein kinase (MAPK), c-Jun-N-terminal kinase (JNK)-MAPK, signal transducer-activated transcription factor (STAT) 3, caspase-1, IL-1beta, IkappaB-alpha protein, and p65 DNA-binding activity. To determine the link between activated placental inflammatory pathways and elevated maternal cytokines, cultured primary human trophoblast (PHT) cells were treated with physiological concentrations of insulin, MCP-1, and TNFalpha, and inflammatory signaling analyzed by Western blot. Maternal BMI was positively correlated with maternal insulin, leptin, MCP-1, and TNFalpha, whereas only fetal leptin was increased with BMI. Placental phosphorylation of p38-MAPK and STAT3, and the expression of IL-1beta protein, were increased with maternal BMI; phosphorylation of p38-MAPK was also correlated with birth weight. In contrast, placental NFkappaB, JNK and caspase-1 signaling, and fetal cytokine levels were unaffected by maternal BMI. In PHT cells, p38-MAPK was activated by MCP-1 and TNFalpha, whereas STAT3 phosphorylation was increased following TNFalpha treatment. Maternal BMI is associated with elevated maternal

  20. Postnatal PPARdelta activation and myostatin inhibition exert distinct yet complimentary effects on the metabolic profile of obese insulin-resistant mice.

    Directory of Open Access Journals (Sweden)

    Barbara L Bernardo

    Full Text Available BACKGROUND: Interventions for T2DM have in part aimed to mimic exercise. Here, we have compared the independent and combined effects of a PPARdelta agonist and endurance training mimetic (GW501516 and a myostatin antibody and resistance training mimetic (PF-879 on metabolic and performance outcomes in obese insulin resistant mice. METHODOLOGY/PRINCIPAL FINDINGS: Male ob/ob mice were treated for 6 weeks with vehicle, GW501516, PF-879, or GW501516 in combination with PF-879. The effects of the interventions on body composition, glucose homeostasis, glucose tolerance, energy expenditure, exercise capacity and metabolic gene expression were compared at the end of study. GW501516 attenuated body weight and fat mass accumulation and increased the expression of genes of oxidative metabolism. In contrast, PF-879 increased body weight by driving muscle growth and altered the expression of genes involved in insulin signaling and glucose metabolism. Despite their differences, both interventions alone improved glucose homeostasis. Moreover, GW501516 more effectively improved serum lipids, and PF-879 uniquely increased energy expenditure, exercise capacity and adiponectin levels. When combined the robust effects of GW501516 and/or PF-879 on body weight, adiposity, muscle mass, glycemia, serum lipids, energy expenditure and exercise capacity were highly conserved. CONCLUSIONS/SIGNIFICANCE: The data, for the first time, demonstrate postnatal inhibition of myostatin not only promotes gains in muscle mass similar to resistance training,but improves metabolic homeostasis. In several instances, these effects were either distinct from or complimentary to those of GW501516. The data further suggest that strategies to increase muscle mass, and not necessarily oxidative capacity, may effectively counter insulin resistance and T2DM.

  1. Subtle distinct regulations of late erythroid molecular events by PI3K/AKT-mediated activation of Spi-1/PU.1 oncogene autoregulation loop.

    Science.gov (United States)

    Breig, O; Théoleyre, O; Douablin, A; Baklouti, F

    2010-05-13

    Spi-1/PU.1 oncogene is downregulated as proerythroblasts undergo terminal differentiation. Insertion of the Friend virus upstream of the Spi-1/PU.1 locus leads to the constitutive upregulation of Spi-1/PU.1, and a subsequent block in the differentiation of the affected erythroblasts. We have shown that sustained overexpression of Spi-1/PU.1 also inhibits the erythroid splicing of protein 4.1R exon 16, irrespective of chemical induction of differentiation. Here, we show a positive feedback loop that couples constitutive phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling to high expression of Spi-1/PU.1 in Friend erythroleukemia cells. Inhibition of PI3K/AKT results in Spi-1/PU.1 downregulation in a stepwise manner and induces cell differentiation. Chromatin immunoprecipitation assays further supported the positive autoregulatory effect of Spi-1/PU.1. Mutational analysis indicated that Ser41, but not Ser148, is necessary for Spi-1/PU.1-mediated repression of hemoglobin expression, whereas both Ser residues are required for Spi-1/PU.1 inhibition of the erythroid splicing event. We further show that inhibition of the erythroid transcriptional and splicing events are strictly dependent on distinct Spi-1/PU.1 phosphorylation modifications rather than Spi-1/PU.1 expression level per se. Our data further support the fact that Spi-1/PU.1 inhibits 4.1R erythroid splicing through two different pathways, and bring new insights into the extracellular signal impact triggered by erythropoietin on late erythroid regulatory program, including pre-mRNA splicing.

  2. Foodborne listeriosis acquired in hospitals.

    Science.gov (United States)

    Silk, Benjamin J; McCoy, Morgan H; Iwamoto, Martha; Griffin, Patricia M

    2014-08-15

    Listeriosis is characterized by bacteremia or meningitis. We searched for listeriosis case series and outbreak investigations published in English by 2013, and assessed the strength of evidence for foodborne acquisition among patients who ate hospital food. We identified 30 reports from 13 countries. Among the case series, the median proportion of cases considered to be hospital-acquired was 25% (range, 9%-67%). The median number of outbreak-related illnesses considered to be hospital-acquired was 4.0 (range, 2-16). All patients were immunosuppressed in 18 of 24 (75%) reports with available data. Eight outbreak reports with strong evidence for foodborne acquisition in a hospital implicated sandwiches (3 reports), butter, precut celery, Camembert cheese, sausage, and tuna salad (1 report each). Foodborne acquisition of listeriosis among hospitalized patients is well documented internationally. The number of listeriosis cases could be reduced substantially by establishing hospital policies for safe food preparation for immunocompromised patients and by not serving them higher-risk foods.

  3. Pruritic acquired nevus of Ota.

    Science.gov (United States)

    Quenan, S; Strueven, V; Saxer, N; Laffitte, E; Kaya, G; Krischer, J; Hafezi, F; Le Gal, F-A

    2013-01-01

    Nevus of Ota is a unilateral, asymptomatic cutaneous and mucosal hyperpigmentation of the face that is congenital or may appear during childhood. We present a case of symptomatic acquired nevus of Ota in an adult, associated with intense pruritus, not described in the literature so far. A 32-year-old woman presented with brownish mottled macules which appeared on her face progressively over 8 days, following the distribution of the first and second divisions of the left trigeminal nerve and partially covering the iris and sclera of the left eye. She reported an intense pruritus in this area. We performed a biopsy on the left forehead, which confirmed the diagnosis of nevus of Ota. Specific stains and immunohistochemistry revealed increased numbers of mast cells. Ophthalmological tests showed acute acquired melanocytosis of the left iris and sclera. The origin of the nevus is still unclear. Several hypotheses suggest a reactivation of melanocytes during their migration from the neural crest. The pruritus reported in our patient may be explained by the increased quantity of mast cells observed in the lesion and/or neuronal stimulation of the ophthalmic and maxillary divisions of the fifth cranial nerve.

  4. Distinct motifs in the intracellular domain of human CD30 differentially activate canonical and alternative transcription factor NF-κB signaling.

    Directory of Open Access Journals (Sweden)

    Sarah L Buchan

    Full Text Available The TNF-receptor superfamily member CD30 is expressed on normal and malignant lymphocytes, including anaplastic large cell lymphoma (ALCL cells. CD30 transmits multiple effects, including activation of NF-κB signaling, cell proliferation, growth arrest and apoptosis. How CD30 generates these pleiotropic effects is currently unknown. Herein we describe ALCL cells expressing truncated forms of the CD30 intracellular domain that allowed us to identify the key regions responsible for transmitting its biological effects in lymphocytes. The first region (CD30(519-537 activated both the alternative and canonical NF-κB pathways as detected by p100 and IκBα degradation, IKKβ-dependent transcription of both IκBα and the cyclin-dependent kinase inhibitor p21(WAF1/CIP1 and induction of cell cycle arrest. In contrast, the second region of CD30 (CD30(538-595 induced some aspects of canonical NF-κB activation, including transcription of IκBα, but failed to activate the alternative NF-κB pathway or drive p21(WAF1/CIP1-mediated cell-cycle arrest. Direct comparison of canonical NF-κB activation by the two motifs revealed 4-fold greater p65 nuclear translocation following CD30(519-537 engagement. These data reveal that independent regions of the CD30 cytoplasmic tail regulate the magnitude and type of NF-κB activation and additionally identify a short motif necessary for CD30-driven growth arrest signals in ALCL cells.

  5. Immobilization of the distal hinge in the labile serpin plasminogen activator inhibitor 1: identification of a transition state with distinct conformational and functional properties.

    Science.gov (United States)

    De Taeye, Bart; Compernolle, Griet; Dewilde, Maarten; Biesemans, Wouter; Declerck, Paul J

    2003-06-27

    The serpin plasminogen activator inhibitor-1 (PAI-1) plays an important role in the regulation of the fibrinolytic activity in blood. In plasma, PAI-1 circulates mainly in the active conformation. However, PAI-1 spontaneously converts to a latent conformation. This conversion comprises drastic conformational changes in both the distal and the proximal hinge region of the reactive center loop. To study the functional and conformational rearrangements associated solely with the mobility of the proximal hinge, disulfide bonds were introduced to immobilize the distal hinge region. These mutants exhibited specific activities comparable with that of PAI-1-wt. However, the engineered disulfide bond had a major effect on the conformational and associated functional transitions. Strikingly, in contrast to PAI-1-wt, inactivation of these mutants yielded a virtually complete conversion to a substrate-like conformation. Comparison of the digestion pattern (with trypsin and elastase) of the mutants and PAI-1-wt revealed that the inactivated mutants have a conformation differing from that of latent and active PAI-1-wt. Unique trypsin-susceptible cleavage sites arose upon inactivation of these mutants. The localization of these exposed residues provides evidence that a displacement of alphahF has occurred, indicating that the proximal hinge is partly inserted between s3A and s5A. In conclusion, immobilization of the distal hinge region in PAI-1 allowed the identification of an "intermediate" conformation characterized by a partial insertion of the proximal hinge region. We hypothesize that locking PAI-1 in this transition state between active and latent conformations is associated with a displacement of alphahF, subsequently resulting in substrate behavior.

  6. Are Environmental Influences on Physical Activity Distinct for Urban, Suburban, and Rural Schools? A Multilevel Study among Secondary School Students in Ontario, Canada

    Science.gov (United States)

    Hobin, Erin P.; Leatherdale, Scott; Manske, Steve; Dubin, Joel A.; Elliott, Susan; Veugelers, Paul

    2013-01-01

    Background: This study examined differences in students' time spent in physical activity (PA) across secondary schools in rural, suburban, and urban environments and identified the environment-level factors associated with these between school differences in students' PA. Methods: Multilevel linear regression analyses were used to examine the…

  7. The differential antiviral activities of chicken interferon α (ChIFN-α and ChIFN-β are related to distinct interferon-stimulated gene expression.

    Directory of Open Access Journals (Sweden)

    Hongren Qu

    Full Text Available Chicken interferon α (ChIFN-α and ChIFN-β are type I IFNs that are important antiviral cytokines in the innate immune system. In the present study, we identified the virus-induced expression of ChIFN-α and ChIFN-β in chicken fibroblast DF-1 cells and systematically evaluated the antiviral activities of recombinant ChIFN-α and ChIFN-β by cytopathic-effect (CPE inhibition assays. We found that ChIFN-α exhibited stronger antiviral activity than ChIFN-β in terms of inhibiting the replication of vesicular stomatitis virus, Newcastle disease virus and avian influenza virus, respectively. To elucidate the mechanism of differential antiviral activities between the two ChIFNs, we measured the relative mRNA levels of IFN-stimulated genes (ISGs in IFN-treated DF-1 cells by real-time PCR. ChIFN-α displayed greater induction potency than ChIFN-β on several ISGs encoding antiviral proteins and MHC-I, whereas ChIFN-α was less potent than ChIFN-β for inducing ISGs involved in signaling pathways. In conclusion, ChIFN-α and ChIFN-β presented differential induction potency on various sets of ISGs, and the stronger antiviral activity of ChIFN-α is likely attributed to the greater expression levels of downstream antiviral ISGs.

  8. Verum and sham acupuncture exert distinct cerebral activation in pain processing areas: a crossover fMRI investigation in healthy volunteers.

    Science.gov (United States)

    Usichenko, Taras I; Wesolowski, Toni; Lotze, Martin

    2015-06-01

    Although acupuncture is effective for treating pain, its site-specificity is questioned. The aim was to compare the cerebral responses of needling applied to an acupuncture point to the needling of a sham point, using functional magnetic resonance imaging (fMRI). Twenty-one healthy male volunteers were enrolled. Manual stimulation of the acupuncture (ST44) and sham points on the dorsum of the left foot was applied during fMRI in a crossover manner. fMRI data analysis was performed contrasting the ST44 and the sham conditions. Stimulation intensity, subjective discrimination of the needling site and the incidence of "Qi" sensation were additionally recorded. Stimulation of ST44 acupoint, in comparison to the sham procedure, was associated with an increased fMRI-activation in the primary somatosensory, the inferior parietal and the prefrontal cortex and the posterior insula. Sham needling was associated with increased activation in the anterior cingulate cortex and the anterior insula. Verum acupuncture increased the activity of discriminative somatosensory and cognitive pain processing areas of the brain, whereas sham needling activated the areas responsible for affective processing of pain. This may explain favorable effects of verum acupuncture in clinical studies about treatment of chronic pain patients.

  9. Functional Analysis of the Glucuronyltransferases GlcAT-P and GlcAT-S of Drosophila melanogaster: Distinct Activities towards the O-linked T-antigen

    Directory of Open Access Journals (Sweden)

    Isabelle Breloy

    2016-01-01

    Full Text Available The Drosophila melanogaster glucuronyltransferases dGlcAT-S and dGlcAT-P were reported to be expressed ubiquitously and results of in vitro activity assays indicate a functional redundancy. We analyzed both transferases in vivo and in vitro and could show significant differences in their activity towards N-and O-glycoproteins in vivo. While GlcAT-P is able to use N-linked N-acetyllactosamine chains and the O-linked T-antigen as a substrate to form non-sulfated HNK1- (GlcAβ1-3Galβ1-4GlcNAcβ1- and glucuronyl-T-antigens in vivo, GlcAT-S adds glucuronic acid only to N-linked chains, thereby synthesizing only the non-sulfated HNK1-antigen.

  10. Functional Analysis of the Glucuronyltransferases GlcAT-P and GlcAT-S of Drosophila melanogaster: Distinct Activities towards the O-linked T-antigen.

    Science.gov (United States)

    Breloy, Isabelle; Schwientek, Tilo; Althoff, Deborah; Holz, Marvin; Koppen, Tim; Krupa, Angelika; Hanisch, Franz-Georg

    2016-01-06

    The Drosophila melanogaster glucuronyltransferases dGlcAT-S and dGlcAT-P were reported to be expressed ubiquitously and results of in vitro activity assays indicate a functional redundancy. We analyzed both transferases in vivo and in vitro and could show significant differences in their activity towards N-and O-glycoproteins in vivo. While GlcAT-P is able to use N-linked N-acetyllactosamine chains and the O-linked T-antigen as a substrate to form non-sulfated HNK1- (GlcAβ1-3Galβ1-4GlcNAcβ1-) and glucuronyl-T-antigens in vivo, GlcAT-S adds glucuronic acid only to N-linked chains, thereby synthesizing only the non-sulfated HNK1-antigen.

  11. Comparative Study of the Catalytic Activities of Three Distinct Carbonaceous Materials through Photocatalytic Oxidation, CO Conversion, Dye Degradation, and Electrochemical Measurements

    Science.gov (United States)

    Lee, Hangil; Kim, Yeonwoo; Kim, Min Ji; Kim, Ki-jeong; Kim, Byung-Kwon

    2016-01-01

    In order to compare the catalytic activities of reduced graphene oxide (rGO), graphene oxide (GO), and graphene, we conducted oxidation of 2-aminothiophenol (2-ATP) and reduction of nitrobenzene (NB) in their presence by using high-resolution photoemission spectroscopy (HRPES). In addition, we determined conversion rates of CO to CO2 in the presence of these catalysts by performing a residual gas analyzer (RGA) under a UHV condition, Orange II and methylene blue degradations UV-vis spectrophotometry, and electrochemistry (EC) measurements in an aqueous solution, as well as by obtaining cyclic voltammograms and determining the change of the condition of electrodes before and after the oxidation of 2-ATP. We found that we can successively fabricate GO (oxidation) and graphene (reduction) from rGO by controlling the oxidation or reduction procedure time and then clearly comparing the critical properties among them as we perform various oxidation and reduction activities. PMID:27762289

  12. Differential extracellular signal-regulated kinases 1 and 2 activation by the angiotensin type 1 receptor supports distinct phenotypes of cardiac myocytes

    DEFF Research Database (Denmark)

    Aplin, Mark; Christensen, Gitte Lund; Schneider, Mikael;

    2007-01-01

    The angiotensin II (AngII) type 1 receptor (AT(1)R) is a seven-transmembrane receptor well established to activate extracellular signal-regulated kinases 1 and 2 (ERK1/2) by discrete G protein-dependent and beta-arrestin2-dependent pathways. The biological importance of this, however, remains...... that phosphorylates p90 Ribosomal S6 Kinase, a ubiquitous and versatile mediator of ERK1/2 signal transduction. Moreover, the beta-arrestin2-dependent ERK1/2 signal supports intact proliferation of cardiac myocytes. In contrast to G(q)-activated ERK1/2, and in keeping with its failure to translocate to the nucleus......, the beta-arrestin2-scaffolded pool of ERK1/2 does not phosphorylate the transcription factor Elk-1, induces no increased transcription of the immediate-early gene c-Fos, and does not entail myocyte hypertrophy. These results clearly demonstrate the biological significance of differential signalling...

  13. Comparative Study of the Catalytic Activities of Three Distinct Carbonaceous Materials through Photocatalytic Oxidation, CO Conversion, Dye Degradation, and Electrochemical Measurements

    Science.gov (United States)

    Lee, Hangil; Kim, Yeonwoo; Kim, Min Ji; Kim, Ki-Jeong; Kim, Byung-Kwon

    2016-10-01

    In order to compare the catalytic activities of reduced graphene oxide (rGO), graphene oxide (GO), and graphene, we conducted oxidation of 2-aminothiophenol (2-ATP) and reduction of nitrobenzene (NB) in their presence by using high-resolution photoemission spectroscopy (HRPES). In addition, we determined conversion rates of CO to CO2 in the presence of these catalysts by performing a residual gas analyzer (RGA) under a UHV condition, Orange II and methylene blue degradations UV-vis spectrophotometry, and electrochemistry (EC) measurements in an aqueous solution, as well as by obtaining cyclic voltammograms and determining the change of the condition of electrodes before and after the oxidation of 2-ATP. We found that we can successively fabricate GO (oxidation) and graphene (reduction) from rGO by controlling the oxidation or reduction procedure time and then clearly comparing the critical properties among them as we perform various oxidation and reduction activities.

  14. Two distinct pools of large-conductance calcium-activated potassium channels in the somatic plasma membrane of central principal neurons

    OpenAIRE

    Kaufmann, W.A.; Kasugai, Y.; Ferraguti, F.; Storm, J F

    2010-01-01

    Although nerve cell membranes are often assumed to be uniform with respect to electrical properties, there is increasing evidence for compartmentalization into subdomains with heterogeneous impacts on the overall cell function. Such microdomains are characterized by specific sets of proteins determining their functional properties. Recently, clustering of large-conductance calcium-activated potassium (BKCa) channels was shown at sites of subsurface membrane cisterns in cerebellar Purkinje cel...

  15. Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells.

    Science.gov (United States)

    Deenick, Elissa K; Avery, Danielle T; Chan, Anna; Berglund, Lucinda J; Ives, Megan L; Moens, Leen; Stoddard, Jennifer L; Bustamante, Jacinta; Boisson-Dupuis, Stephanie; Tsumura, Miyuki; Kobayashi, Masao; Arkwright, Peter D; Averbuch, Diana; Engelhard, Dan; Roesler, Joachim; Peake, Jane; Wong, Melanie; Adelstein, Stephen; Choo, Sharon; Smart, Joanne M; French, Martyn A; Fulcher, David A; Cook, Matthew C; Picard, Capucine; Durandy, Anne; Klein, Christoph; Holland, Steven M; Uzel, Gulbu; Casanova, Jean-Laurent; Ma, Cindy S; Tangye, Stuart G

    2013-11-18

    Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell-dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10- and IL-21-mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21-induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.

  16. Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid-mediated modulation of LPS-induced activation of BV-2 microglial cells.

    Directory of Open Access Journals (Sweden)

    Ana Juknat

    Full Text Available Cannabinoids are known to exert immunosuppressive activities. However, the mechanisms which contribute to these effects are unknown. Using lipopolysaccharide (LPS to activate BV-2 microglial cells, we examined how Δ(9-tetrahydrocannabinol (THC, the major psychoactive component of marijuana, and cannabidiol (CBD the non-psychoactive component, modulate the inflammatory response. Microarray analysis of genome-wide mRNA levels was performed using Illumina platform and the resulting expression patterns analyzed using the Ingenuity Pathway Analysis to identify functional subsets of genes, and the Ingenuity System Database to denote the gene networks regulated by CBD and THC. From the 5338 transcripts that were differentially expressed across treatments, 400 transcripts were found to be upregulated by LPS, 502 by CBD+LPS and 424 by THC+LPS, while 145 were downregulated by LPS, 297 by CBD+LPS and 149 by THC+LPS, by 2-fold or more (p≤0.005. Results clearly link the effects of CBD and THC to inflammatory signaling pathways and identify new cannabinoid targets in the MAPK pathway (Dusp1, Dusp8, Dusp2, cell cycle related (Cdkn2b, Gadd45a as well as JAK/STAT regulatory molecules (Socs3, Cish, Stat1. The impact of CBD on LPS-stimulated gene expression was greater than that of THC. We attribute this difference to the fact that CBD highly upregulated several genes encoding negative regulators of both NFκB and AP-1 transcriptional activities, such as Trib3 and Dusp1 known to be modulated through Nrf2 activation. The CBD-specific expression profile reflected changes associated with oxidative stress and glutathione depletion via Trib3 and expression of ATF4 target genes. Furthermore, the CBD affected genes were shown to be controlled by nuclear factors usually involved in regulation of stress response and inflammation, mainly via Nrf2/Hmox1 axis and the Nrf2/ATF4-Trib3 pathway. These observations indicate that CBD, and less so THC, induce a cellular stress

  17. Lymphoma in acquired generalized lipodystrophy.

    Science.gov (United States)

    Brown, Rebecca J; Chan, Jean L; Jaffe, Elaine S; Cochran, Elaine; DePaoli, Alex M; Gautier, Jean-Francois; Goujard, Cecile; Vigouroux, Corinne; Gorden, Phillip

    2016-01-01

    Acquired generalized lipodystrophy (AGL) is a rare disease thought to result from autoimmune destruction of adipose tissue. Peripheral T-cell lymphoma (PTCL) has been reported in two AGL patients. We report five additional cases of lymphoma in AGL, and analyze the role of underlying autoimmunity and recombinant human leptin (metreleptin) replacement in lymphoma development. Three patients developed lymphoma during metreleptin treatment (two PTCL and one ALK-positive anaplastic large cell lymphoma), and two developed lymphomas (mycosis fungoides and Burkitt lymphoma) without metreleptin. AGL is associated with high risk for lymphoma, especially PTCL. Autoimmunity likely contributes to this risk. Lymphoma developed with or without metreleptin, suggesting metreleptin does not directly cause lymphoma development; a theoretical role of metreleptin in lymphoma progression remains possible. For most patients with AGL and severe metabolic complications, the proven benefits of metreleptin on metabolic disease will likely outweigh theoretical risks of metreleptin in lymphoma development or progression.

  18. Complement's participation in acquired immunity

    DEFF Research Database (Denmark)

    Nielsen, Claus Henrik; Leslie, Robert Graham Quinton

    2002-01-01

    of the B cell receptor for antigen (BCR), a complex composed of the iC3b/C3d fragment-binding complement type 2 receptor (CR2, CD21) and its signaling element CD19 and the IgG-binding receptor FcgammaRIIb (CD32). The positive or negative outcome of signaling through this triad is determined by the context...... in which antigen is seen, be it alone or in association with natural or induced antibodies and/or C3-complement fragments. The aim of this review is to describe the present status of our understanding of complement's participation in acquired immunity and the regulation of autoimmune responses....

  19. Bejel: acquirable only in childhood?

    Science.gov (United States)

    Rothschild, Bruce M; Rothschild, Christine; Naples, Virginia; Billard, Michel; Panero, Barbara

    2006-10-01

    Bejel clearly has a long history in the Middle East and the Sudan, but was it transmitted to Europe? As the major manifestation of bejel is presence of periosteal reaction in 20-40% of afflicted populations, absence of significant population frequency of periosteal reaction in Europe would exclude that diagnosis. Examination of skeletal populations from continental Europe revealed no significant periosteal reaction at the time of and immediately subsequent to the Crusades. Thus, there is no evidence for bejel in Europe, in spite of clear contact (the mechanism of bejel transmission in children) between warring groups, at least during the Crusades. This supports the hypothesis that bejel is a childhood-acquired disease and apparently cannot be contracted in adulthood.

  20. Increased structural flexibility at the active site of a fluorophore-conjugated beta-lactamase distinctively impacts its binding toward diverse cephalosporin antibiotics.

    Science.gov (United States)

    Wong, Wai-Ting; Chan, Kwok-Chu; So, Pui-Kin; Yap, Hong-Kin; Chung, Wai-Hong; Leung, Yun-Chung; Wong, Kwok-Yin; Zhao, Yanxiang

    2011-09-09

    The Ω-loop at the active site of β-lactamases exerts significant impact on the kinetics and substrate profile of these enzymes by forming part of the substrate binding site and posing as steric hindrance toward bulky substrates. Mutating certain residues on the Ω-loop has been a general strategy for molecular evolution of β-lactamases to expand their hydrolytic activity toward extended-spectrum antibiotics through a mechanism believed to involve enhanced structural flexibility of the Ω-loop. Yet no structural information is available that demonstrates such flexibility or its relation to substrate profile and enzyme kinetics. Here we report an engineered β-lactamase that contains an environment-sensitive fluorophore conjugated near its active site to probe the structural dynamics of the Ω-loop and to detect the binding of diverse substrates. Our results show that this engineered β-lactamase has improved binding kinetics and positive fluorescence signal toward oxyimino-cephalosporins, but shows little such effect to non-oxyimino-cephalosporins. Structural studies reveal that the Ω-loop adopts a less stabilized structure, and readily undergoes conformational change to accommodate the binding of bulky oxyimino-cephalosporins while no such change is observed for non-oxyimino-cephalosporins. Mutational studies further confirm that this substrate-induced structural change is directly responsible for the positive fluorescence signal specific to oxyimino-cephalosporins. Our data provide mechanistic evidence to support the long-standing model that the evolutionary strategy of mutating the Ω-loop leads to increased structural flexibility of this region, which in turn facilitates the binding of extended spectrum β-lactam antibiotics. The oxyimino-cephalosporin-specific fluorescence profile of our engineered β-lactamase also demonstrates the possibility of designing substrate-selective biosensing systems.

  1. The classical and alternative pathways of complement activation play distinct roles in spontaneous C3 fragment deposition and membrane attack complex (MAC) formation on human B lymphocytes

    DEFF Research Database (Denmark)

    Leslie, Robert Graham Quinton; Nielsen, Claus Henrik

    2004-01-01

    The contributions of the classical (CP) and alternative (AP) pathways of complement activation to the spontaneous deposition of C3 fragments and the formation of membrane attack complexes (MAC) on human B lymphocytes, were assessed by incubating peripheral blood mononuclear cells with autologous ...... of MAC formation was also found to be highly pathway dependent, with the AP being about 15-fold more efficient at initiating this process than the CP. A model accounting for the effectiveness of the AP in both preserving C3 fragment integrity and initiating MAC is presented....

  2. Two distinct voltage-sensing domains control voltage sensitivity and kinetics of current activation in CaV1.1 calcium channels.

    Science.gov (United States)

    Tuluc, Petronel; Benedetti, Bruno; Coste de Bagneaux, Pierre; Grabner, Manfred; Flucher, Bernhard E

    2016-06-01

    Alternative splicing of the skeletal muscle CaV1.1 voltage-gated calcium channel gives rise to two channel variants with very different gating properties. The currents of both channels activate slowly; however, insertion of exon 29 in the adult splice variant CaV1.1a causes an ∼30-mV right shift in the voltage dependence of activation. Existing evidence suggests that the S3-S4 linker in repeat IV (containing exon 29) regulates voltage sensitivity in this voltage-sensing domain (VSD) by modulating interactions between the adjacent transmembrane segments IVS3 and IVS4. However, activation kinetics are thought to be determined by corresponding structures in repeat I. Here, we use patch-clamp analysis of dysgenic (CaV1.1 null) myotubes reconstituted with CaV1.1 mutants and chimeras to identify the specific roles of these regions in regulating channel gating properties. Using site-directed mutagenesis, we demonstrate that the structure and/or hydrophobicity of the IVS3-S4 linker is critical for regulating voltage sensitivity in the IV VSD, but by itself cannot modulate voltage sensitivity in the I VSD. Swapping sequence domains between the I and the IV VSDs reveals that IVS4 plus the IVS3-S4 linker is sufficient to confer CaV1.1a-like voltage dependence to the I VSD and that the IS3-S4 linker plus IS4 is sufficient to transfer CaV1.1e-like voltage dependence to the IV VSD. Any mismatch of transmembrane helices S3 and S4 from the I and IV VSDs causes a right shift of voltage sensitivity, indicating that regulation of voltage sensitivity by the IVS3-S4 linker requires specific interaction of IVS4 with its corresponding IVS3 segment. In contrast, slow current kinetics are perturbed by any heterologous sequences inserted into the I VSD and cannot be transferred by moving VSD I sequences to VSD IV. Thus, CaV1.1 calcium channels are organized in a modular manner, and control of voltage sensitivity and activation kinetics is accomplished by specific molecular mechanisms

  3. Coordination polymers of Fe(iii) and Al(iii) ions with TCA ligand: distinctive fluorescence, CO2 uptake, redox-activity and oxygen evolution reaction.

    Science.gov (United States)

    Dhara, Barun; Sappati, Subrahmanyam; Singh, Santosh K; Kurungot, Sreekumar; Ghosh, Prasenjit; Ballav, Nirmalya

    2016-04-28

    Fe and Al belong to different groups in the periodic table, one from the p-block and the other from the d-block. In spite of their different groups, they have the similarity of exhibiting a stable 3+ oxidation state. Here we have prepared Fe(iii) and Al(iii) based coordination polymers in the form of metal-organic gels with the 4,4',4''-tricarboxyltriphenylamine (TCA) ligand, namely Fe-TCA and Al-TCA, and evaluated some important physicochemical properties. Specifically, the electrical conductivity, redox-activity, porosity, and electrocatalytic activity (oxygen evolution reaction) of the Fe-TCA system were noted to be remarkably higher than those of the Al-TCA system. As for the photophysical properties, almost complete quenching of the fluorescence originating from TCA was observed in case of the Fe-TCA system, whereas for the Al-TCA system a significant retention of fluorescence with red-shifted emission was observed. Quantum mechanical calculations based on density functional theory (DFT) were performed to unravel the origin of such discriminative behaviour of these coordination polymer systems.

  4. Acquired disorders of elastic tissue: Part II. decreased elastic tissue.

    Science.gov (United States)

    Lewis, Kevan G; Bercovitch, Lionel; Dill, Sara W; Robinson-Bostom, Leslie

    2004-08-01

    Elastic fibers in the extracellular matrix are integral components of dermal connective tissue. The resilience and elasticity required for normal structure and function of the skin are attributable to the network of elastic tissue. Advances in our understanding of elastic tissue physiology provide a foundation for studying the pathogenesis of elastic tissue disorders. Many acquired disorders are nevertheless poorly understood owing to the paucity of reported cases. Several acquired disorders in which loss of dermal elastic tissue produces prominent clinical and histopathologic features have recently been described, including middermal elastolysis, papular elastorrhexis, and pseudoxanthoma-like papillary dermal elastolysis, which must be differentiated from more well-known disorders such as anetoderma, acquired cutis laxa, and acrokeratoelastoidosis. Learning objective At the conclusion of this learning activity, participants should have an understanding of the similarities and differences between acquired disorders of elastic tissue that are characterized by a loss of elastic tissue.

  5. 12 CFR 583.1 - Acquire.

    Science.gov (United States)

    2010-01-01

    ... AND LOAN HOLDING COMPANIES § 583.1 Acquire. The term acquire means to acquire, directly or indirectly, ownership or control through an acquisition of shares, an acquisition of assets or assumption of liabilities, a merger or consolidation, or any similar transaction....

  6. Diagnosis and treatment of chronic acquired demyelinating polyneuropathies.

    Science.gov (United States)

    Latov, Norman

    2014-08-01

    Chronic neuropathies are operationally classified as primarily demyelinating or axonal, on the basis of electrodiagnostic or pathological criteria. Demyelinating neuropathies are further classified as hereditary or acquired-this distinction is important, because the acquired neuropathies are immune-mediated and, thus, amenable to treatment. The acquired chronic demyelinating neuropathies include chronic inflammatory demyelinating polyneuropathy (CIDP), neuropathy associated with monoclonal IgM antibodies to myelin-associated glycoprotein (MAG; anti-MAG neuropathy), multifocal motor neuropathy (MMN), and POEMS syndrome. They have characteristic--though overlapping--clinical presentations, are mediated by distinct immune mechanisms, and respond to different therapies. CIDP is the default diagnosis if the neuropathy is demyelinating and no other cause is found. Anti-MAG neuropathy is diagnosed on the basis of the presence of anti-MAG antibodies, MMN is characterized by multifocal weakness and motor conduction blocks, and POEMS syndrome is associated with IgG or IgA λ-type monoclonal gammopathy and osteosclerotic myeloma. The correct diagnosis, however, can be difficult to make in patients with atypical or overlapping presentations, or nondefinitive laboratory studies. First-line treatments include intravenous immunoglobulin (IVIg), corticosteroids or plasmapheresis for CIDP; IVIg for MMN; rituximab for anti-MAG neuropathy; and irradiation or chemotherapy for POEMS syndrome. A correct diagnosis is required for choosing the appropriate treatment, with the aim of preventing progressive neuropathy.

  7. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes

    DEFF Research Database (Denmark)

    Petrovic, Natasa; Walden, Tomas B; Shabalina, Irina G;

    2009-01-01

    The recent insight that brown adipocytes and muscle cells share a common origin and in this respect are distinct from white adipocytes has spurred questions concerning the origin and molecular characteristics of the UCP1-expressing cells observed in classic white adipose tissue depots under certain...

  8. Expression and characterization of SUMO-conjugated metal-responsive transcription factor 1: SIM-dependent cross-interaction and distinct DNA binding activity.

    Science.gov (United States)

    Lin, Chang-Yi; Liu, Ya-Chuan; Lin, Meng-Chieh; Thi Nguyen, Thao; Tam, Ming F; Chein, Chih-Yuan; Lin, Meng-Ting; Lin, Lih-Yuan

    2013-04-01

    Metal-responsive transcription factor 1 (MTF-1) regulates a variety of genes involving in metal homeostasis and oxidative stress. We have shown that MTF-1 can be conjugated by small ubiquitin-like modifier (SUMO) and forms complexes with cellular factor(s) in a SUMO-interacting motif (SIM)-dependent manner. To investigate whether the interaction of MTF-1 and its SUMO conjugate occurs, we expressed and isolated MTF-1 and sumoylated MTF-1 (S-MTF-1) for functional studies. Various conditions were examined to optimize the expressions of MTF-1 and S-MTF-1. Results from affinity column chromatography demonstrated that the unmodified MTF-1 consistently co-eluted with the S-MTF-1. Mutations at the SIM did not reduce the level of MTF-1 sumoylation but the sumoylated product can then be purified to homogeneity. The presence of MTF-1 cross-interaction was further supported by in vitro pull-down assays. The ability of the purified proteins in binding metal-responsive element (MRE) was assessed with electrophoretic mobility shift assay. Noticeably, MTF-1 required the presence of cell extracts to render the binding activity. However, S-MTF-1 binds MRE in void of other cellular factors. The same characteristic was found for MTF-1 with SUMO fusion at the carboxyl terminus. These results indicate that the presence of SUMO moiety allows the protein to interact directly with MRE.

  9. Depiction of carbohydrate-active enzyme diversity in Caldicellulosiruptor sp. F32 at the genome level reveals insights into distinct polysaccharide degradation features.

    Science.gov (United States)

    Meng, Dong-Dong; Ying, Yu; Zhang, Kun-Di; Lu, Ming; Li, Fu-Li

    2015-11-01

    Thermophilic bacterium Caldicellulosiruptor sp. F32 can utilize cellulose-, hemicellulose-containing biomass, including unpretreated wheat straw. We have conducted a bioinformatics analysis of the carbohydrate-active enzyme (CAZyme) in the genome of Caldicellulosiruptor sp. F32, which reveals a broad substrate range of the strain. Among 2285 predicted open reading frames (ORFs), 73 (3.2%) CAZyme encoding genes, including 44 glycoside hydrolases (GHs) distributing in 22 GH families, 6 carbohydrate esterases (CEs), 3 polysaccharide lyases (PLs), 21 glycosyl transferases (GTs), and 25 carbohydrate-binding modules (CBMs) were found. An in-depth bioinformatics analysis of CAZyme families that target cellulose, hemicellulose, chitin, pectin, starch, and β-1,3-1,4-glucan degradation were performed to highlight specialized polysaccharide degrading abilities of strain F32. A great number of orthologous multimodular CAZymes of Caldicellulosiruptor sp. F32 were found in other strains of genus Caldicellulosiruptor. While, a portion of the CAZymes of Caldicellulosiruptor sp. F32 showed sequence identity with proteins from strains of genus Clostridium. A thermostable β-glucosidase BlgA synergistically facilitated the enzymatic degradation of Avicel by endo-1,4-β-glucanase CelB, which indicated that the synchronous action of synergism between CAZymes enhanced the lignocellulose degradation by Caldicellulosiruptor sp. F32.

  10. Geochemical characterization of two distinctive systems with evidence of chemosynthetic activity, explored at the SE Pacific margin off Chile (46°S and 33°S)

    Science.gov (United States)

    Muñoz, Práxedes; Cárdenas, Lissette J.; Garbe-Schönberg, Dieter; Sellanes, Javier; Dezileau, Laurent; Melville, Ives; Mendes, Stephanie D.

    2016-11-01

    This study presents the geochemical composition of superficial sediment under oxic and suboxic bottom water conditions along the Chilean continental margin (SE Pacific), where evidence for benthic chemosynthetic activity associated with diffuse seeping of chemically reduced fluids has been reported. The exploration was carried out at: (1) the Chilean Triple Junction (CTJ), at a water depth of ∼2900 m, with the additional indication of hydrothermal activity near a methane-rich cold-seep area (46°S) (German et al., 2010); and (2) the El Quisco methane seep site (EQSS), at ∼340 m water depth (33°S) (Melo et al., 2007; Krylova et al., 2014). While the deeper CTJ is located within an oxic environment (dissolved oxygen in the bottom waters: 164 μM), the shallower EQSS lies within a suboxic environment (dissolved oxygen in bottom water: 23 μM), located within the lower limit of the SE Pacific oxygen minimum zone (OMZ). Pore water from short cores was analyzed for dissolved major, minor, and trace elements (Cl, Na, Mg, K, Ca, Sr, Si, B, P, Ba, Pb, Mn, Fe, Cd, U, and Mo), δ13DIC, sulfide, sulfate, and methane. The solid sediment fraction was likewise analyzed for total organic carbon (TOC), metals, and redox potential. Elevated sediment temperatures were found in superficial sediments (5-13 °C) at the CTJ site, which could be due to warm fluids associated with the proximity of the ridge, where hydrothermal vents may occur. Reduced fluids were also present here, indicated by higher Mn fluxes toward the water column even in oxidized sediments (RPD > 8 cm), which contrasted with the lower fluxes in reduced sediments of the EQSS site (RPD ∼ 2 cm). 13C-depleted DIC, anomalously low pore water Cl (∼15 ppb), and low concentrations of other major elements may be the result of dilution by fluid seeping and precipitation of major elements, producing authigenic enrichment (Ca, Mg, Sr). The fluid could also: (a) be diluted by pure water produced during methane hydrate

  11. Two distinct pools of large-conductance calcium-activated potassium channels in the somatic plasma membrane of central principal neurons

    Science.gov (United States)

    Kaufmann, W.A.; Kasugai, Y.; Ferraguti, F.; Storm, J.F.

    2010-01-01

    Although nerve cell membranes are often assumed to be uniform with respect to electrical properties, there is increasing evidence for compartmentalization into subdomains with heterogeneous impacts on the overall cell function. Such microdomains are characterized by specific sets of proteins determining their functional properties. Recently, clustering of large-conductance calcium-activated potassium (BKCa) channels was shown at sites of subsurface membrane cisterns in cerebellar Purkinje cells (PC), where they likely participate in building a subcellular signaling unit, the 'PLasmERosome'. By applying SDS-digested freeze-fracture replica labeling (SDS-FRL) and postembedding immunogold electron microscopy, we have now studied the spatial organization of somatic BKCa channels in neocortical layer 5 pyramidal neurons, principal neurons of the central and basolateral amygdaloid nuclei, hippocampal pyramidal neurons and dentate gyrus (DG) granule cells to establish whether there is a common organizational principle in the distribution of BKCa channels in central principal neurons. In all cell types analyzed, somatic BKCa channels were found to be non-homogenously distributed in the plasma membrane, forming two pools of channels with one pool consisting of clustered channels and the other of scattered channels in the extrasynaptic membrane. Quantitative analysis by means of SDS-FRL revealed that about two-thirds of BKCa channels belong to the scattered pool and about one-third to the clustered pool in principal cell somata. Overall densities of channels in both pools differed in the different cell types analyzed, although being considerably lower compared to cerebellar PC. Postembedding immunogold labeling revealed association of clustered channels with subsurface membrane cisterns and confirmed extrasynaptic localization of scattered channels. This study indicates a common organizational principle for somatic BKCa channels in central principal neurons with the

  12. Inherited or acquired metabolic disorders.

    Science.gov (United States)

    Eichler, Florian; Ratai, Eva; Carroll, Jason J; Masdeu, Joseph C

    2016-01-01

    This chapter starts with a description of imaging of inherited metabolic disorders, followed by a discussion on imaging of acquired toxic-metabolic disorders of the adult brain. Neuroimaging is crucial for the diagnosis and management of a number of inherited metabolic disorders. Among these, inherited white-matter disorders commonly affect both the nervous system and endocrine organs. Magnetic resonance imaging (MRI) has enabled new classifications of these disorders that have greatly enhanced both our diagnostic ability and our understanding of these complex disorders. Beyond the classic leukodystrophies, we are increasingly recognizing new hereditary leukoencephalopathies such as the hypomyelinating disorders. Conventional imaging can be unrevealing in some metabolic disorders, but proton magnetic resonance spectroscopy (MRS) may be able to directly visualize the metabolic abnormality in certain disorders. Hence, neuroimaging can enhance our understanding of pathogenesis, even in the absence of a pathologic specimen. This review aims to present pathognomonic brain MRI lesion patterns, the diagnostic capacity of proton MRS, and information from clinical and laboratory testing that can aid diagnosis. We demonstrate that applying an advanced neuroimaging approach enhances current diagnostics and management. Additional information on inherited and metabolic disorders of the brain can be found in Chapter 63 in the second volume of this series.

  13. Congenital and acquired mandibular asymmetry: Mapping growth and remodeling in 3 dimensions

    Science.gov (United States)

    Solem, R. Christian; Ruellas, Antonio; Miller, Arthur; Kelly, Katherine; Ricks-Oddie, Joni L.; Cevidanes, Lucia

    2016-01-01

    Introduction Disordered craniofacial development frequently results in definitive facial asymmetries that can significantly impact a person's social and functional well-being. The mandible plays a prominent role in defining facial symmetry and, as an active region of growth, commonly acquires asymmetric features. Additionally, syndromic mandibular asymmetry characterizes craniofacial microsomia (CFM), the second most prevalent congenital craniofacial anomaly (1:3000 to 1:5000 live births) after cleft lip and palate. We hypothesized that asymmetric rates of mandibular growth occur in the context of syndromic and acquired facial asymmetries. Methods To test this hypothesis, a spherical harmonic-based shape correspondence algorithm was applied to quantify and characterize asymmetries in mandibular growth and remodeling in 3 groups during adolescence. Longitudinal time points were automatically registered, and regions of the condyle and posterior ramus were selected for growth quantification. The first group (n = 9) had a diagnosis of CFM, limited to Pruzansky-Kaban type I or IIA mandibular deformities. The second group (n = 10) consisted of subjects with asymmetric, nonsyndromic dentofacial asymmetry requiring surgical intervention. A control group (n = 10) of symmetric patients was selected for comparison. A linear mixed model was used for the statistical comparison of growth asymmetry between the groups. Results Initial mandibular shape and symmetry displayed distinct signatures in the 3 groups (P < 0.001), with the greatest asymmetries in the condyle and ramus. Similarly, mandibular growth had unique patterns in the groups. The dentofacial asymmetry group was characterized by significant asymmetry in condylar and posterior ramal remodeling with growth (P < 0.001). The CFM group was characterized by asymmetric growth of the posterior ramus (P < 0.001) but relatively symmetric growth of the condyles (P = 0.47). Conclusions Forms of CFM are characterized by active and

  14. In vivo mechanisms of acquired thymic tolerance

    DEFF Research Database (Denmark)

    Chen, W; Issazadeh-Navikas, Shohreh; Sayegh, M H;

    1997-01-01

    Injection of antigen into the thymus of adult animals induces specific systemic tolerance, but the mechanisms of acquired thymic tolerance are not well understood. To investigate these mechanisms we used a model of intrathymic injection of ovalbumin (OVA) in BALB/c mice. We show an antigen......-specific decrease in proliferative responses to OVA, as well as a significant decrease in antigen-specific IL-2 secretion and IFN-gamma production by splenocytes and lymph node cells of tolerant mice. Addition of recombinant IL-2 in vitro reversed the defect in IFN-gamma production by cells from OVA-tolerized...... expansion of transferred CD4+ TCR transgenic cells in tolerant mice in vivo. There was an increase in clonotype-positive T cells in the thymus after immunization, confirming that activated T cells circulate through the thymus. Furthermore, thymectomy after intrathymic injection abrogates the effect...

  15. Acquired Localized Hypertrichosis Induced by Rivastigmine

    Science.gov (United States)

    Imbernón-Moya, Adrian; Podlipnik, Sebastian; Burgos, Fernando; Vargas-Laguna, Elena; Aguilar-Martínez, Antonio; Fernández-Cogolludo, Eva; Gallego-Valdes, Miguel Angel

    2016-01-01

    Hypertrichosis is the excessive hair growth in any area of the skin surface. Acquired localized hypertrichosis may be secondary to multiple causes and there is a secondary form due to several drugs, which is usually reversible with discontinuation of the causative agent. Rivastigmine is a reversible and competitive inhibitor of acetylcholinesterase and butyrylcholinesterase used for symptomatic treatment of Alzheimer dementia and Parkinson's disease. It has an adequate safety profile and cutaneous side effects are unusual. Irritant contact dermatitis, allergic dermatitis, baboon syndrome, and cutaneous rash due to rivastigmine have been reported. We report on a Caucasian 80-year-old male with personal history of Alzheimer's disease. The patient started therapy with oral rivastigmine one month prior to clinical presentation of localized hypertrichosis on both forearms. Norgalanthamine has been shown to promote hair growth activity via the proliferation of dermal papilla. Acetylcholinesterase inhibitors can induce hair growth. PMID:27073702

  16. Acquired Localized Hypertrichosis Induced by Rivastigmine

    Directory of Open Access Journals (Sweden)

    Adrian Imbernón-Moya

    2016-01-01

    Full Text Available Hypertrichosis is the excessive hair growth in any area of the skin surface. Acquired localized hypertrichosis may be secondary to multiple causes and there is a secondary form due to several drugs, which is usually reversible with discontinuation of the causative agent. Rivastigmine is a reversible and competitive inhibitor of acetylcholinesterase and butyrylcholinesterase used for symptomatic treatment of Alzheimer dementia and Parkinson’s disease. It has an adequate safety profile and cutaneous side effects are unusual. Irritant contact dermatitis, allergic dermatitis, baboon syndrome, and cutaneous rash due to rivastigmine have been reported. We report on a Caucasian 80-year-old male with personal history of Alzheimer’s disease. The patient started therapy with oral rivastigmine one month prior to clinical presentation of localized hypertrichosis on both forearms. Norgalanthamine has been shown to promote hair growth activity via the proliferation of dermal papilla. Acetylcholinesterase inhibitors can induce hair growth.

  17. Acquired hemophilia A in a patient with systemic lupus erythematosus.

    Science.gov (United States)

    Ishikawa, T; Tsukamoto, N; Suto, M; Uchiumi, H; Mitsuhashi, H; Yokohama, A; Maesawa, A; Nojima, Y; Naruse, T

    2001-06-01

    A patient with systemic lupus erythematosus (SLE) developed acquired hemophilia A. The patient, a 24-year-old Japanese woman, was referred to our hospital because of uncontrollable bleeding following a tooth extraction. Laboratory examination revealed prolonged APTT (116 seconds), reduced factor VIII activity (2.8 %) and the presence of factor VIII inhibitor at a titer of 46.5 Bethesda units/ml. Transfusion of prothrombin complex concentrate and activated prothrombin complex concentrate followed by administration of prednisolone and cyclophosphamide successfully arrested bleeding and reduced the factor VIII inhibitor level. Acquired hemophilia A is a rare but lethal condition. Rapid diagnosis and introduction of adequate therapies are critical.

  18. Community-acquired Acinetobacter baumannii: clinical characteristics, epidemiology and pathogenesis.

    Science.gov (United States)

    Dexter, Carina; Murray, Gerald L; Paulsen, Ian T; Peleg, Anton Y

    2015-05-01

    Community-acquired Acinetobacter baumannii (CA-Ab) is a rare but serious cause of community-acquired pneumonia in tropical regions of the world. CA-Ab infections predominantly affect individuals with risk factors, which include excess alcohol consumption, diabetes mellitus, smoking and chronic lung disease. CA-Ab pneumonia presents as a surprisingly fulminant course and is characterized by a rapid onset of fever, severe respiratory symptoms and multi-organ dysfunction, with a mortality rate reported as high as 64%. It is unclear whether the distinct clinical syndrome caused by CA-Ab is because of host predisposing factors or unique bacterial characteristics, or a combination of both. Deepening our understanding of the drivers of overwhelming CA-Ab infection will provide important insights into preventative and therapeutic strategies.

  19. 17 CFR 210.8-04 - Financial statements of businesses acquired or to be acquired.

    Science.gov (United States)

    2010-04-01

    ... businesses acquired or to be acquired. (a) If a business combination has occurred or is probable, financial... section. The required financial statements of related businesses may be presented on a combined basis for... financial statements of the business acquired or to be acquired and the smaller reporting company's...

  20. Idiopathic Acquired Hemophilia A with Undetectable Factor VIII Inhibitor

    Directory of Open Access Journals (Sweden)

    Nicholas B. Abt

    2014-01-01

    Full Text Available Objective. We present the case of a 73-year-old female, with no family or personal history of a bleeding disorder, who had a classic presentation for acquired hemophilia A. Factor VIII activity was low but detectable and a factor VIII inhibitor was undetectable. Methods. The patient’s plasma was comprehensively studied to determine the cause of the acquired coagulopathy. Using the Nijmegen modification of the Bethesda assay, no factor VIII autoantibody was measureable despite varying the incubation time from 1 to 3 hours. Results. The aPTT was prolonged at 46.8 seconds, which did not correct in the 4 : 1 mix but did with 1 : 1 mix. Using a one stage factor VIII activity assay, the FVIII activity was 16% and chromogenic FVIII activity was also 16%. The patient was treated with recombinant FVII and transfusion, significantly reducing bleeding. Long-term therapy was initiated with cyclophosphamide and prednisone with normalization of FVIII activity. Conclusions. Physicians can be presented with the challenging clinical picture of an acquired factor VIII inhibitor without a detectable inhibitor by the Bethesda assay. Standard therapy for an acquired hemophilia A should be considered.

  1. In vivo models of cortical acquired epilepsy.

    Science.gov (United States)

    Chauvette, Sylvain; Soltani, Sara; Seigneur, Josée; Timofeev, Igor

    2016-02-15

    The neocortex is the site of origin of several forms of acquired epilepsy. Here we provide a brief review of experimental models that were recently developed to study neocortical epileptogenesis as well as some major results obtained with these methods. Most of neocortical seizures appear to be nocturnal and it is known that neuronal activities reveal high levels of synchrony during slow-wave sleep. Therefore, we start the review with a description of mechanisms of neuronal synchronization and major forms of synchronized normal and pathological activities. Then, we describe three experimental models of seizures and epileptogenesis: ketamine-xylazine anesthesia as feline seizure triggered factor, cortical undercut as cortical penetrating wound model and neocortical kindling. Besides specific technical details describing these models we also provide major features of pathological brain activities recorded during epileptogenesis and seizures. The most common feature of all models of neocortical epileptogenesis is the increased duration of network silent states that up-regulates neuronal excitability and eventually leads to epilepsy.

  2. Ceftobiprole medocaril in the treatment of hospital-acquired pneumonia

    NARCIS (Netherlands)

    Scheeren, Thomas W. L.

    2015-01-01

    Ceftobiprole medocaril is a fifth-generation cephalosporin approved in Europe as single-agent therapy for hospital-acquired pneumonia (HAP), excluding ventilator-associated pneumonia (VAP). It is rapidly converted to the active metabolite ceftobiprole following intravenous administration. Ceftobipro

  3. Sym004, a Novel EGFR Antibody Mixture, Can Overcome Acquired Resistance to Cetuximab

    Directory of Open Access Journals (Sweden)

    Mari Iida

    2013-10-01

    Full Text Available The epidermal growth factor receptor (EGFR is a central regulator of tumor progression in a variety of human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for head and neck and colorectal cancer treatment, but many patients treated with cetuximab don't respond or eventually acquire resistance. To determine how tumor cells acquire resistance to cetuximab, we previously developed a model of acquired resistance using the non-small cell lung cancer line NCI-H226. These cetuximab-resistant (CtxR cells exhibit increased steady-state EGFR expression secondary to alterations in EGFR trafficking and degradation and, further, retained dependence on EGFR signaling for enhanced growth potential. Here, we examined Sym004, a novel mixture of antibodies directed against distinct epitopes on the extracellular domain of EGFR, as an alternative therapy for CtxR tumor cells. Sym004 treatment of CtxR clones resulted in rapid EGFR degradation, followed by robust inhibition of cell proliferation and down-regulation of several mitogen-activated protein kinase pathways. To determine whether Sym004 could have therapeutic benefit in vivo, we established de novo CtxR NCI-H226 mouse xenografts and subsequently treated CtxR tumors with Sym004. Sym004 treatment of mice harboring CtxR tumors resulted in growth delay compared to mice continued on cetuximab. Levels of total and phospho-EGFR were robustly decreased in CtxR tumors treated with Sym004. Immunohistochemical analysis of these Sym004-treated xenograft tumors further demonstrated decreased expression of Ki67, and phospho-rpS6, as well as a modest increase in cleaved caspase-3. These results indicate that Sym004 may be an effective targeted therapy for CtxR tumors.

  4. Mast cell differentiation and activation is closely linked to expression of genes coding for the serglycin proteoglycan core protein and a distinct set of chondroitin sulfate and heparin sulfotransferases.

    Science.gov (United States)

    Duelli, Annette; Rönnberg, Elin; Waern, Ida; Ringvall, Maria; Kolset, Svein O; Pejler, Gunnar

    2009-12-01

    Serglycin (SG) proteoglycan consists of a small core protein to which glycosaminoglycans of chondroitin sulfate or heparin type are attached. SG is crucial for maintaining mast cell (MC) granule homeostasis through promoting the storage of various basic granule constituents, where the degree of chondroitin sulfate/heparin sulfation is essential for optimal SG functionality. However, the regulation of the SG core protein expression and of the various chondroitin sulfate/heparin sulfotransferases during MC differentiation and activation are poorly understood. Here we addressed these issues and show that expression of the SG core protein, chondroitin 4-sulfotransferase (C4ST)-1, and GalNAc(4S)-6-O-sulfotransferase (GalNAc4S6ST) are closely linked to MC maturation. In contrast, the expression of chondroitin 6-sulfotransferase correlated negatively with MC maturation. The expression of N-deacetylase/N-sulfotransferase (NDST)-2, a key enzyme in heparin synthesis, also correlated strongly with MC maturation, whereas the expression of the NDST-1 isoform was approximately equal at all stages of maturation. MC activation by either calcium ionophore or IgE ligation caused an up-regulated expression of the SG core protein, C4ST-1, and GalNAc4S6ST, accompanied by increased secretion of chondroitin sulfate as shown by biosynthetic labeling experiments. In contrast, NDST-2 was down-regulated after MC activation, suggesting that MC activation modulates the nature of the glycosaminoglycan chains attached to the SG core protein. Taken together, these data show that MC maturation is associated with the expression of a distinct signature of genes involved in SG proteoglycan synthesis, and that MC activation modulates their expression.

  5. Active and accurate trans-translation requires distinct determinants in the C-terminal tail of SmpB protein and the mRNA-like domain of transfer messenger RNA (tmRNA).

    Science.gov (United States)

    Camenares, Devin; Dulebohn, Daniel P; Svetlanov, Anton; Karzai, A Wali

    2013-10-18

    Unproductive ribosome stalling in eubacteria is resolved by the actions of SmpB protein and transfer messenger (tm) RNA. We examined the functional significance of conserved regions of SmpB and tmRNA to the trans-translation process. Our investigations reveal that the N-terminal 20 residues of SmpB, which are located near the ribosomal decoding center, are dispensable for all known SmpB activities. In contrast, a set of conserved residues that reside at the junction between the tmRNA-binding core and the C-terminal tail of SmpB play an important role in tmRNA accommodation. Our data suggest that the highly conserved glycine 132 acts as a flexible hinge that enables movement of the C-terminal tail, thus permitting proper positioning and establishment of the tmRNA open reading frame (ORF) as the surrogate template. To gain further insights into the function of the SmpB C-terminal tail, we examined the tagging activity of hybrid variants of tmRNA and the SmpB protein, in which the tmRNA ORF or the SmpB C-terminal tail was substituted with the equivalent but highly divergent sequences from Francisella tularensis. We observed that the hybrid tmRNA was active but resulted in less accurate selection of the resume codon. Cognate hybrid SmpB was necessary to restore activity. Furthermore, accurate tagging was observed when the identity of the resume codon was reverted from GGC to GCA. Taken together, these data suggest that the engagement of the tmRNA ORF and the selection of the correct translation resumption point are distinct activities that are influenced by independent tmRNA and SmpB determinants.

  6. 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.

  7. Is Face Distinctiveness Gender Based?

    Science.gov (United States)

    Baudouin, Jean-Yves; Gallay, Mathieu

    2006-01-01

    Two experiments were carried out to study the role of gender category in evaluations of face distinctiveness. In Experiment 1, participants had to evaluate the distinctiveness and the femininity-masculinity of real or artificial composite faces. The composite faces were created by blending either faces of the same gender (sexed composite faces,…

  8. And the Winner is – Acquired

    DEFF Research Database (Denmark)

    Henkel, Joachim; Rønde, Thomas; Wagner, Marcus

    value in case of success—that is, a more radical innovation. In the second stage, successful entrants bid to be acquired by the incumbent. We assume that entrants cannot survive on their own, so being acquired amounts to a ‘prize’ in a contest. We identify an equilibrium in which the incumbent chooses...

  9. Optimal Distinctiveness Signals Membership Trust.

    Science.gov (United States)

    Leonardelli, Geoffrey J; Loyd, Denise Lewin

    2016-07-01

    According to optimal distinctiveness theory, sufficiently small minority groups are associated with greater membership trust, even among members otherwise unknown, because the groups are seen as optimally distinctive. This article elaborates on the prediction's motivational and cognitive processes and tests whether sufficiently small minorities (defined by relative size; for example, 20%) are associated with greater membership trust relative to mere minorities (45%), and whether such trust is a function of optimal distinctiveness. Two experiments, examining observers' perceptions of minority and majority groups and using minimal groups and (in Experiment 2) a trust game, revealed greater membership trust in minorities than majorities. In Experiment 2, participants also preferred joining minorities over more powerful majorities. Both effects occurred only when minorities were 20% rather than 45%. In both studies, perceptions of optimal distinctiveness mediated effects. Discussion focuses on the value of relative size and optimal distinctiveness, and when membership trust manifests.

  10. Community-Acquired Methicillin-Resistant "Staphylococcus aureus": Considerations for School Nurses

    Science.gov (United States)

    Alex, Aniltta; Letizia, MariJo

    2007-01-01

    Methicillin-resistant "Staphylococcus aureus" (MRSA) is a disease-causing organism that has been present in hospital settings since the 1960s. However, a genetically distinct strain of MRSA, called community-acquired methicillin-resistant "Staphylococcus aureus" (CA-MRSA), has emerged in recent years in community settings among healthy…

  11. Pathology of thyroid in acquired immunodeficiency syndrome

    Directory of Open Access Journals (Sweden)

    Dhaneshwar Namdeorao Lanjewar

    2016-01-01

    Full Text Available Background: The course of human immunodeficiency virus infection and the acquired immunodeficiency syndrome can be complicated by a variety of endocrine abnormalities, including abnormalities of thyroid gland. Materials and Methods: This study was designed to understand the spectrum of pathology of thyroid in Indian patients with AIDS. The present study describes the findings of retrospective autopsy findings of 158 patients with AIDS which revealed infectious diseases from a time period before the use of highly active antiretroviral regimen. Results: A wide range of bacterial, fungal, and viral infections were observed. Tuberculosis was recorded in 14 (09% patients, Cryptococcus neoformans in 11 (7% patients and cytomegalovirus in 3 (2% patients. Hashimoto's thyroiditis and lymphocytic thyroiditis were seen in 02 (01% patients each. One patient had dual infection comprising of tuberculosis and cytomegalovirus infection. The other microscopic findings observed were goiter (2 patients, interstitial fibrosis in thyroid (7 patients, and calcification in thyroid (8 patients. Conclusions: Abnormalities of thyroid are uncommon findings in patients with HIV infection however several case reports of thyroid involvement by infectious agents and neoplasm are described in these patients; hence patients with HIV infection should be closely followed up for development of goiter or abnormalities of thyroid functions.

  12. 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...

  13. 7 CFR 926.10 - Acquire.

    Science.gov (United States)

    2010-01-01

    ... of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE DATA COLLECTION, REPORTING AND RECORDKEEPING REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire....

  14. Hospital-Acquired Condition Reduction Program

    Data.gov (United States)

    U.S. Department of Health & Human Services — In October 2014, CMS began reducing Medicare payments for subsection (d) hospitals that rank in the worst performing quartile with respect to hospital-acquired...

  15. Enhancing Medicares Hospital Acquired Conditions Policy

    Data.gov (United States)

    U.S. Department of Health & Human Services — The current Medicare policy of non-payment to hospitals for Hospital Acquired Conditions (HAC) seeks to avoid payment for preventable complications identified within...

  16. CD133/CD15 defines distinct cell subpopulations with differential in vitro clonogenic activity and stem cell-related gene expression profile in in vitro propagated glioblastoma multiforme-derived cell line with a PNET-like component.

    Science.gov (United States)

    Kahlert, Ulf D; Bender, Noemi O; Maciaczyk, Donata; Bogiel, Tomasz; Bar, Eli E; Eberhart, Charles G; Nikkhah, Guido; Maciaczyk, Jarosław

    2012-01-01

    Glioblastoma multiforme (GBM), as many other solid tumours, contains a subpopulation of cells termed cancer stem-like cells responsible for the initiation and propagation of tumour growth. However, a unique immunophenotype/surface antigen composition for the clear identification of brain tumour stem cells (BTSC) has not yet been found. Here we report a novel code of cell surface markers for the identification of different cell subpopulations in neurospheres derived from a GBM with a primitive neuroectodermal tumour (PNET)-like component (GBM-PNET). These subgroups differ in their CD133/CD15 expression pattern and resemble cells with different stem-like genotype and developmental pathway activation levels. Strikingly, clonogenic analysis of cultures differentially expressing the investigated markers enabled the identification of distinct subpopulations of cells endowed with stem cell characteristics. High clonogenicity could be found in CD133(-)/CD15(-) and CD133(+)/CD15(+) but not in CD133(-)/CD15(+) cells. Moreover, cell subpopulations with pronounced clonogenic growth were characterized by high expression of stem cell-related genes. Interestingly, these observations were unique for GBM-PNET and differed from ordinary GBM cultures derived from tumours lacking a PNET component. This work elucidates the complex molecular heterogeneity of in vitro propagated glioblastoma-derived cells and potentially contributes to the development of novel diagnostic modalities aiming at the identification of the brain tumour stem-like cell population in a subgroup of GBMs.

  17. Acquiring Evolving Technologies: Web Services Standards

    Science.gov (United States)

    2016-06-30

    2006 Carnegie Mellon University Acquiring Evolving Technologies: Web Services Standards Harry L. Levinson Software Engineering Institute Carnegie...Acquiring Evolving Technologies: Web Services Standards 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...NUMBER OF PAGES 22 19a. NAME OF RESPONSIBLE PERSON a. REPORT unclassified b. ABSTRACT unclassified c. THIS PAGE unclassified Standard Form

  18. Acquired uniparental disomy in myeloproliferative neoplasms.

    Science.gov (United States)

    Score, Joannah; Cross, Nicholas C P

    2012-10-01

    The finding of somatically acquired uniparental disomy, where both copies of a chromosome pair or parts of chromosomes have originated from one parent, has led to the discovery of several novel mutated genes in myeloproliferative neoplasms and related disorders. This article examines how the development of single nucleotide polymorphism array technology has facilitated the identification of regions of acquired uniparental disomy and has led to a much greater understanding of the molecular pathology of these heterogeneous diseases.

  19. Acquiring Secure Systems Through Information Economics

    Science.gov (United States)

    2015-05-01

    Acquiring Secure Systems Through Information Economics Chad Dacus Research Professor of Defense Economics Air Force Research Institute Dr. Pano...to 00-00-2015 4. TITLE AND SUBTITLE Acquiring Secure Systems Through Information Economics 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM...If adversary can hack into mission essential software/hardware, then mission is compromised • Mission assurance requires materiel solutions, educated

  20. Acquired pure red cell aplasia in children

    Directory of Open Access Journals (Sweden)

    Sujata R Dafale

    2012-01-01

    Full Text Available Acquired Pure Red Cell Aplasia (PRCA is a rare occurrence in children.This is a case of an eight year old girl child who developed acquired PRCA secondary to long term intake of sodium Valproate. This case is reported to review the causes of PRCA in children and to reconsider the use of drugs of longer duration in children and adults.

  1. Acquired factor VIII inhibitor syndrome: A rare cause of hematuria

    Directory of Open Access Journals (Sweden)

    Muthuvel Seral Kannan

    2015-01-01

    Full Text Available A 50-year-old woman presented with gross hematuria for 1 month. Clinical examinations, laboratory investigations, ultrasound and contrast computed tomography were normal, except anemia. Cystoscopy revealed bloody efflux from the right side. Retrograde pyelogram showed filling defect in the renal pelvis and biopsy was inconclusive. Renal angiogram was normal. She developed ecchymosis on the right thigh and arm with elevated activated partial thromboplastin time. The partial thromboplastin time correction study and Bethesda study confirmed the presence of acquired factor VIII inhibitor (acquired hemophilia. With flexible ureterorenoscopy, the mass in the renal pelvis was removed and its histopathology revealed clotted blood. The patient was subsequently managed with steroids and Factor eight inhibitor bypass activity.

  2. Chapter 22: Hereditary and acquired angioedema.

    Science.gov (United States)

    Georgy, Mary S; Pongracic, Jacqueline A

    2012-01-01

    Hereditary angioedema (HAE) is an autosomal dominant disorder defined by a deficiency of functional C1 esterase inhibitor (C1-INH). Acquired angioedema (AAE) is caused by either consumption (type 1) or inactivation (type 2) of CI-INH. Both HAE and AAE can be life-threatening. The screening test for both conditions is complement component C4, which is low to absent at times of angioedema or during quiescent periods. A useful test to differentiate HAE from AAE is C1q protein, which is normal in HAE and low in AAE. There are three types of HAE: type 1 HAE is most common, occurring in ∼85% of patients and characterized by decreased production of C1-INH, resulting in reduced functional activity to 5-30% of normal. In type 2, which occurs in 15% of cases, C1-INH is detectable in normal or elevated quantities but is dysfunctional. Finally, type 3, which is rare and almost exclusively occurs in women, is estrogen dependent and associated with normal CI-INH and C4 levels. One-third of these patients have a gain-of-function mutation in clotting factor XII leading to kallikrein-driven bradykinin production. Although the anabolic steroid, danazol, is useful in increasing the concentration of C4 and reducing the episodes of angioedema in HAE and AAE, it has expected adverse effects. Fortunately, disease-specific therapies are available and include C1-INH enzyme for i.v. infusion either acutely or empirically, ecallantide, an inhibitor of kallikrein, and icatibant, a bradykinin B2-receptor antagonist, both approved for acute angioedema and administered, subcutaneously.

  3. Seeing the eyes in acquired prosopagnosia.

    Science.gov (United States)

    Pancaroglu, Raika; Hills, Charlotte S; Sekunova, Alla; Viswanathan, Jayalakshmi; Duchaine, Brad; Barton, Jason J S

    2016-08-01

    Case reports have suggested that perception of the eye region may be impaired more than that of other facial regions in acquired prosopagnosia. However, it is unclear how frequently this occurs, whether such impairments are specific to a certain anatomic subtype of prosopagnosia, and whether these impairments are related to changes in the scanning of faces. We studied a large cohort of 11 subjects with this rare disorder, who had a variety of occipitotemporal or anterior temporal lesions, both unilateral and bilateral. Lesions were characterized by functional and structural imaging. Subjects performed a perceptual discrimination test in which they had to discriminate changes in feature position, shape, or external contour. Test conditions were manipulated to stress focused or divided attention across the whole face. In a second experiment we recorded eye movements while subjects performed a face memory task. We found that greater impairment for eye processing was more typical of subjects with occipitotemporal lesions than those with anterior temporal lesions. This eye selectivity was evident for both eye position and shape, with no evidence of an upper/lower difference for external contour. A greater impairment for eye processing was more apparent under attentionally more demanding conditions. Despite these perceptual deficits, most subjects showed a normal tendency to scan the eyes more than the mouth. We conclude that occipitotemporal lesions are associated with a partially selective processing loss for eye information and that this deficit may be linked to loss of the right fusiform face area, which has been shown to have activity patterns that emphasize the eye region.

  4. Acquired antiprothrombin antibodies: an unusual cause of bleeding

    OpenAIRE

    Carvalho, Cristiana; Viveiro, Carolina; Maia, Paulo; Rezende, Teresa

    2013-01-01

    Acquired inhibitors of coagulation causing bleeding manifestations are rare in children. They emerge, normally in the context of autoimmune diseases or drug ingestion, but transient and self-limiting cases can occur after viral infection. We describe, an otherwise healthy, 7-year-old girl who had gingival bleeding after a tooth extraction. The prothrombin time (PT) and the activated partial thromboplastin time (APTT) were both prolonged with evidence of an immediate acting inhibitor (lupic an...

  5. Response to mTOR inhibition: activity of eIF4E predicts sensitivity in cell lines and acquired changes in eIF4E regulation in breast cancer

    Directory of Open Access Journals (Sweden)

    Bartlett John MS

    2011-02-01

    Full Text Available Abstract Background Inhibitors of the kinase mTOR, such as rapamycin and everolimus, have been used as cancer therapeutics with limited success since some tumours are resistant. Efforts to establish predictive markers to allow selection of patients with tumours likely to respond have centred on determining phosphorylation states of mTOR or its targets 4E-BP1 and S6K in cancer cells. In an alternative approach we estimated eIF4E activity, a key effector of mTOR function, and tested the hypothesis that eIF4E activity predicts sensitivity to mTOR inhibition in cell lines and in breast tumours. Results We found a greater than three fold difference in sensitivity of representative colon, lung and breast cell lines to rapamycin. Using an assay to quantify influences of eIF4E on the translational efficiency specified by structured 5'UTRs, we showed that this estimate of eIF4E activity was a significant predictor of rapamycin sensitivity, with higher eIF4E activities indicative of enhanced sensitivity. Surprisingly, non-transformed cell lines were not less sensitive to rapamycin and did not have lower eIF4E activities than cancer lines, suggesting the mTOR/4E-BP1/eIF4E axis is deregulated in these non-transformed cells. In the context of clinical breast cancers, we estimated eIF4E activity by analysing expression of eIF4E and its functional regulators within tumour cells and combining these scores to reflect inhibitory and activating influences on eIF4E. Estimates of eIF4E activity in cancer biopsies taken at diagnosis did not predict sensitivity to 11-14 days of pre-operative everolimus treatment, as assessed by change in tumour cell proliferation from diagnosis to surgical excision. However, higher pre-treatment eIF4E activity was significantly associated with dramatic post-treatment changes in expression of eIF4E and 4E-binding proteins, suggesting that eIF4E is further deregulated in these tumours in response to mTOR inhibition. Conclusions

  6. A high-resolution computed tomography-based scoring system to differentiate the most infectious active pulmonary tuberculosis from community-acquired pneumonia in elderly and non-elderly patients

    Energy Technology Data Exchange (ETDEWEB)

    Yeh, Jun-Jun [Ditmanson Medical Foundation Chia-Yi Christian Hospital, Section of Thoracic Imaging, Department of Chest Medicine and Family Medicine, Chiayi City (China); Chia Nan University of Pharmacy and Science, Tainan (China); Meiho University, Pingtung (China); Pingtung Christian Hospital, Pingtung (China); Chen, Solomon Chih-Cheng; Chen, Cheng-Ren [Ditmanson Medical Foundation Chia-Yi Christian Hospital, Department of Medical Research, Chiayi City (China); Yeh, Ting-Chun; Lin, Hsin-Kai; Hong, Jia-Bin; Wu, Bing-Tsang [Ditmanson Medical Foundation Chia-Yi Christian Hospital, Department of Family Medicine, Chiayi City (China); Wu, Ming-Ting [Department of Radiology, Kaohsiung Veterans General Hospital, Section of Thoracic and Circulation Imaging, Kaohsiung (China); School of Medicine, National Yang Ming University, Faculty of Medicine, Taipei (China)

    2014-10-15

    The objective of this study was to use high-resolution computed tomography (HRCT) imaging to predict the presence of smear-positive active pulmonary tuberculosis (PTB) in elderly (at least 65 years of age) and non-elderly patients (18-65 years of age). Patients with active pulmonary infections seen from November 2010 through December 2011 received HRCT chest imaging, sputum smears for acid-fast bacilli and sputum cultures for Mycobacterium tuberculosis. Smear-positive PTB was defined as at least one positive sputum smear and a positive culture for M. tuberculosis. Multivariate logistic regression analyses were performed to determine the HRCT predictors of smear-positive active PTB, and a prediction score was developed on the basis of receiver operating characteristic curve analysis. Of 1,255 patients included, 139 were diagnosed with smear-positive active PTB. According to ROC curve analysis, the sensitivity, specificity, positive predictive value, negative predictive value, false positive rates and false negative rates were 98.6 %, 95.8 %, 78.5 %, 99.8 %, 4.2 % and 1.4 %, respectively, for diagnosing smear-positive active PTB in elderly patients, and 100.0 %, 96.9 %, 76.5 %, 100.0 %, 3.1 % and 0.0 %, respectively, for non-elderly patients. HRCT can assist in the early diagnosis of the most infectious active PTB, thereby preventing transmission and minimizing unnecessary immediate respiratory isolation. (orig.)

  7. Defining poverty as distinctively human

    Directory of Open Access Journals (Sweden)

    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.

  8. Educational Psychology: The Distinctive Contribution

    Science.gov (United States)

    Cameron, R. J.

    2006-01-01

    This paper, written in the twenty-first anniversary year of the journal "Educational Psychology in Practice", attempts to uncover those distinctive aspects of the discipline and the practice of applied psychology in general and educational psychology in particular. After considering some of the reasons for attempting this task at this point in…

  9. Cellular memory of acquired stress resistance in Saccharomyces cerevisiae.

    Science.gov (United States)

    Guan, Qiaoning; Haroon, Suraiya; Bravo, Diego González; Will, Jessica L; Gasch, Audrey P

    2012-10-01

    Cellular memory of past experiences has been observed in several organisms and across a variety of experiences, including bacteria "remembering" prior nutritional status and amoeba "learning" to anticipate future environmental conditions. Here, we show that Saccharomyces cerevisiae maintains a multifaceted memory of prior stress exposure. We previously demonstrated that yeast cells exposed to a mild dose of salt acquire subsequent tolerance to severe doses of H(2)O(2). We set out to characterize the retention of acquired tolerance and in the process uncovered two distinct aspects of cellular memory. First, we found that H(2)O(2) resistance persisted for four to five generations after cells were removed from the prior salt treatment and was transmitted to daughter cells that never directly experienced the pretreatment. Maintenance of this memory did not require nascent protein synthesis after the initial salt pretreatment, but rather required long-lived cytosolic catalase Ctt1p that was synthesized during salt exposure and then distributed to daughter cells during subsequent cell divisions. In addition to and separable from the memory of H(2)O(2) resistance, these cells also displayed a faster gene-expression response to subsequent stress at >1000 genes, representing transcriptional memory. The faster gene-expression response requires the nuclear pore component Nup42p and serves an important function by facilitating faster reacquisition of H(2)O(2) tolerance after a second cycle of salt exposure. Memory of prior stress exposure likely provides a significant advantage to microbial populations living in ever-changing environments.

  10. 17 CFR 210.3-05 - Financial statements of businesses acquired or to be acquired.

    Science.gov (United States)

    2010-04-01

    ... General Instructions As to Financial Statements § 210.3-05 Financial statements of businesses acquired or... financial statements of related businesses may be presented on a combined basis for any periods they are... registered to be offered to the security holders of the business to be acquired, the financial...

  11. 17 CFR 210.8-06 - Real estate operations acquired or to be acquired.

    Science.gov (United States)

    2010-04-01

    ... rental market, comparative rents, occupancy rates) and expenses (including but not limited to, utilities... 17 Commodity and Securities Exchanges 2 2010-04-01 2010-04-01 false Real estate operations acquired or to be acquired. 210.8-06 Section 210.8-06 Commodity and Securities Exchanges SECURITIES...

  12. Acquired antiprothrombin antibodies: an unusual cause of bleeding.

    Science.gov (United States)

    Carvalho, Cristiana; Viveiro, Carolina; Maia, Paulo; Rezende, Teresa

    2013-01-07

    Acquired inhibitors of coagulation causing bleeding manifestations are rare in children. They emerge, normally in the context of autoimmune diseases or drug ingestion, but transient and self-limiting cases can occur after viral infection. We describe, an otherwise healthy, 7-year-old girl who had gingival bleeding after a tooth extraction. The prothrombin time (PT) and the activated partial thromboplastin time (APTT) were both prolonged with evidence of an immediate acting inhibitor (lupic anticoagulant). Further coagulation studies demonstrated prothrombin (FII) deficiency and prothrombin directed (FII) antibodies. The serological tests to detect an underlying autoimmune disease were all negative. The coagulation studies normalised alongside the disappearance of the antibody. This article presents lupus anticoagulant hypoprothrombinaemia syndrome (LAHS) as a rare case of acquired bleeding diathesis in childhood.

  13. Acquiring Word-Meaning Mappings for Natural Language Interfaces

    CERN Document Server

    Thompson, C

    2011-01-01

    This paper focuses on a system, WOLFIE (WOrd Learning From Interpreted Examples), that acquires a semantic lexicon from a corpus of sentences paired with semantic representations. The lexicon learned consists of phrases paired with meaning representations. WOLFIE is part of an integrated system that learns to transform sentences into representations such as logical database queries. Experimental results are presented demonstrating WOLFIE's ability to learn useful lexicons for a database interface in four different natural languages. The usefulness of the lexicons learned by WOLFIE are compared to those acquired by a similar system, with results favorable to WOLFIE. A second set of experiments demonstrates WOLFIE's ability to scale to larger and more difficult, albeit artificially generated, corpora. In natural language acquisition, it is difficult to gather the annotated data needed for supervised learning; however, unannotated data is fairly plentiful. Active learning methods attempt to select for annotation...

  14. Monitoring Agitated Behavior After acquired Brain Injury

    DEFF Research Database (Denmark)

    Aadal, Lena; Mortensen, Jesper; Nielsen, Jørgen Feldbaek

    2016-01-01

    Purpose: To describe the onset, duration, intensity, and nursing shift variation of agitated behavior in patients with acquired brain injury (ABI) at a rehabilitation hospital. Design: Prospective descriptive study. Methods: A total of 11 patients with agitated behavior were included. Agitated...

  15. Acquired antibiotic resistance genes:an overview

    NARCIS (Netherlands)

    Hoek, A.H. van; Mevius, D.; Guerra, B.; Mullany, P.; Robberts, A.P.

    2011-01-01

    In this review an overview is given on antibiotic resistance (AR) mechanisms with special attentions to the AR genes described so far preceded by a short introduction on the discovery and mode of action of the different classes of antibiotics. As this review is only dealing with acquired resistance,

  16. Acquired antibiotic resistance genes: an overview

    NARCIS (Netherlands)

    Hoek, van A.H.; Mevius, D.J.; Guerra, B.; Mullany, P.; Roberts, A.P.; Aarts, H.J.

    2011-01-01

    In this review an overview is given on antibiotic resistance (AR) mechanisms with special attentions to the AR genes described so far preceded by a short introduction on the discovery and mode of action of the different classes of antibiotics. As this review is only dealing with acquired resistance,

  17. Acquired double pylorus:A case report

    Institute of Scientific and Technical Information of China (English)

    Qing-Yu Chen; Yan Chen; Liang; Jing Wang; Qin Du; Jian-Ting Cai; Jia-Min Chen

    2012-01-01

    Double pylorus is one of the rare anomalies of the gastrointestinal tract, it can be congenital or acquired. In this case we report a case of double pylorus because of chronic peptic ulcer. Upper GI endoscopy revealed gastroduodenal fistula located on the lesser curve of the antrum, the patient's symptoms were improved rapidly by intensive antiulcer treatment.

  18. Acquired nasal deformities in fighter pilots.

    Science.gov (United States)

    Schreinemakers, Joyce R C; van Amerongen, Pieter; Kon, Moshe

    2010-07-01

    Fighter pilots may develop slowly progressive deformities of their noses during their flying careers. The spectrum of deformities that may be acquired ranges from soft tissue to osseous changes. The main cause is the varying pressure exerted by the oxygen mask on the skin and bony pyramid of the nose during flying.

  19. Sexually acquired Salmonella Typhi urinary tract infection.

    Science.gov (United States)

    Wielding, Sally; Scott, Gordon

    2016-05-01

    We report a case of isolated urinary Salmonella enterica serotype Typhi in an HIV-positive man who has sex with men. He was clinically well and blood and stool cultures were negative, indicating that this may have been a sexually acquired urinary tract infection.

  20. Acquired Demyelinating Syndromes and Pediatric Multiple Sclerosis

    NARCIS (Netherlands)

    I.A. Ketelslegers (Immy)

    2014-01-01

    markdownabstract__Abstract__ Acquired inflammatory demyelinating diseases of the central nervous system (CNS) cause damage to myelin sheaths and typically result in white matter lesions due to inflammation, myelin loss and axonal pathology. Clinically, this may result in transient, relapsing or pro

  1. Mitral valve repair in acquired dextrocardia.

    Science.gov (United States)

    Elmistekawy, Elsayed; Chan, Vincent; Hynes, Mark; Mesana, Thierry

    2015-10-01

    Surgical correction of valvular heart disease in patients with dextrocardia is extremely rare. We report a surgical case of mitral valve repair in a patient with acquired dextrocardia. Successful mitral valve repair was performed through a right lateral thoracotomy. We describe our surgical strategy and summarize the literature.

  2. Severe acquired anaemia in Africa: new concepts

    NARCIS (Netherlands)

    M. Boele van Hensbroek; F. Jonker; I. Bates

    2011-01-01

    Severe anaemia is common in Africa. It has a high mortality and particularly affects young children and pregnant women. Recent research provides new insights into the mechanisms and causes of severe acquired anaemia and overturns accepted dogma. Deficiencies of vitamin B12 and vitamin A, but not of

  3. Chronic Acquired Demyelinating Polyneuropathy following Renal Transplantation

    OpenAIRE

    Younger, D. S.; Stuart Orsher

    2013-01-01

    The clinical, laboratory, and treatment findings of a patient with chronic acquired demyelinating polyneuropathy (CADP) in association with renal transplantation are described. Like the present case, many such patients have been described under the rubric of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

  4. ACQUIRED CUTIS LAXA WITH RECURRENT URTICARIA

    Directory of Open Access Journals (Sweden)

    Ganaparthi

    2015-05-01

    Full Text Available A 30 year old male patient presented with progressive laxity and wrinkling of skin over the face for past 10 years, patient also gives history of recurrent urticaria since 12 years. Skin biopsy using Verhoff Van Gieson stain suggestive of cutis laxa. We are reporting a rare case of acquired cutis laxa with recurrent urticaria

  5. Grima: A Distinct Emotion Concept?

    Science.gov (United States)

    Schweiger Gallo, Inge; Fernández-Dols, José-Miguel; Gollwitzer, Peter M.; Keil, Andreas

    2017-01-01

    People experience an unpleasant sensation when hearing a scratch on a board or plate. The present research focuses on this aversive experience known in Spanish as ‘grima’ with no equivalent term in English and German. We hypothesized that this aversive experience constitutes a distinctive, separate emotional concept. In Study 1, we found that the affective meaning of ‘grima’ was closer to disgust than to other emotion concepts. Thus, in Study 2 we explored the features of grima and compared them with disgust. As grima was reported to be predominantly elicited by certain auditory stimuli and associated with a distinctive physiological pattern, Study 3 used direct measures of physiological arousal to test the assumption of a distinctive pattern of physiological responses elicited by auditory stimuli of grima and disgust, and found different effects on heart rate but not on skin conductance. In Study 4, we hypothesized that only participants with an implementation intention geared toward down-regulating grima would be able to successfully weaken the grima- but not disgust- experience. Importantly, this effect was specific as it held true for the grima-eliciting sounds only, but did not affect disgust-related sounds. Finally, Study 5 found that English and German speakers lack a single accessible linguistic label for the pattern of aversive reactions termed by Spanish speaking individuals as ‘grima’, whereas the elicitors of other emotions were accessible and accurately identified by German, English, as well as Spanish speakers. PMID:28217102

  6. Relationship between Acquired Deficiency of Vitamin K-dependent Clotting Factors And Hemorrhage

    Institute of Scientific and Technical Information of China (English)

    杨锐; 张小平; 魏文宁; 洪梅; 杨焰; 胡豫

    2010-01-01

    This study examined the changes of activities of vitamin K-dependent clotting factors(VKDCF) under various pathological conditions and explored the relationship between acquired deficiency of VKDCFs and hemorrhage.Clinical data of 35 patients who were diagnosed as having acquired deficiency of VKDCF were retrospectively analyzed.Coagulation factors involved in the intrinsic and extrinsic pathways were detected in these patients and 41 control subjects.The results showed that the average activities of VKDCFs...

  7. Subcortical infarction resulting in acquired stuttering.

    Science.gov (United States)

    Ciabarra, A M; Elkind, M S; Roberts, J K; Marshall, R S

    2000-10-01

    Stuttering is an uncommon presentation of acute stroke. Reported cases have often been associated with left sided cortical lesions, aphasia, and difficulties with other non-linguistic tests of rhythmic motor control. Three patients with subcortical lesions resulting in stuttering are discussed. In one patient the ability to perform time estimations with a computerised repetitive time estimation task was characterised. One patient had a pontine infarct with clinical evidence of cerebellar dysfunction. A second patient had a left basal ganglionic infarct and a disruption of timing estimation. A third patient had a left subcortical infarct and a mild aphasia. These findings expand the reported distribution of infarction that can result in acquired stuttering. Subcortical mechanisms of speech control and timing may contribute to the pathophysiology of acquired stuttering.

  8. Recognising and managing community-acquired pneumonia.

    Science.gov (United States)

    Gibson, Vanessa

    2015-11-18

    Pneumonia remains a significant cause of morbidity and mortality in the UK and yet the seriousness of the disease is underestimated. Pneumonia can be life-threatening because the delicate tissues of the alveoli and pulmonary capillaries are susceptible to damage from the inflammatory response. This damage leads to consolidation that prevents the diffusion of oxygen and carbon dioxide, and this in turn can lead to respiratory failure. This article summarises guidance on the diagnosis and management of community-acquired pneumonia, and also includes information on the prevention of pneumonia. This information should be valuable to nurses working in a variety of clinical areas since patients with community-acquired pneumonia are encountered in primary, intermediate, secondary and critical care.

  9. Prevention of hospital-acquired hyponatraemia

    DEFF Research Database (Denmark)

    Lunøe, Mathilde; Overgaard-Steensen, C

    2015-01-01

    BACKGROUND: Large amounts of fluids are daily prescribed to hospitalised patients across different medical specialities. Unfortunately, inappropriate fluid administration commonly causes iatrogenic hyponatraemia with associated increase in morbidity and mortality. METHODS/RESULTS: Fundamental...... for prevention of hospital-acquired hyponatraemia is an understanding of what determines plasma sodium concentration (P-[Na(+) ]) in the individual patient. P-[Na(+) ] is determined by balances of water and cations according to Edelman. This paper discusses the mechanisms influencing water and cation balances...... like Ringer-acetate/Ringer-lactate can increase the intracranial pressure dramatically. Consequently, 0.9 % NaCl is recommended as first-line fluid for such patients. CONCLUSIONS: The occurrence of hospital-acquired hyponatraemia may be reduced by prescribing fluids, type and amount, with the same...

  10. Acquired versus familial demyelinative neuropathies in children.

    Science.gov (United States)

    Miller, R G; Gutmann, L; Lewis, R A; Sumner, A J

    1985-01-01

    The electrophysiologic differences between chronic acquired demyelinative neuropathy and the demyelinative form of Charcot-Marie-Tooth disease have recently been reported. The present report extends these observations to include the genetically determined demyelinating neuropathies seen in metachromatic leukodystrophy, Krabbe's leukodystrophy, and Cockayne's syndrome. The electrophysiologic features of metachromatic leukodystrophy (five patients), Krabbe's (four patients), and Cockayne's syndrome (three patients) were all similar. There was uniform slowing of conduction (both in different nerves and in different nerve segments), and conduction block was not seen. These findings are consistent with a uniform degree of demyelination in multiple nerves and throughout the entire length of individual axons. Thus, uniform slowing of nerve conduction constitutes strong evidence for a familial demyelinative neuropathy, as opposed to the multifocal slowing seen in acute and chronic acquired demyelinative neuropathy.

  11. The Distinction Between English Synonyms

    Institute of Scientific and Technical Information of China (English)

    段佳

    2012-01-01

      A large number of new words and terms flock in the English vocabulary and English has a variety of expressive methods making it possible to express the same meaning by different words. Therefore English synonyms are so abundant that it is possible to describe the colorful world and to express the complicated, delicate human thought and emotions. But they bring people many problems such as the correct choice of words from synonyms. The reason for this problem is the insufficient knowledge of the distinction of English synonyms, which have differences in many aspects. This paper offers three main aspects in distinguishing English synonyms that include words’ meaning, coloring and usage.

  12. The pathophysiology of acquired premature ejaculation

    OpenAIRE

    McMahon, Chris G; Jannini, Emmanuele A.; Serefoglu, Ege C.; Hellstrom, Wayne J.G.

    2016-01-01

    The second Ad Hoc International Society for Sexual Medicine (ISSM) Committee for the Definition of Premature Ejaculation defined acquired premature ejaculation (PE) as a male sexual dysfunction characterized by a the development of a clinically significant and bothersome reduction in ejaculation latency time in men with previous normal ejaculatory experiences, often to about 3 minutes or less, the inability to delay ejaculation on all or nearly all vaginal penetrations, and the presence of ne...

  13. Acquired antibiotic resistance genes: an overview.

    OpenAIRE

    Hoek, Angela H.A.M. van; Dik eMevius; Beatriz eGuerra; Peter eMullany; Adam Paul Roberts; Aarts, Henk J. M.

    2011-01-01

    In this review an overview is given on antibiotic resistance mechanisms with special attentions to the antibiotic resistance genes described so far preceded by a short introduction on the discovery and mode of action of the different classes of antibiotics. As this review is only dealing with acquired resistance, attention is paid to mobile genetic elements such as plasmids, transposons and integrons, which are associated with antibiotic resistance genes, and involved in the dispersal of anti...

  14. Acquired Antibiotic Resistance Genes: An Overview

    OpenAIRE

    Hoek, Angela H.A.M. van; Mevius, Dik; Guerra, Beatriz; Mullany, Peter; Roberts, Adam Paul; Aarts, Henk J. M.

    2011-01-01

    In this review an overview is given on antibiotic resistance (AR) mechanisms with special attentions to the AR genes described so far preceded by a short introduction on the discovery and mode of action of the different classes of antibiotics. As this review is only dealing with acquired resistance, attention is also paid to mobile genetic elements such as plasmids, transposons, and integrons, which are associated with AR genes, and involved in the dispersal of antimicrobial determinants betw...

  15. Differential Protein Expression in Congenital and Acquired Cholesteatomas.

    Directory of Open Access Journals (Sweden)

    Seung-Ho Shin

    Full Text Available Congenital cholesteatomas are epithelial lesions that present as an epithelial pearl behind an intact eardrum. Congenital and acquired cholesteatomas progress quite differently from each other and progress patterns can provide clues about the unique origin and pathogenesis of the abnormality. However, the exact pathogenic mechanisms by which cholesteatomas develop remain unknown. In this study, key proteins that directly affect cholesteatoma pathogenesis are investigated with proteomics and immunohistochemistry. Congenital cholesteatoma matrices and retroauricular skin were harvested during surgery in 4 patients diagnosed with a congenital cholesteatoma. Tissue was also harvested from the retraction pocket in an additional 2 patients during middle ear surgery. We performed 2-dimensional (2D electrophoresis to detect and analyze spots that are expressed only in congenital cholesteatoma and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/MS to separate proteins by molecular weight. Protein expression was confirmed by immunohistochemical staining. The image analysis of 2D electrophoresis showed that 4 congenital cholesteatoma samples had very similar protein expression patterns and that 127 spots were exclusively expressed in congenital cholesteatomas. Of these 127 spots, 10 major spots revealed the presence of titin, forkhead transcription activator homolog (FKH 5-3, plectin 1, keratin 10, and leucine zipper protein 5 by MALDI-TOF/MS analysis. Immunohistochemical staining showed that FKH 5-3 and titin were expressed in congenital cholesteatoma matrices, but not in acquired cholesteatomas. Our study shows that protein expression patterns are completely different in congenital cholesteatomas, acquired cholesteatomas, and skin. Moreover, non-epithelial proteins, including FKH 5-3 and titin, were unexpectedly expressed in congenital cholesteatoma tissue. Our data indicates that congenital cholesteatoma origins

  16. Non-Intensive Care Unit Acquired Pneumonia: A New Clinical Entity?

    Directory of Open Access Journals (Sweden)

    Marta Di Pasquale

    2016-02-01

    Full Text Available Hospital-acquired pneumonia (HAP is a frequent cause of nosocomial infections, responsible for great morbidity and mortality worldwide. The majority of studies on HAP have been conducted in patients hospitalized in the intensive care unit (ICU, as mechanical ventilation represents a major risk factor for nosocomial pneumonia and specifically for ventilator-associated pneumonia. However, epidemiological data seem to be different between patients acquiring HAP in the ICU vs. general wards, suggesting the importance of identifying non ICU-acquired pneumonia (NIAP as a clinical distinct entity in terms of both etiology and management. Early detection of NIAP, along with an individualized management, is needed to reduce antibiotic use and side effects, bacterial resistance and mortality. The present article reviews the pathophysiology, diagnosis, treatment and prevention of NIAP.

  17. The pathophysiology of acquired premature ejaculation.

    Science.gov (United States)

    McMahon, Chris G; Jannini, Emmanuele A; Serefoglu, Ege C; Hellstrom, Wayne J G

    2016-08-01

    The second Ad Hoc International Society for Sexual Medicine (ISSM) Committee for the Definition of Premature Ejaculation defined acquired premature ejaculation (PE) as a male sexual dysfunction characterized by a the development of a clinically significant and bothersome reduction in ejaculation latency time in men with previous normal ejaculatory experiences, often to about 3 minutes or less, the inability to delay ejaculation on all or nearly all vaginal penetrations, and the presence of negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy. The literature contains a diverse range of biological and psychological etiological theories. Acquired PE is commonly due to sexual performance anxiety, psychological or relationship problems, erectile dysfunction (ED), and occasionally prostatitis and hyperthyroidism, consistent with the predominant organic etiology of acquired PE, men with this complaint are usually older, have a higher mean BMI and a greater incidence of comorbid disease including hypertension, sexual desire disorder, diabetes mellitus, chronic prostatitis, and ED compared to lifelong, variable and subjective PE.

  18. MRI of fetal acquired brain lesions

    Energy Technology Data Exchange (ETDEWEB)

    Prayer, Daniela [Department of Radiodiagnostics, Medical University of Vienna (Austria)]. E-mail: daniela.prayer@meduniwien.ac.at; Brugger, Peter C. [Center of Anatomy and Cell Biology, Medical University of Vienna (Austria); Kasprian, Gregor [Department of Radiodiagnostics, Medical University of Vienna (Austria); Witzani, Linde [Department of Radiodiagnostics, Medical University of Vienna (Austria); Helmer, Hanns [Department of Obstetrics and Gynecology, Medical University of Vienna (Austria); Dietrich, Wolfgang [Department of Neurosurgery, Medical University of Vienna (Austria); Eppel, Wolfgang [Department of Obstetrics and Gynecology, Medical University of Vienna (Austria); Langer, Martin [Department of Obstetrics and Gynecology, Medical University of Vienna (Austria)

    2006-02-15

    Acquired fetal brain damage is suspected in cases of destruction of previously normally formed tissue, the primary cause of which is hypoxia. Fetal brain damage may occur as a consequence of acute or chronic maternal diseases, with acute diseases causing impairment of oxygen delivery to the fetal brain, and chronic diseases interfering with normal, placental development. Infections, metabolic diseases, feto-fetal transfusion syndrome, toxic agents, mechanical traumatic events, iatrogenic accidents, and space-occupying lesions may also qualify as pathologic conditions that initiate intrauterine brain damage. MR manifestations of acute fetal brain injury (such as hemorrhage or acute ischemic lesions) can easily be recognized, as they are hardly different from postnatal lesions. The availability of diffusion-weighted sequences enhances the sensitivity in recognizing acute ischemic lesions. Recent hemorrhages are usually readily depicted on T2 (*) sequences, where they display hypointense signals. Chronic fetal brain injury may be characterized by nonspecific changes that must be attributable to the presence of an acquired cerebral pathology. The workup in suspected acquired fetal brain injury also includes the assessment of extra-CNS organs that may be affected by an underlying pathology. Finally, the placenta, as the organ that mediates oxygen delivery from the maternal circulation to the fetus, must be examined on MR images.

  19. [ANEMIC SYNDROME IN PATIENTS WITH COMMUNITY-ACQUIRED PNEUMONIA].

    Science.gov (United States)

    Budnevsky, A V; Esaulenko, I E; Ovsyannikov, E S; Labzhaniya, N B; Voronina, E V; Chernov, A V

    2016-01-01

    Community-acquired pneumonia remains a most widespread acute infectious disease of socio-economic significance all over the world. Up to 30% of the patients present with anemia responsible for the unfavourable prognosis and elevated mortality. Not infrequently, anemia is not diagnosed during the hospital stay und therefore remains uncorrected. Severe anemia results in enhanced hypercapnia and slowed maturation of red blood cells in the bone marrow which facilitates the development of ischemic syndrome. Hepcidin, a mediator of inflammation and iron-regulatory hormone, plays an important role in the clinical course of community-acquired pneumonia. Hepsidin production increases during inflammation; it suppresses erythtropoiesis and depletes the iron depot leading to so-called anemia of inflammation. Hypoxia and anemia activate erythtropoiesis, and the released erythropoietin inhibits hepsidin production. During pneumonia resolution, hepsidin promotes recovery from anemia by activating iron absorption. The curreni literature contains few data on the use of hepcidin as a diagnostic marker of anemia. The necessity oftreating anemia in patients with pneumonia under hospital conditions is a matter of discussion. Direct involvement of hepcidin in iron metabolism creates a prerequisite for the treatment of anemia. Medicamental suppression of its activity by stimulating erythtropoiesis can facilitate normalization of iron metabolism and restoration of hemoglobin level.

  20. Heat Shock Proteins: Stimulators of Innate and Acquired Immunity

    Directory of Open Access Journals (Sweden)

    Camilo A. Colaco

    2013-01-01

    Full Text Available Adjuvants were reintroduced into modern immunology as the dirty little secret of immunologists by Janeway and thus began the molecular definition of innate immunity. It is now clear that the binding of pathogen-associated molecular patterns (PAMPs by pattern recognition receptors (PRRs on antigen presenting cells (APCs activates the innate immune response and provides the host with a rapid mechanism for detecting infection by pathogens and initiates adaptive immunity. Ironically, in addition to advancing the basic science of immunology, Janeway’s revelation on induction of the adaptive system has also spurred an era of rational vaccine design that exploits PRRs. Thus, defined PAMPs that bind to known PRRs are being specifically coupled to antigens to improve their immunogenicity. However, while PAMPs efficiently activate the innate immune response, they do not mediate the capture of antigen that is required to elicit the specific responses of the acquired immune system. Heat shock proteins (HSPs are molecular chaperones that are found complexed to client polypeptides and have been studied as potential cancer vaccines. In addition to binding PRRs and activating the innate immune response, HSPs have been shown to both induce the maturation of APCs and provide chaperoned polypeptides for specific triggering of the acquired immune response.

  1. Radiologic diagnosis and treatment of iatrogenic acquired uterine arteriovenous malformation

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Jung Hyeok [College of Medicine, Keimyung Univ., Taegu (Korea, Republic of)

    2002-05-01

    To analyze gray-scale US, color and duplex Doppler US, and angiographic findings in patients with acquired uterine arteriovenous malformations (AVMs), and to evaluate the usefulness of these modalities in the diagnosis of this disease and the effect of transcatheter arterial embolization in its treatment. During a recent seven-year period, we diagnosed 21 cases of acquired uterine AVM. Nineteen of these patients had a history of causative D and C (between one and seven D and C procedures per patient), one had a history of causative cesarean section, and one had cervical conization. All patients underwent transabdominal and endovaginal gray-scale, color Doppler, and duplex Doppler US and angiography, with therapeutic embolization of bilateral uterine arteries. The majority underwent follow-up Doppler US after embolization. The gray-scale US morphology of uterine AVMs included subtle myometrial inhomogeneity and multiple distinct, small anechoic spaces in the thickened myometrium or endometrium. Color Doppler US showed a tangle of tortuous vessels with multidirectional, high-velocity arterial flow, which was focally or asymmetrically distributed. Duplex Doppler US depicted a waveform of fast arterial flow with low resistance, while angiography demonstrated a complex tangle of vessels supplied by enlarged uterine arteries, in association with early venous drainage during the arterial phase, and staiss of contrast medium within abnormal vasculature. Where AVMs were combined with a pseudoaneurysm, this finding was observed. Transcatheter arterial embolization provided a complete cure, without recurrence. Color and duplex Doppler US in an appropriate modality for the detection and diagnosis of uterine AVMs and for follow-up after embolization. Transcatheter arterial embolization is a safe and effective method of treating this disease.

  2. Sigmoid plate dehiscence: Congenital or acquired condition?

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Zhaohui, E-mail: lzhtrhos@163.com [Capital Medical University, Beijing Tongren Hospital, No 1 Dong Jiao Min Street, Dongcheng District, Beijing 100730 (China); Li, Jing, E-mail: lijingxbh@yahoo.com.cn [Capital Medical University, Beijing Tongren Hospital, No 1 Dong Jiao Min Street, Dongcheng District, Beijing 100730 (China); Zhao, Pengfei, E-mail: zhaopengf05@163.com [Capital Medical University, Beijing Friendship Hospital, No 95 Yongan Road, Xicheng District, Beijing 100050 (China); Lv, Han, E-mail: chrislvhan@126.com [Capital Medical University, Beijing Friendship Hospital, No 95 Yongan Road, Xicheng District, Beijing 100050 (China); Dong, Cheng, E-mail: derc007@sina.com [Capital Medical University, Beijing Friendship Hospital, No 95 Yongan Road, Xicheng District, Beijing 100050 (China); Liu, Wenjuan, E-mail: wenjuanliu@163.com [Jining No. 1 People' s Hospital, No. 6 Health Street, Jining 272100 (China); Wang, Zhenchang, E-mail: cjr.wzhch@vip.163.com [Capital Medical University, Beijing Friendship Hospital, No 95 Yongan Road, Xicheng District, Beijing 100050 (China)

    2015-05-15

    Highlights: • CT with multiplanar reformations can accurately display the sigmoid platet dehiscence. • The prevalence of sigmoid plate dehiscence was no significant difference among different age groups. • The size of sigmoid plate bony defects were not statistically different among different age groups. • The sigmoid plate dehiscence is more commonly a congenital than an acquired condition. - Abstract: Background and purpose: The imaging features of sigmoid plate dehiscence-induced pulsatile tinnitus have been presented. The origin of the sigmoid plate dehiscence, however, remains unclear. Our aim was to assess the prevalence and extent of sigmoid plate dehiscence on computed tomography (CT) images in multiple age groups to determine whether this condition is more likely to be congenital or acquired. Materials and methods: We retrospectively reviewed contrast-enhanced CT images of sigmoid plates of temporal bones in 504 patients. Each temporal bone was characterized as normal or dehiscent. Patients were then subcategorized into four age groups, and the prevalence and extent of dehiscent sigmoid plates in each group were calculated and compared. Results: Overall, 80 patients had sigmoid plate dehiscence, nine of whom had it bilaterally. In successively older age groups, the prevalences of sigmoid plate dehiscence were 18.9%, 20.1%, 14.5%, and 12.7%, respectively. Respective average anteroposterior bony defect diameters were 3.7 ± 1.7, 3.0 ± 1.3, 3.1 ± 1.5, and 3.0 ± 1.1 mm. Respective average vertical bony defect diameters were 3.6 ± 2.3, 2.6 ± 1.2, 3.2 ± 1.5, and 3.0 ± 1.7 mm. The prevalence and extent of sigmoid plate dehiscence were not statistically different among the four age groups. Conclusions: The similar radiologic prevalence and extent of dehiscent sigmoid plates among the age groups suggest that the dehiscence is more commonly a congenital than an acquired condition.

  3. Acquired prosopagnosia without word recognition deficits.

    Science.gov (United States)

    Susilo, Tirta; Wright, Victoria; Tree, Jeremy J; Duchaine, Bradley

    2015-01-01

    It has long been suggested that face recognition relies on specialized mechanisms that are not involved in visual recognition of other object categories, including those that require expert, fine-grained discrimination at the exemplar level such as written words. But according to the recently proposed many-to-many theory of object recognition (MTMT), visual recognition of faces and words are carried out by common mechanisms [Behrmann, M., & Plaut, D. C. ( 2013 ). Distributed circuits, not circumscribed centers, mediate visual recognition. Trends in Cognitive Sciences, 17, 210-219]. MTMT acknowledges that face and word recognition are lateralized, but posits that the mechanisms that predominantly carry out face recognition still contribute to word recognition and vice versa. MTMT makes a key prediction, namely that acquired prosopagnosics should exhibit some measure of word recognition deficits. We tested this prediction by assessing written word recognition in five acquired prosopagnosic patients. Four patients had lesions limited to the right hemisphere while one had bilateral lesions with more pronounced lesions in the right hemisphere. The patients completed a total of seven word recognition tasks: two lexical decision tasks and five reading aloud tasks totalling more than 1200 trials. The performances of the four older patients (3 female, age range 50-64 years) were compared to those of 12 older controls (8 female, age range 56-66 years), while the performances of the younger prosopagnosic (male, 31 years) were compared to those of 14 younger controls (9 female, age range 20-33 years). We analysed all results at the single-patient level using Crawford's t-test. Across seven tasks, four prosopagnosics performed as quickly and accurately as controls. Our results demonstrate that acquired prosopagnosia can exist without word recognition deficits. These findings are inconsistent with a key prediction of MTMT. They instead support the hypothesis that face

  4. Acquired Muscle Weakness in the Surgical Intensive Care Unit: Nosology, Epidemiology, Diagnosis, and Prevention.

    Science.gov (United States)

    Farhan, Hassan; Moreno-Duarte, Ingrid; Latronico, Nicola; Zafonte, Ross; Eikermann, Matthias

    2016-01-01

    Muscle weakness is common in the surgical intensive care unit (ICU). Low muscle mass at ICU admission is a significant predictor of adverse outcomes. The consequences of ICU-acquired muscle weakness depend on the underlying mechanism. Temporary drug-induced weakness when properly managed may not affect outcome. Severe perioperative acquired weakness that is associated with adverse outcomes (prolonged mechanical ventilation, increases in ICU length of stay, and mortality) occurs with persistent (time frame: days) activation of protein degradation pathways, decreases in the drive to the skeletal muscle, and impaired muscular homeostasis. ICU-acquired muscle weakness can be prevented by early treatment of the underlying disease, goal-directed therapy, restrictive use of immobilizing medications, optimal nutrition, activating ventilatory modes, early rehabilitation, and preventive drug therapy. In this article, the authors review the nosology, epidemiology, diagnosis, and prevention of ICU-acquired weakness in surgical ICU patients.

  5. [Iris heterochromia in acquired Horner's syndrome].

    Science.gov (United States)

    Beynat, J; Soichot, P; Bidot, S; Dugas, B; Creuzot-Garcher, C; Bron, A

    2007-09-01

    Horner's syndrome (HS) is related to an interruption of the oculosympathetic nerve pathway. The classic clinical findings associated with this condition are ptosis, miosis, and enophthalmos. Heterochromia is typically described in congenital HS, but it is an uncommon finding in acquired HS. We report a case of post-traumatic HS associated with heterochromia. A literature review indicates that this type of heterochromia may be related to a reduction in the number of iris melanocytes. This mechanism may be the same in the physiological iris color modifications in adulthood.

  6. Clinicopathological correlation of acquired hypopigmentary disorders

    Directory of Open Access Journals (Sweden)

    Anisha B Patel

    2013-01-01

    Full Text Available Acquired hypopigmentary disorders comprise a significant group of disorders that affect Indians and Asians. The pigment disturbance in darker skin individuals can be very distressing to the patient and the family. These disorders cover a wide array of pathologies including infections, autoimmune processes, lymphoproliferative disorders, and sclerosing diseases. Histological diagnosis is particularly important because treatments for these diseases are varied and specific. This review will focus on histopathological diagnosis based on clinicopathological correlation for commonly encountered disorders such as leprosy, vitiligo, lichen sclerosus, pityriasis alba (PA, and pityriasis versicolor (PV. Atypical or uncommon clinical presentation of classic diseases such as hypopigmented mycosis fungoides (HMF and hypopigmented sarcoidosis are also included.

  7. Triple arthrodesis for adult acquired flatfoot.

    Science.gov (United States)

    Catanzariti, Alan R; Dix, Brian T; Richardson, Phillip E; Mendicino, Robert W

    2014-07-01

    The primary goal of triple arthrodesis for stage III and IV adult acquired flatfoot is to obtain a well-aligned plantigrade foot that will support the ankle in optimal alignment. Ancillary procedures including posterior muscle group lengthening, medial displacement calcaneal osteotomy, medial column stabilization, peroneus brevis tenotomy, or transfer and harvest of regional bone graft are often necessary to achieve adequate realignment. Image intensification is helpful in confirming optimal realignment before fixation. Results of triple arthrodesis are enhanced with adequate preparation of joint surfaces, bone graft/orthobiologics, 2-point fixation of all 3 tritarsal joints, and a vertical heel position.

  8. Acquired Inventors’ Productivity after Horizontal Acquisition

    DEFF Research Database (Denmark)

    Colombo, Massimo G.; Moreira, Solon; Rabbiosi, Larissa

    of the multifaceted nature of the integration process further enhances our understanding of which conditions will be more or less detrimental for corporate inventors. We focus on R&D teams which are the immediate organizational context in which inventors operate and drawing on insights from learning theory...... and evolutionary economics we posit and find that the reorganization of R&D teams after acquisition harms acquired inventors? innovative performance. Though, the implementation of other integration decisions can mitigate or aggravate this negative effect....

  9. Distinct monocyte Gene-Expression profiles in autoimmune diabetes

    NARCIS (Netherlands)

    R.C. Padmos (Roos); N.C. Schloot (Nanette); H. Beyan (Huriya); C. Ruwhof (Cindy); F.J.T. Staal (Frank); D. de Ridder (Dick); H-J. Aanstoot (Henk-Jan); W.K. Lam-Tse; H.J. de Wit (Harm); C. Herder (Christian); R.C. Drexhage (Roos); B. Menart (Barbara); R.D. Leslie

    2008-01-01

    textabstractOBJECTIVE-There is evidence that monocytes of patients with type 1 diabetes show proinflammatory activation and disturbed migration/adhesion, but the evidence is inconsistent. Our hypothesis is that monocytes are distinctly activated/disturbed in different subforms of autoimmune diabetes

  10. CASE METHOD. ACTIVE LEARNING METHODOLOGY TO ACQUIRE SIGNIFICANT IN CHEMISTRY

    Directory of Open Access Journals (Sweden)

    Clotilde Pizarro

    2015-09-01

    Full Text Available In this paper the methodology of cases in first year students of the Engineering Risk Prevention and Environment is applied. For this purpose a real case of contamination occurred at a school in the region of Valparaiso called "La Greda" is presented. If the application starts delivering an extract of the information collected from the media and they made a brief induction on the methodology to be applied. A plenary session, which is debate about possible solutions to the problem and establishing a relationship between the case and drives the chemistry program is then performed. Is concluded that the application of the case method, was a fruitful tool in yields obtained by students, since the percentage of approval was 75%, which is considerably higher than previous years.

  11. Identification of a novel genomic island specific to hospital-acquired clonal complex 17 Enterococcus faecium isolates.

    Science.gov (United States)

    Heikens, Esther; van Schaik, Willem; Leavis, Helen L; Bonten, Marc J M; Willems, Rob J L

    2008-11-01

    Hospital-acquired clonal complex 17 (CC17) Enterococcus faecium strains are genetically distinct from indigenous strains and are enriched with resistance genes and virulence genes. We identified a genomic island in CC17 E. faecium tentatively encoding a metabolic pathway involved in carbohydrate transport and metabolism, which may provide a competitive advantage over the indigenous E. faecium microbiota.

  12. Identification of a Novel Genomic Island Specific to Hospital-Acquired Clonal Complex 17 Enterococcus faecium Isolates

    NARCIS (Netherlands)

    Heikens, Esther; van Schaik, Willem; Leavis, Helen L.; Bonten, Marc J. M.; Willems, Rob J. L.

    2008-01-01

    Hospital-acquired clonal complex 17 (CC17) Enterococcus faecium strains are genetically distinct from indigenous strains and are enriched with resistance genes and virulence genes. We identified a genomic island in CC17 E. faecium tentatively encoding a metabolic pathway involved in carbohydrate tra

  13. Treatment of community-acquired pneumonia.

    Science.gov (United States)

    Lee, Young R; Houngue, Coovi; Hall, Ronald G

    2015-01-01

    Community-acquired pneumonia is the sixth leading cause of death in the USA. Adherence to the 2007 Infectious Diseases Society of America/American Thoracic Society community-acquired pneumonia guidelines has been associated with improved clinical outcomes. However, choice between guideline-recommended treatments is at the discretion of the prescribing clinician. This review is intended to discuss the characteristics of these treatment options including dosing frequency, dose adjustment for renal/hepatic dysfunction, serious/common adverse events, drug interactions, lung penetration, pharmacokinetic-pharmacodynamic target and effect of obesity to help guide antimicrobial selection. An increasing portion of patients are receiving expanded empiric coverage for methicillin-resistant Staphylococcus aureus as recommended by the American Thoracic Society and Infectious Diseases Society of America for healthcare-associated pneumonia. However, this expanded coverage may not be achieving the desired improvements in clinical outcomes. We expect this increasingly diverse spectrum of patients with pneumonia to eventually result in the merger of these two guidelines to include all patients with pneumonia.

  14. Asian elephants acquire inaccessible food by blowing.

    Science.gov (United States)

    Mizuno, Kaori; Irie, Naoko; Hiraiwa-Hasegawa, Mariko; Kutsukake, Nobuyuki

    2016-01-01

    Many animals acquire otherwise inaccessible food with the aid of sticks and occasionally water. As an exception, some reports suggest that elephants manipulate breathing through their trunks to acquire inaccessible food. Here, we report on two female Asian elephants (Elephas maximus) in Kamine Zoo, Japan, who regularly blew to drive food within their reach. We experimentally investigated this behaviour by placing foods in inaccessible places. The elephants blew the food until it came within accessible range. Once the food was within range, the elephants were increasingly less likely to blow as the distance to the food became shorter. One subject manipulated her blowing duration based on food distance: longer when the food was distant. These results suggest that the elephants used their breath to achieve goals: that is, they used it not only to retrieve the food but also to fine-tune the food position for easy grasping. We also observed individual differences in the elephants' aptitude for this technique, which altered the efficiency of food acquisition. Thus, we added a new example of spontaneous behaviour for achieving a goal in animals. The use of breath to drive food is probably unique to elephants, with their dexterous trunks and familiarity with manipulating the act of blowing, which is commonly employed for self-comfort and acoustic communication.

  15. Software for Acquiring Image Data for PIV

    Science.gov (United States)

    Wernet, Mark P.; Cheung, H. M.; Kressler, Brian

    2003-01-01

    PIV Acquisition (PIVACQ) is a computer program for acquisition of data for particle-image velocimetry (PIV). In the PIV system for which PIVACQ was developed, small particles entrained in a flow are illuminated with a sheet of light from a pulsed laser. The illuminated region is monitored by a charge-coupled-device camera that operates in conjunction with a data-acquisition system that includes a frame grabber and a counter-timer board, both installed in a single computer. The camera operates in "frame-straddle" mode where a pair of images can be obtained closely spaced in time (on the order of microseconds). The frame grabber acquires image data from the camera and stores the data in the computer memory. The counter/timer board triggers the camera and synchronizes the pulsing of the laser with acquisition of data from the camera. PIVPROC coordinates all of these functions and provides a graphical user interface, through which the user can control the PIV data-acquisition system. PIVACQ enables the user to acquire a sequence of single-exposure images, display the images, process the images, and then save the images to the computer hard drive. PIVACQ works in conjunction with the PIVPROC program which processes the images of particles into the velocity field in the illuminated plane.

  16. Borders and Legal Criteria for Acquiring Nationality

    Directory of Open Access Journals (Sweden)

    María Elósegui Itxaso

    2008-09-01

    Full Text Available Legal criteria for acquiring nationality are crucial in the integration of persons into society, since they provide access to the right to vote. Until now, the criteria most frequently used are those of ius soli (birth and ius sanguinis (nationality is inherited from the parents, which comply with previous anthropological approaches and which jurists accept without reflection, or consider to be unshakeable traditions.The author’s proposal in this article is to accept that some of these legal criteria should be reformed, though not in an anarchic manner. On one hand, some of the ethnic criteria may be respected, but on the other, the processes of acquiring nationality should be streamlined by accepting the desire of persons wanting to change their nationality on moving to a new country of residence. Meanwhile, we must establish channels of demand for accepting the democratic values and legal system of the welcoming country, as a result of which it would be fair to call for a prior learning period before the rights to nationality and suffrage are granted. The author also adds – and accepts as being a fundamental element – some of Habermas’ inclusion theses, though she stresses that this discourse should be organised into two specific, feasible legal solutions or rather, in a realistic manner.

  17. Src mutation induces acquired lapatinib resistance in ERBB2-amplified human gastroesophageal adenocarcinoma models.

    Directory of Open Access Journals (Sweden)

    Yong Sang Hong

    Full Text Available ERBB2-directed therapy is now a routine component of therapy for ERBB2-amplified metastatic gastroesophageal adenocarcinomas. However, there is little knowledge of the mechanisms by which these tumors develop acquired resistance to ERBB2 inhibition. To investigate this question we sought to characterize cell line models of ERBB2-amplified gastroesophageal adenocarcinoma with acquired resistance to ERBB2 inhibition. We generated lapatinib-resistant (LR subclones from an initially lapatinib-sensitive ERBB2-amplified esophageal adenocarcinoma cell line, OE19. We subsequently performed genomic characterization and functional analyses of resistant subclones with acquired lapatinib resistance. We identified a novel, acquired SrcE527K mutation in a subset of LR OE19 subclones. Cells with this mutant allele harbour increased Src phosphorylation. Genetic and pharmacologic inhibition of Src resensitized these subclones to lapatinib. Biochemically, Src mutations could activate both the phosphatidylinositol 3-kinase and mitogen activated protein kinase pathways in the lapatinib-treated LR OE19 cells. Ectopic expression of SrcE527K mutation also was sufficient to induce lapatinib resistance in drug-naïve cells. These results indicate that pathologic activation of Src is a potential mechanism of acquired resistance to ERBB2 inhibition in ERBB2-amplified gastroesophageal cancer. Although Src mutation has not been described in primary tumor samples, we propose that the Src hyperactivation should be investigated in the settings of acquired resistance to ERBB2 inhibition in esophageal and gastric adenocarcinoma.

  18. Regulatory and Functional Aspects of Indolic Metabolism in Plant Systemic Acquired Resistance.

    Science.gov (United States)

    Stahl, Elia; Bellwon, Patricia; Huber, Stefan; Schlaeppi, Klaus; Bernsdorff, Friederike; Vallat-Michel, Armelle; Mauch, Felix; Zeier, Jürgen

    2016-05-02

    Tryptophan-derived, indolic metabolites possess diverse functions in Arabidopsis innate immunity to microbial pathogen infection. Here, we investigate the functional role and regulatory characteristics of indolic metabolism in Arabidopsis systemic acquired resistance (SAR) triggered by the bacterial pathogen Pseudomonas syringae. Indolic metabolism is broadly activated in both P. syringae-inoculated and distant, non-inoculated leaves. At inoculation sites, camalexin, indol-3-ylmethylamine (I3A), and indole-3-carboxylic acid (ICA) are the major accumulating compounds. Camalexin accumulation is positively affected by MYB122, and the cytochrome P450 genes CYP81F1 and CYP81F2. Local I3A production, by contrast, occurs via indole glucosinolate breakdown by PEN2- dependent and independent pathways. Moreover, exogenous application of the defense hormone salicylic acid stimulates I3A generation at the expense of its precursor indol-3-ylmethylglucosinolate (I3M), and the SAR regulator pipecolic acid primes plants for enhanced P. syringae-induced activation of distinct branches of indolic metabolism. In uninfected systemic tissue, the metabolic response is more specific and associated with enhanced levels of the indolics I3A, ICA, and indole-3-carbaldehyde (ICC). Systemic indole accumulation fully depends on functional CYP79B2/3, PEN2, and MYB34/51/122, and requires functional SAR signaling. Genetic analyses suggest that systemically elevated indoles are dispensable for SAR and associated systemic increases of salicylic acid. However, soil-grown but not hydroponically -cultivated cyp79b2/3 and pen2 plants, both defective in indolic secondary metabolism, exhibit pre-induced immunity, which abrogates their intrinsic ability to induce SAR.

  19. Genetic engineering and therapy for inherited and acquired cardiomyopathies.

    Science.gov (United States)

    Day, Sharlene; Davis, Jennifer; Westfall, Margaret; Metzger, Joseph

    2006-10-01

    The cardiac myofilaments consist of a highly ordered assembly of proteins that collectively generate force in a calcium-dependent manner. Defects in myofilament function and its regulation have been implicated in various forms of acquired and inherited human heart disease. For example, during cardiac ischemia, cardiac myocyte contractile performance is dramatically downregulated due in part to a reduced sensitivity of the myofilaments to calcium under acidic pH conditions. Over the last several years, the thin filament regulatory protein, troponin I, has been identified as an important mediator of this response. Mutations in troponin I and other sarcomere genes are also linked to several distinct inherited cardiomyopathic phenotypes, including hypertrophic, dilated, and restrictive cardiomyopathies. With the cardiac sarcomere emerging as a central player for such a diverse array of human heart diseases, genetic-based strategies that target the myofilament will likely have broad therapeutic potential. The development of safe vector systems for efficient gene delivery will be a critical hurdle to overcome before these types of therapies can be successfully applied. Nonetheless, studies focusing on the principles of acute genetic engineering of the sarcomere hold value as they lay the essential foundation on which to build potential gene-based therapies for heart disease.

  20. Systemic Acquired Resistance and Signal Transduction in Plant

    Institute of Scientific and Technical Information of China (English)

    ZHAO Shu-qing; GUO Jian-bo

    2003-01-01

    Systemic acquired resistance (SAR), known as the broad-spectrum, inducible plant immunity,is a defense response triggered by pathogen infection. The response starts from the recognition of plant resist-ance (R) with the corresponding avirulence (avr) gene from the pathogen. There are some genes for conver-gence of signals downstream of different R/avr interacting partners into a single signaling pathway. Salicylicacid (SA) is required for the induction of SAR and involved in transducing the signal in target tissues. The SAsignal is transduced through NPR1, a nuclear-localized protein that interacts with transcription factors thatare involved in regulating SA-mediated gene expression. Some chemicals that mimic natural signaling com-pounds can also activate SAR. The application of biochemical activators to agriculture for plant protection is anovel idea for developing green chemical pesticide.

  1. Clinical, pathological, and etiologic aspects of acquired dermal melanocytosis.

    Science.gov (United States)

    Mizoguchi, M; Murakami, F; Ito, M; Asano, M; Baba, T; Kawa, Y; Kubota, Y

    1997-06-01

    To study the pathogenesis of acquired dermal melanocytosis (ADM), we reviewed the clinical, immunohistochemical, and ultrastructural features of 34 cases (female, 33, and male, 1) of ADM. The patients' ages at onset ranged from 8 to 51 years and averaged 26.8 +/- 12.7 years. There was a positive family history. Gray-brown macules were mostly recognized on the face. Not only active dermal melanocytes but also non-pigmented c-KIT- and TRP-2-positive immature melanocytes were detected in the dermis. Taken together those clinical and histological findings, activation of pre-existing immature melanocytes by sunlight, estrogen, and/or progesterone, and some other factors, may be the most likely mode of the development of ADM. Moreover, using cultured murine neural crest cells as a model of c-KIT-positive immature melanocytes, we confirmed that endothelin-1, which is produced and secreted by keratinocytes after UV-irradiation, affects melanocytes and accelerated melanogenesis.

  2. Acquiring neural signals for developing a perception and cognition model

    Science.gov (United States)

    Li, Wei; Li, Yunyi; Chen, Genshe; Shen, Dan; Blasch, Erik; Pham, Khanh; Lynch, Robert

    2012-06-01

    The understanding of how humans process information, determine salience, and combine seemingly unrelated information is essential to automated processing of large amounts of information that is partially relevant, or of unknown relevance. Recent neurological science research in human perception, and in information science regarding contextbased modeling, provides us with a theoretical basis for using a bottom-up approach for automating the management of large amounts of information in ways directly useful for human operators. However, integration of human intelligence into a game theoretic framework for dynamic and adaptive decision support needs a perception and cognition model. For the purpose of cognitive modeling, we present a brain-computer-interface (BCI) based humanoid robot system to acquire brainwaves during human mental activities of imagining a humanoid robot-walking behavior. We use the neural signals to investigate relationships between complex humanoid robot behaviors and human mental activities for developing the perception and cognition model. The BCI system consists of a data acquisition unit with an electroencephalograph (EEG), a humanoid robot, and a charge couple CCD camera. An EEG electrode cup acquires brainwaves from the skin surface on scalp. The humanoid robot has 20 degrees of freedom (DOFs); 12 DOFs located on hips, knees, and ankles for humanoid robot walking, 6 DOFs on shoulders and arms for arms motion, and 2 DOFs for head yaw and pitch motion. The CCD camera takes video clips of the human subject's hand postures to identify mental activities that are correlated to the robot-walking behaviors. We use the neural signals to investigate relationships between complex humanoid robot behaviors and human mental activities for developing the perception and cognition model.

  3. Time dysperception perspective for acquired brain injury

    Directory of Open Access Journals (Sweden)

    Federica ePiras

    2014-01-01

    Full Text Available Distortions of time perception are presented by a number of neuropsychiatric disorders. Here we survey timing abilities in clinical populations with acquired brain injuries in key cerebral areas recently implicated in human studies of timing. We purposely analyzed the complex relationship between cognitive and contextual factors involved in time estimation, as to characterize the correlation between timed and other cognitive behaviors in each group. We assume that interval timing is a solid construct to study cognitive dysfunctions following brain injury, as timing performance is a sensitive metric of information processing, while temporal cognition has the potential of influencing a wide range of cognitive processes. Moreover, temporal performance is a sensitive assay of damage to the underlying neural substrate after a brain insult. Further research in neurological and psychiatric patients will definitively answer the question of whether time distortions are manifestations of cognitive and behavioral symptoms of brain damage and definitively clarify their mechanisms.

  4. Synesthetic colors for Japanese late acquired graphemes.

    Science.gov (United States)

    Asano, Michiko; Yokosawa, Kazuhiko

    2012-06-01

    Determinants of synesthetic color choice for the Japanese logographic script, Kanji, were studied. The study investigated how synesthetic colors for Kanji characters, which are usually acquired later in life than other types of graphemes in Japanese language (phonetic characters called Hiragana and Katakana, and Arabic digits), are influenced by linguistic properties such as phonology, orthography, and meaning. Of central interest was a hypothesized generalization process from synesthetic colors for graphemes, learned prior to acquisition of Kanji, to Kanji characters learned later. Results revealed that color choices for Kanji characters depend on meaning and phonological information. Some results suggested that colors are generalized from Hiragana characters and Arabic digits to Kanji characters via phonology and meaning, respectively. Little influence of orthographic information was observed. The findings and approach of this study contributes to a clarification of the mechanism underlying grapheme-color synesthesia, especially in terms of its relationship to normal language processing.

  5. Multiple myeloma associated with acquired cutis laxa.

    Science.gov (United States)

    Cho, S Y; Maguire, R F

    1980-08-01

    Acquired cutis laxa is a rare disorder characterized by diffuse laxity of the skin and loss of connective tissue support with involvement of the lungs, gastrointestinal tract, pelvic organs, and aorta. The case report presented herein describes a forty-six year old woman with multiple myeloma and cutis laxa. Her history included several severe allergic reactions and the gradual development of lax skin, loss of connective tissue support throughout the body, and emphysema. At autopsy, multiple myeloma, diffuse laxity of the skin, and panacinar emphysema were found. The amount of elastic fiber in the skin, lungs, and aorta was decreased and showed abnormal fragmentation. Results of direct immunofluorescence study demonstrated IgG bound to dermal elastic fibers. Speculation regarding an immunologic etiology of the elastic tissue abnormality is presented herein.

  6. Acquiring Correct Knowledge for Natural Language Generation

    CERN Document Server

    Reiter, E; Sripada, S G; 10.1613/jair.1176

    2011-01-01

    Natural language generation (NLG) systems are computer software systems that produce texts in English and other human languages, often from non-linguistic input data. NLG systems, like most AI systems, need substantial amounts of knowledge. However, our experience in two NLG projects suggests that it is difficult to acquire correct knowledge for NLG systems; indeed, every knowledge acquisition (KA) technique we tried had significant problems. In general terms, these problems were due to the complexity, novelty, and poorly understood nature of the tasks our systems attempted, and were worsened by the fact that people write so differently. This meant in particular that corpus-based KA approaches suffered because it was impossible to assemble a sizable corpus of high-quality consistent manually written texts in our domains; and structured expert-oriented KA techniques suffered because experts disagreed and because we could not get enough information about special and unusual cases to build robust systems. We bel...

  7. Hospital Acquired Pneumonia: Issues in Therapy

    Directory of Open Access Journals (Sweden)

    Lionel A Mandell

    1994-01-01

    Full Text Available In December 1992. a meeting was convened in Toronto to develop guidelines for the initial treatment of hospital acquired pneumonia. Issues considered related lo the patient. the possible drugs used for treatment, and the pathogen(s. From the perspective of the patient. the two major issues were the presence or absence of risk factors for specific microbial pathogens and the severity of illness upon clinical presentation, Criteria for defining severly ill patients were developed and are presented in this paper. Drug and pathogen related issues focused on selection of antimicrobial agents thal would provide coverage for the likely pathogens. Concern was also expressed regarding use of aminoglycosides as single-agent treatment of Gram-negative infections in the lung. and the issue of monotherapy versus combination therapy of Pseudomonas aeruginosa infections was discussed. The use of various diagnostic tests was briefly reviewed. including the protected specimen brush and bronchoalveolar lavage. Treatment regimens are presented in tabular format.

  8. Acquired hepatocerebral degeneration: A case report

    Institute of Scientific and Technical Information of China (English)

    Wei-Xing Chen; Ping Wang; Sen-Xiang Yan; You-Ming Li; Chao-Hui Yu; Ling-Ling Jiang

    2005-01-01

    AIM: Acquired hepatocerebral degeneration (AHD) is an exceptional type of hepatic encephalopathies (HE). It is characterized by neuropsychiatric and extrapyramidal symptomathology similar to that seen in hepatolenticular degeneration (Wilson's disease). In this paper, we report a case of AHD with unusual presenting features.METHODS: A 28-year-old man with AHD was described and the literature was reviewed.RESULTS: The man had a history of HBV-related liver cirrhosis. He was admitted to our hospital with apathy,dysarthria, mild consciousness impairment and extrapyramidal symptoms after hematemesis. By review of the literature,cases with AHD often did not present consciousness impairment. So our case was once diagnosed incorrectly as Wilson's disease.CONCLUSION: AHD is a rare syndrome and its variable clinical manifestations make it difficult to be diagnosed.But we believe that extensive examination and thorough understanding of the disease are beneficial to a correct diagnosis. Moreover, biocoene is effective in treating the case.

  9. Distinctiveness of Ugandapithecus from Proconsul

    Directory of Open Access Journals (Sweden)

    Gommery, D.

    2009-12-01

    Full Text Available The decision to create the genus Ugandapithecus by Senut et al., 2000 has been criticised, either directly and in detail by MacLatchy & Rossie (2005b who argued that it is a junior synonym of Proconsul, or indirectly without providing reasons, firstly by Harrison (2001 who wrote that he did not retain it as a genus distinct from Proconsul, and then by Suwa et al., (2007 who employed the name “Ugandapithecus” with inverted commas, implying some degree of doubt about its validity as a genus, but without providing details. More recently Harrison & Andrews (2009 have recognised the Meswa sample as a separate species but they argue that it should be maintained within Proconsul, despite the morphological differences that it has from other species of the genus. We here re-examine the question by comparing, on the one hand, the holotype maxilla of Proconsul africanus, the type species of the genus, with the upper dentition of Ugandapithecus major, and, on the other hand, the holotype mandible of Ugandapithecus major with the lower dentition and mandibles previously attributed to Proconsul africanus. We conclude that the differences between the known upper and lower dentitions of P. africanus and U. major are of such a degree that the two taxa warrant generic separation, and that the differences are not related to sexual dimorphism. Where Proconsul africanus differs from Ugandapithecus major, it approaches Proconsul nyanzae and Proconsul heseloni from Rusinga.Furthermore, the range of morphometric variation within the fossil samples previously attributed to Ugandapithecus major is so great that it far surpasses variation in any other hominoid, fossil or extant. Previously this great amount of variation was interpreted to mean that U. major was extremely dimorphic, with huge males and small females, but if this is true, then U. major would be unique among hominoids in having females in which the cheek teeth fall completely outside the range of

  10. Does Acquired Hypothyroidism Affect the Hearing Functions?

    Directory of Open Access Journals (Sweden)

    Ayşe Arduç

    2015-12-01

    Full Text Available Purpose: It is well known that congenital hypothyroidism can cause hearing loss. However, conflicting results were found in studies investigating hearing functions in acquired hypothyroidism. Therefore, we evaluated the audiometric findings in patients with acquired hypothyroidism. Material and Method: The study included 58 patients with hypothyroidism and age- and gender-matched 34 healthy controls. Twenty eight (48.27% patients had subclinical hypothyroidism, and 30 (51.73% had obvious hypothyroidism. All subjects had a normal otoscopic examination and tympanometry. Pure tone audiometry at 250, 500, 1000, 2000, 4000, 6000, and 8000 Hertz (Hz was performed in both groups. Blood pressure measurements and the levels of plasma electrolytes, lipids and vitamin B12 were available in all subjects. Results: Hypothyroidism group and control group were similar with respect to systolic and diastolic blood pressures and plasma glucose, lipid, vitamin B12, calcium, sodium, potassium, and chloride levels. Significantly higher audiometric thresholds (dB at 250 (10 (0-45 vs. 5 (0-15, p<0.001 and 500 Hz (10 (0-40 vs. 10 (-5-15, p=0.003 were recorded in hypothyroid patients compared to that in healthy controls. Hearing thresholds at 250 and 500 Hz correlated positively with thyroid-stimulating hormone (TSH, and negatively with free triiodothyronine and free thyroxine. Subclinical hypothyroid patients had a higher hearing threshold at 250 Hz than healthy controls (p=0.001. Discussion: Our study demonstrated that hearing ability decreases in hypothyroidism, even in subclinical hypothyroidism. The changes in TSH and thyroid hormone levels seem to be directly related to the hearing loss in this population of patients.

  11. Experiences Acquired by a Building Collapse

    Directory of Open Access Journals (Sweden)

    Murat Durusu

    2012-04-01

    Full Text Available In this study, it has been purposed to share practice of event-scene administration, search and rescue and evacuation of injured and acquired experiences carried out throughout a building collapse. After an explosion at Diyarbakir Kurdoglu housings at 11 December 2006 about 08:20AM, five flats of an apartment that has five floors-ten flats were collapsed. Local military hospital ambulances, city ambulances, and fire-fighting vehicles arrived to event-place 10 minutes later. It has been found out that there were 13 people inside, 6 of which were children. Army rescue team arrived event-place about 01:30PM, then all non-professional persons has been sent away from region. Eight dead including five children, and five injured including one child have been taken out. Two people from close area have been also injured mildly due to the explosion. It has been found out that accident caused by boiler tank exploding. Sixth of total eight injured had only superficial wounds. Other two injured have been followed because of head trauma at first one and hepatic contusion and rib fracture at the other one. No complication observed after follow-up. Building collapses can create disaster potential according to the number of people inside and facilities of nearby region of the place accident taken place. The evaluation of the direction of building collapse during search and rescue operation would enhance possibility to reach more living in shorter time. Building collapses which can be considered as a miniature of big disaster potentials like earthquakes can be appraised as an important practical training and experience source on event-place administration, search and rescue operations and injured evacuation. We believe that share of the analysis and acquired experiences of this kind of studies would contribute interfering big disaster potentials. [TAF Prev Med Bull 2012; 11(2.000: 241-244

  12. Late-onset Ito's nevus: an uncommon acquired dermal melanocytosis.

    Science.gov (United States)

    Mataix, Javier; López, Norberto; Haro, Rosario; González, Elena; Angulo, Jorge; Requena, Luis

    2007-08-01

    Dermal melanocytoses comprise a variety of congenital and acquired conditions characterized by a sparse population of intradermal dendritic, variably pigmented, spindle-shaped melanocytes. While Mongolian spot, Ota's and Ito's nevi are usually present at birth or appear around puberty; acquired dermal melanocytoses that appear in adult life are extremely rare. They include the facial lesions of acquired bilateral nevus of Ota-like macules, also named Hori's nevus, and the acquired unilateral nevus of Ota, also known as Sun's nevus. Uncommon extrafacial examples of acquired dermal melanocytoses include lesions involving upper extremities, wrist, back, lower extremities and dorsal aspects of the hands and feet. They are more prevalent among Asian women. In general, dermal melanocytoses are rare lesions in Caucasian patients and acquired variants are exceedingly uncommon. We report a rare example of acquired Ito's nevus that appeared in a Caucasian elderly woman and review the literature about acquired dermal melanocytoses.

  13. 48 CFR 970.4102 - Acquiring utility services.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Acquiring utility services... SUPPLEMENTARY REGULATIONS DOE MANAGEMENT AND OPERATING CONTRACTS Acquisition of Utility Services 970.4102 Acquiring utility services....

  14. Management of bleeding in acquired hemophilia A : results from the European Acquired Haemophilia (EACH2) Registry

    NARCIS (Netherlands)

    Baudo, Francesco; Collins, Peter; Huth-Kuehne, Angela; Levesque, Herve; Marco, Pascual; Nemes, Laszlo; Pellegrini, Fabio; Tengborn, Lilian; Knoebl, Paul; Aspoeck, G.; Heistinger, M.; Knobl, P.; Makipernaa, A.; Andre, H; Aouba, A.; Bellucci, S.; Beurrier, P.; Borg, J.Y.; Darnige, L.; Devignes, J.; d'Oiron, R.; Gautier, P.; Gay, V.; Girault, S.; Gruel, Y.; Guerin, V.; Hezard, N.; Khellaf, M.; Koenig, M.; Levesque, H.; Lifermann, F; Marlu, R; Ninet, J.; Peynet, J.; Quemeneur, T.; Rothschild, C.; Schleinitz, N.; Sigaud, M.; Trouillier, S; Voisin, S.; Giebl, A.; Holstein, K.; Huth-Kuhne, A; Loreth, R.M.; Steigerwald, U.; Tiede, A.; Theodossiades, G.; Nemes, L.; Radvanyi, G.; Schlammadinger, A.; Barillari, G.; Pasca, S.; Baudo, F; Caimi, T.; Contino, L.; D'Angelo Armando, C.L.; Fattorini, A.; Di Minno, G.; Cerbone, A.M.; Di Minno, Matteo Nicola Dario; D'inca, M.; Falanga, A.; Maggioni, A.; Lerede, T.; Franchini, M.; Gaidano, G.; De Paoli, L.; Gamba, G.; Ghirardi, R; Girotto, M.; Tasca, D.; Grandone, E.; Tiscia, G.; Imberti, D.; Iorio, A.; Landolfi, R; Di Gennaro, L.; Novarese, L.; Mariani, G.; Lapecorella, M.; Marietta, M.; Pedrazzi, P.; Mazzucconi, M.G.; Santoro, C.; Morfini, M.; Linari, S.; Moratelli, S.; Paolini, R.; Piseddu, G.; Poggio, R.; Pogliani, E.; Carpenedo, M.; Remiddi, C.; Santagostino, E.; Mancuso, M.E.; Santoro, R.; Papaleo, G.; Schinco, P.; Borchiellini, A.; Valeri, F.; Scortechini, A.R.; Siragusa, S.; Sottilotta, G.; Squizzato, A.; Tagariello, G.; Sartori, R; Tagliaferri, A.R.; Di Perna, C.; Rivolta, G.F.; Testa, S.; Paoletti, O.; Toschi, V.; Zanon, E.; Brandolin, B.; Hamulyak, K.; Kamphuisen, P.; Laros-van Gorkom, B.; Leebeek, F.W.; Marten, N.; Novakova, I.; Schutgens, R.; van der Linden, P.W.; van Esser, J.; van der Meer, J.; Ypma, P.; Campos, M.; Aguilar, C.; Altisent, C.; Bermejo, N.; Del Campo, R.; Ferreiro Arguelles, M.; Gonzalez Bolos', R.; Gutierrez Pimentel, M.J.; Jimenez-Yuste, V.; Jose-Felix, L.; Marco, P.; Mingot, M.E.; Perez Garrido, R.; Perez Gonzale, N.Z.; Prieto Garcia, M.; Rodriguez-Huerta, A.M.; Sedano, C.; Tolosa Munoz, A.; Baghaei, F.; Tengborn, L.; Boehlen, F.; Korte, W.; Chowdary, P.; Collins, P.; Evans, G.; Pavord, S.; Rangarajan, S.; Wilde, J.

    2012-01-01

    Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH

  15. Immunosuppression for acquired hemophilia A : results from the European Acquired Haemophilia Registry (EACH2)

    NARCIS (Netherlands)

    Collins, Peter; Baudo, Francesco; Knoebl, Paul; Levesque, Herve; Nemes, Laszlo; Pellegrini, Fabio; Marco, Pascual; Tengborn, Lilian; Huth-Kuehne, Angela; Aspoeck, Gerold; Heistinger, Max; Knobl, Paul; Makipernaa, Anne; Andre, Helene; Aouba, A; Bellucci, Sylvia; Beurrier, Philippe; Borg, Jeanne Yvonne; Darnige, Luc; Devignes, Jean; dOiron, Roseline; Gautier, Philippe; Gay, Valerie; Girault, Stephane; Gruel, Yves; Guerin, Viviane; Hezard, Nathalie; Khellaf, Mehdi; Koenig, Martial; Levesque, Herve; Lifermann, Francois; Marlu, Raphael; Ninet, J.; Peynet, Jocelyne; Quemeneur, Thomas; Rothschild, Chantal; Schleinitz, Nicolas; Sigaud, Marianne; Trouillier, Sebastien; Voisin, Sophie; Giebl, Andreas; Holstein, Katharina; Huth-Kuhne, Angela; Loreth, Ralph M.; Steigerwald, Udo; Tiede, Andreas; Theodossiades, George; Nemes, Laszlo; Radvanyi, Gaspar; Schlammadinger, Agota; Barillari, Giovanni; Pasca, Samantha; Baudo, Francesco; Caimi, T.; Contino, L.; D'Angelo, Armando; Crippa, Luciano; Fattorini, Annalisa; Di Minno, Giovanni; Cerbone, Anna Maria; Di Minno, Matteo Nicola Dario; D'inca, Marco; Falanga, Anna; Maggioni, Anna; Lerede, Teresa; Franchini, Massimo; Gaidano, Gianluca; De Paoli, Lorenzo; Gamba, Gabriella; Ghirardi, Raffaele; Girotto, Mauro; Tasca, Delios; Grandone, Elvira; Tiscia, Giovanni; Imberti, Davide; Iorio, Alfonso; Landolfi, Raffaele; Di Gennaro, Leonardo; Novarese, Linda; Mariani, Guglielmo; Lapecorella, Mario; Marietta, Marco; Pedrazzi, Paola; Mazzucconi, Maria Gabriella; Santoro, Cristina; Morfini, Massimo; Linari, Silvia; Moratelli, Stefano; Paolini, Rossella; Piseddu, Gavino; Poggio, Renzo; Pogliani, Enrico; Carpenedo, Monica; Remiddi, Chiara; Santagostino, Elena; Mancuso, Maria Elisa; Santoro, Rita; Papaleo, Giuseppina; Schinco, Piercarla; Borchiellini, Alessandra; Valeri, Federica; Scortechini, Anna Rita; Siragusa, Sergio; Sottilotta, Gianluca; Squizzato, Alessandro; Tagariello, Giuseppe; Sartori, Roberto; Tagliaferri, Anna Rita; Di Perna, Caterina; Rivolta, Gianna Franca; Testa, Sophie; Paoletti, Oriana; Toschi, Vincenzo; Zanon, Ezio; Brandolin, Barbara; Hamulyak, Karly; Kamphuisen, Pieter; Laros-van Gorkom, Britta; Leebeek, Frank W.G.; Marten, Nijziel; Novakova, Irena; Schutgens, Roger; van der Linden, P.W.G; van Esser, Joost; van der Meer, J.; Ypma, Paula; Campos, Manuel; Aguilar, Carlos; Altisent, Carmen; Bermejo, Nuria; Del Campo, Raquel; Ferreiro Arguelles, M.; Gonzalez Boullosa, Rosario; Gutierrez Pimentel, Maria Jose; Jimenez-Yuste, Victor [No Value; Jose-Felix, Lucia; Marco, Pascual; Mingot, Maria Eva; Perez Garrido, Rosario; Perez Gonzale, Noelia z; Prieto Garcia, Manuel; Rodriguez-Huerta, Ana Maria; Maranon, HGUG [No Value; Sedano, Carmen; Tolosa Munoz, Alexandra; Baghaei, Fariba; Tengborn, Lilian; Boehlen, Francoise; Korte, Wolfgang; Chowdary, Pratima; Collins, Peter; Evans, Gillian; Pavord, Suzanne; Rangarajan, Savita; Wilde, Jonathan

    2012-01-01

    Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regim

  16. 77 FR 23483 - Notice of Proposals To Engage In or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-04-19

    ... Notice of Proposals To Engage In or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  17. 77 FR 4560 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-01-30

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  18. 78 FR 41929 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-07-12

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  19. 77 FR 46437 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-08-03

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  20. 77 FR 50106 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-08-20

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  1. 77 FR 45352 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-07-31

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y (12 CFR Part 225) to engage de novo, or to acquire or control...

  2. 76 FR 69739 - Notice of Proposals To Engage In or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2011-11-09

    ... Notice of Proposals To Engage In or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  3. 78 FR 52531 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-08-23

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  4. 76 FR 71344 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2011-11-17

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y (12 CFR part 225) to engage de novo, or to acquire or control...

  5. 77 FR 13127 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-03-05

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  6. 77 FR 35387 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-06-13

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  7. 78 FR 24201 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-04-24

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  8. 78 FR 62303 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-10-15

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  9. 77 FR 21100 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-04-09

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C..., Virginia 23261-4528: 1. City Holding Company, Cross Lanes, West Virginia; to acquire 100 percent of...

  10. 78 FR 26032 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-05-03

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  11. 78 FR 9391 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-02-08

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  12. 76 FR 67454 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2011-11-01

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  13. 77 FR 56210 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-09-12

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  14. 78 FR 11648 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-02-19

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  15. 78 FR 9051 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-02-07

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  16. 78 FR 29134 - Notice of Proposals to Engage in or to Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-05-17

    ... Notice of Proposals to Engage in or to Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C...., Atlanta, Georgia 30309: 1. HCBF Holding Company, Inc., Fort Pierce, Florida; to acquire 100 percent of...

  17. 78 FR 35271 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-06-12

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  18. 78 FR 1212 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-01-08

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  19. 76 FR 75549 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2011-12-02

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  20. 77 FR 33460 - Notice of Proposals to Engage in or to Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-06-06

    ... Notice of Proposals to Engage in or to Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  1. 77 FR 43285 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-07-24

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  2. 77 FR 61607 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-10-10

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  3. 78 FR 7784 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-02-04

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  4. 77 FR 285 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-01-04

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y (12 CFR part 225) to engage de novo, or to acquire or control...

  5. 78 FR 65312 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-10-31

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  6. 77 FR 73467 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-12-10

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  7. 78 FR 45536 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-07-29

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  8. 78 FR 52768 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-08-26

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  9. 78 FR 61845 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-10-04

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  10. 78 FR 27239 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-05-09

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  11. 77 FR 8258 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-02-14

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  12. 78 FR 30302 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-05-22

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  13. 77 FR 60996 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-10-05

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C..., Virginia 23261-4528: 1. City Holding Company, Cross Lanes, West Virginia; to acquire 100 percent of...

  14. 76 FR 81940 - Notice of Proposals to Engage in or to Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2011-12-29

    ... Notice of Proposals to Engage in or to Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  15. 78 FR 67147 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-11-08

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  16. 77 FR 66464 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-11-05

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  17. 78 FR 70946 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-11-27

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  18. 77 FR 27061 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-05-08

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  19. 77 FR 6564 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-02-08

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  20. 77 FR 7163 - Notice of Proposals to Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-02-10

    ... Notice of Proposals to Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 ] CFR part 225) to engage de novo, or to acquire or...

  1. 78 FR 42524 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-07-16

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  2. 76 FR 68188 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2011-11-03

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  3. 77 FR 36543 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-06-19

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  4. 77 FR 64994 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-10-24

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  5. 77 FR 60119 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-10-02

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  6. 77 FR 14015 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-03-08

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  7. 76 FR 76413 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2011-12-07

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  8. 78 FR 54648 - Notice of Proposals to Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-09-05

    ... Notice of Proposals to Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  9. 78 FR 8534 - Notice of Proposals to Engage in or to Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-02-06

    ... Notice of Proposals to Engage in or to Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  10. 78 FR 33093 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-06-03

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  11. 78 FR 77684 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-12-24

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  12. 77 FR 12304 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-02-29

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y (12 CFR part 225) to engage de novo, or to acquire or control...

  13. 77 FR 1072 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-01-09

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  14. 76 FR 78924 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2011-12-20

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  15. 77 FR 52033 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-08-28

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  16. 77 FR 39494 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-07-03

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  17. 78 FR 77465 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-12-23

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  18. 78 FR 26369 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-05-06

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  19. 78 FR 52915 - Notice of Proposals to Engage In or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2013-08-27

    ... Notice of Proposals to Engage In or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR Part 225) to engage de novo, or to acquire or control...

  20. 76 FR 82298 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2011-12-30

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  1. 77 FR 29348 - Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2012-05-17

    ... Notice of Proposals To Engage in or To Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  2. 76 FR 78658 - Notice of Proposals to Engage in or to Acquire Companies Engaged in Permissible Nonbanking...

    Science.gov (United States)

    2011-12-19

    ... Notice of Proposals to Engage in or to Acquire Companies Engaged in Permissible Nonbanking Activities The companies listed in this notice have given notice under section 4 of the Bank Holding Company Act (12 U.S.C. 1843) (BHC Act) and Regulation Y, (12 CFR part 225) to engage de novo, or to acquire or control...

  3. Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria

    Directory of Open Access Journals (Sweden)

    Abiola Olumuyiwa Olaitan

    2014-11-01

    Full Text Available Polymyxins are polycationic antimicrobial peptides that are currently the last-resort antibiotics for the treatment of multidrug-resistant, Gram-negative bacterial infections. The reintroduction of polymyxins for antimicrobial therapy has been followed by an increase in reports of resistance among Gram-negative bacteria. Some bacteria, such as Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii, develop resistance to polymyxins in a process referred to as acquired resistance, whereas other bacteria, such as Proteus spp., Serratia spp. and Burkholderia spp., are naturally resistant to these drugs. Reports of polymyxin resistance in clinical isolates have recently increased, including acquired and intrinsically resistant pathogens. This increase is considered a serious issue, prompting concern due to the low number of currently available effective antibiotics. This review summarizes current knowledge concerning the different strategies bacteria employ to resist the activities of polymyxins.Gram-negative bacteria employ several strategies to protect themselves from polymyxin antibiotics (polymyxin B and colistin, including a variety of lipopolysaccharide (LPS modifications, such as modifications of lipid A with phosphoethanolamine and 4-amino-4-deoxy-L-arabinose, in addition to the use of efflux pumps, the formation of capsules and overexpression of the outer membrane protein OprH, which are all effectively regulated at the molecular level. The increased understanding of these mechanisms is extremely vital and timely to facilitate studies of antimicrobial peptides and find new potential drugs targeting clinically relevant Gram-negative bacteria.

  4. 19 CFR 148.33 - Articles acquired abroad.

    Science.gov (United States)

    2010-04-01

    ... combined with the duty in determining which rates are highest. (c) Gifts. An article acquired abroad by a... 19 Customs Duties 2 2010-04-01 2010-04-01 false Articles acquired abroad. 148.33 Section 148.33... Articles acquired abroad. (a) Exemption. Each returning resident is entitled to bring in free of duty...

  5. 14 CFR 1274.402 - Contractor acquired property.

    Science.gov (United States)

    2010-01-01

    ... AGREEMENTS WITH COMMERCIAL FIRMS Property § 1274.402 Contractor acquired property. As provided in § 1274.923(c), title to property acquired with government funds vests in the government. Under a cost shared... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Contractor acquired property....

  6. Anticancer properties of distinct antimalarial drug classes.

    Directory of Open Access Journals (Sweden)

    Rob Hooft van Huijsduijnen

    Full Text Available We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor, emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings.

  7. Broad-spectrum acquired resistance in barley induced by the Pseudomonas pathosystem shares transcriptional components with Arabidopsis systemic acquired resistance.

    Science.gov (United States)

    Colebrook, E H; Creissen, G; McGrann, G R D; Dreos, R; Lamb, C; Boyd, L A

    2012-05-01

    Inducible resistance responses play a central role in the defense of plants against pathogen attack. Acquired resistance (AR) is induced alongside defense toward primary attack, providing broad-spectrum protection against subsequent pathogen challenge. The localization and molecular basis of AR in cereals is poorly understood, in contrast with the well-characterized systemic acquired resistance (SAR) response in Arabidopsis. Here, we use Pseudomonas syringae as a biological inducer of AR in barley, providing a clear frame of reference to the Arabidopsis-P. syringae pathosystem. Inoculation of barley leaf tissue with the nonadapted P. syringae pv. tomato avrRpm1 (PstavrRpm1) induced an active local defense response. Furthermore, inoculation of barley with PstavrRpm1 resulted in the induction of broad-spectrum AR at a distance from the local lesion, "adjacent" AR, effective against compatible isolates of P. syringae and Magnaporthe oryzae. Global transcriptional profiling of this adjacent AR revealed similarities with the transcriptional profile of SAR in Arabidopsis, as well as transcripts previously associated with chemically induced AR in cereals, suggesting that AR in barley and SAR in Arabidopsis may be mediated by analogous pathways.

  8. Homens de negócio: vocabulário social, distinção e atividades mercantis nas Minas setecentistas Businessmen: social vocabulary, distinction and commercial activities in Minas Gerais during the 1700s

    Directory of Open Access Journals (Sweden)

    Aldair Carlos Rodrigues

    2009-01-01

    Full Text Available Este artigo aborda a relação entre os diferentes ramos de atuação mercantil e o seu reflexo nos termos utilizados para definir os agentes que os exerciam. Além disto, o texto analisa as questões ligadas ao vocabulário (para definir os agentes do comércio e a sua relação com o estatuto social dos comerciantes em Minas e as estratégias de distinção social adotadas por esse grupo em diferentes momentos de ascensão.This article discusses the relationship among different mercantile practices and their reflection on the terms used to define the individuals that exercised them. Furthermore, the text examines the vocabulary issues to define the traders, and their relationship to the social status of the merchants in Minas Gerais, and the strategies of social distinction adopted by this group at different points of progress.

  9. ShcA regulates neurite outgrowth stimulated by neural cell adhesion molecule but not by fibroblast growth factor 2: evidence for a distinct fibroblast growth factor receptor response to neural cell adhesion molecule activation

    DEFF Research Database (Denmark)

    Hinsby, Anders M; Lundfald, Line; Ditlevsen, Dorte K;

    2004-01-01

    by two principal routes of signaling: NCAM/Fyn and NCAM/fibroblast growth factor receptor (FGFR), respectively. Previous studies have shown that activation of mitogen-activated protein kinases is a pivotal point of convergence in NCAM signaling, but the mechanisms behind this activation are not clear....... Here, we investigated the involvement of adaptor proteins in NCAM and fibroblast growth factor 2 (FGF2)-mediated neurite outgrowth in the PC12-E2 cell line. We found that both FGFR substrate-2 and Grb2 play important roles in NCAM as well as in FGF2-stimulated events. In contrast, the docking protein...... ShcA was pivotal to neurite outgrowth induced by NCAM, but not by FGF2, in PC12 cells. Moreover, in rat cerebellar granule neurons, phosphorylation of ShcA was stimulated by an NCAM mimicking peptide, but not by FGF2. This activation was blocked by inhibitors of both FGFR and Fyn, indicating that NCAM...

  10. HYSTERESIS BETWEEN DISTINCT MODES OF TURBULENT DYNAMOS

    Energy Technology Data Exchange (ETDEWEB)

    Karak, Bidya Binay; Brandenburg, Axel [Nordita, KTH Royal Institute of Technology and Stockholm University, Roslagstullsbacken 23, SE-10691 Stockholm (Sweden); Kitchatinov, Leonid L., E-mail: bbkarak@nordita.org [Institute of Solar-Terrestrial Physics, P.O. Box 291, Irkutsk 664033 (Russian Federation)

    2015-04-20

    Nonlinear mean-field models of the solar dynamo show long-term variability, which may be relevant to different states of activity inferred from long-term radiocarbon data. This paper is aimed at probing the dynamo hysteresis predicted by the recent mean-field models of Kitchatinov and Olemskoy with direct numerical simulations. We perform three-dimensional (3D) simulations of large-scale dynamos in a shearing box with helically forced turbulence. As an initial condition, we either take a weak random magnetic field or we start from a snapshot of an earlier simulation. Two quasi-stable states are found to coexist in a certain range of parameters close to the onset of the large-scale dynamo. The simulations converge to one of these states depending on the initial conditions. When either the fractional helicity or the magnetic Prandtl number is increased between successive runs above the critical value for onset of the dynamo, the field strength jumps to a finite value. However, when the fractional helicity or the magnetic Prandtl number is then decreased again, the field strength stays at a similar value (strong field branch) even below the original onset. We also observe intermittent decaying phases away from the strong field branch close to the point where large-scale dynamo action is just possible. The dynamo hysteresis seen previously in mean-field models is thus reproduced by 3D simulations. Its possible relation to distinct modes of solar activity such as grand minima is discussed.

  11. Community-acquired pneumonia among smokers.

    Science.gov (United States)

    Almirall, Jordi; Blanquer, José; Bello, Salvador

    2014-06-01

    Recent studies have left absolutely no doubt that tobacco increases susceptibility to bacterial lung infection, even in passive smokers. This relationship also shows a dose-response effect, since the risk reduces spectacularly 10 years after giving up smoking, returning to the level of non-smokers. Streptococcus pneumoniae is the causative microorganism responsible for community-acquired pneumonia (CAP) most frequently associated with smoking, particularly in invasive pneumococcal disease and septic shock. It is not clear how it acts on the progress of pneumonia, but there is evidence to suggest that the prognosis for pneumococcal pneumonia is worse. In CAP caused by Legionella pneumophila, it has also been observed that smoking is the most important risk factor, with the risk rising 121% for each pack of cigarettes smoked a day. Tobacco use may also favor diseases that are also known risk factors for CAP, such as periodontal disease and upper respiratory viral infections. By way of prevention, while giving up smoking should always be proposed, the use of the pneumococcal vaccine is also recommended, regardless of the presence of other comorbidities.

  12. Identification of acquired antimicrobial resistance genes

    DEFF Research Database (Denmark)

    Zankari, Ea; Hasman, Henrik; Cosentino, Salvatore;

    2012-01-01

    ObjectivesIdentification of antimicrobial resistance genes is important for understanding the underlying mechanisms and the epidemiology of antimicrobial resistance. As the costs of whole-genome sequencing (WGS) continue to decline, it becomes increasingly available in routine diagnostic laborato......ObjectivesIdentification of antimicrobial resistance genes is important for understanding the underlying mechanisms and the epidemiology of antimicrobial resistance. As the costs of whole-genome sequencing (WGS) continue to decline, it becomes increasingly available in routine diagnostic...... laboratories and is anticipated to substitute traditional methods for resistance gene identification. Thus, the current challenge is to extract the relevant information from the large amount of generated data.MethodsWe developed a web-based method, ResFinder that uses BLAST for identification of acquired...... antimicrobial resistance genes in whole-genome data. As input, the method can use both pre-assembled, complete or partial genomes, and short sequence reads from four different sequencing platforms. The method was evaluated on 1862 GenBank files containing 1411 different resistance genes, as well as on 23 de...

  13. Acquired Hemophilia A successfully treated with rituximab

    Directory of Open Access Journals (Sweden)

    Giovanni D'Arena

    2015-02-01

    Full Text Available Acquired hemophilia A (AHA is a rare bleeding disorder due to the development of specific autoantibodies against factor VIII. The anti-CD20 monoclonal antibody Rituximab has been proven to be effective in  obtaining a long-term suppression of inhibitors of AHA,  besides other immunosuppressive standard treatments. Here we describe a case of idiopathic AHA in a 60-year old man successfully treated with rituximab. He showed a complete clinical response with  a normalization of clotting  parameters after 5 weekly courses of rituximab given at a dose of 375 mg/sqm. , but after stopping rituximab, an initial worsening of coagulation  parameters  induced the addition of 3 further courses. At present, the patient is in complete clinical and hematological remission after 200 days.  This case confirms that Rituximab may be a safe and useful tool to treat AHA and, a prolonged administration can overcome the initial resistance. However, the precise position of this drug in the therapeutic strategy (first or second-line, alone or in combination with other drugs remains to be established and warrants further investigation.

  14. [Acquired bullous diseases of the oral mucosa].

    Science.gov (United States)

    Vaillant, L; Hüttenberger, B

    2005-11-01

    Bullous diseases of the oral cavity cause painful erosion. They must be distinguished from aphthae and vesicles which may have a similar presentation. Acute, chronic and congenital conditions are recognized. Acute lesions may involve a polymorphous oral erhythema which has an polymorphous erythematous presentation or toxidermia (Stevens-Johnson syndrome, Lyell syndrome, fixed pigmented erythema). Examination of the skin and history taking are the keys to diagnosis. Patients with chronic bullous diseases may have a congenital condition (bullous epidermolysis or lymphangioma) suggested by the age at onset and the clinical presentation. Acquired chronic bullous diseases include lichen planus and autoimmune bullous diseases. Careful examination is essential to identify mucosal or cutaneous involvement and to obtain a biopsy for histological examination. Search for antibodies deposited in the perilesional mucosa is necessary. Chronic erosive gingivitis is a frequent presentation. Most of the patients have cicatricial pemphigoid, lichen planus, and more rarely pemphigus. The pinch sign is highly discriminative to differentiate the cause of this syndrome. Symptomatic treatment of bullous lesions of the oral cavity include adapted diet and correct and early use of antalgesics.

  15. Acquiring, encoding, and re-using clinical knowledge in PRODIGY

    Directory of Open Access Journals (Sweden)

    Richard Hall

    2002-11-01

    Full Text Available The development, implementation and maintenance of computer-executable clinical guidelines encompass a series of complex processes. As they are often performed by more than one organisation, this introduces further complexity. Within the PRODIGY project we attempt to control as many aspects of the process as possible, in order to increase the likelihood of achieving success. To illustrate the complexity of the process and many of the inherent problems and solutions, this paper describes the evolution of the PRODIGY knowledge base, describing the steps from acquiring knowledge, through encoding, to the execution of guidelines, and 'closing the loop' by discussing an approach to knowledge re-use. We will also consider some of the wider implications of our work and propose directions for future research and development activities.

  16. Acquired arteriovenous fistula in a grizzly bear (Ursus arctos horribilis).

    Science.gov (United States)

    Tuttle, Allison D; MacLean, Robert A; Linder, Keith; Cullen, John M; Wolfe, Barbara A; Loomis, Michael

    2009-03-01

    A captive adult male grizzly bear (Ursus arctos horribilis) was evaluated due to multifocal wounds of the skin and subcutaneous tissues sustained as a result of trauma from another grizzly bear. On presentation, one lesion that was located in the perineal region seemed to be a deep puncture with purple tissue protruding from it. This perineal wound did not heal in the same manner or rate as did the other wounds. Twenty-five days after initial detection, substantial active hemorrhage from the lesion occurred and necessitated anesthesia for examination of the bear. The entire lesion was surgically excised, which later proved curative. An acquired arteriovenous fistula was diagnosed via histopathology. Arteriovenous fistulas can develop after traumatic injury and should be considered as a potential complication in bears with nonhealing wounds.

  17. [Chronic hypomania as a stage of acquired cyclothymia].

    Science.gov (United States)

    Moroz, I B; Nefed'ev, O P

    1982-09-01

    The authors examined 28 patients with chronic hypomanic states that form within the bounds of acquired cyclothymia after a schizophrenic psychosis. Two types of the chronic hypomanias were differentiated. The first was hyperthymia, a residual pseudopsychotic state characterized with a combination of cycloid and schizoid features with an invariably elated mood. The patients were energetic, purposeful, indefatigable, and industrious at work. No signs of disease progress were observed for a long time. The second type was subpsychotic hypomania associated with a slow, but still continuing progress of the disease. The elated mood was combined with marked signs of the defect (emotional and intellectual impoverishment, psychopathy-like changes) and still persisting positive symptoms. The activity and ability to adapt themselves enabled these patients to remain sufficiently compensated socially at the new, lower level of the adaptation. Later the psychopathological disorders got deeper, and their scope increased.

  18. The etiology of primary femoroacetabular impingement: genetics or acquired deformity?

    Science.gov (United States)

    Packer, Jonathan D; Safran, Marc R

    2015-10-01

    The etiology of primary femoroacetabular impingement (FAI) remains controversial. Both genetic and acquired causes have been postulated and studied. While recent studies suggest that genetic factors may have a role in the development of FAI, there is no conclusive evidence that FAI is transmitted genetically. Currently, the most popular theory for the development of cam-type deformities is that a repetitive injury to the proximal femoral physis occurs during a critical period of development. There is a correlation between a high volume of impact activities during adolescence and the development of cam-type deformities. Multiple studies have found a high prevalence of FAI in elite football, ice hockey, basketball and soccer players. In this article, we review the current literature relating to the etiology of primary FAI.

  19. The etiology of primary femoroacetabular impingement: genetics or acquired deformity?

    Science.gov (United States)

    Packer, Jonathan D.; Safran, Marc R.

    2015-01-01

    The etiology of primary femoroacetabular impingement (FAI) remains controversial. Both genetic and acquired causes have been postulated and studied. While recent studies suggest that genetic factors may have a role in the development of FAI, there is no conclusive evidence that FAI is transmitted genetically. Currently, the most popular theory for the development of cam-type deformities is that a repetitive injury to the proximal femoral physis occurs during a critical period of development. There is a correlation between a high volume of impact activities during adolescence and the development of cam-type deformities. Multiple studies have found a high prevalence of FAI in elite football, ice hockey, basketball and soccer players. In this article, we review the current literature relating to the etiology of primary FAI. PMID:27011846

  20. Life After Project Effort: Appying Values Acquired in a Responsibility-based Physical Activity Program. [Vida después del “Proyecto Esfuerzo”: Aplicación de los valores adquiridos en un programa de actividad física basado en la responsabilidad].

    Directory of Open Access Journals (Sweden)

    Anthony Meléndez

    2015-07-01

    Full Text Available Among physical activity curricular models used in the youth development field, the Teaching Personal and Social Responsibility (TPSR model has been widely incorporated in many underserved youth community and school physical education programs around the United States and the world (Hellison, 2011. Project Effort is an extended day program that uses the TPSR model as a framework. Literature has shown that TPSR programs and Project Effort have had a positive impact on the life of the participants. The purpose of this study was to investigate what TPSR values former participants’ have acquired in Project Effort and through other sources, and how they have guided their lives. A multiple-case design was implemented to understand this phenomenon. The findings showed that former participants considered that four TPSR values (i.e. respect, effort, self-direction, helping others were really important to their lives. Participants reported that they learned the TPSR values of helping others and leadership in Project Effort. Also they mentioned that they acquired the TPSR life skills of being reflective, teamwork, and goal setting in Project Effort. The TPSR value of helping others, and the TPSR life skill of being reflective acquired in Project Effort were most useful to the participants. Participants learned the TPSR value of self-direction and the TPSR values of respect and caring. Resumen Entre los modelos curriculares de actividad física utilizados para el desarrollo de la juventud, la enseñanza personalizada y el modelo de Enseñanza de la Responsabilidad Personal y Social (TPSR han sido ampliamente incorporados en muchas comunidades los jóvenes marginados y en programas de educación física escolares en Estados Unidos y en el mundo (Hellison, 2011. El proyecto esfuerzo es un programa de día extendido que utiliza el modelo TPSR como fundamento. La literatura ha demostrado que los programas TPSR y el Proyecto Esfuerzo han tenido un impacto